Studies seeking to explain mechanisms associated with or causing fatigue are increasing; however, the underlying causes of fatigue remain largely unknown. Thus, identifying and predicting which patients may be at risk for developing fatigue, and tailoring interventions accordingly, are difficult. Whether fatigue experienced by patients with cancer can be classified into specific clinically significant subtypes would be useful to determine. These clinical subtypes might improve understanding of underlying mechanisms and help tailor treatment accordingly. This article refers to fatigue associated with cancer or its treatment as cancer-related fatigue (CRF). Given this broad designation, meant to encompass the array of causal mechanisms and treatment options, the authors recommend that meaningful clinical subtypes be articulated and differentiated. This article therefore reviews CRF definitions and proposes a nonexhaustive set of clinical subtypes that are intended to help sharpen thinking about causality and, ultimately, treatment recommendations.
Cancer-Related Fatigue: Definitions and Clinical Subtypes
Barbara F. Piper and David Cella
Fatigue is the Most Important Symptom for Advanced Cancer Patients Who Have Had Chemotherapy
Zeeshan Butt, Sarah K. Rosenbloom, Amy P. Abernethy, Jennifer L. Beaumont, Diane Paul, Debra Hampton, Paul B. Jacobsen, Karen L. Syrjala, Jamie H. Von Roenn, and David Cella
Cancer fatigue has been defined and described as an important problem. However, few studies have assessed the relative importance of fatigue compared with other patient symptoms and concerns. To explore this issue, the authors surveyed 534 patients and 91 physician experts from 5 NCCN member institutions and community support agencies. Specifically, they asked patients with advanced bladder, brain, breast, colorectal, head and neck, hepatobiliary/pancreatic, kidney, lung, ovarian, or prostate cancer or lymphoma about their “most important symptoms or concerns to monitor.” Across the entire sample, and individually for patients with 9 cancer types, fatigue emerged as the top-ranked symptom. Fatigue was also ranked most important among patients with 10 of 11 cancer types when asked to rank lists of common concerns. Patient fatigue ratings were most strongly associated with malaise (r = 0.50) and difficulties with activities of daily living, pain, and quality of life. Expert ratings of how much fatigue is attributable to disease versus treatment mostly suggested that both play an important role, with disease-related factors predominant in hepatobiliary and lung cancer, and treatment-related factors playing a stronger role in head and neck cancer.
Communicating About Chemotherapy-Induced Nausea and Vomiting: A Comparison of Patient and Provider Perspectives
John M. Salsman, Steven M. Grunberg, Jennifer L. Beaumont, Miriam Rogers, Diane Paul, Marla L. Clayman, and David Cella
Despite recent progress, chemotherapy-induced nausea and vomiting (CINV), especially delayed CINV, continues to be a problem. Delayed CINV is underestimated and perceived differently by providers and patients. Communication between providers and patients about this side effect may help improve outcomes. This study identifies patients’ and providers’ perceptions of management and barriers to quality CINV care. Provider and patient versions of a Nausea and Vomiting Management Barriers Questionnaire were developed to address potential barriers. Providers and patients were given opportunities to add detail in open-ended questions. Providers were recruited through the NCCN and the Oncology Nursing Society mailing lists. Patients who received at least 2 cycles of chemotherapy and experienced CINV were recruited through a consortium of advocacy groups. Both providers (n = 141) and patients (n = 299) completed the survey. Providers (41%) and patients (42%) agreed medication side effects were a concern, but more patients (63%) than providers (36%) tried to limit the number of medications taken (P < .0001). Many providers (67%) spontaneously reported barriers to managing CINV, with financial and patient-related factors among the most common. Few patients (10%) reported cost as a barrier, but 37% endorsed the desire “to be strong by not complaining.” Barriers to communication and quality care of CINV differ between caregivers and patients. Addressing misconceptions and establishing mutually consistent goals will lead to more effective overall care.
Development and Validation of 11 Symptom Indexes to Evaluate Response to Chemotherapy for Advanced Cancer
David Cella, Sarah K. Rosenbloom, Jennifer L. Beaumont, Susan E. Yount, Diane Paul, Debra Hampton, Amy P. Abernethy, Paul B. Jacobsen, Karen Syrjala, and Jamie H. Von Roenn
Recent guidance from the FDA discusses patient-reported outcomes as end points in clinical trials. Using methods consistent with this guidance, the authors developed symptom indexes for patients with advanced cancer. Input on the most important symptoms was obtained from 533 patients recruited from NCCN Member Institutions and 4 nonprofit social service organizations. Diagnoses included bladder, brain, breast, colorectal, head and neck, hepatobiliary/pancreatic, kidney, lung, ovarian, and prostate cancers and lymphoma. Physician experts in each of these diseases were also surveyed to differentiate symptoms that were predominantly disease-based from those that were predominantly treatment-induced. Results are evaluated alongside previously published indexes for 9 of these 11 advanced cancers that were created based on expert provider surveys, also implemented at NCCN Member Institutions. Final results are 11 symptom indexes that reflect the highest priorities of people affected by these 11 advanced cancers and the experienced perspective of the people who provide their medical treatment. Beyond the clinical value of such indexes, they may also contribute significantly to satisfying regulatory requirements for a standardized tool to evaluate drug efficacy with respect to symptomatology.
Cardiovascular Implications of Vascular Endothelial Growth Factor Inhibition Among Adolescents/Young Adults in ECOG-ACRIN E2805
Wendy J. Bottinor, Yael Flamand, Naomi B. Haas, Anne M. ONeill, Robert S. DiPaola, Pearl Subramanian, David Cella, W. Gregory Hundley, Lynne I. Wagner, John M. Salsman, and Bonnie Ky
Background: Cardiovascular disease (CVD) is a leading cause of morbidity and mortality among adolescents and young adults (AYAs) diagnosed with cancer. The aim of this study was to assess the incidence and predictors of left ventricular systolic dysfunction (LVSD) and hypertension among AYAs receiving VEGF inhibition compared with non-AYAs. Methods: This retrospective analysis used data from the ASSURE trial (ClinicalTrials.gov identifier: NCT00326898), in which participants with nonmetastatic, high-risk, renal cell cancer were randomized to sunitinib, sorafenib, or placebo. The incidence of LVSD (left ventricular ejection fraction decrease >15%) and hypertension (blood pressure ≥140/90 mm Hg) were compared using nonparametric tests. Multivariable logistic regression examined the association between AYA status, LVSD, and hypertension while adjusting for clinical factors. Results: AYAs represented 7% (103/1,572) of the population. Over a study treatment period of 54 weeks, the incidence of LVSD was not significantly different among AYAs (3%; 95% CI, 0.6%–8.3%) versus non-AYAs (2%; 95% CI, 1.2%–2.7%). The incidence of hypertension was significantly lower among AYAs (18%; 95% CI, 7.5%–33.5%) compared with non-AYAs (46%; 95% CI, 41.9%–50.4%) in the placebo arm. In the sunitinib and sorafenib groups, the incidence of hypertension for AYAs compared with non-AYAs was 29% (95% CI, 15.1%–47.5%) versus 47% (95% CI, 42.3%–51.7%), and 54% (95% CI, 33.9%–72.5%) versus 63% (95% CI, 58.6%–67.7%), respectively. AYA status (odds ratio, 0.48; 95% CI, 0.31–0.75) and female sex (odds ratio, 0.74; 95% CI, 0.59–0.92) were each associated with a lower risk of hypertension. Conclusions: LVSD and hypertension were prevalent among AYAs. CVD among AYAs is only partially explained by cancer therapy. Understanding CVD risk among AYA cancer survivors is important for promoting cardiovascular health in this growing population.
HSR19-107: Nivolumab for Newly Diagnosed Classical Hodgkin Lymphoma: Patient-Reported Outcomes From CheckMate 205 Cohort D
Radhakrishnan Ramchandren, Stephen M. Ansell, Philippe Armand, Andreas Engert, Fiona Taylor, Kim Cocks, Clara Chen, Bryan Bennett, Alejandro Moreno-Koehler, Adam Roeder, Anne Sumbul, Mariana Sacchi, and David Cella
Background: Patients (pts) with classical Hodgkin lymphoma (cHL) frequently experience reduced health-related quality of life (HRQoL) (Oerlemans et al, Ann Hematol 2011). Nivolumab, a fully human IgG4 anti-programmed death-1 (PD-1) immune checkpoint inhibitor monoclonal antibody, demonstrated efficacy and clinically meaningful improvement in pt-reported outcomes (PROs) in pts with relapsed/refractory cHL in cohorts A, B, and C of CheckMate 205 (NCT02181738) (Armand et al, J Clin Oncol 2018; Engert et al, ASH 2017). Nivolumab monotherapy followed by nivolumab + doxorubicin, vinblastine and dacarbazine (N-AVD) demonstrated an objective response rate of 84% in newly diagnosed cHL (cohort D of CheckMate 205; Ramchandren et al, EHA 2018). We present PROs in CheckMate 205 cohort D. Methods: Pts ≥18 years of age with untreated, advanced-stage cHL, with ECOG performance status (PS) of 0–1 received 4 doses of nivolumab monotherapy (240 mg IV Q2W) followed by N-AVD for 6 cycles (12 doses). Pts then entered the follow-up (FU) period. PROs were an exploratory endpoint, assessed using the EuroQol 5 Dimensions-3 level (EQ-5D-3L) and associated visual analog scale (EQ-VAS) in all treated pts who had both a baseline (monotherapy cycle 1) and post-baseline assessment. EQ-VAS ranges from 0–100, with higher scores indicating better HRQoL. In EQ-5D-3L, pts can report no, some, or extreme problems in each of 5 dimensions (mobility, self-care, activity, pain, and anxiety). Results: 51 pts were treated. At baseline, median age was 37 years, 63% were male, 59% had ECOG PS of 0. 49 pts (96%) completed baseline EQ-VAS. Mean EQ-VAS scores exceeded the mean baseline score at the end of monotherapy, after 2 combination cycles, at the end of therapy, and during follow-up (). The proportion of pts reporting some or extreme problems in EQ-5D-3L was numerically lower than or similar to baseline after monotherapy for all dimensions, but was numerically higher than baseline (dimensions of mobility and activity) after 2 combination cycles, and remained close to or numerically below baseline during follow-up (dimensions of self-care, activity, pain, and anxiety). Conclusions: Pt-reported HRQoL, as assessed by observed mean EQ-VAS scores, did not deteriorate from baseline during treatment with nivolumab followed by N-AVD. Proportions of pts reporting problems in individual EQ-5D-3L dimensions were generally similar to baseline during treatment and follow-up.
Cancer- and Chemotherapy-Induced Anemia
George M. Rodgers III, Pamela Sue Becker, Morey Blinder, David Cella, Asher Chanan-Khan, Charles Cleeland, Peter F. Coccia, Benjamin Djulbegovic, Jeffrey A. Gilreath, Eric H. Kraut, Ursula A. Matulonis, Michael M. Millenson, Denise Reinke, Joseph Rosenthal, Rowena N. Schwartz, Gerald Soff, Richard S. Stein, Gordana Vlahovic, and Alva B. Weir III
Anemia is prevalent in 30% to 90% of patients with cancer. Anemia can be corrected through either treating the underlying cause or providing supportive care through transfusion with packed red blood cells or administration of erythropoiesis-stimulating agents (ESAs), with or without iron supplementation. Recent studies showing detrimental health effects of ESAs sparked a series of FDA label revisions and a sea change in the perception of these once commonly used agents. In light of this, the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Cancer- and Chemotherapy-Induced Anemia underwent substantial revisions this year. The purpose of these NCCN Guidelines is twofold: 1) to operationalize the evaluation and treatment of anemia in adult cancer patients, with an emphasis on those who are receiving concomitant chemotherapy, and 2) to enable patients and clinicians to individualize anemia treatment options based on patient condition.
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
Cancer-Related Fatigue, Version 2.2015
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.