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Lung Cancer Non-Small Cell Lung Cancer stage I, II, or IIIA cancer survive 5 years. Chemotherapy con- sists of cisplatin with a second agent and is typically given for Treatment of NSCLC, similar to that of most other solid malig- four cycles. The most commonly used chemotherapy partners nancies, is based largely on disease stage. For the purposes of are vinorelbine, pemetrexed, gemcitabine, and docetaxel. this discussion, it is best to divide NSCLC into early-stage, After treatment is completed, patients with early-stage locally advanced, and metastatic categories. disease remain at risk for both distant and local recurrence. Many patients with smoking histories are also at risk for devel- Early-Stage Disease oping a second primary lung cancer and cancers of the head, Early-stage disease refers to lung cancer that is amenable to neck, and other sites. Recommendations for surveillance surgical resection at the time of diagnosis. This typically include history, physical examination, and chest CT at least encompasses stage I and II cancers, although some patients every 6 months for the first 2 years and then annually. Smoking with stage II cancer are not amenable to resection based on cessation decreases the risk of new primary lung cancers by location or extent of the primary tumor. Stages I and II are dif- 20% to 90%; the risk steadily declines beginning 5 years after ferentiated by hilar nodal metastatic disease and also by the quitting, but it never quite reaches the incidence found in size and invasiveness of the primary tumor into adjacent nonsmokers. structures. Patients deemed potential surgical candidates based on imaging need to have a rigorous functional evaluation to help ¢ Lobectomy is the preferred surgical procedure in early-

Non-Small Cell Lung Cancer stage I, II, or IIIA cancer survive 5 years. Chemotherapy con- sists of cisplatin with a second agent and is typically given for Treatment of NSCLC, similar to that of most other solid malig- four cycles. The most commonly used chemotherapy partners nancies, is based largely on disease stage. For the purposes of are vinorelbine, pemetrexed, gemcitabine, and docetaxel. this discussion, it is best to divide NSCLC into early-stage, After treatment is completed, patients with early-stage locally advanced, and metastatic categories. disease remain at risk for both distant and local recurrence. Many patients with smoking histories are also at risk for devel- Early-Stage Disease oping a second primary lung cancer and cancers of the head, Early-stage disease refers to lung cancer that is amenable to neck, and other sites. Recommendations for surveillance surgical resection at the time of diagnosis. This typically include history, physical examination, and chest CT at least encompasses stage I and II cancers, although some patients every 6 months for the first 2 years and then annually. Smoking with stage II cancer are not amenable to resection based on cessation decreases the risk of new primary lung cancers by location or extent of the primary tumor. Stages I and II are dif- 20% to 90%; the risk steadily declines beginning 5 years after ferentiated by hilar nodal metastatic disease and also by the quitting, but it never quite reaches the incidence found in size and invasiveness of the primary tumor into adjacent nonsmokers. structures. Patients deemed potential surgical candidates based on imaging need to have a rigorous functional evaluation to help ¢ Lobectomy is the preferred surgical procedure in early- predict their anticipated pulmonary reserve after surgery. The stage non-small cell lung cancer.

Non-Small Cell Lung Cancer stage I, II, or IIIA cancer survive 5 years. Chemotherapy con- sists of cisplatin with a second agent and is typically given for Treatment of NSCLC, similar to that of most other solid malig- four cycles. The most commonly used chemotherapy partners nancies, is based largely on disease stage. For the purposes of are vinorelbine, pemetrexed, gemcitabine, and docetaxel. this discussion, it is best to divide NSCLC into early-stage, After treatment is completed, patients with early-stage locally advanced, and metastatic categories. disease remain at risk for both distant and local recurrence. Many patients with smoking histories are also at risk for devel- Early-Stage Disease oping a second primary lung cancer and cancers of the head, Early-stage disease refers to lung cancer that is amenable to neck, and other sites. Recommendations for surveillance surgical resection at the time of diagnosis. This typically include history, physical examination, and chest CT at least encompasses stage I and II cancers, although some patients every 6 months for the first 2 years and then annually. Smoking with stage II cancer are not amenable to resection based on cessation decreases the risk of new primary lung cancers by location or extent of the primary tumor. Stages I and II are dif- 20% to 90%; the risk steadily declines beginning 5 years after ferentiated by hilar nodal metastatic disease and also by the quitting, but it never quite reaches the incidence found in size and invasiveness of the primary tumor into adjacent nonsmokers. structures. Patients deemed potential surgical candidates based on imaging need to have a rigorous functional evaluation to help ¢ Lobectomy is the preferred surgical procedure in early- predict their anticipated pulmonary reserve after surgery. The stage non-small cell lung cancer. initial evaluation consists of FEV, and DLco measurement. If e Potential surgical candidates with early-stage lung can- both test variables are favorable, then no further evaluation is cer must have FEV, and DLco measurement to predict needed. However, if one or the other variable falls in a range their anticipated postoperative pulmonary reserve and suggesting impaired lung function, then calculation of the suitability for resection. predicted postoperative FEV, and Dico should be performed, e Patients with early-stage lung cancer who are not surgi- which is determined by baseline values and assessment of the cal candidates can be treated with radiation therapy: fractional contribution of the lung to be resected and, in some stereotactic body irradiation is appropriate for small instances, exercise testing. Based on the results of these assess- tumors, but conventional irradiation is used for large ments, a decision can be made regarding suitability for resec- tumors. tion. Patients with pathologic stage I cancer who are e Postoperative radiation therapy is used to treat patients undergoing surgical resection have a 60% to 70% survival rate with resected localized lung cancer and positive tumor at 5 years, and patients with stage II cancer have approxi- margins; cisplatin-based adjuvant chemotherapy is mately a 40% survival rate. standard treatment of all resected stage II and III lung Other options are available for patients who are not surgi- cancer. cal candidates, including stereotactic body irradiation that can be used to treat the primary tumor. Such treatments have excellent rates of local control, but they are only suitable for Locally Advanced Disease patients with small stage I cancers. For larger tumors, conven- Locally advanced lung cancer is most commonly defined by tional irradiation is used. There are no data supporting the use the presence of clinically detectable lymphadenopathy in the of chemotherapy combined with irradiation in patients with mediastinum or by a primary tumor that invades into local stage I or II disease. Patients with localized tumors treated structures, such as the mediastinum, heart, trachea, esopha- with irradiation have a mean survival of greater than 3 years. gus, or great vessels. Lobectomy is the preferred surgical procedure in early- Improvements in surgical technique and in the accuracy stage disease. Proximal tumors may be less amenable to lobec- of staging studies have expanded the number of patients eligi- tomy. In those patients, sleeve resection (resection of the ble for surgical resection, although it is unclear whether this involved lobe and a portion of the main stem bronchus) has has resulted in improved survival outcomes. For example, fewer postoperative complications and is preferable to pneu- some patients with T4 tumors showing invasion into adjacent monectomy. Sublobar resection can be considered in elderly vital structures, with no evidence of mediastinal node involve- patients or those with small stage I cancers. ment, can have surgical resection and their disease treated as Patients treated surgically for stage I or II disease who stage III disease. Patients with satellite nodules in the same have positive margins benefit from postoperative radiation lobe (T3) or in another ipsilateral lobe (T4) can be resected therapy with an improvement in overall survival. with curative intent. Even patients with an isolated tumor Cisplatin-based adjuvant chemotherapy after resection in nodule in the contralateral lung, traditionally considered patients with resected stage II or III lung cancer results in incurable metastatic disease, can undergo resection to remove approximately a 5% decrease in the risk of death at 5 years. all sites of cancer under the assumption that the nodule could Approximately 50% of patients who have surgically resected represent a second localized primary lung cancer. Finally,

initial evaluation consists of FEV, and DLco measurement. If e Potential surgical candidates with early-stage lung can- both test variables are favorable, then no further evaluation is cer must have FEV, and DLco measurement to predict needed. However, if one or the other variable falls in a range their anticipated postoperative pulmonary reserve and suggesting impaired lung function, then calculation of the suitability for resection. predicted postoperative FEV, and Dico should be performed, e Patients with early-stage lung cancer who are not surgi- which is determined by baseline values and assessment of the cal candidates can be treated with radiation therapy: fractional contribution of the lung to be resected and, in some stereotactic body irradiation is appropriate for small instances, exercise testing. Based on the results of these assess- tumors, but conventional irradiation is used for large ments, a decision can be made regarding suitability for resec- tumors. tion. Patients with pathologic stage I cancer who are e Postoperative radiation therapy is used to treat patients undergoing surgical resection have a 60% to 70% survival rate with resected localized lung cancer and positive tumor at 5 years, and patients with stage II cancer have approxi- margins; cisplatin-based adjuvant chemotherapy is mately a 40% survival rate. standard treatment of all resected stage II and III lung Other options are available for patients who are not surgi- cancer. cal candidates, including stereotactic body irradiation that can be used to treat the primary tumor. Such treatments have excellent rates of local control, but they are only suitable for Locally Advanced Disease patients with small stage I cancers. For larger tumors, conven- Locally advanced lung cancer is most commonly defined by tional irradiation is used. There are no data supporting the use the presence of clinically detectable lymphadenopathy in the of chemotherapy combined with irradiation in patients with mediastinum or by a primary tumor that invades into local stage I or II disease. Patients with localized tumors treated structures, such as the mediastinum, heart, trachea, esopha- with irradiation have a mean survival of greater than 3 years. gus, or great vessels. Lobectomy is the preferred surgical procedure in early- Improvements in surgical technique and in the accuracy stage disease. Proximal tumors may be less amenable to lobec- of staging studies have expanded the number of patients eligi- tomy. In those patients, sleeve resection (resection of the ble for surgical resection, although it is unclear whether this involved lobe and a portion of the main stem bronchus) has has resulted in improved survival outcomes. For example, fewer postoperative complications and is preferable to pneu- some patients with T4 tumors showing invasion into adjacent monectomy. Sublobar resection can be considered in elderly vital structures, with no evidence of mediastinal node involve- patients or those with small stage I cancers. ment, can have surgical resection and their disease treated as Patients treated surgically for stage I or II disease who stage III disease. Patients with satellite nodules in the same have positive margins benefit from postoperative radiation lobe (T3) or in another ipsilateral lobe (T4) can be resected therapy with an improvement in overall survival. with curative intent. Even patients with an isolated tumor Cisplatin-based adjuvant chemotherapy after resection in nodule in the contralateral lung, traditionally considered patients with resected stage II or III lung cancer results in incurable metastatic disease, can undergo resection to remove approximately a 5% decrease in the risk of death at 5 years. all sites of cancer under the assumption that the nodule could Approximately 50% of patients who have surgically resected represent a second localized primary lung cancer. Finally, 22

Lung Cancer patients with limited ipsilateral mediastinal node involve- ROS1 translocation is identified, initial treatment with alec- ment, a single node station, and non-bulky disease can tinib is recommended. These agents are small molecule tyro- undergo surgical resection. These patients will all generally sine kinase inhibitors that are specific for those genetic receive neoadjuvant or adjuvant chemotherapy or radiation alterations. There are data and approved agents for the treat- treatment. ment of other molecular abnormalities in lung cancer, for Locally advanced lung cancer presenting with bulky or example, BRAF V600E mutations, TRK, and c-Met. The list of widespread mediastinal or hilar lymph node involvement is targetable mutations and translocations is expanding rapidly, generally considered unresectable, so patients are treated with and there is an emerging consensus that all patients with combined platinum-based chemotherapy and irradiation, advanced NSCLC should have their tumors tested by next- which has been found to be superior to sequential treatment. generation sequencing. Next-generation sequencing uses par- Unfortunately, the risk of recurrence, both locoregional and allel sequencing of multiple small fragments of DNA to distant, is very high despite chemoradiation treatment determine genome sequence and can be performed on blood (approaching 90%). The use of the anti-programmed death leukocytes or a variety of other sources. ligand 1 agent durvalumab has been demonstrated to signifi- Immunotherapy targeting programmed death 1 or PD-L1 cantly improve overall survival when used after chemotherapy has transformed treatment of metastatic NSCLC. It can be and radiation therapy in patients who have stable disease or combined with platinum-based combination chemotherapy objective response after at least two cycles of treatment. in the front-line treatment setting for both adenocarcinoma and squamous cell carcinoma. It can also be used as a single e Locally advanced lung cancer presenting with bulky or agent in the front-line setting or after prior treatment with widespread mediastinal or hilar lymph node involve- chemotherapy. Combining chemotherapy and immunother- ment is generally considered unresectable, so patients apy has been shown to improve survival regardless of PD-L1 are treated with combined platinum-based chemother- status, although it also increases risk of adverse effects. Single- apy and irradiation. agent immunotherapy, however, is only appropriate for

patients with limited ipsilateral mediastinal node involve- ROS1 translocation is identified, initial treatment with alec- ment, a single node station, and non-bulky disease can tinib is recommended. These agents are small molecule tyro- undergo surgical resection. These patients will all generally sine kinase inhibitors that are specific for those genetic receive neoadjuvant or adjuvant chemotherapy or radiation alterations. There are data and approved agents for the treat- treatment. ment of other molecular abnormalities in lung cancer, for Locally advanced lung cancer presenting with bulky or example, BRAF V600E mutations, TRK, and c-Met. The list of widespread mediastinal or hilar lymph node involvement is targetable mutations and translocations is expanding rapidly, generally considered unresectable, so patients are treated with and there is an emerging consensus that all patients with combined platinum-based chemotherapy and irradiation, advanced NSCLC should have their tumors tested by next- which has been found to be superior to sequential treatment. generation sequencing. Next-generation sequencing uses par- Unfortunately, the risk of recurrence, both locoregional and allel sequencing of multiple small fragments of DNA to distant, is very high despite chemoradiation treatment determine genome sequence and can be performed on blood (approaching 90%). The use of the anti-programmed death leukocytes or a variety of other sources. ligand 1 agent durvalumab has been demonstrated to signifi- Immunotherapy targeting programmed death 1 or PD-L1 cantly improve overall survival when used after chemotherapy has transformed treatment of metastatic NSCLC. It can be and radiation therapy in patients who have stable disease or combined with platinum-based combination chemotherapy objective response after at least two cycles of treatment. in the front-line treatment setting for both adenocarcinoma and squamous cell carcinoma. It can also be used as a single e Locally advanced lung cancer presenting with bulky or agent in the front-line setting or after prior treatment with widespread mediastinal or hilar lymph node involve- chemotherapy. Combining chemotherapy and immunother- ment is generally considered unresectable, so patients apy has been shown to improve survival regardless of PD-L1 are treated with combined platinum-based chemother- status, although it also increases risk of adverse effects. Single- apy and irradiation. agent immunotherapy, however, is only appropriate for patients with adequate PD-L1 tumor expression. In the front- Metastatic Disease line setting, pembrolizumab improves response rate, progres- Metastatic lung cancer is defined as the spread of disease to sion-free survival, and overall survival if PD-L1 expression is distant sites such as the liver, bone, or brain. The presence of 50% or higher. Other reports have found 5-year survival rates one or more tumor nodules in the contralateral lung also of 25% to 30% in patients treated with pembrolizumab in the qualifies as metastatic disease, but as the prognosis for that front-line setting when PD-L1 expression is at least 50%. It is pattern of metastatic disease is notably better than that of also FDA approved for use in patients with PD-L1 expression patients with distant disease, it is classified as Mla, with other from 1% to 49%, although it is less active as a single agent for distant sites given the designation of Mic. Patients with a soli- such patients. tary site of metastatic disease are classed as M1b. Patients with Patients without a relevant molecular alteration and who only a single site of metastatic disease (most frequently in the are not candidates for immunotherapy are treated with brain) are potentially curable after resection. platinum-based chemotherapy. Cisplatin is slightly more active, In the past, all patients with metastatic NSCLC were but carboplatin is commonly used because of its more favorable treated with the same chemotherapy regimens. Current treat- adverse effect profile. Histologic assessment can help guide ment options depend on the presence of specific molecular choice of the second agent, as patients with adenocarcinoma alterations, expression of programmed death ligand 1 (PD-L1) have been shown to respond well to pemetrexed, whereas those in tumor tissue, and also on histology. The number of available with squamous cell carcinoma respond better to gemcitabine. treatments has expanded, and the median survival has Chemotherapy is administered for four to six cycles. improved. Despite these advances, however, metastatic NSCLC Bevacizumab, a monoclonal antibody directed against vascular remains an incurable disease for most patients. Early palliative endothelial growth factor, can be added to platinum -based care interventions in this patient population will improve

patients with adequate PD-L1 tumor expression. In the front- Metastatic Disease line setting, pembrolizumab improves response rate, progres- Metastatic lung cancer is defined as the spread of disease to sion-free survival, and overall survival if PD-L1 expression is distant sites such as the liver, bone, or brain. The presence of 50% or higher. Other reports have found 5-year survival rates one or more tumor nodules in the contralateral lung also of 25% to 30% in patients treated with pembrolizumab in the qualifies as metastatic disease, but as the prognosis for that front-line setting when PD-L1 expression is at least 50%. It is pattern of metastatic disease is notably better than that of also FDA approved for use in patients with PD-L1 expression patients with distant disease, it is classified as Mla, with other from 1% to 49%, although it is less active as a single agent for distant sites given the designation of Mic. Patients with a soli- such patients. tary site of metastatic disease are classed as M1b. Patients with Patients without a relevant molecular alteration and who only a single site of metastatic disease (most frequently in the are not candidates for immunotherapy are treated with brain) are potentially curable after resection. platinum-based chemotherapy. Cisplatin is slightly more active, In the past, all patients with metastatic NSCLC were but carboplatin is commonly used because of its more favorable treated with the same chemotherapy regimens. Current treat- adverse effect profile. Histologic assessment can help guide ment options depend on the presence of specific molecular choice of the second agent, as patients with adenocarcinoma alterations, expression of programmed death ligand 1 (PD-L1) have been shown to respond well to pemetrexed, whereas those in tumor tissue, and also on histology. The number of available with squamous cell carcinoma respond better to gemcitabine. treatments has expanded, and the median survival has Chemotherapy is administered for four to six cycles. improved. Despite these advances, however, metastatic NSCLC Bevacizumab, a monoclonal antibody directed against vascular remains an incurable disease for most patients. Early palliative endothelial growth factor, can be added to platinum -based care interventions in this patient population will improve quality of life even as they continue to receive aggressive chemotherapy in patients not treated with immunotherapy. It

patients with adequate PD-L1 tumor expression. In the front- Metastatic Disease line setting, pembrolizumab improves response rate, progres- Metastatic lung cancer is defined as the spread of disease to sion-free survival, and overall survival if PD-L1 expression is distant sites such as the liver, bone, or brain. The presence of 50% or higher. Other reports have found 5-year survival rates one or more tumor nodules in the contralateral lung also of 25% to 30% in patients treated with pembrolizumab in the qualifies as metastatic disease, but as the prognosis for that front-line setting when PD-L1 expression is at least 50%. It is pattern of metastatic disease is notably better than that of also FDA approved for use in patients with PD-L1 expression patients with distant disease, it is classified as Mla, with other from 1% to 49%, although it is less active as a single agent for distant sites given the designation of Mic. Patients with a soli- such patients. tary site of metastatic disease are classed as M1b. Patients with Patients without a relevant molecular alteration and who only a single site of metastatic disease (most frequently in the are not candidates for immunotherapy are treated with brain) are potentially curable after resection. platinum-based chemotherapy. Cisplatin is slightly more active, In the past, all patients with metastatic NSCLC were but carboplatin is commonly used because of its more favorable treated with the same chemotherapy regimens. Current treat- adverse effect profile. Histologic assessment can help guide ment options depend on the presence of specific molecular choice of the second agent, as patients with adenocarcinoma alterations, expression of programmed death ligand 1 (PD-L1) have been shown to respond well to pemetrexed, whereas those in tumor tissue, and also on histology. The number of available with squamous cell carcinoma respond better to gemcitabine. treatments has expanded, and the median survival has Chemotherapy is administered for four to six cycles. improved. Despite these advances, however, metastatic NSCLC Bevacizumab, a monoclonal antibody directed against vascular remains an incurable disease for most patients. Early palliative endothelial growth factor, can be added to platinum -based care interventions in this patient population will improve quality of life even as they continue to receive aggressive chemotherapy in patients not treated with immunotherapy. It chemotherapy. provides only modest improvement in progression-free survival

patients with adequate PD-L1 tumor expression. In the front- Metastatic Disease line setting, pembrolizumab improves response rate, progres- Metastatic lung cancer is defined as the spread of disease to sion-free survival, and overall survival if PD-L1 expression is distant sites such as the liver, bone, or brain. The presence of 50% or higher. Other reports have found 5-year survival rates one or more tumor nodules in the contralateral lung also of 25% to 30% in patients treated with pembrolizumab in the qualifies as metastatic disease, but as the prognosis for that front-line setting when PD-L1 expression is at least 50%. It is pattern of metastatic disease is notably better than that of also FDA approved for use in patients with PD-L1 expression patients with distant disease, it is classified as Mla, with other from 1% to 49%, although it is less active as a single agent for distant sites given the designation of Mic. Patients with a soli- such patients. tary site of metastatic disease are classed as M1b. Patients with Patients without a relevant molecular alteration and who only a single site of metastatic disease (most frequently in the are not candidates for immunotherapy are treated with brain) are potentially curable after resection. platinum-based chemotherapy. Cisplatin is slightly more active, In the past, all patients with metastatic NSCLC were but carboplatin is commonly used because of its more favorable treated with the same chemotherapy regimens. Current treat- adverse effect profile. Histologic assessment can help guide ment options depend on the presence of specific molecular choice of the second agent, as patients with adenocarcinoma alterations, expression of programmed death ligand 1 (PD-L1) have been shown to respond well to pemetrexed, whereas those in tumor tissue, and also on histology. The number of available with squamous cell carcinoma respond better to gemcitabine. treatments has expanded, and the median survival has Chemotherapy is administered for four to six cycles. improved. Despite these advances, however, metastatic NSCLC Bevacizumab, a monoclonal antibody directed against vascular remains an incurable disease for most patients. Early palliative endothelial growth factor, can be added to platinum -based care interventions in this patient population will improve quality of life even as they continue to receive aggressive chemotherapy in patients not treated with immunotherapy. It chemotherapy. provides only modest improvement in progression-free survival Before deciding the optimal treatment for any given and overall survival. It carries the risk of thrombosis, stroke,

quality of life even as they continue to receive aggressive chemotherapy in patients not treated with immunotherapy. It chemotherapy. provides only modest improvement in progression-free survival Before deciding the optimal treatment for any given and overall survival. It carries the risk of thrombosis, stroke, patient, it is essential to define histology, assess for molecular myocardial infarction, and hemoptysis in some patients. It is not alterations, especially for patients with adenocarcinoma, indicated in patients with squamous cell carcinoma due to risk PD-L1 status, and determine performance status. Mutations in of hemoptysis. For patients who respond to front-line chemo- the epidermal growth factor receptor gene and for transloca- therapy, maintenance treatment with docetaxel, pemetrexed, or tions involving ALK or ROS1 should be tested. If an epidermal gemcitabine has been shown to improve progression-free sur- growth factor receptor mutation is identified, initial treatment vival, and pemetrexed has also been shown to improve overall with erlotinib or osimertinib is recommended. If an ALK or survival. 23

Head and Neck Cancer Stereotactic body irradiation can be used to treat residual occult nodal involvement. Those patients should also receive metastatic sites after response to systemic therapy. Progression- adjuvant chemotherapy. free survival is improved compared with maintenance chemo- Most patients with SCLC will not meet the criteria for therapy alone. It can also be used to treat isolated or limited primary surgery. Treatment of limited disease consists of com- areas of disease progression in patients receiving otherwise bined cisplatin-based chemotherapy, typically cisplatin plus active systemic therapy. etoposide, and irradiation. Chemotherapy is continued after Patients with poor performance status do not benefit irradiation for up to six cycles; prophylactic cranial irradiation from chemotherapy or immunotherapy and should be consid- can be used in patients with responsive disease to decrease the ered for hospice care. rate of subsequent brain metastases and improve overall sur- vival. This treatment increases risk of cognitive impairment in patients 60 years and older, however, and is not indicated in HVC e Patients with poor performance status do not benefit patients with poor performance or those with pre-existing from chemotherapy or immunotherapy and should be neurocognitive impairment. considered for hospice care. For patients with extensive disease, treatment consists of e Metastatic non-small cell lung cancer that demonstrates combination platinum-etoposide and immunotherapy with- an epidermal growth factor receptor gene mutation out irradiation for up to six cycles with continuation of immu- should be treated initially with erlotinib or osimertinib; notherapy until progression. Patients with lower-volume if an ALK or ROS1 translocation is identified, initial disease that is responsive to treatment and without brain treatment should be with alectinib. metastases can be considered for prophylactic cranial irradia-

Stereotactic body irradiation can be used to treat residual occult nodal involvement. Those patients should also receive metastatic sites after response to systemic therapy. Progression- adjuvant chemotherapy. free survival is improved compared with maintenance chemo- Most patients with SCLC will not meet the criteria for therapy alone. It can also be used to treat isolated or limited primary surgery. Treatment of limited disease consists of com- areas of disease progression in patients receiving otherwise bined cisplatin-based chemotherapy, typically cisplatin plus active systemic therapy. etoposide, and irradiation. Chemotherapy is continued after Patients with poor performance status do not benefit irradiation for up to six cycles; prophylactic cranial irradiation from chemotherapy or immunotherapy and should be consid- can be used in patients with responsive disease to decrease the ered for hospice care. rate of subsequent brain metastases and improve overall sur- vival. This treatment increases risk of cognitive impairment in patients 60 years and older, however, and is not indicated in HVC e Patients with poor performance status do not benefit patients with poor performance or those with pre-existing from chemotherapy or immunotherapy and should be neurocognitive impairment. considered for hospice care. For patients with extensive disease, treatment consists of e Metastatic non-small cell lung cancer that demonstrates combination platinum-etoposide and immunotherapy with- an epidermal growth factor receptor gene mutation out irradiation for up to six cycles with continuation of immu- should be treated initially with erlotinib or osimertinib; notherapy until progression. Patients with lower-volume if an ALK or ROS1 translocation is identified, initial disease that is responsive to treatment and without brain treatment should be with alectinib. metastases can be considered for prophylactic cranial irradia- e If metastatic non-small cell lung cancer is negative for a tion. Patients with extensive disease who have a favorable

Stereotactic body irradiation can be used to treat residual occult nodal involvement. Those patients should also receive metastatic sites after response to systemic therapy. Progression- adjuvant chemotherapy. free survival is improved compared with maintenance chemo- Most patients with SCLC will not meet the criteria for therapy alone. It can also be used to treat isolated or limited primary surgery. Treatment of limited disease consists of com- areas of disease progression in patients receiving otherwise bined cisplatin-based chemotherapy, typically cisplatin plus active systemic therapy. etoposide, and irradiation. Chemotherapy is continued after Patients with poor performance status do not benefit irradiation for up to six cycles; prophylactic cranial irradiation from chemotherapy or immunotherapy and should be consid- can be used in patients with responsive disease to decrease the ered for hospice care. rate of subsequent brain metastases and improve overall sur- vival. This treatment increases risk of cognitive impairment in patients 60 years and older, however, and is not indicated in HVC e Patients with poor performance status do not benefit patients with poor performance or those with pre-existing from chemotherapy or immunotherapy and should be neurocognitive impairment. considered for hospice care. For patients with extensive disease, treatment consists of e Metastatic non-small cell lung cancer that demonstrates combination platinum-etoposide and immunotherapy with- an epidermal growth factor receptor gene mutation out irradiation for up to six cycles with continuation of immu- should be treated initially with erlotinib or osimertinib; notherapy until progression. Patients with lower-volume if an ALK or ROS1 translocation is identified, initial disease that is responsive to treatment and without brain treatment should be with alectinib. metastases can be considered for prophylactic cranial irradia- e If metastatic non-small cell lung cancer is negative for a tion. Patients with extensive disease who have a favorable driver mutation, treatment options include immuno- response to chemotherapy but persistent involvement in the

Stereotactic body irradiation can be used to treat residual occult nodal involvement. Those patients should also receive metastatic sites after response to systemic therapy. Progression- adjuvant chemotherapy. free survival is improved compared with maintenance chemo- Most patients with SCLC will not meet the criteria for therapy alone. It can also be used to treat isolated or limited primary surgery. Treatment of limited disease consists of com- areas of disease progression in patients receiving otherwise bined cisplatin-based chemotherapy, typically cisplatin plus active systemic therapy. etoposide, and irradiation. Chemotherapy is continued after Patients with poor performance status do not benefit irradiation for up to six cycles; prophylactic cranial irradiation from chemotherapy or immunotherapy and should be consid- can be used in patients with responsive disease to decrease the ered for hospice care. rate of subsequent brain metastases and improve overall sur- vival. This treatment increases risk of cognitive impairment in patients 60 years and older, however, and is not indicated in HVC e Patients with poor performance status do not benefit patients with poor performance or those with pre-existing from chemotherapy or immunotherapy and should be neurocognitive impairment. considered for hospice care. For patients with extensive disease, treatment consists of e Metastatic non-small cell lung cancer that demonstrates combination platinum-etoposide and immunotherapy with- an epidermal growth factor receptor gene mutation out irradiation for up to six cycles with continuation of immu- should be treated initially with erlotinib or osimertinib; notherapy until progression. Patients with lower-volume if an ALK or ROS1 translocation is identified, initial disease that is responsive to treatment and without brain treatment should be with alectinib. metastases can be considered for prophylactic cranial irradia- e If metastatic non-small cell lung cancer is negative for a tion. Patients with extensive disease who have a favorable driver mutation, treatment options include immuno- response to chemotherapy but persistent involvement in the therapy, platinum-based chemotherapy, or a combina- lung can be treated with additional radiation therapy.

e If metastatic non-small cell lung cancer is negative for a tion. Patients with extensive disease who have a favorable driver mutation, treatment options include immuno- response to chemotherapy but persistent involvement in the therapy, platinum-based chemotherapy, or a combina- lung can be treated with additional radiation therapy. tion of both. Despite treatment response, recurrences are very com- mon, even in patients with limited disease at the time of diag- nosis. For patients with recurrent disease who had a disease-free interval of more than 3 months, treatment with Small Cell Lung Cancer the initial platinum-based doublet regimen can be used SCLC, a neuroendocrine neoplasm, currently accounts for because the likelihood of response is favorable. However, for approximately 10% of lung cancer cases. SCLC is almost exclu- patients who relapse earlier, treatment with different agents is sively caused by smoking. Most patients initially present with indicated. Although immunotherapy has been shown to be distant metastatic disease. SCLC can be associated with para- beneficial in this setting, the results are not as remarkable as in neoplastic syndromes, most prominently the syndromes of patients with NSCLC. As in NSCLC, addressing goals of care inappropriate antidiuretic hormone secretion and Lambert- and aggressive symptom management are of significant Eaton myasthenia. Although the staging system used for SCLC importance in this setting. is the same as that for NSCLC, most therapeutic decisions are made based on whether patients have “limited disease,” usu- ally defined as disease limited to the hemithorax and regional e Routine staging of patients with small cell lung cancer lymph nodes and can be safely encompassed in a radiotherapy includes CT scan of the thorax, abdomen, and pelvis as

tion of both. Despite treatment response, recurrences are very com- mon, even in patients with limited disease at the time of diag- nosis. For patients with recurrent disease who had a disease-free interval of more than 3 months, treatment with Small Cell Lung Cancer the initial platinum-based doublet regimen can be used SCLC, a neuroendocrine neoplasm, currently accounts for because the likelihood of response is favorable. However, for approximately 10% of lung cancer cases. SCLC is almost exclu- patients who relapse earlier, treatment with different agents is sively caused by smoking. Most patients initially present with indicated. Although immunotherapy has been shown to be distant metastatic disease. SCLC can be associated with para- beneficial in this setting, the results are not as remarkable as in neoplastic syndromes, most prominently the syndromes of patients with NSCLC. As in NSCLC, addressing goals of care inappropriate antidiuretic hormone secretion and Lambert- and aggressive symptom management are of significant Eaton myasthenia. Although the staging system used for SCLC importance in this setting. is the same as that for NSCLC, most therapeutic decisions are made based on whether patients have “limited disease,” usu- ally defined as disease limited to the hemithorax and regional e Routine staging of patients with small cell lung cancer lymph nodes and can be safely encompassed in a radiotherapy includes CT scan of the thorax, abdomen, and pelvis as field (stage I-IIIb). All others, including those with distant well as PET or whole-body bone scintigraphy and MRI

tion of both. Despite treatment response, recurrences are very com- mon, even in patients with limited disease at the time of diag- nosis. For patients with recurrent disease who had a disease-free interval of more than 3 months, treatment with Small Cell Lung Cancer the initial platinum-based doublet regimen can be used SCLC, a neuroendocrine neoplasm, currently accounts for because the likelihood of response is favorable. However, for approximately 10% of lung cancer cases. SCLC is almost exclu- patients who relapse earlier, treatment with different agents is sively caused by smoking. Most patients initially present with indicated. Although immunotherapy has been shown to be distant metastatic disease. SCLC can be associated with para- beneficial in this setting, the results are not as remarkable as in neoplastic syndromes, most prominently the syndromes of patients with NSCLC. As in NSCLC, addressing goals of care inappropriate antidiuretic hormone secretion and Lambert- and aggressive symptom management are of significant Eaton myasthenia. Although the staging system used for SCLC importance in this setting. is the same as that for NSCLC, most therapeutic decisions are made based on whether patients have “limited disease,” usu- ally defined as disease limited to the hemithorax and regional e Routine staging of patients with small cell lung cancer lymph nodes and can be safely encompassed in a radiotherapy includes CT scan of the thorax, abdomen, and pelvis as field (stage I-IIIb). All others, including those with distant well as PET or whole-body bone scintigraphy and MRI metastases, have “extensive disease” (stage IV). Patients should of the brain. undergo a routine CT of the thorax, abdomen, and pelvis, but ¢ Patients with early-stage disease (stage I) small cell lung even those who have no bone or central nervous system symp- cancer can be considered for resection and adjuvant toms should undergo a PET or whole-body bone scintigraphy chemotherapy without irradiation if surgical margins and an MRI of the brain, as asymptomatic metastases are not are negative. uncommon. e Patients with both limited- and extensive-stage small Typically, patients with primary SCLC present with proxi- cell lung cancer who respond to chemotherapy should mal and often large tumors, but occasionally exhibit a solitary consider prophylactic irradiation to the central nervous pulmonary nodule (see Pulmonary and Critical Care Medicine). system. They are often not diagnosed until after surgical resection. After resection, these rare patients should be treated with adju- vant chemotherapy, but radiation therapy can be avoided if surgical margins are negative. Surgery can also be performed Head and Neck Cancer for small primary tumors without lymph node spread, although Squamous cell carcinoma is the most common form of head preoperative evaluation in those patients should include endo- and neck cancer, including primary tumors of the oral cavity, bronchial ultrasonography or mediastinoscopy to rule out oropharynx, nasopharynx, hypopharynx, larynx, paranasal

metastases, have “extensive disease” (stage IV). Patients should of the brain. undergo a routine CT of the thorax, abdomen, and pelvis, but ¢ Patients with early-stage disease (stage I) small cell lung even those who have no bone or central nervous system symp- cancer can be considered for resection and adjuvant toms should undergo a PET or whole-body bone scintigraphy chemotherapy without irradiation if surgical margins and an MRI of the brain, as asymptomatic metastases are not are negative. uncommon. e Patients with both limited- and extensive-stage small Typically, patients with primary SCLC present with proxi- cell lung cancer who respond to chemotherapy should mal and often large tumors, but occasionally exhibit a solitary consider prophylactic irradiation to the central nervous pulmonary nodule (see Pulmonary and Critical Care Medicine). system. They are often not diagnosed until after surgical resection. After resection, these rare patients should be treated with adju- vant chemotherapy, but radiation therapy can be avoided if surgical margins are negative. Surgery can also be performed Head and Neck Cancer for small primary tumors without lymph node spread, although Squamous cell carcinoma is the most common form of head preoperative evaluation in those patients should include endo- and neck cancer, including primary tumors of the oral cavity, bronchial ultrasonography or mediastinoscopy to rule out oropharynx, nasopharynx, hypopharynx, larynx, paranasal 24

Head and Neck Cancer sinuses, thyroid, and salivary glands. Thyroid cancer is dis- primary tumor. PET/CT is useful to evaluate regional nodes cussed in Endocrinology and Metabolism. and rule out distant metastatic disease, although it is not accu- rate in nodes 5 mm or smaller. The staging of head and neck cancers is complex, as each Risk Factors subsite uses a different staging system. Stage is the most The most important risk factor for head and neck cancer is important determinant of prognosis. Staging of primary smoked and smokeless tobacco use. Alcohol use is also a tumors is based on both size and extent of invasion into adja- known risk factor, and the combination of alcohol and tobacco cent structures. Nodal staging is predicated on the number of synergistically increases the risk. nodes involved, size, and presence or absence of bilateral lym- Human papillomavirus (HPV) is an increasingly impor- phadenopathy. HPV-related cancer of the oropharynx has a tant cause of head and neck cancer, with most HPV-associated different staging system than non-HPV-related cancer based cancers arising in the tonsils or base of the tongue. Although on significant differences in prognosis. Patients with early- treatment is not altered, the prognosis of HPV-associated oro- stage head and neck cancers have 70% to 90% long-term sur- pharynx cancer in nonsmokers is significantly better than that vival. Multimodality tumor board discussion is valuable for for non-HPV-related cancer. determining the proper course of treatment.

sinuses, thyroid, and salivary glands. Thyroid cancer is dis- primary tumor. PET/CT is useful to evaluate regional nodes cussed in Endocrinology and Metabolism. and rule out distant metastatic disease, although it is not accu- rate in nodes 5 mm or smaller. The staging of head and neck cancers is complex, as each Risk Factors subsite uses a different staging system. Stage is the most The most important risk factor for head and neck cancer is important determinant of prognosis. Staging of primary smoked and smokeless tobacco use. Alcohol use is also a tumors is based on both size and extent of invasion into adja- known risk factor, and the combination of alcohol and tobacco cent structures. Nodal staging is predicated on the number of synergistically increases the risk. nodes involved, size, and presence or absence of bilateral lym- Human papillomavirus (HPV) is an increasingly impor- phadenopathy. HPV-related cancer of the oropharynx has a tant cause of head and neck cancer, with most HPV-associated different staging system than non-HPV-related cancer based cancers arising in the tonsils or base of the tongue. Although on significant differences in prognosis. Patients with early- treatment is not altered, the prognosis of HPV-associated oro- stage head and neck cancers have 70% to 90% long-term sur- pharynx cancer in nonsmokers is significantly better than that vival. Multimodality tumor board discussion is valuable for for non-HPV-related cancer. determining the proper course of treatment. ¢ Tobacco and alcohol use are important risk factors for e Malignant neck masses are commonly painless, firm head and neck cancer, and their combined use syner- and/or fixed on examination, and not associated with gistically increases risk. antecedent infection. ¢ Human papillomavirus (HPV) infection is an important cause of oropharyngeal cancer; in nonsmokers, the prog- nosis is better than that for non—-HPV-related cancer. Treatment Approximately one third of patients who present with small

¢ Tobacco and alcohol use are important risk factors for e Malignant neck masses are commonly painless, firm head and neck cancer, and their combined use syner- and/or fixed on examination, and not associated with gistically increases risk. antecedent infection. ¢ Human papillomavirus (HPV) infection is an important cause of oropharyngeal cancer; in nonsmokers, the prog- nosis is better than that for non—-HPV-related cancer. Treatment Approximately one third of patients who present with small tumors without lymph node metastases are effectively treated Clinical Manifestations with either surgery or radiation therapy. Treatment decisions Presenting symptoms vary with the cancer’s location, but weigh tumor location and postoperative complications, concerning signs and symptoms include persistent or progres- including appearance and preservation of speech, with the sive lymph node enlargement or other neck mass, unilateral expected morbidity of radiation therapy, including acute hearing loss or ear pain, nasal obstruction, oral pain, nonheal- mucositis and fatigue, along with more long-lasting altera- ing oral ulcers, dysphagia, odynophagia, and hoarseness. HPV- tions in taste, xerostomia, dental disease, and an increased risk

tumors without lymph node metastases are effectively treated Clinical Manifestations with either surgery or radiation therapy. Treatment decisions Presenting symptoms vary with the cancer’s location, but weigh tumor location and postoperative complications, concerning signs and symptoms include persistent or progres- including appearance and preservation of speech, with the sive lymph node enlargement or other neck mass, unilateral expected morbidity of radiation therapy, including acute hearing loss or ear pain, nasal obstruction, oral pain, nonheal- mucositis and fatigue, along with more long-lasting altera- ing oral ulcers, dysphagia, odynophagia, and hoarseness. HPV- tions in taste, xerostomia, dental disease, and an increased risk related oropharynx cancers commonly present with a painless of second malignancies. Additional dissection of lymph nodes neck mass, sometimes arising rapidly, and are often cystic on in the neck is determined by the site and stage of the primary ultrasonography. tumor, presence of enlarged nodes, and the results of diagnos- tic imaging. Adjuvant irradiation for patients with primary surgical Evaluation and Staging resection is recommended for those with one or more high- Initial evaluation of patients suspected of having head and risk pathology features (Table 10). Combined chemotherapy, neck cancer includes history and physical examination. typically single-agent cisplatin, and irradiation can be used Infection should be suspected in patients with a rapidly devel- for patients felt to be at very high risk for recurrence, espe- oping neck mass, particularly in the setting of upper respira- cially with extracapsular extension or positive or close tory symptoms or with typical physical findings of infection, margins. such as warmth, tenderness, and erythema. In contrast, malig- nant neck masses are commonly painless, firm, and/or fixed TABLE 10. High-Risk Pathologic Features in Head and on examination and not associated with antecedent infection. Neck Cancer If malignancy is a potential concern, prompt referral to an | T3 or T4 tumor otolaryngologist for assessment and direct laryngoscopy is | Positive resection margins essential. Fine-needle aspiration of suspicious neck masses is | Lymph node extracapsular extension accurate for diagnosis of squamous cell carcinoma. Tumor staining for p16, which is overexpressed in HPV-positive can- 22 positive lymph nodes (N2 or N3)

related oropharynx cancers commonly present with a painless of second malignancies. Additional dissection of lymph nodes neck mass, sometimes arising rapidly, and are often cystic on in the neck is determined by the site and stage of the primary ultrasonography. tumor, presence of enlarged nodes, and the results of diagnos- tic imaging. Adjuvant irradiation for patients with primary surgical Evaluation and Staging resection is recommended for those with one or more high- Initial evaluation of patients suspected of having head and risk pathology features (Table 10). Combined chemotherapy, neck cancer includes history and physical examination. typically single-agent cisplatin, and irradiation can be used Infection should be suspected in patients with a rapidly devel- for patients felt to be at very high risk for recurrence, espe- oping neck mass, particularly in the setting of upper respira- cially with extracapsular extension or positive or close tory symptoms or with typical physical findings of infection, margins. such as warmth, tenderness, and erythema. In contrast, malig- nant neck masses are commonly painless, firm, and/or fixed TABLE 10. High-Risk Pathologic Features in Head and on examination and not associated with antecedent infection. Neck Cancer If malignancy is a potential concern, prompt referral to an | T3 or T4 tumor otolaryngologist for assessment and direct laryngoscopy is | Positive resection margins essential. Fine-needle aspiration of suspicious neck masses is | Lymph node extracapsular extension accurate for diagnosis of squamous cell carcinoma. Tumor staining for p16, which is overexpressed in HPV-positive can- 22 positive lymph nodes (N2 or N3) cers, is standard for oropharynx cancers. Perineural invasion

related oropharynx cancers commonly present with a painless of second malignancies. Additional dissection of lymph nodes neck mass, sometimes arising rapidly, and are often cystic on in the neck is determined by the site and stage of the primary ultrasonography. tumor, presence of enlarged nodes, and the results of diagnos- tic imaging. Adjuvant irradiation for patients with primary surgical Evaluation and Staging resection is recommended for those with one or more high- Initial evaluation of patients suspected of having head and risk pathology features (Table 10). Combined chemotherapy, neck cancer includes history and physical examination. typically single-agent cisplatin, and irradiation can be used Infection should be suspected in patients with a rapidly devel- for patients felt to be at very high risk for recurrence, espe- oping neck mass, particularly in the setting of upper respira- cially with extracapsular extension or positive or close tory symptoms or with typical physical findings of infection, margins. such as warmth, tenderness, and erythema. In contrast, malig- nant neck masses are commonly painless, firm, and/or fixed TABLE 10. High-Risk Pathologic Features in Head and on examination and not associated with antecedent infection. Neck Cancer If malignancy is a potential concern, prompt referral to an | T3 or T4 tumor otolaryngologist for assessment and direct laryngoscopy is | Positive resection margins essential. Fine-needle aspiration of suspicious neck masses is | Lymph node extracapsular extension accurate for diagnosis of squamous cell carcinoma. Tumor staining for p16, which is overexpressed in HPV-positive can- 22 positive lymph nodes (N2 or N3) cers, is standard for oropharynx cancers. Perineural invasion When a diagnosis of malignancy has been established, Lymphovascular invasion imaging studies are indicated for accurate assessment of the | Data from Colevas AD, Yom SS, Pfister DG, Spencer S, Adelstein D, et al. NCCN extent of local disease and evaluation of nodal and distant | Guidelines Insights: Head and Neck Cancers, Version 1.2018.J Natl Compr Canc | Netw. 2018;16(5):479-90. [PMID:29752322] metastatic disease. MRI is preferred for assessment of the

When a diagnosis of malignancy has been established, Lymphovascular invasion imaging studies are indicated for accurate assessment of the | Data from Colevas AD, Yom SS, Pfister DG, Spencer S, Adelstein D, et al. NCCN extent of local disease and evaluation of nodal and distant | Guidelines Insights: Head and Neck Cancers, Version 1.2018.J Natl Compr Canc | Netw. 2018;16(5):479-90. [PMID:29752322] metastatic disease. MRI is preferred for assessment of the 25

Genitourinary Cancer Radiation therapy and larynx-sparing surgery, consisting surgery and adjuvant therapy as needed. For patients with of either transoral laser surgery or open partial laryngectomy, unresectable local recurrence, treatment with irradiation or offer equivalent survival benefit in patients with early-stage chemoradiation is appropriate in some cases. Reirradiation laryngeal cancer. These treatments focus on attaining optimal can be associated with long-term survival but also with a survival and function of voice, swallowing, and airway potentially significant risk of toxicity including pain, tissue mechanics. For patients with an unresectable primary tumor necrosis, infection, and fatal bleeding. or extensive nodal disease, initial treatment with combined For patients with distant metastatic disease or unresect- chemotherapy, either cisplatin or cetuximab, a monoclonal able persistent local disease not amenable to surgery or epidermal growth factor receptor antibody, and irradiation is irradiation, systemic therapy is the mainstay of treatment. recommended. Surgery is reserved for treatment of persistent The current standard front-line treatment is either a combi- disease or in the setting of inadequate response to treatment. nation of platinum-based chemotherapy and pembro- Treatment of nasopharyngeal carcinoma with irradiation lizumab, or in patients with programmed death ligand alone can be used with excellent outcomes in patients with 1-positive cancer, use of pembrolizumab alone. Patients very early-stage disease. For all other patients, however, treat- with distant metastases and unresectable local disease have ment consists of combined chemotherapy and irradiation. a poor prognosis, especially if their performance status is declining; treatment decisions should include options for palliative and hospice care. e Patients with small head and neck tumors without lymph node metastases are effectively treated with either surgery or radiation therapy. e Patients with small, localized recurrent head and neck cancer following a long disease-free interval may be cured with additional surgery and adjuvant therapy.

Radiation therapy and larynx-sparing surgery, consisting surgery and adjuvant therapy as needed. For patients with of either transoral laser surgery or open partial laryngectomy, unresectable local recurrence, treatment with irradiation or offer equivalent survival benefit in patients with early-stage chemoradiation is appropriate in some cases. Reirradiation laryngeal cancer. These treatments focus on attaining optimal can be associated with long-term survival but also with a survival and function of voice, swallowing, and airway potentially significant risk of toxicity including pain, tissue mechanics. For patients with an unresectable primary tumor necrosis, infection, and fatal bleeding. or extensive nodal disease, initial treatment with combined For patients with distant metastatic disease or unresect- chemotherapy, either cisplatin or cetuximab, a monoclonal able persistent local disease not amenable to surgery or epidermal growth factor receptor antibody, and irradiation is irradiation, systemic therapy is the mainstay of treatment. recommended. Surgery is reserved for treatment of persistent The current standard front-line treatment is either a combi- disease or in the setting of inadequate response to treatment. nation of platinum-based chemotherapy and pembro- Treatment of nasopharyngeal carcinoma with irradiation lizumab, or in patients with programmed death ligand alone can be used with excellent outcomes in patients with 1-positive cancer, use of pembrolizumab alone. Patients very early-stage disease. For all other patients, however, treat- with distant metastases and unresectable local disease have ment consists of combined chemotherapy and irradiation. a poor prognosis, especially if their performance status is declining; treatment decisions should include options for palliative and hospice care. e Patients with small head and neck tumors without lymph node metastases are effectively treated with either surgery or radiation therapy. e Patients with small, localized recurrent head and neck cancer following a long disease-free interval may be cured with additional surgery and adjuvant therapy. Posttreatment Surveillance e Patients with advanced head and neck cancer not ame-

Radiation therapy and larynx-sparing surgery, consisting surgery and adjuvant therapy as needed. For patients with of either transoral laser surgery or open partial laryngectomy, unresectable local recurrence, treatment with irradiation or offer equivalent survival benefit in patients with early-stage chemoradiation is appropriate in some cases. Reirradiation laryngeal cancer. These treatments focus on attaining optimal can be associated with long-term survival but also with a survival and function of voice, swallowing, and airway potentially significant risk of toxicity including pain, tissue mechanics. For patients with an unresectable primary tumor necrosis, infection, and fatal bleeding. or extensive nodal disease, initial treatment with combined For patients with distant metastatic disease or unresect- chemotherapy, either cisplatin or cetuximab, a monoclonal able persistent local disease not amenable to surgery or epidermal growth factor receptor antibody, and irradiation is irradiation, systemic therapy is the mainstay of treatment. recommended. Surgery is reserved for treatment of persistent The current standard front-line treatment is either a combi- disease or in the setting of inadequate response to treatment. nation of platinum-based chemotherapy and pembro- Treatment of nasopharyngeal carcinoma with irradiation lizumab, or in patients with programmed death ligand alone can be used with excellent outcomes in patients with 1-positive cancer, use of pembrolizumab alone. Patients very early-stage disease. For all other patients, however, treat- with distant metastases and unresectable local disease have ment consists of combined chemotherapy and irradiation. a poor prognosis, especially if their performance status is declining; treatment decisions should include options for palliative and hospice care. e Patients with small head and neck tumors without lymph node metastases are effectively treated with either surgery or radiation therapy. e Patients with small, localized recurrent head and neck cancer following a long disease-free interval may be cured with additional surgery and adjuvant therapy. Posttreatment Surveillance e Patients with advanced head and neck cancer not ame- After treatment of localized disease, a history and physical exami- nable to surgery or irradiation should first receive a

Radiation therapy and larynx-sparing surgery, consisting surgery and adjuvant therapy as needed. For patients with of either transoral laser surgery or open partial laryngectomy, unresectable local recurrence, treatment with irradiation or offer equivalent survival benefit in patients with early-stage chemoradiation is appropriate in some cases. Reirradiation laryngeal cancer. These treatments focus on attaining optimal can be associated with long-term survival but also with a survival and function of voice, swallowing, and airway potentially significant risk of toxicity including pain, tissue mechanics. For patients with an unresectable primary tumor necrosis, infection, and fatal bleeding. or extensive nodal disease, initial treatment with combined For patients with distant metastatic disease or unresect- chemotherapy, either cisplatin or cetuximab, a monoclonal able persistent local disease not amenable to surgery or epidermal growth factor receptor antibody, and irradiation is irradiation, systemic therapy is the mainstay of treatment. recommended. Surgery is reserved for treatment of persistent The current standard front-line treatment is either a combi- disease or in the setting of inadequate response to treatment. nation of platinum-based chemotherapy and pembro- Treatment of nasopharyngeal carcinoma with irradiation lizumab, or in patients with programmed death ligand alone can be used with excellent outcomes in patients with 1-positive cancer, use of pembrolizumab alone. Patients very early-stage disease. For all other patients, however, treat- with distant metastases and unresectable local disease have ment consists of combined chemotherapy and irradiation. a poor prognosis, especially if their performance status is declining; treatment decisions should include options for palliative and hospice care. e Patients with small head and neck tumors without lymph node metastases are effectively treated with either surgery or radiation therapy. e Patients with small, localized recurrent head and neck cancer following a long disease-free interval may be cured with additional surgery and adjuvant therapy. Posttreatment Surveillance e Patients with advanced head and neck cancer not ame- After treatment of localized disease, a history and physical exami- nable to surgery or irradiation should first receive a nation, including laryngopharyngoscopy, should be conducted combination of platinum-based chemotherapy and

Posttreatment Surveillance e Patients with advanced head and neck cancer not ame- After treatment of localized disease, a history and physical exami- nable to surgery or irradiation should first receive a nation, including laryngopharyngoscopy, should be conducted combination of platinum-based chemotherapy and every 1 to 3 months for the first year after primary treatment, pembrolizumab, or pembrolizumab alone in patients decreasing in frequency thereafter, with annual evaluation with programmed death ligand 1-positive cancer. 5 years and beyond. Patients treated with radiotherapy that includes the thyroid bed are at risk for hypothyroidism and thy-

every 1 to 3 months for the first year after primary treatment, pembrolizumab, or pembrolizumab alone in patients decreasing in frequency thereafter, with annual evaluation with programmed death ligand 1-positive cancer. 5 years and beyond. Patients treated with radiotherapy that includes the thyroid bed are at risk for hypothyroidism and thy- Genitourinary Cancer roid carcinoma. Periodic assessment of thyroid function and a physical examination of the thyroid are indicated, although thy- roid ultrasonography should not be performed. Similarly, Prostate Cancer repeated PET/CT or other imaging surveillance following a Epidemiology and Risk Factors negative posttreatment scan is not indicated in the absence of Adenocarcinoma of the prostate remains one of the most com- worrisome signs or symptoms. monly diagnosed types of cancer among men in the United Up to 20% of head and neck cancer survivors develop a States. Age is a very important risk factor; prostate cancer is second primary cancer related to smoking and alcohol expo- rarely diagnosed before age 40 years, but after that point, the sure. In addition to lifestyle modification, screening for lung incidence increases significantly. Ethnicity is also an impor- cancer should be implemented in persons at increased risk. tant risk factor, with the incidence greater for Black men than for White or Hispanic men. Further, Black men are more likely HVC ¢ Routine imaging for head and neck cancer after a nega- to be diagnosed at a younger age with higher-risk disease. tive posttreatment scan is not indicated unless signs Genetics and family history also play an important role in risk. and symptoms suggest recurrent disease. Men witha first-degree relative diagnosed with prostate can-

Genitourinary Cancer roid carcinoma. Periodic assessment of thyroid function and a physical examination of the thyroid are indicated, although thy- roid ultrasonography should not be performed. Similarly, Prostate Cancer repeated PET/CT or other imaging surveillance following a Epidemiology and Risk Factors negative posttreatment scan is not indicated in the absence of Adenocarcinoma of the prostate remains one of the most com- worrisome signs or symptoms. monly diagnosed types of cancer among men in the United Up to 20% of head and neck cancer survivors develop a States. Age is a very important risk factor; prostate cancer is second primary cancer related to smoking and alcohol expo- rarely diagnosed before age 40 years, but after that point, the sure. In addition to lifestyle modification, screening for lung incidence increases significantly. Ethnicity is also an impor- cancer should be implemented in persons at increased risk. tant risk factor, with the incidence greater for Black men than for White or Hispanic men. Further, Black men are more likely HVC ¢ Routine imaging for head and neck cancer after a nega- to be diagnosed at a younger age with higher-risk disease. tive posttreatment scan is not indicated unless signs Genetics and family history also play an important role in risk. and symptoms suggest recurrent disease. Men witha first-degree relative diagnosed with prostate can- HVC e Although patients who receive radiation therapy that cer are twice as likely to be diagnosed. Prostate cancer is also

Genitourinary Cancer roid carcinoma. Periodic assessment of thyroid function and a physical examination of the thyroid are indicated, although thy- roid ultrasonography should not be performed. Similarly, Prostate Cancer repeated PET/CT or other imaging surveillance following a Epidemiology and Risk Factors negative posttreatment scan is not indicated in the absence of Adenocarcinoma of the prostate remains one of the most com- worrisome signs or symptoms. monly diagnosed types of cancer among men in the United Up to 20% of head and neck cancer survivors develop a States. Age is a very important risk factor; prostate cancer is second primary cancer related to smoking and alcohol expo- rarely diagnosed before age 40 years, but after that point, the sure. In addition to lifestyle modification, screening for lung incidence increases significantly. Ethnicity is also an impor- cancer should be implemented in persons at increased risk. tant risk factor, with the incidence greater for Black men than for White or Hispanic men. Further, Black men are more likely HVC ¢ Routine imaging for head and neck cancer after a nega- to be diagnosed at a younger age with higher-risk disease. tive posttreatment scan is not indicated unless signs Genetics and family history also play an important role in risk. and symptoms suggest recurrent disease. Men witha first-degree relative diagnosed with prostate can- HVC e Although patients who receive radiation therapy that cer are twice as likely to be diagnosed. Prostate cancer is also includes the thyroid bed are at increased risk of thyroid linked with germline mutations in different genes, such as

Genitourinary Cancer roid carcinoma. Periodic assessment of thyroid function and a physical examination of the thyroid are indicated, although thy- roid ultrasonography should not be performed. Similarly, Prostate Cancer repeated PET/CT or other imaging surveillance following a Epidemiology and Risk Factors negative posttreatment scan is not indicated in the absence of Adenocarcinoma of the prostate remains one of the most com- worrisome signs or symptoms. monly diagnosed types of cancer among men in the United Up to 20% of head and neck cancer survivors develop a States. Age is a very important risk factor; prostate cancer is second primary cancer related to smoking and alcohol expo- rarely diagnosed before age 40 years, but after that point, the sure. In addition to lifestyle modification, screening for lung incidence increases significantly. Ethnicity is also an impor- cancer should be implemented in persons at increased risk. tant risk factor, with the incidence greater for Black men than for White or Hispanic men. Further, Black men are more likely HVC ¢ Routine imaging for head and neck cancer after a nega- to be diagnosed at a younger age with higher-risk disease. tive posttreatment scan is not indicated unless signs Genetics and family history also play an important role in risk. and symptoms suggest recurrent disease. Men witha first-degree relative diagnosed with prostate can- HVC e Although patients who receive radiation therapy that cer are twice as likely to be diagnosed. Prostate cancer is also includes the thyroid bed are at increased risk of thyroid linked with germline mutations in different genes, such as cancer, screening thyroid ultrasonography is not indicated. BRCA1and 2, ATM, CHEK2, HOXB13, and the Lynch syndrome genes, among others.

includes the thyroid bed are at increased risk of thyroid linked with germline mutations in different genes, such as cancer, screening thyroid ultrasonography is not indicated. BRCA1and 2, ATM, CHEK2, HOXB13, and the Lynch syndrome genes, among others. Diagnosis and Staging Management of Recurrent Head Prostate cancer is most commonly diagnosed after identifica- and Neck Cancer tion of an elevated serum prostate-specific antigen (PSA) level Recurrent head and neck cancer is curable in selected patients, during screening and in the absence of symptoms. See General such as those with small localized lesions and a long disease- Internal Medicine 2 for a discussion of current issues relating free interval. Patients with limited recurrence are treated with to prostate cancer screening. ’ 26

Genitourinary Cancer Although urinary symptoms might be present in patients Treatment with prostate cancer, they are usually related to benign pros- Treatment options for men with newly diagnosed localized tatic hyperplasia. In some men with metastatic disease at the prostate cancer include active surveillance, irradiation, and time of initial presentation, bone pain or back pain can be the radical prostatectomy. For men with limited life expectancy presenting symptom. If the diagnosis is suspected on the basis or significant medical comorbidities, observation is most of an elevated serum PSA level, the elevation should first be appropriate. confirmed by a second measurement at least 1 month later. Active surveillance is deferral of curative-intent therapy Persistent serum PSA elevation should prompt urology refer- in lieu of regular monitoring for evidence of disease progres- ral, as should an abnormal finding in the prostate on digital sion. It is an option for men with very-low-risk or low-risk rectal examination (DRE). prostate cancer who have a life expectancy of at least 10 years. Prostate biopsy is performed using transrectal ultrasonog- Active surveillance should consist of DRE (not more than every raphy for guidance, and several cores should be taken from dif- 12 months), serial measurement of serum PSA (assessing level ferent regions of the gland. Most commonly, at least five to seven changes and calculating PSA doubling time), and repeat cores are taken per side to provide a sufficient diagnostic yield. biopsy. Repeat biopsy is typically done at 1 year, and ifno high- Atypical small acinar proliferation and multifocal high-grade grade disease is identified, it can be done less often after that. prostatic intraepithelial neoplasia are both associated with a A PSA doubling time of less than 3 years warrants an addi- high risk of underlying cancer and should prompt rebiopsy. tional prostate biopsy. Fifteen-year metastasis-free survival is Risk stratification using serum PSA, Grade Group (based as high as 97% in appropriately selected patients. on Gleason score), and TNM cancer staging based on biopsy Active treatment of low-risk localized prostate cancer is results and DRE determines prognosis and treatment options typically a choice between external beam irradiation and radi- (Table 11). Imaging studies need not be done in patients cal prostatectomy. Brachytherapy, in which radioactive whose risk is very low or low but should be obtained in oth- implants are inserted into the prostate, is also an option for ers to evaluate regional lymph node involvement and meta- men with low-risk cancer or selected men with low-volume static disease. Genetic testing for BRCA gene mutation intermediate-risk cancer. should be done in all men with high-risk disease, including Irradiation is associated with short-term risks of enteritis patients with positive lymph nodes or metastatic disease. (approximately 20% of men) and cystitis (approximately 50% The risk of an underlying mutation in patients with meta- of men). These conditions become long-term complications in static disease is 11.8%. a very small percentage of patients. Erectile dysfunction typi- cally increases over time after irradiation, such that by 2 years,

Although urinary symptoms might be present in patients Treatment with prostate cancer, they are usually related to benign pros- Treatment options for men with newly diagnosed localized tatic hyperplasia. In some men with metastatic disease at the prostate cancer include active surveillance, irradiation, and time of initial presentation, bone pain or back pain can be the radical prostatectomy. For men with limited life expectancy presenting symptom. If the diagnosis is suspected on the basis or significant medical comorbidities, observation is most of an elevated serum PSA level, the elevation should first be appropriate. confirmed by a second measurement at least 1 month later. Active surveillance is deferral of curative-intent therapy Persistent serum PSA elevation should prompt urology refer- in lieu of regular monitoring for evidence of disease progres- ral, as should an abnormal finding in the prostate on digital sion. It is an option for men with very-low-risk or low-risk rectal examination (DRE). prostate cancer who have a life expectancy of at least 10 years. Prostate biopsy is performed using transrectal ultrasonog- Active surveillance should consist of DRE (not more than every raphy for guidance, and several cores should be taken from dif- 12 months), serial measurement of serum PSA (assessing level ferent regions of the gland. Most commonly, at least five to seven changes and calculating PSA doubling time), and repeat cores are taken per side to provide a sufficient diagnostic yield. biopsy. Repeat biopsy is typically done at 1 year, and ifno high- Atypical small acinar proliferation and multifocal high-grade grade disease is identified, it can be done less often after that. prostatic intraepithelial neoplasia are both associated with a A PSA doubling time of less than 3 years warrants an addi- high risk of underlying cancer and should prompt rebiopsy. tional prostate biopsy. Fifteen-year metastasis-free survival is Risk stratification using serum PSA, Grade Group (based as high as 97% in appropriately selected patients. on Gleason score), and TNM cancer staging based on biopsy Active treatment of low-risk localized prostate cancer is results and DRE determines prognosis and treatment options typically a choice between external beam irradiation and radi- (Table 11). Imaging studies need not be done in patients cal prostatectomy. Brachytherapy, in which radioactive whose risk is very low or low but should be obtained in oth- implants are inserted into the prostate, is also an option for ers to evaluate regional lymph node involvement and meta- men with low-risk cancer or selected men with low-volume static disease. Genetic testing for BRCA gene mutation intermediate-risk cancer. should be done in all men with high-risk disease, including Irradiation is associated with short-term risks of enteritis patients with positive lymph nodes or metastatic disease. (approximately 20% of men) and cystitis (approximately 50% The risk of an underlying mutation in patients with meta- of men). These conditions become long-term complications in static disease is 11.8%. a very small percentage of patients. Erectile dysfunction typi- cally increases over time after irradiation, such that by 2 years, ¢ Genetic testing for BRCA gene mutation is recommended approximately 60% to 70% of men have at least moderate erec-

Although urinary symptoms might be present in patients Treatment with prostate cancer, they are usually related to benign pros- Treatment options for men with newly diagnosed localized tatic hyperplasia. In some men with metastatic disease at the prostate cancer include active surveillance, irradiation, and time of initial presentation, bone pain or back pain can be the radical prostatectomy. For men with limited life expectancy presenting symptom. If the diagnosis is suspected on the basis or significant medical comorbidities, observation is most of an elevated serum PSA level, the elevation should first be appropriate. confirmed by a second measurement at least 1 month later. Active surveillance is deferral of curative-intent therapy Persistent serum PSA elevation should prompt urology refer- in lieu of regular monitoring for evidence of disease progres- ral, as should an abnormal finding in the prostate on digital sion. It is an option for men with very-low-risk or low-risk rectal examination (DRE). prostate cancer who have a life expectancy of at least 10 years. Prostate biopsy is performed using transrectal ultrasonog- Active surveillance should consist of DRE (not more than every raphy for guidance, and several cores should be taken from dif- 12 months), serial measurement of serum PSA (assessing level ferent regions of the gland. Most commonly, at least five to seven changes and calculating PSA doubling time), and repeat cores are taken per side to provide a sufficient diagnostic yield. biopsy. Repeat biopsy is typically done at 1 year, and ifno high- Atypical small acinar proliferation and multifocal high-grade grade disease is identified, it can be done less often after that. prostatic intraepithelial neoplasia are both associated with a A PSA doubling time of less than 3 years warrants an addi- high risk of underlying cancer and should prompt rebiopsy. tional prostate biopsy. Fifteen-year metastasis-free survival is Risk stratification using serum PSA, Grade Group (based as high as 97% in appropriately selected patients. on Gleason score), and TNM cancer staging based on biopsy Active treatment of low-risk localized prostate cancer is results and DRE determines prognosis and treatment options typically a choice between external beam irradiation and radi- (Table 11). Imaging studies need not be done in patients cal prostatectomy. Brachytherapy, in which radioactive whose risk is very low or low but should be obtained in oth- implants are inserted into the prostate, is also an option for ers to evaluate regional lymph node involvement and meta- men with low-risk cancer or selected men with low-volume static disease. Genetic testing for BRCA gene mutation intermediate-risk cancer. should be done in all men with high-risk disease, including Irradiation is associated with short-term risks of enteritis patients with positive lymph nodes or metastatic disease. (approximately 20% of men) and cystitis (approximately 50% The risk of an underlying mutation in patients with meta- of men). These conditions become long-term complications in static disease is 11.8%. a very small percentage of patients. Erectile dysfunction typi- cally increases over time after irradiation, such that by 2 years, ¢ Genetic testing for BRCA gene mutation is recommended approximately 60% to 70% of men have at least moderate erec- for all men with high-risk prostate cancer, including tile dysfunction. However, a recent series found similar rates of

Although urinary symptoms might be present in patients Treatment with prostate cancer, they are usually related to benign pros- Treatment options for men with newly diagnosed localized tatic hyperplasia. In some men with metastatic disease at the prostate cancer include active surveillance, irradiation, and time of initial presentation, bone pain or back pain can be the radical prostatectomy. For men with limited life expectancy presenting symptom. If the diagnosis is suspected on the basis or significant medical comorbidities, observation is most of an elevated serum PSA level, the elevation should first be appropriate. confirmed by a second measurement at least 1 month later. Active surveillance is deferral of curative-intent therapy Persistent serum PSA elevation should prompt urology refer- in lieu of regular monitoring for evidence of disease progres- ral, as should an abnormal finding in the prostate on digital sion. It is an option for men with very-low-risk or low-risk rectal examination (DRE). prostate cancer who have a life expectancy of at least 10 years. Prostate biopsy is performed using transrectal ultrasonog- Active surveillance should consist of DRE (not more than every raphy for guidance, and several cores should be taken from dif- 12 months), serial measurement of serum PSA (assessing level ferent regions of the gland. Most commonly, at least five to seven changes and calculating PSA doubling time), and repeat cores are taken per side to provide a sufficient diagnostic yield. biopsy. Repeat biopsy is typically done at 1 year, and ifno high- Atypical small acinar proliferation and multifocal high-grade grade disease is identified, it can be done less often after that. prostatic intraepithelial neoplasia are both associated with a A PSA doubling time of less than 3 years warrants an addi- high risk of underlying cancer and should prompt rebiopsy. tional prostate biopsy. Fifteen-year metastasis-free survival is Risk stratification using serum PSA, Grade Group (based as high as 97% in appropriately selected patients. on Gleason score), and TNM cancer staging based on biopsy Active treatment of low-risk localized prostate cancer is results and DRE determines prognosis and treatment options typically a choice between external beam irradiation and radi- (Table 11). Imaging studies need not be done in patients cal prostatectomy. Brachytherapy, in which radioactive whose risk is very low or low but should be obtained in oth- implants are inserted into the prostate, is also an option for ers to evaluate regional lymph node involvement and meta- men with low-risk cancer or selected men with low-volume static disease. Genetic testing for BRCA gene mutation intermediate-risk cancer. should be done in all men with high-risk disease, including Irradiation is associated with short-term risks of enteritis patients with positive lymph nodes or metastatic disease. (approximately 20% of men) and cystitis (approximately 50% The risk of an underlying mutation in patients with meta- of men). These conditions become long-term complications in static disease is 11.8%. a very small percentage of patients. Erectile dysfunction typi- cally increases over time after irradiation, such that by 2 years, ¢ Genetic testing for BRCA gene mutation is recommended approximately 60% to 70% of men have at least moderate erec- for all men with high-risk prostate cancer, including tile dysfunction. However, a recent series found similar rates of patients with positive lymph nodes or metastatic disease. decline in men treated with active surveillance. With radical prostatectomy, the main risks are urinary incontinence and erectile dysfunction. Urinary incontinence TABLE 11. Prostate Cancer Risk Stratification is relatively common immediately after surgery. The rate of Risk Category Definition? chronic moderate to severe incontinence is approximately 5% Very low/low Stage T1-T2a, serum PSA <10 ng/mL to 10%. Erectile dysfunction is relatively common after surgery (10 ug/L), Grade Group 1 (Gleason 3+3) and can persist for several years. Approximately 40% of men Intermediate T2b-T2c OR Grade Group 2-3 (Gleason reported erectile dysfunction 2 years after surgery. score 7) OR PSA 10-20 ng/mL (10-20 ug/L) A large study showed no difference in survival after High T3a OR Grade Group 4-5 (Gleason score 10 years for patients with localized prostate cancer detected 8-10) OR PSA >20 ng/mL (20 ug/L) through serum PSA screening who were randomized to receive | Very high T3b-T4, primary Gleason pattern 5, active surveillance, surgery, or radiation therapy. There was a | >4 cores with Grade Group 4-5 | trend toward improved survival for patients older than PSA = prostate-specific antigen. 65 years who received either of the active interventions. °T1 tumors are not palpable or seen on imaging; T1a (<5% of specimen) andT1b | Patients receiving surgery or irradiation had decreased disease (>5% of specimen) are discovered incidentally in a pathologic specimen resected for benign disease; T1c is discovered in prostate biopsy for elevated serum PSA. progression and decreased metastatic disease. T2 tumors are palpable; T2a involves <50% of one lobe; T2b involves >50% of one For men with intermediate-risk or higher-risk localized lobe; T2c are in both lobes of the prostate. disease who are treated with radiation therapy, the addition of a T3a tumors extend through the prostate capsule; T3b involves the seminal vesicles. gonadotropin-releasing hormone (GnRH) agonist will delay dis-

patients with positive lymph nodes or metastatic disease. decline in men treated with active surveillance. With radical prostatectomy, the main risks are urinary incontinence and erectile dysfunction. Urinary incontinence TABLE 11. Prostate Cancer Risk Stratification is relatively common immediately after surgery. The rate of Risk Category Definition? chronic moderate to severe incontinence is approximately 5% Very low/low Stage T1-T2a, serum PSA <10 ng/mL to 10%. Erectile dysfunction is relatively common after surgery (10 ug/L), Grade Group 1 (Gleason 3+3) and can persist for several years. Approximately 40% of men Intermediate T2b-T2c OR Grade Group 2-3 (Gleason reported erectile dysfunction 2 years after surgery. score 7) OR PSA 10-20 ng/mL (10-20 ug/L) A large study showed no difference in survival after High T3a OR Grade Group 4-5 (Gleason score 10 years for patients with localized prostate cancer detected 8-10) OR PSA >20 ng/mL (20 ug/L) through serum PSA screening who were randomized to receive | Very high T3b-T4, primary Gleason pattern 5, active surveillance, surgery, or radiation therapy. There was a | >4 cores with Grade Group 4-5 | trend toward improved survival for patients older than PSA = prostate-specific antigen. 65 years who received either of the active interventions. °T1 tumors are not palpable or seen on imaging; T1a (<5% of specimen) andT1b | Patients receiving surgery or irradiation had decreased disease (>5% of specimen) are discovered incidentally in a pathologic specimen resected for benign disease; T1c is discovered in prostate biopsy for elevated serum PSA. progression and decreased metastatic disease. T2 tumors are palpable; T2a involves <50% of one lobe; T2b involves >50% of one For men with intermediate-risk or higher-risk localized lobe; T2c are in both lobes of the prostate. disease who are treated with radiation therapy, the addition of a T3a tumors extend through the prostate capsule; T3b involves the seminal vesicles. gonadotropin-releasing hormone (GnRH) agonist will delay dis- T4 tumors are fixed to adjacent structures. ease progression. It has also been shown to improve overall sur- vival in men with high-risk and very-high-risk prostate cancer. Data from NCCN Clinical Guidelines in Oncology. Prostate Cancer. Version 2.2019. NCCN.org. https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf. ) After definitive local treatment, men are monitored for Accessed July 14, 2019. evidence of recurrence with serial serum PSA measurements

T4 tumors are fixed to adjacent structures. ease progression. It has also been shown to improve overall sur- vival in men with high-risk and very-high-risk prostate cancer. Data from NCCN Clinical Guidelines in Oncology. Prostate Cancer. Version 2.2019. NCCN.org. https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf. ) After definitive local treatment, men are monitored for Accessed July 14, 2019. evidence of recurrence with serial serum PSA measurements 27

Genitourinary Cancer every 3 to 4 months and DRE yearly, although DRE can be omit- Metastatic Prostate Cancer ted if PSA is undetectable. After radical prostatectomy, the PSA Once distant metastatic disease is diagnosed, the mainstay of should rapidly become undetectable, but after radiation treat- therapy is ADT. Options for providing ADT include orchiec- ment, the PSA will fall gradually and reach a nadir but will not tomy, GnRH-agonist therapy (with or without antiandrogen), necessarily become undetectable. PSA recurrence after surgery and GnRH-antagonist therapy (Table 12). Psychological aver- is defined as a detectable PSA level that increases on at least two sion to orchiectomy has limited its use in the United States, measurements; after irradiation, PSA recurrence is defined although it is a rapidly acting and cost-effective way to achieve as an increase in the PSA level by at least 2 ng/mL (2 ug/L) androgen depletion. above the nadir PSA. In patients who have clinical metastatic disease, short- For men with PSA-only recurrence, an evaluation to term antiandrogen therapy should precede or be started at the look for evidence of clinical local or metastatic disease with same time as a GnRH agonist, and the combination should be imaging studies is indicated. If men were treated with initial continued for at least 7 days because of the risk of a transient surgery, and metastatic disease has not been identified, sal- worsening of disease-related symptoms, termed a flare reac- vage irradiation with or without androgen deprivation ther- tion. Initial anti-androgen therapy is not necessary if a GnRH apy (ADT) can be offered. Likewise, if men were treated antagonist is used. Intermittent ADT is not typically recom- initially with irradiation, local therapy (such as surgery or mended in men with clinical metastatic disease, although it cryotherapy) can be offered, provided a transrectal ultra- can be offered to mitigate adverse effects. Response can be sound-guided biopsy specimen is positive and no metastatic assessed most easily by serial serum PSA measurement, but disease is identified. If the result of the specimen is negative, imaging also plays a role. The serum testosterone level should then ADT can be considered. Men with metastatic disease be less than 50 ng/dL (1.7 nmol/L) in men treated with ADT. can also be treated with ADT, although the benefit in that Men with clinical metastatic disease who respond to ADT setting is uncertain. are considered to have castrate-sensitive prostate cancer. ADT results in many short-term and long-term adverse In this population, ADT can be combined with docetaxel, effects. Short-term effects include loss of lean body mass, abiraterone/prednisone, enzalutamide, or apalutamide to fatigue, gynecomastia, hair loss, decreased libido, erectile improve survival. Irradiation to the primary tumor can also be dysfunction, and vasomotor symptoms. Long-term risks considered for men with low-volume metastatic M1 disease. include a possible increase in cardiovascular disease, After identifying progressive disease in men being treated increased risk of venous thromboembolism, and reduction in with ADT (castrate-resistant prostate cancer), many treatment bone density. All men being treated with ADT should take options exist (see Table 12). Osteoclast inhibitors (bisphospho- supplemental calcium and vitamin D, and baseline fracture nates or denosumab) will reduce bone pain and lower fracture risk assessment is recommended using a dual-energy x-ray risk in men with castrate-resistant, metastatic prostate cancer absorptiometry scan, although the impact on outcomes is and should be routinely prescribed. Initial treatment options for uncertain. castrate-resistant prostate cancer include docetaxel with pred- For men with PSA recurrence, with or without clinical nisone, abiraterone with prednisone, enzalutamide and, for metastatic disease, observation is a reasonable consideration symptomatic bone metastases, radium-223. Patients with MO depending on patient and disease-specific factors, such as (without evidence of distant metastasis) castrate-resistant dis- symptoms and PSA doubling time. This is especially true for ease do not clearly require treatment. The decision to treat is men with PSA-only recurrence. For such men with a rapid based on PSA doubling time among other factors. For men with doubling time (<10 months), treatment is generally recom- a rapid doubling time, both enzalutamide and apalutamide are mended; however, men with a slow PSA doubling time effective. For patients who develop progressive disease, a differ- (>10 months) do not require immediate treatment because it ent agent can be used. Cabazitaxel, a chemotherapy agent, can can take several years for clinical metastatic disease to develop be combined with prednisone for patients who have cancer in that setting. progression after treatment with docetaxel. Pembrolizumab can

every 3 to 4 months and DRE yearly, although DRE can be omit- Metastatic Prostate Cancer ted if PSA is undetectable. After radical prostatectomy, the PSA Once distant metastatic disease is diagnosed, the mainstay of should rapidly become undetectable, but after radiation treat- therapy is ADT. Options for providing ADT include orchiec- ment, the PSA will fall gradually and reach a nadir but will not tomy, GnRH-agonist therapy (with or without antiandrogen), necessarily become undetectable. PSA recurrence after surgery and GnRH-antagonist therapy (Table 12). Psychological aver- is defined as a detectable PSA level that increases on at least two sion to orchiectomy has limited its use in the United States, measurements; after irradiation, PSA recurrence is defined although it is a rapidly acting and cost-effective way to achieve as an increase in the PSA level by at least 2 ng/mL (2 ug/L) androgen depletion. above the nadir PSA. In patients who have clinical metastatic disease, short- For men with PSA-only recurrence, an evaluation to term antiandrogen therapy should precede or be started at the look for evidence of clinical local or metastatic disease with same time as a GnRH agonist, and the combination should be imaging studies is indicated. If men were treated with initial continued for at least 7 days because of the risk of a transient surgery, and metastatic disease has not been identified, sal- worsening of disease-related symptoms, termed a flare reac- vage irradiation with or without androgen deprivation ther- tion. Initial anti-androgen therapy is not necessary if a GnRH apy (ADT) can be offered. Likewise, if men were treated antagonist is used. Intermittent ADT is not typically recom- initially with irradiation, local therapy (such as surgery or mended in men with clinical metastatic disease, although it cryotherapy) can be offered, provided a transrectal ultra- can be offered to mitigate adverse effects. Response can be sound-guided biopsy specimen is positive and no metastatic assessed most easily by serial serum PSA measurement, but disease is identified. If the result of the specimen is negative, imaging also plays a role. The serum testosterone level should then ADT can be considered. Men with metastatic disease be less than 50 ng/dL (1.7 nmol/L) in men treated with ADT. can also be treated with ADT, although the benefit in that Men with clinical metastatic disease who respond to ADT setting is uncertain. are considered to have castrate-sensitive prostate cancer. ADT results in many short-term and long-term adverse In this population, ADT can be combined with docetaxel, effects. Short-term effects include loss of lean body mass, abiraterone/prednisone, enzalutamide, or apalutamide to fatigue, gynecomastia, hair loss, decreased libido, erectile improve survival. Irradiation to the primary tumor can also be dysfunction, and vasomotor symptoms. Long-term risks considered for men with low-volume metastatic M1 disease. include a possible increase in cardiovascular disease, After identifying progressive disease in men being treated increased risk of venous thromboembolism, and reduction in with ADT (castrate-resistant prostate cancer), many treatment bone density. All men being treated with ADT should take options exist (see Table 12). Osteoclast inhibitors (bisphospho- supplemental calcium and vitamin D, and baseline fracture nates or denosumab) will reduce bone pain and lower fracture risk assessment is recommended using a dual-energy x-ray risk in men with castrate-resistant, metastatic prostate cancer absorptiometry scan, although the impact on outcomes is and should be routinely prescribed. Initial treatment options for uncertain. castrate-resistant prostate cancer include docetaxel with pred- For men with PSA recurrence, with or without clinical nisone, abiraterone with prednisone, enzalutamide and, for metastatic disease, observation is a reasonable consideration symptomatic bone metastases, radium-223. Patients with MO depending on patient and disease-specific factors, such as (without evidence of distant metastasis) castrate-resistant dis- symptoms and PSA doubling time. This is especially true for ease do not clearly require treatment. The decision to treat is men with PSA-only recurrence. For such men with a rapid based on PSA doubling time among other factors. For men with doubling time (<10 months), treatment is generally recom- a rapid doubling time, both enzalutamide and apalutamide are mended; however, men with a slow PSA doubling time effective. For patients who develop progressive disease, a differ- (>10 months) do not require immediate treatment because it ent agent can be used. Cabazitaxel, a chemotherapy agent, can can take several years for clinical metastatic disease to develop be combined with prednisone for patients who have cancer in that setting. progression after treatment with docetaxel. Pembrolizumab can be used for select patients characterized by high levels of micro- satellite instability or deficient mismatch repair after progression ¢ Treatment options for men with newly diagnosed local- on front-line therapy and absence of an alternative treatment. ized prostate cancer include active surveillance, irradia- tion, and radical prostatectomy.

be used for select patients characterized by high levels of micro- satellite instability or deficient mismatch repair after progression ¢ Treatment options for men with newly diagnosed local- on front-line therapy and absence of an alternative treatment. ized prostate cancer include active surveillance, irradia- tion, and radical prostatectomy. ¢ Gonadotropin-releasing hormone agonist therapy is ¢ Continuous androgen deprivation therapy (ADT), including typically administered with radiation therapy for local- orchiectomy, gonadotropin-releasing hormone-agonist ized intermediate- or high-risk prostate cancer. therapy, and gonadotropin-releasing hormone-antagonist HVC e Patients with PSA-only recurrence of prostate cancer therapy, is most appropriate for metastatic prostate may be treated with androgen deprivation therapy, cancer. although observation is also a reasonable choice. (Continued) 28

Genitourinary Cancer TABLE 12. Treatments for Metastatic Prostate Cancer Class Agents Mechanism of Action Indications GnRH agonist Leuprolide, goserelin, Binds to GnRH receptor, causes initial Metastatic prostate cancer; | | triptorelin, buserelin, release of FSH/LH (and also testosterone) neoadjuvant/adjuvant ADT in | followed by suppression combination with radiation histrelin | | GnRH antagonist Degarelix Binds to GnRH receptor and suppresses Metastatic prostate cancer; activity without initial increase in activity neoadjuvant/adjuvant ADT in seen with GnRH agonists combination with radiation Antiandrogen Bicalutamide, flutamide Binds to androgen receptor with Metastatic castrate-sensitive prostate competitive inhibition of testosterone cancer (not indicated as monotherapy, binding only in combination with GnRH agonist or antagonist)

Antiandrogen Bicalutamide, flutamide Binds to androgen receptor with Metastatic castrate-sensitive prostate competitive inhibition of testosterone cancer (not indicated as monotherapy, binding only in combination with GnRH agonist or antagonist) CYP17 inhibitor Abiraterone plus Blocks androgen synthesis in tumor tissue, Metastatic castrate-resistant prostate prednisone testes, and adrenal glands cancer; used in combination with prednisone as it can cause adrenal insufficiency _ Androgen receptor Enzalutamide Binds to the androgen binding site of the Metastatic castrate-resistant prostate blockade androgen receptor in a noncompetitive cancer and M0 castrate-resistant fashion prostate cancer Androgen receptor Apalutamide Same as enzalutamide MO castrate-resistant prostate cancer blockade

_ Androgen receptor Enzalutamide Binds to the androgen binding site of the Metastatic castrate-resistant prostate blockade androgen receptor in a noncompetitive cancer and M0 castrate-resistant fashion prostate cancer Androgen receptor Apalutamide Same as enzalutamide MO castrate-resistant prostate cancer blockade Tumor vaccine Sipuleucel-T Autologous dendritic cell therapeutic Asymptomatic or minimally vaccine symptomatic metastatic castrate- resistant prostate cancer with no Aims to increase T-cell response to visceral metastatic disease prostatic acid phosphatase Not indicated for PSA-only relapse; does not result in PSA response

Tumor vaccine Sipuleucel-T Autologous dendritic cell therapeutic Asymptomatic or minimally vaccine symptomatic metastatic castrate- resistant prostate cancer with no Aims to increase T-cell response to visceral metastatic disease prostatic acid phosphatase Not indicated for PSA-only relapse; does not result in PSA response Bone-seeking Radium-223 Alpha particle-emitting isotope that Metastatic castrate-resistant prostate isotope concentrates in bone cancer with symptomatic bone metastases and no known visceral metastatic disease Chemotherapeutic Docetaxel plus Antimicrotubule agent Metastatic castrate-resistant prostate prednisone cancer with clinical metastatic disease

Chemotherapeutic Docetaxel plus Antimicrotubule agent Metastatic castrate-resistant prostate prednisone cancer with clinical metastatic disease Metastatic castrate-sensitive prostate cancer in combination with ADT in men with clinical metastatic disease Adjuvant therapy after radiation in men with high-risk or very-high-risk prostate cancer, in combination with ADT Chemotherapeutic Cabazitaxel plus Antimicrotubule agent Metastatic castrate-resistant prostate prednisone cancer following disease progression after docetaxel treatment ADT = androgen-deprivation therapy; CYP17 = 17a-hydroxy/17,20-lyase; FSH =follicle-stimulating hormone; GnRH = gonadotropin-releasing hormone; LH = luteinizing hormone; MO = without evidence of distant metastasis; PSA = prostate-specific antigen.

Chemotherapeutic Cabazitaxel plus Antimicrotubule agent Metastatic castrate-resistant prostate prednisone cancer following disease progression after docetaxel treatment ADT = androgen-deprivation therapy; CYP17 = 17a-hydroxy/17,20-lyase; FSH =follicle-stimulating hormone; GnRH = gonadotropin-releasing hormone; LH = luteinizing hormone; MO = without evidence of distant metastasis; PSA = prostate-specific antigen. Testicular Cancer ¢ Men with metastatic prostate cancer who respond to Testicular cancer is the most common solid tumor diagnosed ADT and then receive docetaxel abiraterone/prednisone, in men aged 15 to 35 years, although it accounts for only about enzalutamide, or apalutamide will have improved 1% of all cancers diagnosed in the United States. It is also one survival. of the most curable forms of cancer, due in large part to its e All men who are treated with ADT should take supple- sensitivity to chemotherapy. Patients most commonly present

Testicular Cancer ¢ Men with metastatic prostate cancer who respond to Testicular cancer is the most common solid tumor diagnosed ADT and then receive docetaxel abiraterone/prednisone, in men aged 15 to 35 years, although it accounts for only about enzalutamide, or apalutamide will have improved 1% of all cancers diagnosed in the United States. It is also one survival. of the most curable forms of cancer, due in large part to its e All men who are treated with ADT should take supple- sensitivity to chemotherapy. Patients most commonly present mental calcium and vitamin D. with a unilateral testicular swelling or mass. Patients with localized symptoms should have a scrotal e Osteoclast inhibitors will reduce bone pain and lower ultrasound and baseline tumor markers, including o-fetoprotein fracture risk in men with castrate-resistant, metastatic and B-human chorionic gonadotropin. Diagnosis is made most prostate cancer. commonly through radical inguinal orchiectomy. Needle biopsy 29