Cohen, Harvey Jay

The NCCN Guidelines for Older Adult Oncology address specific issues related to the management of cancer in older adults, including screening and comprehensive geriatric assessment (CGA), assessing the risks and benefits of treatment, preventing or decreasing complications from therapy, and managing patients deemed to be at high risk for treatment-related toxicity. CGA is a multidisciplinary, in-depth evaluation that assesses the objective health of the older adult while evaluating multiple domains, which may affect cancer prognosis and treatment choices. These NCCN Guidelines Insights focus on recent updates to the NCCN Guidelines providing specific practical framework for the use of CGA when evaluating older adults with cancer.

PURPOSE This study determined whether an electronic version of the geriatric assessment is feasible in a multi-institutional, diverse setting. METHODs Ten sites within the Alliance for Clinical Trials in Oncology participated. Patients who had active cancer or a history of cancer and were 65 years of age or older were eligible. The geriatric assessment was completed with an electronic data capture system that had been loaded onto iPads. Feasibility was defined a priori as completion in at least 70% of patients either with or without help. To enhance racial diversity, the original sample size was later changed and augmented by 50% with the intention of increasing enrollment of older minority patients. RESULTS A total of one hundred fifty-four patients were registered with a median age of 72 years (range, 65-91 years). Forty-three (28%) identified themselves as African American or Black. One hundred forty-one patients (92%) completed the electronic geriatric assessment. Feasibility was observed across all subgroups, regardless of race, education, performance status, comorbidities, and cognition; 124 patients (81%) completed the geriatric assessment without help. Reasons for not completing the geriatric assessment are as follows: clinic visit did not occur (n = 6), no iPad connection to the Internet (n = 3), patient declined (n = 2), prolonged hospitalization (n = 1), and patient died (n = 1). Reasons for needing help, as reported by study personnel, were as follows: the patient preferred that research personnel ask the questions (n = 9), vision problem (n = 3), lack of comfort with the iPad (n = 2), questions were not clear (n = 1), less proficient in English (n = 1), and challenge in pressing the green button to go to the next question (n = 1). CONCLUSION The electronic geriatric assessment is feasible in a multi-institutional setting that includes a notable proportion of African American or Black patients.

Abstract Cancer is a disease of aging and, as the world's population ages, the number of older persons with cancer is increasing and will make up a growing share of the oncology population in virtually every country. Despite this, older patients remain vastly underrepresented in research that sets the standards for cancer treatments. Consequently, most of what we know about cancer therapeutics is based on clinical trials conducted in younger, healthier patients, and effective strategies to improve clinical trial participation of older adults with cancer remain sparse. For this systematic review, the authors evaluated published studies regarding barriers to participation and interventions to improve participation of older adults in cancer trials. The quality of the available evidence was low and, despite a literature describing multifaceted barriers, only one intervention study aimed to increase enrollment of older adults in trials. The findings starkly amplify the paucity of evidence‐based, effective strategies to improve participation of this underrepresented population in cancer trials. Within these limitations, the authors provide their opinion on how the current cancer research infrastructure must be modified to accommodate the needs of older patients. Several underused solutions are offered to expand clinical trials to include older adults with cancer. However, as currently constructed, these recommendations alone will not solve the evidence gap in geriatric oncology, and efforts are needed to meet older and frail adults where they are by expanding clinical trials designed specifically for this population and leveraging real‐world data.

Abstract Background Prior comparisons of chemotherapy adverse events (AEs) by age and performance status (PS) are limited by the traditional maximum grade approach, which ignores low-grade AEs and longitudinal changes. Materials and Methods To compare fatigue and neuropathy longitudinally by age (<65, ≥65 years) and PS (0–1, 2), we analyzed data from a large phase III trial of carboplatin and paclitaxel versus paclitaxel for advanced non-small cell lung cancer (CALGB 9730, n = 529). We performed multivariable (a) linear mixed models to estimate mean AE grade over time, (b) linear regression to estimate area under the curve (AUC), and (c) proportional hazards models to estimate the hazard ratio of developing grade ≥2 AE, as well as traditional maximum grade analyses. Results Older patients had on average a 0.17-point (95% confidence interval [CI], 0.00–0.34; p = .049) higher mean fatigue grade longitudinally compared with younger patients. PS 2 was associated with earlier development of grade ≥2 fatigue (hazard ratio [HR], 1.56; 95% CI, 1.07–2.27; p = .02). For neuropathy, older age was associated with earlier development of grade ≥2 neuropathy (HR, 1.41; 95% CI, 1.00–1.97; p = .049). Patients with PS 2 had a 1.30 point lower neuropathy AUC (95% CI, −2.36 to −0.25; p = .02) compared with PS 0–1. In contrast, maximum grade analyses only detected a higher percentage of older adults with grade ≥3 fatigue and neuropathy at some point during treatment. Conclusion Our comparison of complementary but distinct aspects of chemotherapy toxicity identified important longitudinal differences in fatigue and neuropathy by age and PS that are missed by the traditional maximum grade approach. Clinical trial identification number: NCT00003117 (CALGB 9730) Implications for Practice The traditional maximum grade approach ignores persistent low-grade adverse events (AEs) and changes over time. This toxicity over time analysis of fatigue and neuropathy during chemotherapy for advanced non-small cell lung cancer demonstrates how to use longitudinal methods to comprehensively characterize AEs over time by age and performance status (PS). We identified important longitudinal differences in fatigue and neuropathy that are missed by the maximum grade approach. This new information about how older adults and patients with PS 2 experience these toxicities longitudinally may be used clinically to improve discussions about treatment options and what to expect to inform shared decision making and symptom management.

9515 Background: CC 49907 showed superiority of standard therapy (cyclophosphamide/doxorubicin [AC] or cyclophosphamide/methotrexate/5-fluorouracil [CMF]) over capecitabine[C]. Dose adjustments made for renal insufficiency (RI) for methotrexate and C; ideal body weight used. Purpose was to analyze the relationship between RF at baseline and 5 endpoints: toxicity, dose modification, therapy completion, relapse-free survival [RFS] and overall survival [OS]. Methods: Pre-treatment RF was calculated (Cockcroft-Gault). Endpoints assessed by regimen. RF was tested as a dichotomous and continuous variable of stages 1,2 vs. 3,4 kidney disease (National Kidney Foundation). Logistic regression modeled the relationship between renal stage and the first three endpoints of toxicity, dose modification and therapy completion. Toxicity divided by hematologic or not. The relationship of RFS and OS with RF was assessed with the logrank test and as a continuous variable with Wald chi square. Results: 619 patients; incidence of stage 3/4 RI(<60 ml/min) was: CMF=72%; AC=64%; C=75%. With AC the incidence of toxicity differed by renal function. 31% of patients with poorer function >grade 3 non-hematologic toxicity vs. 14% with better function(p=0.011). There was a suggestion of effect of RF on OS and RFS for C-treated patients. RF was not associated with dose modification, premature therapy termination, RFS or OS for the CMF-treated patients. Conclusions: 1) AC: declining RF was associated with increased non-hematologic toxicity. 2)Patients with RI who received dose modifications were not at increased risk for complications in comparison to those who did not have renal insufficiency and received full dose. 3)Declining RF did not affect therapy completion. 4)C: suggestion that worse RF was related to poorer RFS or OS. 5)Exclusion of patients from clinical trials with RI based on concern of excessive hematologic toxicity may not be justified with appropriate modification. 6)Results should be considered in the design of clinical trials for older patients.

6015 Background: Comorbidity increases with age. We evaluated how comorbidity was associated with toxicity and clinical outcomes among older women with BC who received adjuvant chemotherapy. Methods: Cancer and Leukemia Group B (CALGB 49907) enrolled 633 women ≥65 years with early stage BC and randomized them to standard adjuvant chemotherapy (AC or CMF) or capecitabine (N Eng J Med 360:2055, 2009). 329 women on the Quality of Life companion study completed a pre-treatment health survey (Older American Resources and Services Questionnaire, physical health subscale). The survey evaluates 14 conditions and the degree to which each interferes with daily activities (rated from 1 “not at all” to 3 “a great deal”). Comorbidity was analyzed as follows: 1) total number 2) comorbidity burden score (summed conditions multiplied by interference rating); and 3) individual diseases. Primary outcomes were: 1) grade 3-5 toxicity (incident and cumulative); 2) time to relapse (TTR), and 3) overall survival (OS). Contingency table methods were used to evaluate the association between comorbidity and toxicity. Cox proportional hazards models were used to evaluate TTR and survival outcomes. Results: Among 329 women [median age 71 years (range 65-89), 86% white, 98% ECOG performance score 0-1, 75% stage 1-2] the median number of comorbidities was 2 (0-10), median comorbidity burden score was 3 (0-25), and most common conditions were arthritis (58%) and hypertension (54%). Few patients had diabetes (17%), heart disease (16%), and pulmonary disease (9%). No comorbidity measure was associated with toxicity or TTR. With a median follow-up of 5.4 years, increasing comorbidity was associated with shorter OS. For each additional comorbid condition the hazard of death increased by 18% (HR 1.18 [95% CI; 1.06-1.33]) after adjusting for age, tumor size, treatment, node status and receptor status. Comorbidity burden score was similarly associated with OS (HR 1.08 [95% CI; 1.03-1.14]), while no specific condition was independently associated. Conclusions: Among older women with good functional status, comorbidity was not associated with toxicity or BC relapse. However, comorbidity burden was associated with shorter OS.

Abstract Background: Contemporary approaches to non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL) incorporate chemo-immunotherapy, biologic combinations, and immune modulating agents; toxicities in elderly pts (³65 years) receiving these therapies are not well studied. Further, clinical and biologic factors predicting these toxicities in pts receiving biologic therapy remain undefined. Methods: We reviewed data on NHL and/or CLL pts treated prospectively on 14 studies by the Alliance for Clinical Trials in Oncology from 2004-2014 (Table 1). Toxicity was assessed per the NCI CTCAE at the time of trial enrollment, and the probabilities of experiencing grade 3 and grade 4 hematologic (hem) and non-hematologic (non-hem) toxicities were modeled as a function of age (³65 years vs. < 65), time on study, treatment (biologics only vs. biologic + chemotherapy), gender, race, LDH, performance status (PS), stage, and an age-by-treatment interaction using logistic regression. Results: A total of 1199 pts (409 age ³ 65; 790 age < 65; 736=CLL and 463=NHL) were included. Among these patients, 493 received only biologic therapy (166 age ³ 65; 327 age < 65; 104 CLL; 389 NHL), and 706 received biologic + chemotherapy (243 age ³ 65; 463 age < 65; 632 CLL; 74 NHL). Among CLL pts (259 pts ³ 65), the effect of age on the probability of experiencing a grade 3 heme toxicity differed by treatment type (age-by-treatment interaction p = 0.047). Specifically, the adjusted odds ratio (OR) (age ³ 65 vs. < 65) for pts receiving only biologic therapy was 3.075 (95% CI: 1,15-8.25), and that for pts receiving biologic + chemotherapy was 1.044 (95% CI: 0.69 - 1.57). Similar results were seen in CLL pts for grade 4 heme toxicities (age-by-treatment interaction p = 0.033; biologic OR 6.937, 95% CI: 1.76-27.35; biologic + chemo OR 1.484, 95% CI: 1.04-2.13). No such interactions were found in CLL pts for grade 3 and 4 non-hem toxicities; however, older pts had significantly higher odds of experiencing a grade 3 non-hem toxicity than younger pts (adjusted OR 1.40; p = 0.047; 95% CI: 1.004-1.96). No age group differences were found in CLL pts for grade 4 non-hem toxicity. Similar analyses were performed for NHL pts (150 pts ³ 65), but no significant age group differences were found. Among CLL pts, women had significantly higher odds of experiencing a grade 3 heme toxicity than men (OR 2.01; p = 0.0007); no difference in grade 3 non-hem or any grade 4 toxicity was noted. Non-Caucasian CLL pts had higher odds of experiencing a grade 4 non-hem toxicity than Caucasians (OR 2.892; p = 0.0029), but no other toxicity differences were found. Worse PS was associated with increased toxicities (OR 1.871; p = 0.0009: grade 3 heme; OR 1.647; p = 0.0025: grade 3 non-hem; OR 1.410; p = 0.0448: grade 4 heme, and OR 1.931; p = 0.0252: grade 4 non-hem). CLL pts with advanced stage disease had higher odds of experiencing a heme toxicity (grade 3: OR 1.95; p = 0.0007, grade 4: OR 1.451; p = 0.0329), but no stage associations were found for non-hem toxicities. Among NHL pts, men had significantly higher odds of experiencing a grade 4 hematologic toxicity than women (OR 4.351; p = 0.0169), but no other toxicity differences were found. An increase in LDH was associated with significantly higher odds of experiencing grade 3 non-hem and grade 4 heme toxicities (grade 3 non-heme: OR 1.633; p = 0.021, grade 4 heme: OR 2.039, p = 0.0182), but no such effect was found for grade 3 heme or grade 4 non-hem. Worse PS was associated with higher odds of experiencing grade 3 toxicities (heme: OR 2.025; p = 0.0344, non-hem: OR 2.458; p = 0.0013), but no such differences were found for grade 4 toxicities. No significant stage or race effects were found in NHL patients. Conclusion: In pts ³65 years who have CLL or NHL, we identified several clinical and disease-related factors as potential predictors of developing grade 3 and/or 4 heme and non-hem toxicities (Table 2). A prognostic model is being constructed to predict toxicities in these under-studied pts to guide management and monitoring. Further, the impact of these toxicities on outcomes is being analyzed and will be presented at the meeting. Disclosures Hurria: Celgene: Other: Research; Optum Health Care SOlutions: Consultancy, Other: Conference panel, research; Boehringer Ingelheim Pharmaceuticals: Consultancy; Sanofi: Consultancy; Carevive: Consultancy; Novartis: Other: Research; GTx, Inc: Consultancy. Bartlett:Gilead: Consultancy. Cheson:Gilead: Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Nabhan:Infinity: Consultancy; Abbvie: Consultancy; Cardinal Health: Consultancy; Seattle Genetics: Research Funding; Genentech: Consultancy, Research Funding; Astellas: Research Funding; Celgene Corporation: Consultancy, Research Funding.

PURPOSE Older women with breast cancer remain under-represented in clinical trials. The Cancer and Leukemia Group B 49907 trial focused on women age 65 years and older. We previously reported the primary analysis after a median follow-up of 2.4 years. Standard adjuvant chemotherapy showed significant improvements in recurrence-free survival (RFS) and overall survival compared with capecitabine. We now update results at a median follow-up of 11.4 years. PATIENTS AND METHODS Patients age 65 years or older with early breast cancer were randomly assigned to either standard adjuvant chemotherapy (physician’s choice of either cyclophosphamide, methotrexate, and fluorouracil or cyclophosphamide and doxorubicin) or capecitabine. An adaptive Bayesian design was used to determine sample size and test noninferiority of capecitabine. The primary end point was RFS. RESULTS The design stopped accrual with 633 patients at its first sample size assessment. RFS remains significantly longer for patients treated with standard chemotherapy. At 10 years, in patients treated with standard chemotherapy versus capecitabine, the RFS rates were 56% and 50%, respectively (hazard ratio [HR], 0.80; P = .03); breast cancer–specific survival rates were 88% and 82%, respectively (HR, 0.62; P = .03); and overall survival rates were 62% and 56%, respectively (HR, 0.84; P = .16). With longer follow-up, standard chemotherapy remains superior to capecitabine among hormone receptor–negative patients (HR, 0.66; P = .02), but not among hormone receptor–positive patients (HR, 0.89; P = .43). Overall, 43.9% of patients have died (13.1% from breast cancer, 16.4% from causes other than breast cancer, and 14.1% from unknown causes). Second nonbreast cancers occurred in 14.1% of patients. CONCLUSION With longer follow-up, RFS remains superior for standard adjuvant chemotherapy versus capecitabine, especially in patients with hormone receptor–negative disease. Competing risks in this older population dilute overall survival benefits.

Advances in understanding fundamental processes of aging have led to a variety of investigational therapies to delay or prevent age‐related diseases and conditions. These geroscience therapeutics hold the promise of revolutionizing medical care of older adults by treating the complex syndromes of aging and preserving health and independence. A crucial bottleneck is the study of geroscience therapeutics in early‐stage, first‐in‐human, or proof‐of‐concept clinical trials. There is a limited pool of clinical investigators with the combination of knowledge and skills at the interface of clinical research, care of older adults, and aging biology needed to successfully design, fund, and implement geroscience trials. Current training pipelines are insufficient to meet the need. The sixth retreat of the National Institute on Aging R24 Geroscience Network brought together basic scientists, gerontologists, clinicians, and clinical researchers from the United States and Europe to discuss how to identify, recruit, and train investigators who can perform early‐stage clinical trials in geroscience. We present herein the group's consensus on necessary subject domains and competencies, identification of candidate learners, credentialing learners, and the efficient and rapid implementation of training programs. Foundations and funding agencies have crucial roles to play in catalyzing the development of these programs. Geriatrician investigators are indispensable but cannot meet the need alone. Translational geroscience training programs can create a cadre of groundbreaking investigators from a variety of backgrounds and foster institutional cultures supportive of multidisciplinary translational aging research to turn innovative ideas into transformative therapeutics that can improve the health and independence of older adults. J Am Geriatr Soc 67:1934–1939, 2019

e18132 Background: Older adults (65+ years) make up > 50% of cancer patients in the US,1 yet, older patient enrollment onto trials remains < 30%.2 This study’s aim was to determine the association between trial level variables and accrual rates of adults 65+ to better design trials that can more improve enrollment of these patients. Methods: We analyzed enrollment percentages of patients age 65+ in non-age specific Alliance trials with > 50 patients, that completed accrual between 1995- 2015. Enrollment percentage by 65+ for each study was compared to cancer incidence percentage by 65+ according to the Surveillance, Epidemiology, and End Results (SEER) Program for the same time periods. Enrollment Disparity Difference (EDD)3, defined as the difference between SEER incidence percentage of patients 65+ and the trial percentage enrollment of 65+ was calculated for each trial ( SEER % – trial %). Univariate analyses (UVA) were performed using simple linear regression to determine trial variables associated with larger EDDs (higher disparity). Variables that had an F-test p-value < 0.20 were included in a multivariable fixed-effects linear model for multivariate analysis (MVA). Results: Median age of 66,708 patients across 237 trials with 10 cancer types was 60 years. Average % of 65+ in trials was lower than average SEER comparison % 65+ per trial (37.6% vs. 57.8%). The median trial EDD, was 16.7%. On UVA, cancer type was significantly associated with higher EDD (see Table). Use of fewer modalities (1, 2, vs 3+) was associated with lower estimated EDDs (1 = -11 [+/-3.6], 2 = -8.9 [+/-3.9], F-test p = .012). On MVA, non-genitourinary (GU) cancer type, number of treatment modalities, and the phase (II or III compared to observational/other) were all significantly associated with higher EDD. Conclusions: Older adults were under-represented in this large sample of trials. This information can be used as a platform to better design disease-specific trials to improve older patient accrual, particularly in disease areas which are under-performing. Support: U10CA180821, U10CA180882, UG1CA189823: https://acknowledgments.alliancefound.org . References: 1. Smith BD et al. J Clin Oncol 27:2758-65, 2009; 2. Hurria A, et al. J Geriatr Oncol 1:40-44, 2010; 3. Pang HH, et al. J Clin Oncol, 2016.[Table: see text]