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Oncology Committee Deputy Editor Caroline Block, MD, Section Editor Richard S. Eisenstaedt, MD, MACP Assistant Professor of Medicine Chair, Department of Medicine Harvard Medical School Abington Hospital, Jefferson Health Division for Women’s Cancers Abington, Pennsylvania Dana-Farber Cancer Institute Boston, Massachusetts Oncology Reviewers Lee P. Hartner, MD Ross C. Donehower, MD, FACP Abramson Cancer Center at Pennsylvania Hospital Martin J. Edelman, MD, FACP Clinical Professor of Medicine Maria Juarez, MD, FACP Perelman School of Medicine Carol A. Rosenberg, MD, FACP University of Pennsylvania Warren A. Chow, MD Philadelphia, Pennsylvania Shahab Babakoohi, MD, FACP David Mintzer, MD David Greenberg, MD, FACP Chief, Section of Hematology and Medical Oncology Scott Okuno, MD, FACP Abramson Cancer Center at Pennsylvania Hospital Praveen Vikas, MD, FACP

Committee Deputy Editor Caroline Block, MD, Section Editor Richard S. Eisenstaedt, MD, MACP Assistant Professor of Medicine Chair, Department of Medicine Harvard Medical School Abington Hospital, Jefferson Health Division for Women’s Cancers Abington, Pennsylvania Dana-Farber Cancer Institute Boston, Massachusetts Oncology Reviewers Lee P. Hartner, MD Ross C. Donehower, MD, FACP Abramson Cancer Center at Pennsylvania Hospital Martin J. Edelman, MD, FACP Clinical Professor of Medicine Maria Juarez, MD, FACP Perelman School of Medicine Carol A. Rosenberg, MD, FACP University of Pennsylvania Warren A. Chow, MD Philadelphia, Pennsylvania Shahab Babakoohi, MD, FACP David Mintzer, MD David Greenberg, MD, FACP Chief, Section of Hematology and Medical Oncology Scott Okuno, MD, FACP Abramson Cancer Center at Pennsylvania Hospital Praveen Vikas, MD, FACP Clinical Professor of Medicine Perelman School of Medicine Hospital Medicine Oncology Reviewers University of Pennsylvania Harsha Tathireddy, MD, FACP Philadelphia, Pennsylvania Radhakrishna Vegunta, MD Philip D. Poorvu, MD Tara A. Ryan, MD, MS, MBA Breast Oncology Center Anil Shah, MD Dana-Farber Cancer Institute Boston, Massachusetts Oncology ACP Editorial Staff Leonard B. Saltz, MD Amanda Cowley, Medical Editor, Assessment and Professor of Medicine Education Programs Weill Cornell Medical College Margaret Wells, Ed.M., Director, Assessment and Education Attending Physician and Member Programs Memorial Sloan Kettering Cancer Center Becky Krumm, Senior Managing Editor, Assessment and New York, New York Education Programs

Clinical Professor of Medicine Perelman School of Medicine Hospital Medicine Oncology Reviewers University of Pennsylvania Harsha Tathireddy, MD, FACP Philadelphia, Pennsylvania Radhakrishna Vegunta, MD Philip D. Poorvu, MD Tara A. Ryan, MD, MS, MBA Breast Oncology Center Anil Shah, MD Dana-Farber Cancer Institute Boston, Massachusetts Oncology ACP Editorial Staff Leonard B. Saltz, MD Amanda Cowley, Medical Editor, Assessment and Professor of Medicine Education Programs Weill Cornell Medical College Margaret Wells, Ed.M., Director, Assessment and Education Attending Physician and Member Programs Memorial Sloan Kettering Cancer Center Becky Krumm, Senior Managing Editor, Assessment and New York, New York Education Programs Editor-in-Chief ACP Principal Staff Davoren Chick, MD, FACP Davoren Chick, MD, FACP Senior Vice President, Medical Education Senior Vice President, Medical Education American College of Physicians Philadelphia, Pennsylvania Tabassum Salam, MD, MBA, FACP Vice President, Medical Education Senior Deputy Editor Patrick C. Alguire, MD, FACP MKSAP Senior Deputy Editor Patrick C. Alguire, MD, FACP American College of Physicians Margaret Wells, Ed.M. Philadelphia, Pennsylvania Director, Assessment and Education Programs

Oncology Issues in Oncology Staging To plan a treatment strategy, a clinician must first determine Introduction the stage, or extent, of the cancer. Early-stage cancers are often Medical oncology is undergoing constant change and cured by local therapy, such as surgery or irradiation, whereas improvement. Among the most important advances of the more advanced-stage cancers require a systemic approach. past decade has been the incorporation of immune check- Solid tumors are staged using the TNM system. In the TNM point inhibitors into the standard treatment of many malig- system, T (T1-T4) refers to the size or extent of local invasion of nancies. These agents, although not directly attacking the the primary tumor, N (NO-N3) indicates locoregional lymph patient’s cancer, deactivate checkpoints that would other- node involvement, and M indicates the absence (MO) or pres- wise suppress the immune system, and so facilitate the ence (M1) of distant metastases. Some hematologic (liquid) patient’s own immune surveillance efforts to destroy the tumors have unique tumor-specific staging systems. cancer. Another major advance includes the expanded role of Appropriate imaging techniques depend on the expected molecular profiling and precision therapeutics. Current behavior pattern of each cancer type and differ from one techniques allow for genomic profiling of tumor tissue, tumor type to the next. Therefore, a proper cancer evaluation either from fresh biopsies, from archived, paraffin-embedded requires knowledge of the specific disease entity so that the specimens, or from blood-based tumor mutation profiling. necessary tests can be done and unnecessary tests avoided. With the knowledge of the mutational profile, oncologists Tests with very low yield should not be ordered in the absence can make more informed decisions in the selection and of specific directing symptoms. For example, bone and brain rejection of different therapeutic options and inclusion of imaging is appropriate in the staging of patients with lung so-called targeted therapies that are designed to inhibit a cancer because bone and brain metastases are common and particular molecular mutation or aberration. However, many may be asymptomatic. However, in patients with presumed traditional aspects of oncology, including the use of histologic locoregional colorectal cancer, asymptomatic bone or brain diagnosis and clinical staging, as well as extensive use of metastases are exceedingly rare; consequently, routine imag- cytotoxic chemotherapy, radiation therapy, and surgery, ing of these sites is not warranted. Staging in a patient with remain central to current oncologic practice. The cancer care cancer is generally the most accurate indicator of prognosis continuum is now recognized to include not only diagnosis and largely dictates the therapeutic strategy. and treatment but also supportive/palliative care, survivor- ship care, and end-of-life care. ¢ Most solid tumors are staged using the TNM cancer staging Careful clinical evaluation and staging, understanding system, in which Trepresents the size or extent of local and communicating realistic goals of care, and recognizing invasion of the primary tumor (T1-T4), N indicates locore- and promoting patient preferences remain central to the prac- gional lymph node involvement (NO-N3), and M indicates tice of oncology. Meaningful progress has been made in many the absence (MO) or presence (M1) of distant metastases. types of cancer. However, most cancers, once metastasized, although treatable with substantial potential for improve- e Appropriate cancer-staging imaging techniques depend ments in overall survival and quality of life, are still incurable. on the expected behavior pattern of each cancer type; Supportive management of adverse effects has also improved; therefore, proper cancer evaluation requires knowledge however, the adverse effects of cancer chemotherapy remain of the specific disease entity so that the necessary tests problematic for many patients, and sensitivity to the risks can be done and unnecessary tests avoided. versus benefits must be considered when discussing treatment e Within a particular type of cancer, staging is generally options with patients. Burdensome increases in the cost of the most accurate prognostic indicator and largely dic- new oncology drugs has become a focus of concern. Some of tates the therapeutic strategy. these high-cost drugs are highly active and offer substantial benefits, whereas others result in survival advantages meas- ured in months or even weeks that, although statistically sig- nificant, are of debatable clinical relevance. The impact of Performance Status financial toxicity has become an important consideration in Performance status is a means of quantifying how medically oncologic care. fit a patient is. A good performance status predicts favorable

Issues in Oncology tolerance and response to treatment. Patients with a poor per- formance status are much more likely to experience serious or ¢ Patients with poor performance status may be divided life-threatening toxicity and much less likely to benefit from into two groups: patients who are debilitated by chronic treatment. comorbidities and may need less aggressive treatment It is important to differentiate patients with a poor perfor- and those who are debilitated by the cancer but are oth- mance status who are debilitated due to chronic comorbidities erwise medically fit and might benefit from aggressive from patients who would otherwise be medically fit but are treatment. acutely debilitated by their cancer. The latter situation may ¢ Most clinical trials used to determine treatment efficacy warrant an attempt at aggressive treatment because reversing and safety are based on patients with good performance the cancer is the only strategy that will improve the patient’s status; the results of such trials should generally not be overall condition, whereas the former may need to be treated expected in patients with poor performance status. with less aggressive treatment or possibly no specific antican- cer treatment. Cancer drug approvals are based on clinical trials, virtually all of which limit participants to patients with good performance status, so the degree to which the results of Goals of Therapy these trials are relevant to patients with poor performance Clear and candid communication between clinicians and status is limited. patients is essential for good oncologic care. When communi- Age alone should not be a reason to avoid aggressive treat- cating treatment options and recommendations, clinicians ment. Elderly patients who are otherwise medically fit and must work to establish realistic treatment goals. When a cure healthy and have a good performance status may tolerate is not realistically possible, goals such as lengthening survival, aggressive therapy well. shrinking a tumor, controlling disease growth, palliation or The two most commonly used performance status scales preventing disease-related symptoms, and maintaining qual-

tolerance and response to treatment. Patients with a poor per- formance status are much more likely to experience serious or ¢ Patients with poor performance status may be divided life-threatening toxicity and much less likely to benefit from into two groups: patients who are debilitated by chronic treatment. comorbidities and may need less aggressive treatment It is important to differentiate patients with a poor perfor- and those who are debilitated by the cancer but are oth- mance status who are debilitated due to chronic comorbidities erwise medically fit and might benefit from aggressive from patients who would otherwise be medically fit but are treatment. acutely debilitated by their cancer. The latter situation may ¢ Most clinical trials used to determine treatment efficacy warrant an attempt at aggressive treatment because reversing and safety are based on patients with good performance the cancer is the only strategy that will improve the patient’s status; the results of such trials should generally not be overall condition, whereas the former may need to be treated expected in patients with poor performance status. with less aggressive treatment or possibly no specific antican- cer treatment. Cancer drug approvals are based on clinical trials, virtually all of which limit participants to patients with good performance status, so the degree to which the results of Goals of Therapy these trials are relevant to patients with poor performance Clear and candid communication between clinicians and status is limited. patients is essential for good oncologic care. When communi- Age alone should not be a reason to avoid aggressive treat- cating treatment options and recommendations, clinicians ment. Elderly patients who are otherwise medically fit and must work to establish realistic treatment goals. When a cure healthy and have a good performance status may tolerate is not realistically possible, goals such as lengthening survival, aggressive therapy well. shrinking a tumor, controlling disease growth, palliation or The two most commonly used performance status scales preventing disease-related symptoms, and maintaining qual- are the Karnofsky Performance Scale and the Eastern ity of life should be discussed. The potential benefits of treat- Cooperative Oncology Group/World Health Organization sys- ment must be weighed and considered against their risks and

tolerance and response to treatment. Patients with a poor per- formance status are much more likely to experience serious or ¢ Patients with poor performance status may be divided life-threatening toxicity and much less likely to benefit from into two groups: patients who are debilitated by chronic treatment. comorbidities and may need less aggressive treatment It is important to differentiate patients with a poor perfor- and those who are debilitated by the cancer but are oth- mance status who are debilitated due to chronic comorbidities erwise medically fit and might benefit from aggressive from patients who would otherwise be medically fit but are treatment. acutely debilitated by their cancer. The latter situation may ¢ Most clinical trials used to determine treatment efficacy warrant an attempt at aggressive treatment because reversing and safety are based on patients with good performance the cancer is the only strategy that will improve the patient’s status; the results of such trials should generally not be overall condition, whereas the former may need to be treated expected in patients with poor performance status. with less aggressive treatment or possibly no specific antican- cer treatment. Cancer drug approvals are based on clinical trials, virtually all of which limit participants to patients with good performance status, so the degree to which the results of Goals of Therapy these trials are relevant to patients with poor performance Clear and candid communication between clinicians and status is limited. patients is essential for good oncologic care. When communi- Age alone should not be a reason to avoid aggressive treat- cating treatment options and recommendations, clinicians ment. Elderly patients who are otherwise medically fit and must work to establish realistic treatment goals. When a cure healthy and have a good performance status may tolerate is not realistically possible, goals such as lengthening survival, aggressive therapy well. shrinking a tumor, controlling disease growth, palliation or The two most commonly used performance status scales preventing disease-related symptoms, and maintaining qual- are the Karnofsky Performance Scale and the Eastern ity of life should be discussed. The potential benefits of treat- Cooperative Oncology Group/World Health Organization sys- ment must be weighed and considered against their risks and tem (also called the Zubrod scale). These are outlined and toxicities. Patients with incurable cancer face choices of more contrasted in Table 1. aggressive therapy designed to prolong their life, associated

are the Karnofsky Performance Scale and the Eastern ity of life should be discussed. The potential benefits of treat- Cooperative Oncology Group/World Health Organization sys- ment must be weighed and considered against their risks and tem (also called the Zubrod scale). These are outlined and toxicities. Patients with incurable cancer face choices of more contrasted in Table 1. aggressive therapy designed to prolong their life, associated TABLE 1. Oncology Performance Status Systems ECOG/WHO Performance Status? _ 0-Fully active; no restrictions on activities 1 - Unable to do strenuous activities, but able to carry out office work, light housework, or sedentary activities 2 - Able to walk and manage self-care, but unable to work; out of bed or chair >50% of waking hours | 3-Confined to bed or chair >50% of waking hours; capable of limited self-care 4 - Moribund. Fully confined to a bed or chair; unable to do any self-care 5 - Death Karnofsky Performance Status 100 - Normal; no symptoms or evidence of disease | 90-Minor symptoms, but able to carry on normal activities | 80 - Some symptoms; normal activity requires effort | 70 -Unable to carry on normal activities, but able to care for self | 60- Needs frequent care for most needs; some occasional assistance with self-care | 50 - Needs considerable assistance with self-care and frequent medical care 40 - Disabled; needs special care and assistance 30 - Severely disabled; hospitalized 20 - Very ill; significant supportive care is needed | 10-Actively dying 0 - Death | ECOG = Eastern Cooperative Oncology Group; WHO = World Health Organization. | Also called the Zubrod scale. L =

Issues in Oncology with more unpleasant and potentially dangerous adverse seeing that cancer again. Cure should not be confused with the effects. Similarly, more aggressive initial therapy may result in term overall survival, which is defined as the amount of time prolonged remission or disease-free survival but may not nec- from the start of treatment until death. Overall survival is often essarily change overall survival. All patients will have a unique misunderstood by patients to be synonymous with cure. perspective on how they interpret this equation. Median survival outcomes that are reported in studies are too A cancer diagnosis has been shown to be a leading cause often explained to patients as indicating how long they will of personal bankruptcy, and studies show financial worries live, but it must be understood and explained that medians contribute to patients’ anxiety. Inability to meet copays or coin- identify the center of an often-broad, bell-shaped curve, and surance requirements, especially for expensive oral anticancer may be meaningful for populations, but cannot predict an medications, is a leading cause of failure to properly receive outcome for any one individual patient. therapy. A clear understanding of the goals of care and the tox- Patient expectations can be further confused by the icities, including financial toxicity, is necessary for patients and frequent use of the phrase significant improvement in sur- physicians to make informed choices in treatment options. This vival, in which significant refers to the statistical certainty concept of financial toxicity goes beyond individual patients in of the finding but is often misinterpreted as a substantial affecting the overall health care economy. Quantifying the improvement in survival. Many drugs have been approved overall benefit of extending a patient’s life by relatively short with significant improvements in median survival that are periods (less than 2 months’ median benefit) and contrasting limited to less than 2 or 3 months, a quantity that most that benefit by the financial cost of care require complex ethi- would agree is not substantial. Furthermore, one must be cal, economic, and public health decisions. cautious about interpreting nonrandomized comparisons of Early-stage cancers often have a high chance of cure. With older versus newer survival data. Randomized controlled increasing cancer stage, the possibility of cure diminishes. Most trials are the only reliable means of comparing one treat- metastatic cancers are treatable but not curable. The risks of ment with another. treatment are higher and may outweigh the benefit in patients One of the most misrepresented and misunderstood with poor performance status due to chronic medical comor- terms is progression-free survival. It is the time from when a bidities or those who have not been able to tolerate initial treat- treatment is started until that treatment is no longer control- ment attempts. For such patients or for those who have ling the cancer. The word survival was initially included in the exhausted standard treatment options, supportive, comfort- term because the duration of progression-free survival is oriented care may be most appropriate. Use of adequate anal- defined by either growth of the cancer (progression) or patient gesia, as well as involving supportive care specialists, is death, whichever occurs first; thus, the term has nothing to do important throughout the continuum of care but particularly with overall survival and is often confused with it. Progression- so in patients with pain or with symptoms from either disease free interval would be a more apt term. or therapy. Studies suggest that such supportive care, when Response rate is the percentage of patients in a clinical instituted early in conjunction with anticancer therapy, helps trial whose tumors shrink to a prespecified degree (as indi- patients better tolerate their cancer care and should not be cated on imaging studies such as CT or MRI) with treatment. delayed to the point at which no more active cancer therapy is Response in hematologic malignancies is defined by other considered. clinical criteria. Response rate may not correlate with overall survival, but there is a strong emotional benefit to patients when the tumor is regressing, and in symptomatic patients, e The potential benefits of treatment must be weighed such shrinkage is likely to alleviate or delay symptoms. and discussed along with its risks and toxicities, includ- ing financial toxicity, because the costs of anticancer treatments have increased substantially. e An increase in overall survival is not synonymous with cure, median survival is only relevant to populations, e Palliative care should be instituted early in the manage- and “significant” improvements reported in clinical tri- ment of patients with cancer and not reserved only for the als do not necessarily mean substantial improvements. time when they are no longer receiving cancer therapy. e Progression-free survival measures the time from initia- tion of treatment until the cancer progresses or the Understanding Cancer patient dies; it would be better termed progression-free Terminology interval. A clear understanding of cancer terminology is necessary to facilitate informed discussions and develop realistic treatment goals. Treatment Approaches The one pure and simple term is cure. Cure means that The classic cancer treatment modalities are surgery, irradia- the cancer is gone, no further treatment is required, and the tion, and chemotherapy. As current technology has advanced, patient can be expected to live out his or her life without chemotherapy is best subdivided into the more classical

with more unpleasant and potentially dangerous adverse seeing that cancer again. Cure should not be confused with the effects. Similarly, more aggressive initial therapy may result in term overall survival, which is defined as the amount of time prolonged remission or disease-free survival but may not nec- from the start of treatment until death. Overall survival is often essarily change overall survival. All patients will have a unique misunderstood by patients to be synonymous with cure. perspective on how they interpret this equation. Median survival outcomes that are reported in studies are too A cancer diagnosis has been shown to be a leading cause often explained to patients as indicating how long they will of personal bankruptcy, and studies show financial worries live, but it must be understood and explained that medians contribute to patients’ anxiety. Inability to meet copays or coin- identify the center of an often-broad, bell-shaped curve, and surance requirements, especially for expensive oral anticancer may be meaningful for populations, but cannot predict an medications, is a leading cause of failure to properly receive outcome for any one individual patient. therapy. A clear understanding of the goals of care and the tox- Patient expectations can be further confused by the icities, including financial toxicity, is necessary for patients and frequent use of the phrase significant improvement in sur- physicians to make informed choices in treatment options. This vival, in which significant refers to the statistical certainty concept of financial toxicity goes beyond individual patients in of the finding but is often misinterpreted as a substantial affecting the overall health care economy. Quantifying the improvement in survival. Many drugs have been approved overall benefit of extending a patient’s life by relatively short with significant improvements in median survival that are periods (less than 2 months’ median benefit) and contrasting limited to less than 2 or 3 months, a quantity that most that benefit by the financial cost of care require complex ethi- would agree is not substantial. Furthermore, one must be cal, economic, and public health decisions. cautious about interpreting nonrandomized comparisons of Early-stage cancers often have a high chance of cure. With older versus newer survival data. Randomized controlled increasing cancer stage, the possibility of cure diminishes. Most trials are the only reliable means of comparing one treat- metastatic cancers are treatable but not curable. The risks of ment with another. treatment are higher and may outweigh the benefit in patients One of the most misrepresented and misunderstood with poor performance status due to chronic medical comor- terms is progression-free survival. It is the time from when a bidities or those who have not been able to tolerate initial treat- treatment is started until that treatment is no longer control- ment attempts. For such patients or for those who have ling the cancer. The word survival was initially included in the exhausted standard treatment options, supportive, comfort- term because the duration of progression-free survival is oriented care may be most appropriate. Use of adequate anal- defined by either growth of the cancer (progression) or patient gesia, as well as involving supportive care specialists, is death, whichever occurs first; thus, the term has nothing to do important throughout the continuum of care but particularly with overall survival and is often confused with it. Progression- so in patients with pain or with symptoms from either disease free interval would be a more apt term. or therapy. Studies suggest that such supportive care, when Response rate is the percentage of patients in a clinical instituted early in conjunction with anticancer therapy, helps trial whose tumors shrink to a prespecified degree (as indi- patients better tolerate their cancer care and should not be cated on imaging studies such as CT or MRI) with treatment. delayed to the point at which no more active cancer therapy is Response in hematologic malignancies is defined by other considered. clinical criteria. Response rate may not correlate with overall survival, but there is a strong emotional benefit to patients when the tumor is regressing, and in symptomatic patients, e The potential benefits of treatment must be weighed such shrinkage is likely to alleviate or delay symptoms. and discussed along with its risks and toxicities, includ- ing financial toxicity, because the costs of anticancer treatments have increased substantially. e An increase in overall survival is not synonymous with cure, median survival is only relevant to populations, e Palliative care should be instituted early in the manage- and “significant” improvements reported in clinical tri- ment of patients with cancer and not reserved only for the als do not necessarily mean substantial improvements. time when they are no longer receiving cancer therapy. e Progression-free survival measures the time from initia- tion of treatment until the cancer progresses or the Understanding Cancer patient dies; it would be better termed progression-free Terminology interval. A clear understanding of cancer terminology is necessary to facilitate informed discussions and develop realistic treatment goals. Treatment Approaches The one pure and simple term is cure. Cure means that The classic cancer treatment modalities are surgery, irradia- the cancer is gone, no further treatment is required, and the tion, and chemotherapy. As current technology has advanced, patient can be expected to live out his or her life without chemotherapy is best subdivided into the more classical 3