Life expectancy in older adults with advanced cancer: Evaluation of a geriatric assessment-based prognostic model.

OBJECTIVES: Oncologists estimate patients' prognosis to guide care. Evidence suggests oncologists tend to overestimate life expectancy, which can lead to care with questionable benefits. Information obtained from geriatric assessment may improve prognostication for older adults. In this study, we created a geriatric assessment-based prognostic model for older adults with advanced cancer and compared its performance to alternative models. MATERIALS AND METHODS: We conducted a secondary analysis of a trial (URCC 13070; PI: Mohile) capturing geriatric assessment and vital status up to one year for adults age ≥ 70 years with advanced cancer. Oncologists estimated life expectancy as 0-6 months, 7-12 months, and > 1 year. Three statistical models were developed: (1) a model including age, sex, cancer type, and stage (basic model), (2) basic model + Karnofsky Performance Status (≤50, 60-70, and 80+) (KPS model), and (3) basic model +16 binary indicators of geriatric assessment impairments (GA model). Cox regression was used to model one-year survival; c-indices and time-dependent c-statistics assessed model discrimination and stratified survival curves assessed model calibration. RESULTS: We included 484 participants; mean age was 75; 48% had gastrointestinal or lung cancer. Overall, 43% of patients died within one year. Oncologists classified prognosis accurately for 55% of patients, overestimated for 35%, and underestimated for 10%. C-indices were 0.61 (basic model), 0.62 (KPS model), and 0.63 (GA model). The GA model was well-calibrated. CONCLUSIONS: The GA model showed moderate discrimination for survival, similar to alternative models, but calibration was improved. Further research is needed to optimize geriatric assessment-based prognostic models for use in older adults with advanced cancer.

Prevalence of and factors associated with treatment modification at first cycle in older adults with advanced cancer receiving palliative treatment.

INTRODUCTION: Treatment toxicities are common in older adults with cancer and consequently, treatment modifications are sometimes considered. We evaluated the prevalence and factors associated with treatment modifications at the first cycle in older patients receiving palliative systemic treatment. METHODS: Patients (n = 369) from the GAP 70+ Trial (NCT02054741; PI: Mohile) usual care arm were included. Enrolled patients were aged 70+ with advanced cancer and ≥ 1 Geriatric Assessment (GA) domain impairment. Treatment modification was defined as any change from National Comprehensive Cancer Network guidelines or published clinical trials. Baseline variables included: 1) sociodemographic factors; 2) clinical variables; 3) GA domains; and 4) physician beliefs about life expectancy. Bivariate analyses and multivariable cluster-weighted generalized estimating equation model were conducted to assess the association of baseline variables with cycle 1 treatment modifications. RESULTS: Mean age was 77.2 years (range: 70-94); 62% had lung or gastrointestinal cancers, and 35% had treatment modifications at cycle 1. Increasing age by one year (odds ratio (OR) 1.1, 95% confidence interval [CI] 1.0-1.2), receipt of ≥second line of chemotherapy (OR 1.8, CI 1.1-3.0), functional impairment (OR 1.6, CI 1.1-2.3) and income ≤$50,000 (OR 1.7, CI 1.1-2.4) were independently associated with a higher likelihood of cycle 1 treatment modification. CONCLUSION: Treatment modifications occurred in 35% of older adults with advanced cancer at cycle 1. Increasing age, receipt of ≥second line of chemotherapy, functional impairment, and lower income were independently associated with treatment modifications. These findings emphasize the need for evidence-based regimens in older adults with cancer and GA impairments.

Psychological predictors of chemotherapy-induced nausea in women with breast cancer: Expectancies and perceived susceptibility.

OBJECTIVE: Chemotherapy-induced nausea is challenging to predict and treat. Research indicates that pretreatment psychological variables including patients' perceptions of their susceptibility to nausea, expectancies of treatment-related nausea and nausea history (i.e., motion sickness, morning sickness and baseline levels of nausea) may aid in predicting nausea severity during chemotherapy. However, this research is dated and limited in quantity. We investigated whether psychological variables could improve prediction of nausea severity to inform interventions targeting chemotherapy-induced nausea. METHODS: In this secondary analysis, a subgroup of women receiving chemotherapy (for the first time) for breast cancer completed pretreatment measures: perceived nausea susceptibility, nausea expectancies, nausea history and baseline nausea. They rated subsequent nausea severity across 4-days, during treatment and posttreatment in a self-report diary. Structural Equation Modelling was used to explore associations. RESULTS: Across the women (N = 481), perceived nausea susceptibility predicted subsequent nausea severity (ß = 0.16), but nausea expectancies did not (ß = 0.05). Nausea history variables demonstrated small-moderate associations with perceived susceptibility (ß = 0.21-0.32) and negligible-small associations with nausea expectancies (ß = 0.07-0.14). CONCLUSION: Perceived nausea susceptibility appears to capture patients' nausea history, to a degree, and is related to nausea severity during treatment. This is an important variable to include in pretreatment prediction of patients at risk of severe nausea.

Associations of inflammation with frailty in patients with breast cancer aged 50 and over receiving chemotherapy.

PURPOSE: Chronic inflammation is a significant physiologic feature of frailty; however, its role and clinical utility in cancer-related frailty remains unknown. We sought to determine if pre-chemotherapy inflammation is predictive of frailty after chemotherapy in patients with breast cancer. METHODS: Female patients (N = 144; age ≥ 50) with stage I-III breast cancer scheduled to receive chemotherapy and age-matched non-cancer controls (N = 142) were included in this secondary analysis and assessed pre- and post-chemotherapy. Controls were assessed at equivalent time-points. Frailty was assessed using a modified Fried's score (0-4) using self-reported measures of weakness, exhaustion, walking speed, and physical activity. Serum levels of interleukin (IL) 6, and soluble tumor necrosis factor-alpha (sTNFR) I and II were measured. Associations between pre-chemotherapy cytokine and receptors level (median as cutoff) and post-chemotherapy frailty were evaluated using t-tests. RESULTS: Pre-chemotherapy, patients with breast cancer were more frail than non-cancer controls (mean score: 1.17 vs 0.65; p < .01). Patients also became more frail post-chemotherapy (mean score: 1.17 vs 2.08; p < .01). Patients with pre-chemotherapy serum levels of IL-6, sTNFRI, and sTNFRII above the median were more frail after chemotherapy than those with levels below the median [IL-6 (2.31 vs. 1.86; p = .03), sTNFRI (2.30 vs. 1.88; p = .04), and sTNFRII (2.30 vs. 1.88; p = .04)]. No differences were observed in non-cancer controls within the same timeframe. CONCLUSIONS: Both cancer and chemotherapy were associated with frailty. Higher pre-chemotherapy inflammatory cytokine levels were associated with post-chemotherapy frailty. This supports the utility of inflammatory cytokines to identify patients who develop worsening of frailty characteristics with chemotherapy.

Longitudinal Relationship Between Frailty and Cognition in Patients 50 Years and Older with Breast Cancer.

OBJECTIVES: To evaluate relationships between frailty and cognition longitudinally in adults 50 years and older with breast cancer receiving chemotherapy. DESIGN: Secondary analysis of a prospective longitudinal observational study. SETTING: University of Rochester NCI Community Oncology Research Program community oncology clinics. PARTICIPANTS: Patients with breast cancer age 50 and older receiving adjuvant/neoadjuvant chemotherapy (n = 376) and age-matched controls without cancer (n = 234). MEASUREMENTS: Frailty was assessed using a modified frailty score from self-reported assessments (weakness, exhaustion, physical activity, and gait speed). Cognition was assessed by patient report (Functional Assessment of Cancer Therapy-Cognition [FACT-Cog]) and objective measures. Frailty and cognition were measured at three time points (prechemotherapy [A1], postchemotherapy [A2], and 6 months postchemotherapy [A3]; similar time interval for controls). Linear regression models evaluated associations between frailty and cognition adjusting for covariates. RESULTS: The average age was 59 years (standard deviation = 6.4 y). At baseline, patients with cancer had a higher mean frailty score (1.21 vs .73; P < .001) and lower mean FACT-Cog score (158.4 vs 167.3; P < .001) compared with controls. Objective cognitive measures were not statistically different. Longitudinal decline in FACT-Cog between A1 and A2 (P < .05) and between A1 and A3 (P < .01) was associated with increased frailty score in patients compared with controls. Longitudinal worsening in Controlled Oral Word Association (P < .05) and Trail-Making Test (P < .01) were associated with an increase in frailty between A1 and A2 in patients compared with controls; longitudinal decline in the Delayed Match to Sample test was associated with an increase in frailty between A1 and A3 (P < .05) in patients compared with controls. This finding remained significant for a subset analysis of those aged 65 and older. CONCLUSION: In patients with breast cancer aged 50 and older, longitudinal decline in FACT-Cog and objective measures of attention and memory were associated with increased frailty during treatment and up to 6 months posttreatment. Overall, our study suggests cognition and frailty are both important factors to assess in breast cancer patients. J Am Geriatr Soc 67:928-936, 2019.

Multimedia psychoeducation for patients with cancer who are eligible for clinical trials: A randomized clinical trial.

BACKGROUND: Supporting patients' decision making about clinical trials may enhance trial participation. To date, few theory-based interventions have been tested to address this issue. The objective of the current study was aimed to evaluate the effect of a multimedia psychoeducation (MP) intervention, relative to a print education (PE) intervention, on patients' decision support needs and attitudes about clinical trials. METHODS: Patients with cancer who were eligible for participation in a National Cancer Institute therapeutic cancer clinical trial were recruited through the nationwide University of Rochester Cancer Center National Cancer Institute Community Oncology Research Program from 2014 to 2016 and were randomized to the MP or PE intervention. Assessments at baseline (before intervention), postintervention, and at a 2-month follow-up visit included patients' decision support needs, attitudes regarding clinical trials, and clinical trial participation. RESULTS: In total, 418 patients with various types of cancer were recruited (ages 26-89 years). Relative to the PE intervention, the MP intervention did not significantly affect decision support needs. However, patients in the MP arm reported significantly more positive attitudes about clinical trials and were more likely to participate in a clinical trial than those in the PE arm (69% vs 62%; P = .01). Furthermore, an improvement in attitudes about clinical trials significantly mediated the effect of the intervention on participation in clinical trials. CONCLUSIONS: The MP intervention was able to improve patient attitudes toward clinical trials compared with the PE intervention, and this improvement led to increased rates of participation in trials. The MP intervention could be disseminated to improve attitudes about clinical trials among patients with cancer.

Self-reported adherence and biomarker levels of CoQ10 and alpha-tocopherol.

PURPOSE: Women with breast cancer were randomized to receive coenzyme Q10 (CoQ10) plus Vitamin E or placebo in a clinical trial. The objective of this evaluation is to examine the association between participant self-reported adherence to the study supplements and changes in plasma biomarker levels. PATIENTS AND METHODS: Correlation coefficients quantified the association between changes in alpha-tocopherol and CoQ10 levels and the association between self-reported adherence and changes in biomarkers. Participants were categorized by self-reported adherence; Kruskal- Wallis tests compared changes in alpha-tocopherol and CoQ10 levels between self-reported adherence groups. RESULTS: Women (N=155) provided baseline and post-treatment biomarkers; 147 completed at least one diary. While changes in alpha-tocopherol and CoQ10 levels were moderately correlated, correlations ranged from 0.40 to 0.48, association between self-reported adherence and plasma alpha-tocopherol or CoQ10 levels was weak; correlations ranged from 0.10 to 0.29 at weeks 8, 16, and 24. Some participants with high self-reported adherence actually had decreases in their biomarker levels. CONCLUSION: These findings support that self-reported adherence is likely to be overestimated. Biological and other measures of adherence that can better identify true adherence to study pills provided in clinical trials are greatly needed as they may assist in improving the interpretation of findings of future clinical trials.

Quality of life of irradiated brain tumor survivors treated with donepezil or placebo: Results of the WFU CCOP research base protocol 91105.

BACKGROUND: The health-related quality of life (HRQL) and fatigue of brain cancer survivors treated with donepezil or placebo for cognitive symptoms after radiation therapy were examined. METHODS: One hundred ninety-eight patients who completed >30 Gy fractionated whole or partial brain irradiation at least 6 months prior to enrollment were randomized to either placebo or donepezil (5 mg for 6 weeks followed by 10 mg for 18 weeks) in a phase 3 trial. A neurocognitive battery, the Functional Assessment of Cancer Therapy-Brain (FACT-Br) and the Functional Assessment of Chronic Illness Therapy (FACIT)-fatigue, was administered at baseline, 12 weeks, and 24 weeks. RESULTS: At 12 weeks, donepezil resulted in improvements in only emotional functioning (P = .04), with no significant effects at week 24. Associations by level of baseline cognitive symptoms (above or below the median score of the baseline FACT-Br "additional concerns/brain" subscale), indicated that participants with more baseline symptoms who received donepezil versus placebo, showed improvements in social (P = .02) and emotional well-being (P = .038), other concerns/brain (P = .003) and the FACT-Br total score (P = .004) at 12 weeks, but not 24 weeks. However, participants with fewer baseline symptoms randomized to donepezil versus placebo reported lower functional well-being at both 12 (P = .015) and 24 weeks (P = .009), and greater fatigue (P = .02) at 24 weeks. CONCLUSIONS: The positive impact of donepezil on HRQL was greater in survivors reporting more baseline cognitive symptoms. Donepezil had significantly worse effects on fatigue and functional well-being among participants with fewer baseline symptoms. Future interventions with donepezil should target participants with more baseline cognitive complaints to achieve greater therapeutic impact and lessen potential side effects of treatment.

Effects of exercise during chemotherapy on chemotherapy-induced peripheral neuropathy: a multicenter, randomized controlled trial.

PURPOSE: Over half of all cancer patients receiving taxane-, platinum-, or vinca alkaloid-based chemotherapy experience chemotherapy-induced peripheral neuropathy (CIPN), which includes numbness, tingling, pain, cold sensitivity, and motor impairment in the hands and feet. CIPN is a dose-limiting toxicity, potentially increasing mortality. There are no FDA-approved drugs to treat CIPN, and behavioral interventions such as exercise are promising yet understudied. This secondary analysis of our nationwide phase III randomized controlled trial of exercise for fatigue examines (1) effects of exercise on CIPN symptoms, (2) factors that predict CIPN symptoms, and (3) factors that moderate effects of exercise on CIPN symptoms. METHODS: Cancer patients (N = 355, 56 ± 11 years, 93% female, 79% breast cancer) receiving taxane-, platinum-, or vinca alkaloid-based chemotherapy were randomized to chemotherapy or chemotherapy plus Exercise for Cancer Patients (EXCAP©®). EXCAP is a standardized, individualized, moderate-intensity, home-based, six-week progressive walking and resistance exercise program. Patients reported CIPN symptoms of numbness and tingling and hot/coldness in hands/feet (0-10 scales) pre- and post-intervention. We explored baseline neuropathy, sex, age, body mass index, cancer stage, and cancer type as possible factors associated with CIPN symptoms and exercise effectiveness. RESULTS: Exercise reduced CIPN symptoms of hot/coldness in hands/feet (-0.46 units, p = 0.045) and numbness and tingling (- 0.42 units, p = 0.061) compared to the control. Exercise reduced CIPN symptoms more for patients who were older (p = 0.086), male (p = 0.028), or had breast cancer (p = 0.076). CONCLUSIONS: Exercise appears to reduce CIPN symptoms in patients receiving taxane-, platinum-, or vinca alkaloid-based chemotherapy. Clinicians should consider prescribing exercise for these patients. TRIAL REGISTRATION: Clinical Trials.gov , # NCT00924651, http://www.clinicaltrials.gov .

Effect of the Addition of Cetuximab to Paclitaxel, Cisplatin, and Radiation Therapy for Patients With Esophageal Cancer: The NRG Oncology RTOG 0436 Phase 3 Randomized Clinical Trial.

IMPORTANCE: The role of epidermal growth factor receptor (EGFR) inhibition in chemoradiation strategies in the nonoperative treatment of patients with esophageal cancer remains uncertain. OBJECTIVE: To evaluate the benefit of cetuximab added to concurrent chemoradiation therapy for patients undergoing nonoperative treatment of esophageal carcinoma. DESIGN, SETTING, AND PARTICIPANTS: A National Cancer Institute (NCI) sponsored, multicenter, phase 3, randomized clinical trial open to patients with biopsy-proven carcinoma of the esophagus. The study accrued 344 patients from 2008 to 2013. INTERVENTIONS: Patients were randomized to weekly concurrent cisplatin (50 mg/m2), paclitaxel (25 mg/m2), and daily radiation of 50.4 Gy/1.8 Gy fractions with or without weekly cetuximab (400 mg/m2 on day 1 then 250 mg/m2 weekly). MAIN OUTCOMES AND MEASURES: Overall survival (OS) was the primary endpoint, with a study designed to detect an increase in 2-year OS from 41% to 53%; 80% power and 1-sided α = .025. RESULTS: Between June 30, 2008, and February 8, 2013, 344 patients were enrolled. This analysis used all data received at NRG Oncology through April 12, 2015. Sixteen patients were ineligible, resulting in 328 evaluable patients, 159 in the experimental arm and 169 in the control arm. Patients were well matched between the treatment arms for patient and tumor characteristics: 263 (80%) with T3 or T4 disease, 215 (66%) N1, and 62 (19%) with celiac nodal involvement. Incidence of grade 3, 4, or 5 treatment-related adverse events at any time was 71 (46%), 35 (23%), or 6 (4%) in the experimental arm and 83 (50%), 28 (17%), or 2 (1%) in the control arm, respectively. A clinical complete response (cCR) rate of 81 (56%) was observed in the experimental arm vs 92 (58%) in the control arm (Fisher exact test, P = .66). No differences were seen in cCR between treatment arms for either histology (adenocarcinoma or squamous cell). Median follow-up for all patients was 18.6 months. The 24- and 36-month local failure for the experimental arm was 47% (95% CI, 38%-57%) and 49% (95% CI, 40%-59%) vs 49% (95% CI, 41%-58%) and 49% (95% CI, 41%-58%) for the control arm (HR, 0.92; 95% CI, 0.66-1.28; P = .65). The 24- and 36-month OS rates for the experimental arm were 45% (95% CI, 37%-53%) and 34% (95% CI, 26%-41%) vs 44% (95% CI, 36%-51%) and 28% (95% CI, 21%-35%) for the control arm (HR, 0.90; 95% CI, 0.70-1.16; P = .47). CONCLUSIONS AND RELEVANCE: The addition of cetuximab to concurrent chemoradiation did not improve OS. These phase 3 trial results point to little benefit to current EGFR-targeted agents in an unselected patient population, and highlight the need for predictive biomarkers in the treatment of esophageal cancer. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00655876.

Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial.

BACKGROUND: Results from phase 2 and 3 trials in patients with advanced melanoma have shown significant improvements in the proportion of patients achieving an objective response and prolonged progression-free survival with the combination of nivolumab (an anti-PD-1 antibody) plus ipilimumab (an anti-CTLA-4 antibody) compared with ipilimumab alone. We report 2-year overall survival data from a randomised controlled trial assessing this treatment in previously untreated advanced melanoma. METHODS: In this multicentre, double-blind, randomised, controlled, phase 2 trial (CheckMate 069) we recruited patients from 19 specialist cancer centres in two countries (France and the USA). Eligible patients were aged 18 years or older with previously untreated, unresectable stage III or IV melanoma and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned 2:1 to receive an intravenous infusion of nivolumab 1 mg/kg plus ipilimumab 3 mg/kg or ipilimumab 3 mg/kg plus placebo, every 3 weeks for four doses. Subsequently, patients assigned to nivolumab plus ipilimumab received nivolumab 3 mg/kg every 2 weeks until disease progression or unacceptable toxicity, whereas patients allocated to ipilimumab alone received placebo every 2 weeks during this phase. Randomisation was done via an interactive voice response system with a permuted block schedule (block size of six) and stratification by BRAF mutation status. The study funder, patients, investigators, and study site staff were masked to treatment assignment. The primary endpoint, which has been reported previously, was the proportion of patients with BRAFV600 wild-type melanoma achieving an investigator-assessed objective response. Overall survival was an exploratory endpoint and is reported in this Article. Efficacy analyses were done on the intention-to-treat population, whereas safety was assessed in all treated patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01927419, and is ongoing but no longer enrolling patients. FINDINGS: Between Sept 16, 2013, and Feb 6, 2014, we screened 179 patients and enrolled 142, randomly assigning 95 patients to nivolumab plus ipilimumab and 47 to ipilimumab alone. In each treatment group, one patient no longer met the study criteria following randomisation and thus did not receive study drug. At a median follow-up of 24·5 months (IQR 9·1-25·7), 2-year overall survival was 63·8% (95% CI 53·3-72·6) for those assigned to nivolumab plus ipilimumab and 53·6% (95% CI 38·1-66·8) for those assigned to ipilimumab alone; median overall survival had not been reached in either group (hazard ratio 0·74, 95% CI 0·43-1·26; p=0·26). Treatment-related grade 3-4 adverse events were reported in 51 (54%) of 94 patients who received nivolumab plus ipilimumab compared with nine (20%) of 46 patients who received ipilimumab alone. The most common treatment-related grade 3-4 adverse events were colitis (12 [13%] of 94 patients) and increased alanine aminotransferase (ten [11%]) in the combination group and diarrhoea (five [11%] of 46 patients) and hypophysitis (two [4%]) in the ipilimumab alone group. Serious grade 3-4 treatment-related adverse events were reported in 34 (36%) of 94 patients who received nivolumab plus ipilimumab (including colitis in ten [11%] of 94 patients, and diarrhoea in five [5%]) compared with four (9%) of 46 patients who received ipilimumab alone (including diarrhoea in two [4%] of 46 patients, colitis in one [2%], and hypophysitis in one [2%]). No new types of treatment-related adverse events or treatment-related deaths occurred in this updated analysis. INTERPRETATION: Although follow-up of the patients in this study is ongoing, the results of this analysis suggest that the combination of first-line nivolumab plus ipilimumab might lead to improved outcomes compared with first-line ipilimumab alone in patients with advanced melanoma. The results suggest encouraging survival outcomes with immunotherapy in this population of patients. FUNDING: Bristol-Myers Squibb.

YOCAS©® Yoga Reduces Self-reported Memory Difficulty in Cancer Survivors in a Nationwide Randomized Clinical Trial: Investigating Relationships Between Memory and Sleep.

UNLABELLED: Background Interventions are needed to alleviate memory difficulty in cancer survivors. We previously showed in a phase III randomized clinical trial that YOCAS©® yoga-a program that consists of breathing exercises, postures, and meditation-significantly improved sleep quality in cancer survivors. This study assessed the effects of YOCAS©® on memory and identified relationships between memory and sleep. STUDY DESIGN AND METHODS: Survivors were randomized to standard care (SC) or SC with YOCAS©® . 328 participants who provided data on the memory difficulty item of the MD Anderson Symptom Inventory are included. Sleep quality was measured using the Pittsburgh Sleep Quality Index. General linear modeling (GLM) determined the group effect of YOCAS©® on memory difficulty compared with SC. GLM also determined moderation of baseline memory difficulty on postintervention sleep and vice versa. Path modeling assessed the mediating effects of changes in memory difficulty on YOCAS©® changes in sleep and vice versa. RESULTS: YOCAS©® significantly reduced memory difficulty at postintervention compared with SC (mean change: yoga=-0.60; SC=-0.16; P<.05). Baseline memory difficulty did not moderate the effects of postintervention sleep quality in YOCAS©® compared with SC. Baseline sleep quality did moderate the effects of postintervention memory difficulty in YOCAS©® compared with SC (P<.05). Changes in sleep quality was a significant mediator of reduced memory difficulty in YOCAS©® compared with SC (P<.05); however, changes in memory difficulty did not significantly mediate improved sleep quality in YOCAS©® compared with SC. CONCLUSIONS: In this large nationwide trial, YOCAS©® yoga significantly reduced patient-reported memory difficulty in cancer survivors.

Randomized Trial of Lenalidomide Alone Versus Lenalidomide Plus Rituximab in Patients With Recurrent Follicular Lymphoma: CALGB 50401 (Alliance).

PURPOSE: Lenalidomide and rituximab (LR) are active agents in follicular lymphoma (FL). Combination regimens have not been previously assessed in randomized studies. PATIENTS AND METHODS: The Cancer and Leukemia Group B (Alliance) 50401 trial is a randomized phase II trial studying rituximab (375 mg/m(2) weekly for 4 weeks), lenalidomide (15 mg per day on days 1 to 21, followed by 7 days of rest, in cycle 1 and then 20 mg per day on days 1 to 21, followed by 7 days of rest, in cycles 2 to 12), or LR. The rituximab-alone arm was discontinued as a result of poor accrual. Eligibility included recurrent FL and prior rituximab with time to progression of ≥ 6 months from last dose. Aspirin or heparin was recommended for patients at high thrombosis risk. RESULTS: Ninety-one patients (lenalidomide, n = 45; LR, n = 46) received treatment; median age was 63 years (range, 34 to 89 years), and 58% were intermediate or high risk according to the Follicular Lymphoma International Prognostic Index. In the lenalidomide and LR arms, grade 3 to 4 adverse events occurred in 58% and 53% of patients, with 9% and 11% of patients experiencing grade 4 toxicity, respectively; grade 3 to 4 adverse events included neutropenia (16% v 20%, respectively), fatigue (9% v 13%, respectively), and thrombosis (16% [n = 7] v 4% [n = 2], respectively; P = .157). Thirty-six percent of lenalidomide patients and 63% of LR patients completed 12 cycles. Lenalidomide alone was associated with more treatment failures, with 22% of patients discontinuing treatment as a result of adverse events. Dose-intensity exceeded 80% in both arms. Overall response rate was 53% (20% complete response) and 76% (39% complete response) for lenalidomide alone and LR, respectively (P = .029). At the median follow-up of 2.5 years, median time to progression was 1.1 year for lenalidomide alone and 2 years for LR (P = .0023). CONCLUSION: LR is more active than lenalidomide alone in recurrent FL with similar toxicity, warranting further study in B-cell non-Hodgkin lymphoma as a platform for addition of novel agents.

Donepezil for Irradiated Brain Tumor Survivors: A Phase III Randomized Placebo-Controlled Clinical Trial.

PURPOSE: Neurotoxic effects of brain irradiation include cognitive impairment in 50% to 90% of patients. Prior studies have suggested that donepezil, a neurotransmitter modulator, may improve cognitive function. PATIENTS AND METHODS: A total of 198 adult brain tumor survivors ≥ 6 months after partial- or whole-brain irradiation were randomly assigned to receive a single daily dose (5 mg for 6 weeks, 10 mg for 18 weeks) of donepezil or placebo. A cognitive test battery assessing memory, attention, language, visuomotor, verbal fluency, and executive functions was administered before random assignment and at 12 and 24 weeks. A cognitive composite score (primary outcome) and individual cognitive domains were evaluated. RESULTS: Of this mostly middle-age, married, non-Hispanic white sample, 66% had primary brain tumors, 27% had brain metastases, and 8% underwent prophylactic cranial irradiation. After 24 weeks of treatment, the composite scores did not differ significantly between groups (P = .48); however, significant differences favoring donepezil were observed for memory (recognition, P = .027; discrimination, P = .007) and motor speed and dexterity (P = .016). Significant interactions between pretreatment cognitive function and treatment were found for cognitive composite (P = .01), immediate recall (P = .05), delayed recall (P = .004), attention (P = .01), visuomotor skills (P = .02), and motor speed and dexterity (P < .001), with the benefits of donepezil greater for those who were more cognitively impaired before study treatment. CONCLUSION: Treatment with donepezil did not significantly improve the overall composite score, but it did result in modest improvements in several cognitive functions, especially among patients with greater pretreatment impairments.

Nivolumab and ipilimumab versus ipilimumab in untreated melanoma.

BACKGROUND: In a phase 1 dose-escalation study, combined inhibition of T-cell checkpoint pathways by nivolumab and ipilimumab was associated with a high rate of objective response, including complete responses, among patients with advanced melanoma. METHODS: In this double-blind study involving 142 patients with metastatic melanoma who had not previously received treatment, we randomly assigned patients in a 2:1 ratio to receive ipilimumab (3 mg per kilogram of body weight) combined with either nivolumab (1 mg per kilogram) or placebo once every 3 weeks for four doses, followed by nivolumab (3 mg per kilogram) or placebo every 2 weeks until the occurrence of disease progression or unacceptable toxic effects. The primary end point was the rate of investigator-assessed, confirmed objective response among patients with BRAF V600 wild-type tumors. RESULTS: Among patients with BRAF wild-type tumors, the rate of confirmed objective response was 61% (44 of 72 patients) in the group that received both ipilimumab and nivolumab (combination group) versus 11% (4 of 37 patients) in the group that received ipilimumab and placebo (ipilimumab-monotherapy group) (P<0.001), with complete responses reported in 16 patients (22%) in the combination group and no patients in the ipilimumab-monotherapy group. The median duration of response was not reached in either group. The median progression-free survival was not reached with the combination therapy and was 4.4 months with ipilimumab monotherapy (hazard ratio associated with combination therapy as compared with ipilimumab monotherapy for disease progression or death, 0.40; 95% confidence interval, 0.23 to 0.68; P<0.001). Similar results for response rate and progression-free survival were observed in 33 patients with BRAF mutation-positive tumors. Drug-related adverse events of grade 3 or 4 were reported in 54% of the patients who received the combination therapy as compared with 24% of the patients who received ipilimumab monotherapy. Select adverse events with potential immunologic causes were consistent with those in a phase 1 study, and most of these events resolved with immune-modulating medication. CONCLUSIONS: The objective-response rate and the progression-free survival among patients with advanced melanoma who had not previously received treatment were significantly greater with nivolumab combined with ipilimumab than with ipilimumab monotherapy. Combination therapy had an acceptable safety profile. (Funded by Bristol-Myers Squibb; ClinicalTrials.gov number, NCT01927419.).

Feasibility of implementing a community-based randomized trial of yoga for women undergoing chemotherapy for breast cancer.

BACKGROUND: Treatment-related symptoms and decreased health-related quality of life (HRQoL) frequently occur during chemotherapy for breast cancer. Although research findings suggest that yoga can reduce symptoms and Improve HRQoL after treatment, potential benefits of yoga during chemotherapy have received minimal attention. OBJECTIVE: To estimate accrual, adherence, study retention, and preliminary efficacy of a yoga intervention compared with an active control group for breast cancer patients during chemotherapy. METHODS: Women with stage I-III breast cancer were recruited from 3 community cancer clinics and randomized to 10 weeks of gentle yoga or wellness education. Depressive symptoms, fatigue, sleep, and HRQoL were assessed at baseline, mid-intervention (Week 5), and after intervention (Week 10). RESULTS: 40 women aged 29-83 years (median, 48 years; 88% white) were randomized to yoga (n = 22) or wellness education (n = 18). The groups did not differ significantly on baseline characteristics, adherence, or study retention. Participant feedback was positive and comparable between groups. Meaningful within-group differences were identified For sleep adequacy and quantity in yoga participants and for somnolence in wellness-education participants. LIMITATIONS: Small sample size and lack of a usual-care control group. CONCLUSIONS: This study established Feasibility of a community-based randomized trial of yoga and an active comparison group for women undergoing chemotherapy for breast cancer. Preliminary efficacy estimates suggest that yoga improves sleep adequacy Symptom severity and interference remained stable during chemotherapy for the yoga group and snowed a trend toward increasing in the control group. The study highlighted obstacles to multisite yoga research during cancer treatment. FUNDING/SPONSORSHIP: National Cancer Institute (3U10 CA081851, PI; Shaw; R25 CA122061, PI: Avis); Translational Science Institute, Wake Forest School of Medicine.

Effects of yoga on cancer-related fatigue and global side-effect burden in older cancer survivors.

BACKGROUND: Sixty percent of cancer survivors are 65years of age or older. Cancer and its treatments lead to cancer-related fatigue and many other side effects, in turn, creating substantial global side-effect burden (total burden from all side effects) which, ultimately, compromises functional independence and quality of life. Various modes of exercise, such as yoga, reduce cancer-related fatigue and global side-effect burden in younger cancer survivors, but no studies have specifically examined the effects of yoga on older cancer survivors. OBJECTIVES: The purpose of this study was to assess the effects of a 4-week yoga intervention (Yoga for Cancer Survivors: YOCAS©®) on overall cancer-related fatigue, and due to its multidimensional nature, the subdomains of cancer-related fatigue (general, physical, emotional, and mental) and global side-effect burden in older cancer survivors. MATERIALS AND METHODS: We conducted a secondary analysis on data from a multicenter phase III randomized controlled clinical trial with 2 arms (standard care and standard care plus a 4-week YOCAS©® intervention). The sample for this secondary analysis was 97 older cancer survivors (≥60years of age), between 2months and 2years post-treatment, who participated in the original trial. RESULTS: Participants in the YOCAS©® intervention arm reported significantly lower cancer-related fatigue, physical fatigue, mental fatigue, and global side-effect burden than participants in the standard care arm following the 4-week intervention period (p<0.05). CONCLUSIONS: YOCAS©® is an effective standardized yoga intervention for reducing cancer-related fatigue, physical fatigue, mental fatigue, and global side-effect burden among older cancer survivors.

A phase 2 trial of ixabepilone plus cetuximab in first-line treatment of metastatic pancreatic cancer.

BACKGROUND: The aim of this phase 2 study was to evaluate the safety and efficacy of ixabepilone plus cetuximab in patients with advanced pancreatic cancer. METHODS: Eligible patients had advanced pancreatic adenocarcinoma that was metastatic or not amenable to resection, a Karnofsky performance status ≥70%, and no prior therapy for advanced disease. Patients received ixabepilone 32 mg/m(2) (3-hour IV infusion) every 3 weeks and cetuximab 250 mg/m(2) (1-hour IV infusion) weekly. The primary efficacy end point was the 6-month survival rate. Secondary end points included tumor response rate, overall survival, progression-free survival, and tolerability. RESULTS: A total of 54 patients were enrolled on this study. The 6-month survival rate was 57% (31/54: 95% CI: 43-71%) with a median overall survival of 7.6 months (95% CI: 5.5-12.2 months). Patients who developed acneiform rash (n = 36) had a median survival of 8.8 months, compared with 2.6 months for those without rash (n = 18). Of 31 patients with measurable disease (defined as response-evaluable), 4 had confirmed partial responses and an additional 24 had stable disease. The combination was generally well-tolerated with the most common grade 3/4 hematological toxicities being leucopenia (39%) and neutropenia (33%). The most common grade 3/4 nonhematologic toxicity was fatigue (17%). CONCLUSIONS: The combination of ixabepilone and cetuximab was active and had acceptable toxicity. The efficacy results are similar to single-agent ixabepilone and gemcitabine-based combination therapies in patients with advanced pancreatic cancer. Exploratory analyses suggest a trend toward improved survival for patients who experienced rash.

Primary mFOLFOX6 plus bevacizumab without resection of the primary tumor for patients presenting with surgically unresectable metastatic colon cancer and an intact asymptomatic colon cancer: definitive analysis of NSABP trial C-10.

PURPOSE: Major concerns surround combining chemotherapy with bevacizumab in patients with colon cancer presenting with an asymptomatic intact primary tumor (IPT) and synchronous yet unresectable metastatic disease. Surgical resection of asymptomatic IPT is controversial. PATIENTS AND METHODS: Eligibility for this prospective, multicenter phase II trial included Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1, asymptomatic IPT, and unresectable metastases. All received infusional fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) combined with bevacizumab. The primary end point was major morbidity events, defined as surgical resection because of symptoms at or death related to the IPT. A 25% major morbidity rate was considered acceptable. Secondary end points included overall survival (OS) and minor morbidity related to IPT requiring hospitalization, transfusion, or nonsurgical intervention. RESULTS: Ninety patients registered between March 2006 and June 2009: 86 were eligible with follow-up, median age was 58 years, and 52% were female. Median follow-up was 20.7 months. There were 12 patients (14%) with major morbidity related to IPT: 10 required surgery (eight, obstruction; one, perforation; and one, abdominal pain), and two patients died. The 24-month cumulative incidence of major morbidity was 16.3% (95% CI, 7.6% to 25.1%). Eleven IPTs were resected without a morbidity event: eight for attempted cure and three for other reasons. Two patients had minor morbidity events only: one hospitalization and one nonsurgical intervention. Median OS was 19.9 months (95% CI, 15.0 to 27.2 months). CONCLUSION: This trial met its primary end point. Combining mFOLFOX6 with bevacizumab did not result in an unacceptable rate of obstruction, perforation, bleeding, or death related to IPT. Survival was not compromised. These patients can be spared initial noncurative resection of their asymptomatic IPT.