Browse the corpus

Answers and Critiques Bibliography Grothey A, Sobrero AF, Shields AF, et al. Duration of adjuvant chemotherapy for stage III colon cancer. N Engl J Med. 2018;378:1177-88. [PMID: e In patients with cancer of unknown primary, diag- 29590544] doi:10.1056/NEJMoa1713709 nostic efforts should focus on identifying a limited number of more treatable subtypes of cancer. Item 5 Answer: E Bibliography Educational Objective: Evaluate cancer of unknown Tomuleasa C, Zaharie F, Muresan MS, et al. How to diagnose and treat a cancer of unknown primary site. J Gastrointestin Liver Dis. 2017;26:69- primary. 79. [PMID: 28338116]

Item 5 Answer: E Bibliography Educational Objective: Evaluate cancer of unknown Tomuleasa C, Zaharie F, Muresan MS, et al. How to diagnose and treat a cancer of unknown primary site. J Gastrointestin Liver Dis. 2017;26:69- primary. 79. [PMID: 28338116] The most appropriate management is no additional testing and to initiate combination chemotherapy (Option E). This patient has advanced metastatic adenocarcinoma from a can- Item 6 Answer: D cer of unknown primary (CUP). Diagnostic efforts should 1) Educational Objective: Stage newly diagnosed large a focus on identifying whether a patient is among the approx- | B-cell lymphoma with serum lactate dehydrogenase — imately 20% of patients with CUP who have a more favorable measurement. 7. prognosis and who can benefit from a specific treatment ws strategy. A biopsy obtained from the site that can be sampled Before considering treatment, serum lactate dehydrogenase sc = in the safest, least invasive manner is performed, and spec- (LDH) should be measured to help complete the patient’s o nA imens are evaluated by immunohistochemical stains con- staging and serve as a prognostic marker for those with large eed o sistent with the tumor’s pattern of presentation to attempt B-cell lymphoma (Option D). Large B-cell lymphoma rep- F a) to establish a diagnosis of a more treatable subtype of CUP resents approximately 30% of non-Hodgkin lymphomas. s (for example, germ cell tumor or lymphoma). The clini- These patients often present with symptomatic enlarging Lg

The most appropriate management is no additional testing and to initiate combination chemotherapy (Option E). This patient has advanced metastatic adenocarcinoma from a can- Item 6 Answer: D cer of unknown primary (CUP). Diagnostic efforts should 1) Educational Objective: Stage newly diagnosed large a focus on identifying whether a patient is among the approx- | B-cell lymphoma with serum lactate dehydrogenase — imately 20% of patients with CUP who have a more favorable measurement. 7. prognosis and who can benefit from a specific treatment ws strategy. A biopsy obtained from the site that can be sampled Before considering treatment, serum lactate dehydrogenase sc = in the safest, least invasive manner is performed, and spec- (LDH) should be measured to help complete the patient’s o nA imens are evaluated by immunohistochemical stains con- staging and serve as a prognostic marker for those with large eed o sistent with the tumor’s pattern of presentation to attempt B-cell lymphoma (Option D). Large B-cell lymphoma rep- F a) to establish a diagnosis of a more treatable subtype of CUP resents approximately 30% of non-Hodgkin lymphomas. s (for example, germ cell tumor or lymphoma). The clini- These patients often present with symptomatic enlarging Lg cal evaluation should not involve an exhaustive search for lymphadenopathy in the neck or abdomen. Approximately a primary site because detection of an asymptomatic and 40% may have signs or symptoms of extranodal disease, and occult primary tumor does not improve outcome. Physi- one third have systemic symptoms. Sixty percent of patients cians should discuss with patients and their families that have advanced (stage III or IV) disease at diagnosis. The B-cell focusing on identification of the primary tumor can distract lymphoma 6 gene shows rearrangement or other mutations from the more important issue of managing the metastatic that lead to overexpression in most patients. Patients with cancer. Efforts to identify primary tumors should focus only higher LDH levels have a poorer prognosis, and the result on tumors that are suggested by the clinical presentation or is used in calculating the patient’s International Prognostic could be managed with a specific, effective therapy. In this Index score, which incorporates LDH along with age, stage, case, metastatic disease located below the diaphragm is best performance status, and the presence or absence of extra- managed as gastrointestinal cancer without additional test- nodal involvement. The International Prognostic Index score ing for a primary cancer. correlates with progression-free and overall survival after Nonspecific tumor markers, such as serum carcinoem- standard therapy. Patients with poor prognosis may be con- bryonic antigen, CA-19-9, CA-15-3, or CA-125 (Option A), sidered for more aggressive treatment. are not definitive for identifying a specific site of origin and Bone marrow biopsies (Option A) are no longer rou- are not routinely recommended in patients with CUP. tinely performed as part of staging for large cell lymphoma, The use of gene expression arrays (Option B) has been and in most cases, results would not change management. commercially promoted, but the clinical utility of these tests Likewise, in this patient where multiple bony sites of to identify more effective therapy has not been established, involvement are seen on the PET scan, bone marrow biopsy and their routine use in the evaluation of CUP is not recom- would not have an impact on his staging. mended. More importantly, identifying the primary source Brain MRI (Option B) is not generally needed as part of of this patient’s metastatic adenocarcinoma will not change the initial staging for non-Hodgkin lymphoma unless the the outcome in this case. patient has neurologic signs or symptoms. Central nervous In some patients, PET (Option C) may suggest the pos- system involvement in patients with non-Hodgkin lym- sible primary location, but false-positive results are sig- phoma occurs more commonly in individuals with high- nificant, and PET scan findings are not apt to change the grade disease, peripheral blood and bone marrow, sinus, or treatment plan in a patient with metastatic adenocarcinoma testicular involvement, and coexistent HIV infection. It most located primarily below the diaphragm. commonly manifests with leptomeningeal disease. In the evaluation of CUP, specific symptoms may There would generally be no need to biopsy another area be pursued, such as upper endoscopy and colonoscopy of involvement, such as the retroperitoneal node (Option C), (Option D) in patients with symptoms or evidence of if adequate material were obtained from the axillary node gastrointestinal bleeding. This patient has no evidence of showing large cell lymphoma. Although discordant histol- gastrointestinal bleeding or gastrointestinal symptoms, ogy could sometimes be seen at alternate sites (lower grade and extensive evaluation of the gastrointestinal tract is not or follicular elements), this is uncommon and would not be warranted. likely to change the initial treatment approach.

cal evaluation should not involve an exhaustive search for lymphadenopathy in the neck or abdomen. Approximately a primary site because detection of an asymptomatic and 40% may have signs or symptoms of extranodal disease, and occult primary tumor does not improve outcome. Physi- one third have systemic symptoms. Sixty percent of patients cians should discuss with patients and their families that have advanced (stage III or IV) disease at diagnosis. The B-cell focusing on identification of the primary tumor can distract lymphoma 6 gene shows rearrangement or other mutations from the more important issue of managing the metastatic that lead to overexpression in most patients. Patients with cancer. Efforts to identify primary tumors should focus only higher LDH levels have a poorer prognosis, and the result on tumors that are suggested by the clinical presentation or is used in calculating the patient’s International Prognostic could be managed with a specific, effective therapy. In this Index score, which incorporates LDH along with age, stage, case, metastatic disease located below the diaphragm is best performance status, and the presence or absence of extra- managed as gastrointestinal cancer without additional test- nodal involvement. The International Prognostic Index score ing for a primary cancer. correlates with progression-free and overall survival after Nonspecific tumor markers, such as serum carcinoem- standard therapy. Patients with poor prognosis may be con- bryonic antigen, CA-19-9, CA-15-3, or CA-125 (Option A), sidered for more aggressive treatment. are not definitive for identifying a specific site of origin and Bone marrow biopsies (Option A) are no longer rou- are not routinely recommended in patients with CUP. tinely performed as part of staging for large cell lymphoma, The use of gene expression arrays (Option B) has been and in most cases, results would not change management. commercially promoted, but the clinical utility of these tests Likewise, in this patient where multiple bony sites of to identify more effective therapy has not been established, involvement are seen on the PET scan, bone marrow biopsy and their routine use in the evaluation of CUP is not recom- would not have an impact on his staging. mended. More importantly, identifying the primary source Brain MRI (Option B) is not generally needed as part of of this patient’s metastatic adenocarcinoma will not change the initial staging for non-Hodgkin lymphoma unless the the outcome in this case. patient has neurologic signs or symptoms. Central nervous In some patients, PET (Option C) may suggest the pos- system involvement in patients with non-Hodgkin lym- sible primary location, but false-positive results are sig- phoma occurs more commonly in individuals with high- nificant, and PET scan findings are not apt to change the grade disease, peripheral blood and bone marrow, sinus, or treatment plan in a patient with metastatic adenocarcinoma testicular involvement, and coexistent HIV infection. It most located primarily below the diaphragm. commonly manifests with leptomeningeal disease. In the evaluation of CUP, specific symptoms may There would generally be no need to biopsy another area be pursued, such as upper endoscopy and colonoscopy of involvement, such as the retroperitoneal node (Option C), (Option D) in patients with symptoms or evidence of if adequate material were obtained from the axillary node gastrointestinal bleeding. This patient has no evidence of showing large cell lymphoma. Although discordant histol- gastrointestinal bleeding or gastrointestinal symptoms, ogy could sometimes be seen at alternate sites (lower grade and extensive evaluation of the gastrointestinal tract is not or follicular elements), this is uncommon and would not be warranted. likely to change the initial treatment approach. 69

Bpewere ang Soares ¢ The International Prognostic Index score correlates with e In women with metastatic cancer of unknown pri- progression-free and overall survival after standard mary, breast examination and mammography should therapy for large B-cell lymphoma. be done to search for breast cancer, and a gynecologic evaluation should be performed to look for ovarian e Patients with large B-cell lymphoma and poor prog- cancer. nosis based on the International Prognostic Index score may be considered for more aggressive treat- ¢ Women who have adenocarcinoma with abdominal ment. carcinomatosis and ascites should be presumptively treated for ovarian cancer. Bibliography Martelli M, Ferreri AJ, Agostinelli C, Di Rocco A, Pfreundschuh M, Pileri SA. Bibliography Diffuse large B-cell lymphoma. Crit Rev Oncol Hematol. 2013;87(2):146- > Qaseem A, Usman N, Jayaraj JS, et al. Cancer of unknown primary: a review = 71. [PMID: 23375551] doi:10.1016/j.critrevonc.2012.12.009 on clinical guidelines in the development and targeted management of wo patients with the unknown primary site. Cureus. 2019;11:e5552. [PMID: = © 31695975] doi:10.7759/cureus.5552 = wn Item 7 Answer: B po) = a Educational Objective: Treat cancer of unknown origin a with features suggesting an ovarian primary. Item 8 Answer: A =e = Educational Objective: Treat a patient with high-risk St Chemotherapy with an ovarian cancer regimen (Option stage III cervical cancer. bon B) is the most appropriate adjuvant management for this oO wn patient. The source of cancer in some patients presenting This patient has stage III cervical cancer and should be treated with metastatic cancer is never identified. This group of with concurrent radiation therapy and platinum chemo- patients is classified as having cancer of unknown primary therapy (Option A). Patients with early cervical cancer are (CUP). On identification of metastatic cancer, a full med- frequently asymptomatic. The most common symptoms are ical history and physical examination should be obtained. abnormal or heavy vaginal bleeding or vaginal discharge. In female patients, breast examination and mammography Pelvic or back pain and bowel or bladder symptoms are pre- should be done to search for a breast primary cancer, and sentations of advanced disease. Diagnosis is made by direct a gynecologic evaluation should be performed to look for biopsy of a visible lesion, colposcopy, or cone biopsy (con- an ovarian primary. Imaging studies typically include con- ization). The 5-year relative survival for all stages of cervical trast-enhanced CT of the chest, abdomen, and pelvis. For cancer is 67.5%. The anatomic stage is the most important patients with CUP, the identification of a favorable prog- predictor of prognosis. Ninety percent of patients with local- nostic subgroup allows selection of specific surgical, radi- ized disease survive 5 years. The 5-year survival rate drops to ation, or chemotherapy to which patients are more likely 58% for patients with regional disease and 17% for patients to respond. The patient is a woman with CUP who pres- with disease extending outside of the true pelvis or involving ents with ascites and abdominal carcinomatosis. Although the bladder or rectum. Stage III cervical cancer extends to the this patient does not have visible abnormalities in her pelvic sidewall and/or involves the lower third of the vagina ovaries on CT and no indication of a primary tumor site, and/or causes hydronephrosis or a nonfunctioning kidney. she should be presumptively treated for ovarian cancer, This patient’s tumor extends to the pelvic sidewall. The addi- which includes debulking the peritoneal tumor followed tion of platinum chemotherapy to radiation therapy in this by chemotherapy, usually with a platinum-based agent setting reduces the risk of recurrence by 34% and improves and a taxane. overall survival versus treatment with radiation alone (Option For a patient with substantial evidence of gastroin- C). Peripheral sensory neuropathy is a common adverse effect testinal tract involvement, such as anemia and blood in of platinum chemotherapy, and patients should be monitored the stools, endoscopic search for a gastrointestinal primary for the development of peripheral neuropathy. Patients with would be appropriate, and a gastrointestinal cancer regimen preexisting diabetic neuropathy may be more likely to experi- (Option A) would be appropriate for palliation. ence worsened neuropathy as a result of chemotherapy. In the Immune checkpoint inhibitors, such as programmed absence of more severe peripheral sensory neuropathy, plat- death receptor 1 inhibitors (Option C), are active in cer- inum chemotherapy should be incorporated into treatment, tain types of cancers, such as melanoma, kidney, and lung given the associated improvement in outcomes. cancers, but are not part of the routine management of Hysterectomy and pelvic node dissection (Option B) are CUP site. recommended for patients with stage I and II cervical cancer Total abdominal irradiation (Option D) for adeno- but not for patients with stage III disease. Patients with stage carcinoma is not a reasonable option because the radia- III cervical cancer have extension to the pelvic sidewall, tion tolerance of the small intestines and kidneys is low, lower third of the vagina, or pelvic adenopathy, are at higher and such treatment would therefore cause unacceptable risk for locoregional and distant recurrence, and are treated toxicity. with concurrent chemoradiation.

progression-free and overall survival after standard mary, breast examination and mammography should therapy for large B-cell lymphoma. be done to search for breast cancer, and a gynecologic evaluation should be performed to look for ovarian e Patients with large B-cell lymphoma and poor prog- cancer. nosis based on the International Prognostic Index score may be considered for more aggressive treat- ¢ Women who have adenocarcinoma with abdominal ment. carcinomatosis and ascites should be presumptively treated for ovarian cancer. Bibliography Martelli M, Ferreri AJ, Agostinelli C, Di Rocco A, Pfreundschuh M, Pileri SA. Bibliography Diffuse large B-cell lymphoma. Crit Rev Oncol Hematol. 2013;87(2):146- > Qaseem A, Usman N, Jayaraj JS, et al. Cancer of unknown primary: a review = 71. [PMID: 23375551] doi:10.1016/j.critrevonc.2012.12.009 on clinical guidelines in the development and targeted management of wo patients with the unknown primary site. Cureus. 2019;11:e5552. [PMID: = © 31695975] doi:10.7759/cureus.5552 = wn Item 7 Answer: B po) = a Educational Objective: Treat cancer of unknown origin a with features suggesting an ovarian primary. Item 8 Answer: A =e = Educational Objective: Treat a patient with high-risk St Chemotherapy with an ovarian cancer regimen (Option stage III cervical cancer. bon B) is the most appropriate adjuvant management for this oO wn patient. The source of cancer in some patients presenting This patient has stage III cervical cancer and should be treated with metastatic cancer is never identified. This group of with concurrent radiation therapy and platinum chemo- patients is classified as having cancer of unknown primary therapy (Option A). Patients with early cervical cancer are (CUP). On identification of metastatic cancer, a full med- frequently asymptomatic. The most common symptoms are ical history and physical examination should be obtained. abnormal or heavy vaginal bleeding or vaginal discharge. In female patients, breast examination and mammography Pelvic or back pain and bowel or bladder symptoms are pre- should be done to search for a breast primary cancer, and sentations of advanced disease. Diagnosis is made by direct a gynecologic evaluation should be performed to look for biopsy of a visible lesion, colposcopy, or cone biopsy (con- an ovarian primary. Imaging studies typically include con- ization). The 5-year relative survival for all stages of cervical trast-enhanced CT of the chest, abdomen, and pelvis. For cancer is 67.5%. The anatomic stage is the most important patients with CUP, the identification of a favorable prog- predictor of prognosis. Ninety percent of patients with local- nostic subgroup allows selection of specific surgical, radi- ized disease survive 5 years. The 5-year survival rate drops to ation, or chemotherapy to which patients are more likely 58% for patients with regional disease and 17% for patients to respond. The patient is a woman with CUP who pres- with disease extending outside of the true pelvis or involving ents with ascites and abdominal carcinomatosis. Although the bladder or rectum. Stage III cervical cancer extends to the this patient does not have visible abnormalities in her pelvic sidewall and/or involves the lower third of the vagina ovaries on CT and no indication of a primary tumor site, and/or causes hydronephrosis or a nonfunctioning kidney. she should be presumptively treated for ovarian cancer, This patient’s tumor extends to the pelvic sidewall. The addi- which includes debulking the peritoneal tumor followed tion of platinum chemotherapy to radiation therapy in this by chemotherapy, usually with a platinum-based agent setting reduces the risk of recurrence by 34% and improves and a taxane. overall survival versus treatment with radiation alone (Option For a patient with substantial evidence of gastroin- C). Peripheral sensory neuropathy is a common adverse effect testinal tract involvement, such as anemia and blood in of platinum chemotherapy, and patients should be monitored the stools, endoscopic search for a gastrointestinal primary for the development of peripheral neuropathy. Patients with would be appropriate, and a gastrointestinal cancer regimen preexisting diabetic neuropathy may be more likely to experi- (Option A) would be appropriate for palliation. ence worsened neuropathy as a result of chemotherapy. In the Immune checkpoint inhibitors, such as programmed absence of more severe peripheral sensory neuropathy, plat- death receptor 1 inhibitors (Option C), are active in cer- inum chemotherapy should be incorporated into treatment, tain types of cancers, such as melanoma, kidney, and lung given the associated improvement in outcomes. cancers, but are not part of the routine management of Hysterectomy and pelvic node dissection (Option B) are CUP site. recommended for patients with stage I and II cervical cancer Total abdominal irradiation (Option D) for adeno- but not for patients with stage III disease. Patients with stage carcinoma is not a reasonable option because the radia- III cervical cancer have extension to the pelvic sidewall, tion tolerance of the small intestines and kidneys is low, lower third of the vagina, or pelvic adenopathy, are at higher and such treatment would therefore cause unacceptable risk for locoregional and distant recurrence, and are treated toxicity. with concurrent chemoradiation. 70

_ Answers and Critiques Pembrolizumab (Option D) is not currently used as adjuvant therapy for patients with stage I to III cervical e¢ The more common immunotherapy-related adverse cancer. Pembrolizumab is approved for use as second-line events include dermatitis/mucositis, autoimmune therapy for patients with advanced cervical cancer with endocrinopathies (thyroiditis, adrenalitis, hypophysi- programmed cell death ligand 1-positive tumors. tis), pneumonitis, and hepatotoxicity. ¢ The most appropriate treatment for immunotherapy- e Patients with bulky or locally advanced stage III cervi- induced adverse events is stopping the checkpoint cal cancer are treated with cisplatin-based chemo- inhibitors and beginning high-dose glucocorticoid therapy and radiation therapy. therapy.

¢ The most appropriate treatment for immunotherapy- e Patients with bulky or locally advanced stage III cervi- induced adverse events is stopping the checkpoint cal cancer are treated with cisplatin-based chemo- inhibitors and beginning high-dose glucocorticoid therapy and radiation therapy. therapy. Bibliography Bibliography Monk BJ, Tewari KS, Koh WJ. Multimodality therapy for locally advanced Brahmer JR, Lacchetti C, Schneider BJ, et al; National Comprehensive wn c<*) cervical carcinoma: state of the art and future directions. J Clin Oncol. Cancer Network. Management of immune-related adverse events in = 2007;25:2952-65. [PMID: 17617527] patients treated with immune checkpoint inhibitor therapy: American = Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2018;36:1714-68. [PMID: 29442540] doi:10.1200/JCO.2017.77.6385 = =] i =] Item 9 Answer: D ij

Bibliography Bibliography Monk BJ, Tewari KS, Koh WJ. Multimodality therapy for locally advanced Brahmer JR, Lacchetti C, Schneider BJ, et al; National Comprehensive wn c<*) cervical carcinoma: state of the art and future directions. J Clin Oncol. Cancer Network. Management of immune-related adverse events in = 2007;25:2952-65. [PMID: 17617527] patients treated with immune checkpoint inhibitor therapy: American = Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2018;36:1714-68. [PMID: 29442540] doi:10.1200/JCO.2017.77.6385 = =] i =] Item 9 Answer: D ij Educational Objective: Treat moderately severe diarrhea Item 10 Answer: C cs wn bee related to immunotherapy. Educational Objective: Treat hypogammaglobinemia in <5)

Educational Objective: Treat moderately severe diarrhea Item 10 Answer: C cs wn bee related to immunotherapy. Educational Objective: Treat hypogammaglobinemia in <5) a patient with chronic lymphocytic leukemia. = wn The most appropriate treatment for this patient is to stop < ipilimumab and nivolumab and begin intravenous methyl- This patient has recurrent pneumonia, chronic lymphocytic <f

a patient with chronic lymphocytic leukemia. = wn The most appropriate treatment for this patient is to stop < ipilimumab and nivolumab and begin intravenous methyl- This patient has recurrent pneumonia, chronic lymphocytic <f prednisolone (Option D). He most likely has immunother- leukemia (CLL), and hypogammaglobulinemia, and the most apy-induced colitis. Colitis is just one of myriad potential appropriate treatment is intravenous gamma globulin (Option autoimmune complications of immunotherapy. The more C). Many patients with CLL, particularly when the disease is common complications include dermatitis/mucositis, more advanced, develop low antibody levels that can lead to autoimmune endocrinopathies (thyroiditis, adrenalitis, and recurrent infections. For patients who have hypogammaglo- hypophysitis), pneumonitis, and hepatotoxicity. Colitis is binemia, randomized trials demonstrate a lower rate of recur- a relatively frequent complication with immunotherapy rent infections with administration of intravenous gamma and is most common with the combination of the CTLA-4 globulin every 3 to 4 weeks. Intravenous gamma globulin is antibody ipilimumab and a programmed death-1 antibody usually given with the goal of raising the IgG level to at least such as nivolumab. It can, however, occur with either drug 600 mg/dL (6.0 g/L). Seasonal influenza vaccinations as well alone. It presents with mild to severe diarrhea and can as COVID-19 and pneumococcal vaccinations (13-valent con- be life-threatening. Prompt recognition, discontinuation jugate vaccine and 23-valent polysaccharide vaccine) should of immunotherapy, and initiation of glucocorticoid ther be given to patients with CLL, although it is known that the apy are crucial for moderate or severe cases. Infections response to these vaccines may be impaired from the under- with enteric pathogens and Clostridioides difficile should lying disease and its treatment. be ruled out. Stool testing for lactoferrin and calprotectin Neutropenia may complicate CLL or its treatment; how- suggest bowel inflammation and can be used to monitor ever, this patient, although having a low percentage of neu- disease activity. Proctoscopy or colonoscopy with biopsy trophils on his differential count, does not have absolute can confirm the diagnosis. neutropenia (<1500 cells/uL). Absolute neutrophil count Oral budesonide (Option A) might be considered (ANC) is calculated as the total leukocyte count multiplied by in patients with mild noninfectious diarrhea (<4 stools the percentage of polymorphonuclear and band neutrophils. daily) associated with immunotherapy but is inadequate In this case, the ANC is 3200/uL, so granulocyte-colony for symptomatic patients with moderate to severe diar- stimulating factor (Option A) would not be indicated. rhea. Ibrutinib (Option B) is a first-line treatment as well For patients who do not respond to glucocorticoids, as later treatment for CLL. However, treatment would have addition of a tumor necrosis factor inhibitor such as inflix no immediate benefit for this patient’s recurrent risk of imab (Option B) may be helpful. However, high-dose gluco infection. In fact, the risk of infection, including some cases corticoids are the initial therapy of choice. of Pneumocystis jirovecii pneumonia, may be increased 5-Aminosalicylates such as mesalamine (Option C) are during the first 6 months of treatment, although effective believed to have an anti-inflammatory mechanism of action remission may be associated with some later reconstitution and are the mainstay of treatment of mild to moderate of humoral immunity. ulcerative colitis. This patient is much more likely to have an Splenectomy (Option D) would rarely be performed immunotherapy-related adverse event (colitis) than ulcer- in patients with CLL, except in circumstances such as for ative colitis, and treatment with mesalamine is not indicated immune thrombocytopenia or immune hemolytic anemia and will not be helpful. unresponsive to other systemic therapies. Splenectomy

prednisolone (Option D). He most likely has immunother- leukemia (CLL), and hypogammaglobulinemia, and the most apy-induced colitis. Colitis is just one of myriad potential appropriate treatment is intravenous gamma globulin (Option autoimmune complications of immunotherapy. The more C). Many patients with CLL, particularly when the disease is common complications include dermatitis/mucositis, more advanced, develop low antibody levels that can lead to autoimmune endocrinopathies (thyroiditis, adrenalitis, and recurrent infections. For patients who have hypogammaglo- hypophysitis), pneumonitis, and hepatotoxicity. Colitis is binemia, randomized trials demonstrate a lower rate of recur- a relatively frequent complication with immunotherapy rent infections with administration of intravenous gamma and is most common with the combination of the CTLA-4 globulin every 3 to 4 weeks. Intravenous gamma globulin is antibody ipilimumab and a programmed death-1 antibody usually given with the goal of raising the IgG level to at least such as nivolumab. It can, however, occur with either drug 600 mg/dL (6.0 g/L). Seasonal influenza vaccinations as well alone. It presents with mild to severe diarrhea and can as COVID-19 and pneumococcal vaccinations (13-valent con- be life-threatening. Prompt recognition, discontinuation jugate vaccine and 23-valent polysaccharide vaccine) should of immunotherapy, and initiation of glucocorticoid ther be given to patients with CLL, although it is known that the apy are crucial for moderate or severe cases. Infections response to these vaccines may be impaired from the under- with enteric pathogens and Clostridioides difficile should lying disease and its treatment. be ruled out. Stool testing for lactoferrin and calprotectin Neutropenia may complicate CLL or its treatment; how- suggest bowel inflammation and can be used to monitor ever, this patient, although having a low percentage of neu- disease activity. Proctoscopy or colonoscopy with biopsy trophils on his differential count, does not have absolute can confirm the diagnosis. neutropenia (<1500 cells/uL). Absolute neutrophil count Oral budesonide (Option A) might be considered (ANC) is calculated as the total leukocyte count multiplied by in patients with mild noninfectious diarrhea (<4 stools the percentage of polymorphonuclear and band neutrophils. daily) associated with immunotherapy but is inadequate In this case, the ANC is 3200/uL, so granulocyte-colony for symptomatic patients with moderate to severe diar- stimulating factor (Option A) would not be indicated. rhea. Ibrutinib (Option B) is a first-line treatment as well For patients who do not respond to glucocorticoids, as later treatment for CLL. However, treatment would have addition of a tumor necrosis factor inhibitor such as inflix no immediate benefit for this patient’s recurrent risk of imab (Option B) may be helpful. However, high-dose gluco infection. In fact, the risk of infection, including some cases corticoids are the initial therapy of choice. of Pneumocystis jirovecii pneumonia, may be increased 5-Aminosalicylates such as mesalamine (Option C) are during the first 6 months of treatment, although effective believed to have an anti-inflammatory mechanism of action remission may be associated with some later reconstitution and are the mainstay of treatment of mild to moderate of humoral immunity. ulcerative colitis. This patient is much more likely to have an Splenectomy (Option D) would rarely be performed immunotherapy-related adverse event (colitis) than ulcer- in patients with CLL, except in circumstances such as for ative colitis, and treatment with mesalamine is not indicated immune thrombocytopenia or immune hemolytic anemia and will not be helpful. unresponsive to other systemic therapies. Splenectomy 71

further increases this patient’s risk for infection with encap- Needle biopsy (Option B) is contraindicated due to an sulated bacteria and blood-borne parasites. increase in risk of recurrence associated with this procedure. Patients who have scrotal violation may be at increased risk of inguinal node metastases from tumor seeding to the scro- ¢ In patients with chronic lymphocytic leukemia, tum and inguinal nodes. repeated infections, and hypogammaglobulinemia, PET/CT (Option C) does not play a role in the initial regular treatment with intravenous gamma globulin evaluation of patients suspected of having testicular cancer. reduces infectious events. It is not a standard test in this setting but does play a role in

further increases this patient’s risk for infection with encap- Needle biopsy (Option B) is contraindicated due to an sulated bacteria and blood-borne parasites. increase in risk of recurrence associated with this procedure. Patients who have scrotal violation may be at increased risk of inguinal node metastases from tumor seeding to the scro- ¢ In patients with chronic lymphocytic leukemia, tum and inguinal nodes. repeated infections, and hypogammaglobulinemia, PET/CT (Option C) does not play a role in the initial regular treatment with intravenous gamma globulin evaluation of patients suspected of having testicular cancer. reduces infectious events. It is not a standard test in this setting but does play a role in e Seasonal influenza vaccinations as well as 13-valent the evaluation of residual masses after treatment is com- pleted. conjugate vaccine and 23-valent polysaccharide vaccine should be given to patients with chronic lymphocytic leukemia. e Patients with testicular cancer most commonly pre- p> —J sent with swelling or a solid mass, and the initial 172) Bibliography = diagnostic study is scrotal ultrasonography. @o Hilal T, Gea-Banacloche JC, Leis JE Chronic lymphocytic leukemia and = wn infection risk in the era of targeted therapies: linking mechanisms with e Testicular cancer is most commonly managed with g infections. Blood Rev. 2018;32:387-99. [PMID: 29571669] doi:10.1016/j. s radical inguinal orchiectomy. blre.2018.03.004 Q. (=) = Bibliography st Smith ZL, Werntz RP, Eggener SE. Testicular cancer: epidemiology, diagno- 2 Item 11 Answer: D = sis, and management. Med Clin North Am. 2018;102:251-64. [PMID: oO n Educational Objective: Manage testicular cancer with 29406056] doi:10.1016/j.mcna.2017.10.003 radical inguinal orchiectomy.

e Seasonal influenza vaccinations as well as 13-valent the evaluation of residual masses after treatment is com- pleted. conjugate vaccine and 23-valent polysaccharide vaccine should be given to patients with chronic lymphocytic leukemia. e Patients with testicular cancer most commonly pre- p> —J sent with swelling or a solid mass, and the initial 172) Bibliography = diagnostic study is scrotal ultrasonography. @o Hilal T, Gea-Banacloche JC, Leis JE Chronic lymphocytic leukemia and = wn infection risk in the era of targeted therapies: linking mechanisms with e Testicular cancer is most commonly managed with g infections. Blood Rev. 2018;32:387-99. [PMID: 29571669] doi:10.1016/j. s radical inguinal orchiectomy. blre.2018.03.004 Q. (=) = Bibliography st Smith ZL, Werntz RP, Eggener SE. Testicular cancer: epidemiology, diagno- 2 Item 11 Answer: D = sis, and management. Med Clin North Am. 2018;102:251-64. [PMID: oO n Educational Objective: Manage testicular cancer with 29406056] doi:10.1016/j.mcna.2017.10.003 radical inguinal orchiectomy. This patient’s findings are consistent with testicular cancer, Item 12 Answer: A and the most appropriate management is radical inguinal Educational Objective: Evaluate metastatic disease in a orchiectomy (Option D). Patients with testicular cancer most patient with a history of breast cancer. commonly present with swelling or a solid testicular mass. Although pain is commonly present, not all patients report it. This patient likely has metastatic breast cancer, and a pulmo- Keeping this diagnosis in mind is important even in men who nary nodule should be biopsied to confirm this before initiat- present with testicular pain without a clearly evident mass. ing treatment (Option A). Metastatic breast cancer is treatable Initial evaluation is typically made with scrotal ultrasound. but not curable and is treated in a palliative manner to control Cancers are characteristically solid, so cystic masses are rarely disease growth and spread and to prolong life, rather than indicative of cancer. Seminoma and nonseminomatous germ with curative intent. Essentially all patients with metastatic cell tumors have different ultrasound characteristics, but breast cancer should undergo a biopsy of the metastatic site identification of any solid mass contained within the testicle to confirm the presence of metastatic disease and treatment should prompt further evaluation for cancer. Other studies goals. Breast cancer may be heterogeneous and, in some cir- commonly performed are serum tumor markers and other cumstances, important features such as estrogen receptor

This patient’s findings are consistent with testicular cancer, Item 12 Answer: A and the most appropriate management is radical inguinal Educational Objective: Evaluate metastatic disease in a orchiectomy (Option D). Patients with testicular cancer most patient with a history of breast cancer. commonly present with swelling or a solid testicular mass. Although pain is commonly present, not all patients report it. This patient likely has metastatic breast cancer, and a pulmo- Keeping this diagnosis in mind is important even in men who nary nodule should be biopsied to confirm this before initiat- present with testicular pain without a clearly evident mass. ing treatment (Option A). Metastatic breast cancer is treatable Initial evaluation is typically made with scrotal ultrasound. but not curable and is treated in a palliative manner to control Cancers are characteristically solid, so cystic masses are rarely disease growth and spread and to prolong life, rather than indicative of cancer. Seminoma and nonseminomatous germ with curative intent. Essentially all patients with metastatic cell tumors have different ultrasound characteristics, but breast cancer should undergo a biopsy of the metastatic site identification of any solid mass contained within the testicle to confirm the presence of metastatic disease and treatment should prompt further evaluation for cancer. Other studies goals. Breast cancer may be heterogeneous and, in some cir- commonly performed are serum tumor markers and other cumstances, important features such as estrogen receptor imaging studies, such as CT of the abdomen and pelvis and and human epidermal growth factor receptor 2 status can chest radiograph. In patients who have findings consistent differ between the initial primary breast cancer and the met- with a possible diagnosis of testicular cancer, resection by astatic lesion. Therefore, biopsying the metastatic site allows radical inguinal orchiectomy is indicated. This step is both treatment to be tailored to the metastatic disease subtype. diagnostic and therapeutic, as it provides important local Biopsy of the pulmonary lesion will not only assess whether tumor control. there has been such a subtype switch, but it will also confirm Tumors with elevated o-fetoprotein levels are clas- stage IV disease. If choosing among biopsy site options, the sified as nonseminomatous germ cell tumors. Following lesion that upstages the patient to the greatest degree should resection, patients with early-stage nonseminomatous be biopsied. germ cell tumors can be managed with active surveillance The right axillary mass does not need to be biopsied (in selected patients), retroperitoneal lymph node dissec- if the diagnosis of metastatic breast cancer is established tion (RPLND), or limited chemotherapy (Option A). Adju- through biopsy of one of the pulmonary nodules (Option B). vant chemotherapy is recommended in patients with nodal A positive biopsy result of a regional nodal recurrence does involvement on RPLND. Persistence of tumor marker eleva- not establish the diagnosis of metastatic disease and would tion after orchiectomy without abnormal imaging findings not avoid the need to biopsy a lung nodule in this case. is also an indication for chemotherapy. Staging includes This patient should undergo a biopsy to confirm the evaluation with chest radiography, CT of the abdomen and diagnosis of metastatic breast cancer before initiating treat- pelvis, and tumor marker levels after orchiectomy. Because ment. If the patient is found to have metastatic estrogen

imaging studies, such as CT of the abdomen and pelvis and and human epidermal growth factor receptor 2 status can chest radiograph. In patients who have findings consistent differ between the initial primary breast cancer and the met- with a possible diagnosis of testicular cancer, resection by astatic lesion. Therefore, biopsying the metastatic site allows radical inguinal orchiectomy is indicated. This step is both treatment to be tailored to the metastatic disease subtype. diagnostic and therapeutic, as it provides important local Biopsy of the pulmonary lesion will not only assess whether tumor control. there has been such a subtype switch, but it will also confirm Tumors with elevated o-fetoprotein levels are clas- stage IV disease. If choosing among biopsy site options, the sified as nonseminomatous germ cell tumors. Following lesion that upstages the patient to the greatest degree should resection, patients with early-stage nonseminomatous be biopsied. germ cell tumors can be managed with active surveillance The right axillary mass does not need to be biopsied (in selected patients), retroperitoneal lymph node dissec- if the diagnosis of metastatic breast cancer is established tion (RPLND), or limited chemotherapy (Option A). Adju- through biopsy of one of the pulmonary nodules (Option B). vant chemotherapy is recommended in patients with nodal A positive biopsy result of a regional nodal recurrence does involvement on RPLND. Persistence of tumor marker eleva- not establish the diagnosis of metastatic disease and would tion after orchiectomy without abnormal imaging findings not avoid the need to biopsy a lung nodule in this case. is also an indication for chemotherapy. Staging includes This patient should undergo a biopsy to confirm the evaluation with chest radiography, CT of the abdomen and diagnosis of metastatic breast cancer before initiating treat- pelvis, and tumor marker levels after orchiectomy. Because ment. If the patient is found to have metastatic estrogen the staging process has not been completed, chemotherapy receptor-positive/human epidermal growth factor receptor is not indicated. 2-negative breast cancer, endocrine therapy plus a CDK4/6

imaging studies, such as CT of the abdomen and pelvis and and human epidermal growth factor receptor 2 status can chest radiograph. In patients who have findings consistent differ between the initial primary breast cancer and the met- with a possible diagnosis of testicular cancer, resection by astatic lesion. Therefore, biopsying the metastatic site allows radical inguinal orchiectomy is indicated. This step is both treatment to be tailored to the metastatic disease subtype. diagnostic and therapeutic, as it provides important local Biopsy of the pulmonary lesion will not only assess whether tumor control. there has been such a subtype switch, but it will also confirm Tumors with elevated o-fetoprotein levels are clas- stage IV disease. If choosing among biopsy site options, the sified as nonseminomatous germ cell tumors. Following lesion that upstages the patient to the greatest degree should resection, patients with early-stage nonseminomatous be biopsied. germ cell tumors can be managed with active surveillance The right axillary mass does not need to be biopsied (in selected patients), retroperitoneal lymph node dissec- if the diagnosis of metastatic breast cancer is established tion (RPLND), or limited chemotherapy (Option A). Adju- through biopsy of one of the pulmonary nodules (Option B). vant chemotherapy is recommended in patients with nodal A positive biopsy result of a regional nodal recurrence does involvement on RPLND. Persistence of tumor marker eleva- not establish the diagnosis of metastatic disease and would tion after orchiectomy without abnormal imaging findings not avoid the need to biopsy a lung nodule in this case. is also an indication for chemotherapy. Staging includes This patient should undergo a biopsy to confirm the evaluation with chest radiography, CT of the abdomen and diagnosis of metastatic breast cancer before initiating treat- pelvis, and tumor marker levels after orchiectomy. Because ment. If the patient is found to have metastatic estrogen the staging process has not been completed, chemotherapy receptor-positive/human epidermal growth factor receptor is not indicated. 2-negative breast cancer, endocrine therapy plus a CDK4/6 72

Answers and Critiques inhibitor (abemaciclib, palbociclib, or ribociclib) would be Tyrosine kinase inhibitors (Option D), such oral rego- the preferred option. This combined treatment is associated rafenib, have very limited antitumor activity in patients such with substantial improvement in progression-free survival as this but may be a reasonable consideration when all other relative to endocrine therapy alone. effective therapies have been exhausted. Endocrine therapy has long been preferred over first- line chemotherapy in the absence of a visceral crisis, a term used to describe patients with a heavy burden of visceral ¢ Immune checkpoint inhibitors, specifically pro- disease and threatened organ function. However, neither grammed death receptor 1 inhibitors, are indicated for endocrine therapy nor chemotherapy (Options C, D) should otherwise treatment-refractory metastatic mismatch

inhibitor (abemaciclib, palbociclib, or ribociclib) would be Tyrosine kinase inhibitors (Option D), such oral rego- the preferred option. This combined treatment is associated rafenib, have very limited antitumor activity in patients such with substantial improvement in progression-free survival as this but may be a reasonable consideration when all other relative to endocrine therapy alone. effective therapies have been exhausted. Endocrine therapy has long been preferred over first- line chemotherapy in the absence of a visceral crisis, a term used to describe patients with a heavy burden of visceral ¢ Immune checkpoint inhibitors, specifically pro- disease and threatened organ function. However, neither grammed death receptor 1 inhibitors, are indicated for endocrine therapy nor chemotherapy (Options C, D) should otherwise treatment-refractory metastatic mismatch be initiated before biopsy and confirmation of metastatic repair—deficient colon cancer. breast cancer. Bibliography Le DT, Kim TW, Van Cutsem E, et al. Phase II open-label study of pembroli- wn o e Breast cancer can undergo subtype switch between zumab in treatment-refractory, microsatellite instability-high/mismatch s repair-deficient metastatic colorectal cancer: KEYNOTE-164. J Clin Oncol. the primary disease and metastatic disease, and biop- 2020;38:11-19. [PMID: 31725351] doi:10.1200/JCO.19.02107 ae sying the metastatic site allows treatment to be tai- = cs) lored to the metastatic disease subtype. sc = Item 14 Answer: B e When evaluating a patient with newly diagnosed met- o wn astatic breast cancer, the lesion that upstages the hn

be initiated before biopsy and confirmation of metastatic repair—deficient colon cancer. breast cancer. Bibliography Le DT, Kim TW, Van Cutsem E, et al. Phase II open-label study of pembroli- wn o e Breast cancer can undergo subtype switch between zumab in treatment-refractory, microsatellite instability-high/mismatch s repair-deficient metastatic colorectal cancer: KEYNOTE-164. J Clin Oncol. the primary disease and metastatic disease, and biop- 2020;38:11-19. [PMID: 31725351] doi:10.1200/JCO.19.02107 ae sying the metastatic site allows treatment to be tai- = cs) lored to the metastatic disease subtype. sc = Item 14 Answer: B e When evaluating a patient with newly diagnosed met- o wn astatic breast cancer, the lesion that upstages the hn Educational Objective: Screen for bone loss in a patient o patient to the greatest degree should be biopsied. = on an aromatase inhibitor. wn = x Bibliography Patients on aromatase inhibitors are recommended to have

Educational Objective: Screen for bone loss in a patient o patient to the greatest degree should be biopsied. = on an aromatase inhibitor. wn = x Bibliography Patients on aromatase inhibitors are recommended to have National Comprehensive Cancer Network (NCCN). Breast Cancer Version bone density evaluated with dual-energy x-ray absorptiome- 3.2019. NCCN. https://www.nccn.org/professionals/physician_gls/pdf/ try (Option B) at the start of treatment to establish a baseline breast.pdf. Accessed 13 December 2019. and periodically, every 2 years, while on treatment. Aromatase inhibitors are associated with bone loss and an elevated risk of

National Comprehensive Cancer Network (NCCN). Breast Cancer Version bone density evaluated with dual-energy x-ray absorptiome- 3.2019. NCCN. https://www.nccn.org/professionals/physician_gls/pdf/ try (Option B) at the start of treatment to establish a baseline breast.pdf. Accessed 13 December 2019. and periodically, every 2 years, while on treatment. Aromatase inhibitors are associated with bone loss and an elevated risk of Item 13 Answer: 8B fracture. The risk of fracture with 5 years of aromatase inhib- itor therapy is about 8% to 10%. Patients receiving extended Educational Objective: Treat metastatic mismatch aromatase inhibitor therapy have a higher risk of bone loss repair—deficient colon cancer. and fracture. Consensus guidelines recommend obtaining This patient now has treatment-refractory metastatic colorectal bone density tests routinely to assess fracture risk. Clinical cancer with a mismatch repair-deficient tumor that should be tools such as the Fracture Risk Assessment Tool can be used to treated with immunotherapy with a programmed death recep- estimate fracture risk using bone density measurement. Frac- tor 1 (PD-1) inhibitor (Option B). Tumors may be mismatch ture risk informs management strategies for osteoporosis and repair-deficient either due to a germline mutation, a condition osteopenia, including use of supplemental vitamin D and/or a known as Lynch syndrome, or a somatic mutation (or epi- bone-modifying agent such as a bisphosphonate. genetic silencing) that is limited to the tumor. Because mis- Breast cancer survivors without symptoms suggestive of match repair-deficient tumors carry a better prognosis than distant recurrence are not recommended to undergo routine the more common mismatch repair-proficient tumors, mis- surveillance CTs (Option A). Multiple randomized trials have match repair-deficient tumors rarely become metastatic and compared an intensive surveillance strategy (with CTs and comprise only 3% to 4% of all metastatic colorectal cancer cases. tumor markers) versus routine care and found no difference Patients in this rare subset, however, have shown substantial in long-term outcomes except that intensive surveillance benefit from treatment with immune checkpoint inhibitors, was associated with inferior quality of life. specifically PD-1 inhibitors. Unfortunately for most patients Echocardiograms (Option C) are not routinely recom- with metastatic colorectal cancer (>95%) whose tumors are mended for breast cancer survivors taking aromatase inhib- mismatch repair-proficient, PD-1 inhibitors and other immune itors or after postmastectomy irradiation. Echocardiograms checkpoint inhibitors have thus far been essentially inactive. are performed before receipt of cardiotoxic chemotherapy Supportive comfort care and hospice management such as anthracyclines or trastuzumab. Patients with higher (Option A) is an important consideration in patients who are cumulative doses and evidence of reduced ejection fraction too sick for treatment or who have exhausted all reasonable should have a cardiology consultation. For asymptomatic treatment options. Such a course of action would not be the patients treated with human epidermal growth factor recep- most appropriate consideration in a fully functional patient tor 2-targeted therapy, routine testing posttherapy is not with a meaningful treatment option available. recommended. Potential complications of radiation therapy Stereotactic radiation therapy (Option C) can be used include coronary artery disease, cardiomyopathy, valvular for ablation of a limited number of lesions but would not be disease, pericardial disease, and arrhythmias. However, a reasonable consideration in the patient described who has there is no consensus on cardiac testing in asymptomatic innumerable lesions in the liver and retroperitoneum. patients after chest irradiation.

Item 13 Answer: 8B fracture. The risk of fracture with 5 years of aromatase inhib- itor therapy is about 8% to 10%. Patients receiving extended Educational Objective: Treat metastatic mismatch aromatase inhibitor therapy have a higher risk of bone loss repair—deficient colon cancer. and fracture. Consensus guidelines recommend obtaining This patient now has treatment-refractory metastatic colorectal bone density tests routinely to assess fracture risk. Clinical cancer with a mismatch repair-deficient tumor that should be tools such as the Fracture Risk Assessment Tool can be used to treated with immunotherapy with a programmed death recep- estimate fracture risk using bone density measurement. Frac- tor 1 (PD-1) inhibitor (Option B). Tumors may be mismatch ture risk informs management strategies for osteoporosis and repair-deficient either due to a germline mutation, a condition osteopenia, including use of supplemental vitamin D and/or a known as Lynch syndrome, or a somatic mutation (or epi- bone-modifying agent such as a bisphosphonate. genetic silencing) that is limited to the tumor. Because mis- Breast cancer survivors without symptoms suggestive of match repair-deficient tumors carry a better prognosis than distant recurrence are not recommended to undergo routine the more common mismatch repair-proficient tumors, mis- surveillance CTs (Option A). Multiple randomized trials have match repair-deficient tumors rarely become metastatic and compared an intensive surveillance strategy (with CTs and comprise only 3% to 4% of all metastatic colorectal cancer cases. tumor markers) versus routine care and found no difference Patients in this rare subset, however, have shown substantial in long-term outcomes except that intensive surveillance benefit from treatment with immune checkpoint inhibitors, was associated with inferior quality of life. specifically PD-1 inhibitors. Unfortunately for most patients Echocardiograms (Option C) are not routinely recom- with metastatic colorectal cancer (>95%) whose tumors are mended for breast cancer survivors taking aromatase inhib- mismatch repair-proficient, PD-1 inhibitors and other immune itors or after postmastectomy irradiation. Echocardiograms checkpoint inhibitors have thus far been essentially inactive. are performed before receipt of cardiotoxic chemotherapy Supportive comfort care and hospice management such as anthracyclines or trastuzumab. Patients with higher (Option A) is an important consideration in patients who are cumulative doses and evidence of reduced ejection fraction too sick for treatment or who have exhausted all reasonable should have a cardiology consultation. For asymptomatic treatment options. Such a course of action would not be the patients treated with human epidermal growth factor recep- most appropriate consideration in a fully functional patient tor 2-targeted therapy, routine testing posttherapy is not with a meaningful treatment option available. recommended. Potential complications of radiation therapy Stereotactic radiation therapy (Option C) can be used include coronary artery disease, cardiomyopathy, valvular for ablation of a limited number of lesions but would not be disease, pericardial disease, and arrhythmias. However, a reasonable consideration in the patient described who has there is no consensus on cardiac testing in asymptomatic innumerable lesions in the liver and retroperitoneum. patients after chest irradiation. 73

Answers and Critiques _ Pelvic ultrasonography (Option D) is not performed course of platinum-based chemotherapy than those who routinely for patients on aromatase inhibitors, which do not relapse before 6 months. This patient has responded to ini- increase the risk of endometrial cancer. Tamoxifen is associ- tial therapy, and the addition of maintenance PARP inhibi- ated with a small increase in the risk of endometrial cancer. tor therapy further improves progression-free survival and If a postmenopausal woman on tamoxifen experiences vagi- delays the need for a second course of platinum-based nal bleeding, pelvic ultrasonography should be performed to chemotherapy. evaluate for uterine abnormalities. No additional therapy (Option D) is inappropriate for this patient with advanced epithelial ovarian cancer. The addition of a PARP inhibitor results in substantial improve- e Aromatase inhibitors are associated with bone loss ments in progression-free survival and delays the need for a and an elevated risk of fracture; patients on aromatase second course of chemotherapy. inhibitors should have bone density studies every

Pelvic ultrasonography (Option D) is not performed course of platinum-based chemotherapy than those who routinely for patients on aromatase inhibitors, which do not relapse before 6 months. This patient has responded to ini- increase the risk of endometrial cancer. Tamoxifen is associ- tial therapy, and the addition of maintenance PARP inhibi- ated with a small increase in the risk of endometrial cancer. tor therapy further improves progression-free survival and If a postmenopausal woman on tamoxifen experiences vagi- delays the need for a second course of platinum-based nal bleeding, pelvic ultrasonography should be performed to chemotherapy. evaluate for uterine abnormalities. No additional therapy (Option D) is inappropriate for this patient with advanced epithelial ovarian cancer. The addition of a PARP inhibitor results in substantial improve- e Aromatase inhibitors are associated with bone loss ments in progression-free survival and delays the need for a and an elevated risk of fracture; patients on aromatase second course of chemotherapy. inhibitors should have bone density studies every > 2 years. = e Women with advanced ovarian cancer and BRCA ” = Bibliography mutations who achieve some response to platinum- o = wn Shapiro CL, Van Poznak C, Lacchetti C, et al. Management of osteoporosis in based chemotherapy should receive subsequent g@ survivors of adult cancers with nonmetastatic disease: ASCO clinical maintenance therapy with a poly (ADP-ribose) poly- 3 practice guideline. J Clin Oncol. 2019;37:2916-46. [PMID: 31532726] a. doi:10.1200/JCO.19.01696 merase inhibitor. (2) = =. Bibliography 2 a Gonzalez-Martin A, Pothuri B, Vergote I, et al; PRIMA/ENGOT-OV26/GOG- o Item 15 Answer: B wn 3012 Investigators. Niraparib in patients with newly diagnosed advanced Educational Objective: Treat a patient with germline ovarian cancer. N Engl J Med. 2019;381:2391-2402. [PMID: 31562799] doi:10.1056/NEJMoal1910962 BRCAI1 mutation and advanced ovarian cancer.

> 2 years. = e Women with advanced ovarian cancer and BRCA ” = Bibliography mutations who achieve some response to platinum- o = wn Shapiro CL, Van Poznak C, Lacchetti C, et al. Management of osteoporosis in based chemotherapy should receive subsequent g@ survivors of adult cancers with nonmetastatic disease: ASCO clinical maintenance therapy with a poly (ADP-ribose) poly- 3 practice guideline. J Clin Oncol. 2019;37:2916-46. [PMID: 31532726] a. doi:10.1200/JCO.19.01696 merase inhibitor. (2) = =. Bibliography 2 a Gonzalez-Martin A, Pothuri B, Vergote I, et al; PRIMA/ENGOT-OV26/GOG- o Item 15 Answer: B wn 3012 Investigators. Niraparib in patients with newly diagnosed advanced Educational Objective: Treat a patient with germline ovarian cancer. N Engl J Med. 2019;381:2391-2402. [PMID: 31562799] doi:10.1056/NEJMoal1910962 BRCAI1 mutation and advanced ovarian cancer. This patient has advanced epithelial ovarian cancer and a germline BRCA1 mutation and should receive maintenance Item 16 Answer: D therapy with a poly (ADP-ribose) polymerase (PARP) inhibi- Educational Objective: Assess breast cancer-related tor (Option B). She had optimal debulking, defined as residual risk and risk of congenital malformations following breast tumor deposits less than 1 cm in size, which is associated with cancer treatment. improved outcomes. The addition of adjuvant platinum-tax- ane chemotherapy also improves disease-free and overall This patient should be counseled that pregnancy after breast survival. For BRCA1 or BRCA2 mutation carriers with plat- cancer treatment is safe, and there is no increased risk of inum-sensitive disease (a disease-free interval greater than congenital malformations following breast cancer treatment 6 months), the addition of a maintenance PARP inhibitor (Option D). The best available data regarding the safety of following the completion of adjuvant chemotherapy is asso- pregnancy after breast cancer come from matched cohort ciated with substantial improvements in progression-free studies and have found that women with estrogen receptor survival. PARPs are involved in repair of single-strand breaks. (ER)-positive and ER-negative breast cancer who become PARP inhibition leads to DNA breaks that activate homolo- pregnant after breast cancer treatment have outcomes no gous recombination (HR) repair. Patients with BRCA muta- worse than women who do not become pregnant. These tions have defective HR repair, which results in an error-prone data suggest concerns that pregnancy, a high estrogen state, repair mechanism that cannot repair these breaks, leading to would increase the risk of recurrence of ER-positive breast cell death. In this way, PARP inhibitors are cytotoxic for cancer cancer are unfounded. Consensus guidelines indicate that cells, especially those with a germline or somatic BRCA1/2 pregnancy after breast cancer should not be discouraged. mutation. Maintenance PARP inhibition is also recommended Fertility is a very important survivorship issue and should be for patients without BRCA1/2 mutations, but benefits in pro- discussed with all patients of reproductive age before begin- gression-free survival are lesser. ning cancer treatment. Fertility preservation options, includ- Irradiation (Option A) does not play a role in the adju- ing embryo and oocyte cryopreservation, should be discussed vant management of patients with advanced ovarian cancer. as options to preserve fertility before gonadotoxic treatment. Ovarian cancer has a tendency to disseminate within the Breast cancer survivors’ fertility can be diminished as a direct peritoneal cavity along the peritoneal surface and requires a result of chemotherapy, particularly alkylating agents such systemic therapy approach following initial surgery. as cyclophosphamide; however, other drugs including tax- Repeat treatment with platinum-taxane chemother- anes and platinum chemotherapy may also have an impact apy (Option C) is not recommended in this patient who on fertility. Trastuzumab and endocrine therapies, such as has responded to initial therapy and has no evidence of tamoxifen or ovarian suppression, are not believed to directly recurrent disease. Platinum-based chemotherapy is indi- impair fertility, although the delay in pregnancy to complete cated in patients who relapse 6 months or longer after endocrine therapy may be associated with reduced fertility initial therapy and are more likely to respond to a second due to an age-related decline in ovarian reserve. The standard

This patient has advanced epithelial ovarian cancer and a germline BRCA1 mutation and should receive maintenance Item 16 Answer: D therapy with a poly (ADP-ribose) polymerase (PARP) inhibi- Educational Objective: Assess breast cancer-related tor (Option B). She had optimal debulking, defined as residual risk and risk of congenital malformations following breast tumor deposits less than 1 cm in size, which is associated with cancer treatment. improved outcomes. The addition of adjuvant platinum-tax- ane chemotherapy also improves disease-free and overall This patient should be counseled that pregnancy after breast survival. For BRCA1 or BRCA2 mutation carriers with plat- cancer treatment is safe, and there is no increased risk of inum-sensitive disease (a disease-free interval greater than congenital malformations following breast cancer treatment 6 months), the addition of a maintenance PARP inhibitor (Option D). The best available data regarding the safety of following the completion of adjuvant chemotherapy is asso- pregnancy after breast cancer come from matched cohort ciated with substantial improvements in progression-free studies and have found that women with estrogen receptor survival. PARPs are involved in repair of single-strand breaks. (ER)-positive and ER-negative breast cancer who become PARP inhibition leads to DNA breaks that activate homolo- pregnant after breast cancer treatment have outcomes no gous recombination (HR) repair. Patients with BRCA muta- worse than women who do not become pregnant. These tions have defective HR repair, which results in an error-prone data suggest concerns that pregnancy, a high estrogen state, repair mechanism that cannot repair these breaks, leading to would increase the risk of recurrence of ER-positive breast cell death. In this way, PARP inhibitors are cytotoxic for cancer cancer are unfounded. Consensus guidelines indicate that cells, especially those with a germline or somatic BRCA1/2 pregnancy after breast cancer should not be discouraged. mutation. Maintenance PARP inhibition is also recommended Fertility is a very important survivorship issue and should be for patients without BRCA1/2 mutations, but benefits in pro- discussed with all patients of reproductive age before begin- gression-free survival are lesser. ning cancer treatment. Fertility preservation options, includ- Irradiation (Option A) does not play a role in the adju- ing embryo and oocyte cryopreservation, should be discussed vant management of patients with advanced ovarian cancer. as options to preserve fertility before gonadotoxic treatment. Ovarian cancer has a tendency to disseminate within the Breast cancer survivors’ fertility can be diminished as a direct peritoneal cavity along the peritoneal surface and requires a result of chemotherapy, particularly alkylating agents such systemic therapy approach following initial surgery. as cyclophosphamide; however, other drugs including tax- Repeat treatment with platinum-taxane chemother- anes and platinum chemotherapy may also have an impact apy (Option C) is not recommended in this patient who on fertility. Trastuzumab and endocrine therapies, such as has responded to initial therapy and has no evidence of tamoxifen or ovarian suppression, are not believed to directly recurrent disease. Platinum-based chemotherapy is indi- impair fertility, although the delay in pregnancy to complete cated in patients who relapse 6 months or longer after endocrine therapy may be associated with reduced fertility initial therapy and are more likely to respond to a second due to an age-related decline in ovarian reserve. The standard 74

Answers and Critiques for patients with ER-positive breast cancer is to complete the preferred therapy for patients with good performance status recommended full course of endocrine therapy before trying who do not have a driver mutation. Contraindications to to conceive. immunotherapy include connective tissue disease, rheuma- Breast cancer outcomes, including recurrence and mor- tologic diseases, or interstitial lung disease. tality (Options A, B), are not increased in patients who Combination chemotherapy (Option A) without pem- become pregnant after treatment. brolizumab has been shown to be inferior to chemotherapy Pregnancy is contraindicated while on tamoxifen, given plus pembrolizumab in patients who have good perfor- an increase in risk of birth defects (genitourinary defects) mance status with metastatic non-small cell lung cancer. and should be avoided for a period of 3 months after stop- Use of combination chemotherapy alone is only indicated ping tamoxifen. There seems to be no increased teratoge- in patients who are not candidates for immunotherapy nicity 1 year after stopping the medication. Pregnancy is treatment. This patient has no apparent contraindication to contraindicated while on trastuzumab, given an increase in immunotherapy treatment. risk of oligohydramnios and for 7 months following the last Pembrolizumab alone (Option C) can be used in patients wn” a administration. There is no long-term increase in the terato- with PD-L1 expression greater than 50%. Furthermore, it ss

for patients with ER-positive breast cancer is to complete the preferred therapy for patients with good performance status recommended full course of endocrine therapy before trying who do not have a driver mutation. Contraindications to to conceive. immunotherapy include connective tissue disease, rheuma- Breast cancer outcomes, including recurrence and mor- tologic diseases, or interstitial lung disease. tality (Options A, B), are not increased in patients who Combination chemotherapy (Option A) without pem- become pregnant after treatment. brolizumab has been shown to be inferior to chemotherapy Pregnancy is contraindicated while on tamoxifen, given plus pembrolizumab in patients who have good perfor- an increase in risk of birth defects (genitourinary defects) mance status with metastatic non-small cell lung cancer. and should be avoided for a period of 3 months after stop- Use of combination chemotherapy alone is only indicated ping tamoxifen. There seems to be no increased teratoge- in patients who are not candidates for immunotherapy nicity 1 year after stopping the medication. Pregnancy is treatment. This patient has no apparent contraindication to contraindicated while on trastuzumab, given an increase in immunotherapy treatment. risk of oligohydramnios and for 7 months following the last Pembrolizumab alone (Option C) can be used in patients wn” a administration. There is no long-term increase in the terato- with PD-L1 expression greater than 50%. Furthermore, it ss genicity risk. Children of female and male cancer survivors is also approved as initial therapy in patients with PD-L1 = 7. treated with chemotherapy, radiation therapy, or both have expression from 1% to 49%, although it is less active in this rs) no increased risk of congenital anomalies or genetic disor- setting, and combined pembrolizumab and chemotherapy is <s = ders (Option C). preferred for such patients. This patient has negative PD-L1 cs wn expression, however, and single-agent pembrolizumab plays Ban @ no role in the treatment of such patients. = ¢ Breast cancer outcomes, including recurrence and Single-agent chemotherapy (Option D) is not a standard wn = mortality, are not increased in patients who become treatment option for first-line treatment of patients with <

genicity risk. Children of female and male cancer survivors is also approved as initial therapy in patients with PD-L1 = 7. treated with chemotherapy, radiation therapy, or both have expression from 1% to 49%, although it is less active in this rs) no increased risk of congenital anomalies or genetic disor- setting, and combined pembrolizumab and chemotherapy is <s = ders (Option C). preferred for such patients. This patient has negative PD-L1 cs wn expression, however, and single-agent pembrolizumab plays Ban @ no role in the treatment of such patients. = ¢ Breast cancer outcomes, including recurrence and Single-agent chemotherapy (Option D) is not a standard wn = mortality, are not increased in patients who become treatment option for first-line treatment of patients with < pregnant after treatment. non-small cell lung cancer.

genicity risk. Children of female and male cancer survivors is also approved as initial therapy in patients with PD-L1 = 7. treated with chemotherapy, radiation therapy, or both have expression from 1% to 49%, although it is less active in this rs) no increased risk of congenital anomalies or genetic disor- setting, and combined pembrolizumab and chemotherapy is <s = ders (Option C). preferred for such patients. This patient has negative PD-L1 cs wn expression, however, and single-agent pembrolizumab plays Ban @ no role in the treatment of such patients. = ¢ Breast cancer outcomes, including recurrence and Single-agent chemotherapy (Option D) is not a standard wn = mortality, are not increased in patients who become treatment option for first-line treatment of patients with < pregnant after treatment. non-small cell lung cancer. ¢ Congenital malformations are not increased in chil- dren of patients after treatment with irradiation or e In the absence of a driver mutation (epidermal growth chemotherapy. factor receptor, ALK, ROS1), combination of pem- brolizumab with chemotherapy has been shown to Bibliography improve survival in patients who have good perfor- Lambertini M, Kroman N, Ameye L, et al. Long-term safety of pregnancy following breast cancer according to estrogen receptor status. J Natl mance with metastatic non-small cell lung cancer Cancer Inst. 2018;110:426-29. [PMID: 29087485] doi:10.1093/jnci/djx206 regardless of programmed cell death ligand-1 level.

¢ Congenital malformations are not increased in chil- dren of patients after treatment with irradiation or e In the absence of a driver mutation (epidermal growth chemotherapy. factor receptor, ALK, ROS1), combination of pem- brolizumab with chemotherapy has been shown to Bibliography improve survival in patients who have good perfor- Lambertini M, Kroman N, Ameye L, et al. Long-term safety of pregnancy following breast cancer according to estrogen receptor status. J Natl mance with metastatic non-small cell lung cancer Cancer Inst. 2018;110:426-29. [PMID: 29087485] doi:10.1093/jnci/djx206 regardless of programmed cell death ligand-1 level. ¢ Inthe absence of a driver mutation (epidermal growth Item 17 Answer: B factor receptor, ALK, ROS1), pembrolizumab monother- Educational Objective: Treat metastatic non-small cell apy is first-line therapy in patients with programmed lung cancer without a driver mutation with pembroli- cell death ligand-1 expression greater than 50%.

¢ Inthe absence of a driver mutation (epidermal growth Item 17 Answer: B factor receptor, ALK, ROS1), pembrolizumab monother- Educational Objective: Treat metastatic non-small cell apy is first-line therapy in patients with programmed lung cancer without a driver mutation with pembroli- cell death ligand-1 expression greater than 50%. zumab plus chemotherapy. Bibliography This patient should be treated with pembrolizumab plus che- Gandhi L, Rodriguez-Abreu D, Gadgeel S, et al; KEYNOTE-189 Investigators. motherapy (Option B). Immunotherapy is playing an increas- Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med. 2018;378:2078-92. [PMID: 29658856] doi:10.1056/ ingly important role in the management of patients with NEJMoal1801005 metastatic non-small cell lung cancer. Many different immu- notherapy agents, mostly directed against the programmed death-1/programmed cell death ligand-1 (PD-1/PD-L1) axis, Item 18 Answer: C have been shown to be effective for the treatment of advanced Educational Objective: Diagnose histologic transforma- non-small cell lung cancer. Immunotherapy can be used as tion in low-grade non-Hodgkin lymphoma. single-agent therapy based on expression of the PD-L1 bio- marker. However, in patients without a driver mutation (epi- The appropriate next step is to biopsy the left inguinal lymph dermal growth factor receptor, ALK, ROS1), the combination nodes (Option C) to look for evidence of transformation. This of pembrolizumab with carboplatin and pemetrexed has been patient’s clinical picture with rapid growth in a single nodal shown to improve survival in those with metastatic non-small area with disproportionately higher PET standardized uptake cell lung cancer regardless of PD-L1 level. This was shown values (SUVs) is suggestive of transformation of his low-grade in a randomized phase III trial that tested this combination follicular lymphoma to a more aggressive phenotype, typically in comparison to carboplatin/pemetrexed in the first-line to diffuse large cell lymphoma. Other features that can suggest treatment setting. This study found that the combination of transformation include new onset of B symptoms, declining chemotherapy and pembrolizumab improved survival regard- performance status, marked rise in lactate dehydrogenase, less of PD-L1 status. Based on this result, the combination of hypercalcemia, and the development of new sites of extra- pembrolizumab and platinum-based chemotherapy is the nodal disease. SUV on PET scan over 17 is strongly suggestive

zumab plus chemotherapy. Bibliography This patient should be treated with pembrolizumab plus che- Gandhi L, Rodriguez-Abreu D, Gadgeel S, et al; KEYNOTE-189 Investigators. motherapy (Option B). Immunotherapy is playing an increas- Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med. 2018;378:2078-92. [PMID: 29658856] doi:10.1056/ ingly important role in the management of patients with NEJMoal1801005 metastatic non-small cell lung cancer. Many different immu- notherapy agents, mostly directed against the programmed death-1/programmed cell death ligand-1 (PD-1/PD-L1) axis, Item 18 Answer: C have been shown to be effective for the treatment of advanced Educational Objective: Diagnose histologic transforma- non-small cell lung cancer. Immunotherapy can be used as tion in low-grade non-Hodgkin lymphoma. single-agent therapy based on expression of the PD-L1 bio- marker. However, in patients without a driver mutation (epi- The appropriate next step is to biopsy the left inguinal lymph dermal growth factor receptor, ALK, ROS1), the combination nodes (Option C) to look for evidence of transformation. This of pembrolizumab with carboplatin and pemetrexed has been patient’s clinical picture with rapid growth in a single nodal shown to improve survival in those with metastatic non-small area with disproportionately higher PET standardized uptake cell lung cancer regardless of PD-L1 level. This was shown values (SUVs) is suggestive of transformation of his low-grade in a randomized phase III trial that tested this combination follicular lymphoma to a more aggressive phenotype, typically in comparison to carboplatin/pemetrexed in the first-line to diffuse large cell lymphoma. Other features that can suggest treatment setting. This study found that the combination of transformation include new onset of B symptoms, declining chemotherapy and pembrolizumab improved survival regard- performance status, marked rise in lactate dehydrogenase, less of PD-L1 status. Based on this result, the combination of hypercalcemia, and the development of new sites of extra- pembrolizumab and platinum-based chemotherapy is the nodal disease. SUV on PET scan over 17 is strongly suggestive 75

eee Se of transformation, but lower SUV levels cannot reliably rule paroxetine, and other antidepressants such as bupropion, are in or rule out transformation, so biopsy is necessary if there is strong inhibitors of CYP2D6 and may interact with tamoxifen, clinical concern based on other features. reducing tamoxifen activation. The impact of this interaction Transformation of low-grade follicular lymphoma to on long-term breast cancer outcomes is unknown, but use of diffuse large cell lymphoma may occur in about one third of strong CYP2D6 inhibitors is generally not recommended, and patients over time. Transformation has important prognos- other SSRIs, such as sertraline or escitalopram, or venlafaxine, tic and therapeutic implications, as such events indicate a a serotonin-norepinephrine reuptake inhibitor, are felt to be worse prognosis and require more aggressive therapy. If his safe and are preferred. Breast cancer survivors, particularly lymphoma has undergone transformation to a higher grade those diagnosed at young ages, are at increased risk of anxiety of disease, combination anthracycline-based chemotherapy, and depression, and evaluating and managing mood symp- autologous hematopoietic stem cell transplantation, and in toms is an important aspect of survivorship care. some cases, CD19-targerted CAR-T cell therapy would be a Tamoxifen (Option A) may cause mood symptoms Pd treatment option. such as depression, but given the associated improvement = wn Transformation to diffuse large B-cell lymphoma or in breast cancer outcomes and survival, tamoxifen should = Burkitt lymphoma is also described in other subtypes of not be discontinued in this patient. Mood symptoms could oO ay wn indolent lymphoma including marginal zone lymphoma, be managed with the addition of an antidepressant. If the @ = lymphoplasmacytic lymphoma, small lymphocytic lym- patient has depression that persists despite incorporation of Qa. phoma/chronic lymphocytic leukemia (Richter syndrome), antidepressants and/or counseling, it would be reasonable a Oy and lymphocyte-predominant Hodgkin lymphoma but is to consider alternatives. In a premenopausal woman, this =. best described in follicular lymphoma. treatment would include use of ovarian suppression with an 2 b 4 Treatment strategy depends on the results of the lymph aromatase inhibitor, although these medications may also @o wn node biopsy. Initiating treatment without a histological diag- contribute to mood symptoms. nosis is not appropriate. Furthermore, treatment with ritux- Bupropion (Option B) is another antidepressant that imab, rituximab and bendamustine, or irradiation (Options is used for the treatment of depression and should also A, B, and D) may be effective in low-grade lymphoma but be avoided for patients on tamoxifen, given the possible not if transformation to higher-grade disease has occurred. decrease in tamoxifen activation due to CYP2D6 inhibition. Fluoxetine (Option C) is often used for the treatment of depression but is a strong CYP2D6 inhibitor and is therefore e Histologic transformation of follicular lymphoma is not recommended for patients on tamoxifen because it can suggested by new onset of systemic symptoms, decrease tamoxifen activation. declining performance status, lactate dehydrogenase or calcium elevation, new sites of extranodal disease, or characteristic CT/PET findings. e Depression and anxiety are common in women with breast cancer. ¢ Suspected histological transformation of low-grade non-Hodgkin lymphoma should be confirmed by e Antidepressants with strong CYP2D6 inhibition, such

of transformation, but lower SUV levels cannot reliably rule paroxetine, and other antidepressants such as bupropion, are in or rule out transformation, so biopsy is necessary if there is strong inhibitors of CYP2D6 and may interact with tamoxifen, clinical concern based on other features. reducing tamoxifen activation. The impact of this interaction Transformation of low-grade follicular lymphoma to on long-term breast cancer outcomes is unknown, but use of diffuse large cell lymphoma may occur in about one third of strong CYP2D6 inhibitors is generally not recommended, and patients over time. Transformation has important prognos- other SSRIs, such as sertraline or escitalopram, or venlafaxine, tic and therapeutic implications, as such events indicate a a serotonin-norepinephrine reuptake inhibitor, are felt to be worse prognosis and require more aggressive therapy. If his safe and are preferred. Breast cancer survivors, particularly lymphoma has undergone transformation to a higher grade those diagnosed at young ages, are at increased risk of anxiety of disease, combination anthracycline-based chemotherapy, and depression, and evaluating and managing mood symp- autologous hematopoietic stem cell transplantation, and in toms is an important aspect of survivorship care. some cases, CD19-targerted CAR-T cell therapy would be a Tamoxifen (Option A) may cause mood symptoms Pd treatment option. such as depression, but given the associated improvement = wn Transformation to diffuse large B-cell lymphoma or in breast cancer outcomes and survival, tamoxifen should = Burkitt lymphoma is also described in other subtypes of not be discontinued in this patient. Mood symptoms could oO ay wn indolent lymphoma including marginal zone lymphoma, be managed with the addition of an antidepressant. If the @ = lymphoplasmacytic lymphoma, small lymphocytic lym- patient has depression that persists despite incorporation of Qa. phoma/chronic lymphocytic leukemia (Richter syndrome), antidepressants and/or counseling, it would be reasonable a Oy and lymphocyte-predominant Hodgkin lymphoma but is to consider alternatives. In a premenopausal woman, this =. best described in follicular lymphoma. treatment would include use of ovarian suppression with an 2 b 4 Treatment strategy depends on the results of the lymph aromatase inhibitor, although these medications may also @o wn node biopsy. Initiating treatment without a histological diag- contribute to mood symptoms. nosis is not appropriate. Furthermore, treatment with ritux- Bupropion (Option B) is another antidepressant that imab, rituximab and bendamustine, or irradiation (Options is used for the treatment of depression and should also A, B, and D) may be effective in low-grade lymphoma but be avoided for patients on tamoxifen, given the possible not if transformation to higher-grade disease has occurred. decrease in tamoxifen activation due to CYP2D6 inhibition. Fluoxetine (Option C) is often used for the treatment of depression but is a strong CYP2D6 inhibitor and is therefore e Histologic transformation of follicular lymphoma is not recommended for patients on tamoxifen because it can suggested by new onset of systemic symptoms, decrease tamoxifen activation. declining performance status, lactate dehydrogenase or calcium elevation, new sites of extranodal disease, or characteristic CT/PET findings. e Depression and anxiety are common in women with breast cancer. ¢ Suspected histological transformation of low-grade non-Hodgkin lymphoma should be confirmed by e Antidepressants with strong CYP2D6 inhibition, such lymph node biopsy. as bupropion or fluoxetine, may decrease tamoxifen activation and should be avoided.

of transformation, but lower SUV levels cannot reliably rule paroxetine, and other antidepressants such as bupropion, are in or rule out transformation, so biopsy is necessary if there is strong inhibitors of CYP2D6 and may interact with tamoxifen, clinical concern based on other features. reducing tamoxifen activation. The impact of this interaction Transformation of low-grade follicular lymphoma to on long-term breast cancer outcomes is unknown, but use of diffuse large cell lymphoma may occur in about one third of strong CYP2D6 inhibitors is generally not recommended, and patients over time. Transformation has important prognos- other SSRIs, such as sertraline or escitalopram, or venlafaxine, tic and therapeutic implications, as such events indicate a a serotonin-norepinephrine reuptake inhibitor, are felt to be worse prognosis and require more aggressive therapy. If his safe and are preferred. Breast cancer survivors, particularly lymphoma has undergone transformation to a higher grade those diagnosed at young ages, are at increased risk of anxiety of disease, combination anthracycline-based chemotherapy, and depression, and evaluating and managing mood symp- autologous hematopoietic stem cell transplantation, and in toms is an important aspect of survivorship care. some cases, CD19-targerted CAR-T cell therapy would be a Tamoxifen (Option A) may cause mood symptoms Pd treatment option. such as depression, but given the associated improvement = wn Transformation to diffuse large B-cell lymphoma or in breast cancer outcomes and survival, tamoxifen should = Burkitt lymphoma is also described in other subtypes of not be discontinued in this patient. Mood symptoms could oO ay wn indolent lymphoma including marginal zone lymphoma, be managed with the addition of an antidepressant. If the @ = lymphoplasmacytic lymphoma, small lymphocytic lym- patient has depression that persists despite incorporation of Qa. phoma/chronic lymphocytic leukemia (Richter syndrome), antidepressants and/or counseling, it would be reasonable a Oy and lymphocyte-predominant Hodgkin lymphoma but is to consider alternatives. In a premenopausal woman, this =. best described in follicular lymphoma. treatment would include use of ovarian suppression with an 2 b 4 Treatment strategy depends on the results of the lymph aromatase inhibitor, although these medications may also @o wn node biopsy. Initiating treatment without a histological diag- contribute to mood symptoms. nosis is not appropriate. Furthermore, treatment with ritux- Bupropion (Option B) is another antidepressant that imab, rituximab and bendamustine, or irradiation (Options is used for the treatment of depression and should also A, B, and D) may be effective in low-grade lymphoma but be avoided for patients on tamoxifen, given the possible not if transformation to higher-grade disease has occurred. decrease in tamoxifen activation due to CYP2D6 inhibition. Fluoxetine (Option C) is often used for the treatment of depression but is a strong CYP2D6 inhibitor and is therefore e Histologic transformation of follicular lymphoma is not recommended for patients on tamoxifen because it can suggested by new onset of systemic symptoms, decrease tamoxifen activation. declining performance status, lactate dehydrogenase or calcium elevation, new sites of extranodal disease, or characteristic CT/PET findings. e Depression and anxiety are common in women with breast cancer. ¢ Suspected histological transformation of low-grade non-Hodgkin lymphoma should be confirmed by e Antidepressants with strong CYP2D6 inhibition, such lymph node biopsy. as bupropion or fluoxetine, may decrease tamoxifen activation and should be avoided. Bibliography Casulo C, Burack WR, Friedberg JW. Transformed follicular non-Hodgkin Bibliography lymphoma. Blood. 2015;125:40-7. [PMID: 25499449] doi:10.1182/blood- Hansten PD. The underrated risks of tamoxifen drug interactions. Eur J 2014-04-516815 Drug Metab Pharmacokinet. 2018;43:495-508. [PMID: 29637493] doi:10.1007/s13318-018-0475-9

Bibliography Casulo C, Burack WR, Friedberg JW. Transformed follicular non-Hodgkin Bibliography lymphoma. Blood. 2015;125:40-7. [PMID: 25499449] doi:10.1182/blood- Hansten PD. The underrated risks of tamoxifen drug interactions. Eur J 2014-04-516815 Drug Metab Pharmacokinet. 2018;43:495-508. [PMID: 29637493] doi:10.1007/s13318-018-0475-9 Item 19 Answer: D Educational Objective: Manage depression in a breast Item 20 Answer: C cancer survivor taking tamoxifen. Educational Objective: Manage a patient with newly diagnosed inflammatory breast cancer. This patient is experiencing depression, and it would be appropriate to prescribe venlafaxine (Option D). Depres- This patient has inflammatory breast cancer (IBC) and should sive symptoms are frequently encountered in patients with undergo preoperative chemotherapy followed by mastectomy chronic medical disease either as a result of the illness itself and irradiation (Option C). IBC is diagnosed on the basis (such as hypothyroidism) or as a response to the disability of the clinical examination and is usually characterized by caused by the illness. Depression commonly accompanies erythematous and thickened skin, which is due to occlusion many medical conditions, including cancer, neurologic dis- of dermal lymphatic vessels. Patients frequently present with eases (Parkinson disease), heart failure, and HIV infection. breast enlargement or swelling that is often misdiagnosed Medications, including tamoxifen, glucocorticoids, and inter- as mastitis with subsequent delay in management. A palpa- feron, may also trigger depressive symptoms. Some selective ble breast mass may be present. One-third of patients have serotonin reuptake inhibitors (SSRIs), such as fluoxetine and distant metastases at diagnosis, and nearly all have lymph 76

ess ane Crees node involvement. For this reason, these patients should have include signs and symptoms of herniation. In this patient, routine staging with either CT and bone scan imaging or PET, morning nausea and headache are symptoms that should even in the absence of symptoms of metastatic disease. IBC is prompt concern for increased intracranial pressure, which associated with a high risk of both locoregional and distant is confirmed by the funduscopic examination showing pap- recurrence and requires multimodality treatment. Patients illedema. The characteristic findings of late papilledema as with IBC should receive preoperative chemotherapy rather shown in the image include elevation of the optic disc with than mastectomy followed by chemotherapy and irradiation blurring of the margins and loss of the optic cup. Blood ves- (Option A). Preoperative chemotherapy aims to shrink the sels are buried as they course the disc. Multiple flame hem- tumor to maximize the chance that mastectomy will be a orrhages and cotton wool spots, resulting from nerve fiber complete resection with negative margins. Mastectomy is infarction, are present. Glucocorticoids reduce tumor-related associated with decreased risk of locoregional recurrence and vasogenic edema in 75% of patients and often provide rapid improved disease-free survival relative to breast-conserving symptom improvement. Although this patient will require surgery. Postmastectomy radiation therapy is recommended irradiation, surgery, or both to directly address the new brain wa a for cancers greater than 5 cm in size, inadequate or positive metastasis, glucocorticoids should be initiated upon diagnosis 3

node involvement. For this reason, these patients should have include signs and symptoms of herniation. In this patient, routine staging with either CT and bone scan imaging or PET, morning nausea and headache are symptoms that should even in the absence of symptoms of metastatic disease. IBC is prompt concern for increased intracranial pressure, which associated with a high risk of both locoregional and distant is confirmed by the funduscopic examination showing pap- recurrence and requires multimodality treatment. Patients illedema. The characteristic findings of late papilledema as with IBC should receive preoperative chemotherapy rather shown in the image include elevation of the optic disc with than mastectomy followed by chemotherapy and irradiation blurring of the margins and loss of the optic cup. Blood ves- (Option A). Preoperative chemotherapy aims to shrink the sels are buried as they course the disc. Multiple flame hem- tumor to maximize the chance that mastectomy will be a orrhages and cotton wool spots, resulting from nerve fiber complete resection with negative margins. Mastectomy is infarction, are present. Glucocorticoids reduce tumor-related associated with decreased risk of locoregional recurrence and vasogenic edema in 75% of patients and often provide rapid improved disease-free survival relative to breast-conserving symptom improvement. Although this patient will require surgery. Postmastectomy radiation therapy is recommended irradiation, surgery, or both to directly address the new brain wa a for cancers greater than 5 cm in size, inadequate or positive metastasis, glucocorticoids should be initiated upon diagnosis 3 of increased intracranial pressure and should not be withheld = margins or skin involvement, IBCs, or four or more positive _ axillary nodes. Postmastectomy radiation therapy decreases for a therapeutic plan to be established. Cw) both the risk of local recurrence and the risk of distant metas- For the patient with an isolated brain metastasis, the sc = tases and increases overall survival. decision to perform surgical resection or stereotactic radia- © nr Breast-conserving surgery (Option B) is not recom- tion therapy (Options B, C) may depend on the size and loca- be o mended for patients with IBC. Mastectomy is associated with tion of the lesion, symptom burden, performance status, and = 2) improved locoregional control relative to breast-conserving comorbidities and is best made through multidisciplinary = discussion. < surgery.

of increased intracranial pressure and should not be withheld = margins or skin involvement, IBCs, or four or more positive _ axillary nodes. Postmastectomy radiation therapy decreases for a therapeutic plan to be established. Cw) both the risk of local recurrence and the risk of distant metas- For the patient with an isolated brain metastasis, the sc = tases and increases overall survival. decision to perform surgical resection or stereotactic radia- © nr Breast-conserving surgery (Option B) is not recom- tion therapy (Options B, C) may depend on the size and loca- be o mended for patients with IBC. Mastectomy is associated with tion of the lesion, symptom burden, performance status, and = 2) improved locoregional control relative to breast-conserving comorbidities and is best made through multidisciplinary = discussion. < surgery. Irradiation should not be the initial therapy. The tumor Whole brain radiation therapy (Option D) is not ideal may decrease in size significantly with up-front chemo- for this patient who has an isolated brain metastasis, which therapy allowing greater likelihood of surgical resection. could be addressed through surgery or stereotactic radiation Administering radiation therapy before surgery (Option D) therapy. Whole brain radiation therapy is associated with a increases the risk of poor wound healing and other compli- greater burden of symptoms including fatigue and cognitive cations. impairment. Whole brain radiation therapy is generally used for patients presenting with multiple brain metastases.

Irradiation should not be the initial therapy. The tumor Whole brain radiation therapy (Option D) is not ideal may decrease in size significantly with up-front chemo- for this patient who has an isolated brain metastasis, which therapy allowing greater likelihood of surgical resection. could be addressed through surgery or stereotactic radiation Administering radiation therapy before surgery (Option D) therapy. Whole brain radiation therapy is associated with a increases the risk of poor wound healing and other compli- greater burden of symptoms including fatigue and cognitive cations. impairment. Whole brain radiation therapy is generally used for patients presenting with multiple brain metastases. ¢ Patients with inflammatory breast cancer often pre- sent with breast enlargement or swelling that is often ¢ Symptoms of increased intracranial pressure include misdiagnosed as mastitis. headache, depressed global consciousness, and vomit- ing, and may include signs and symptoms of herniation. e Inflammatory breast cancer is usually treated initially with neoadjuvant chemotherapy, followed by surgery, © Glucocorticoids reduce tumor-related vasogenic and then radiation therapy. edema in patients with brain metastases and often provide rapid symptom improvement. Bibliography Rosenbluth JM, Overmoyer BA. Inflammatory breast cancer: a separate Bibliography entity. Curr Oncol Rep. 2019;21:86. [PMID: 31414257] doi:10.1007/s11912- Achrol AS, Rennert RC, Anders C, et al. Brain metastases. Nat Rev Dis 019-0842-y Primers. 2019;5:5. [PMID: 30655533] doi:10.1038/s41572-018-0055-y

Bibliography Rosenbluth JM, Overmoyer BA. Inflammatory breast cancer: a separate Bibliography entity. Curr Oncol Rep. 2019;21:86. [PMID: 31414257] doi:10.1007/s11912- Achrol AS, Rennert RC, Anders C, et al. Brain metastases. Nat Rev Dis 019-0842-y Primers. 2019;5:5. [PMID: 30655533] doi:10.1038/s41572-018-0055-y Item 21 Answer: A Item 22 Answer: C Educational Objective: Treat a patient with brain Educational Objective: Treat locally advanced anal metastases and elevated intracranial pressure. cancer. This patient has elevated intracranial pressure from a newly This patient has locally invasive squamous cell cancer of the diagnosed brain metastasis and should receive initial treat- anal canal, and curative-intent treatment with the combina- ment with dexamethasone (Option A). Elevated intracranial tion of pelvic radiation therapy and concurrent systemic che- pressure can result from primary brain malignancies or from motherapy (Option C) is indicated. This would be appropriate brain metastases, which occur in 10% to 20% of adult cancer for patients with stages I, II, or III anal cancer. Anal cancer is a patients. The most common types of primary cancer that squamous cell carcinoma, whereas the more common cancer cause brain metastases are lung cancer, breast cancer, and of the rectum is an adenocarcinoma derived from the colum- melanoma. Median survival after diagnosis of brain metasta- nar epithelium of the rectum. Anal cancers are a human pap- ses varies from less than 3 months to more than 25 months. illomavirus (HPV)-associated tumor and are of squamous cell Symptoms of increased intracranial pressure include head- histology. Rectal adenocarcinomas are not HPV-related. Risk ache, depressed global consciousness, and vomiting, and may of anal cancer is increased in men who have sex with men 77

Answers and Critiques and in patients with HIV infection, history of condylomata, include loss of lean body mass, fatigue, gynecomastia, hair and kidney or liver transplantation. Presenting symptoms of loss, decreased libido, erectile dysfunction, and vasomotor anal cancer may include bleeding, pain, or pruritus; however, symptoms. Long-term risks include a possible increase in 25% of patients present without any anorectal symptoms. cardiovascular disease and cognitive dysfunction, increased Although no formal recommendations address screening for risk of venous thromboembolism, and reduction in bone anal dysplasia in at-risk populations, screening modalities density. Patients with nonmetastatic cancer with one or more to consider include digital rectal examination, anal Pap test, risk factors for osteoporotic fracture should be offered DEXA HPV testing, and high-resolution anoscopy. Mitomycin plus screening. ADT is a risk factor for osteoporosis. Patients who a fluoropyrimidine (now most commonly oral capecitabine, are prescribed a drug that causes bone loss or whose bone although some centers still use intravenous fluorouracil) is mineral density is near the threshold of treatment should the standard chemotherapy regimen used concurrently with be screened every 2 years. For patients with osteoporosis, radiation therapy in patients with anal cancer. bisphosphonates or denosumab may be offered to reduce the > Unlike most colorectal cancers, anal cancer, if meta- risk of fracture. = 2) static, has shown sensitivity to immunotherapy with pro- There is increasing but inconsistent evidence that ADT = grammed death receptor 1 inhibitors (Option A); however, is associated with cognitive impairment and Alzheimer @o = wn use of these agents as first-line treatment of local-regional disease. However, there is no recommendation for routine r-*) = disease is just beginning to undergo investigation and is not dementia screening (Option A) in patients taking ATD, and 2. a proven or recommended strategy at this time. the U.S. Preventive Services Task Force has concluded that OO = Randomized studies have shown irradiation plus che- there is insufficient evidence for or against routine dementia fe motherapy to be superior to irradiation alone (Option B), screening in older adults. 2 < and 5-fluorouracil plus mitomycin to be superior to 5-fluo- Patients treated with ADT may be at risk for cardiovas- @o wn rouracil alone. cular disease and are at increased risk for venous throm- Surgery (Option D) is reserved as a salvage treatment boembolism. However, there are no recommendations for for either local recurrence or incomplete response to che- screening with either exercise electrocardiography (Option motherapy plus radiation therapy and is potentially curative. D) or Doppler ultrasonography (Option B) in asymptomatic However, because definitive surgery must remove the anal patients. sphincter, a placement of a permanent colostomy would be required. Therefore, surgery is reserved for when other reasonable options have been exhausted. e Patients with nonmetastatic cancer with one or more risk factors for osteoporotic fracture should be offered dual-energy x-ray absorptiometry screening. e Anal cancers are a human papillomavirus—associated e Patients with nonmetastatic cancer who are pre- tumor, and risk is increased in men who have sex scribed a drug that causes bone loss or whose bone with men, in patients with HIV infection, history of mineral density is near the threshold of treatment condylomata, and kidney or liver transplantation. should be screened every 2 years. e Anal cancer is often curable with combined irradiation and chemotherapy; surgery is typically not indicated. Bibliography Shapiro CL, Van Poznak C, Lacchetti C, et al. Management of osteoporosis in survivors of adult cancers with nonmetastatic disease: ASCO clinical Bibliography practice guideline. J Clin Oncol. 2019;37:2916-46. [PMID: 31532726] Jones CM, Adams R, Downing A, et al. Toxicity, tolerability, and compliance doi:10.1200/JCO.19.01696 of concurrent capecitabine or 5-fluorouracil in radical management of anal cancer with single-dose mitomycin-C and intensity modulated radiation therapy: evaluation of a national cohort. Int J Radiat Oncol Biol Phys. 2018;101:1202-11. [PMID: 29859793] doi:10.1016/j.ijrobp.2018. Item 24 Answer: A 04.033

and in patients with HIV infection, history of condylomata, include loss of lean body mass, fatigue, gynecomastia, hair and kidney or liver transplantation. Presenting symptoms of loss, decreased libido, erectile dysfunction, and vasomotor anal cancer may include bleeding, pain, or pruritus; however, symptoms. Long-term risks include a possible increase in 25% of patients present without any anorectal symptoms. cardiovascular disease and cognitive dysfunction, increased Although no formal recommendations address screening for risk of venous thromboembolism, and reduction in bone anal dysplasia in at-risk populations, screening modalities density. Patients with nonmetastatic cancer with one or more to consider include digital rectal examination, anal Pap test, risk factors for osteoporotic fracture should be offered DEXA HPV testing, and high-resolution anoscopy. Mitomycin plus screening. ADT is a risk factor for osteoporosis. Patients who a fluoropyrimidine (now most commonly oral capecitabine, are prescribed a drug that causes bone loss or whose bone although some centers still use intravenous fluorouracil) is mineral density is near the threshold of treatment should the standard chemotherapy regimen used concurrently with be screened every 2 years. For patients with osteoporosis, radiation therapy in patients with anal cancer. bisphosphonates or denosumab may be offered to reduce the > Unlike most colorectal cancers, anal cancer, if meta- risk of fracture. = 2) static, has shown sensitivity to immunotherapy with pro- There is increasing but inconsistent evidence that ADT = grammed death receptor 1 inhibitors (Option A); however, is associated with cognitive impairment and Alzheimer @o = wn use of these agents as first-line treatment of local-regional disease. However, there is no recommendation for routine r-*) = disease is just beginning to undergo investigation and is not dementia screening (Option A) in patients taking ATD, and 2. a proven or recommended strategy at this time. the U.S. Preventive Services Task Force has concluded that OO = Randomized studies have shown irradiation plus che- there is insufficient evidence for or against routine dementia fe motherapy to be superior to irradiation alone (Option B), screening in older adults. 2 < and 5-fluorouracil plus mitomycin to be superior to 5-fluo- Patients treated with ADT may be at risk for cardiovas- @o wn rouracil alone. cular disease and are at increased risk for venous throm- Surgery (Option D) is reserved as a salvage treatment boembolism. However, there are no recommendations for for either local recurrence or incomplete response to che- screening with either exercise electrocardiography (Option motherapy plus radiation therapy and is potentially curative. D) or Doppler ultrasonography (Option B) in asymptomatic However, because definitive surgery must remove the anal patients. sphincter, a placement of a permanent colostomy would be required. Therefore, surgery is reserved for when other reasonable options have been exhausted. e Patients with nonmetastatic cancer with one or more risk factors for osteoporotic fracture should be offered dual-energy x-ray absorptiometry screening. e Anal cancers are a human papillomavirus—associated e Patients with nonmetastatic cancer who are pre- tumor, and risk is increased in men who have sex scribed a drug that causes bone loss or whose bone with men, in patients with HIV infection, history of mineral density is near the threshold of treatment condylomata, and kidney or liver transplantation. should be screened every 2 years. e Anal cancer is often curable with combined irradiation and chemotherapy; surgery is typically not indicated. Bibliography Shapiro CL, Van Poznak C, Lacchetti C, et al. Management of osteoporosis in survivors of adult cancers with nonmetastatic disease: ASCO clinical Bibliography practice guideline. J Clin Oncol. 2019;37:2916-46. [PMID: 31532726] Jones CM, Adams R, Downing A, et al. Toxicity, tolerability, and compliance doi:10.1200/JCO.19.01696 of concurrent capecitabine or 5-fluorouracil in radical management of anal cancer with single-dose mitomycin-C and intensity modulated radiation therapy: evaluation of a national cohort. Int J Radiat Oncol Biol Phys. 2018;101:1202-11. [PMID: 29859793] doi:10.1016/j.ijrobp.2018. Item 24 Answer: A 04.033 Educational Objective: Manage an incidentally discov- ered neuroendocrine tumor. Item 23 Answer: C The most appropriate management for this patient is expectant Educational Objective: Screen for osteoporosis in observation (Option A) and a repeat CT in 3 months. He is inci- patients treated with androgen deprivation therapy. dentally found to have an asymptomatic, well-differentiated, The most appropriate screening test to perform next for this low-grade, small bowel gastrointestinal neuroendocrine tumor patient is a dual-energy x-ray absorptiometry (DEXA) scan (previously known as carcinoid) with multiple small metasta- (Option C) to establish baseline bone density and to assess ses to the liver. Such tumors are often present for many years for fracture risk. Patients diagnosed with high-risk nonmeta- before diagnosis and are often very indolent. Nonfunctional static prostate cancer are usually treated with a combination neuroendocrine tumors are often discovered incidentally. The of androgen deprivation therapy (ADT) and radiation therapy, liver is the most common site of metastases. Asymptomatic which has been shown to improve survival. ADT results in patients may have minimal growth and no symptoms for many many short- and long-term adverse effects. Short-term effects months or years, even with metastatic disease. Therefore, there

Educational Objective: Manage an incidentally discov- ered neuroendocrine tumor. Item 23 Answer: C The most appropriate management for this patient is expectant Educational Objective: Screen for osteoporosis in observation (Option A) and a repeat CT in 3 months. He is inci- patients treated with androgen deprivation therapy. dentally found to have an asymptomatic, well-differentiated, The most appropriate screening test to perform next for this low-grade, small bowel gastrointestinal neuroendocrine tumor patient is a dual-energy x-ray absorptiometry (DEXA) scan (previously known as carcinoid) with multiple small metasta- (Option C) to establish baseline bone density and to assess ses to the liver. Such tumors are often present for many years for fracture risk. Patients diagnosed with high-risk nonmeta- before diagnosis and are often very indolent. Nonfunctional static prostate cancer are usually treated with a combination neuroendocrine tumors are often discovered incidentally. The of androgen deprivation therapy (ADT) and radiation therapy, liver is the most common site of metastases. Asymptomatic which has been shown to improve survival. ADT results in patients may have minimal growth and no symptoms for many many short- and long-term adverse effects. Short-term effects months or years, even with metastatic disease. Therefore, there 78

_Answers and Critiques is no urgency to intervene, and all interventions carry the non-small cell lung cancer, identifying a driver mutation potential for risk and expense. A 3-month follow-up exam- has therapeutic implications. These patients may respond to ination with repeat imaging is appropriate in asymptomatic inhibitors of driver mutations with manageable toxicity and patients with relatively low-volume, asymptomatic disease. overall benefit. In the absence of driver mutations, combina Approximately one-third to half of metastatic gastrointestinal tion chemotherapy or immunotherapy is more likely to harm neuroendocrine tumors will produce serotonin, a hormone than to help patients with poor performance status. that causes diarrhea and/or facial flushing; however, most Immunotherapy can be given as a single-agent therapy patients have a hormonally nonfunctional tumor and will not and also given in combination with chemotherapy. Nei- require treatment for these symptoms. In patients who have _ ther chemotherapy (Option B) nor immunotherapy with stable disease at the 3-month scan, further monitoring with bevacizumab (Option A) is effective in patients with poor serial imaging at 3- to 6-month intervals is appropriate. performance status. Combination chemotherapy has been Hepatic arterial embolization (Option B) is a procedure shown to actually worsen outcomes in patients with poor that may be helpful in shrinking liver metastases or reducing performance status and is not recommended for this patient ” @ hormonal output from functional tumors. It may be appro- population. 3

is no urgency to intervene, and all interventions carry the non-small cell lung cancer, identifying a driver mutation potential for risk and expense. A 3-month follow-up exam- has therapeutic implications. These patients may respond to ination with repeat imaging is appropriate in asymptomatic inhibitors of driver mutations with manageable toxicity and patients with relatively low-volume, asymptomatic disease. overall benefit. In the absence of driver mutations, combina Approximately one-third to half of metastatic gastrointestinal tion chemotherapy or immunotherapy is more likely to harm neuroendocrine tumors will produce serotonin, a hormone than to help patients with poor performance status. that causes diarrhea and/or facial flushing; however, most Immunotherapy can be given as a single-agent therapy patients have a hormonally nonfunctional tumor and will not and also given in combination with chemotherapy. Nei- require treatment for these symptoms. In patients who have _ ther chemotherapy (Option B) nor immunotherapy with stable disease at the 3-month scan, further monitoring with bevacizumab (Option A) is effective in patients with poor serial imaging at 3- to 6-month intervals is appropriate. performance status. Combination chemotherapy has been Hepatic arterial embolization (Option B) is a procedure shown to actually worsen outcomes in patients with poor that may be helpful in shrinking liver metastases or reducing performance status and is not recommended for this patient ” @ hormonal output from functional tumors. It may be appro- population. 3 priate in a patient with progressive or symptomatic disease Radiation therapy (Option C) is a palliative treatment, = 1 but is not indicated in this patient. largely for control of pain due to metastatic disease. This rs) Peptide-receptor radiotherapy with a radiolabeled patient has widely metastatic disease but is not noted to sc fs somatostatin analogue (Option C) is a potentially useful have significant difficulty with pain. As a result, there is no © wn treatment for patients with progressing or symptomatic dis- clear indication for radiation therapy in the treatment of this = o ease; however, the toxicity and expense of such an interven- patient. = wn tion would not be appropriate in an asymptomatic patient = <= with a new diagnosis and a moderate disease burden. Obstruction of the bowel from a well-differentiated e Patients with poor performance status and advanced

priate in a patient with progressive or symptomatic disease Radiation therapy (Option C) is a palliative treatment, = 1 but is not indicated in this patient. largely for control of pain due to metastatic disease. This rs) Peptide-receptor radiotherapy with a radiolabeled patient has widely metastatic disease but is not noted to sc fs somatostatin analogue (Option C) is a potentially useful have significant difficulty with pain. As a result, there is no © wn treatment for patients with progressing or symptomatic dis- clear indication for radiation therapy in the treatment of this = o ease; however, the toxicity and expense of such an interven- patient. = wn tion would not be appropriate in an asymptomatic patient = <= with a new diagnosis and a moderate disease burden. Obstruction of the bowel from a well-differentiated e Patients with poor performance status and advanced neuroendocrine primary is very uncommon, and so prophy- non-small cell lung cancer without a driver mutation

priate in a patient with progressive or symptomatic disease Radiation therapy (Option C) is a palliative treatment, = 1 but is not indicated in this patient. largely for control of pain due to metastatic disease. This rs) Peptide-receptor radiotherapy with a radiolabeled patient has widely metastatic disease but is not noted to sc fs somatostatin analogue (Option C) is a potentially useful have significant difficulty with pain. As a result, there is no © wn treatment for patients with progressing or symptomatic dis- clear indication for radiation therapy in the treatment of this = o ease; however, the toxicity and expense of such an interven- patient. = wn tion would not be appropriate in an asymptomatic patient = <= with a new diagnosis and a moderate disease burden. Obstruction of the bowel from a well-differentiated e Patients with poor performance status and advanced neuroendocrine primary is very uncommon, and so prophy- non-small cell lung cancer without a driver mutation lactic surgery to remove the mesenteric mass (Option D) in do not benefit from chemotherapy or immunotherapy

priate in a patient with progressive or symptomatic disease Radiation therapy (Option C) is a palliative treatment, = 1 but is not indicated in this patient. largely for control of pain due to metastatic disease. This rs) Peptide-receptor radiotherapy with a radiolabeled patient has widely metastatic disease but is not noted to sc fs somatostatin analogue (Option C) is a potentially useful have significant difficulty with pain. As a result, there is no © wn treatment for patients with progressing or symptomatic dis- clear indication for radiation therapy in the treatment of this = o ease; however, the toxicity and expense of such an interven- patient. = wn tion would not be appropriate in an asymptomatic patient = <= with a new diagnosis and a moderate disease burden. Obstruction of the bowel from a well-differentiated e Patients with poor performance status and advanced neuroendocrine primary is very uncommon, and so prophy- non-small cell lung cancer without a driver mutation lactic surgery to remove the mesenteric mass (Option D) in do not benefit from chemotherapy or immunotherapy an asymptomatic patient with metastases is not indicated. and are best served with supportive care.

neuroendocrine primary is very uncommon, and so prophy- non-small cell lung cancer without a driver mutation lactic surgery to remove the mesenteric mass (Option D) in do not benefit from chemotherapy or immunotherapy an asymptomatic patient with metastases is not indicated. and are best served with supportive care. e Patients with poor performance status and advanced non-small cell lung cancer with a driver mutation e Well-differentiated, low-grade, metastatic gastrointesti- may benefit from therapies that inhibit the mutation. nal neuroendocrine tumors are often indolent and asymptomatic and do not require immediate treatment. Bibliography Hirsch FR, Scagliotti GV, Mulshine JL, et al. Lung cancer: current therapies Bibliography and new targeted treatments. Lancet. 2017;389:299-311. [PMID: 27574741] Raj N, Fazio N, Strosberg J. Biology and systemic treatment of advanced gas- doi:10.1016/S0140-6736(16)30958-8 troenteropancreatic neuroendocrine tumors. Am Soc Clin Oncol Educ Book. 2018;38:292-99. [PMID: 30231344] doi:10.1200/EDBK_200893

e Patients with poor performance status and advanced non-small cell lung cancer with a driver mutation e Well-differentiated, low-grade, metastatic gastrointesti- may benefit from therapies that inhibit the mutation. nal neuroendocrine tumors are often indolent and asymptomatic and do not require immediate treatment. Bibliography Hirsch FR, Scagliotti GV, Mulshine JL, et al. Lung cancer: current therapies Bibliography and new targeted treatments. Lancet. 2017;389:299-311. [PMID: 27574741] Raj N, Fazio N, Strosberg J. Biology and systemic treatment of advanced gas- doi:10.1016/S0140-6736(16)30958-8 troenteropancreatic neuroendocrine tumors. Am Soc Clin Oncol Educ Book. 2018;38:292-99. [PMID: 30231344] doi:10.1200/EDBK_200893 Item 26 Answer: D Educational Objective: Prevent tumor lysis syndrome. Item 25 Answer: D This patient should receive rasburicase (Option D) to prevent Educational Objective: Manage a patient with poor tumor lysis syndrome (TLS). TLS occurs when ‘tumor cells performance status and metastatic non-small cell lung release their contents into the bloodstream, either sponta- cancer with supportive care/hospice. neously or as a result of treatment, leading to hyperuricemia, Supportive care/hospice care (Option D) is the most appro- hyperkalemia, hyperphosphatemia, and hypocalcemia. These priate management. This patient with metastatic non-small electrolyte abnormalities can lead to acute kidney injury, car- cell lung cancer has poor performance status and should be diac arrhythmias, seizures, and death. The risk of TLS can be counseled that supportive care/hospice is in her best interest. categorized based on the volume of cancer mass present, the Patients with metastatic non-small cell lung cancer can derive cell-lysis potential of the cancer, and patient characteristics significant benefit from treatment, and multiple treatment of preexisting kidney failure, dehydration, acidosis, hypo- options are available. These include not just chemotherapy but tension, or nephrotoxin exposure. TLS is seen most often in molecular therapies based on identification of relevant driver patients with highly proliferative hematologic malignancies, mutations and also immunotherapy. Performance status is a such as acute leukemia and high-grade lymphomas, such as means of quantifying how medically fit a patient is overall. Burkitt lymphoma, but can develop in other cancers. Patients A good performance status predicts favorable tolerance and at intermediate risk for TLS can be managed with monitoring response to treatment. Patients with a poor performance sta- of laboratory values, hydration, and allopurinol, and those tus are much more likely to experience serious or life-threat- at high risk, such as this patient, should receive vigorous ening toxicity and much less likely to benefit from treatment. intravenous hydration and rasburicase, a urate oxidase In patients with poor performance status and metastatic enzyme that metabolizes urate to allantoin, before receiving

Item 26 Answer: D Educational Objective: Prevent tumor lysis syndrome. Item 25 Answer: D This patient should receive rasburicase (Option D) to prevent Educational Objective: Manage a patient with poor tumor lysis syndrome (TLS). TLS occurs when ‘tumor cells performance status and metastatic non-small cell lung release their contents into the bloodstream, either sponta- cancer with supportive care/hospice. neously or as a result of treatment, leading to hyperuricemia, Supportive care/hospice care (Option D) is the most appro- hyperkalemia, hyperphosphatemia, and hypocalcemia. These priate management. This patient with metastatic non-small electrolyte abnormalities can lead to acute kidney injury, car- cell lung cancer has poor performance status and should be diac arrhythmias, seizures, and death. The risk of TLS can be counseled that supportive care/hospice is in her best interest. categorized based on the volume of cancer mass present, the Patients with metastatic non-small cell lung cancer can derive cell-lysis potential of the cancer, and patient characteristics significant benefit from treatment, and multiple treatment of preexisting kidney failure, dehydration, acidosis, hypo- options are available. These include not just chemotherapy but tension, or nephrotoxin exposure. TLS is seen most often in molecular therapies based on identification of relevant driver patients with highly proliferative hematologic malignancies, mutations and also immunotherapy. Performance status is a such as acute leukemia and high-grade lymphomas, such as means of quantifying how medically fit a patient is overall. Burkitt lymphoma, but can develop in other cancers. Patients A good performance status predicts favorable tolerance and at intermediate risk for TLS can be managed with monitoring response to treatment. Patients with a poor performance sta- of laboratory values, hydration, and allopurinol, and those tus are much more likely to experience serious or life-threat- at high risk, such as this patient, should receive vigorous ening toxicity and much less likely to benefit from treatment. intravenous hydration and rasburicase, a urate oxidase In patients with poor performance status and metastatic enzyme that metabolizes urate to allantoin, before receiving 79

Answers and Critiques chemotherapy. Rasburicase is contraindicated in patients Combined chemotherapy and irradiation (Option B) is with glucose-6-phosphate dehydrogenase deficiency, and used to treat locally advanced unresectable non-small cell CONT. allopurinol should be used instead. lung cancer. It is not routinely employed following resection Acetazolamide (Option A) or bicarbonate is not recom and plays no role in the adjuvant treatment of patients who mended in the prevention of TLS because urine alkalization undergo negative margin resection. Such patients require will increase the risk of hyperphosphatemia and the precip- treatment with adjuvant chemotherapy, not combined che- itation of calcium phosphate crystals. motherapy and irradiation. Allopurinol (Option B) may be used to prevent TLS For patients with metastatic non-squamous histology, in patients at intermediate risk. Allopurinol is not the testing for molecular alterations is mandatory. If an epider- first-line agent for prophylaxis in patients at high risk mal growth factor receptor (EGFR) mutation is identified, for TLS because it does not work as quickly or consis initial treatment with erlotinib (Option C) is recommended tently as rasburicase. Allopurinol prevents the formation for patients with metastatic disease. If an ALK or ROSI1 > of serum urate through xanthine oxidase inhibition but translocation is identified, initial treatment with alectinib is J an does not reduce existing serum urate levels by metabo- recommended. This patient does not have metastatic disease, = lizing urate to a more soluble metabolic end product as @ so testing for EGFR mutation is not recommended. Erlotinib = 2) does rasburicase. is not currently a standard adjuvant treatment for patients r-*) = Furosemide (Option C) might be considered in some with resected stage II and III non-small cell lung cancer. a. patients to increase urine flow, particularly in those who Prophylactic cranial irradiation (Option D) is used fol- (=) me become volume overloaded with aggressive intravenous lowing treatment for selected patients with treated small bags volume expansion. This patient displays some evidence of 2 cell lung cancer but has not been shown to be beneficial for ij hypovolemia with low blood pressure and tachycardia, how- those with non-small cell lung cancer. @o wa ever, and furosemide is contraindicated.

chemotherapy. Rasburicase is contraindicated in patients Combined chemotherapy and irradiation (Option B) is with glucose-6-phosphate dehydrogenase deficiency, and used to treat locally advanced unresectable non-small cell CONT. allopurinol should be used instead. lung cancer. It is not routinely employed following resection Acetazolamide (Option A) or bicarbonate is not recom and plays no role in the adjuvant treatment of patients who mended in the prevention of TLS because urine alkalization undergo negative margin resection. Such patients require will increase the risk of hyperphosphatemia and the precip- treatment with adjuvant chemotherapy, not combined che- itation of calcium phosphate crystals. motherapy and irradiation. Allopurinol (Option B) may be used to prevent TLS For patients with metastatic non-squamous histology, in patients at intermediate risk. Allopurinol is not the testing for molecular alterations is mandatory. If an epider- first-line agent for prophylaxis in patients at high risk mal growth factor receptor (EGFR) mutation is identified, for TLS because it does not work as quickly or consis initial treatment with erlotinib (Option C) is recommended tently as rasburicase. Allopurinol prevents the formation for patients with metastatic disease. If an ALK or ROSI1 > of serum urate through xanthine oxidase inhibition but translocation is identified, initial treatment with alectinib is J an does not reduce existing serum urate levels by metabo- recommended. This patient does not have metastatic disease, = lizing urate to a more soluble metabolic end product as @ so testing for EGFR mutation is not recommended. Erlotinib = 2) does rasburicase. is not currently a standard adjuvant treatment for patients r-*) = Furosemide (Option C) might be considered in some with resected stage II and III non-small cell lung cancer. a. patients to increase urine flow, particularly in those who Prophylactic cranial irradiation (Option D) is used fol- (=) me become volume overloaded with aggressive intravenous lowing treatment for selected patients with treated small bags volume expansion. This patient displays some evidence of 2 cell lung cancer but has not been shown to be beneficial for ij hypovolemia with low blood pressure and tachycardia, how- those with non-small cell lung cancer. @o wa ever, and furosemide is contraindicated. ¢ Cisplatin-based adjuvant chemotherapy has been ¢ Tumor lysis syndrome is seen most often in patients shown to improve survival after resection in patients with highly proliferative hematologic malignancies, with resected stage II or III non-small cell lung cancer. such as acute leukemia and high-grade lymphomas, such as Burkitt lymphoma. Bibliography

¢ Cisplatin-based adjuvant chemotherapy has been ¢ Tumor lysis syndrome is seen most often in patients shown to improve survival after resection in patients with highly proliferative hematologic malignancies, with resected stage II or III non-small cell lung cancer. such as acute leukemia and high-grade lymphomas, such as Burkitt lymphoma. Bibliography e Patients at high risk for tumor lysis syndrome should Herbst RS, Morgensztern D, Boshoff C. The biology and management of non-small cell lung cancer. Nature. 2018;553:446-54. [PMID: 29364287] receive vigorous intravenous hydration and rasburicase. doi:10.1038/nature25183 Venue Bibliography Jones GL, Will A, Jackson GH, et al; British Committee for Standards in Item 28 Answer: D Haematology. Guidelines for the management of tumour lysis syndrome in adults and children with haematological malignancies on behalf of the Educational Objective: Treat melanoma with a solitary British Committee for Standards in Haematology. BrJHaematol. 2015;169: metastasis with surgical resection. 661-71. [PMID: 25876990] doi:10.1111/bjh.13403 The most appropriate treatment for this patient is surgical resection of the lung lesion (Option D). Metastasectomy can

Bibliography Jones GL, Will A, Jackson GH, et al; British Committee for Standards in Item 28 Answer: D Haematology. Guidelines for the management of tumour lysis syndrome in adults and children with haematological malignancies on behalf of the Educational Objective: Treat melanoma with a solitary British Committee for Standards in Haematology. BrJHaematol. 2015;169: metastasis with surgical resection. 661-71. [PMID: 25876990] doi:10.1111/bjh.13403 The most appropriate treatment for this patient is surgical resection of the lung lesion (Option D). Metastasectomy can Item 27 Answer: A be the optimal therapy in appropriately selected patients with solitary or oligometastatic metastases in a variety of Educational Objective: Treat stage II non-small cell malignancies (mostly commonly melanoma, renal cell can- lung cancer with adjuvant cisplatin-based chemotherapy. cer, colorectal cancer, and sarcomas). Metastatic melanoma The most appropriate management is cisplatin-based chemo- can be cured in some cases with metastasectomy. Melanoma therapy (Option A). Cisplatin-based adjuvant chemotherapy may be more likely than some other more common cancers has been shown in multiple trials to improve survival in to manifest solitary or oligometastatic disease. The lung is patients with resected stage II and stage II] non-small cell the most common site of visceral metastasis for melanoma, lung cancer. This survival benefit was confirmed in a large although it has the potential to go anywhere and is more meta-analysis (the LACE meta-analysis), which found that likely than other tumors to involve unusual sites such as the use of a cisplatin-based combination regimen was associated heart and small bowel. Although patients with fully resected with a clear improvement in survival. Cisplatin can be com- metastatic melanoma are prone to develop other sites of bined with multiple potential partner agents, none clearly disease, some do not. In some cases, repeated excisions of more efficacious than any other. Adjuvant chemotherapy is solitary metastases can lead to long-term remission. Solitary typically given for four cycles; following that, surveillance is pulmonary metastases could also be addressed in some cases started with periodic CT chest imaging combined with history by radiosurgery or percutaneous radiofrequency. Positive and physical examination. This patient underwent resection prognostic factors for patients undergoing metastasectomy for stage II non-small cell lung cancer, and adjuvant chemo- include longer disease-free intervals, fewer than three pul- therapy is indicated. monary nodules, the absence of extrathoracic and lymph

Item 27 Answer: A be the optimal therapy in appropriately selected patients with solitary or oligometastatic metastases in a variety of Educational Objective: Treat stage II non-small cell malignancies (mostly commonly melanoma, renal cell can- lung cancer with adjuvant cisplatin-based chemotherapy. cer, colorectal cancer, and sarcomas). Metastatic melanoma The most appropriate management is cisplatin-based chemo- can be cured in some cases with metastasectomy. Melanoma therapy (Option A). Cisplatin-based adjuvant chemotherapy may be more likely than some other more common cancers has been shown in multiple trials to improve survival in to manifest solitary or oligometastatic disease. The lung is patients with resected stage II and stage II] non-small cell the most common site of visceral metastasis for melanoma, lung cancer. This survival benefit was confirmed in a large although it has the potential to go anywhere and is more meta-analysis (the LACE meta-analysis), which found that likely than other tumors to involve unusual sites such as the use of a cisplatin-based combination regimen was associated heart and small bowel. Although patients with fully resected with a clear improvement in survival. Cisplatin can be com- metastatic melanoma are prone to develop other sites of bined with multiple potential partner agents, none clearly disease, some do not. In some cases, repeated excisions of more efficacious than any other. Adjuvant chemotherapy is solitary metastases can lead to long-term remission. Solitary typically given for four cycles; following that, surveillance is pulmonary metastases could also be addressed in some cases started with periodic CT chest imaging combined with history by radiosurgery or percutaneous radiofrequency. Positive and physical examination. This patient underwent resection prognostic factors for patients undergoing metastasectomy for stage II non-small cell lung cancer, and adjuvant chemo- include longer disease-free intervals, fewer than three pul- therapy is indicated. monary nodules, the absence of extrathoracic and lymph 80

Answers and Critiques node metastases, and a response to chemotherapy or immu- Endocrine therapy itself is not thought to be gonad- notherapy. otoxic. However, pregnancy is contraindicated while on Following metastasectomy, data would support the use endocrine therapy (Option A), which can be teratogenic of adjuvant systemic therapy to improve overall outcome. (tamoxifen) or prevent pregnancy (ovarian suppression). In this patient with BRAF V600E-mutated disease, either Endocrine therapy is recommended for a period of at least 5 immunotherapy or targeted therapy with a BRAF or a BRAF/ years, during which time fertility can decline due to natural MEK inhibitor would be appropriate. aging, and this process accelerates at age 35 years. Although the use of immunotherapy with ipilimumab This patient is at risk for treatment-related infertility and nivolumab (Option C) or a BRAF or BRAF/MEK inhib- due to her exposure to the gonadotoxic agents cyclophos- itor (if tumor is BRAF-mutated) (Options A, B) would be phamide and docetaxel. Attempting to conceive after endo- appropriate systemic therapy for patients with metastatic crine therapy and exposure to these agents will likely result melanoma, and in some patients might be associated with in decreased fertility (Option B). durable complete responses, the patient likely has a higher Gonadotropin-releasing hormone agonists such as w ov probability of cure via surgical resection followed by adju- depot leuprolide (Option C) appear to reduce the risk of ] oa vant treatment. treatment-related ovarian insufficiency, but the impact on P= fertility is less well-defined and should not be recommended yo ad as a replacement for embryo or oocyte cryopreservation. mo] ¢ Surgical resection of solitary or oligometastatic dis- < bss] ease followed by systemic therapy can be curative in 4) Foe

node metastases, and a response to chemotherapy or immu- Endocrine therapy itself is not thought to be gonad- notherapy. otoxic. However, pregnancy is contraindicated while on Following metastasectomy, data would support the use endocrine therapy (Option A), which can be teratogenic of adjuvant systemic therapy to improve overall outcome. (tamoxifen) or prevent pregnancy (ovarian suppression). In this patient with BRAF V600E-mutated disease, either Endocrine therapy is recommended for a period of at least 5 immunotherapy or targeted therapy with a BRAF or a BRAF/ years, during which time fertility can decline due to natural MEK inhibitor would be appropriate. aging, and this process accelerates at age 35 years. Although the use of immunotherapy with ipilimumab This patient is at risk for treatment-related infertility and nivolumab (Option C) or a BRAF or BRAF/MEK inhib- due to her exposure to the gonadotoxic agents cyclophos- itor (if tumor is BRAF-mutated) (Options A, B) would be phamide and docetaxel. Attempting to conceive after endo- appropriate systemic therapy for patients with metastatic crine therapy and exposure to these agents will likely result melanoma, and in some patients might be associated with in decreased fertility (Option B). durable complete responses, the patient likely has a higher Gonadotropin-releasing hormone agonists such as w ov probability of cure via surgical resection followed by adju- depot leuprolide (Option C) appear to reduce the risk of ] oa vant treatment. treatment-related ovarian insufficiency, but the impact on P= fertility is less well-defined and should not be recommended yo ad as a replacement for embryo or oocyte cryopreservation. mo] ¢ Surgical resection of solitary or oligometastatic dis- < bss] ease followed by systemic therapy can be curative in 4) Foe many patients with melanoma. e Women with breast cancer of childbearing age who vo = wish to preserve fertility may undergo oocyte or 2) a Bibliography embryo banking before chemotherapy. < Bello DM. Indications for the surgical resection of stage IV disease. J Surg e Ovarian stimulation followed by oocyte collection Oncol. 2019;119:249-61. [PMID: 30561079] doi:10.1002/jso.25326 does not appear to be associated with worse breast cancer outcomes.

many patients with melanoma. e Women with breast cancer of childbearing age who vo = wish to preserve fertility may undergo oocyte or 2) a Bibliography embryo banking before chemotherapy. < Bello DM. Indications for the surgical resection of stage IV disease. J Surg e Ovarian stimulation followed by oocyte collection Oncol. 2019;119:249-61. [PMID: 30561079] doi:10.1002/jso.25326 does not appear to be associated with worse breast cancer outcomes. Item 29 Answer: D

many patients with melanoma. e Women with breast cancer of childbearing age who vo = wish to preserve fertility may undergo oocyte or 2) a Bibliography embryo banking before chemotherapy. < Bello DM. Indications for the surgical resection of stage IV disease. J Surg e Ovarian stimulation followed by oocyte collection Oncol. 2019;119:249-61. [PMID: 30561079] doi:10.1002/jso.25326 does not appear to be associated with worse breast cancer outcomes. Item 29 Answer: D Educational Objective: Manage a young woman with Bibliography Oktay K, Harvey BE, Partridge AH, et al. Fertility preservation in patients breast cancer while preserving fertility. with cancer: ASCO clinical practice guideline update. J Clin Oncol. 2018;36:1994-2001. [PMID: 29620997] doi:10.1200/JCO.2018.78.1914 This patient should be referred to a reproductive endocrinol- ogist for consideration of embryo/oocyte cryopreservation (Option D). Fertility is a key survivorship issue for young Item 30 Answer: D patients with cancer. Premenopausal women with breast can- Educational Objective: Screen for BRCA mutation ina cer who receive chemotherapy are at risk of chemotherapy- patient with high-risk prostate cancer. induced menopause and infertility. Alkylating chemother- apy agents (including cyclophosphamide) are known to be This patient should be referred to a genetic counselor to dis- gonadotoxic and are included in most adjuvant chemother- cuss genetic testing for BRCA1 and BRCA2 mutations (Option apy regimens for breast cancer. The risk of gonadotoxicity D). He has been diagnosed with metastatic prostate cancer. depends on age with very young women (age <35 years) His biopsy revealed high-risk disease based on a Gleason having a low risk of permanent menopause from chemo- score of 9. Genetic testing for BRCA gene mutation should therapy. All premenopausal women receiving chemotherapy be done in all men with high-risk disease, including patients should be counseled on the risk of permanent menopause with a Gleason score >7, positive lymph nodes, or metastatic and infertility associated with chemotherapy and the avail- disease. The risk of an underlying mutation in patients with ability of fertility preservation options. Fertility counseling metastatic disease is 11.8%. A family history of breast cancer in this situation is associated with improved psychosocial in a first-degree relative diagnosed before the age of 50 years outcomes. Oocyte and embryo cryopreservation involves is also an indication for genetic counseling and BRCA testing. ovarian stimulation followed by collection of oocytes, which Therefore, based on both personal and family history, this are then cryopreserved as oocytes or as embryos. Embryo patient is clearly a candidate for BRCA testing. and oocyte cryopreservation may be performed before start- Cystoscopy (Option A) is used to evaluate patients ing chemotherapy and does not appear to be associated suspected of having bladder cancer or symptoms, such as with worse breast cancer outcomes. Aromatase inhibitors hematuria, that might indicate bladder wall involvement are often used during ovarian stimulation in this setting by an adjacent neoplasm. Cystoscopy would not be done to to prevent an increase in estradiol levels. Cryopreservation evaluate otherwise asymptomatic prostate cancer. of oocytes/embryos usually takes 2 to 3 weeks leading to PET/CT (Option B) is not indicated for this patient, as minimal or short delays in care. This is the gold-standard he already has evidence of metastatic disease. PET/CT will approach for fertility preservation, although it does not not change his management and is not a standard test in guarantee the ability to conceive in the future. this setting.

Educational Objective: Manage a young woman with Bibliography Oktay K, Harvey BE, Partridge AH, et al. Fertility preservation in patients breast cancer while preserving fertility. with cancer: ASCO clinical practice guideline update. J Clin Oncol. 2018;36:1994-2001. [PMID: 29620997] doi:10.1200/JCO.2018.78.1914 This patient should be referred to a reproductive endocrinol- ogist for consideration of embryo/oocyte cryopreservation (Option D). Fertility is a key survivorship issue for young Item 30 Answer: D patients with cancer. Premenopausal women with breast can- Educational Objective: Screen for BRCA mutation ina cer who receive chemotherapy are at risk of chemotherapy- patient with high-risk prostate cancer. induced menopause and infertility. Alkylating chemother- apy agents (including cyclophosphamide) are known to be This patient should be referred to a genetic counselor to dis- gonadotoxic and are included in most adjuvant chemother- cuss genetic testing for BRCA1 and BRCA2 mutations (Option apy regimens for breast cancer. The risk of gonadotoxicity D). He has been diagnosed with metastatic prostate cancer. depends on age with very young women (age <35 years) His biopsy revealed high-risk disease based on a Gleason having a low risk of permanent menopause from chemo- score of 9. Genetic testing for BRCA gene mutation should therapy. All premenopausal women receiving chemotherapy be done in all men with high-risk disease, including patients should be counseled on the risk of permanent menopause with a Gleason score >7, positive lymph nodes, or metastatic and infertility associated with chemotherapy and the avail- disease. The risk of an underlying mutation in patients with ability of fertility preservation options. Fertility counseling metastatic disease is 11.8%. A family history of breast cancer in this situation is associated with improved psychosocial in a first-degree relative diagnosed before the age of 50 years outcomes. Oocyte and embryo cryopreservation involves is also an indication for genetic counseling and BRCA testing. ovarian stimulation followed by collection of oocytes, which Therefore, based on both personal and family history, this are then cryopreserved as oocytes or as embryos. Embryo patient is clearly a candidate for BRCA testing. and oocyte cryopreservation may be performed before start- Cystoscopy (Option A) is used to evaluate patients ing chemotherapy and does not appear to be associated suspected of having bladder cancer or symptoms, such as with worse breast cancer outcomes. Aromatase inhibitors hematuria, that might indicate bladder wall involvement are often used during ovarian stimulation in this setting by an adjacent neoplasm. Cystoscopy would not be done to to prevent an increase in estradiol levels. Cryopreservation evaluate otherwise asymptomatic prostate cancer. of oocytes/embryos usually takes 2 to 3 weeks leading to PET/CT (Option B) is not indicated for this patient, as minimal or short delays in care. This is the gold-standard he already has evidence of metastatic disease. PET/CT will approach for fertility preservation, although it does not not change his management and is not a standard test in guarantee the ability to conceive in the future. this setting. 81

aneaers ord SO uaues. Prostate-specific antigen (PSA) density (Option C) is the Breast MRI alone (Option C), like mammography alone, PSA divided by prostate volume. This is calculated to correct is insufficient in a patient with previous mantle irradiation the PSA for differences in prostate volume between different for HL. Studies have shown that mammography and MRI patients. After definitive treatment for localized prostate complement each other and provide superior early detection cancer, PSA density is used to help with decision-making of such disease. regarding active surveillance and treatment. This is espe- Ultrasonography (Option D) is the preferred method cially true for asymptomatic men with PSA-only recurrence, of evaluation of a breast mass in women younger than as it can take several years for clinical metastatic disease to 30 years, in whom mammography has low sensitivity due to develop in that setting. PSA density measurement has no dense breast tissue. This patient, who is over 30 years of age, role in the evaluation of men with clinical metastatic disease. does not have a breast mass, so ultrasonography would not be appropriate. Ultrasonography is not recommended as the breast cancer screening strategy after chest irradiation. Pa ¢ Patients with high-risk prostate cancers (high Gleason J wn score, lymph node metastases, or distant metastatic = disease) should be referred for genetic counseling, as e For women survivors of Hodgkin lymphoma who oO fe w the risk of a BRCA mutation is approximately 12%. received chest irradiation, annual breast cancer rs) screening is recommended to begin 8 to 10 years post- = _ © In men with prostate cancer, a family history of breast Qa therapy or at age 40 years, whichever comes first. cancer in a first-degree relative diagnosed before the a =e age of 50 years is also an indication for BRCA-related e Breast MRI is recommended as an adjunct to mam- s 2 genetic counseling. mography for breast cancer screening in Hodgkin = oO lymphoma survivors who were treated with chest wn Bibliography irradiation between ages 10 and 30 years. Das S, Salami SS, Spratt DE, et al. Bringing prostate cancer germline genetics into clinical practice. J Urol. 2019;202:223-30. [PMID: 30730411] doi:10.1097/JU.0000000000000137 Bibliography Eichenauer DA, Aleman BMP, André M, et al; ESMO Guidelines Committee. Hodgkin lymphoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2018;29:iv19-iv29. [PMID: Item 31 Answer: B 29796651] doi:10.1093/annonc/mdy080

Prostate-specific antigen (PSA) density (Option C) is the Breast MRI alone (Option C), like mammography alone, PSA divided by prostate volume. This is calculated to correct is insufficient in a patient with previous mantle irradiation the PSA for differences in prostate volume between different for HL. Studies have shown that mammography and MRI patients. After definitive treatment for localized prostate complement each other and provide superior early detection cancer, PSA density is used to help with decision-making of such disease. regarding active surveillance and treatment. This is espe- Ultrasonography (Option D) is the preferred method cially true for asymptomatic men with PSA-only recurrence, of evaluation of a breast mass in women younger than as it can take several years for clinical metastatic disease to 30 years, in whom mammography has low sensitivity due to develop in that setting. PSA density measurement has no dense breast tissue. This patient, who is over 30 years of age, role in the evaluation of men with clinical metastatic disease. does not have a breast mass, so ultrasonography would not be appropriate. Ultrasonography is not recommended as the breast cancer screening strategy after chest irradiation. Pa ¢ Patients with high-risk prostate cancers (high Gleason J wn score, lymph node metastases, or distant metastatic = disease) should be referred for genetic counseling, as e For women survivors of Hodgkin lymphoma who oO fe w the risk of a BRCA mutation is approximately 12%. received chest irradiation, annual breast cancer rs) screening is recommended to begin 8 to 10 years post- = _ © In men with prostate cancer, a family history of breast Qa therapy or at age 40 years, whichever comes first. cancer in a first-degree relative diagnosed before the a =e age of 50 years is also an indication for BRCA-related e Breast MRI is recommended as an adjunct to mam- s 2 genetic counseling. mography for breast cancer screening in Hodgkin = oO lymphoma survivors who were treated with chest wn Bibliography irradiation between ages 10 and 30 years. Das S, Salami SS, Spratt DE, et al. Bringing prostate cancer germline genetics into clinical practice. J Urol. 2019;202:223-30. [PMID: 30730411] doi:10.1097/JU.0000000000000137 Bibliography Eichenauer DA, Aleman BMP, André M, et al; ESMO Guidelines Committee. Hodgkin lymphoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2018;29:iv19-iv29. [PMID: Item 31 Answer: B 29796651] doi:10.1093/annonc/mdy080 Educational Objective: Screen for breast cancer ina patient with previous chest irradiation. item 32 Answer: D This patient had previous mantle irradiation treatment for Educational Objective: Treat a low-grade mucosa- Hodgkin lymphoma (HL), and she should have both mam- associated lymphoid tissue lymphoma involving the lung. mography and breast MRI (Option B). The second leading cause of death for survivors of HL are second cancers. Most This patient has mucosa-associated lymphoma tissue (MALT) second cancers are solid tumors, and among those, the most lymphoma, and the most appropriate management is single- frequent are breast, lung, and colon cancers. The increased agent rituximab (Option D). MALT lymphomas are low-grade risk begins about 5 to 8 years posttreatment but continues to B lymphomas of the marginal zone type (a category that increase for at least 20 years. Secondary malignancies may also includes splenic marginal zone and nodal marginal zone develop in cancer survivors either from previous carcino- lymphomas). They account for 5% to 8% of B-cell lymphomas gen exposure or late effects of previous cancer treatments. and arise from B cells in the “marginal zone,” the external Women receiving chest irradiation for HL have a markedly part of secondary lymphoid follicles. The stomach is the most increased risk of breast cancer, especially if they received common site for MALT lymphomas, and it has been linked to treatment when younger than 35 years, with an increased risk infection with Helicobacter pylori. Chronic infection and/or beginning within 8 years of treatment. Annual breast cancer antigenic stimulation may play a role in the development of screening is recommended to begin 8 to 10 years post-therapy MALT lymphomas in other sites as well (e.g., Hashimoto thy- or at age 40 years, whichever comes first. The National Com- roiditis and thyroid MALT lymphomas or Sjégren syndrome prehensive Cancer Network (NCCN) guideline recommends and parotid lymphomas), but antibiotic therapy has only been breast MRI in addition to mammography for women who definitively proven to be effective for H. pylori-associated received irradiation to the chest between the ages of 10 and 30 gastric MALT lymphomas (Option C). MALT lymphomas typ- years. The NCCN also recommends consideration of referral to ically have a relatively indolent course, and asymptomatic a breast specialist. patients may be observed without treatment, although radi- Screening mammography (Option A) is necessary for ation therapy can be considered for those with localized dis- early detection of breast cancer in patients treated for HL ease. For other MALT lymphomas, such as in this patient who with mantle irradiation, but a prospective trial demonstrated is symptomatic and has disease in multiple lobes of the lung, that the use of MRI, in addition to screening mammograms, single-agent rituximab, an anti-CD20 monoclonal antibody, identified additional breast cancers when compared with would be an appropriate treatment. This therapy is generally mammography alone in these high-risk patients. quite active and well tolerated.

Educational Objective: Screen for breast cancer ina patient with previous chest irradiation. item 32 Answer: D This patient had previous mantle irradiation treatment for Educational Objective: Treat a low-grade mucosa- Hodgkin lymphoma (HL), and she should have both mam- associated lymphoid tissue lymphoma involving the lung. mography and breast MRI (Option B). The second leading cause of death for survivors of HL are second cancers. Most This patient has mucosa-associated lymphoma tissue (MALT) second cancers are solid tumors, and among those, the most lymphoma, and the most appropriate management is single- frequent are breast, lung, and colon cancers. The increased agent rituximab (Option D). MALT lymphomas are low-grade risk begins about 5 to 8 years posttreatment but continues to B lymphomas of the marginal zone type (a category that increase for at least 20 years. Secondary malignancies may also includes splenic marginal zone and nodal marginal zone develop in cancer survivors either from previous carcino- lymphomas). They account for 5% to 8% of B-cell lymphomas gen exposure or late effects of previous cancer treatments. and arise from B cells in the “marginal zone,” the external Women receiving chest irradiation for HL have a markedly part of secondary lymphoid follicles. The stomach is the most increased risk of breast cancer, especially if they received common site for MALT lymphomas, and it has been linked to treatment when younger than 35 years, with an increased risk infection with Helicobacter pylori. Chronic infection and/or beginning within 8 years of treatment. Annual breast cancer antigenic stimulation may play a role in the development of screening is recommended to begin 8 to 10 years post-therapy MALT lymphomas in other sites as well (e.g., Hashimoto thy- or at age 40 years, whichever comes first. The National Com- roiditis and thyroid MALT lymphomas or Sjégren syndrome prehensive Cancer Network (NCCN) guideline recommends and parotid lymphomas), but antibiotic therapy has only been breast MRI in addition to mammography for women who definitively proven to be effective for H. pylori-associated received irradiation to the chest between the ages of 10 and 30 gastric MALT lymphomas (Option C). MALT lymphomas typ- years. The NCCN also recommends consideration of referral to ically have a relatively indolent course, and asymptomatic a breast specialist. patients may be observed without treatment, although radi- Screening mammography (Option A) is necessary for ation therapy can be considered for those with localized dis- early detection of breast cancer in patients treated for HL ease. For other MALT lymphomas, such as in this patient who with mantle irradiation, but a prospective trial demonstrated is symptomatic and has disease in multiple lobes of the lung, that the use of MRI, in addition to screening mammograms, single-agent rituximab, an anti-CD20 monoclonal antibody, identified additional breast cancers when compared with would be an appropriate treatment. This therapy is generally mammography alone in these high-risk patients. quite active and well tolerated. 82

Answers and Critiques Aggressive combination chemoimmunotherapy with a Cefepime (Option A) is an antipseudomonal B-lactam regimen such as rituximab, cyclophosphamide, doxorubicin, that is often used as empiric parenteral therapy for febrile vincristine, and prednisone (R-CHOP) (Option A) would not neutropenia in hospitalized patients. However, studies have be appropriate as initial treatment of a MALT lymphoma in demonstrated that there is a similar level of safety and effi- an elderly patient. R-CHOP is more typically used in patients cacy with oral versus intravenous regimens as initial empiric with more aggressive lymphomas, such as diffuse large cell therapy for the treatment of low-risk febrile neutropenia. lymphoma. Although MALT lymphomas can undergo trans- Clinical studies have also demonstrated that there formation to more aggressive histologies, such changes are is no better survival or therapeutic success but rather an not common. increased risk of toxicity from adding an aminoglycoside to Other than for establishing a diagnosis and managing a broad-spectrum B-lactam, such as cefepime (Option B), in complications, surgery would generally have little role in the treatment of febrile neutropenia. the treatment of most low-grade lymphomas. A pneumo- Given the patient’s neutropenia and documented fever, nectomy (Option B) would not be appropriate for a patient observation without antibiotics (Option D) would not be w ® with a low-grade lymphoma of the lung. That would be an appropriate, as patients with fever and neutropenia can =

Aggressive combination chemoimmunotherapy with a Cefepime (Option A) is an antipseudomonal B-lactam regimen such as rituximab, cyclophosphamide, doxorubicin, that is often used as empiric parenteral therapy for febrile vincristine, and prednisone (R-CHOP) (Option A) would not neutropenia in hospitalized patients. However, studies have be appropriate as initial treatment of a MALT lymphoma in demonstrated that there is a similar level of safety and effi- an elderly patient. R-CHOP is more typically used in patients cacy with oral versus intravenous regimens as initial empiric with more aggressive lymphomas, such as diffuse large cell therapy for the treatment of low-risk febrile neutropenia. lymphoma. Although MALT lymphomas can undergo trans- Clinical studies have also demonstrated that there formation to more aggressive histologies, such changes are is no better survival or therapeutic success but rather an not common. increased risk of toxicity from adding an aminoglycoside to Other than for establishing a diagnosis and managing a broad-spectrum B-lactam, such as cefepime (Option B), in complications, surgery would generally have little role in the treatment of febrile neutropenia. the treatment of most low-grade lymphomas. A pneumo- Given the patient’s neutropenia and documented fever, nectomy (Option B) would not be appropriate for a patient observation without antibiotics (Option D) would not be w ® with a low-grade lymphoma of the lung. That would be an appropriate, as patients with fever and neutropenia can = become quite ill rather quickly without antibiotics. = aggressive, morbid, and generally high-risk procedure. = = o = < ¢ Helicobacter pylori eradication therapy has only been ¢ For selected patients with low-risk neutropenic fever, ©

become quite ill rather quickly without antibiotics. = aggressive, morbid, and generally high-risk procedure. = = o = < ¢ Helicobacter pylori eradication therapy has only been ¢ For selected patients with low-risk neutropenic fever, © definitively proven to be effective for H. pylori- recommended empiric outpatient treatment includes wr tear ® associated gastric mucosa-associated lymphoma a fluoroquinolone (i.e., ciprofloxacin or levofloxacin) = 2) tissue lymphomas. plus amoxicillin/clavulanate. = =< e The treatment of mucosa-associated lymphoma tissue ¢ There is no better therapeutic success but rather an (MALT) lymphomas other than gastric MALT lym- increased risk of toxicity from adding an aminoglyco- phoma may include irradiation for localized disease side to a broad-spectrum B-lactam in the treatment of or rituximab when systemic therapy is required. febrile neutropenia.

definitively proven to be effective for H. pylori- recommended empiric outpatient treatment includes wr tear ® associated gastric mucosa-associated lymphoma a fluoroquinolone (i.e., ciprofloxacin or levofloxacin) = 2) tissue lymphomas. plus amoxicillin/clavulanate. = =< e The treatment of mucosa-associated lymphoma tissue ¢ There is no better therapeutic success but rather an (MALT) lymphomas other than gastric MALT lym- increased risk of toxicity from adding an aminoglyco- phoma may include irradiation for localized disease side to a broad-spectrum B-lactam in the treatment of or rituximab when systemic therapy is required. febrile neutropenia. Bibliography Bibliography Zucca E, Bertoni F. The spectrum of MALT lymphoma at different sites: Taplitz RA, Kennedy EB, Bow EJ, et al. Outpatient management of fever and biological and therapeutic relevance. Blood. 2016;127:2082-92. [PMID: neutropenia in adults treated for malignancy: American Society of 26989205] doi:10.1182/blood-2015-12-624304 Clinical Oncology and Infectious Diseases Society of America Clinical Practice Guideline Update. J Clin Oncol. 2018;36:1443-53. [PMID: 29461916] doi:10.1200/JCO.2017.77.6211

Bibliography Bibliography Zucca E, Bertoni F. The spectrum of MALT lymphoma at different sites: Taplitz RA, Kennedy EB, Bow EJ, et al. Outpatient management of fever and biological and therapeutic relevance. Blood. 2016;127:2082-92. [PMID: neutropenia in adults treated for malignancy: American Society of 26989205] doi:10.1182/blood-2015-12-624304 Clinical Oncology and Infectious Diseases Society of America Clinical Practice Guideline Update. J Clin Oncol. 2018;36:1443-53. [PMID: 29461916] doi:10.1200/JCO.2017.77.6211 Item 33 Answer: C Educational Objective: Treat low-risk neutropenic fever in an outpatient. Item 34 Answer: D

Bibliography Bibliography Zucca E, Bertoni F. The spectrum of MALT lymphoma at different sites: Taplitz RA, Kennedy EB, Bow EJ, et al. Outpatient management of fever and biological and therapeutic relevance. Blood. 2016;127:2082-92. [PMID: neutropenia in adults treated for malignancy: American Society of 26989205] doi:10.1182/blood-2015-12-624304 Clinical Oncology and Infectious Diseases Society of America Clinical Practice Guideline Update. J Clin Oncol. 2018;36:1443-53. [PMID: 29461916] doi:10.1200/JCO.2017.77.6211 Item 33 Answer: C Educational Objective: Treat low-risk neutropenic fever in an outpatient. Item 34 Answer: D Educational Objective: Treat bone metastases from The most appropriate treatment is to begin ciprofloxacin breast cancer. and amoxicillin/clavulanic acid and discharge the patient home (Option C). Selected patients with fever and neu- This patient should receive zoledronic acid (Option D). A tropenia can be managed as outpatients. If the patient is bone-modifying agent is administered routinely to all patients compliant, uncomplicated, hemodynamically stable, does with metastatic breast cancer and bone metastases to prevent not have significant comorbidities, has no known increased the development of skeletal-related events, including bone risk to be harboring resistant organisms, and has an antic- pain, cord compression, need for palliative radiation therapy, ipated short duration of neutropenia, outpatient manage- and hypercalcemia. Appropriate agents include zoledronic ment is an option. Published criteria for risk stratification acid (a bisphosphonate) or denosumab (a receptor activator of for outpatient management include the Multinational Asso- nuclear factor «B ligand inhibitor). Zoledronic acid and deno- ciation for Supportive Care in Cancer index, Talcott’s rules, sumab are generally administered every 3 months because of or Clinical Index of Stable Febrile Neutropenia. Published similar efficacy to monthly dosing. Zoledronic acid is cleared criteria for outpatient management include (1) residence through the kidneys and is contraindicated among patients <1 hour or <30 miles (48 km) from the clinic or hospital, with creatinine clearance less than 30 mL/min. Dose adjust- (2) patient’s primary care physician or oncologist agrees to ment is not recommended for denosumab in patients with outpatient management, (3) ability to comply with logistic renal insufficiency. Both agents may cause symptomatic hypo- requirements, including frequent clinic visits, (4) family calcemia. Additionally, both agents are associated with small member or caregiver at home 24 hours/day, (5) access to a risks of osteonecrosis of the jaw, and treatment should gener- telephone and transportation 24 hours/day, and (6) no his- ally be held for patients who have active dental issues for which tory of noncompliance with treatment protocols. Patients extractions or other dental work is needed. Zoledronic acid is should have frequent follow-up by phone or in the office to substantially less costly than denosumab and, given similar reassess their status. efficacy, should be the preferred option for most patients.

Educational Objective: Treat bone metastases from The most appropriate treatment is to begin ciprofloxacin breast cancer. and amoxicillin/clavulanic acid and discharge the patient home (Option C). Selected patients with fever and neu- This patient should receive zoledronic acid (Option D). A tropenia can be managed as outpatients. If the patient is bone-modifying agent is administered routinely to all patients compliant, uncomplicated, hemodynamically stable, does with metastatic breast cancer and bone metastases to prevent not have significant comorbidities, has no known increased the development of skeletal-related events, including bone risk to be harboring resistant organisms, and has an antic- pain, cord compression, need for palliative radiation therapy, ipated short duration of neutropenia, outpatient manage- and hypercalcemia. Appropriate agents include zoledronic ment is an option. Published criteria for risk stratification acid (a bisphosphonate) or denosumab (a receptor activator of for outpatient management include the Multinational Asso- nuclear factor «B ligand inhibitor). Zoledronic acid and deno- ciation for Supportive Care in Cancer index, Talcott’s rules, sumab are generally administered every 3 months because of or Clinical Index of Stable Febrile Neutropenia. Published similar efficacy to monthly dosing. Zoledronic acid is cleared criteria for outpatient management include (1) residence through the kidneys and is contraindicated among patients <1 hour or <30 miles (48 km) from the clinic or hospital, with creatinine clearance less than 30 mL/min. Dose adjust- (2) patient’s primary care physician or oncologist agrees to ment is not recommended for denosumab in patients with outpatient management, (3) ability to comply with logistic renal insufficiency. Both agents may cause symptomatic hypo- requirements, including frequent clinic visits, (4) family calcemia. Additionally, both agents are associated with small member or caregiver at home 24 hours/day, (5) access to a risks of osteonecrosis of the jaw, and treatment should gener- telephone and transportation 24 hours/day, and (6) no his- ally be held for patients who have active dental issues for which tory of noncompliance with treatment protocols. Patients extractions or other dental work is needed. Zoledronic acid is should have frequent follow-up by phone or in the office to substantially less costly than denosumab and, given similar reassess their status. efficacy, should be the preferred option for most patients. 83

Answers and Critiques ee Patients receiving bone-modifying agents may be at risk distant spread, or recurrence, chemotherapy and/or radiation for the development of hypocalcemia and, in the absence therapy may be indicated. Treatment is not yet standardized, of hypercalcemia, should be treated with vitamin D and and recommendations continue to evolve for this entity. calcium to prevent hypocalcemia. However, calcium and Some reports have suggested an increase in Sjogren vitamin D alone (Option A) are an insufficient preventive syndrome, scleroderma, and rheumatoid arthritis syn- therapy for this patient with metastatic bone disease. dromes associated with silicone implants; however, such an This patient has asymptomatic bone metastases and association was never definitively confirmed. Autoimmune should not receive spine irradiation. Metastatic breast cancer inflammation of the breast implant with associated serositis is managed primarily with systemic treatments to control (Option B) is not seen with these conditions. growth and spread of the disease and to prevent treatment Prophylactic mastectomies lead to at least a 90% reduc- symptoms that arise from metastases. Palliative irradiation tion in the risk of developing breast cancer (Option C) in (Option B) is often useful for patients with focal areas of patients at high risk. Although breast cancer can arise in Pa pain caused by bone metastases but is not indicated in this residual breast cells even after prophylactic mastectomy, it —] n asymptomatic woman. would be uncommon and more likely to present as a cuta- = Teriparatide (Option C) is a form of parathyroid hor- neous or subcutaneous mass rather than a fluid collection. oO = wm mone and acts as an anabolic agent to promote bone forma- Although breast implants can become infected (Option o tion for the treatment of osteoporosis. It is not used to treat D), the absence of fever, leukocytosis, and erythema and pm] Q. bone metastases from solid tumors. Additionally, its use is the presence of serous, nonpurulent fluid are not suggestive (2) = contraindicated for patients with a history of irradiation due of infection in this patient. These infections usually occur =. to concerns regarding an increased risk of osteosarcoma in shortly after the prosthesis is placed but can develop years 2 i=| the treatment field. later. © wn

Patients receiving bone-modifying agents may be at risk distant spread, or recurrence, chemotherapy and/or radiation for the development of hypocalcemia and, in the absence therapy may be indicated. Treatment is not yet standardized, of hypercalcemia, should be treated with vitamin D and and recommendations continue to evolve for this entity. calcium to prevent hypocalcemia. However, calcium and Some reports have suggested an increase in Sjogren vitamin D alone (Option A) are an insufficient preventive syndrome, scleroderma, and rheumatoid arthritis syn- therapy for this patient with metastatic bone disease. dromes associated with silicone implants; however, such an This patient has asymptomatic bone metastases and association was never definitively confirmed. Autoimmune should not receive spine irradiation. Metastatic breast cancer inflammation of the breast implant with associated serositis is managed primarily with systemic treatments to control (Option B) is not seen with these conditions. growth and spread of the disease and to prevent treatment Prophylactic mastectomies lead to at least a 90% reduc- symptoms that arise from metastases. Palliative irradiation tion in the risk of developing breast cancer (Option C) in (Option B) is often useful for patients with focal areas of patients at high risk. Although breast cancer can arise in Pa pain caused by bone metastases but is not indicated in this residual breast cells even after prophylactic mastectomy, it —] n asymptomatic woman. would be uncommon and more likely to present as a cuta- = Teriparatide (Option C) is a form of parathyroid hor- neous or subcutaneous mass rather than a fluid collection. oO = wm mone and acts as an anabolic agent to promote bone forma- Although breast implants can become infected (Option o tion for the treatment of osteoporosis. It is not used to treat D), the absence of fever, leukocytosis, and erythema and pm] Q. bone metastases from solid tumors. Additionally, its use is the presence of serous, nonpurulent fluid are not suggestive (2) = contraindicated for patients with a history of irradiation due of infection in this patient. These infections usually occur =. to concerns regarding an increased risk of osteosarcoma in shortly after the prosthesis is placed but can develop years 2 i=| the treatment field. later. © wn e For patients who have breast cancer with bone metas- e Anaplastic large cell lymphoma associated with tex- tases, bone-modifying agents such as zoledronic acid tured breast implants most commonly presents with a or denosumab are recommended to prevent bone- periprosthetic fluid collection and is best detected on related events such as bone pain, cord compression, ultrasound. need for palliative irradiation, and hypercalcemia. Bibliography Bibliography Ebner PJ, Liu A, Gould DJ, et al. Breast implant-associated anaplastic large cell lymphoma, a systematic review and in-depth evaluation of the cur- Tahara RK, Brewer TM, Theriault RL, et al. Bone metastasis of breast cancer. rent understanding. J Surg Oncol. 2019;120:573-77. [PMID: 31373010] Ady Exp Med Biol. 2019;1152:105-29. [PMID: 31456182] doi:10.1007/978- doi:10.1002/jso.25626 3-030-20301-6_7

e For patients who have breast cancer with bone metas- e Anaplastic large cell lymphoma associated with tex- tases, bone-modifying agents such as zoledronic acid tured breast implants most commonly presents with a or denosumab are recommended to prevent bone- periprosthetic fluid collection and is best detected on related events such as bone pain, cord compression, ultrasound. need for palliative irradiation, and hypercalcemia. Bibliography Bibliography Ebner PJ, Liu A, Gould DJ, et al. Breast implant-associated anaplastic large cell lymphoma, a systematic review and in-depth evaluation of the cur- Tahara RK, Brewer TM, Theriault RL, et al. Bone metastasis of breast cancer. rent understanding. J Surg Oncol. 2019;120:573-77. [PMID: 31373010] Ady Exp Med Biol. 2019;1152:105-29. [PMID: 31456182] doi:10.1007/978- doi:10.1002/jso.25626 3-030-20301-6_7 Item 35 Answer: A Item 36 Answer: C Educational Objective: Diagnose anaplastic T-cell Educational Objective: Treat early-stage Hodgkin non-Hodgkin lymphoma in a patient with textured breast lymphoma. implants. For this patient with early-stage Hodgkin lymphoma, the The most likely diagnosis is anaplastic T-cell lymphoma most appropriate treatment options would be combination (Option A). Although uncommon, there are increasing reports chemotherapy with doxorubicin, bleomycin, vinblastine, of non-Hodgkin lymphoma, typically anaplastic T-cell lym- and dacarbazine followed by radiation therapy (Option C). phoma, arising around breast implants. The major association Unfavorable prognostic factors for early-stage Hodgkin lym- has been with textured breast implants, which are now no phoma include the presence of a large mediastinal mass, an longer being used. Patients with these lymphomas typically elevated sedimentation rate, involvement of multiple nodal present with swelling and discomfort with a median time sites, extranodal involvement, age 50 years and older, or of 8 to 9 years after prosthesis placement. Initial evaluation massive splenic disease. The combination of chemotherapy after physical examination is by ultrasound (which appears to and irradiation is associated with a high rate of cure in ear- be superior to mammography, CT, or MRI) to look for a fluid ly-stage disease, even with adverse prognostic features. Using collection and aspiration if fluid is present. Cytology may both modalities in combination has allowed for high cure confirm malignant cells compatible with anaplastic T-cell rates while using shorter courses of chemotherapy (two to lymphoma. These anaplastic T-cell lymphomas are typically four cycles) and lower cumulative doses of radiation given to CD30+ and ALK negative. If the disease is diagnosed early, it smaller fields, thus minimizing the potential for long-term may be cured with surgery alone with removal of the implant toxicities. Chemotherapy alone could also be an appropriate and complete resection of the surrounding capsule. If a con- option for this patient, avoiding irradiation entirely, if she has tralateral implant was placed, it should be removed as well. In a complete metabolic response by interim PET/CT after two cases of more advanced disease with nodal involvement, more to three cycles of treatment (risk-adapted therapy). Avoiding

Item 35 Answer: A Item 36 Answer: C Educational Objective: Diagnose anaplastic T-cell Educational Objective: Treat early-stage Hodgkin non-Hodgkin lymphoma in a patient with textured breast lymphoma. implants. For this patient with early-stage Hodgkin lymphoma, the The most likely diagnosis is anaplastic T-cell lymphoma most appropriate treatment options would be combination (Option A). Although uncommon, there are increasing reports chemotherapy with doxorubicin, bleomycin, vinblastine, of non-Hodgkin lymphoma, typically anaplastic T-cell lym- and dacarbazine followed by radiation therapy (Option C). phoma, arising around breast implants. The major association Unfavorable prognostic factors for early-stage Hodgkin lym- has been with textured breast implants, which are now no phoma include the presence of a large mediastinal mass, an longer being used. Patients with these lymphomas typically elevated sedimentation rate, involvement of multiple nodal present with swelling and discomfort with a median time sites, extranodal involvement, age 50 years and older, or of 8 to 9 years after prosthesis placement. Initial evaluation massive splenic disease. The combination of chemotherapy after physical examination is by ultrasound (which appears to and irradiation is associated with a high rate of cure in ear- be superior to mammography, CT, or MRI) to look for a fluid ly-stage disease, even with adverse prognostic features. Using collection and aspiration if fluid is present. Cytology may both modalities in combination has allowed for high cure confirm malignant cells compatible with anaplastic T-cell rates while using shorter courses of chemotherapy (two to lymphoma. These anaplastic T-cell lymphomas are typically four cycles) and lower cumulative doses of radiation given to CD30+ and ALK negative. If the disease is diagnosed early, it smaller fields, thus minimizing the potential for long-term may be cured with surgery alone with removal of the implant toxicities. Chemotherapy alone could also be an appropriate and complete resection of the surrounding capsule. If a con- option for this patient, avoiding irradiation entirely, if she has tralateral implant was placed, it should be removed as well. In a complete metabolic response by interim PET/CT after two cases of more advanced disease with nodal involvement, more to three cycles of treatment (risk-adapted therapy). Avoiding 84

_ Answers and Critiques radiation therapy may be associated with a slightly higher risk the metabolic abnormalities. Prevention is with vigorous of relapse but avoids the risk of late radiation therapy—induced hydration and rasburicase. toxicities. Acute anthracycline toxicity (Option A) can present as Treatment with checkpoint inhibitors such as heart block, arrhythmias, heart failure, myocarditis, and nivolumab and pembrolizumab (Option A) may be con- pericarditis. However, this complication occurs in less than sidered for patients experiencing a second or later relapse 1% of patients and may be reversible. Chronic progressive and those who relapse after autologous hematopoietic stem anthracycline toxicity usually presents as dilated cardiomy- cell transplantation. Combination chemotherapy and irra- opathy, which is most closely linked with the use of doxoru- diation, or in some instances, chemotherapy alone is the bicin. TLS is a much more likely immediate complication in preferred first-line therapy and is associated with nearly a patients with Burkitt lymphoma, with risk estimates gener- 75% cure rate. ally greater than 5%. Chemotherapy with ifosfamide, carboplatin, and etopo- Hypercalcemia of malignancy (Option B) occurs in 20% side followed by autologous hematopoietic stem cell trans- to 30% of patients with advanced cancer. It is most frequent wn a plantation (Option B) is an option for patients with relapsed, in patients with myeloma and cancer of the lung, breast, =

radiation therapy may be associated with a slightly higher risk the metabolic abnormalities. Prevention is with vigorous of relapse but avoids the risk of late radiation therapy—induced hydration and rasburicase. toxicities. Acute anthracycline toxicity (Option A) can present as Treatment with checkpoint inhibitors such as heart block, arrhythmias, heart failure, myocarditis, and nivolumab and pembrolizumab (Option A) may be con- pericarditis. However, this complication occurs in less than sidered for patients experiencing a second or later relapse 1% of patients and may be reversible. Chronic progressive and those who relapse after autologous hematopoietic stem anthracycline toxicity usually presents as dilated cardiomy- cell transplantation. Combination chemotherapy and irra- opathy, which is most closely linked with the use of doxoru- diation, or in some instances, chemotherapy alone is the bicin. TLS is a much more likely immediate complication in preferred first-line therapy and is associated with nearly a patients with Burkitt lymphoma, with risk estimates gener- 75% cure rate. ally greater than 5%. Chemotherapy with ifosfamide, carboplatin, and etopo- Hypercalcemia of malignancy (Option B) occurs in 20% side followed by autologous hematopoietic stem cell trans- to 30% of patients with advanced cancer. It is most frequent wn a plantation (Option B) is an option for patients with relapsed, in patients with myeloma and cancer of the lung, breast, = refractory Hodgkin lymphoma, but this is a salvage approach kidney, and head and neck. Lymphomas can cause hyper- = and is not used as first-line treatment. calcemia by overproduction of 1,25-dihydroxyvitamin D. = 1S Although radiation therapy alone (Option D) can be This patient is more likely to experience hyperphosphatemia Ss i= curative for early-stage classical Hodgkin lymphoma, the and hypocalcemia from TLS in the absence of aggressive c wn cure rate is higher with the addition of chemotherapy. preventive treatment. ios an) Furthermore, older studies using radiation therapy alone, Superior vena cava (SVC) syndrome (Option D) is = wn with larger fields and higher doses, were associated with caused by acute obstruction of blood flow to the right = an increased risk of late second malignancies as well as atrium from the upper torso, can result in symptoms of <x

refractory Hodgkin lymphoma, but this is a salvage approach kidney, and head and neck. Lymphomas can cause hyper- = and is not used as first-line treatment. calcemia by overproduction of 1,25-dihydroxyvitamin D. = 1S Although radiation therapy alone (Option D) can be This patient is more likely to experience hyperphosphatemia Ss i= curative for early-stage classical Hodgkin lymphoma, the and hypocalcemia from TLS in the absence of aggressive c wn cure rate is higher with the addition of chemotherapy. preventive treatment. ios an) Furthermore, older studies using radiation therapy alone, Superior vena cava (SVC) syndrome (Option D) is = wn with larger fields and higher doses, were associated with caused by acute obstruction of blood flow to the right = an increased risk of late second malignancies as well as atrium from the upper torso, can result in symptoms of <x organ (cardiac, pulmonary, thyroid) dysfunction. Thus, progressive dyspnea and cough, and may be associated essentially all patients with early-stage Hodgkin lym- with swelling of the face and neck. The most common phoma currently receive chemotherapy as part of their cause of SVC syndrome is lung cancer. Other malignancies treatment. less commonly associated with SVC syndrome include dif- fuse large B-cell lymphoma, lymphoblastic lymphoma, and germ cell tumors. Mediastinal widening and pleural effu- e Early-stage Hodgkin lymphoma is most commonly sions are common radiographic findings. This patient with treated with combination chemotherapy followed by a normal chest radiograph and elevated serum creatinine radiation therapy. and urate level is much more likely to develop spontaneous

organ (cardiac, pulmonary, thyroid) dysfunction. Thus, progressive dyspnea and cough, and may be associated essentially all patients with early-stage Hodgkin lym- with swelling of the face and neck. The most common phoma currently receive chemotherapy as part of their cause of SVC syndrome is lung cancer. Other malignancies treatment. less commonly associated with SVC syndrome include dif- fuse large B-cell lymphoma, lymphoblastic lymphoma, and germ cell tumors. Mediastinal widening and pleural effu- e Early-stage Hodgkin lymphoma is most commonly sions are common radiographic findings. This patient with treated with combination chemotherapy followed by a normal chest radiograph and elevated serum creatinine radiation therapy. and urate level is much more likely to develop spontaneous ¢ Chemotherapy alone is a treatment option for early-stage or treatment-related TLS. Hodgkin lymphoma after a complete metabolic response assessed by interim PET/CT after two to e¢ Tumor lysis syndrome is usually seen in aggressive three cycles of treatment (risk-adapted therapy). non-Hodgkin lymphoma, Burkitt lymphoma, as well as some leukemias. Bibliography Ansell SM. Hodgkin lymphoma: 2018 update on diagnosis, risk-stratifica- e Metabolic complications of tumor lysis syndrome tion, and management. AmJ Hematol. 2018;93:704-15. [PMID: 29634090] include hyperuricemia, hyperphosphatemia, hyper- doi:10.1002/ajh.25071 kalemia, and hypocalcemia.

Hodgkin lymphoma after a complete metabolic response assessed by interim PET/CT after two to e¢ Tumor lysis syndrome is usually seen in aggressive three cycles of treatment (risk-adapted therapy). non-Hodgkin lymphoma, Burkitt lymphoma, as well as some leukemias. Bibliography Ansell SM. Hodgkin lymphoma: 2018 update on diagnosis, risk-stratifica- e Metabolic complications of tumor lysis syndrome tion, and management. AmJ Hematol. 2018;93:704-15. [PMID: 29634090] include hyperuricemia, hyperphosphatemia, hyper- doi:10.1002/ajh.25071 kalemia, and hypocalcemia. Item 37 Answer: C Bibliography Rahmani B, Patel S, Seyam O, et al. Current understanding of tumor lysis Educational Objective: Identify Burkitt lymphoma as syndrome. Hematol Oncol. 2019;37:537-47. [PMID: 31461568] high risk for tumor lysis syndrome. doi:10.1002/hon.2668

Item 37 Answer: C Bibliography Rahmani B, Patel S, Seyam O, et al. Current understanding of tumor lysis Educational Objective: Identify Burkitt lymphoma as syndrome. Hematol Oncol. 2019;37:537-47. [PMID: 31461568] high risk for tumor lysis syndrome. doi:10.1002/hon.2668 The most likely immediate treatment-associated complication for this patient is tumor lysis syndrome (TLS) (Option C). Item 38 Answer: C TLS is most likely to occur in patients who have larger tumor Educational Objective: Manage progressing prostate burdens and more chemotherapy-sensitive disease. It is usu- cancer in a man on active surveillance. ally seen in aggressive non-Hodgkin lymphoma, Burkitt lym- phoma, as well as some leukemias and is rarely seen in solid This patient should have a repeat prostate biopsy (Option tumors. TLS typically manifests in the first 24 to 48 hours after C). Active surveillance is a management option that con- chemotherapy initiation but may even develop spontaneously sists of planned monitoring and deferred therapy for patients before treatment. Patients develop hyperuricemia, hyper- with low-grade prostate cancer. Monitoring during active phosphatemia, hyperkalemia, and hypocalcemia, which can surveillance consists of a repeat biopsy done approximately be associated with arrhythmias, tetany, and seizures. Kidney 1 year from the original diagnosis and, assuming no high- failure may ensue from acute urate nephropathy, worsening grade tumor has developed, less often thereafter; annual 85

Answers and Critiques digital rectal examination should be done yearly, and serial prostate cancer occurs when the prostate-specific antigen prostate-specific antigen (PSA) measurements should be (PSA) level rises without evidence of clinical metastatic dis- done every 6 to 12 months. Sustained rise in PSA or new ease in men being treated with androgen deprivation therapy abnormalities on digital rectal examination warrant an addi- (ADT). This condition does not always require treatment, tional prostate biopsy, perhaps guided by MRI imaging. The as in men with a very slowly rising PSA level because it can goal of active surveillance is to more promptly identify men take years before there is development of clinical metastatic with evidence of cancer progression that requires treatment disease. However, in a patient with a rapidly rising PSA level while also avoiding treatment in men who do not have pro- (e.g., doubling time <10 months), treatment is indicated, as gressive cancer. In men with low-risk prostate cancer, active development of clinical metastatic disease typically occurs surveillance is a reasonable strategy because some men will much sooner. Treatment with androgen receptor blockers never require treatment, and outcomes are no worse if men improves overall survival in this patient population. A large, with low-grade cancer are treated at the time of progression randomized, placebo-controlled trial study concluded that b rather than when first diagnosed. This patient has experi- apalutamide improved median metastasis-free survival from —] wn enced a doubling of PSA in just 1 year. Although PSA alone 16.2 months to 40.5 months. Apalutamide and enzalutamide = cannot definitely identify men who require treatment, a dou- are both standard treatments for this patient population. @ = wn bling time of less than 3 years is grounds for reassessment Bone-seeking isotope treatment with radium-223 Q with a repeat biopsy. (Option B) is indicated for treatment of castrate-resistant i] Qa. At this time, the patient does not require a bone scan metastatic prostate cancer with bone-only or bone-pre- (=) (Option A). A bone scan might be warranted if there is doc- dominant metastatic disease. This agent is not indicted for —s es umentation of disease progression, such as the assignment treatment of men without metastatic disease. 2 < to a different risk group based on the results of the prostate Chemotherapy (Option C) is indicated for treatment @o wn biopsy. Until that time, imaging is not indicated. of M1 castrate-resistant prostate cancer. This patient does Measurement of free PSA (Option B) may increase the not have M1 disease as discussed previously. In the form of sensitivity of PSA screening for prostate cancer and can be docetaxel, it can also be used in combination with ADT in helpful in cases of borderline elevated PSA measurements the initial treatment of men with castrate-sensitive meta- due to its greater specificity. Measurement of free PSA does static prostate cancer. not play a role in the management of men who are being Treatment with a CYP17 inhibitor (abiraterone) (Option managed with active surveillance, however, and is not indi- D) is an established treatment for M1 castrate-resistant met- cated in this man who already has an indication for repeat astatic prostate cancer. It is not indicated for MO castrate- biopsy. resistant prostate cancer.

digital rectal examination should be done yearly, and serial prostate cancer occurs when the prostate-specific antigen prostate-specific antigen (PSA) measurements should be (PSA) level rises without evidence of clinical metastatic dis- done every 6 to 12 months. Sustained rise in PSA or new ease in men being treated with androgen deprivation therapy abnormalities on digital rectal examination warrant an addi- (ADT). This condition does not always require treatment, tional prostate biopsy, perhaps guided by MRI imaging. The as in men with a very slowly rising PSA level because it can goal of active surveillance is to more promptly identify men take years before there is development of clinical metastatic with evidence of cancer progression that requires treatment disease. However, in a patient with a rapidly rising PSA level while also avoiding treatment in men who do not have pro- (e.g., doubling time <10 months), treatment is indicated, as gressive cancer. In men with low-risk prostate cancer, active development of clinical metastatic disease typically occurs surveillance is a reasonable strategy because some men will much sooner. Treatment with androgen receptor blockers never require treatment, and outcomes are no worse if men improves overall survival in this patient population. A large, with low-grade cancer are treated at the time of progression randomized, placebo-controlled trial study concluded that b rather than when first diagnosed. This patient has experi- apalutamide improved median metastasis-free survival from —] wn enced a doubling of PSA in just 1 year. Although PSA alone 16.2 months to 40.5 months. Apalutamide and enzalutamide = cannot definitely identify men who require treatment, a dou- are both standard treatments for this patient population. @ = wn bling time of less than 3 years is grounds for reassessment Bone-seeking isotope treatment with radium-223 Q with a repeat biopsy. (Option B) is indicated for treatment of castrate-resistant i] Qa. At this time, the patient does not require a bone scan metastatic prostate cancer with bone-only or bone-pre- (=) (Option A). A bone scan might be warranted if there is doc- dominant metastatic disease. This agent is not indicted for —s es umentation of disease progression, such as the assignment treatment of men without metastatic disease. 2 < to a different risk group based on the results of the prostate Chemotherapy (Option C) is indicated for treatment @o wn biopsy. Until that time, imaging is not indicated. of M1 castrate-resistant prostate cancer. This patient does Measurement of free PSA (Option B) may increase the not have M1 disease as discussed previously. In the form of sensitivity of PSA screening for prostate cancer and can be docetaxel, it can also be used in combination with ADT in helpful in cases of borderline elevated PSA measurements the initial treatment of men with castrate-sensitive meta- due to its greater specificity. Measurement of free PSA does static prostate cancer. not play a role in the management of men who are being Treatment with a CYP17 inhibitor (abiraterone) (Option managed with active surveillance, however, and is not indi- D) is an established treatment for M1 castrate-resistant met- cated in this man who already has an indication for repeat astatic prostate cancer. It is not indicated for MO castrate- biopsy. resistant prostate cancer. Rechecking PSA in 6 months (Option D) is not indicated because this man already meets criteria for repeat biopsy. e¢ Men with nonmetastatic prostate cancer and a very slowly rising prostate-specific antigen level do not e In men with low-risk prostate cancer, active surveil- always need treatment because development of clini- lance is a reasonable strategy because some men will cal metastatic disease may take years. never require treatment, and outcomes are no worse e Androgen receptor blockers have been shown to if men with low-grade cancer are treated at the time improve metastasis-free survival in patients with non- of progression rather than when first diagnosed. metastatic, castrate-resistant prostate cancer with e In men undergoing active surveillance for prostate rapidly rising prostate-specific antigen levels. cancer, a doubling time of less than 3 years is grounds for reassessment with a repeat biopsy. Bibliography Smith MR, Saad F, Chowdhury S, et al; SPARTAN Investigators. Apalutamide treatment and metastasis-free survival in prostate cancer. N EnglJ Med. Bibliography 2018;378:1408-18. [PMID: 29420164] doi:10.1056/NEJMoal1715546 Chen RC, Rumble RB, Loblaw DA, et al. Active surveillance for the manage- ment of localized prostate cancer (Cancer Care Ontario Guideline): American Society of Clinical Oncology Clinical Practice Guideline Endorsement. J Clin Oncol. 2016;34:2182-90. [PMID: 26884580] item 40 Answer: C doi:10.1200/JCO.2015.65.7759 Educational Objective: Diagnose inflammatory breast cancer.

Rechecking PSA in 6 months (Option D) is not indicated because this man already meets criteria for repeat biopsy. e¢ Men with nonmetastatic prostate cancer and a very slowly rising prostate-specific antigen level do not e In men with low-risk prostate cancer, active surveil- always need treatment because development of clini- lance is a reasonable strategy because some men will cal metastatic disease may take years. never require treatment, and outcomes are no worse e Androgen receptor blockers have been shown to if men with low-grade cancer are treated at the time improve metastasis-free survival in patients with non- of progression rather than when first diagnosed. metastatic, castrate-resistant prostate cancer with e In men undergoing active surveillance for prostate rapidly rising prostate-specific antigen levels. cancer, a doubling time of less than 3 years is grounds for reassessment with a repeat biopsy. Bibliography Smith MR, Saad F, Chowdhury S, et al; SPARTAN Investigators. Apalutamide treatment and metastasis-free survival in prostate cancer. N EnglJ Med. Bibliography 2018;378:1408-18. [PMID: 29420164] doi:10.1056/NEJMoal1715546 Chen RC, Rumble RB, Loblaw DA, et al. Active surveillance for the manage- ment of localized prostate cancer (Cancer Care Ontario Guideline): American Society of Clinical Oncology Clinical Practice Guideline Endorsement. J Clin Oncol. 2016;34:2182-90. [PMID: 26884580] item 40 Answer: C doi:10.1200/JCO.2015.65.7759 Educational Objective: Diagnose inflammatory breast cancer. Item 39 Answer: A This patient most likely has inflammatory breast cancer (IBC) (Option C). IBC is suspected on the basis of clinical find- Educational Objective: Treat castrate-resistant MO ings including erythema, peau d’orange, and skin thickening. prostate cancer with apalutamide. Patients often present with breast enlargement or swelling This patient has castrate-resistant MO prostate cancer and developed during a few weeks or months, and younger, lac- should be treated with an androgen receptor blocker (apa- tating women may have been treated for presumed mastitis lutamide or enzalutamide) (Option A). MO castrate-resistant with antibiotics. It is important to consider that IBC may be

Item 39 Answer: A This patient most likely has inflammatory breast cancer (IBC) (Option C). IBC is suspected on the basis of clinical find- Educational Objective: Treat castrate-resistant MO ings including erythema, peau d’orange, and skin thickening. prostate cancer with apalutamide. Patients often present with breast enlargement or swelling This patient has castrate-resistant MO prostate cancer and developed during a few weeks or months, and younger, lac- should be treated with an androgen receptor blocker (apa- tating women may have been treated for presumed mastitis lutamide or enzalutamide) (Option A). MO castrate-resistant with antibiotics. It is important to consider that IBC may be 86

Answers and Critiques the underlying cause in lactating women who do not respond or lung that may be resectable. Contrast-enhanced CT of the to antibiotics for an apparent mastitis. A palpable breast mass chest, abdomen, and pelvis is recommended annually for up may be present. The skin changes are due to the obstruction to 5 years postoperatively. Patients with metastatic lesions of dermal lymphatic vessels by cancer cells. The initial diag- confined to the liver or lung should be referred for surgi- nostic test is mammography followed by core biopsy of any cal evaluation. Surgery has become standard treatment for suspicious lesion. The finding of dermal lymphatic invasion patients with resectable oligometastatic disease confined to with a punch skin biopsy supports but is not necessary for the liver and can be curative in approximately 25% of these the diagnosis of IBC. Patients with IBC have a higher risk patients. Previous guidelines defined resectability of hepatic of distant recurrence and also a higher risk of locoregional metastases based on the number of lesions, tumor size, and recurrence and should be treated with aggressive local and potential for clear surgical margins, but newer approaches systemic therapy. All patients with IBC should receive preop- define resectable disease as metastatic tumors that can be erative chemotherapy to optimize the likelihood of obtaining completely resected while leaving an adequate functional negative surgical margins. Patients with IBC often have a residual liver volume. wn AF) greater extent of disease in the breast, and all should undergo Hepatic arterial embolization (Option A) is a technique =

the underlying cause in lactating women who do not respond or lung that may be resectable. Contrast-enhanced CT of the to antibiotics for an apparent mastitis. A palpable breast mass chest, abdomen, and pelvis is recommended annually for up may be present. The skin changes are due to the obstruction to 5 years postoperatively. Patients with metastatic lesions of dermal lymphatic vessels by cancer cells. The initial diag- confined to the liver or lung should be referred for surgi- nostic test is mammography followed by core biopsy of any cal evaluation. Surgery has become standard treatment for suspicious lesion. The finding of dermal lymphatic invasion patients with resectable oligometastatic disease confined to with a punch skin biopsy supports but is not necessary for the liver and can be curative in approximately 25% of these the diagnosis of IBC. Patients with IBC have a higher risk patients. Previous guidelines defined resectability of hepatic of distant recurrence and also a higher risk of locoregional metastases based on the number of lesions, tumor size, and recurrence and should be treated with aggressive local and potential for clear surgical margins, but newer approaches systemic therapy. All patients with IBC should receive preop- define resectable disease as metastatic tumors that can be erative chemotherapy to optimize the likelihood of obtaining completely resected while leaving an adequate functional negative surgical margins. Patients with IBC often have a residual liver volume. wn AF) greater extent of disease in the breast, and all should undergo Hepatic arterial embolization (Option A) is a technique = mastectomy and postmastectomy irradiation to minimize the that can be used for control of more vascular tumors such = risk of locoregional recurrence. as hepatocellular carcinoma or neuroendocrine tumors, but TS YY Mammary ductal ectasia (Option B) is an inflamma- it is not routinely used in colorectal cancer because these Ss = tory breast condition most prevalent in middle-aged women. tumors tend to be relatively low in vascularity. Further, cs wn The genesis of the findings is related to collection of debris in such embolizations are palliative, noncurative interventions, Mane oe mammary ducts resulting in ductal inflammation. It may be whereas surgery has curative potential. = associated with nipple discharge. On occasion, the distended A needle biopsy (Option B) should not be done because wn & mammary duct can be visualized as a blue mass under the nip- it will not affect management. This patient’s clinical presen- <

mastectomy and postmastectomy irradiation to minimize the that can be used for control of more vascular tumors such = risk of locoregional recurrence. as hepatocellular carcinoma or neuroendocrine tumors, but TS YY Mammary ductal ectasia (Option B) is an inflamma- it is not routinely used in colorectal cancer because these Ss = tory breast condition most prevalent in middle-aged women. tumors tend to be relatively low in vascularity. Further, cs wn The genesis of the findings is related to collection of debris in such embolizations are palliative, noncurative interventions, Mane oe mammary ducts resulting in ductal inflammation. It may be whereas surgery has curative potential. = associated with nipple discharge. On occasion, the distended A needle biopsy (Option B) should not be done because wn & mammary duct can be visualized as a blue mass under the nip- it will not affect management. This patient’s clinical presen- < ple. The blocked ducts may become infected resulting in breast tation is compelling enough for recurrent colorectal cancer abscess or mastitis. The condition often resolves spontaneously. that a negative needle biopsy would be assumed to be a Mammary ductal ectasia usually results in localized inflamma- false-negative result, and so would not alter management, tory changes, not the diffuse changes as noted in this patient. and surgical resection would be the appropriate interven- Infections of the breast, specifically mastitis and breast tion regardless of the biopsy results. A needle biopsy may abscess (Options A, D), most commonly occur in lactating be appropriate if the diagnosis is in doubt or if there is women and would be unusual in a 50-year-old woman. consideration for neoadjuvant chemotherapy. Consideration Infectious mastitis can have a similar clinical and mam- of neoadjuvant chemotherapy in some treatment centers is mographic appearance to IBC. However, infectious mastitis based on the potential to convert patients with an initially and breast abscesses are typically associated with breast unresectable large volume of liver metastases to resectable tenderness, fever, and leukocytosis, whereas IBC—despite disease. Although data on the frequency of success with this its name—is not a true inflammatory process and is not strategy are not available, they are probably low. associated with these findings. Because this patient is potentially curable, systemic chemotherapy (Option D), which is not curative, would not be a correct consideration. e Inflammatory breast cancer is suspected on the basis of clinical findings including erythema, peau d’orange, and skin thickening. e Postoperative surveillance following curative resection for colorectal cancer is used to identify oligometastatic e Diagnostic modalities for suspected inflammatory disease in the liver or lung that may be resectable. breast cancer include mammography, core biopsy, and skin biopsy. e Surgical resection is a curative option for patients with oligometastatic colorectal cancer. Bibliography Waldman RA, Finch J, Grant-Kels JM, et al. Skin diseases of the breast and Bibliography nipple: inflammatory and infectious diseases. J Am Acad Dermatol. Creasy JM, Sadot E, Koerkamp BG, et al. Actual 10-year survival after hepatic 2019;80:1483-94. [PMID: 30452953] doi:10.1016/j.jaad.2018.08.067 resection of colorectal liver metastases: what factors preclude cure? Surgery. 2018;163:1238-44. [PMID: 29455841] doi:10.1016/j.surg. 2018.01.004

ple. The blocked ducts may become infected resulting in breast tation is compelling enough for recurrent colorectal cancer abscess or mastitis. The condition often resolves spontaneously. that a negative needle biopsy would be assumed to be a Mammary ductal ectasia usually results in localized inflamma- false-negative result, and so would not alter management, tory changes, not the diffuse changes as noted in this patient. and surgical resection would be the appropriate interven- Infections of the breast, specifically mastitis and breast tion regardless of the biopsy results. A needle biopsy may abscess (Options A, D), most commonly occur in lactating be appropriate if the diagnosis is in doubt or if there is women and would be unusual in a 50-year-old woman. consideration for neoadjuvant chemotherapy. Consideration Infectious mastitis can have a similar clinical and mam- of neoadjuvant chemotherapy in some treatment centers is mographic appearance to IBC. However, infectious mastitis based on the potential to convert patients with an initially and breast abscesses are typically associated with breast unresectable large volume of liver metastases to resectable tenderness, fever, and leukocytosis, whereas IBC—despite disease. Although data on the frequency of success with this its name—is not a true inflammatory process and is not strategy are not available, they are probably low. associated with these findings. Because this patient is potentially curable, systemic chemotherapy (Option D), which is not curative, would not be a correct consideration. e Inflammatory breast cancer is suspected on the basis of clinical findings including erythema, peau d’orange, and skin thickening. e Postoperative surveillance following curative resection for colorectal cancer is used to identify oligometastatic e Diagnostic modalities for suspected inflammatory disease in the liver or lung that may be resectable. breast cancer include mammography, core biopsy, and skin biopsy. e Surgical resection is a curative option for patients with oligometastatic colorectal cancer. Bibliography Waldman RA, Finch J, Grant-Kels JM, et al. Skin diseases of the breast and Bibliography nipple: inflammatory and infectious diseases. J Am Acad Dermatol. Creasy JM, Sadot E, Koerkamp BG, et al. Actual 10-year survival after hepatic 2019;80:1483-94. [PMID: 30452953] doi:10.1016/j.jaad.2018.08.067 resection of colorectal liver metastases: what factors preclude cure? Surgery. 2018;163:1238-44. [PMID: 29455841] doi:10.1016/j.surg. 2018.01.004 Item 41 Answer: C Educational Objective: Treat oligometastatic liver metastases. Item 42 Answer: C Educational Objective: Manage high-emetic-risk che- This patient has oligometastatic disease in the liver and is a motherapy. candidate for surgery with curative intent (Option C). Postop- erative surveillance following curative resection for colorectal This patient is anticipated to have severe nausea and vomit- cancer is used to identify oligometastatic disease in the liver ing from her high-emetic-risk chemotherapy and should be

Item 41 Answer: C Educational Objective: Treat oligometastatic liver metastases. Item 42 Answer: C Educational Objective: Manage high-emetic-risk che- This patient has oligometastatic disease in the liver and is a motherapy. candidate for surgery with curative intent (Option C). Postop- erative surveillance following curative resection for colorectal This patient is anticipated to have severe nausea and vomit- cancer is used to identify oligometastatic disease in the liver ing from her high-emetic-risk chemotherapy and should be 87

Answers and Critiques given ondansetron, aprepitant, olanzapine, and dexameth- Bibliography asone (Option C). There has been substantial progress in Hesketh PJ, Kris MG, Basch E, et al. Antiemetics: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol. reducing chemotherapy-induced nausea and vomiting. Che- 2017;35:3240-61. [PMID: 28759346] doi:10.1200/JCO.2017.74.4789 motherapeutic agents can be stratified by their emetogenic potential into high, moderate, low, and minimal risk. For patients receiving highly emetogenic chemotherapy, such as Item 43 Answer: B an anthracycline (e.g., doxorubicin) combined with cyclo- Educational Objective: Treat hypercalcemia of malig- phosphamide, standard antiemetic treatments include a four- nancy. drug combination of an NK1 receptor antagonist (such as aprepitant or netupitant), a 5-hydroxytryptamine-3 (5-HT;) This patient has hypercalcemia, likely due to malignancy, and receptor antagonist (such as ondansetron, granisetron, or should be treated urgently with intravenous isotonic saline and palonosetron), dexamethasone, and olanzapine (an atypical calcitonin (Option B). Hypercalcemia of malignancy occurs in > antipsychotic). Olanzapine should be continued on days 2 20% to 30% of patients with advanced cancer. It is most fre = nn to 4. These drug combinations have markedly reduced the quent in patients with myeloma and cancer of the lung, breast, = incidence of acute emesis (in the first 24 hours) and improve kidney, head, and neck. Patients with severe or symptomatic @o = nn the risk of delayed emesis (after 24 hours). Olanzapine, when hypercalcemia should receive isotonic saline volume expan ro) added to standard antiemetic regimens, has been found to be sion, which will increase renal perfusion and urine calcium = a. effective for the treatment of delayed chemotherapy-induced excretion. The administration of isotonic saline at an initial rate a = nausea and vomiting (although some oncologists may not of 200 to 300 mL/hour that is then adjusted to maintain the =. routinely prescribe this as first-line therapy due to the risk urine output at 100 to 150 mL/hour is a reasonable goal. Cal — = of sedation). Other examples of high-emetic-risk chemo- citonin increases kidney excretion of calcium and decreases @o 777 therapeutic drugs (vomiting risk >90%) include carmustine, bone resorption; it can decrease calcium within several hours cisplatin, cyclophosphamide (>1,500 mg/m/?), dacarbazine, in responsive patients. Tachyphylaxis to calcitonin may appear mechlorethamine, and streptozocin. after 24 to 48 hours, so therapy is usually discontinued after Many patients treated with moderate-emetic-risk che- this time period. This patient has an elevated serum creatinine motherapeutic agents (excluding higher-dose carboplatin) can level, which is a common complication of hypercalcemia, and be offered a two-drug combination of a 5-HT; receptor antag- intravenous isotonic saline may improve renal function as well. onist and dexamethasone. Certain chemotherapeutic agents Denosumab (Option A), a receptor activator of nuclear in this category may cause delayed nausea and vomiting (e.g., factor «B ligand inhibitor, is very effective in reducing serum cyclophosphamide, doxorubicin, and oxaliplatin), and in this calcium levels. It is typically reserved for patients who do not case, patients can be offered dexamethasone on days 2 and 3. respond to bisphosphonate therapy. Denosumab can be used Benzodiazepines, such as lorazepam (Option A), may when bisphosphonate therapy is contraindicated, such as in be used as adjuncts for nausea, although they should not be patients with kidney failure. Patients receiving denosumab used as single agents. should be monitored for the subsequent development of There is insufficient evidence regarding the value of med- hypocalcemia.

given ondansetron, aprepitant, olanzapine, and dexameth- Bibliography asone (Option C). There has been substantial progress in Hesketh PJ, Kris MG, Basch E, et al. Antiemetics: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol. reducing chemotherapy-induced nausea and vomiting. Che- 2017;35:3240-61. [PMID: 28759346] doi:10.1200/JCO.2017.74.4789 motherapeutic agents can be stratified by their emetogenic potential into high, moderate, low, and minimal risk. For patients receiving highly emetogenic chemotherapy, such as Item 43 Answer: B an anthracycline (e.g., doxorubicin) combined with cyclo- Educational Objective: Treat hypercalcemia of malig- phosphamide, standard antiemetic treatments include a four- nancy. drug combination of an NK1 receptor antagonist (such as aprepitant or netupitant), a 5-hydroxytryptamine-3 (5-HT;) This patient has hypercalcemia, likely due to malignancy, and receptor antagonist (such as ondansetron, granisetron, or should be treated urgently with intravenous isotonic saline and palonosetron), dexamethasone, and olanzapine (an atypical calcitonin (Option B). Hypercalcemia of malignancy occurs in > antipsychotic). Olanzapine should be continued on days 2 20% to 30% of patients with advanced cancer. It is most fre = nn to 4. These drug combinations have markedly reduced the quent in patients with myeloma and cancer of the lung, breast, = incidence of acute emesis (in the first 24 hours) and improve kidney, head, and neck. Patients with severe or symptomatic @o = nn the risk of delayed emesis (after 24 hours). Olanzapine, when hypercalcemia should receive isotonic saline volume expan ro) added to standard antiemetic regimens, has been found to be sion, which will increase renal perfusion and urine calcium = a. effective for the treatment of delayed chemotherapy-induced excretion. The administration of isotonic saline at an initial rate a = nausea and vomiting (although some oncologists may not of 200 to 300 mL/hour that is then adjusted to maintain the =. routinely prescribe this as first-line therapy due to the risk urine output at 100 to 150 mL/hour is a reasonable goal. Cal — = of sedation). Other examples of high-emetic-risk chemo- citonin increases kidney excretion of calcium and decreases @o 777 therapeutic drugs (vomiting risk >90%) include carmustine, bone resorption; it can decrease calcium within several hours cisplatin, cyclophosphamide (>1,500 mg/m/?), dacarbazine, in responsive patients. Tachyphylaxis to calcitonin may appear mechlorethamine, and streptozocin. after 24 to 48 hours, so therapy is usually discontinued after Many patients treated with moderate-emetic-risk che- this time period. This patient has an elevated serum creatinine motherapeutic agents (excluding higher-dose carboplatin) can level, which is a common complication of hypercalcemia, and be offered a two-drug combination of a 5-HT; receptor antag- intravenous isotonic saline may improve renal function as well. onist and dexamethasone. Certain chemotherapeutic agents Denosumab (Option A), a receptor activator of nuclear in this category may cause delayed nausea and vomiting (e.g., factor «B ligand inhibitor, is very effective in reducing serum cyclophosphamide, doxorubicin, and oxaliplatin), and in this calcium levels. It is typically reserved for patients who do not case, patients can be offered dexamethasone on days 2 and 3. respond to bisphosphonate therapy. Denosumab can be used Benzodiazepines, such as lorazepam (Option A), may when bisphosphonate therapy is contraindicated, such as in be used as adjuncts for nausea, although they should not be patients with kidney failure. Patients receiving denosumab used as single agents. should be monitored for the subsequent development of There is insufficient evidence regarding the value of med- hypocalcemia. ical marijuana (Option B) for chemotherapy-induced nausea. Furosemide (Option C), a loop diuretic, is not recom Evidence is also insufficient for recommending the use of med- mended unless kidney failure or heart failure is present, in which

given ondansetron, aprepitant, olanzapine, and dexameth- Bibliography asone (Option C). There has been substantial progress in Hesketh PJ, Kris MG, Basch E, et al. Antiemetics: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol. reducing chemotherapy-induced nausea and vomiting. Che- 2017;35:3240-61. [PMID: 28759346] doi:10.1200/JCO.2017.74.4789 motherapeutic agents can be stratified by their emetogenic potential into high, moderate, low, and minimal risk. For patients receiving highly emetogenic chemotherapy, such as Item 43 Answer: B an anthracycline (e.g., doxorubicin) combined with cyclo- Educational Objective: Treat hypercalcemia of malig- phosphamide, standard antiemetic treatments include a four- nancy. drug combination of an NK1 receptor antagonist (such as aprepitant or netupitant), a 5-hydroxytryptamine-3 (5-HT;) This patient has hypercalcemia, likely due to malignancy, and receptor antagonist (such as ondansetron, granisetron, or should be treated urgently with intravenous isotonic saline and palonosetron), dexamethasone, and olanzapine (an atypical calcitonin (Option B). Hypercalcemia of malignancy occurs in > antipsychotic). Olanzapine should be continued on days 2 20% to 30% of patients with advanced cancer. It is most fre = nn to 4. These drug combinations have markedly reduced the quent in patients with myeloma and cancer of the lung, breast, = incidence of acute emesis (in the first 24 hours) and improve kidney, head, and neck. Patients with severe or symptomatic @o = nn the risk of delayed emesis (after 24 hours). Olanzapine, when hypercalcemia should receive isotonic saline volume expan ro) added to standard antiemetic regimens, has been found to be sion, which will increase renal perfusion and urine calcium = a. effective for the treatment of delayed chemotherapy-induced excretion. The administration of isotonic saline at an initial rate a = nausea and vomiting (although some oncologists may not of 200 to 300 mL/hour that is then adjusted to maintain the =. routinely prescribe this as first-line therapy due to the risk urine output at 100 to 150 mL/hour is a reasonable goal. Cal — = of sedation). Other examples of high-emetic-risk chemo- citonin increases kidney excretion of calcium and decreases @o 777 therapeutic drugs (vomiting risk >90%) include carmustine, bone resorption; it can decrease calcium within several hours cisplatin, cyclophosphamide (>1,500 mg/m/?), dacarbazine, in responsive patients. Tachyphylaxis to calcitonin may appear mechlorethamine, and streptozocin. after 24 to 48 hours, so therapy is usually discontinued after Many patients treated with moderate-emetic-risk che- this time period. This patient has an elevated serum creatinine motherapeutic agents (excluding higher-dose carboplatin) can level, which is a common complication of hypercalcemia, and be offered a two-drug combination of a 5-HT; receptor antag- intravenous isotonic saline may improve renal function as well. onist and dexamethasone. Certain chemotherapeutic agents Denosumab (Option A), a receptor activator of nuclear in this category may cause delayed nausea and vomiting (e.g., factor «B ligand inhibitor, is very effective in reducing serum cyclophosphamide, doxorubicin, and oxaliplatin), and in this calcium levels. It is typically reserved for patients who do not case, patients can be offered dexamethasone on days 2 and 3. respond to bisphosphonate therapy. Denosumab can be used Benzodiazepines, such as lorazepam (Option A), may when bisphosphonate therapy is contraindicated, such as in be used as adjuncts for nausea, although they should not be patients with kidney failure. Patients receiving denosumab used as single agents. should be monitored for the subsequent development of There is insufficient evidence regarding the value of med- hypocalcemia. ical marijuana (Option B) for chemotherapy-induced nausea. Furosemide (Option C), a loop diuretic, is not recom Evidence is also insufficient for recommending the use of med- mended unless kidney failure or heart failure is present, in which ical marijuana in place of the tested and approved cannabinoids case volume expansion should precede the administration of dronabinol and nabilone for the treatment of nausea and furosemide to avoid hypotension and further kidney injury. vomiting caused by chemotherapy or radiation therapy. Bisphosphonates (Option D) are effective medications for Patients treated with low-emetic-risk antineoplastic correcting hypercalcemia of malignancy and are frequently agents should be offered either a single dose of a 5-HT; used as a key part of management. However, their maximum receptor antagonist, such as ondansetron, or a single dose effect occurs in 2 to 4 days, so they are usually given in con of dexamethasone (Option D). A few examples of chemo- junction with intravenous isotonic saline. Bisphosphonates therapeutic agents with low emetic risk (10%-30%) include are contraindicated in the setting of kidney failure. fluorouracil, methotrexate, and docetaxel.

ical marijuana in place of the tested and approved cannabinoids case volume expansion should precede the administration of dronabinol and nabilone for the treatment of nausea and furosemide to avoid hypotension and further kidney injury. vomiting caused by chemotherapy or radiation therapy. Bisphosphonates (Option D) are effective medications for Patients treated with low-emetic-risk antineoplastic correcting hypercalcemia of malignancy and are frequently agents should be offered either a single dose of a 5-HT; used as a key part of management. However, their maximum receptor antagonist, such as ondansetron, or a single dose effect occurs in 2 to 4 days, so they are usually given in con of dexamethasone (Option D). A few examples of chemo- junction with intravenous isotonic saline. Bisphosphonates therapeutic agents with low emetic risk (10%-30%) include are contraindicated in the setting of kidney failure. fluorouracil, methotrexate, and docetaxel. e Patients with severe or symptomatic hypercalcemia e For patients receiving high-emetic-risk chemother- should receive intravenous isotonic saline to expand apy, standard antiemetic treatments include a four- vascular volume, renal perfusion, and urine calcium drug combination of an NK1 receptor antagonist, a excretion. 5-hydroxytryptamine-3 receptor antagonist, dexa- ¢ Loop diuretics are not indicated in the treatment of methasone, and olanzapine. hypercalcemia of malignancy unless kidney failure or e Olanzapine, when added to standard antiemetic regi- heart failure is present; in these circumstances, intra- mens, has been found to be effective for the treatment of venous expansion of vascular volume should precede delayed chemotherapy-induced nausea and vomiting. the administration of loop diuretics. 88

Answers and Critiques Bibliography Item 45 Answer: D Goldner W. Cancer-related hypercalcemia. J Oncol Pract. 2016;12:426-32. Educational Objective: Select breast cancer therapy [PMID: 27170690] doi:10.1200/JOP.2016.011155 informed by a multigene recurrence assay.

Bibliography Item 45 Answer: D Goldner W. Cancer-related hypercalcemia. J Oncol Pract. 2016;12:426-32. Educational Objective: Select breast cancer therapy [PMID: 27170690] doi:10.1200/JOP.2016.011155 informed by a multigene recurrence assay. This patient with estrogen receptor (ER)-positive, human epi- Item 44 Answer: A dermal growth factor 2 (HER2)-negative breast cancer should Educational Objective: Treat midline poorly differenti- have a multigene recurrence assay or gene expression profile ated carcinoma of unknown primary site. (Option D), such as the 21-gene recurrence score, to inform chemotherapy decision making. If the result is low/interme- The most appropriate management is chemotherapy with diate, she should have hormone therapy alone and, if high, a cisplatin-based germ cell regimen (Option A). Despite chemotherapy and hormone therapy. ER-positive, HER2- steady improvements in diagnostic and imaging techniques negative breast cancer risk may vary considerably based on during the past decades, a reasonable evaluation will not the anatomic extent of disease (as indicated by tumor size and wn identify the source of cancer in a small number (less than rt} axillary lymph node involvement) as well as features that indi- 3 5%) of all patients presenting with metastatic cancer. This cate the biology of disease, including grade and degree of ER a heterogeneous group of patients is classified as having can- positivity. Gene expression profiles performed on the tumor 7 cer of unknown primary (CUP). Standard evaluation of CUP oO itself are independently associated with risk of recurrence sc includes a full medical history and physical examination = and the degree of chemotherapy benefit. The Oncotype Dx and contrast-enhanced CT of the chest, abdomen, and pel- cs Recurrence Score has the highest-quality data available and is wn vis. Histologic evaluation of the most accessible tumor mass ih o the most widely used test in the United States. Patients with should include a limited number of immunohistochemical = node-negative, ER-positive/ HER2-negative breast cancer and wn stains to assess the nature of the tumor and to identify or <= low (RS 0-10) and intermediate (RS 11-25) scores do not ben- <t exclude treatable histologies (such as lymphoma or germ efit from chemotherapy, although there remains controversy cell tumor). Ultimately, CUP is a diagnosis of exclusion after regarding the role of chemotherapy for women younger than evaluation has failed to identify the primary tumor, which 50 years and with an RS of 16 to 25. However, patients with a may either be too small to be detected or may have been high RS (231) do benefit from chemotherapy. These tests have destroyed immunologically and is no longer present. The dramatically improved the ability to avoid chemotherapy for patient is a young male with a poorly differentiated CUP patients at low risk of recurrence who will not benefit from that is predominantly presenting in a midline distribution. chemotherapy and to identify patients at greater risk and In the absence of a clearly identified primary, these patients who do benefit from chemotherapy. Consensus guidelines should be treated presumptively for metastatic testicular recommend sending a gene expression profile for patients (germ cell) cancer with a cisplatin-based chemotherapy reg- with stage II, ER-positive/HER2-negative breast cancer to imen. The absence of serum o-fetoprotein and B-human inform chemotherapy decision making. If the results of the chorionic gonadotropin, normal testicular examination, or gene expression profile would not inform decision making (if even normal ultrasonography does not exclude this treat- she would not take chemotherapy regardless of the score), a ment approach. gene expression profile should not be sent. A fluorouracil-based chemotherapy regimen (Option B) Chemotherapy followed by endocrine therapy for focused on digestive tract malignancies would be an appro- 5 years (Option B) should not be recommended to this priate consideration for an adenocarcinoma of unknown patient without a gene expression profile to inform the deci- primary that was predominantly below the diaphragm with sion. Most patients with ER-positive/HER2-negative breast liver and/or peritoneal involvement. cancer who have the 21-gene recurrence score performed The extent of disease described makes initial treatment have low- or intermediate-risk tumors and therefore do not with either surgery or radiation therapy (Options C, D) inap- benefit from adjuvant chemotherapy. Administering adjuvant propriate, although these modalities might be considered chemotherapy without this information could expose the for consolidation therapy at a later date ifa good response to patient to unnecessary risk without the potential for benefit. chemotherapy is obtained first. This patient will need adjuvant endocrine therapy. Chemotherapy alone (Option A) would be inappropriate. e Poorly differentiated carcinoma of unknown primary Endocrine therapy alone (Option C) may be appropriate

This patient with estrogen receptor (ER)-positive, human epi- Item 44 Answer: A dermal growth factor 2 (HER2)-negative breast cancer should Educational Objective: Treat midline poorly differenti- have a multigene recurrence assay or gene expression profile ated carcinoma of unknown primary site. (Option D), such as the 21-gene recurrence score, to inform chemotherapy decision making. If the result is low/interme- The most appropriate management is chemotherapy with diate, she should have hormone therapy alone and, if high, a cisplatin-based germ cell regimen (Option A). Despite chemotherapy and hormone therapy. ER-positive, HER2- steady improvements in diagnostic and imaging techniques negative breast cancer risk may vary considerably based on during the past decades, a reasonable evaluation will not the anatomic extent of disease (as indicated by tumor size and wn identify the source of cancer in a small number (less than rt} axillary lymph node involvement) as well as features that indi- 3 5%) of all patients presenting with metastatic cancer. This cate the biology of disease, including grade and degree of ER a heterogeneous group of patients is classified as having can- positivity. Gene expression profiles performed on the tumor 7 cer of unknown primary (CUP). Standard evaluation of CUP oO itself are independently associated with risk of recurrence sc includes a full medical history and physical examination = and the degree of chemotherapy benefit. The Oncotype Dx and contrast-enhanced CT of the chest, abdomen, and pel- cs Recurrence Score has the highest-quality data available and is wn vis. Histologic evaluation of the most accessible tumor mass ih o the most widely used test in the United States. Patients with should include a limited number of immunohistochemical = node-negative, ER-positive/ HER2-negative breast cancer and wn stains to assess the nature of the tumor and to identify or <= low (RS 0-10) and intermediate (RS 11-25) scores do not ben- <t exclude treatable histologies (such as lymphoma or germ efit from chemotherapy, although there remains controversy cell tumor). Ultimately, CUP is a diagnosis of exclusion after regarding the role of chemotherapy for women younger than evaluation has failed to identify the primary tumor, which 50 years and with an RS of 16 to 25. However, patients with a may either be too small to be detected or may have been high RS (231) do benefit from chemotherapy. These tests have destroyed immunologically and is no longer present. The dramatically improved the ability to avoid chemotherapy for patient is a young male with a poorly differentiated CUP patients at low risk of recurrence who will not benefit from that is predominantly presenting in a midline distribution. chemotherapy and to identify patients at greater risk and In the absence of a clearly identified primary, these patients who do benefit from chemotherapy. Consensus guidelines should be treated presumptively for metastatic testicular recommend sending a gene expression profile for patients (germ cell) cancer with a cisplatin-based chemotherapy reg- with stage II, ER-positive/HER2-negative breast cancer to imen. The absence of serum o-fetoprotein and B-human inform chemotherapy decision making. If the results of the chorionic gonadotropin, normal testicular examination, or gene expression profile would not inform decision making (if even normal ultrasonography does not exclude this treat- she would not take chemotherapy regardless of the score), a ment approach. gene expression profile should not be sent. A fluorouracil-based chemotherapy regimen (Option B) Chemotherapy followed by endocrine therapy for focused on digestive tract malignancies would be an appro- 5 years (Option B) should not be recommended to this priate consideration for an adenocarcinoma of unknown patient without a gene expression profile to inform the deci- primary that was predominantly below the diaphragm with sion. Most patients with ER-positive/HER2-negative breast liver and/or peritoneal involvement. cancer who have the 21-gene recurrence score performed The extent of disease described makes initial treatment have low- or intermediate-risk tumors and therefore do not with either surgery or radiation therapy (Options C, D) inap- benefit from adjuvant chemotherapy. Administering adjuvant propriate, although these modalities might be considered chemotherapy without this information could expose the for consolidation therapy at a later date ifa good response to patient to unnecessary risk without the potential for benefit. chemotherapy is obtained first. This patient will need adjuvant endocrine therapy. Chemotherapy alone (Option A) would be inappropriate. e Poorly differentiated carcinoma of unknown primary Endocrine therapy alone (Option C) may be appropriate site that is predominantly presenting in a midline dis- depending on the results of the multigene recurrence assay.

This patient with estrogen receptor (ER)-positive, human epi- Item 44 Answer: A dermal growth factor 2 (HER2)-negative breast cancer should Educational Objective: Treat midline poorly differenti- have a multigene recurrence assay or gene expression profile ated carcinoma of unknown primary site. (Option D), such as the 21-gene recurrence score, to inform chemotherapy decision making. If the result is low/interme- The most appropriate management is chemotherapy with diate, she should have hormone therapy alone and, if high, a cisplatin-based germ cell regimen (Option A). Despite chemotherapy and hormone therapy. ER-positive, HER2- steady improvements in diagnostic and imaging techniques negative breast cancer risk may vary considerably based on during the past decades, a reasonable evaluation will not the anatomic extent of disease (as indicated by tumor size and wn identify the source of cancer in a small number (less than rt} axillary lymph node involvement) as well as features that indi- 3 5%) of all patients presenting with metastatic cancer. This cate the biology of disease, including grade and degree of ER a heterogeneous group of patients is classified as having can- positivity. Gene expression profiles performed on the tumor 7 cer of unknown primary (CUP). Standard evaluation of CUP oO itself are independently associated with risk of recurrence sc includes a full medical history and physical examination = and the degree of chemotherapy benefit. The Oncotype Dx and contrast-enhanced CT of the chest, abdomen, and pel- cs Recurrence Score has the highest-quality data available and is wn vis. Histologic evaluation of the most accessible tumor mass ih o the most widely used test in the United States. Patients with should include a limited number of immunohistochemical = node-negative, ER-positive/ HER2-negative breast cancer and wn stains to assess the nature of the tumor and to identify or <= low (RS 0-10) and intermediate (RS 11-25) scores do not ben- <t exclude treatable histologies (such as lymphoma or germ efit from chemotherapy, although there remains controversy cell tumor). Ultimately, CUP is a diagnosis of exclusion after regarding the role of chemotherapy for women younger than evaluation has failed to identify the primary tumor, which 50 years and with an RS of 16 to 25. However, patients with a may either be too small to be detected or may have been high RS (231) do benefit from chemotherapy. These tests have destroyed immunologically and is no longer present. The dramatically improved the ability to avoid chemotherapy for patient is a young male with a poorly differentiated CUP patients at low risk of recurrence who will not benefit from that is predominantly presenting in a midline distribution. chemotherapy and to identify patients at greater risk and In the absence of a clearly identified primary, these patients who do benefit from chemotherapy. Consensus guidelines should be treated presumptively for metastatic testicular recommend sending a gene expression profile for patients (germ cell) cancer with a cisplatin-based chemotherapy reg- with stage II, ER-positive/HER2-negative breast cancer to imen. The absence of serum o-fetoprotein and B-human inform chemotherapy decision making. If the results of the chorionic gonadotropin, normal testicular examination, or gene expression profile would not inform decision making (if even normal ultrasonography does not exclude this treat- she would not take chemotherapy regardless of the score), a ment approach. gene expression profile should not be sent. A fluorouracil-based chemotherapy regimen (Option B) Chemotherapy followed by endocrine therapy for focused on digestive tract malignancies would be an appro- 5 years (Option B) should not be recommended to this priate consideration for an adenocarcinoma of unknown patient without a gene expression profile to inform the deci- primary that was predominantly below the diaphragm with sion. Most patients with ER-positive/HER2-negative breast liver and/or peritoneal involvement. cancer who have the 21-gene recurrence score performed The extent of disease described makes initial treatment have low- or intermediate-risk tumors and therefore do not with either surgery or radiation therapy (Options C, D) inap- benefit from adjuvant chemotherapy. Administering adjuvant propriate, although these modalities might be considered chemotherapy without this information could expose the for consolidation therapy at a later date ifa good response to patient to unnecessary risk without the potential for benefit. chemotherapy is obtained first. This patient will need adjuvant endocrine therapy. Chemotherapy alone (Option A) would be inappropriate. e Poorly differentiated carcinoma of unknown primary Endocrine therapy alone (Option C) may be appropriate site that is predominantly presenting in a midline dis- depending on the results of the multigene recurrence assay. tribution should be treated presumptively for metastatic germ cell cancer with a cisplatin-based chemotherapy regimen. e For patients with hormone receptor-positive, human epidermal growth factor 2—negative breast cancers Bibliography with zero to three positive axillary nodes, the use of Qaseem A, Usman N, Jayaraj JS, et al. Cancer of unknown primary: a review on clinical guidelines in the development and targeted management of multigene assays informs the decision regarding the patients with the unknown primary site. Cureus. 2019;11:e5552. [PMID: need for chemotherapy. 31695975] doi:10.7759/cureus.5552

tribution should be treated presumptively for metastatic germ cell cancer with a cisplatin-based chemotherapy regimen. e For patients with hormone receptor-positive, human epidermal growth factor 2—negative breast cancers Bibliography with zero to three positive axillary nodes, the use of Qaseem A, Usman N, Jayaraj JS, et al. Cancer of unknown primary: a review on clinical guidelines in the development and targeted management of multigene assays informs the decision regarding the patients with the unknown primary site. Cureus. 2019;11:e5552. [PMID: need for chemotherapy. 31695975] doi:10.7759/cureus.5552 89

Answers and Critiques — Bibliography Item 47 Answer: D Sparano JA, Gray RJ, Makower DF, et al. Adjuvant chemotherapy guided by Educational Objective: Understand the meaning of a 21-gene expression assay in breast cancer. N Engl J Med. 2018;379:111- 21. [PMID: 29860917] doi:10.1056/NEJMoa1804710 progression-free survival.

Bibliography Item 47 Answer: D Sparano JA, Gray RJ, Makower DF, et al. Adjuvant chemotherapy guided by Educational Objective: Understand the meaning of a 21-gene expression assay in breast cancer. N Engl J Med. 2018;379:111- 21. [PMID: 29860917] doi:10.1056/NEJMoa1804710 progression-free survival. A longer time without further cancer growth (Option D) can be most reasonably expected with this patient’s new chemo- Item 46 Answer: A therapy regimen. Progression-free survival is a metric char- Educational Objective: Treat metastatic non-small cell acterized as the time from when a treatment is started until lung cancer with an ALK translocation with alectinib. the time that either the tumor progresses or the patient dies. It is therefore a measure of how long the patient will live with This patient has non-small cell lung cancer with an ALK the disease under control, but it is not a measure of how long translocation and should be treated with alectinib (Option A). the patient will live (Option C). Progression-free survival is a Molecular alterations are playing an increasingly important = term that is easily misunderstood and confused with overall role in the evaluation and treatment of patients with metastatic = survival. Progression-free interval would more accurately wn non-small cell lung cancer. Current evidence supports use = describe what is referred to as progression-free survival. @o of specific targeted agents based on identification of certain = wn The one pure and simple term is cure (Option A). Cure molecular alterations in tumor tissue. Such testing is a routine o means, as one would expect, that the cancer is gone, no fur- = component of the evaluation of any patient with metastatic a. ther treatment is required, and the patient will live out his or non-small cell lung cancer. Treatment is selected as appropri- (@) her life without seeing that type of cancer again. This should = ate based on the presence or absence of alterations. The patient oS. not be confused with overall survival. Overall survival is the 2 in this case underwent such testing and was found to have a << term used to describe the time from when a treatment is oO translocation involving the ALK gene, resulting in constitutive wn started until the time of patient death, and so it is a metric of activation of the ALK tyrosine kinase. Alectinib is a tyrosine how long a patient lived. Overall survival is often misunder- kinase inhibitor with specific activity against the ALK gene and stood by patients to be synonymous with cure. This misun- has been shown to be very active in this patient population. It derstanding can be further compounded by the frequent use is a standard treatment and is recommended as front-line treat- of the phrase significant improvement in survival, in which ment for a patient found to have an ALK translocation. significant refers to the statistical certainty of the finding The combination of chemotherapy and pembrolizumab but is often misinterpreted as a substantial improvement in (Option B) can be used as initial treatment regardless of pro- survival. Many drugs have been approved with significant grammed death ligand-1 expression level. However, it is indi- improvements in survival that are limited to less than 2 or cated only in patients who do not have a driver mutation for 3 months, a quantity that may not be clinically significant. which there is an applicable targeted therapy available. Because Quality of life (Option B) is a complex metric that incor- this patient does have a driver mutation, treatment with this porates many physical and psychological aspects of a patient’s combination is not recommended as first-line treatment. overall condition. However, in a patient with low symptom Although platinum-based chemotherapy (Option C) burden such as the one described here, a drug that has added is sometimes used as initial therapy before the results of toxicity is unlikely to contribute favorably to quality of life. mutation testing are available, this patient is already known to have an ALK translocation. Alectinib has been shown to improve survival compared with chemotherapy in patients e Progression-free survival is the time from when a with an ALK translocation and is the preferred therapy. treatment is started until that treatment is no longer Stereotactic radiation therapy (Option D) is an effective controlling the cancer; progression-free survival may treatment for patients with stage I non-small cell lung cancer not correlate with overall survival. who cannot tolerate surgery. Stereotactic radiation therapy is not indicated in the treatment of metastatic lung cancer. Bibliography Sato T, Soejima K, Fujisawa D, et al. Prognostic understanding at diagnosis and associated factors in patients with advanced lung cancer and their ¢ Testing for molecular alterations (epidermal growth caregivers. Oncologist. 2018;23:1218-29. [PMID: 30120158] doi:10.1634/ theoncologist.2017-0329 factor receptor, ALK, ROS1) is a routine component of the evaluation of any patient with metastatic non-small cell lung cancer.

A longer time without further cancer growth (Option D) can be most reasonably expected with this patient’s new chemo- Item 46 Answer: A therapy regimen. Progression-free survival is a metric char- Educational Objective: Treat metastatic non-small cell acterized as the time from when a treatment is started until lung cancer with an ALK translocation with alectinib. the time that either the tumor progresses or the patient dies. It is therefore a measure of how long the patient will live with This patient has non-small cell lung cancer with an ALK the disease under control, but it is not a measure of how long translocation and should be treated with alectinib (Option A). the patient will live (Option C). Progression-free survival is a Molecular alterations are playing an increasingly important = term that is easily misunderstood and confused with overall role in the evaluation and treatment of patients with metastatic = survival. Progression-free interval would more accurately wn non-small cell lung cancer. Current evidence supports use = describe what is referred to as progression-free survival. @o of specific targeted agents based on identification of certain = wn The one pure and simple term is cure (Option A). Cure molecular alterations in tumor tissue. Such testing is a routine o means, as one would expect, that the cancer is gone, no fur- = component of the evaluation of any patient with metastatic a. ther treatment is required, and the patient will live out his or non-small cell lung cancer. Treatment is selected as appropri- (@) her life without seeing that type of cancer again. This should = ate based on the presence or absence of alterations. The patient oS. not be confused with overall survival. Overall survival is the 2 in this case underwent such testing and was found to have a << term used to describe the time from when a treatment is oO translocation involving the ALK gene, resulting in constitutive wn started until the time of patient death, and so it is a metric of activation of the ALK tyrosine kinase. Alectinib is a tyrosine how long a patient lived. Overall survival is often misunder- kinase inhibitor with specific activity against the ALK gene and stood by patients to be synonymous with cure. This misun- has been shown to be very active in this patient population. It derstanding can be further compounded by the frequent use is a standard treatment and is recommended as front-line treat- of the phrase significant improvement in survival, in which ment for a patient found to have an ALK translocation. significant refers to the statistical certainty of the finding The combination of chemotherapy and pembrolizumab but is often misinterpreted as a substantial improvement in (Option B) can be used as initial treatment regardless of pro- survival. Many drugs have been approved with significant grammed death ligand-1 expression level. However, it is indi- improvements in survival that are limited to less than 2 or cated only in patients who do not have a driver mutation for 3 months, a quantity that may not be clinically significant. which there is an applicable targeted therapy available. Because Quality of life (Option B) is a complex metric that incor- this patient does have a driver mutation, treatment with this porates many physical and psychological aspects of a patient’s combination is not recommended as first-line treatment. overall condition. However, in a patient with low symptom Although platinum-based chemotherapy (Option C) burden such as the one described here, a drug that has added is sometimes used as initial therapy before the results of toxicity is unlikely to contribute favorably to quality of life. mutation testing are available, this patient is already known to have an ALK translocation. Alectinib has been shown to improve survival compared with chemotherapy in patients e Progression-free survival is the time from when a with an ALK translocation and is the preferred therapy. treatment is started until that treatment is no longer Stereotactic radiation therapy (Option D) is an effective controlling the cancer; progression-free survival may treatment for patients with stage I non-small cell lung cancer not correlate with overall survival. who cannot tolerate surgery. Stereotactic radiation therapy is not indicated in the treatment of metastatic lung cancer. Bibliography Sato T, Soejima K, Fujisawa D, et al. Prognostic understanding at diagnosis and associated factors in patients with advanced lung cancer and their ¢ Testing for molecular alterations (epidermal growth caregivers. Oncologist. 2018;23:1218-29. [PMID: 30120158] doi:10.1634/ theoncologist.2017-0329 factor receptor, ALK, ROS1) is a routine component of the evaluation of any patient with metastatic non-small cell lung cancer. e For metastatic non-small cell lung cancer with an Item 48 Answer: A ALK translocation, initial treatment should be with Educational Objective: Screen for osteoporosis in a alectinib. patient taking an aromatase inhibitor.

e For metastatic non-small cell lung cancer with an Item 48 Answer: A ALK translocation, initial treatment should be with Educational Objective: Screen for osteoporosis in a alectinib. patient taking an aromatase inhibitor. The most appropriate management of this patient’s bone Bibliography health is to screen for osteoporosis with dual-energy x-ray Herbst RS, Morgensztern D, Boshoff C. The biology and management of absorptiometry (DEXA) (Option A). Bone loss occurs at an non-small cell lung cancer. Nature. 2018;553:446-54. [PMID: 29364287] doi:10.1038/nature25183 increased rate in cancer survivors who have taken long-term 90

Answers and Critiques glucocorticoids and in women who have undergone surgical, proceed with surgery (Option D). CLL is a low-grade B-cell irradiation, or chemotherapy-induced premature menopause lymphoproliferative disorder. Many patients are not symp- or who are taking aromatase inhibitors such as anastrozole for tomatic at presentation and are diagnosed when noted to have breast cancer. Adverse effects of aromatase inhibitors include a lymphocytosis on a routine complete blood count (CBC). arthralgia, vaginal dryness, sexual dysfunction, cardiovascu- Bone marrow aspiration and biopsy (Option A) are lar events, hyperlipidemia, and higher risks of osteoporosis generally unnecessary for patients newly diagnosed with and fractures. Compared with tamoxifen, aromatase inhib- CLL. In most cases, the diagnosis is suggested by an absolute itors have a lower risk of venous thrombosis and endome- lymphocytosis on CBC with an abundance of predominantly trial cancer. Up to one third of women develop aromatase mature-appearing lymphocytes on peripheral smear, char- inhibitor-associated symmetric arthralgia, joint stiffness, and acteristically associated with “smudge cells.” The diagnosis bone pain. Assessment of bone density and treatment or is confirmed by flow cytometry, which shows monoclonal B prophylaxis should be considered to reduce the risk of frac- cells that usually co-express CD5 (typically a T-cell marker) ture. Management commonly includes routine supplements along with the B-cell antigens CD19 and CD20. Routinely, ) A) of vitamin D and calcium (while monitoring serum calcium cytogenetics and fluorescence in situ hybridization studies =

glucocorticoids and in women who have undergone surgical, proceed with surgery (Option D). CLL is a low-grade B-cell irradiation, or chemotherapy-induced premature menopause lymphoproliferative disorder. Many patients are not symp- or who are taking aromatase inhibitors such as anastrozole for tomatic at presentation and are diagnosed when noted to have breast cancer. Adverse effects of aromatase inhibitors include a lymphocytosis on a routine complete blood count (CBC). arthralgia, vaginal dryness, sexual dysfunction, cardiovascu- Bone marrow aspiration and biopsy (Option A) are lar events, hyperlipidemia, and higher risks of osteoporosis generally unnecessary for patients newly diagnosed with and fractures. Compared with tamoxifen, aromatase inhib- CLL. In most cases, the diagnosis is suggested by an absolute itors have a lower risk of venous thrombosis and endome- lymphocytosis on CBC with an abundance of predominantly trial cancer. Up to one third of women develop aromatase mature-appearing lymphocytes on peripheral smear, char- inhibitor-associated symmetric arthralgia, joint stiffness, and acteristically associated with “smudge cells.” The diagnosis bone pain. Assessment of bone density and treatment or is confirmed by flow cytometry, which shows monoclonal B prophylaxis should be considered to reduce the risk of frac- cells that usually co-express CD5 (typically a T-cell marker) ture. Management commonly includes routine supplements along with the B-cell antigens CD19 and CD20. Routinely, ) A) of vitamin D and calcium (while monitoring serum calcium cytogenetics and fluorescence in situ hybridization studies = levels), DEXA screening for osteoporosis, and for patients are performed, along with determination of immunoglobu- = = with confirmed osteoporosis, bisphosphonate or denosumab lin variable region heavy chain (IgVH) status, to help confirm ed therapy. Vigilance is required to detect bisphosphonate com- the diagnosis and provide prognostic information. Favorable a] < plications such as osteonecrosis of the jaw and atypical sub- prognostic features include the presence of del(13), absence C) %) trochanteric spiral fractures of the femur. of del(17p), and the presence of a mutated IgVH as opposed hee a Alendronate (Option B), a bisphosphonate, or denos- to unmutated status. Patients with CLL without systemic = n umab (Option C), a monoclonal antibody directed against symptoms, bulky adenopathy, or significant cytopenias a the receptor activator of nuclear factor «B ligand, could be should not be treated. =

levels), DEXA screening for osteoporosis, and for patients are performed, along with determination of immunoglobu- = = with confirmed osteoporosis, bisphosphonate or denosumab lin variable region heavy chain (IgVH) status, to help confirm ed therapy. Vigilance is required to detect bisphosphonate com- the diagnosis and provide prognostic information. Favorable a] < plications such as osteonecrosis of the jaw and atypical sub- prognostic features include the presence of del(13), absence C) %) trochanteric spiral fractures of the femur. of del(17p), and the presence of a mutated IgVH as opposed hee a Alendronate (Option B), a bisphosphonate, or denos- to unmutated status. Patients with CLL without systemic = n umab (Option C), a monoclonal antibody directed against symptoms, bulky adenopathy, or significant cytopenias a the receptor activator of nuclear factor «B ligand, could be should not be treated. = considered if the patient is diagnosed with osteoporosis. In the Although chemoimmunotherapy regimens such as ben- absence of a bone density measurement, initiating treatment damustine or fludarabine and cyclophosphamide combined for osteoporosis is premature. Bone mineral density should be with an anti-CD20 antibody such as rituximab (Option C) measured now, and in the absence of osteoporosis, repeated are very active, these have been increasingly replaced by in 2 years. If the patient develops more severe osteopenia oral targeted therapies such as ibrutinib (Option B) (which (T-score less than 2) or osteoporosis (T-score less than 2.5), inhibits Bruton tyrosine kinase) and venetoclax (a B-cell then a bisphosphonate or denosumab would be appropriate. lymphoma 2 inhibitor). These targeted agents were initially Raloxifene (Option D) is in the same family as tamox- studied in patients with CLL who had relapsed or refrac- ifen and works as a selective estrogen receptor modulator. tory disease, but studies now support their use as first-line It also has positive effects on bone density but is an inferior therapy. At this time, despite the availability of many active agent for breast cancer, so substituting raloxifene for anas- agents and regimens, there is no evidence that earlier insti- trozole is not indicated. Raloxifene is approved for osteo- tution of therapy is associated with better outcomes. Many porosis and for breast cancer chemoprevention in patients patients will go for years, and some indefinitely, without with high risk of breast cancer but not for adjuvant therapy requiring therapy for their disease. of breast cancer, as is needed in this case.

considered if the patient is diagnosed with osteoporosis. In the Although chemoimmunotherapy regimens such as ben- absence of a bone density measurement, initiating treatment damustine or fludarabine and cyclophosphamide combined for osteoporosis is premature. Bone mineral density should be with an anti-CD20 antibody such as rituximab (Option C) measured now, and in the absence of osteoporosis, repeated are very active, these have been increasingly replaced by in 2 years. If the patient develops more severe osteopenia oral targeted therapies such as ibrutinib (Option B) (which (T-score less than 2) or osteoporosis (T-score less than 2.5), inhibits Bruton tyrosine kinase) and venetoclax (a B-cell then a bisphosphonate or denosumab would be appropriate. lymphoma 2 inhibitor). These targeted agents were initially Raloxifene (Option D) is in the same family as tamox- studied in patients with CLL who had relapsed or refrac- ifen and works as a selective estrogen receptor modulator. tory disease, but studies now support their use as first-line It also has positive effects on bone density but is an inferior therapy. At this time, despite the availability of many active agent for breast cancer, so substituting raloxifene for anas- agents and regimens, there is no evidence that earlier insti- trozole is not indicated. Raloxifene is approved for osteo- tution of therapy is associated with better outcomes. Many porosis and for breast cancer chemoprevention in patients patients will go for years, and some indefinitely, without with high risk of breast cancer but not for adjuvant therapy requiring therapy for their disease. of breast cancer, as is needed in this case. e The diagnosis of chronic lymphocytic leukemia is sug- e Aromatase inhibitors are associated with an increased gested by absolute lymphocytosis with an abundance risk of osteoporosis and fracture. of predominantly mature-appearing lymphocytes on e Calcium and vitamin D supplements are recom- peripheral smear and confirmed by flow cytometry.

e The diagnosis of chronic lymphocytic leukemia is sug- e Aromatase inhibitors are associated with an increased gested by absolute lymphocytosis with an abundance risk of osteoporosis and fracture. of predominantly mature-appearing lymphocytes on e Calcium and vitamin D supplements are recom- peripheral smear and confirmed by flow cytometry. mended for patients taking aromatase inhibitors, as is ¢ Chronic lymphocytic leukemia is typically an indolent screening for osteoporosis with dual-energy x-ray disease, and many patients require no therapy for absorptiometry. many years. Bibliography Bibliography Bruyére O, Bergmann P, Cavalier E, et al. Skeletal health in breast cancer Yeung CCS, Shadman M. How to choose the best treatment and testing for survivors. Maturitas. 2017;105:78-82. [PMID: 28838807] doi:10.1016/j. chronic lymphocytic leukemia in the tsunami of new treatment options. Curr maturitas.2017.08.008 Oncol Rep. 2019;21:74. [PMID: 31327069] doi:10.1007/s11912-019-0819-x Item 49 Answer: D Item 50 Answer: C Educational Objective: Manage early-stage chronic Educational Objective: Treat a patient with low-risk lymphocytic leukemia. cervical cancer who wishes to maintain fertility. For this patient with early-stage chronic lymphocytic leuke- The most appropriate treatment is fertility-preserving surgery mia (CLL), there is no indication for therapy, and it is safe to (Option C). This patient has early-stage and low-risk disease, 91

Answers and Critiques _ and large case series have demonstrated that radical trachelec- establishes the diagnosis. Approximately 25% of such patients tomy (in which the cervix is removed) and cervical conization will have tumors that show HER2 amplification; such tumors are both effective procedures associated with low risks of achieve a superior response to chemotherapy when the anti- recurrence. The choice between trachelectomy and coniza- HER2 monoclonal antibody trastuzumab is added to standard tion is determined by depth of microscopic invasion, among chemotherapy. For this reason, determination of HER2 ampli- other factors. Only select patients with low-risk disease are fication status is necessary when initiating chemotherapy. appropriate candidates for these procedures. Large series have BRAF mutation status (Option A) is of paramount demonstrated that pregnancy rates are approximately 50%, importance in patients with melanoma, 40% of whom will and many women may become pregnant spontaneously. have BRAF-mutated tumors. These tumors are highly likely Concurrent radiation therapy and cisplatin (Option A) to respond to tyrosine kinase inhibitors targeting BRAF, but is recommended for patients with stage III cervical cancer such mutations are exceedingly rare in upper gastrointesti- but not for patients with stage I cervical cancer. This treat- nal malignancies, and routine testing is not indicated. > ment is associated with greater morbidity and is reserved Epidermal growth factor receptor (EGFR) mutation status 4] a) for patients with greater risks of locoregional and distant (Option B) is relevant to the use of anti-EGFR tyrosine kinase = recurrence with higher-stage disease. Furthermore, chemo- inhibitors in non-small cell lung cancer; however, these agents Oo — 2) radiation is not a fertility-sparing approach, and this patient have not been demonstrated to be active in gastrointestinal o wishes to preserve fertility. cancers and so are not part of the treatment paradigm. J Qa. Continuous progestin therapy (Option B) may be used A PET/CT (Option D) will not add useful information a = as a fertility-sparing approach for select patients with early- because the available CT scan demonstrates unequivocal =. stage endometrial cancer but is not a treatment for cervi- metastatic disease, and any further information from the 2 = cal cancer. Cervical cancer is generally not an endocrine- PET scan would not change the treatment approach, which © wn sensitive cancer, and systemic therapy focuses mostly on the will be systemic chemotherapy. Any further information use of chemotherapy. regarding extent of disease that might be found on PET/CT Hysterectomy and pelvic node dissection (Option D) would not be expected to change management. is appropriate treatment for cervical cancer but does not preserve fertility. This patient could undergo a trachelectomy or cone biopsy with the aim of preserving her fertility. It is e Gastroesophageal tumors should be evaluated for

and large case series have demonstrated that radical trachelec- establishes the diagnosis. Approximately 25% of such patients tomy (in which the cervix is removed) and cervical conization will have tumors that show HER2 amplification; such tumors are both effective procedures associated with low risks of achieve a superior response to chemotherapy when the anti- recurrence. The choice between trachelectomy and coniza- HER2 monoclonal antibody trastuzumab is added to standard tion is determined by depth of microscopic invasion, among chemotherapy. For this reason, determination of HER2 ampli- other factors. Only select patients with low-risk disease are fication status is necessary when initiating chemotherapy. appropriate candidates for these procedures. Large series have BRAF mutation status (Option A) is of paramount demonstrated that pregnancy rates are approximately 50%, importance in patients with melanoma, 40% of whom will and many women may become pregnant spontaneously. have BRAF-mutated tumors. These tumors are highly likely Concurrent radiation therapy and cisplatin (Option A) to respond to tyrosine kinase inhibitors targeting BRAF, but is recommended for patients with stage III cervical cancer such mutations are exceedingly rare in upper gastrointesti- but not for patients with stage I cervical cancer. This treat- nal malignancies, and routine testing is not indicated. > ment is associated with greater morbidity and is reserved Epidermal growth factor receptor (EGFR) mutation status 4] a) for patients with greater risks of locoregional and distant (Option B) is relevant to the use of anti-EGFR tyrosine kinase = recurrence with higher-stage disease. Furthermore, chemo- inhibitors in non-small cell lung cancer; however, these agents Oo — 2) radiation is not a fertility-sparing approach, and this patient have not been demonstrated to be active in gastrointestinal o wishes to preserve fertility. cancers and so are not part of the treatment paradigm. J Qa. Continuous progestin therapy (Option B) may be used A PET/CT (Option D) will not add useful information a = as a fertility-sparing approach for select patients with early- because the available CT scan demonstrates unequivocal =. stage endometrial cancer but is not a treatment for cervi- metastatic disease, and any further information from the 2 = cal cancer. Cervical cancer is generally not an endocrine- PET scan would not change the treatment approach, which © wn sensitive cancer, and systemic therapy focuses mostly on the will be systemic chemotherapy. Any further information use of chemotherapy. regarding extent of disease that might be found on PET/CT Hysterectomy and pelvic node dissection (Option D) would not be expected to change management. is appropriate treatment for cervical cancer but does not preserve fertility. This patient could undergo a trachelectomy or cone biopsy with the aim of preserving her fertility. It is e Gastroesophageal tumors should be evaluated for appropriate to counsel the patient about both options to human epidermal growth factor 2 overexpression.

and large case series have demonstrated that radical trachelec- establishes the diagnosis. Approximately 25% of such patients tomy (in which the cervix is removed) and cervical conization will have tumors that show HER2 amplification; such tumors are both effective procedures associated with low risks of achieve a superior response to chemotherapy when the anti- recurrence. The choice between trachelectomy and coniza- HER2 monoclonal antibody trastuzumab is added to standard tion is determined by depth of microscopic invasion, among chemotherapy. For this reason, determination of HER2 ampli- other factors. Only select patients with low-risk disease are fication status is necessary when initiating chemotherapy. appropriate candidates for these procedures. Large series have BRAF mutation status (Option A) is of paramount demonstrated that pregnancy rates are approximately 50%, importance in patients with melanoma, 40% of whom will and many women may become pregnant spontaneously. have BRAF-mutated tumors. These tumors are highly likely Concurrent radiation therapy and cisplatin (Option A) to respond to tyrosine kinase inhibitors targeting BRAF, but is recommended for patients with stage III cervical cancer such mutations are exceedingly rare in upper gastrointesti- but not for patients with stage I cervical cancer. This treat- nal malignancies, and routine testing is not indicated. > ment is associated with greater morbidity and is reserved Epidermal growth factor receptor (EGFR) mutation status 4] a) for patients with greater risks of locoregional and distant (Option B) is relevant to the use of anti-EGFR tyrosine kinase = recurrence with higher-stage disease. Furthermore, chemo- inhibitors in non-small cell lung cancer; however, these agents Oo — 2) radiation is not a fertility-sparing approach, and this patient have not been demonstrated to be active in gastrointestinal o wishes to preserve fertility. cancers and so are not part of the treatment paradigm. J Qa. Continuous progestin therapy (Option B) may be used A PET/CT (Option D) will not add useful information a = as a fertility-sparing approach for select patients with early- because the available CT scan demonstrates unequivocal =. stage endometrial cancer but is not a treatment for cervi- metastatic disease, and any further information from the 2 = cal cancer. Cervical cancer is generally not an endocrine- PET scan would not change the treatment approach, which © wn sensitive cancer, and systemic therapy focuses mostly on the will be systemic chemotherapy. Any further information use of chemotherapy. regarding extent of disease that might be found on PET/CT Hysterectomy and pelvic node dissection (Option D) would not be expected to change management. is appropriate treatment for cervical cancer but does not preserve fertility. This patient could undergo a trachelectomy or cone biopsy with the aim of preserving her fertility. It is e Gastroesophageal tumors should be evaluated for appropriate to counsel the patient about both options to human epidermal growth factor 2 overexpression. inform her regarding the potential risks and benefits of each e Adding trastuzumab to chemotherapy regimens for approach. patients with metastatic gastroesophageal tumors and human epidermal growth factor 2 overexpression pro- vides a modest survival benefit. e For patients with early-stage, low-risk cervical cancer, fertility-sparing surgeries are options. Bibliography Greally M, Agarwal R, Ilson DH. Optimal management of gastroesophageal Bibliography junction cancer. Cancer. 2019;125:1990-2001. [PMID: 30973648] Bentivegna E, Maulard A, Pautier P, et al. Fertility results and pregnancy doi:10.1002/encr.32066 outcomes after conservative treatment of cervical cancer: a systematic review of the literature. Fertil Steril. 2016;106:1195-1211.e5. [PMID: 27430207] doi:10.1016/j.fertnstert.2016.06.032 Item 52 Answer: D Educational Objective: Treat stage I non-small lung cancer with stereotactic radiation therapy. Item 51 Answer: C The most appropriate treatment for this patient’s stage I non- Educational Objective: Evaluate metastatic gastro- small cell lung cancer is stereotactic radiation therapy (Option esophageal cancer. D). Surgery is the standard treatment for stage I and some The most appropriate test to perform next is assessment of the stage II non-small cell lung cancers, and in patients treated tumor for human epidermal growth factor 2 (HER2) ampli- with surgery, 5-year survival is about 60% to 70%. However, fication (Option C). This patient has an adenocarcinoma of not all patients are surgical candidates. Before undergoing the distal esophagus/gastroesophageal junction, which has surgery, it is critical to perform a medical evaluation to ensure metastasized to the liver and supraclavicular lymph node. that surgery would not be associated with undue risk. That Risk factors for adenocarcinoma include smoking along with was done in this case, and it was determined that this patient gastroesophageal reflux disease (GERD) and obesity. The was not a surgical candidate. Multiple studies have shown development of Barrett esophagus as a result of GERD, espe- that stereotactic radiation therapy is an effective treatment cially with dysplastic features, is a further risk for developing for this patient population, with demonstrated excellent rates adenocarcinoma of the esophagus. Pain or difficulty on swal- of local control, particularly in patients with stage I cancers. lowing, weight loss, nausea, vomiting, or persistent dyspepsia This patient, who is not fit for surgery, is a good candidate for may be presenting symptoms. Upper endoscopy and biopsy such treatment.

inform her regarding the potential risks and benefits of each e Adding trastuzumab to chemotherapy regimens for approach. patients with metastatic gastroesophageal tumors and human epidermal growth factor 2 overexpression pro- vides a modest survival benefit. e For patients with early-stage, low-risk cervical cancer, fertility-sparing surgeries are options. Bibliography Greally M, Agarwal R, Ilson DH. Optimal management of gastroesophageal Bibliography junction cancer. Cancer. 2019;125:1990-2001. [PMID: 30973648] Bentivegna E, Maulard A, Pautier P, et al. Fertility results and pregnancy doi:10.1002/encr.32066 outcomes after conservative treatment of cervical cancer: a systematic review of the literature. Fertil Steril. 2016;106:1195-1211.e5. [PMID: 27430207] doi:10.1016/j.fertnstert.2016.06.032 Item 52 Answer: D Educational Objective: Treat stage I non-small lung cancer with stereotactic radiation therapy. Item 51 Answer: C The most appropriate treatment for this patient’s stage I non- Educational Objective: Evaluate metastatic gastro- small cell lung cancer is stereotactic radiation therapy (Option esophageal cancer. D). Surgery is the standard treatment for stage I and some The most appropriate test to perform next is assessment of the stage II non-small cell lung cancers, and in patients treated tumor for human epidermal growth factor 2 (HER2) ampli- with surgery, 5-year survival is about 60% to 70%. However, fication (Option C). This patient has an adenocarcinoma of not all patients are surgical candidates. Before undergoing the distal esophagus/gastroesophageal junction, which has surgery, it is critical to perform a medical evaluation to ensure metastasized to the liver and supraclavicular lymph node. that surgery would not be associated with undue risk. That Risk factors for adenocarcinoma include smoking along with was done in this case, and it was determined that this patient gastroesophageal reflux disease (GERD) and obesity. The was not a surgical candidate. Multiple studies have shown development of Barrett esophagus as a result of GERD, espe- that stereotactic radiation therapy is an effective treatment cially with dysplastic features, is a further risk for developing for this patient population, with demonstrated excellent rates adenocarcinoma of the esophagus. Pain or difficulty on swal- of local control, particularly in patients with stage I cancers. lowing, weight loss, nausea, vomiting, or persistent dyspepsia This patient, who is not fit for surgery, is a good candidate for may be presenting symptoms. Upper endoscopy and biopsy such treatment. 92

Answers and Critiques Combination platinum-based chemotherapy (Option Although a CT of the neck, chest, abdomen, and pelvis A) is another accepted treatment for patients with metastatic (Option A) or PET/CT (Option C) could be obtained if there non-small cell lung cancer. However, it is not an accepted were concern about a relapse of Hodgkin lymphoma, relapse treatment for early-stage disease. Although treatment with after 7 years would be unusual and thus a less likely cause stereotactic radiation therapy can be curative, treatment for his symptoms. with combination chemotherapy would not be curative and Patients who have received mantle irradiation for Hodg- is not indicated for this patient. kin lymphoma also have a high risk of cardiac disease, Combined chemotherapy and radiation therapy including accelerated coronary artery disease, pericar- (Option B) are used commonly for the treatment of stage III dial disease, and valvular disease. However, these risks for non-small cell lung cancer and is an accepted treatment for Hodgkin lymphoma survivors have likely been reduced this group of patients. However, it has not been shown to be from the past, as fewer patients receive radiation therapy of benefit in patients with stage I or stage II disease and is not and those who do have smaller fields, lower total cumula- indicated for treatment of this patient. tive doses, and more sophisticated treatment planning to 4) a Immunotherapy (Option C) plays an increasingly minimize toxicities. This patient received neck, not mantle 3 important role in the treatment of non-small cell lung can- irradiation, and has no signs or symptoms of cardiovascular = _—_

Combination platinum-based chemotherapy (Option Although a CT of the neck, chest, abdomen, and pelvis A) is another accepted treatment for patients with metastatic (Option A) or PET/CT (Option C) could be obtained if there non-small cell lung cancer. However, it is not an accepted were concern about a relapse of Hodgkin lymphoma, relapse treatment for early-stage disease. Although treatment with after 7 years would be unusual and thus a less likely cause stereotactic radiation therapy can be curative, treatment for his symptoms. with combination chemotherapy would not be curative and Patients who have received mantle irradiation for Hodg- is not indicated for this patient. kin lymphoma also have a high risk of cardiac disease, Combined chemotherapy and radiation therapy including accelerated coronary artery disease, pericar- (Option B) are used commonly for the treatment of stage III dial disease, and valvular disease. However, these risks for non-small cell lung cancer and is an accepted treatment for Hodgkin lymphoma survivors have likely been reduced this group of patients. However, it has not been shown to be from the past, as fewer patients receive radiation therapy of benefit in patients with stage I or stage II disease and is not and those who do have smaller fields, lower total cumula- indicated for treatment of this patient. tive doses, and more sophisticated treatment planning to 4) a Immunotherapy (Option C) plays an increasingly minimize toxicities. This patient received neck, not mantle 3 important role in the treatment of non-small cell lung can- irradiation, and has no signs or symptoms of cardiovascular = _—_ cer. It works by reversing inhibition of the cellular immune disease. An echocardiogram (Option B) is not indicated. = =) response caused by cancers. Although it has a role in the Although the risk of thyroid cancer is also increased <s treatment of some patients with metastatic non-small cell S after radiation therapy to the neck, the overall incidence 6 lung cancer, it is not a standard treatment for patients with remains low. Routine ultrasound screening (Option E) is not wn ad

cer. It works by reversing inhibition of the cellular immune disease. An echocardiogram (Option B) is not indicated. = =) response caused by cancers. Although it has a role in the Although the risk of thyroid cancer is also increased <s treatment of some patients with metastatic non-small cell S after radiation therapy to the neck, the overall incidence 6 lung cancer, it is not a standard treatment for patients with remains low. Routine ultrasound screening (Option E) is not wn ad nonmetastatic disease. o recommended, but diagnostic ultrasonography should be FE performed if the patient develops a palpable nodule. wr = 4 e Surgery is the standard treatment for stage I and most stage IT non-small cell lung cancers. ¢ Irradiation to the neck significantly increases the risk ¢ For patients with non-small cell lung cancer who are of hypothyroidism.

nonmetastatic disease. o recommended, but diagnostic ultrasonography should be FE performed if the patient develops a palpable nodule. wr = 4 e Surgery is the standard treatment for stage I and most stage IT non-small cell lung cancers. ¢ Irradiation to the neck significantly increases the risk ¢ For patients with non-small cell lung cancer who are of hypothyroidism. not candidates for surgery, stereotactic radiation ther- e Annual measurement of serum thyroid-stimulating apy can be used to treat stage I cancers. hormone is recommended in patients who received irradiation to the neck or mediastinum. Bibliography Schneider BJ, Daly ME, Kennedy EB, et al. Stereotactic body radiotherapy for Bibliography early-stage non-small-cell lung cancer: American Society of Clinical Ng AK. Current survivorship recommendations for patients with Hodgkin Oncology Endorsement of the American Society for Radiation Oncology lymphoma: focus on late effects. Blood. 2014;124:3373-79. [PMID: Evidence-Based Guideline. J Clin Oncol. 2018;36:710-19. [PMID: 29106810] 25428219] doi:10.1182/blood-2014-05-579193 doi:10.1200/JCO.2017.74.9671

not candidates for surgery, stereotactic radiation ther- e Annual measurement of serum thyroid-stimulating apy can be used to treat stage I cancers. hormone is recommended in patients who received irradiation to the neck or mediastinum. Bibliography Schneider BJ, Daly ME, Kennedy EB, et al. Stereotactic body radiotherapy for Bibliography early-stage non-small-cell lung cancer: American Society of Clinical Ng AK. Current survivorship recommendations for patients with Hodgkin Oncology Endorsement of the American Society for Radiation Oncology lymphoma: focus on late effects. Blood. 2014;124:3373-79. [PMID: Evidence-Based Guideline. J Clin Oncol. 2018;36:710-19. [PMID: 29106810] 25428219] doi:10.1182/blood-2014-05-579193 doi:10.1200/JCO.2017.74.9671 Item 54 Answer: A Item 53 Answer: D Educational Objective: Evaluate a patient with newly Educational Objective: Diagnose radiation-induced diagnosed colon cancer for metastatic disease. hypothyroidism. A contrast-enhanced CT (Option A) is the most accurate and The most appropriate test to perform next is measurement of useful imaging modality for staging of patients with a new thyroid-stimulating hormone (TSH) (Option D). This patient diagnosis of colon cancer. Staging with the TNM cancer stag- is at risk for radiation-induced hypothyroidism. Risk factors ing system is the first step in treatment planning. Preoperative for radiation-induced hypothyroidism include higher doses clinical staging begins with a history to identify localizing and treatment at a younger age. Rates of hypothyroidism may symptoms that may represent metastatic disease and physical approach 50%. Patients who have received radiation therapy to examination to detect ascites, hepatomegaly, and lymphade- the thyroid may develop subclinical or clinical hypothyroidism nopathy. Laboratory evaluation includes serum carcinoem- many years or decades later. These patients are also at increased bryonic antigen (CEA) in addition to routine chemical and risk for thyroid cancer compared with the general population, metabolic studies. An elevated CEA level indicates a worse although the overall risk remains low. Annual measurement prognosis for patients at any stage of colon cancer compared to of TSH is recommended in patients who received radiation patients with normal levels. In addition, failure of an elevated therapy to the neck or mediastinum. An elevated TSH con- CEA level to normalize after resection suggests the continued centration should be followed by measurement of thyroxine presence of metastatic disease and need for additional evalu- to confirm the diagnosis of hypothyroidism. Other late effects ation. A rising CEA level during the surveillance period after of irradiation in Hodgkin lymphoma survivors can include an surgical resection indicates recurrent disease and the need for increased risk of breast cancer in women who receive thoracic diagnostic imaging. Additional staging evaluation includes a irradiation, particularly in adolescence and early adulthood. full colonoscopy (if possible) and contrast-enhanced CT of There is also an increased risk of sarcoma and lung cancers. the abdomen and pelvis. In addition to imaging the abdomen

Item 54 Answer: A Item 53 Answer: D Educational Objective: Evaluate a patient with newly Educational Objective: Diagnose radiation-induced diagnosed colon cancer for metastatic disease. hypothyroidism. A contrast-enhanced CT (Option A) is the most accurate and The most appropriate test to perform next is measurement of useful imaging modality for staging of patients with a new thyroid-stimulating hormone (TSH) (Option D). This patient diagnosis of colon cancer. Staging with the TNM cancer stag- is at risk for radiation-induced hypothyroidism. Risk factors ing system is the first step in treatment planning. Preoperative for radiation-induced hypothyroidism include higher doses clinical staging begins with a history to identify localizing and treatment at a younger age. Rates of hypothyroidism may symptoms that may represent metastatic disease and physical approach 50%. Patients who have received radiation therapy to examination to detect ascites, hepatomegaly, and lymphade- the thyroid may develop subclinical or clinical hypothyroidism nopathy. Laboratory evaluation includes serum carcinoem- many years or decades later. These patients are also at increased bryonic antigen (CEA) in addition to routine chemical and risk for thyroid cancer compared with the general population, metabolic studies. An elevated CEA level indicates a worse although the overall risk remains low. Annual measurement prognosis for patients at any stage of colon cancer compared to of TSH is recommended in patients who received radiation patients with normal levels. In addition, failure of an elevated therapy to the neck or mediastinum. An elevated TSH con- CEA level to normalize after resection suggests the continued centration should be followed by measurement of thyroxine presence of metastatic disease and need for additional evalu- to confirm the diagnosis of hypothyroidism. Other late effects ation. A rising CEA level during the surveillance period after of irradiation in Hodgkin lymphoma survivors can include an surgical resection indicates recurrent disease and the need for increased risk of breast cancer in women who receive thoracic diagnostic imaging. Additional staging evaluation includes a irradiation, particularly in adolescence and early adulthood. full colonoscopy (if possible) and contrast-enhanced CT of There is also an increased risk of sarcoma and lung cancers. the abdomen and pelvis. In addition to imaging the abdomen 93

vé MOU SIIIUBI [PJDIIO[OI DI} LISLJOUW [[e ‘ALOJOIDUL, “SJUISe asay} UO paseq SI IUALINIaI OJ YOO] 0} SUISeUIT “ayeY *saurODjyno Aq paterajao0e aq UaAa AeU sIOWN) payeInU-syy au} Jo aAOICUT 0} UMOYS Usaq JOU sey SUNSa} Fons *payeorpur jou are YIMoIs ay} oul UL pue ‘qeumumyued pue qeutxnjed sal sasodind sour][IaAis Ioj saipnys Suse Jayyny “Waunear -poqnjue [euopouOoU! ay} 0} puodsai jou op auas 4Wyg JO Jo UoHes[duios Jaye aseasip aatjoe ou BULATQUap! Apis Bur 4VUN ‘SVAN 9) Ul suoryenNU SULIOGIey s1dd.Ud UO]OD “130 Sell] Ue SULMOTIO,] ‘s1aouRd AreutLid puodas Jo yUuIdojaaap -UBD [PIDIIO[OD II] 10 ‘T] ‘] AdeIS JO JUDWIASeUPLL IO sUOTSTDap pUe sd.UdLINIaI [edO] YO JOJ 3OeI} aaTJsasrpoise Jaddn ay}

MOU SIIIUBI [PJDIIO[OI DI} LISLJOUW [[e ‘ALOJOIDUL, “SJUISe asay} UO paseq SI IUALINIaI OJ YOO] 0} SUISeUIT “ayeY *saurODjyno Aq paterajao0e aq UaAa AeU sIOWN) payeInU-syy au} Jo aAOICUT 0} UMOYS Usaq JOU sey SUNSa} Fons *payeorpur jou are YIMoIs ay} oul UL pue ‘qeumumyued pue qeutxnjed sal sasodind sour][IaAis Ioj saipnys Suse Jayyny “Waunear -poqnjue [euopouOoU! ay} 0} puodsai jou op auas 4Wyg JO Jo UoHes[duios Jaye aseasip aatjoe ou BULATQUap! Apis Bur 4VUN ‘SVAN 9) Ul suoryenNU SULIOGIey s1dd.Ud UO]OD “130 Sell] Ue SULMOTIO,] ‘s1aouRd AreutLid puodas Jo yUuIdojaaap -UBD [PIDIIO[OD II] 10 ‘T] ‘] AdeIS JO JUDWIASeUPLL IO sUOTSTDap pUe sd.UdLINIaI [edO] YO JOJ 3OeI} aaTJsasrpoise Jaddn ay} JUSI}LIT] IY} UI S[OI OU SAB INQ IDURD [eJDIIOTOD JT}e}S ayenyead 0} AdoososuATe] ddYJO-Ul sapnpour UoTeUTUTeXd Teor -ejoul YUM sjuered ur Suruueld juoureer Joy yueyodut -skyq ‘edUaLINdaI Jo aayjsassns suro}durds 10] JUatussasse pur a18 (9 ‘VW suond() snjejs [euOHeINU SyYY pure AVA UONCUTUTeXe [eoISAY JO S}SISUOD ddURT[I9AINS pIepUe]S “payed “SWOIPUAS YUL] JO} SUTUIIDUOD st ArOISTY ATIUTRT -IPUT MOU SI IUSLINIAI OJ IDUL|[JAAING “UOISSTUaI a}a;duu09 Sjuatjed sty] Os ‘aULJayN puke [B}DIIO[OD are aUOIPUAS YOUAT Padalyoe pue JSUT] eal} Sty} pojaqduiod ays ‘papuswiutosar UL SI99URD UOUWIUIOD JSOU dU], ‘2OURTIIAIMS pu BSUTUIdINS SPM UONPIpe pue AdeIayJOWyo paulquiod YIM JWsUT Ajfurey Joy suoyyeoyduy Jueyodur sey ose Uoreoyuep! os year] ‘Tooued Jo ad] Sty} UT UOWOD SI sy ‘JoouRd xuATeyd pue ‘UeUTUOp [euOsoOyNe st swOIpUAS YUL] ‘sofouBUsTTeUr -odéy paourape AT[ed0] YM pasouserp sem ays ‘(vy uoNdo) JdY}]O PUL SISOULD [eJDSIO[OD [PUOT}IPpe IO} SOULITIAAINS aAIs Ieak | Ul JSaypD ay} JO JD asop-Moy & aavy prnoys Jared sty], -Ua}x9 aI0U aImMbel sworpUAS YOUAT YIM s}Uaeg ‘auIOIp ‘JIDULD Yau PUL PeRdT] YIM PIasouseIp Joyous JauI0y -UAS YOUAT SB UMOUY SI SIM ‘AouaTOYap Iyedar yor ewstuw B UI Ja0Ued SUN] 10J U9919g 2:9ANDefqoO JeuoNeonpy SUT[ULIAS B aAvY [IM dAy UT duo AjayeuUTxoidde ‘Aouatayap ulojoid ITedor YDJeUISILU YIM %ST dsatf} JO Taoued [eJDa1OTOO y wemsuy gg way

JUSI}LIT] IY} UI S[OI OU SAB INQ IDURD [eJDIIOTOD JT}e}S ayenyead 0} AdoososuATe] ddYJO-Ul sapnpour UoTeUTUTeXd Teor -ejoul YUM sjuered ur Suruueld juoureer Joy yueyodut -skyq ‘edUaLINdaI Jo aayjsassns suro}durds 10] JUatussasse pur a18 (9 ‘VW suond() snjejs [euOHeINU SyYY pure AVA UONCUTUTeXe [eoISAY JO S}SISUOD ddURT[I9AINS pIepUe]S “payed “SWOIPUAS YUL] JO} SUTUIIDUOD st ArOISTY ATIUTRT -IPUT MOU SI IUSLINIAI OJ IDUL|[JAAING “UOISSTUaI a}a;duu09 Sjuatjed sty] Os ‘aULJayN puke [B}DIIO[OD are aUOIPUAS YOUAT Padalyoe pue JSUT] eal} Sty} pojaqduiod ays ‘papuswiutosar UL SI99URD UOUWIUIOD JSOU dU], ‘2OURTIIAIMS pu BSUTUIdINS SPM UONPIpe pue AdeIayJOWyo paulquiod YIM JWsUT Ajfurey Joy suoyyeoyduy Jueyodur sey ose Uoreoyuep! os year] ‘Tooued Jo ad] Sty} UT UOWOD SI sy ‘JoouRd xuATeyd pue ‘UeUTUOp [euOsoOyNe st swOIpUAS YUL] ‘sofouBUsTTeUr -odéy paourape AT[ed0] YM pasouserp sem ays ‘(vy uoNdo) JdY}]O PUL SISOULD [eJDSIO[OD [PUOT}IPpe IO} SOULITIAAINS aAIs Ieak | Ul JSaypD ay} JO JD asop-Moy & aavy prnoys Jared sty], -Ua}x9 aI0U aImMbel sworpUAS YOUAT YIM s}Uaeg ‘auIOIp ‘JIDULD Yau PUL PeRdT] YIM PIasouseIp Joyous JauI0y -UAS YOUAT SB UMOUY SI SIM ‘AouaTOYap Iyedar yor ewstuw B UI Ja0Ued SUN] 10J U9919g 2:9ANDefqoO JeuoNeonpy SUT[ULIAS B aAvY [IM dAy UT duo AjayeuUTxoidde ‘Aouatayap ulojoid ITedor YDJeUISILU YIM %ST dsatf} JO Taoued [eJDa1OTOO y wemsuy gg way YUM sjuared Jo %ST Afayeurxoidde ut pajyoadxa aq prnom sufajoid iedai yoyeus{ut Jo uoIssaidxa Jo ssoy ‘(q uond¢) 120081 WddUl/ 009° OT-IOp 0 [SSOzE96z *CINd] snjyejs UOlssoidxe ulajoid Iedai yoyeurstu Jo uonenyeaa “69-686: (F)9T8T0T MIAN JUeD IdWIOD PRN [ *S107%'Z UOIs1a, “JaoueD UO}OD armbar 1dduUed WOOD Jo slsouseIp Mau ke YIM sjuared [TV ‘S]YSISU] SOUTTEPIND NOON ‘Te 32 ‘WI Aremey-[y dV Yooua, ‘qy uosuag Aydeasorqig ‘SUIOIPUAS YDUAT IOJ UddI19g :9AIDE[qo jeuOIe Npy

YUM sjuared Jo %ST Afayeurxoidde ut pajyoadxa aq prnom sufajoid iedai yoyeus{ut Jo uoIssaidxa Jo ssoy ‘(q uond¢) 120081 WddUl/ 009° OT-IOp 0 [SSOzE96z *CINd] snjyejs UOlssoidxe ulajoid Iedai yoyeurstu Jo uonenyeaa “69-686: (F)9T8T0T MIAN JUeD IdWIOD PRN [ *S107%'Z UOIs1a, “JaoueD UO}OD armbar 1dduUed WOOD Jo slsouseIp Mau ke YIM sjuared [TV ‘S]YSISU] SOUTTEPIND NOON ‘Te 32 ‘WI Aremey-[y dV Yooua, ‘qy uosuag Aydeasorqig ‘SUIOIPUAS YDUAT IOJ UddI19g :9AIDE[qo jeuOIe Npy aq wemsuy 9g wa} ‘I9dUed UOTOD YIM sjuatyed UT sdUeT[TaAINs dATeIOdO}sod Ioj IO BUIseIS SILSTLTEIIN[AN/9SOT OL:10p [9ISE68TE aATeJodooid 1d}19 IOJ pPAPUdSIUUIODAI JOU SI [D/LAd e :CINd] °CZ-09'78€'070z ‘PAN [ [SUy N JaouRd Yoou puke pray “WOT Moyo ‘stajad pure ‘uawopqe Aydersorqig ‘JsaYo 9Y} JO [D psoueyUs-jsesjUod pur [arg] UasHUe OUOATQUIBOUIDIES UINIas JO JUSTIAIMsvaU SapNnyoUt ‘TOOULI BUN] 1OJ pAUddI1Ds dq POTS ‘sIaYOUIS JOULIOJ IO I9dULD UOTOD pasouseIp A[MAU JO UOT eNTeAdD BUISLIS JUaLIno Alfe}oadsa “Ta0ued You pue PRay[ YIM SJUSNeg e ‘po}BdIpUI JOU are sasod Ind SsduUe][aAINS IOF SaTpNys SULZeUUT IoyANy “Ia.ued ‘oreo

OUOATQUIBOUIDIES UINIas JO JUSTIAIMsvaU SapNnyoUt ‘TOOULI BUN] 1OJ pAUddI1Ds dq POTS ‘sIaYOUIS JOULIOJ IO I9dULD UOTOD pasouseIp A[MAU JO UOT eNTeAdD BUISLIS JUaLIno Alfe}oadsa “Ta0ued You pue PRay[ YIM SJUSNeg e ‘po}BdIpUI JOU are sasod Ind SsduUe][aAINS IOF SaTpNys SULZeUUT IoyANy “Ia.ued ‘oreo yoou pue peal] 1OJ JUOUIZBAI} JO UOTaTdutod Jaye asea quatjed jeurjdoqns ut qnsar Avur (q uordQ) Ara81ns a1ojaq wn oy -SIP dATJOB OU SUIAJHUAp! Apnjs SUISeUTT Ue SUTMOTIO] e SUISE]S OSIOJ OF, AJOsINs 0} IoLId pauuryd st Surse}s ‘suoye 3 “IMIS JUSSISUISUOU UI ‘alojaroyy, Advsay} yURAN[pe IO} pasu = Sd ead

yoou pue peal] 1OJ JUOUIZBAI} JO UOTaTdutod Jaye asea quatjed jeurjdoqns ut qnsar Avur (q uordQ) Ara81ns a1ojaq wn oy -SIP dATJOB OU SUIAJHUAp! Apnjs SUISeUTT Ue SUTMOTIO] e SUISE]S OSIOJ OF, AJOsINs 0} IoLId pauuryd st Surse}s ‘suoye 3 “IMIS JUSSISUISUOU UI ‘alojaroyy, Advsay} yURAN[pe IO} pasu = Sd ead om oY} SUIPNyUT ‘dared aayeiado}jsod pure Ssuruueyd sateradoaid — cS ‘(q UoNndQC) SuIseul [euUOTIppe OU Ue] JauyeI “YST 0} [eUassa SI UOTOasaI [RIISINS ATTUYap dalojaq Surse}S <7 PasvaIOUT Jv STENPIAIPUI UT pa}uatua[duil aq pynoys JaouRD ‘LD paoueyus S c SUN] IO} SUTUIAINS “UOBOYIPOW a|AjsajI] 0} UONIppe Uy ‘ams -jseU0d & UO SUIPUY Teooarnba ue BuTeENTeAs IO} [nJasn 2 -odxe [oYyoo[e pue SUNOUIs 0} pa}efar Iaoued Arewtid puosas oq ABU [D/LAd ‘S8oUR}SUT tos UT “BuTSeIS dAT]eIOdoaI1d $

om oY} SUIPNyUT ‘dared aayeiado}jsod pure Ssuruueyd sateradoaid — cS ‘(q UoNndQC) SuIseul [euUOTIppe OU Ue] JauyeI “YST 0} [eUassa SI UOTOasaI [RIISINS ATTUYap dalojaq Surse}S <7 PasvaIOUT Jv STENPIAIPUI UT pa}uatua[duil aq pynoys JaouRD ‘LD paoueyus S c SUN] IO} SUTUIAINS “UOBOYIPOW a|AjsajI] 0} UONIppe Uy ‘ams -jseU0d & UO SUIPUY Teooarnba ue BuTeENTeAs IO} [nJasn 2 -odxe [oYyoo[e pue SUNOUIs 0} pa}efar Iaoued Arewtid puosas oq ABU [D/LAd ‘S8oUR}SUT tos UT “BuTSeIS dAT]eIOdoaI1d $ v dojaAap SIOAIAINS Ja.uBd YOU pu pray Jo %0z 0} dn Jo Aoemdoe ay] UO adcidull 0} UMOYs Udaq JOU aAvYy pue = “QdUdTIMNIAI JO sATsassns ayel sATJLBOU-as|e] PUL dAT}ISOd-asyey payerooidde uayyo ueyy < sulo}duiAs 10 suBIS YIM s}uaned Joy paArasal st SuUISeUIT Joysry & savy ASU], ‘ddULT[AAIMs dAtetadojsod oj Io Sulse}s poourApy *(q{ UONdOC) YOou au} JO [YW AOJ an.1] st sures dU], aAnetadoaid Jay} Io} (OQ uondO) LDd/Lad Apoq-ajoym jo “Sat09INO dAoIdut JOU saop HI asnedaq sasodind asoueyIaAIns asn JSUTESE PUSUTWODaI ATTBYIOads sauljapmMms TeuoneN Joy yuored sty} Ul payeopul jou st (9 UoNdO) LO/LAd ‘Adodsouojoo ‘siseq [enuue Ue UO JD asOp-MO] B YJIM BUTUV—aINS patayjo aq piepue}s B WOT ased STU] UI pauleiqo Usaq Apearye sey yey

v dojaAap SIOAIAINS Ja.uBd YOU pu pray Jo %0z 0} dn Jo Aoemdoe ay] UO adcidull 0} UMOYs Udaq JOU aAvYy pue = “QdUdTIMNIAI JO sATsassns ayel sATJLBOU-as|e] PUL dAT}ISOd-asyey payerooidde uayyo ueyy < sulo}duiAs 10 suBIS YIM s}uaned Joy paArasal st SuUISeUIT Joysry & savy ASU], ‘ddULT[AAIMs dAtetadojsod oj Io Sulse}s poourApy *(q{ UONdOC) YOou au} JO [YW AOJ an.1] st sures dU], aAnetadoaid Jay} Io} (OQ uondO) LDd/Lad Apoq-ajoym jo “Sat09INO dAoIdut JOU saop HI asnedaq sasodind asoueyIaAIns asn JSUTESE PUSUTWODaI ATTBYIOads sauljapmMms TeuoneN Joy yuored sty} Ul payeopul jou st (9 UoNdO) LO/LAd ‘Adodsouojoo ‘siseq [enuue Ue UO JD asOp-MO] B YJIM BUTUV—aINS patayjo aq piepue}s B WOT ased STU] UI pauleiqo Usaq Apearye sey yey Plnoys Suyusaids 199d BUN] IO} CLI9}LI9 Jat oYM sjuaryed UONPULIOJUL oY} 0} ppk Jou pnom jnq Ja0Ued pajoadsns IO IV Atolsty SUD[OUs Ieak-yoed-0Z k JsvaT Je aABY OM puR O8e UMOUY JNOYHM suosiod Yst-sselaae JO SUTUdINS Ioy Adoo sieaXk ST UPY] Ssoz JINb saey IO SIdYOUIS JUILIND are OYM sIeak ~SOUOTOD 0} dAT]VUIATe Ue ST (q UONdC) AYdersoUOjOD ID 08 0} OS pase syuated ut on AqfeIoadsa st sty, JaouRo Bunt ‘IOMIJON Jeoue) [129 [[BUIS—UOU ATqe}OU JSOW ‘S19DULd PUODAS OJ JST 7 are 199 dATSUDYaICUIOD [eUOTJeBN 94} Aq pasiopus st yYovoidde Sursejs -UBD YoU PUL PkRal{ TIM pasouselp syuatjed “aAIMOP *SUIO} SIU], “OUL][I9AINS IO} sUTTeseq & YSI[Ge}sd 0} puke sase}se}aUI -durAs pur susis Aq payoaiIp se ddulaLIndel Jo uoTordsns [eoruryo Areuowynd jno a[nz 0} paseut aq prnoys ysayp arp ‘statad pue : senbau5 pue ssamsuy

Answers and Critiques require tumor genotyping for KRAS, BRAF and NRAS muta- ular stage of disease but is far less significant prognostically tions, and only tumors lacking all three of these mutations than the staging itself. It is important to differentiate patients are appropriate for treatment with cetuximab or panitu- with a poor performance status who are debilitated due to mumab. chronic comorbidities from patients who would otherwise Epidermal growth factor receptor (EGFR) mutational be medically fit but are acutely debilitated by their cancer. status (Option B) is important for the management of The latter situation may warrant an attempt at aggressive patients with metastatic non-small cell lung cancer but is not treatment because reversing the cancer process is the only relevant in the management of colorectal cancer. For patients option that will improve the patient’s overall condition, with non-small cell lung cancer who have non-squamous whereas the former may need to be treated with less aggres- histology (particularly adenocarcinoma), testing for molec- sive treatment or possibly no specific anticancer treatment. ular alterations is mandatory. At present, it is considered Tumor size (Option D) may be a component of the “T” standard care to test non-small cell lung cancers for muta- stage, but by itself, it has only modest prognostic significance tions in the EGFR gene and for translocations involving ALK relative to overall stage. ) a or ROS1. If an EGFR mutation is identified, initial treatment 3

require tumor genotyping for KRAS, BRAF and NRAS muta- ular stage of disease but is far less significant prognostically tions, and only tumors lacking all three of these mutations than the staging itself. It is important to differentiate patients are appropriate for treatment with cetuximab or panitu- with a poor performance status who are debilitated due to mumab. chronic comorbidities from patients who would otherwise Epidermal growth factor receptor (EGFR) mutational be medically fit but are acutely debilitated by their cancer. status (Option B) is important for the management of The latter situation may warrant an attempt at aggressive patients with metastatic non-small cell lung cancer but is not treatment because reversing the cancer process is the only relevant in the management of colorectal cancer. For patients option that will improve the patient’s overall condition, with non-small cell lung cancer who have non-squamous whereas the former may need to be treated with less aggres- histology (particularly adenocarcinoma), testing for molec- sive treatment or possibly no specific anticancer treatment. ular alterations is mandatory. At present, it is considered Tumor size (Option D) may be a component of the “T” standard care to test non-small cell lung cancers for muta- stage, but by itself, it has only modest prognostic significance tions in the EGFR gene and for translocations involving ALK relative to overall stage. ) a or ROS1. If an EGFR mutation is identified, initial treatment 3 with erlotinib or osimertinib is recommended. If an ALK = or ROSi translocation is identified, initial treatment with e Staging is generally the most accurate prognostic indi- ‘Ss cs) alectinib is recommended. These agents are small-molecule cator and largely dictates the therapeutic strategy for <c patients with cancer. s tyrosine kinase inhibitors that are specific for those genetic c alterations. n Feme o Bibliography = Daly MC, Paquette IM. Surveillance, epidemiology, and end results (SEER) wn S e All patients with a new diagnosis of colon cancer and SEER-medicare databases: use in clinical research for improving < colorectal cancer outcomes. Clin Colon Rectal Surg. 2019;32:61-68. require evaluation of mismatch repair protein expres- [PMID: 30647547] doi:10.1055/s-0038-1673355 sion status.

with erlotinib or osimertinib is recommended. If an ALK = or ROSi translocation is identified, initial treatment with e Staging is generally the most accurate prognostic indi- ‘Ss cs) alectinib is recommended. These agents are small-molecule cator and largely dictates the therapeutic strategy for <c patients with cancer. s tyrosine kinase inhibitors that are specific for those genetic c alterations. n Feme o Bibliography = Daly MC, Paquette IM. Surveillance, epidemiology, and end results (SEER) wn S e All patients with a new diagnosis of colon cancer and SEER-medicare databases: use in clinical research for improving < colorectal cancer outcomes. Clin Colon Rectal Surg. 2019;32:61-68. require evaluation of mismatch repair protein expres- [PMID: 30647547] doi:10.1055/s-0038-1673355 sion status. Item 58 Answer: D Bibliography Kang YJ, Killen J, Caruana M, et al. The predicted impact and cost-effective- Educational Objective: Treat stage I rectal cancer. ness of systematic testing of people with incident colorectal cancer for Lynch syndrome. Med J Aust. 2020;212:72-81. [PMID: 31595523] doi:10. The most appropriate treatment is surgery (Option D). Based 5694/mja2.50356 on the results of clinical staging, this patient has a T2NO, stage I cancer of the upper third of the rectum. If pathol-

Item 58 Answer: D Bibliography Kang YJ, Killen J, Caruana M, et al. The predicted impact and cost-effective- Educational Objective: Treat stage I rectal cancer. ness of systematic testing of people with incident colorectal cancer for Lynch syndrome. Med J Aust. 2020;212:72-81. [PMID: 31595523] doi:10. The most appropriate treatment is surgery (Option D). Based 5694/mja2.50356 on the results of clinical staging, this patient has a T2NO, stage I cancer of the upper third of the rectum. If pathol- Item 57 Answer: E ogy following surgery confirms these preoperative findings, then no further therapy would be warranted. Therefore, for Educational Objective: Evaluate cancer prognosis. stage I rectal cancer, surgery alone is the preferred initial Tumor stage (Option E) is usually the most important prog- management. With the tumor located 10 cm from the anal nostic factor in determining a patient’s outcome. All tumors verge, the surgical procedure of choice would be a low ante- are staged using the American Joint Commission on Cancer rior resection, performed with the total mesorectal excision staging system. This involves the TNM system, in which the technique, with either a direct anastomosis, or, more likely, extent of the tumor (size and/or depth of penetration), nodes a temporary diverting ileostomy, which would be reversed (number of local-regional nodes that contain cancer), and after 2 to 3 months. Such a resection would be anticipated to metastases (present or absent) are considered. TNM scorings be sphincter-sparing, and so the patient should not require are placed on a scale of stage I though IV, with stage I having a permanent colostomy. After therapy, patients with rec- the best prognosis and stage IV the worst. tal cancer should be evaluated at approximately 6-month Poorly differentiated tumors (Option A) have, in gen- intervals for up to 5 years with a history, physical examina- eral, a worse prognosis than well-differentiated tumors; tion, and serum carcinoembryonic antigen level assessment. however, this too is a modest prognostic factor compared Contrast-enhanced CTs of the chest, abdomen, and pelvis are with staging. typically obtained annually for 5 years. Although molecular profiling for driver mutations in If postoperative findings upstage the tumor to stage II or genes such as KRAS, NRAS, and BRAF (Option B) may influ- III, then there may be a need to consider further interven- ence prognosis and may have implications for chemotherapy tions such as irradiation and/or chemotherapy (Options A, selections in advanced disease, they have far less influence B). Evidence is insufficient to define an optimal sequencing on outcome than tumor stage. In addition, they are not rel- of the three treatment modalities, although total neoadju- evant in the management of stage I colon cancer, which has vant therapy in which all planned chemotherapy and irradi- a very favorable prognosis and would not require further ation is given before surgery, is becoming a more widespread therapy after surgery. practice. Capecitabine, an oral prodrug that is converted Performance status (Option C), which is a designation into 5-fluorouracil (5-FU), or, less commonly, intravenous of the overall medical wellness, or lack thereof, of the patient 5-FU, is given concurrently with radiation therapy (Option may have important prognostic implications within a partic- C). However, data do not support a role for adding either

Item 57 Answer: E ogy following surgery confirms these preoperative findings, then no further therapy would be warranted. Therefore, for Educational Objective: Evaluate cancer prognosis. stage I rectal cancer, surgery alone is the preferred initial Tumor stage (Option E) is usually the most important prog- management. With the tumor located 10 cm from the anal nostic factor in determining a patient’s outcome. All tumors verge, the surgical procedure of choice would be a low ante- are staged using the American Joint Commission on Cancer rior resection, performed with the total mesorectal excision staging system. This involves the TNM system, in which the technique, with either a direct anastomosis, or, more likely, extent of the tumor (size and/or depth of penetration), nodes a temporary diverting ileostomy, which would be reversed (number of local-regional nodes that contain cancer), and after 2 to 3 months. Such a resection would be anticipated to metastases (present or absent) are considered. TNM scorings be sphincter-sparing, and so the patient should not require are placed on a scale of stage I though IV, with stage I having a permanent colostomy. After therapy, patients with rec- the best prognosis and stage IV the worst. tal cancer should be evaluated at approximately 6-month Poorly differentiated tumors (Option A) have, in gen- intervals for up to 5 years with a history, physical examina- eral, a worse prognosis than well-differentiated tumors; tion, and serum carcinoembryonic antigen level assessment. however, this too is a modest prognostic factor compared Contrast-enhanced CTs of the chest, abdomen, and pelvis are with staging. typically obtained annually for 5 years. Although molecular profiling for driver mutations in If postoperative findings upstage the tumor to stage II or genes such as KRAS, NRAS, and BRAF (Option B) may influ- III, then there may be a need to consider further interven- ence prognosis and may have implications for chemotherapy tions such as irradiation and/or chemotherapy (Options A, selections in advanced disease, they have far less influence B). Evidence is insufficient to define an optimal sequencing on outcome than tumor stage. In addition, they are not rel- of the three treatment modalities, although total neoadju- evant in the management of stage I colon cancer, which has vant therapy in which all planned chemotherapy and irradi- a very favorable prognosis and would not require further ation is given before surgery, is becoming a more widespread therapy after surgery. practice. Capecitabine, an oral prodrug that is converted Performance status (Option C), which is a designation into 5-fluorouracil (5-FU), or, less commonly, intravenous of the overall medical wellness, or lack thereof, of the patient 5-FU, is given concurrently with radiation therapy (Option may have important prognostic implications within a partic- C). However, data do not support a role for adding either 95

96 Joy SulUTeM xOq YouIq & sey puke (FLA) WsToquisoquio1yy AjayTUN ST Jey} AUCUBI[eU B JO SUTI9S dU} Ul atOIpUAS DAS SNOUSA JO ASH posvoOUl ATJURIYIUSIS B YIM payeloosse ST onewoydurds ATYSIY sey JUsed ay} Jt pasn aq Aeut Adeszayy UdfIXOWe], “-%OE Ajoyewurxoidde Aq Ja.uevd JsvaIq JO YS ay} uOoleIpey ‘osvasiIp SULALJapUN dy} JO JUsWAseUPU IO] parvo soonpel puke UsttOM [esnedousurjsod pue -aid yjoq UI 139 -IPUI ASIMIOU}O ST II JI PUB PaUIe}QO ST SISOUSeIp anssT} B Jaye -UBD ]SP9I JO UONUSASIGOWDYD JY} UI ALIAYa ST UIJIXOUIL], pauttojtod aq ATU prnoys (9 UoNd¢) Adesay) UoNeIpey ‘(qd ‘9 suondo) Ayfeyt0ul asnvd-][e Io dy1dads—19.ued }svaIq “SISOUSEBIP aNssi} SUIMOTIOJ donpal JOU Op jnq JIdUvd JsvdIq SUT}STXddId NOYIIM UdauUIOM UdWISaI JUSUT] LAI] [PIIUI oy JO Ved sev splootj10D0NnN {8 Wor UI I9DUBD JSBIIG DATSPAUT DONPal d[OZOI]SVUB PUL dUB}SIUIAXO JJouoq ABUL S}UaTJed SSdU], *“SPIODTAODOINIS 0} SATISuas ATOA SIOJIQIUUT dSsvjeWIOIe dY} PUR ‘dUdJIXO[RI ‘UdJTXOUIe], aq Ae YOTYM ‘seuLoydurAy datssaisse YIM syuatyed 10y ATIET ‘TL [ROTUI[D B JO apIsjno pasn aq jou prnoys nosed ‘s[souseip anssl] dq} aimdsqo ued splodtjA0D0NnN{s pure poysi[qe}sa Jou st asn st jnq ‘Aso}e.s UOTUaAatdowayo UUM JUSWRaTo1g “sWOIpPUAS DAS UIIM syuated 0} AfauTNOI IJIUBO ISB B SB PaIO[dxa Usaq sey (Y UONdO) uLIdsy Poeroa\sTuTUpe aq JOU p[noys (gq UodO) splootzos0on|[H *SJDAJJO ISIOAPS JO POOUTOY!] POSBaIOUI YIM Ia.Uv JsvaIq JO “MUOIPUAS DAS UT JWataAoI1dut SH poonpar oy} SUTYSIOM Ul satjIolId pue sanyea sueUIOM pure OUI} st} Jo aseyULIYs UrTe}GO 0} AderayJOUaYo prepueys YoRa UO pkaJSUI SUISNIO} s}sassns Inq YSLI pasevaioul Suruyep TIM pojyeed] aq Avi erxodAy sv yons sarjyeuiouqe USsIS [eyIA Joy yuTod Jyo-jnd prey Aue SUISN JSUTeSe SASIAPP ALSdSN OUL Jo swioduAs Jo Uaping Aaeay & YIM JWwWasaid OM aso} UdAT “IQOUB JS¥OIQ JO YSII 34} SUTeUUT]SA UT j10ddns UolsIdap aplA “euloyduIAT UN|SpoH-UoU aatssarsse IO Sun] dt} JO eUIOUTO -O1d ‘([OO}YSLIDQ/AOS‘I9DURIMMM) [OO] JWAdLUssassy ASI 189 [[9d [[eUIS sv YONs ‘solueUsT[eU aAT{IsUds-AderayoUTayo [PPO [feDH at} SULPNUI ‘s[oo} Jo AJALIVA Y “NYS Ul BUTOUTOIeD ATYSIY Savy IUOIPUAS DAS YIM syusHed AuByy “YSHI [eUTUTUT Te}onp IO Ja.uRvd JsvaIq JO SIsOUSeIP snotAaid Jo JWoeTINd & tam Asdorq [eosins Io} afqissaoov A[Isea st apou YdurAq eyn oABY OYM UswIOM 0} A[dde jOU sa0p UOTepUsUTWMODAT STU], -o1AvpPvidns JUS posie[Us oy} ‘Waned sty} Uy ‘aseasip SUTAT ‘(UIs Ul PUIOUTOIeO Jeno] pue ersefdiadAy Iepngqoy Jo ye}onp —IapUN JU} OJ JUS] AI} SSTULOIGUIOD ABU STU} ‘WUAaUaAOIdUUT [eordAye se yons) Asdorq uo suorsay Jseaiq UsTtIaq snorAaid oeUo}durAs pst ABUT SasseUl [eUTJSPIPSU Je payoarp sarde UM syusned Surpnyout “apjo pue sieak cE UdUIOM dTyeUIO} -JoY] [RdO| YSnouy ‘Aoueuseu SuLApIapun ayy Aq paprns aq -durAse 0} sayjdde uonepuswituodsal SIU, ‘s}dayJa UoNeotpout P[hoys suorpuds DAS YUM BuTUasaid syuaned Jo yusURAT], OSIDAPPC IOJ YS MOT JW PUL IIDULd }SPdIq IO] YSLI pasvarout ‘UOMUSATOUT ADUdSIOUId aIMbai Jou op sjaned ysopy ‘adoo JB Je OYM USWIOM O} ‘SIO}JIQIYUT dSeJeUIOI® IO ‘dUATIXO[PI -uAS Io ‘ssouiasieoy ‘eaudsAp ‘Ysnoo ‘ayoepeay aaey Abu ASU], ‘UdJIXOUIL] SB YONS ‘SUONBdIPSUI SUTONpPdal-ysit aquiosaid 01 “S[OSSIA [PJOJe[[OD SNOSUKIND papus)sip pur ‘e1oyjaqd ‘stsouesd JaYJO SULLTUTPD JY] SPUSUTWIODAI (4 LSdSN) 9010-] ASP], SPdA YIM Usljo ‘sue pue ‘yoou ‘pray ay} JO BUTapa YM JUasoid -Iag sAtUaAeTg “SQ SUL ‘(Gq UONdGC) ouR}sowexe sI JUaed AT[eo1dA] syuatyeg “SASS [BULSPIPSUL dBIL] YIM SafouUBUsTTeUL SI} LO} UOFUSASIGOWOY 19dUBd JsevaIq d}eLIdoidde Jsow sy, Aq posned are autorIpuds DAS JO Saseo JsOJ ‘JUaWAseUPUT JoyjAny spins 0} (y uoydo) Asdorq anssij & O81apuN prnoys “SISOquIO1Yy} snousA d3ap pue atwopuds (OAS) PAB BUDA JOLIadns sey Juared sty, SnorAaid YIM URWIOM YSII-YSIy & Ul JOVIQIyUT aseyeUIOIe UB YIM IIDULD Js¥aIq JUDAIIg :aaNvVelqo jeuolnesNnpy “SWIOIPUAS BABI BUDA

Joy SulUTeM xOq YouIq & sey puke (FLA) WsToquisoquio1yy AjayTUN ST Jey} AUCUBI[eU B JO SUTI9S dU} Ul atOIpUAS DAS SNOUSA JO ASH posvoOUl ATJURIYIUSIS B YIM payeloosse ST onewoydurds ATYSIY sey JUsed ay} Jt pasn aq Aeut Adeszayy UdfIXOWe], “-%OE Ajoyewurxoidde Aq Ja.uevd JsvaIq JO YS ay} uOoleIpey ‘osvasiIp SULALJapUN dy} JO JUsWAseUPU IO] parvo soonpel puke UsttOM [esnedousurjsod pue -aid yjoq UI 139 -IPUI ASIMIOU}O ST II JI PUB PaUIe}QO ST SISOUSeIp anssT} B Jaye -UBD ]SP9I JO UONUSASIGOWDYD JY} UI ALIAYa ST UIJIXOUIL], pauttojtod aq ATU prnoys (9 UoNd¢) Adesay) UoNeIpey ‘(qd ‘9 suondo) Ayfeyt0ul asnvd-][e Io dy1dads—19.ued }svaIq “SISOUSEBIP aNssi} SUIMOTIOJ donpal JOU Op jnq JIdUvd JsvdIq SUT}STXddId NOYIIM UdauUIOM UdWISaI JUSUT] LAI] [PIIUI oy JO Ved sev splootj10D0NnN {8 Wor UI I9DUBD JSBIIG DATSPAUT DONPal d[OZOI]SVUB PUL dUB}SIUIAXO JJouoq ABUL S}UaTJed SSdU], *“SPIODTAODOINIS 0} SATISuas ATOA SIOJIQIUUT dSsvjeWIOIe dY} PUR ‘dUdJIXO[RI ‘UdJTXOUIe], aq Ae YOTYM ‘seuLoydurAy datssaisse YIM syuatyed 10y ATIET ‘TL [ROTUI[D B JO apIsjno pasn aq jou prnoys nosed ‘s[souseip anssl] dq} aimdsqo ued splodtjA0D0NnN{s pure poysi[qe}sa Jou st asn st jnq ‘Aso}e.s UOTUaAatdowayo UUM JUSWRaTo1g “sWOIpPUAS DAS UIIM syuated 0} AfauTNOI IJIUBO ISB B SB PaIO[dxa Usaq sey (Y UONdO) uLIdsy Poeroa\sTuTUpe aq JOU p[noys (gq UodO) splootzos0on|[H *SJDAJJO ISIOAPS JO POOUTOY!] POSBaIOUI YIM Ia.Uv JsvaIq JO “MUOIPUAS DAS UT JWataAoI1dut SH poonpar oy} SUTYSIOM Ul satjIolId pue sanyea sueUIOM pure OUI} st} Jo aseyULIYs UrTe}GO 0} AderayJOUaYo prepueys YoRa UO pkaJSUI SUISNIO} s}sassns Inq YSLI pasevaioul Suruyep TIM pojyeed] aq Avi erxodAy sv yons sarjyeuiouqe USsIS [eyIA Joy yuTod Jyo-jnd prey Aue SUISN JSUTeSe SASIAPP ALSdSN OUL Jo swioduAs Jo Uaping Aaeay & YIM JWwWasaid OM aso} UdAT “IQOUB JS¥OIQ JO YSII 34} SUTeUUT]SA UT j10ddns UolsIdap aplA “euloyduIAT UN|SpoH-UoU aatssarsse IO Sun] dt} JO eUIOUTO -O1d ‘([OO}YSLIDQ/AOS‘I9DURIMMM) [OO] JWAdLUssassy ASI 189 [[9d [[eUIS sv YONs ‘solueUsT[eU aAT{IsUds-AderayoUTayo [PPO [feDH at} SULPNUI ‘s[oo} Jo AJALIVA Y “NYS Ul BUTOUTOIeD ATYSIY Savy IUOIPUAS DAS YIM syusHed AuByy “YSHI [eUTUTUT Te}onp IO Ja.uRvd JsvaIq JO SIsOUSeIP snotAaid Jo JWoeTINd & tam Asdorq [eosins Io} afqissaoov A[Isea st apou YdurAq eyn oABY OYM UswIOM 0} A[dde jOU sa0p UOTepUsUTWMODAT STU], -o1AvpPvidns JUS posie[Us oy} ‘Waned sty} Uy ‘aseasip SUTAT ‘(UIs Ul PUIOUTOIeO Jeno] pue ersefdiadAy Iepngqoy Jo ye}onp —IapUN JU} OJ JUS] AI} SSTULOIGUIOD ABU STU} ‘WUAaUaAOIdUUT [eordAye se yons) Asdorq uo suorsay Jseaiq UsTtIaq snorAaid oeUo}durAs pst ABUT SasseUl [eUTJSPIPSU Je payoarp sarde UM syusned Surpnyout “apjo pue sieak cE UdUIOM dTyeUIO} -JoY] [RdO| YSnouy ‘Aoueuseu SuLApIapun ayy Aq paprns aq -durAse 0} sayjdde uonepuswituodsal SIU, ‘s}dayJa UoNeotpout P[hoys suorpuds DAS YUM BuTUasaid syuaned Jo yusURAT], OSIDAPPC IOJ YS MOT JW PUL IIDULd }SPdIq IO] YSLI pasvarout ‘UOMUSATOUT ADUdSIOUId aIMbai Jou op sjaned ysopy ‘adoo JB Je OYM USWIOM O} ‘SIO}JIQIYUT dSeJeUIOI® IO ‘dUATIXO[PI -uAS Io ‘ssouiasieoy ‘eaudsAp ‘Ysnoo ‘ayoepeay aaey Abu ASU], ‘UdJIXOUIL] SB YONS ‘SUONBdIPSUI SUTONpPdal-ysit aquiosaid 01 “S[OSSIA [PJOJe[[OD SNOSUKIND papus)sip pur ‘e1oyjaqd ‘stsouesd JaYJO SULLTUTPD JY] SPUSUTWIODAI (4 LSdSN) 9010-] ASP], SPdA YIM Usljo ‘sue pue ‘yoou ‘pray ay} JO BUTapa YM JUasoid -Iag sAtUaAeTg “SQ SUL ‘(Gq UONdGC) ouR}sowexe sI JUaed AT[eo1dA] syuatyeg “SASS [BULSPIPSUL dBIL] YIM SafouUBUsTTeUL SI} LO} UOFUSASIGOWOY 19dUBd JsevaIq d}eLIdoidde Jsow sy, Aq posned are autorIpuds DAS JO Saseo JsOJ ‘JUaWAseUPUT JoyjAny spins 0} (y uoydo) Asdorq anssij & O81apuN prnoys “SISOquIO1Yy} snousA d3ap pue atwopuds (OAS) PAB BUDA JOLIadns sey Juared sty, SnorAaid YIM URWIOM YSII-YSIy & Ul JOVIQIyUT aseyeUIOIe UB YIM IIDULD Js¥aIq JUDAIIg :aaNvVelqo jeuolnesNnpy “SWIOIPUAS BABI BUDA q JoLadns yim Juaned & aseury] :eAi2efqo jeuonesnpy wemsuy 09 wz wn vy womsuy 6g Wa}| o SS

q JoLadns yim Juaned & aseury] :eAi2efqo jeuonesnpy wemsuy 09 wz wn vy womsuy 6g Wa}| o SS TLO"vO'S10G nay ‘oulaf/9TOL'OL-10p [prrZeo0E ‘CINd] “v8-Z2S:9€'8T0t “WIV N UND pew = SIOUIY ‘AWOIPUAS BARD LUDA JOLIadns ‘ary pldey “WW stAeq ‘Ss UPULIAUIWIZ EIZPT 'PO/TITT OF1Op [ZLOSOTTE rs) :CINd] ‘0S-OFIETZ610Z “SIC [R}DI10[0D “sauUTODNO WHd}-LOYsS Ul syUdUI s Aydessorqig -dAOICUT] payelOsse PUP SIOZ O} 600T WO AddDUBd [eJDaI Jo JUsWIAaseULUT = Azeurd}osipyNu sy} UI sasueyD ‘Te Ja ‘q UUAT g WIOqWONS ‘qso Y8inqxoy cs wn Aydersorqia ed ‘JUSUTASeUPU Jayynj aps pue Aoueusiyeur o

TLO"vO'S10G nay ‘oulaf/9TOL'OL-10p [prrZeo0E ‘CINd] “v8-Z2S:9€'8T0t “WIV N UND pew = SIOUIY ‘AWOIPUAS BARD LUDA JOLIadns ‘ary pldey “WW stAeq ‘Ss UPULIAUIWIZ EIZPT 'PO/TITT OF1Op [ZLOSOTTE rs) :CINd] ‘0S-OFIETZ610Z “SIC [R}DI10[0D “sauUTODNO WHd}-LOYsS Ul syUdUI s Aydessorqig -dAOICUT] payelOsse PUP SIOZ O} 600T WO AddDUBd [eJDaI Jo JUsWIAaseULUT = Azeurd}osipyNu sy} UI sasueyD ‘Te Ja ‘q UUAT g WIOqWONS ‘qso Y8inqxoy cs wn Aydersorqia ed ‘JUSUTASeUPU Jayynj aps pue Aoueusiyeur o SUTATIOPUN dU} SUTULIDJap 0} paule}qo aq prnoys = nn “SIBOA ¢ IO} S Asdoiq ansst} B ‘SUOIPUAS BARD BUDA IOLIodns IOJ e 4 PonuTJUOD st soURT[JoAINS ‘slAjad pue ‘UatuOpae “saya “‘UOTUSATO}UT ADUASIOW arInbar jou op sjuaryed sour 9} JO SLD paouvyus-jse.1juoo [enuue puke JUaUssasse pUe ‘sasseUL [CUTJSPIPSU SSIv] YIM SotoueUsTTeU Aq [PAQ] UsstuP dTUOATQUIBOUTOIeD UINJas pue ‘UOT pasned oie SWOIpUAS BABS BUDA IOLIadns Jo sased JSOJ e -BUTUIeXd [BoIsAYC ‘A1OJsIY & YIM S[CAIA}UT Y}UOUI-9 J PIJLNBAD Te IIDUBD [BDI Pdyet} YIM S}UITeq

SUTATIOPUN dU} SUTULIDJap 0} paule}qo aq prnoys = nn “SIBOA ¢ IO} S Asdoiq ansst} B ‘SUOIPUAS BARD BUDA IOLIodns IOJ e 4 PonuTJUOD st soURT[JoAINS ‘slAjad pue ‘UatuOpae “saya “‘UOTUSATO}UT ADUASIOW arInbar jou op sjuaryed sour 9} JO SLD paouvyus-jse.1juoo [enuue puke JUaUssasse pUe ‘sasseUL [CUTJSPIPSU SSIv] YIM SotoueUsTTeU Aq [PAQ] UsstuP dTUOATQUIBOUTOIeD UINJas pue ‘UOT pasned oie SWOIpUAS BABS BUDA IOLIadns Jo sased JSOJ e -BUTUIeXd [BoIsAYC ‘A1OJsIY & YIM S[CAIA}UT Y}UOUI-9 J PIJLNBAD Te IIDUBD [BDI Pdyet} YIM S}UITeq “YSLI oAT}eJodo ssay YM Asdoiq “UOT DaSAT [BOISINS YIM payear] ae ue | asejs are 0} s[qvuoWe st spou IepNdAepeidns syy Aoueusiyeur SurAT Sapou YAULAT TeUOISaI SATOAUT JOU Op pur [eM Jamogq du} -IapUN 9} 0} paro[{[e}] aq pnoys JUaw}va1} asnedaq JUaTed JO SSOUYTY} [[NJ oY 9]e1}9Ued JOU Op Jel} SIBOUBI [BIDIYe ST} Ul ayettdordde jou st aworpuAs DAS aaatfas 0} (q UoNdO) Ayyedousape [eUNseIpsul dy} Jo WoTjdaso1 [eorsims ‘Ad eIDU} ITUID}SAS JATIIAI 0} I ‘IQDUBO [DIT | ISIS paLLIYUOD AT[eoTsIns OU SI Usted oY} JI 10 ‘Ade1oy} STUIa}sAs 0} APyornb puodsai 0} JO JUstUAseUPU dt} 0} AdeJay} UOHeIpel 10 Adesayjouayo senbizi5D pue siomsuy

Answers and Critiques use among patients with a previous history of VTE. Ralox- disease progression, although actual tumor shrinkage is rare. ifene, effective in breast cancer chemoprevention for post- Somatostatin analogues are highly effective in controlling menopausal women, also increases the risk of VTE, although hormonal disease and should be given if hormone-related not to as great an extent. Both drugs should be avoided in symptoms are present. women with prior VTE if there are suitable alternatives. Peptide-receptor radiotherapy (Option C) is a treatment Exemestane is an option for chemoprevention of breast can- that is appropriate for patients with either a substantial dis- cer in postmenopausal women with a previous history of ease burden or clinically significant growth under observa- VTE. Exemestane is not associated with an increased risk tion but would not be warranted in an asymptomatic patient of VTE. with small-volume disease. Cytotoxic chemotherapy (Option E) is of limited utility in patients with well-differentiated neuroendocrine tumors. e Tamoxifen, raloxifene, and the aromatase inhibitors exemestane and anastrozole reduce invasive breast wn <7) cancer in women without preexisting breast cancer e Well-differentiated neuroendocrine tumors are indo- = but do not reduce breast cancer-specific or all-cause lent, frequently discovered incidentally, and often ini- = mortality. tially only require observation and serial imaging. = Ss) e Exemestane may be used as a preventive measure in e Somatostatin analogues are highly effective in control- cs J women who are at high risk of breast cancer with a ling hormonal manifestations of gastrointestinal Cs]

use among patients with a previous history of VTE. Ralox- disease progression, although actual tumor shrinkage is rare. ifene, effective in breast cancer chemoprevention for post- Somatostatin analogues are highly effective in controlling menopausal women, also increases the risk of VTE, although hormonal disease and should be given if hormone-related not to as great an extent. Both drugs should be avoided in symptoms are present. women with prior VTE if there are suitable alternatives. Peptide-receptor radiotherapy (Option C) is a treatment Exemestane is an option for chemoprevention of breast can- that is appropriate for patients with either a substantial dis- cer in postmenopausal women with a previous history of ease burden or clinically significant growth under observa- VTE. Exemestane is not associated with an increased risk tion but would not be warranted in an asymptomatic patient of VTE. with small-volume disease. Cytotoxic chemotherapy (Option E) is of limited utility in patients with well-differentiated neuroendocrine tumors. e Tamoxifen, raloxifene, and the aromatase inhibitors exemestane and anastrozole reduce invasive breast wn <7) cancer in women without preexisting breast cancer e Well-differentiated neuroendocrine tumors are indo- = but do not reduce breast cancer-specific or all-cause lent, frequently discovered incidentally, and often ini- = mortality. tially only require observation and serial imaging. = Ss) e Exemestane may be used as a preventive measure in e Somatostatin analogues are highly effective in control- cs J women who are at high risk of breast cancer with a ling hormonal manifestations of gastrointestinal Cs] previous history of venous thromboembolic disease. neuroendocrine tumors and should be given if hormone- 2 <8) related symptoms are present. 2 wn Bibliography ij zt Nelson HD, Fu R, Zakher B, et al. Medication use for the risk reduction of Bibliography primary breast cancer in women: updated evidence report and system- Raj N, Fazio N, Strosberg J. Biology and systemic treatment of advanced atic review for the US preventive services task force. JAMA. 2019;322:868- gastroenteropancreatic neuroendocrine tumors. Am Soc Clin Oncol 86. [PMID: 31479143] doi:10.1001/jama.2019.5780 Educ Book. 2018;38:292-99. [PMID: 30231344] doi:10.1200/EDBK_ 200893

previous history of venous thromboembolic disease. neuroendocrine tumors and should be given if hormone- 2 <8) related symptoms are present. 2 wn Bibliography ij zt Nelson HD, Fu R, Zakher B, et al. Medication use for the risk reduction of Bibliography primary breast cancer in women: updated evidence report and system- Raj N, Fazio N, Strosberg J. Biology and systemic treatment of advanced atic review for the US preventive services task force. JAMA. 2019;322:868- gastroenteropancreatic neuroendocrine tumors. Am Soc Clin Oncol 86. [PMID: 31479143] doi:10.1001/jama.2019.5780 Educ Book. 2018;38:292-99. [PMID: 30231344] doi:10.1200/EDBK_ 200893 Item 61 Answer: D Educational Objective: Treat well-differentiated Item 62 Answer: A

previous history of venous thromboembolic disease. neuroendocrine tumors and should be given if hormone- 2 <8) related symptoms are present. 2 wn Bibliography ij zt Nelson HD, Fu R, Zakher B, et al. Medication use for the risk reduction of Bibliography primary breast cancer in women: updated evidence report and system- Raj N, Fazio N, Strosberg J. Biology and systemic treatment of advanced atic review for the US preventive services task force. JAMA. 2019;322:868- gastroenteropancreatic neuroendocrine tumors. Am Soc Clin Oncol 86. [PMID: 31479143] doi:10.1001/jama.2019.5780 Educ Book. 2018;38:292-99. [PMID: 30231344] doi:10.1200/EDBK_ 200893 Item 61 Answer: D Educational Objective: Treat well-differentiated Item 62 Answer: A pancreatic neuroendocrine tumor. Educational Objective: Treat locally advanced rectal cancer. The most appropriate management is repeat imaging in 3 months (Option D). This patient has an incidental finding The most appropriate treatment for this patient is chemother- of a well-differentiated, low-grade, gastrointestinal neuro- apy followed by irradiation and then surgery (Option A). This endocrine tumor with multiple metastases to the liver. These patient has a tumor in the proximal third of the rectum. The tumors are often asymptomatic and indolent, and asymp- tumor is bulky and involves the full thickness through the tomatic patients may do well with minimal growth and no rectal wall, with bulky perirectal adenopathy. This is a stage symptoms for years without intervention. As such, there is no III rectal cancer, and optimal standard management would urgency to intervene, and it is beneficial to evaluate the pace involve the use of all three modalities: chemotherapy, radia- of the disease before making a decision regarding whether tion therapy, and surgery. Clinical trials have shown that use of to treat. Follow-up examination and imaging at approxi- irradiation after surgery has greater toxicity and a higher risk mately a 3-month interval is appropriate in asymptomatic of tumor recurrence in the irradiated field than when irradi- patients with relatively modest-volume, asymptomatic dis- ation is given before surgery. Whereas a more traditional and ease. Approximately one third to one half of metastatic gas- still acceptable approach would be to use irradiation followed trointestinal neuroendocrine tumors will elaborate serotonin, by surgery and then plan to give chemotherapy afterward, a hormone that causes “carcinoid syndrome” with diarrhea current practice is shifting toward the concept of total neoad- and/or facial flushing; however, most patients have a hormo- juvant therapy, in which both irradiation and chemotherapy nally nonfunctional tumor and so will not require treatment are completed before surgery. Clinical trials have established for these symptoms. In patients who have stable disease at the that 5-fluorouracil given by protracted intravenous infusion 3-month scan, further monitoring with serial imaging at 3- to or capecitabine is an equally acceptable chemotherapeutic 6-month intervals is appropriate. option to be given concurrently with radiation therapy. Care- Hepatic arterial embolization (Option A) is a procedure ful observation without surgery is becoming more widely that may be helpful in shrinking liver metastases or reducing accepted as a possible alternative strategy in patients who hormonal output from functional tumors. It may be appro- have a complete clinical response by examination and MRI priate in a patient with progressive, bulky, or symptomatic after chemotherapy and irradiation. disease. Patients with rectal tumors that are not full thickness For moderate progression, a somatostatin ana- and do not have lymph node involvement (stage I) on pre- logue (Option B) can be used. This treatment often slows treatment imaging usually undergo surgery (Option B); a

pancreatic neuroendocrine tumor. Educational Objective: Treat locally advanced rectal cancer. The most appropriate management is repeat imaging in 3 months (Option D). This patient has an incidental finding The most appropriate treatment for this patient is chemother- of a well-differentiated, low-grade, gastrointestinal neuro- apy followed by irradiation and then surgery (Option A). This endocrine tumor with multiple metastases to the liver. These patient has a tumor in the proximal third of the rectum. The tumors are often asymptomatic and indolent, and asymp- tumor is bulky and involves the full thickness through the tomatic patients may do well with minimal growth and no rectal wall, with bulky perirectal adenopathy. This is a stage symptoms for years without intervention. As such, there is no III rectal cancer, and optimal standard management would urgency to intervene, and it is beneficial to evaluate the pace involve the use of all three modalities: chemotherapy, radia- of the disease before making a decision regarding whether tion therapy, and surgery. Clinical trials have shown that use of to treat. Follow-up examination and imaging at approxi- irradiation after surgery has greater toxicity and a higher risk mately a 3-month interval is appropriate in asymptomatic of tumor recurrence in the irradiated field than when irradi- patients with relatively modest-volume, asymptomatic dis- ation is given before surgery. Whereas a more traditional and ease. Approximately one third to one half of metastatic gas- still acceptable approach would be to use irradiation followed trointestinal neuroendocrine tumors will elaborate serotonin, by surgery and then plan to give chemotherapy afterward, a hormone that causes “carcinoid syndrome” with diarrhea current practice is shifting toward the concept of total neoad- and/or facial flushing; however, most patients have a hormo- juvant therapy, in which both irradiation and chemotherapy nally nonfunctional tumor and so will not require treatment are completed before surgery. Clinical trials have established for these symptoms. In patients who have stable disease at the that 5-fluorouracil given by protracted intravenous infusion 3-month scan, further monitoring with serial imaging at 3- to or capecitabine is an equally acceptable chemotherapeutic 6-month intervals is appropriate. option to be given concurrently with radiation therapy. Care- Hepatic arterial embolization (Option A) is a procedure ful observation without surgery is becoming more widely that may be helpful in shrinking liver metastases or reducing accepted as a possible alternative strategy in patients who hormonal output from functional tumors. It may be appro- have a complete clinical response by examination and MRI priate in a patient with progressive, bulky, or symptomatic after chemotherapy and irradiation. disease. Patients with rectal tumors that are not full thickness For moderate progression, a somatostatin ana- and do not have lymph node involvement (stage I) on pre- logue (Option B) can be used. This treatment often slows treatment imaging usually undergo surgery (Option B); a 97

86 sainjeay OTydesSOUOs Savy ACU JEU] SSPUET [eUAI B [RaAAT ATOYIT sisaredeied JI asop Yysiy 10 ayeapoul & Joya 3e (yY UONdOC) TEM punosez(n [eurwuopge uy “YJ Jo ‘says aeISeJaU ‘IOWIN} SplOoM1OI0NNIS YM paleaty AT[PNIUL aie syuaTeg Areutlid ot} JO UoWdasar YIM aAordut Ud SUOTIPUOD asaty ‘sadA] IOUUN] JSOW 10} UONRIpe.L Aq pamoTfoy ‘uorssaid Jo Aueyy ‘sisoyAd01uj Ata pue ‘eoneuUmMays eIspeAurAjod ‘stsoyAo -WOdep [BOISINs ]UISIN puk SplOd}A0DONNIS asop-Ysry Jo asn -OQUIOIY} ‘sIsoprojAue WY ‘eruaoTeoradAy “1aAaq ‘(auOIpUAS JUas1oUId SorINbal asvasip d1vIseJSU WHOA] UOTSsatduIOD p4sod Jayjnv1s Se UWMOU) Sase}seJaUt JBAT] JO ddUaSe dU} Ul UOTOUNYy jeuids yypem 0} AqyIqe ay} Ulesa1 sjuated Aroyepnquieuou Jo -skp oneday ‘erwuaue SUIpNpUl ‘eUOUTOIeD [Jao TeUal YIM %OT UCU} SSo] ‘JOAOMOY :ATOJINGUIL ULES 08 ‘WWAaLyBaI} syjuatjed UT Udas 3q Ud satoIpUAS dyse[dosuered JworaTIp SUILIR]S USYM YPM 0} JIGe o1e OYM s}UIaned JO ‘dutI0Dyno Jo Aue ‘oworpuAs ayjse[dooueied v& se ons ‘ertuaxodAy Jo yuap JoJoIpaid juR}IOdtU! JSOU dy} SI SIsOUseIP Je snye}s IsO[OI -uadopul uljatodoryy Aja Jo uonjonpoid snourouoyne Aq pasned -nou sjuaned ayy, ‘syaam [elaAas Aq suto}durAs o18ofomnou aq osye APUL JJ “sIsouays Ala}Ie [eual pue ‘arnsodxa aprxouour sapadeid ATfensn pue sjuaned Jo %0Og UeU} d10LU UT JUasaid st uoqies dTUOIYD ‘apnyyye Ys ‘erxodAy drwajsks Surpnyput ‘ADUSQUUNIAI YIM ISIOM Udo ‘UTeg “UOIssaduiod pod asneo SUOTJIPUOD Jo AJOLIRA BO} ONp aq ABU SIso]ADOIYAIa ATepuooas 0} PUILURIO} [eINdU ay] YSsnorY] spua}xe yey] sseuu peuTdsesed ‘PPA, UNslodoryyATa payeasja ue puke sIso}AD0IyAIa JO aqua B QATOAUL 0} ATOYI] DOU are seULOYdUIAT ‘saseysejotU Apog -soid ayy} Aq pauyap siso}Ad01y Ata Atepuooas sey uated STU, [PIQOLIOA WIOIJ UOISUa}x9 [eInpids Aq pasnvo aie sasea UOIssaid ‘(q UoNdO) eWOUTSIED [[9d [RUDI SI sIsouseIp ATaYI] JSOUT SUT, -u109 pio [eulds [einpida Jo %,¢g Ajayeutxoiddy ‘euoydurAy pue BWO[PAU se [Jom se ‘JoouRd ayejsoid pue ‘Ysvaiq ‘Bunt *SISOJAD0INJ AIO Atepucooas YIM JuaTyed ale synpe Ul uoIsserdwod p1od [eulds feinpidd asned yey} 8 Ul JQOUB [[99 [BUDI asoUuseIG: :aAIDAeIGC jeUuoNneNnpy Ja0ued JO SadA} UOUTLUOD JSOUL dU], ‘UOHR[Nquie pue yISuats 3 «wemsuy 79 wey AVWo1}X9 Jamo] edu Ae pue Ja.ued oNeIseJOW YIM sjuaned Jo %¢°% Ul sInd90 UOIssaiduiod p1od yeulds “uoHey

sainjeay OTydesSOUOs Savy ACU JEU] SSPUET [eUAI B [RaAAT ATOYIT sisaredeied JI asop Yysiy 10 ayeapoul & Joya 3e (yY UONdOC) TEM punosez(n [eurwuopge uy “YJ Jo ‘says aeISeJaU ‘IOWIN} SplOoM1OI0NNIS YM paleaty AT[PNIUL aie syuaTeg Areutlid ot} JO UoWdasar YIM aAordut Ud SUOTIPUOD asaty ‘sadA] IOUUN] JSOW 10} UONRIpe.L Aq pamoTfoy ‘uorssaid Jo Aueyy ‘sisoyAd01uj Ata pue ‘eoneuUmMays eIspeAurAjod ‘stsoyAo -WOdep [BOISINs ]UISIN puk SplOd}A0DONNIS asop-Ysry Jo asn -OQUIOIY} ‘sIsoprojAue WY ‘eruaoTeoradAy “1aAaq ‘(auOIpUAS JUas1oUId SorINbal asvasip d1vIseJSU WHOA] UOTSsatduIOD p4sod Jayjnv1s Se UWMOU) Sase}seJaUt JBAT] JO ddUaSe dU} Ul UOTOUNYy jeuids yypem 0} AqyIqe ay} Ulesa1 sjuated Aroyepnquieuou Jo -skp oneday ‘erwuaue SUIpNpUl ‘eUOUTOIeD [Jao TeUal YIM %OT UCU} SSo] ‘JOAOMOY :ATOJINGUIL ULES 08 ‘WWAaLyBaI} syjuatjed UT Udas 3q Ud satoIpUAS dyse[dosuered JworaTIp SUILIR]S USYM YPM 0} JIGe o1e OYM s}UIaned JO ‘dutI0Dyno Jo Aue ‘oworpuAs ayjse[dooueied v& se ons ‘ertuaxodAy Jo yuap JoJoIpaid juR}IOdtU! JSOU dy} SI SIsOUseIP Je snye}s IsO[OI -uadopul uljatodoryy Aja Jo uonjonpoid snourouoyne Aq pasned -nou sjuaned ayy, ‘syaam [elaAas Aq suto}durAs o18ofomnou aq osye APUL JJ “sIsouays Ala}Ie [eual pue ‘arnsodxa aprxouour sapadeid ATfensn pue sjuaned Jo %0Og UeU} d10LU UT JUasaid st uoqies dTUOIYD ‘apnyyye Ys ‘erxodAy drwajsks Surpnyput ‘ADUSQUUNIAI YIM ISIOM Udo ‘UTeg “UOIssaduiod pod asneo SUOTJIPUOD Jo AJOLIRA BO} ONp aq ABU SIso]ADOIYAIa ATepuooas 0} PUILURIO} [eINdU ay] YSsnorY] spua}xe yey] sseuu peuTdsesed ‘PPA, UNslodoryyATa payeasja ue puke sIso}AD0IyAIa JO aqua B QATOAUL 0} ATOYI] DOU are seULOYdUIAT ‘saseysejotU Apog -soid ayy} Aq pauyap siso}Ad01y Ata Atepuooas sey uated STU, [PIQOLIOA WIOIJ UOISUa}x9 [eInpids Aq pasnvo aie sasea UOIssaid ‘(q UoNdO) eWOUTSIED [[9d [RUDI SI sIsouseIp ATaYI] JSOUT SUT, -u109 pio [eulds [einpida Jo %,¢g Ajayeutxoiddy ‘euoydurAy pue BWO[PAU se [Jom se ‘JoouRd ayejsoid pue ‘Ysvaiq ‘Bunt *SISOJAD0INJ AIO Atepucooas YIM JuaTyed ale synpe Ul uoIsserdwod p1od [eulds feinpidd asned yey} 8 Ul JQOUB [[99 [BUDI asoUuseIG: :aAIDAeIGC jeUuoNneNnpy Ja0ued JO SadA} UOUTLUOD JSOUL dU], ‘UOHR[Nquie pue yISuats 3 «wemsuy 79 wey AVWo1}X9 Jamo] edu Ae pue Ja.ued oNeIseJOW YIM sjuaned Jo %¢°% Ul sInd90 UOIssaiduiod p1od yeulds “uoHey “Nque JO pooy!fary]] Isoysty oy} YIM payeloosse st (q uondO) II¢l8Z 810c OOL UONVIPPLI] PUB *UOTDaSa [BoISINs ‘MUOSBYJOUUIeXAp YIM JUIUL /OOZTOL:10p [88PS6E0E *CINd] “IZ-19:ZE*610Z ‘JOIUO UND f£ MalAdi Azeuydrosipyynur e :uolssaidutoa pioa jeuids oyeysvjawt YM sjuaned jea1] pure ‘uolssaiduioo pioo yeulds [empida sey juaned siyy, jo JUoWAseURL PUR JUDLUSsassy ‘[B 39 “TV AT[FAeUD ‘VN 20T ‘fy UOMMeT

“Nque JO pooy!fary]] Isoysty oy} YIM payeloosse st (q uondO) II¢l8Z 810c OOL UONVIPPLI] PUB *UOTDaSa [BoISINs ‘MUOSBYJOUUIeXAp YIM JUIUL /OOZTOL:10p [88PS6E0E *CINd] “IZ-19:ZE*610Z ‘JOIUO UND f£ MalAdi Azeuydrosipyynur e :uolssaidutoa pioa jeuids oyeysvjawt YM sjuaned jea1] pure ‘uolssaiduioo pioo yeulds [empida sey juaned siyy, jo JUoWAseURL PUR JUDLUSsassy ‘[B 39 “TV AT[FAeUD ‘VN 20T ‘fy UOMMeT ‘T2dUI JT}¥}SEJOU 0} aNp UOIssaidui0d Aydersorqig pioo yeurds yim Juaned eb Jeary, :@ANDefqoO jeuoHeonpy ‘quoye Adeioy} UoTeIpel YIM Aussi q wemsuy €9 we} poalear aq Aew syuatjed ‘peajsut pue uorssaidwiosap [eorsms [erqur armbar jou Aetu ‘stow [[ao wes TZ00°810Z [ooucKUteL/ TOOT OT:10p [60199S6z :CIINd] pure ‘eurojacur ‘euroydury ‘erwuayney se yons ‘sadA} “TLOOSTIAF:810% JOOUD VINVE Taouvo [e}Da1 paoueape AT[ed0[ oJ AderdyI IOUIN} SAT}ISUASOIPeI WOT UOTSsaIdut0d prod jeutds e quean{peoou [e]0] JO UoNdopy ‘[R 12 ‘gq WIOqUIONS ‘GSO YBInqxoy ‘y Ya0189

‘quoye Adeioy} UoTeIpel YIM Aussi q wemsuy €9 we} poalear aq Aew syuatjed ‘peajsut pue uorssaidwiosap [eorsms [erqur armbar jou Aetu ‘stow [[ao wes TZ00°810Z [ooucKUteL/ TOOT OT:10p [60199S6z :CIINd] pure ‘eurojacur ‘euroydury ‘erwuayney se yons ‘sadA} “TLOOSTIAF:810% JOOUD VINVE Taouvo [e}Da1 paoueape AT[ed0[ oJ AderdyI IOUIN} SAT}ISUASOIPeI WOT UOTSsaIdut0d prod jeutds e quean{peoou [e]0] JO UoNdopy ‘[R 12 ‘gq WIOqUIONS ‘GSO YBInqxoy ‘y Ya0189 ‘sadA] IOUIN] SOUL OJ UOT}eIP Aydersorqia -eiIl Aq paMmoT[oJ ‘Uorssoiduiodap [ea1s1ns JussIn pue ‘ATAB.INS I1OJ9q USAIS ST UOTIVIPRLI UIYM UeY} SplOd1090NNIS asop-YsIY Jo asn JUdaBIoUla satmnbat POY PoyeIpeAI oY} UT 9dUSLINIAI JOUIN}] JO SLI JY SI ASBASIP IT}VISPISW WIOIJ UOTssaiduiod pod teulds e wn B pue A}IDIXO} JoyBaI8 JO asnvdIA|q SION] [eIDaI IOI 9Tq o =} -[SBaJ USYM Paploae ST UOHeIpelt Aq paMmoyjoy ATasing e = “uolssaiduloo ‘Alasins pue ‘Adeiatyjouayo ‘uonerpest ortnbar = So poo jeulds JueUsI[eW oyNoe YIM s}Uaed 1OJ papudstwwio0da1 AJSUTNOI ([]] 93eIS) sapou YdurAyT paaToautT YIM cs jou st (q UoHdQC) JUSWIe1] PIodT}.1090NN {8 Noy WM Ajasing = 9SOY]} 1O/PUP (]] AdB}S) SION} [e199 SSOUYOIYI-[[Ne cs ‘ssauyvam pue ‘ured ‘vuepea poo [eulds ul uoNonpai pides n tay

‘sadA] IOUIN] SOUL OJ UOT}eIP Aydersorqia -eiIl Aq paMmoT[oJ ‘Uorssoiduiodap [ea1s1ns JussIn pue ‘ATAB.INS I1OJ9q USAIS ST UOTIVIPRLI UIYM UeY} SplOd1090NNIS asop-YsIY Jo asn JUdaBIoUla satmnbat POY PoyeIpeAI oY} UT 9dUSLINIAI JOUIN}] JO SLI JY SI ASBASIP IT}VISPISW WIOIJ UOTssaiduiod pod teulds e wn B pue A}IDIXO} JoyBaI8 JO asnvdIA|q SION] [eIDaI IOI 9Tq o =} -[SBaJ USYM Paploae ST UOHeIpelt Aq paMmoyjoy ATasing e = “uolssaiduloo ‘Alasins pue ‘Adeiatyjouayo ‘uonerpest ortnbar = So poo jeulds JueUsI[eW oyNoe YIM s}Uaed 1OJ papudstwwio0da1 AJSUTNOI ([]] 93eIS) sapou YdurAyT paaToautT YIM cs jou st (q UoHdQC) JUSWIe1] PIodT}.1090NN {8 Noy WM Ajasing = 9SOY]} 1O/PUP (]] AdB}S) SION} [e199 SSOUYOIYI-[[Ne cs ‘ssauyvam pue ‘ured ‘vuepea poo [eulds ul uoNonpai pides n tay B YUM pajeposse oie pur JUdLU}BdI] UOTJRIPel pue [eoIsins o > yjoq jusatuatddns sploonszosoonfyH ‘auoye Adeiay] uonerp ‘AlasINs a10jaq 72) <= CLIT YIM poredwuod uonRnque Jo pooylfayl] ay} Sasvaioul UdAIS ST UOTJRIPRIIT USM UY} ple payerpesqt oy} Ul sour <x uoneipettt Aq pemoj[o} Alasing "[O1JUOD IOUIN} [BIO] [PUI -MddI IOUIN] JO ASL JOYSIY & PUB APIOTXO} J9}ea18 Jo asnvoaq -do aaatyoe 0} paiinbai st uonerpesy yeorsins}sog a[qisvay UIYM paploae st (q ‘O suondg) (Adeviayjourays ‘JUSAA STU} I10Jaq snyeys FeuOTOUNy pue uorerpesy Aq 10) uonepeti Aq pamoy[oy Aresng poos YIM Juaned sj ul Ajrepnoried ‘stsousoid poos & yy ‘poyeoIpul ore Adesoy] UOTeIpelt pure AdesayOUIoyp aatyesa juatjed & 10} pue Ajadins 0} ajqeuaure Jr Adesay] uoNerper -dojsod usy} ‘Ajeanetedoaid | a8ejs aq 01 1Y8noy) syuaed pure Aras.ins Yyjoq YM payeai} aq prnoys Ja0ue. BUNT o1VRIS ul Atasins Joye punoy st uoerjaued JoUIN) ssauyatyy-[[ny -BJOU “TAADMOYH{ *(Q UONdO) suOTe UOT}eIpeL YIM ATUasin JO sase}sejou spou YdurAy [eso] JT “WINydaI ay} YIM oT UA pajvar oq APU peojsul puv Uolssaidwoseap [voIsms [eNTul JORJUL AT[NJ WINIDIIOSIW dU} JO TRAOUWIAI MOTTL 0} WUNJDa10SaUT arnba JOU ABU ‘SIOUUIN] [[39 ULIa8 pue ‘euULOfaAtU ‘euTOYydUA] ay} JO apisjno stajad ay} JO UOTassip dieys k s[feyua UOTs ‘elUlayNe] se yons ‘sadA} JOUIN] dANISUaSOIpeA UTRLIAD -Joxo [PJOaIOSOUI [P10] VY “‘Sopou YCUIA] [eUOTBaI ay} suTe) ‘Ppapaau aq [JIM Adeiay} aALUYap doy “}Yauag Jo -UOD JBY]} UINJDa1 SY} SUTIBAOD YJeays AYR] B SI UINDaIOSOUT UOHPINP paUW]]-dUI1} & SI stay} Inq ‘Juasaid si visajdesed 10 ay], ‘ainpesdsoid patiayoid 3} S} UOTSTSXd [eJDaIOSAUI [e]0}

B YUM pajeposse oie pur JUdLU}BdI] UOTJRIPel pue [eoIsins o > yjoq jusatuatddns sploonszosoonfyH ‘auoye Adeiay] uonerp ‘AlasINs a10jaq 72) <= CLIT YIM poredwuod uonRnque Jo pooylfayl] ay} Sasvaioul UdAIS ST UOTJRIPRIIT USM UY} ple payerpesqt oy} Ul sour <x uoneipettt Aq pemoj[o} Alasing "[O1JUOD IOUIN} [BIO] [PUI -MddI IOUIN] JO ASL JOYSIY & PUB APIOTXO} J9}ea18 Jo asnvoaq -do aaatyoe 0} paiinbai st uonerpesy yeorsins}sog a[qisvay UIYM paploae st (q ‘O suondg) (Adeviayjourays ‘JUSAA STU} I10Jaq snyeys FeuOTOUNy pue uorerpesy Aq 10) uonepeti Aq pamoy[oy Aresng poos YIM Juaned sj ul Ajrepnoried ‘stsousoid poos & yy ‘poyeoIpul ore Adesoy] UOTeIpelt pure AdesayOUIoyp aatyesa juatjed & 10} pue Ajadins 0} ajqeuaure Jr Adesay] uoNerper -dojsod usy} ‘Ajeanetedoaid | a8ejs aq 01 1Y8noy) syuaed pure Aras.ins Yyjoq YM payeai} aq prnoys Ja0ue. BUNT o1VRIS ul Atasins Joye punoy st uoerjaued JoUIN) ssauyatyy-[[ny -BJOU “TAADMOYH{ *(Q UONdO) suOTe UOT}eIpeL YIM ATUasin JO sase}sejou spou YdurAy [eso] JT “WINydaI ay} YIM oT UA pajvar oq APU peojsul puv Uolssaidwoseap [voIsms [eNTul JORJUL AT[NJ WINIDIIOSIW dU} JO TRAOUWIAI MOTTL 0} WUNJDa10SaUT arnba JOU ABU ‘SIOUUIN] [[39 ULIa8 pue ‘euULOfaAtU ‘euTOYydUA] ay} JO apisjno stajad ay} JO UOTassip dieys k s[feyua UOTs ‘elUlayNe] se yons ‘sadA} JOUIN] dANISUaSOIpeA UTRLIAD -Joxo [PJOaIOSOUI [P10] VY “‘Sopou YCUIA] [eUOTBaI ay} suTe) ‘Ppapaau aq [JIM Adeiay} aALUYap doy “}Yauag Jo -UOD JBY]} UINJDa1 SY} SUTIBAOD YJeays AYR] B SI UINDaIOSOUT UOHPINP paUW]]-dUI1} & SI stay} Inq ‘Juasaid si visajdesed 10 ay], ‘ainpesdsoid patiayoid 3} S} UOTSTSXd [eJDaIOSAUI [e]0} senbiziia pue siomsuy

_Answers and Critiques pathognomonic for renal cell carcinoma. If the ultrasound is lymph node sampling, omentectomy, and peritoneal wash- equivocal, CT should be performed, typically revealing find- ings. Gynecologic oncologists are more likely to optimally ings specific enough for renal cell cancer to avoid the need for cytoreduce patients with ovarian cancer than those without a confirmatory biopsy. specific training in gynecologic oncology. Lung cancer (Option A) may be associated with a vari- BRCA1/2 testing (Option A) is recommended for ety of paraneoplastic syndromes, including hypercalcemia all patients with ovarian cancer, but the first step in this and the syndrome of inappropriate antidiuretic hormone patient’s evaluation is to establish a diagnosis. secretion, but it has not been associated with ectopic eryth- CT-guided biopsy (Option B) should not be performed ropoietin production and would not be expected to cause for an isolated adnexal mass, in part to avoid rupture of hematuria. the tumor, and instead a surgical procedure should be per- Myelodysplastic syndrome (Option B) is a stem cell formed to resect the tumor intact and to perform com- disorder that results in ineffective hematopoiesis and var- prehensive staging. A CT-guided biopsy is an appropriate ious cytopenias, the most common of which is anemia, diagnostic procedure for a patient who presents with ww Qe often macrocytic. Myelodysplastic syndrome is not a cause advanced ovarian cancer in which there is radiographic = of erythrocytosis. evidence of spread in the peritoneum or to a distant site, and = had

pathognomonic for renal cell carcinoma. If the ultrasound is lymph node sampling, omentectomy, and peritoneal wash- equivocal, CT should be performed, typically revealing find- ings. Gynecologic oncologists are more likely to optimally ings specific enough for renal cell cancer to avoid the need for cytoreduce patients with ovarian cancer than those without a confirmatory biopsy. specific training in gynecologic oncology. Lung cancer (Option A) may be associated with a vari- BRCA1/2 testing (Option A) is recommended for ety of paraneoplastic syndromes, including hypercalcemia all patients with ovarian cancer, but the first step in this and the syndrome of inappropriate antidiuretic hormone patient’s evaluation is to establish a diagnosis. secretion, but it has not been associated with ectopic eryth- CT-guided biopsy (Option B) should not be performed ropoietin production and would not be expected to cause for an isolated adnexal mass, in part to avoid rupture of hematuria. the tumor, and instead a surgical procedure should be per- Myelodysplastic syndrome (Option B) is a stem cell formed to resect the tumor intact and to perform com- disorder that results in ineffective hematopoiesis and var- prehensive staging. A CT-guided biopsy is an appropriate ious cytopenias, the most common of which is anemia, diagnostic procedure for a patient who presents with ww Qe often macrocytic. Myelodysplastic syndrome is not a cause advanced ovarian cancer in which there is radiographic = of erythrocytosis. evidence of spread in the peritoneum or to a distant site, and = had Polycythemia vera (Option C) is a myeloproliferative which is not amenable to surgical resection. In this case, the <7 ww disorder that is caused by a mutation in the JAK-2 gene. patient may undergo an initial biopsy followed by neoadju- i =] < This disorder results in unregulated blood cell production. vant chemotherapy to facilitate optimal debulking surgery. c Although erythrocytosis may be most striking, leukocytosis According to recent guidelines by the American Society os a and thrombocytosis are often seen as well. Physical findings of Clinical Oncology and Society of Gynecologic Oncology, = include hepatosplenomegaly. The dysregulated erythrocyte patients with stage IIIC or IV ovarian cancer who are at high av SS production and erythrocytosis cause a marked reduction in perioperative risk or who have a low likelihood of optimal Ze

Polycythemia vera (Option C) is a myeloproliferative which is not amenable to surgical resection. In this case, the <7 ww disorder that is caused by a mutation in the JAK-2 gene. patient may undergo an initial biopsy followed by neoadju- i =] < This disorder results in unregulated blood cell production. vant chemotherapy to facilitate optimal debulking surgery. c Although erythrocytosis may be most striking, leukocytosis According to recent guidelines by the American Society os a and thrombocytosis are often seen as well. Physical findings of Clinical Oncology and Society of Gynecologic Oncology, = include hepatosplenomegaly. The dysregulated erythrocyte patients with stage IIIC or IV ovarian cancer who are at high av SS production and erythrocytosis cause a marked reduction in perioperative risk or who have a low likelihood of optimal Ze erythropoietin secretion. Hematuria would not be expected. tumor debulking should receive neoadjuvant chemother- Relative erythrocytosis (Option D) occurs in patients apy (Option C) followed by reevaluation for cytoreductive who have intravascular volume contraction, often in the surgery. Tumors that involve the porta hepatis, have metas- setting of diuretic use. These patients are characteristically tasized to the liver or lungs, or that cause massive ascites are obese, have hypertension, and smoke cigarettes. Relative examples of disease that might be best treated with neoadju- erythrocytosis would not cause the dramatic hemoglobin vant chemotherapy. This patient appears to have an isolated elevation seen in this patient and would not explain the adnexal mass, which is best treated with surgical removal by hematuria. a gynecologic oncologist.

erythropoietin secretion. Hematuria would not be expected. tumor debulking should receive neoadjuvant chemother- Relative erythrocytosis (Option D) occurs in patients apy (Option C) followed by reevaluation for cytoreductive who have intravascular volume contraction, often in the surgery. Tumors that involve the porta hepatis, have metas- setting of diuretic use. These patients are characteristically tasized to the liver or lungs, or that cause massive ascites are obese, have hypertension, and smoke cigarettes. Relative examples of disease that might be best treated with neoadju- erythrocytosis would not cause the dramatic hemoglobin vant chemotherapy. This patient appears to have an isolated elevation seen in this patient and would not explain the adnexal mass, which is best treated with surgical removal by hematuria. a gynecologic oncologist. ¢ Secondary polycythemia is the presence of erythrocy- ¢ BRCA1/2 testing is recommended for all patients with tosis and an elevated erythropoietin level. ovarian cancer. ¢ Secondary polycythemia is commonly caused by ¢ Surgical exploration is recommended for diagnosis of hypoxemia but may be due to a paraneoplastic syn- early ovarian cancer; removing the ovarian cancer intact drome, such as that associated with renal cell carci- without rupture improves survival. noma. Bibliography Bibliography Walker M, Sobel M. Diagnosing ovarian cancer. CMAJ. 2018;190:E1259. Hegemann M, Kroeger N, Stenzl A, et al. Rare and changeable as a chame- [PMID: 30348741] doi:10.1503/cmaj.180499 leon: paraneoplastic syndromes in renal cell carcinoma. World J Urol. 2018;36:849-54. [PMID: 29429069] doi:10.1007/s00345-018-2215-9 Item 66 Answer: A

Hegemann M, Kroeger N, Stenzl A, et al. Rare and changeable as a chame- [PMID: 30348741] doi:10.1503/cmaj.180499 leon: paraneoplastic syndromes in renal cell carcinoma. World J Urol. 2018;36:849-54. [PMID: 29429069] doi:10.1007/s00345-018-2215-9 Item 66 Answer: A Educational Objective: Manage a patient presenting Item 65 Answer: D with a neck mass. Educational Objective: Diagnose a patient with an The most appropriate management at this time is fine- ovarian mass. needle aspiration (FNA) (Option A). This patient, who pre- This patient appears to have stage I ovarian cancer (confined sents with a painless, rapidly developing, partially cystic to the ovary) and should therefore be referred to a gyneco- neck mass, should be considered to have squamous cell logic oncologist for surgical removal of the mass (Option carcinoma until proven otherwise. Based on this patient’s D). Removal of the tumor intact is associated with improved presentation, the most appropriate initial management is survival. The patient should undergo comprehensive surgical FNA. FNA is very accurate for diagnosis of squamous cell staging to evaluate for additional disease that would upstage carcinoma and is preferred over more invasive biopsy tech- the patient. This procedure is usually performed through a niques. It has a diagnostic accuracy of 88% to 89% and can laparotomy and involves inspection of the peritoneal cav- be done rapidly in the office with limited or no morbidity. ity including the paracolic gutters, dome of the diaphragm, A more invasive form of biopsy would only be needed if 99

OOL WOUVaAL]L *IUITINIaI ATUO-YSd ®B SBY AY ‘A1OJaIOY], ‘asvasIp IM uUsutom jesnedousurjsod Joy papuduUIIODaI ST IONQIYUT ONeISeIOU JO BdUapPIAD AUB [BaAAT JOU PIP salpms Surlseuly ase]euloIe UP JO UdjixOUle] pUe ‘sdUATINIAI JO YS Ul UoN ‘JUS ea] Jaye SIVA 6 (1/31 7g) Tu/3u ZE JO WSd & Sey MOU -onpal %Or B YIM pajeposse st Adeiay} aULIDOpuy “BuIas pure (1/81 [) Tur/su | Ajayeutxosdde jo ySq Irpeu e pey quanyed STW] Ul popustwwodal st Advidy} UOTeIpel pue ‘doUaLINIAI SIU, Iypeu Ader1oy} uoTeIpersod ay} aaoqe (7/81 Z) Tur/su Z [Boo] TOF ToJoRJ Yslt e st Apatsod TYAH ‘Adessy} uoTeper jsea] Je Aq [OAd| WSd OU} Ul SsvaIOUI Ue Se Palap SI doUaLINdaI JO UOISSTWIO Japisuod APU sIOUIN} aatesau-zyW_H /aattsod ATUO-YSq “ITpeu & YORaI pueB JUdUT}eAT TIM [Te [IM WSd ou} -(Yq) Jojda.a1 uasosa ][eUIs YM UdaUIOM Japfo sealsy\\, ‘Toyyey ‘Aradins Jaye Udas ATUOUMUOD SI se ‘WSq atqe}oajapun ‘TRAIAINS [[BIOAO SaSvaIOUT If pUv ‘soseB}se}OUI JURISIP JO ASI ue adatyoe Ajarer Aderioy] UoHeIpel YM payeay usyy (qd a4} PUB BUATINIAI [PIOT JO YS ds} YJOQ sasvaidap uoye uoNdO) JUSWIeAT] NOYIM [PAI] WSd IOWUOUT 0} st JUaUTASe -IPBLUL [ROISIMs}sog “UOLIPRLI [eoIsims}sod spaau yNsar vB -uevuwl ojelidoidde jsour ay} pue ‘“aouva ajeysoid Jo aouar se pue Atasins SUJATaSUOD-jsvaiq pey sey juoted si, (Vv -Idai ATUO-(YSd) UesyUP syfoads-ayelsoid & sey yuaTed sTyL uondo) Adeioy] supdopua pue ‘uoNerpert yseaiq ‘Aderay} (CMAH) 7% Jo\dsde1 JOJOR} YWMoIs TeULapida UeUMY-hue ‘J2OULD 9}¥}SO1d JUSIINIe1 ATUO pue Adeisyjowayd YM peyeal} aq prnoys yuaned sty, —uasue syoads-ajejsoid aseuryy :aan29efqo jeuoneonpy

uoNdO) JUSWIeAT] NOYIM [PAI] WSd IOWUOUT 0} st JUaUTASe -IPBLUL [ROISIMs}sog “UOLIPRLI [eoIsims}sod spaau yNsar vB -uevuwl ojelidoidde jsour ay} pue ‘“aouva ajeysoid Jo aouar se pue Atasins SUJATaSUOD-jsvaiq pey sey juoted si, (Vv -Idai ATUO-(YSd) UesyUP syfoads-ayelsoid & sey yuaTed sTyL uondo) Adeioy] supdopua pue ‘uoNerpert yseaiq ‘Aderay} (CMAH) 7% Jo\dsde1 JOJOR} YWMoIs TeULapida UeUMY-hue ‘J2OULD 9}¥}SO1d JUSIINIe1 ATUO pue Adeisyjowayd YM peyeal} aq prnoys yuaned sty, —uasue syoads-ajejsoid aseuryy :aan29efqo jeuoneonpy “IQDUBD JSPIIq q wemsuy 89 we} aatsod-—Z 10}da901 10}9¥J YIMOIS [eULIapide ueuny [ a8e}s YIM JUaTIed & JeaI], :aANIE[qC JeEUONeNpy 99000°61'OOL/00ZT OL:10P [9606E60E :CIINd] “SZ-898T:ZE ‘610% “JOOUD UT[D f ‘JeoURd Jsvaiq aaTyIsod-zZ 10}dada1 1OJORJ YZMOIS [eu vy wemsuy L9 wey -Jopide ueumy ‘aatjesau-apou oj [el] qetunznyses} pue faxeyoed yea -nfpe Jo sisjeue dn-moj[oj 1ea4-WdAag ‘Te Jd ‘§ svUIag ‘H OND ‘WS Aourjoy Aydessorqig 609€TZLLIS66SF610/ZLIT OL‘10p [PGF1688G :CINd] ‘IZ-SSE:ZSTZ107 “SNS YOON pea} [OSUAIRIOIO ‘AIBUIWINS SANDAXA S}[NpPe UT SSPU YIU dt] JO UOT ‘SIQOUBD JSPOIg dATJISOd-z YAH oJ papusurutodar -NYPAS :OUTfEpIns so1deAd [RITUT]-D ‘[e 19 ‘g URUIOY ‘GW aIdsaTpED ‘vy Usuouusg ST ‘qeuunznjseq) Apoqyue [eUC[IOUOU dy} sB Yons ‘USUI Aydexsorqia -Jead] pojes1e]-(Z YAH) 7 10}dada1 10jdej Y}MoIs [eULIap -Ido ueuIny YIM peautquios Adeiayjoursyp yuean{[py e ‘IadURd YIU PUB PRdY IO} snototdsns sseut yooau v

ST ‘qeuunznjseq) Apoqyue [eUC[IOUOU dy} sB Yons ‘USUI Aydexsorqia -Jead] pojes1e]-(Z YAH) 7 10}dada1 10jdej Y}MoIs [eULIap -Ido ueuIny YIM peautquios Adeiayjoursyp yuean{[py e ‘IadURd YIU PUB PRdY IO} snototdsns sseut yooau v SUTJeN[eAD UT da}s [BAIUI dy} SI UoNerdse a[paou-oUTy] e “(qeumnznjse1}) Adetoul 7YqH-Hue pue Adeiay} -OW AYO WO JYouaq [eUe]sqns YIM OsyTe Inq ddUaIINdIAI Jo ‘s][N'SOI WN UO paseq YSH IOYSIY & YIM payelsosse ST J[as}i Jaoued Jseaiq aATIsod PoasouseIp dq ATISvd UBD BUIOUTIOIeO [Jao snourenbs se ‘sasod -~CaaAH Adersyjouayp wor yyouaq op AT[e19uas Sa1O0dg soUaT -Ind o1souselp 10} papaau jou st Aiasing ‘jsa] oNsouserp -Indaxy YSH-YSY YIM sjuetjed svaioym ‘Adersyoulsya wWioly PIQIOUL Ssof PUB JUDIOYJo 91OU YONU & SI WNA ‘IaAIMOF] “199

YSH IOYSIY & YIM payelsosse ST J[as}i Jaoued Jseaiq aATIsod PoasouseIp dq ATISvd UBD BUIOUTIOIeO [Jao snourenbs se ‘sasod -~CaaAH Adersyjouayp wor yyouaq op AT[e19uas Sa1O0dg soUaT -Ind o1souselp 10} papaau jou st Aiasing ‘jsa] oNsouserp -Indaxy YSH-YSY YIM sjuetjed svaioym ‘Adersyoulsya wWioly PIQIOUL Ssof PUB JUDIOYJo 91OU YONU & SI WNA ‘IaAIMOF] “199 JYoaulaq JOU Op AT[eIOUDS Sa1OdS ddUaLINIIY YS o]vIpsut -UBD YOU PUP PkoY OJ JUS VAI] JO JWsUOdUIOD B se JUSTIed -Ia}U] IO MOT PUB JIdUBI JsBvaIq SATTeSOU-Z YAH /aatisod-yq SIU} LO} payBoIpu! aq JYSIW (q UONdG) [eAouaL TeoIsMg aAT}VS9U-9pOU YIM sjuayeg Adeiayjoulayo woy jyeuaq “‘SUIPUY dANeSoU-as|R] B w Ja0UeD JsvoIq sATeSOU-ZYAH/AAMIsod-yy YIM sjuaned o JO YSH SUISTeI ‘[.D/LAd UO plAe AIdA JOU are sapoU o1Ve}seIOUT a YPIYM UTULII}9p 0} Pasn SI d109G ddUdaLIMIIy SY], “Jaoue osAO ATas1e[ sWOs ‘aye}dn dsoon{shxoapoionyy pasearour s qseaigq dAtIsod-z YAH YIM syuated 10} SUPP UOTs|Oap JUsUI AABY] 0} P9}dadxa oq P[NOM sseUI sIy} YSnoy py “sseur sty — S -}€91] UWIOJUT 0} pasn jou 1k (9 UONdQC) a109g s0UaLIMIIy Asdotq 0} poou dy] S8uRYp JOU P[NoM weds [D/LAd &Jo s}[Nsor 3 xd edAjoouCQ ay} se yons sayoid uolssaidxa sua5 oY} pue ‘Ta0uvd JO sIsouseIp & dIOJaq Pd}BdIPUI JOU SI ID . cs ‘Adeioy) ZYAH-Hue spnpoaid pynom yey} /LAd 190UBd YoU PUP pedal YJIM pasouseIp Usaq JaA Jou sey w Fees (AyyedoAUMOTpIVd dI9AIS) SUOTIPUOD PIqIOWIOD Jo JvoUasqe Juotyed sty} “IaAQMOH{ “‘pasouselp SI 120Uvd YoU pue peat o > 24} Ul payjtwio oq JOU pyNoys JUawi}ead} ‘sjaye asiaape 20U0 BUISe}s IO} payeoIpUT aq plnom (9 uoNdO) LD/LAd wy Ss a10ul sduattedxe Aewi sjuatjed Japlo ysnoulTy ‘yuaned sty} ‘IQDULD JO POOUT[EY!] YSIY dy} UO paseq <x Joy Adeitay} auyJoopus pue ‘Aderoy} pajosie1-cyyqH ‘Adesoy} Azessaoou St YN UM uonenyena jduio1g ‘Bulseuyt uo paseq -OWdYD ‘UOTLIPBLIT JO UOTUIQUIOD dy} SaOp se [eAIAINS SseUI YoU [euULIOUgR ATIeaID B sey JUaHed SITY] ‘asvo stu} SUIAOICUI IO ddUdIINIAI JO YS ay} BuloNpar Jo JYaueq ur ayefidoidde 9q jou pnom (g UoNdO) UOTeAIasqO sues ay} apraoid jou [IM (q ‘q suondgo) Adeioy} uoTerper “sIsousOId PoAOCIGUI! UL YIM payeloosse ST If ‘SUOISTIap YUM poulquuios Jo suoTe Adeisy} suLIDOpua JueAn[py JUST}eaI] UO JOVCUITT UB dABY JOU Saop snjiejs AqH Ysnoyly ‘a[yord APOIXO} a[qvioavj AIDA B puke YZ JapuN aouaI "sIvak 6S 0} OF S88e UddMjoq ATUOWIWUOD }SOU 1Nd90 SIadUed -INda1 JURISIP JO YS & YJIM JUdTJIoXa a1eB sattODnNo “BuNjas PelPTPI-AdH JOUPD P9]L[AI-UOTIOJUT STU} 1OJ OISTIa}DeIeYO

JYoaulaq JOU Op AT[eIOUDS Sa1OdS ddUaLINIIY YS o]vIpsut -UBD YOU PUP PkoY OJ JUS VAI] JO JWsUOdUIOD B se JUSTIed -Ia}U] IO MOT PUB JIdUBI JsBvaIq SATTeSOU-Z YAH /aatisod-yq SIU} LO} payBoIpu! aq JYSIW (q UONdG) [eAouaL TeoIsMg aAT}VS9U-9pOU YIM sjuayeg Adeiayjoulayo woy jyeuaq “‘SUIPUY dANeSoU-as|R] B w Ja0UeD JsvoIq sATeSOU-ZYAH/AAMIsod-yy YIM sjuaned o JO YSH SUISTeI ‘[.D/LAd UO plAe AIdA JOU are sapoU o1Ve}seIOUT a YPIYM UTULII}9p 0} Pasn SI d109G ddUdaLIMIIy SY], “Jaoue osAO ATas1e[ sWOs ‘aye}dn dsoon{shxoapoionyy pasearour s qseaigq dAtIsod-z YAH YIM syuated 10} SUPP UOTs|Oap JUsUI AABY] 0} P9}dadxa oq P[NOM sseUI sIy} YSnoy py “sseur sty — S -}€91] UWIOJUT 0} pasn jou 1k (9 UONdQC) a109g s0UaLIMIIy Asdotq 0} poou dy] S8uRYp JOU P[NoM weds [D/LAd &Jo s}[Nsor 3 xd edAjoouCQ ay} se yons sayoid uolssaidxa sua5 oY} pue ‘Ta0uvd JO sIsouseIp & dIOJaq Pd}BdIPUI JOU SI ID . cs ‘Adeioy) ZYAH-Hue spnpoaid pynom yey} /LAd 190UBd YoU PUP pedal YJIM pasouseIp Usaq JaA Jou sey w Fees (AyyedoAUMOTpIVd dI9AIS) SUOTIPUOD PIqIOWIOD Jo JvoUasqe Juotyed sty} “IaAQMOH{ “‘pasouselp SI 120Uvd YoU pue peat o > 24} Ul payjtwio oq JOU pyNoys JUawi}ead} ‘sjaye asiaape 20U0 BUISe}s IO} payeoIpUT aq plnom (9 uoNdO) LD/LAd wy Ss a10ul sduattedxe Aewi sjuatjed Japlo ysnoulTy ‘yuaned sty} ‘IQDULD JO POOUT[EY!] YSIY dy} UO paseq <x Joy Adeitay} auyJoopus pue ‘Aderoy} pajosie1-cyyqH ‘Adesoy} Azessaoou St YN UM uonenyena jduio1g ‘Bulseuyt uo paseq -OWdYD ‘UOTLIPBLIT JO UOTUIQUIOD dy} SaOp se [eAIAINS SseUI YoU [euULIOUgR ATIeaID B sey JUaHed SITY] ‘asvo stu} SUIAOICUI IO ddUdIINIAI JO YS ay} BuloNpar Jo JYaueq ur ayefidoidde 9q jou pnom (g UoNdO) UOTeAIasqO sues ay} apraoid jou [IM (q ‘q suondgo) Adeioy} uoTerper “sIsousOId PoAOCIGUI! UL YIM payeloosse ST If ‘SUOISTIap YUM poulquuios Jo suoTe Adeisy} suLIDOpua JueAn[py JUST}eaI] UO JOVCUITT UB dABY JOU Saop snjiejs AqH Ysnoyly ‘a[yord APOIXO} a[qvioavj AIDA B puke YZ JapuN aouaI "sIvak 6S 0} OF S88e UddMjoq ATUOWIWUOD }SOU 1Nd90 SIadUed -INda1 JURISIP JO YS & YJIM JUdTJIoXa a1eB sattODnNo “BuNjas PelPTPI-AdH JOUPD P9]L[AI-UOTIOJUT STU} 1OJ OISTIa}DeIeYO SIq} Ul pue ‘qeumznjse] pue jexeyped Apjoom YIM payear} SI SUISPLUT JD UO sseU dI}SAD ATaBIL] & PUB ‘BUTOUTOIvO [Ia aq UBD SIIDUBD JsvaIq dAT}ISOd-Z YAH [Cus UJIM UstuoA\ “S190 snouenbs paje[al-AdH Joj a8uei a8e ayetidoidde ayy ut -UBd dATHTSOd-ZYAH JO} papusurwiosai st ‘qeumnznyser Apoq SI Juaned sty} se ‘uoTdeyul (AqH) SHIA ewiorpided ueumy -HUB [BUOPOUOUL dU} SB YONs ‘TUdWI}AI} Pa}a81e}-TYAH YM Jo} payenyeaa aq os[e plnoys Ja.ued SITY} ‘eULOUTOIeD [90

SIq} Ul pue ‘qeumznjse] pue jexeyped Apjoom YIM payear} SI SUISPLUT JD UO sseU dI}SAD ATaBIL] & PUB ‘BUTOUTOIvO [Ia aq UBD SIIDUBD JsvaIq dAT}ISOd-Z YAH [Cus UJIM UstuoA\ “S190 snouenbs paje[al-AdH Joj a8uei a8e ayetidoidde ayy ut -UBd dATHTSOd-ZYAH JO} papusurwiosai st ‘qeumnznyser Apoq SI Juaned sty} se ‘uoTdeyul (AqH) SHIA ewiorpided ueumy -HUB [BUOPOUOUL dU} SB YONs ‘TUdWI}AI} Pa}a81e}-TYAH YM Jo} payenyeaa aq os[e plnoys Ja.ued SITY} ‘eULOUTOIeD [90 pourtquios Aderayjowayp Juean{[py “a0 Iseaiq aATISOd-yAyq snowenbs 9q 0} punoy J] ‘osouserpuou aiam s}fnsat YNA senbiyia pue saamsuy

Answers and Critiques for patients with PSA-only recurrence is informed by the of melanomas do not. Patients who have a BRAF mutation degree of PSA elevation and the rate of rise in the PSA level. may respond to therapy with BRAF inhibitors (vemurafenib, For men with a rapid doubling time, defined as 10 months or dabrafenib, and encorafenib) along with MEK inhibitors less, treatment is generally recommended. Standard treat- (trametinib, cobimetinib, and binimetinib). However, BRAF ment in this setting is an androgen receptor blocker (such inhibitors are not effective in patients with tumors such as as enzalutamide). Men with a slow PSA doubling time (for this one that is not BRAF mutated (Option B). Thus, there is example, more than 10 months) do not require immediate no role for the use of a BRAF inhibitor in this patient who treatment, however, as it can take years for them to develop lacks a BRAF mutation. Other driver mutations identified in clinical metastatic disease. They can be monitored with serial patients with melanoma include NRAS and c-KIT. PSA assessment, and treatment can be deferred. MEK inhibitors (Option D) do have single-agent activ- Androgen deprivation therapy (Option A) is not indi- ity in melanoma but are usually used in combination with cated in this case, given the slow PSA doubling time and the BRAF inhibitors. Adding a MEK inhibitor to a BRAF inhibitor absence of biopsy-positive recurrent or metastatic disease. improves the response rate and the durability of response in wa a Chemotherapy (Option B) with docetaxel is reserved BRAF-mutated melanoma. A MEK inhibitor combined with =

for patients with PSA-only recurrence is informed by the of melanomas do not. Patients who have a BRAF mutation degree of PSA elevation and the rate of rise in the PSA level. may respond to therapy with BRAF inhibitors (vemurafenib, For men with a rapid doubling time, defined as 10 months or dabrafenib, and encorafenib) along with MEK inhibitors less, treatment is generally recommended. Standard treat- (trametinib, cobimetinib, and binimetinib). However, BRAF ment in this setting is an androgen receptor blocker (such inhibitors are not effective in patients with tumors such as as enzalutamide). Men with a slow PSA doubling time (for this one that is not BRAF mutated (Option B). Thus, there is example, more than 10 months) do not require immediate no role for the use of a BRAF inhibitor in this patient who treatment, however, as it can take years for them to develop lacks a BRAF mutation. Other driver mutations identified in clinical metastatic disease. They can be monitored with serial patients with melanoma include NRAS and c-KIT. PSA assessment, and treatment can be deferred. MEK inhibitors (Option D) do have single-agent activ- Androgen deprivation therapy (Option A) is not indi- ity in melanoma but are usually used in combination with cated in this case, given the slow PSA doubling time and the BRAF inhibitors. Adding a MEK inhibitor to a BRAF inhibitor absence of biopsy-positive recurrent or metastatic disease. improves the response rate and the durability of response in wa a Chemotherapy (Option B) with docetaxel is reserved BRAF-mutated melanoma. A MEK inhibitor combined with = for treatment of men with symptomatic metastatic disease. a BRAF inhibitor (Option C) is not indicated in this patient a This patient does not have metastatic disease and has no with a tumor that lacks a BRAF-related mutation. Finally, 9 Ye symptoms. There is no reason to subject him to the toxicity treatment with an anti-CTLA-4 antibody plus an anti-PD-1 <c = of chemotherapy when he does not require treatment. antibody results in superior clinical outcomes compared to c

for treatment of men with symptomatic metastatic disease. a BRAF inhibitor (Option C) is not indicated in this patient a This patient does not have metastatic disease and has no with a tumor that lacks a BRAF-related mutation. Finally, 9 Ye symptoms. There is no reason to subject him to the toxicity treatment with an anti-CTLA-4 antibody plus an anti-PD-1 <c = of chemotherapy when he does not require treatment. antibody results in superior clinical outcomes compared to c Cryotherapy (Option C) is not indicated in this case. This treatment with MEK inhibitor monotherapy. = o patient underwent transrectal ultrasound-guided biopsy to In a patient with metastatic disease who has a BRAF = 2] assess for focal lesions in the prostate amenable to local ther- mutation, treatment with either immunotherapy or = apy. Given that biopsy result was negative, there is no role for BRAF-targeted therapy would be appropriate without a <—t cryotherapy or other local treatment to the prostate. clear indication as of yet which treatment is superior. In patients who are ill and in need of a rapid response or in those with underlying autoimmune disorders who would e Patients with prostate-specific antigen (PSA)-only be at increased risk for adverse immune-related events, recurrence of prostate cancer and a slow PSA dou- BRAF/ MEK inhibition may be favored, given the potential bling time do not require immediate treatment. for more rapid response and the lower rate of autoimmune

Cryotherapy (Option C) is not indicated in this case. This treatment with MEK inhibitor monotherapy. = o patient underwent transrectal ultrasound-guided biopsy to In a patient with metastatic disease who has a BRAF = 2] assess for focal lesions in the prostate amenable to local ther- mutation, treatment with either immunotherapy or = apy. Given that biopsy result was negative, there is no role for BRAF-targeted therapy would be appropriate without a <—t cryotherapy or other local treatment to the prostate. clear indication as of yet which treatment is superior. In patients who are ill and in need of a rapid response or in those with underlying autoimmune disorders who would e Patients with prostate-specific antigen (PSA)-only be at increased risk for adverse immune-related events, recurrence of prostate cancer and a slow PSA dou- BRAF/ MEK inhibition may be favored, given the potential bling time do not require immediate treatment. for more rapid response and the lower rate of autoimmune e Many patients with PSA-only recurrent prostate can- complications. cer can be monitored with serial PSA assessment.

Cryotherapy (Option C) is not indicated in this case. This treatment with MEK inhibitor monotherapy. = o patient underwent transrectal ultrasound-guided biopsy to In a patient with metastatic disease who has a BRAF = 2] assess for focal lesions in the prostate amenable to local ther- mutation, treatment with either immunotherapy or = apy. Given that biopsy result was negative, there is no role for BRAF-targeted therapy would be appropriate without a <—t cryotherapy or other local treatment to the prostate. clear indication as of yet which treatment is superior. In patients who are ill and in need of a rapid response or in those with underlying autoimmune disorders who would e Patients with prostate-specific antigen (PSA)-only be at increased risk for adverse immune-related events, recurrence of prostate cancer and a slow PSA dou- BRAF/ MEK inhibition may be favored, given the potential bling time do not require immediate treatment. for more rapid response and the lower rate of autoimmune e Many patients with PSA-only recurrent prostate can- complications. cer can be monitored with serial PSA assessment. e¢ Immunotherapy with an anti-CTLA-4 antibody plus Bibliography an anti-programmed death antibody improves Van den Broeck T, van den Bergh RCN, Briers E, et al. Biochemical recur- rence in prostate cancer: the European Association of Urology Prostate response rates compared with either agent alone and Cancer Guidelines Panel Recommendations. Eur Urol Focus. 2020;6:231- is the preferred treatment for patients with metastatic 34. [PMID: 31248850] doi:10.1016/j.euf.2019.06.004 melanoma without a BRAF mutation.

e¢ Immunotherapy with an anti-CTLA-4 antibody plus Bibliography an anti-programmed death antibody improves Van den Broeck T, van den Bergh RCN, Briers E, et al. Biochemical recur- rence in prostate cancer: the European Association of Urology Prostate response rates compared with either agent alone and Cancer Guidelines Panel Recommendations. Eur Urol Focus. 2020;6:231- is the preferred treatment for patients with metastatic 34. [PMID: 31248850] doi:10.1016/j.euf.2019.06.004 melanoma without a BRAF mutation. e Ina patient with metastatic melanoma with a BRAF

e¢ Immunotherapy with an anti-CTLA-4 antibody plus Bibliography an anti-programmed death antibody improves Van den Broeck T, van den Bergh RCN, Briers E, et al. Biochemical recur- rence in prostate cancer: the European Association of Urology Prostate response rates compared with either agent alone and Cancer Guidelines Panel Recommendations. Eur Urol Focus. 2020;6:231- is the preferred treatment for patients with metastatic 34. [PMID: 31248850] doi:10.1016/j.euf.2019.06.004 melanoma without a BRAF mutation. e Ina patient with metastatic melanoma with a BRAF Item 69 Answer: A mutation, treatment with either immunotherapy or BRAF-targeted therapy is appropriate. Educational Objective: Treat BRAF-nonmutated mela- noma with immunotherapy. Bibliography This patient has BRAF-nonmutated melanoma, and the best Bomar L, Senithilnathan A, Ahn C. Systemic therapies for advanced mela- treatment is immunotherapy with an anti-CTLA-4 antibody noma. Dermatol Clin. 2019;37:409-23. [PMID: 31466582] doi:10.1016 /j.det. 2019.05.001 plus an anti-programmed death (anti-PD-1) antibody (Option A). Ipilimumab is an anti-CTLA-4 antibody, and nivolumab is an anti-PD-1 antibody. Individually, they each have activity ltem 70 Answer: D against malignant melanoma. Ipilimumab has a response rate Educational Objective: Treat a patient with ductal car- as a Single agent of 10% to 15%. Nivolumab and other anti- cinoma in situ following bilateral mastectomy. PD-1 antibodies, such as pembrolizumab, have a response rate of about 40%. The combination is more active than either drug No adjuvant treatment is recommended following bilateral alone, although it is associated with more immune toxicities. mastectomy as treatment for ductal carcinoma in situ (DCIS) This immunotherapy combination is effective whether the (Option D). After bilateral mastectomy for DCIS, neither radi- melanoma is BRAF mutated or not. Some of these responses ation therapy nor hormonal therapy provides benefit. DCIS is are quite durable with a minority of patients remaining free of a preinvasive proliferative growth and does not have the abil- recurrence for many years. ity to metastasize outside of the breast. Treatment is aimed at Although about 50% of melanomas have a BRAF muta- reducing the risk of local recurrences, of which half are DCIS tion (most commonly BRAF V600E or V600R), the other half and half are invasive cancers, the latter of which have the

Item 69 Answer: A mutation, treatment with either immunotherapy or BRAF-targeted therapy is appropriate. Educational Objective: Treat BRAF-nonmutated mela- noma with immunotherapy. Bibliography This patient has BRAF-nonmutated melanoma, and the best Bomar L, Senithilnathan A, Ahn C. Systemic therapies for advanced mela- treatment is immunotherapy with an anti-CTLA-4 antibody noma. Dermatol Clin. 2019;37:409-23. [PMID: 31466582] doi:10.1016 /j.det. 2019.05.001 plus an anti-programmed death (anti-PD-1) antibody (Option A). Ipilimumab is an anti-CTLA-4 antibody, and nivolumab is an anti-PD-1 antibody. Individually, they each have activity ltem 70 Answer: D against malignant melanoma. Ipilimumab has a response rate Educational Objective: Treat a patient with ductal car- as a Single agent of 10% to 15%. Nivolumab and other anti- cinoma in situ following bilateral mastectomy. PD-1 antibodies, such as pembrolizumab, have a response rate of about 40%. The combination is more active than either drug No adjuvant treatment is recommended following bilateral alone, although it is associated with more immune toxicities. mastectomy as treatment for ductal carcinoma in situ (DCIS) This immunotherapy combination is effective whether the (Option D). After bilateral mastectomy for DCIS, neither radi- melanoma is BRAF mutated or not. Some of these responses ation therapy nor hormonal therapy provides benefit. DCIS is are quite durable with a minority of patients remaining free of a preinvasive proliferative growth and does not have the abil- recurrence for many years. ity to metastasize outside of the breast. Treatment is aimed at Although about 50% of melanomas have a BRAF muta- reducing the risk of local recurrences, of which half are DCIS tion (most commonly BRAF V600E or V600R), the other half and half are invasive cancers, the latter of which have the 101

cOL UOHPUILUeXe [BOIsSAY [e1oUss B sARY P[NOYs pue (WW g°C UeU} SuIdojeaasp JO YS dy} “a0ued Suny [[99 [[eus asejs-partuny sso] YJdap Mo|seig) BLUOUR[AW (UTY}) YSLI-Moy pey Usted STU], JO dAISUA}X9 JoYIlo YIM sjuaed oJ JUsUIeAaN Jo uoNatd -W09 SUIMOTIOT ‘TY Ulerg spnypour prnoys Sulsels [eNIUI ‘ySTI ‘DOUL][IOAINS JUSUI}v9193}S0d a}yeLIdoidde WIM JEU] UALD *([[Od] UONeIpeL [eTUeID STDe[AYod) sasejse}aul BUIOUR[AW YsLI-Mo] aseuvyy :eanvefqo jeuoNnesnpy ureiq Suldojaaap Jo yslt ysIy B aABy Ja0Ued Suny [Jao [Teurs q cwemsuy ZZ way WM svete ‘(Dp UondoC) uorerpeLy Terueid syoe[Aydoid aq P[nom jJustyed sty} Joy JusWseueU djetidoidde ysour ayy, 6£00°810¢ UsoUul/ F009 OT-TOp [L80ETE0E *CIINd] “78 ‘UONeIPeL [ered sde[AYdord YIM J390Ued SUNT -IZIFOLSTOT MIAN OURD IdwioD PRN f ‘8TOZ'Z UOISIAA ‘Ia0ued Bun [[29 [[ewWs :s]YSIsuT sauT[apIns NOON ‘Te 12 ‘MM AePayV ‘Mg OO] GD UeLeyWeley [29 [Tews asejs-poywy year, :aaIafqoC jeuonesnpy Aydersorqid > wemsuy LZ wey Ade1dU} [CHIT I1dY} 0} papuodsar aavy oYM Ia0ueD €10°90'8T0c sins(uref/9TOT' OL10p [9T8PrZOE *CINd] ‘EOOT SUN] [[9d [[eUs d8e}S-PayTUT] YILM syUatyed Ul [RATA -866°91Z'810G “SINS [ WY “aIN}eJo}] JO MATAAT PUR ‘SdISIOAOI]UOD ‘spuaz} -INS [[PIDAO SOAOICUI UOTIPeAI [eTUeID ODe[AYdoIg e WUoaLINd NYS Ul PWOUTDIeO [eIONG ‘Te J2 “AW 1383q ‘WY SlaysePW “MA SuoH

Ade1dU} [CHIT I1dY} 0} papuodsar aavy oYM Ia0ueD €10°90'8T0c sins(uref/9TOT' OL10p [9T8PrZOE *CINd] ‘EOOT SUN] [[9d [[eUs d8e}S-PayTUT] YILM syUatyed Ul [RATA -866°91Z'810G “SINS [ WY “aIN}eJo}] JO MATAAT PUR ‘SdISIOAOI]UOD ‘spuaz} -INS [[PIDAO SOAOICUI UOTIPeAI [eTUeID ODe[AYdoIg e WUoaLINd NYS Ul PWOUTDIeO [eIONG ‘Te J2 “AW 1383q ‘WY SlaysePW “MA SuoH AdeIOU} [PHI I1dy} 0} papuodsar Aydersorqia JAKY OYM IIOUBd SUNT [9d [[PUIS d3e}S-JAISUD] XO “SUT]AS STU} Ul [PALAINS ][[e19AO UO JORdUIT 10 po}TUT] 1dY}19 YIM syUaTyed UI saseysejJoUl UTeIq JO ou sey Adeiay} SUTIDOpUS “AaAdMoyY ‘ddUdLAINIAI OUIPIOUT JY} SAONPal UOTSIPBAII [eTUeID DDeTAYdoIg e [P90] JO YSI dy} SoNpa 0} Ns Ul BPULOUTOI [eJonp dAT}Isod—10}da0e1 Uasor}sa YIM syustjed 0} pasayjo ‘(qd uondo) Adoossoysuolg Jeadal & 10 UONBOIPUT OU ST 319, st Aderoy} suou0y JueAn{pe ‘Auto}Dadumny Jay e ‘IQOUBD Ia JO Snes dU} poyenyead ATaATJOaPa sey SUISBUUT LD “TYIS Ul BULOUTOIeD TeJONp YIM ‘ssoooid Areuowynd satjoe ue Jo suio}durAs 10 susIs OU sey sjuatyed 1oyJ AUIO}D9}SeUL [eIDIeIIq Jaye }auaq SapIA pure [jem Azan SuIOp st JUaTyed sty} ‘auT] Juasaid au} IV -oid Adeiay} Teuowoy ou Adeioy] UONPIPeI ISYION e “WOTLOIPULI SITY] 1OJ papUdWUWUODAI JOU ST FT ‘9OURT[IOAINS IO}

‘ssoooid Areuowynd satjoe ue Jo suio}durAs 10 susIs OU sey sjuatyed 1oyJ AUIO}D9}SeUL [eIDIeIIq Jaye }auaq SapIA pure [jem Azan SuIOp st JUaTyed sty} ‘auT] Juasaid au} IV -oid Adeiay} Teuowoy ou Adeioy] UONPIPeI ISYION e “WOTLOIPULI SITY] 1OJ papUdWUWUODAI JOU ST FT ‘9OURT[IOAINS IO} Pasn USM SoW0dINO dAOICUA WUBI JD/LAd JEU} AdUAPIAd Jo YOR] UdALD “SUISPUIT Jsay dtIpotod YM Suoye [eotsAyd pue ‘AULOJOIJSCUT [RID eTIG Jaye SIOd UIIM syuaned ut Ade AIO|SIY JO S|SISUOD DURT[IaAINS prepuR}S “Ia0Ued BUNT [90 -19Y] SUOWWIOY JURAN[pe IOJ J[OI OU SI 31D, “WYouaq [PALAINS [[euls Io} JUsUTvA1) Jo UONaTduio0d BuLMOTIO] souRTTIaAINs B JO YOR] poyuowmMoop k ayIdsap Ia0Ued JseaIq ATeULId ammyny IO} }Sa} plepue}s B JOU ST (q UONdO) SuIseUl [D/LAd ® JUaAaid 0} Adeiay} JUOULIOY UPY} JayyeI AUIOJDa}SeU [PIO ‘J20URd SUNT [[99 [Tes YM sjuatjed -yJeTIq otoe[Aydoid asooyp SIoOd YIM sjuarTyed atut0s JO JUS} 91] IY] UT s[OI poysi[qeysa OU sey Jf “UdUISa1 JUST “QUOTE UdJIXOW} SUISN 0} JATBUAI[e -Jea1] [PNIUI Ioy} 0} asuodsar a[qei1oaRy B aABY OM Ss}uaTyed UB SB S}[NsoI IoLJodns saplAaoid Adeidy} JOJIQIYUT asejyeUIOIe UI [RATAINS 391J-UOTssoi1s01d SAOIdUITI 0} UMOYS Udaq sey pue ‘UdUIOM Tesnedousutjsod 10,4 ‘UduOM [esnedouatuaid ut aan JaoUvd SUNT [[99 [[BWIS—UOU deIseIJOU YIM s]UaTyed UT pasn -dayja 10U oe (Y UOC) d[0zZOI]seUe PUL 3[0Z0I}9] SIOUGIYUT wn <b ATUOUIWIOD SI (Y UOHdO) AdersyjoWaYD sdUeUDIUTeI aSP]LUIOI SUT, ‘UstOM [esnedousunsod pure -aid y}0q UT aan = ‘aSOp MOTO] JAMO] B PUB ISOP [P}O} JAMO] -dayjo SI (9 UoNdO) UsfIXOWR], ‘saya dsIaApe pd}e[ai-Snup = - ® UJIM payesiiuw oq Uv YS SIU} Je] PUNO] aavy Sarpnyjs Wa [enuajod au] JsuTese paysiam aq prnoys s]youaq pure ‘jseaiq i (=) -poul oO Ysnoujye ‘pajou useq aaey JUsUITedumT sAnTUs0o [e1o}e[PI]UOS dy} UI JooUvd Js¥aiq ATeUTId MoU B JO YS ay} co SUIPILSal SUIIOUOD Ajayes ‘pasaouoid AyTeHTUT sem JUaTUyeAT] ssonpei Adeioy} suowoy jueaAni[pe ‘s[oq I0j Awo}a\seur aad Da SIU} aouTS AdeIO} [BNIUT Id} 0] papuodsar aaey OYM aseasIp Jay “SUTIJaS STU} Ul [RAIAINS [[e19A0 UO JORdUUT OU sey Ade wn” Time

Pasn USM SoW0dINO dAOICUA WUBI JD/LAd JEU} AdUAPIAd Jo YOR] UdALD “SUISPUIT Jsay dtIpotod YM Suoye [eotsAyd pue ‘AULOJOIJSCUT [RID eTIG Jaye SIOd UIIM syuaned ut Ade AIO|SIY JO S|SISUOD DURT[IaAINS prepuR}S “Ia0Ued BUNT [90 -19Y] SUOWWIOY JURAN[pe IOJ J[OI OU SI 31D, “WYouaq [PALAINS [[euls Io} JUsUTvA1) Jo UONaTduio0d BuLMOTIO] souRTTIaAINs B JO YOR] poyuowmMoop k ayIdsap Ia0Ued JseaIq ATeULId ammyny IO} }Sa} plepue}s B JOU ST (q UONdO) SuIseUl [D/LAd ® JUaAaid 0} Adeiay} JUOULIOY UPY} JayyeI AUIOJDa}SeU [PIO ‘J20URd SUNT [[99 [Tes YM sjuatjed -yJeTIq otoe[Aydoid asooyp SIoOd YIM sjuarTyed atut0s JO JUS} 91] IY] UT s[OI poysi[qeysa OU sey Jf “UdUISa1 JUST “QUOTE UdJIXOW} SUISN 0} JATBUAI[e -Jea1] [PNIUI Ioy} 0} asuodsar a[qei1oaRy B aABY OM Ss}uaTyed UB SB S}[NsoI IoLJodns saplAaoid Adeidy} JOJIQIYUT asejyeUIOIe UI [RATAINS 391J-UOTssoi1s01d SAOIdUITI 0} UMOYS Udaq sey pue ‘UdUIOM Tesnedousutjsod 10,4 ‘UduOM [esnedouatuaid ut aan JaoUvd SUNT [[99 [[BWIS—UOU deIseIJOU YIM s]UaTyed UT pasn -dayja 10U oe (Y UOC) d[0zZOI]seUe PUL 3[0Z0I}9] SIOUGIYUT wn <b ATUOUIWIOD SI (Y UOHdO) AdersyjoWaYD sdUeUDIUTeI aSP]LUIOI SUT, ‘UstOM [esnedousunsod pure -aid y}0q UT aan = ‘aSOp MOTO] JAMO] B PUB ISOP [P}O} JAMO] -dayjo SI (9 UoNdO) UsfIXOWR], ‘saya dsIaApe pd}e[ai-Snup = - ® UJIM payesiiuw oq Uv YS SIU} Je] PUNO] aavy Sarpnyjs Wa [enuajod au] JsuTese paysiam aq prnoys s]youaq pure ‘jseaiq i (=) -poul oO Ysnoujye ‘pajou useq aaey JUsUITedumT sAnTUs0o [e1o}e[PI]UOS dy} UI JooUvd Js¥aiq ATeUTId MoU B JO YS ay} co SUIPILSal SUIIOUOD Ajayes ‘pasaouoid AyTeHTUT sem JUaTUyeAT] ssonpei Adeioy} suowoy jueaAni[pe ‘s[oq I0j Awo}a\seur aad Da SIU} aouTS AdeIO} [BNIUT Id} 0] papuodsar aaey OYM aseasIp Jay “SUTIJaS STU} Ul [RAIAINS [[e19A0 UO JORdUUT OU sey Ade wn” Time 988]S-dATSUD]XS IO POPU] JoUIIE TIM sjuaned Joy youTeaT Id} SULIOOpUSD “TIAIMOY !9dUILINIAI [BIO] JO YSL ay} sonpar a = JO JUSUOdUIOD pIepUR]s B PAIIPISUOD SI STU} ‘s}auaq asay} UO 0} SIO aantsod—10}da0ea1 UasOI}sa YIM sjuaTyed 0} parayo aA S paseg ‘(aseasip o8e]s-payull] UJIM syuatyed oy UMoUSs AprIeayo st Adeiay} suouoy JuRAN{[pe Atuojsadumny SuIMoTjoO i ¢

988]S-dATSUD]XS IO POPU] JoUIIE TIM sjuaned Joy youTeaT Id} SULIOOpUSD “TIAIMOY !9dUILINIAI [BIO] JO YSL ay} sonpar a = JO JUSUOdUIOD pIepUR]s B PAIIPISUOD SI STU} ‘s}auaq asay} UO 0} SIO aantsod—10}da0ea1 UasOI}sa YIM sjuaTyed 0} parayo aA S paseg ‘(aseasip o8e]s-payull] UJIM syuatyed oy UMoUSs AprIeayo st Adeiay} suouoy JuRAN{[pe Atuojsadumny SuIMoTjoO i ¢ ATUO SBM JJoUaq Ise] SI) AWTEIIOW UT UOTJONpar JuRdyTUsIS & ‘DOUILINIAI [BIO] JO SB [JOM SB SdSEISEIJOUL UTeIG JO IDUSPIOUT dy} Ul UOTONpar yuK YS oy] asvaisap 0} Adeviay} UoTerpes JuBAN [pe WOT JYauaq -IIUSIS B UT pa}[nsal [Od YIM JUsUeAT] Jey] Pamoys sjuaryed ABUL UdUIOM dos ‘AuLOJDaduuN] IayFY MOT OS SI IdUaLINIOI OOST Ue} SOU SUTPNIUL S[eL1} JUdIDYIP ZT JO siskyeue-vyaUL [B90] JO YSI at} asnvdaq AUWI0}D9]SeU SUTMOTIOJ SIO Jo sun B pue ‘JUSW}AI] SITY} JO asn passarppe aaey sarpmis Aueyy -JaS dY]}] UL papUsWIWOIaI JOU SI (q UONdO) UOHeIpery] ‘JUSUT}eoI] Ia0uRd pouurd Jo uoTatdwiod ay} Jaye aseastp ‘sayovoidde aaterodo deIseOU! UTeIG JNOYIM JUaTIed & UT UTeIq S;OUM ay] 0} UaATS OM] dU} UdIMJaq [PAIAINS WLI9}-SUOT Ul JDUdIAYIP OU SI aIDY], JUST] UONPIPRI 0} SIajal [Od ‘sase}sejJoUI UleIq JO YS ‘UISICL ATJRSOU & SULINSUSD ‘PaAOUad SI J[OS} 1owINy ayy Isn{ dU} SUTONpar JO suBdUT B SB ATAATSUD}X9 PoIpNys Udaq sey [Od UPIYM UI ‘AWIO}DaduM] IO ‘p3AoUta are ansst}) Isvarq [eULIOU ‘SII JUBIYIUSIS STU} UdAED ‘JUSU}BAI) [PNIUL YIM UOTSSTUIdI au] Jo [Te ATjeuassa YJLM BuUOTe IOUIN} dy} YOTYM UT ‘AuL0}09} ajo[duod Jo JUaUIUTeye SUTMOTO} syuatyed Jo spIty om} 01 -SPUI Joule apnpoul Aewl pue s[oq ym sjuayed Joy yUSUT dn. Ut SULLINDDO ‘JUBSYTUSIS SUTBUIDI SUOTSI] OTB}SBIOU UTeIq year Ateulid dy} St UOISIOXa [eoISINS ‘azIse}se}aU 0} ATITIGV

and dermatologic evaluation every 6 months (Option D). cT1aN0 indicating a depth of invasion less than 0.8 mm), the Particular attention should be directed to the primary resec- overall cure rate is approximately 95%. tion site for evidence of local recurrence (satellite lesions), In the absence of signs or symptoms of recurrence, rou- in-transit metastases (looking for disease traveling along the tine laboratory evaluation (Option C) or imaging with chest course of draining lymphatics), and regional nodal involve- radiograph (Option A), PET/CT, or brain MRI (Options B, E) ment. Regional lymph node ultrasound can be performed have a very low yield and are not routinely recommended. to better assess for adenopathy in patients with an equivocal However, in patients with higher stages of disease (stage lymph node examination. The patient should also be carefully IIB-IV), serial imaging with CT or whole-body fluorodeoxy- assessed for the development of second primary melanomas, glucose-PET with or without brain MRI may be considered as patients who have had one melanoma have a significantly appropriate for 3 to 5 years. higher risk of developing second primary melanomas. Fur- thermore, patients should be educated to perform routine skin self-examinations to screen for both recurrence and for ¢ Patients with low-risk (thin) melanoma should be w a new primary lesions. encouraged to perform skin self-examinations as well =]

and dermatologic evaluation every 6 months (Option D). cT1aN0 indicating a depth of invasion less than 0.8 mm), the Particular attention should be directed to the primary resec- overall cure rate is approximately 95%. tion site for evidence of local recurrence (satellite lesions), In the absence of signs or symptoms of recurrence, rou- in-transit metastases (looking for disease traveling along the tine laboratory evaluation (Option C) or imaging with chest course of draining lymphatics), and regional nodal involve- radiograph (Option A), PET/CT, or brain MRI (Options B, E) ment. Regional lymph node ultrasound can be performed have a very low yield and are not routinely recommended. to better assess for adenopathy in patients with an equivocal However, in patients with higher stages of disease (stage lymph node examination. The patient should also be carefully IIB-IV), serial imaging with CT or whole-body fluorodeoxy- assessed for the development of second primary melanomas, glucose-PET with or without brain MRI may be considered as patients who have had one melanoma have a significantly appropriate for 3 to 5 years. higher risk of developing second primary melanomas. Fur- thermore, patients should be educated to perform routine skin self-examinations to screen for both recurrence and for ¢ Patients with low-risk (thin) melanoma should be w a new primary lesions. encouraged to perform skin self-examinations as well =] Breslow staging indicates the depth of invasion of the as receive skin evaluations by a dermatologist regularly = melanoma below the surface of the skin. The risk of recur- for life. = oO rence increases as the depth of invasion increases. Ulceration sc < at presentation and high mitotic rate are also associated with cs Bibliography a higher risk of recurrence. Melanoma can be a very aggres- wa Pes Dowling J, McGregor SP, Williford P. Update on current treatment recom- o sive cancer and can metastasize widely, but if caught early, it mendations for primary cutaneous melanoma. Dermatol Clin. = has a very high cure rate. In patients such as this one (stage I, 2019;37:397-407. [PMID: 31466581] doi:10.1016 /j.det.2019.06.001 wn = <x

Breslow staging indicates the depth of invasion of the as receive skin evaluations by a dermatologist regularly = melanoma below the surface of the skin. The risk of recur- for life. = oO rence increases as the depth of invasion increases. Ulceration sc < at presentation and high mitotic rate are also associated with cs Bibliography a higher risk of recurrence. Melanoma can be a very aggres- wa Pes Dowling J, McGregor SP, Williford P. Update on current treatment recom- o sive cancer and can metastasize widely, but if caught early, it mendations for primary cutaneous melanoma. Dermatol Clin. = has a very high cure rate. In patients such as this one (stage I, 2019;37:397-407. [PMID: 31466581] doi:10.1016 /j.det.2019.06.001 wn = <x 103