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William Breitbart and Yesne Alici-Evcimen

Fatigue is a common and highly distressing symptom of cancer associated with reduced quality of life and considerable psychological and functional morbidity. The reported prevalence of cancer-related fatigue ranges from 4% to 91%, depending on the specific cancer population studied and the methods of assessment. Cancer-related fatigue has typically been underreported, underdiagnosed, and undertreated. Fatigue and depression may coexist in cancer patients, and considerable overlap of symptoms occurs. This is partly the reason for the interest in examining the role of psychotropic medications in treating fatigue. Clarifying the relationship between depression and fatigue is necessary to effectively evaluate and treat cancer-related fatigue. Even with International Classification of Diseases criteria, differentiating cancer-related fatigue is difficult. Psychotropic drugs that have been studied for cancer-related fatigue include psychostimulants, wakefulness-promoting agents, and anti-depressants. Methylphenidate has been studied most and seems to be effective and well tolerated despite common side effects. Some preliminary data support using modafinil in cancer-related fatigue with less concern about tolerance or dependence. Antidepressant studies have shown mixed results. Paroxetine seems to show benefit for fatigue primarily when it is a symptom of clinical depression. Bupropion, a norepinephrine/dopamine reuptake inhibitor, may have psychostimulant-like effects, and therefore may be more beneficial for treating fatigue. However, studies are currently limited. Randomized, placebo-controlled trials with specific agents are needed to further assess the efficacy and tolerability of psychotropic medications in the treatment of cancer-related fatigue.

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William Breitbart and Yesne Alici

Fatigue is a highly prevalent and distressing symptom associated with significant psychological and functional morbidity and decreased quality of life among patients with cancer. Despite its impact on patients and caregivers, fatigue is underreported and underrecognized, and remains untreated among patients with cancer because of various patient- and clinician-related factors. In addition to assessment for potentially reversible medical causes or medications exacerbating fatigue, and the implementation of nonpharmacologic interventions, several pharmacologic treatment options have been considered for the treatment of cancer-related fatigue. Among traditional psychostimulants, methylphenidate has been studied the most and is effective and well tolerated among patients with cancer despite common side effects. Modafinil, a novel psychostimulant commonly referred to as wakefulness-promoting agents as a group, has also been studied and seems to be well tolerated among patients with cancer. A large placebo effect has been reported in most randomized controlled trials with psychostimulants. Thus, randomized placebo-controlled trials with large sample sizes are needed to further assess the efficacy and tolerability of psychostimulants in the treatment of cancer-related fatigue. This article presents a comprehensive review of the use of psychostimulant agents for fatigue among patients with cancer, including an overview of the clinical trials with psychostimulants and of the clinical guidelines available for treatment of cancer-related fatigue.

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Daniel C. McFarland, Devika R. Jutagir, Andrew H. Miller, William Breitbart, Christian Nelson and Barry Rosenfeld

Background: Patients with lung cancer with greater systemic inflammation have higher rates of depression. Tumor mutation burden (TMB) predicts immunotherapy response in patients with lung cancer and is associated with intratumoral inflammation, which may contribute to systemic inflammation and depression. This study evaluated whether higher TMB was associated with increased depression and systemic inflammation in patients with lung cancer. Patients and Methods: Patients with metastatic lung cancers were evaluated for depression severity using the Hospital Anxiety and Depression Scale. TMB was measured using the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets. Inflammation was evaluated using C-reactive protein (CRP) level and neutrophil-to-lymphocyte ratio (NLR). Results: A total of 96 patients with adequate TMB testing were evaluated. The average number of mutations (TMB) was 10.8 (SD, 10.9). A total of 19% of patients endorsed clinically significant depression symptoms. TMB was significantly correlated with depression severity (r = 0.34; P=.001) and NLR (r = 0.37; P=.002) but not CRP level (r = 0.19; P=.07). TMB was also higher in patients receiving chemotherapy (mean, 12.0) and immunotherapy (mean, 14.4) versus targeted therapy (mean, 4.8). A multivariate model found that TMB (β = 0.30; P=.01) and CRP level (β = 0.31; P=.01) were independently associated with depression; there was no significant interaction effect of TMB × CRP and depression. A similar multivariate model showed no independent effect for NLR and depression (β = 0.16; P=.17) after accounting for TMB. Conclusions: These data provide evidence for biologic depression risk in patients with lung cancer who have high levels of TMB. The underlying mechanism of the association is not clearly related to inflammation but warrants further analysis to broadly elucidate the mechanism of biologically derived depression in cancer.

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Ann M. Berger, Amy Pickar Abernethy, Ashley Atkinson, Andrea M. Barsevick, William S. Breitbart, David Cella, Bernadine Cimprich, Charles Cleeland, Mario A. Eisenberger, Carmen P. Escalante, Paul B. Jacobsen, Phyllis Kaldor, Jennifer A. Ligibel, Barbara A. Murphy, Tracey O'Connor, William F. Pirl, Eve Rodler, Hope S. Rugo, Jay Thomas and Lynne I. Wagner

OverviewFatigue is a common symptom in patients with cancer and is nearly universal in those undergoing cytotoxic chemotherapy, radiation therapy, bone marrow transplantation, or treatment with biologic response modifiers.1–10 The symptom is experienced by 70% to 100% of patients with cancer who undergo multi-modal treatments and dose–dense, dose-intense protocols.11 In patients with metastatic disease, the prevalence of cancer-related fatigue exceeds 75%. Cancer survivors report that fatigue is a disruptive symptom months or even years after treatment ends.12–21 The distinction between tiredness, fatigue, and exhaustion has not been made, despite conceptual differences.22,23 Patients perceive fatigue to be the most distressing symptom associated with cancer and its treatment, more distressing even than pain or nausea and vomiting, which, for most patients, can generally be managed with medications.24,25Fatigue in patients with cancer has been underreported, underdiagnosed, and undertreated. Persistent cancer-related fatigue affects quality of life (QOL), because patients become too tired to fully participate in the roles and activities that make their lives meaningful.16,26–28 Health care professionals have been challenged in their efforts to help patients manage this distressful symptom and remain as fully engaged in life as possible. Because of the successes in cancer treatment, health care professionals are now likely to see patients with prolonged states of fatigue related to the late effects of treatment. Disability-related issues are relevant and often challenging, especially for patients who are cured of their malignancy but experience continued fatigue.29 Despite biomedical literature documenting this entity, patients with cancer-related fatigue often have difficulty obtaining...
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Ann M. Berger, Kathi Mooney, Amy Alvarez-Perez, William S. Breitbart, Kristen M. Carpenter, David Cella, Charles Cleeland, Efrat Dotan, Mario A. Eisenberger, Carmen P. Escalante, Paul B. Jacobsen, Catherine Jankowski, Thomas LeBlanc, Jennifer A. Ligibel, Elizabeth Trice Loggers, Belinda Mandrell, Barbara A. Murphy, Oxana Palesh, William F. Pirl, Steven C. Plaxe, Michelle B. Riba, Hope S. Rugo, Carolina Salvador, Lynne I. Wagner, Nina D. Wagner-Johnston, Finly J. Zachariah, Mary Anne Bergman and Courtney Smith

Cancer-related fatigue is defined as a distressing, persistent, subjective sense of physical, emotional, and/or cognitive tiredness or exhaustion related to cancer or cancer treatment that is not proportional to recent activity and interferes with usual functioning. It is one of the most common side effects in patients with cancer. Fatigue has been shown to be a consequence of active treatment, but it may also persist into posttreatment periods. Furthermore, difficulties in end-of-life care can be compounded by fatigue. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Cancer-Related Fatigue provide guidance on screening for fatigue and recommendations for interventions based on the stage of treatment. Interventions may include education and counseling, general strategies for the management of fatigue, and specific nonpharmacologic and pharmacologic interventions. Fatigue is a frequently underreported complication in patients with cancer and, when reported, is responsible for reduced quality of life. Therefore, routine screening to identify fatigue is an important component in improving the quality of life for patients living with cancer.

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Jimmie C. Holland, Barbara Andersen, William S. Breitbart, Bruce Compas, Moreen M. Dudley, Stewart Fleishman, Caryl D. Fulcher, Donna B. Greenberg, Carl B. Greiner, George F. Handzo, Laura Hoofring, Paul B. Jacobsen, Sara J. Knight, Kate Learson, Michael H. Levy, Matthew J. Loscalzo, Sharon Manne, Randi McAllister-Black, Michelle B. Riba, Kristin Roper, Alan D. Valentine, Lynne I. Wagner and Michael A. Zevon

Overview In the United States, a total of 1,479,350 new cancer cases and 562,340 deaths from cancer were estimated to occur in 2009. 1 All patients experience some level of distress associated with the diagnosis and treatment of cancer at all stages of the disease. Surveys have found that 20% to 40% of patients with newly diagnosed and recurrent cancer show a significant level of distress. 2 However, fewer than 10% are actually identified and referred for psychosocial help. 3 Many cancer patients who are in need of psychosocial care are not able to get the help they need due to the under recognition of patient's psychological needs by the primary oncology team and lack of knowledge of community resources. The need is particularly acute in community oncology practices that have few to no psychosocial resources, and cancer care is often provided in short visits. 4 For many centuries, patients were not told their diagnosis of cancer because of the stigma attached to the disease. Since the 1970s, this situation has changed and patients are well aware of their diagnosis and treatment options. However, patients are reluctant to reveal emotional problems to the oncologist. The words psychological, psychiatric, and emotional are as stigmatizing as cancer. Psychological issues remain stigmatized even in the context of coping with cancer. Consequently, patients often do not tell their physicians about their distress and physicians do not inquire about the psychological concerns of their patients. Recognition of patients' distress has become more difficult as cancer care has shifted to the...
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Michelle B. Riba, Kristine A. Donovan, Barbara Andersen, IIana Braun, William S. Breitbart, Benjamin W. Brewer, Luke O. Buchmann, Matthew M. Clark, Molly Collins, Cheyenne Corbett, Stewart Fleishman, Sofia Garcia, Donna B. Greenberg, Rev. George F. Handzo, Laura Hoofring, Chao-Hui Huang, Robin Lally, Sara Martin, Lisa McGuffey, William Mitchell, Laura J. Morrison, Megan Pailler, Oxana Palesh, Francine Parnes, Janice P. Pazar, Laurel Ralston, Jaroslava Salman, Moreen M. Shannon-Dudley, Alan D. Valentine, Nicole R. McMillian and Susan D. Darlow

Distress is defined in the NCCN Guidelines for Distress Management as a multifactorial, unpleasant experience of a psychologic (ie, cognitive, behavioral, emotional), social, spiritual, and/or physical nature that may interfere with the ability to cope effectively with cancer, its physical symptoms, and its treatment. Early evaluation and screening for distress leads to early and timely management of psychologic distress, which in turn improves medical management. The panel for the Distress Management Guidelines recently added a new principles section including guidance on implementation of standards of psychosocial care for patients with cancer.

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Jimmie C. Holland, Barbara Andersen, William S. Breitbart, Luke O. Buchmann, Bruce Compas, Teresa L. Deshields, Moreen M. Dudley, Stewart Fleishman, Caryl D. Fulcher, Donna B. Greenberg, Carl B. Greiner, George F. Handzo, Laura Hoofring, Charles Hoover, Paul B. Jacobsen, Elizabeth Kvale, Michael H. Levy, Matthew J. Loscalzo, Randi McAllister-Black, Karen Y. Mechanic, Oxana Palesh, Janice P. Pazar, Michelle B. Riba, Kristin Roper, Alan D. Valentine, Lynne I. Wagner, Michael A. Zevon, Nicole R. McMillian and Deborah A. Freedman-Cass

The integration of psychosocial care into the routine care of all patients with cancer is increasingly being recognized as the new standard of care. These NCCN Clinical Practice Guidelines in Oncology for Distress Management discuss the identification and treatment of psychosocial problems in patients with cancer. They are intended to assist oncology teams identify patients who require referral to psychosocial resources and to give oncology teams guidance on interventions for patients with mild distress to ensure that all patients with distress are recognized and treated.