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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 FROM AUTHOR]

Background : Older adults are under-represented in cancer clinical trials. However, it remains unclear which types of trials under-enroll aging patients. We aimed to identify associations between trial characteristics and disparate enrollment of older adults onto trials sponsored by the Alliance for Clinical Trials in Oncology (Alliance). Methods : Actual age ≥ 65 percentage and trial data were extracted from the Alliance closed study list. Each trial, based on its cancer type and years of enrollment, was assigned an expected age ≥ 65 percentage extracted from the Surveillance, Epidemiology, and End Results (SEER) US population-based database. Enrollment disparity difference (EDD), the difference between the expected age ≥ 65 percentage and the actual age ≥ 65 percentage, was calculated for each trial. Linear regression determined trial variables associated with larger EDDs and variables with an overall association p -value <0.20 were included in a multivariable fixed-effects linear model. Results : The median age of 66,708 patients across 237 trials was 60 years (range 18–102). The average actual age ≥ 65 percentage enrolled per trial was lower than each trial's expected age ≥ 65 percentage average (39% vs. 58%; EDD 19, 95% CI 17.1–21.3%, p < 0.0001). In multivariable analyses, non-genitourinary (GU) cancer types (p < 0.001), trimodality+ trials (estimate 8.78, 95%CI 2.21–15.34, p = 0.009), and phase 2 trials (estimate 4.43 95% CI -0.06-8.91; p = 0.05) were all associated with larger EDDs. Conclusions : Disparate enrollment of older adults is not equal across cancer trials. Future strategies to improve older adult inclusion should focus on trial types associated with the highest disparate enrollment. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the presence of a placebo dose–response effect in four randomized, double-blind, placebo-controlled, multi-dose hot flash clinical trials conducted at Mayo Clinic. Methods: Hot flash score, frequency, and hot flash-related distress for each placebo dose level were summarized at each time point by mean and standard deviation and changes from baseline were plotted to visualize a possible placebo dose–effect response. Furthermore, a meta-analysis was conducted for each endpoint in the highest and lowest dosage arms across the four trials. Results: Longitudinal plots of mean hot flash scores, frequencies, and hot flash-related distress scores in patients taking placebo in each study showed a decline in hot flash scores over time without any clinically meaningful differences between the lowest and highest dosage arms in each study. The meta-analysis for each endpoint in the highest and lowest dosage arms across the four trials revealed no clinically important differences either. Conclusion: While the current study cannot rule out the existence of a placebo dose–response effect in multi-dose placebo-controlled trials in patients with hot flashes or other conditions, it suggests, along with the available data in the placebo literature, that, at least in well-conducted multi-dose clinical trials in which the placebo was used as control, such an effect, if it exists at all, should be very small. Therefore, pooling data from different placebo subgroups is unlikely to compromise the validity of comparisons between the combined placebo arms and each treatment arm. [ABSTRACT FROM AUTHOR]

PURPOSE This randomized, double-blind study sought to understand whether cancer clinical trial consent form verbosity detracts from patients' decision making on trial enrollment. METHODS This trial tested mock consent forms of 2,000, 4,000, and 6,000 words. The first two comprised the two experimental arms and the third the control arm. Phase II was conducted to identify the promising arm, which, in phase III, was compared with the control arm. Each consent form described the same trial. Eligible adult patients reported a cancer history and English literacy. The primary end point used a patient-reported Likert scale to assess the relationship between information in the consent form and trial decision making. RESULTS In phase II, 93 patients were accrued and prompted the selection of the 2,000-word consent form for phase III. In phase III, 182 patients were recruited, resulting in 240 total evaluable patients to compare the 2,000-word versus the 6,000-word arm (control). For the primary end point, 103 (84%) and 107 (91%) patients in the 2,000- and 6,000-word arms, respectively, strongly agreed or agreed with the following: "The information in this consent form helped me make a decision about whether or not to enroll in the trial" (two-sided, P = .14). Median time to read each consent form was 8 and 12 minutes, respectively (two-sided, P < .0001). Among those assigned these consent forms, 84% and 73%, respectively (two-sided, P = .04) signed or expressed a willingness to sign. CONCLUSION This study's primary end point was not met. However, secondary outcomes suggest a need to further study the efficiency and efficacy of shorter consent forms for cancer clinical trial enrollment. [ABSTRACT FROM AUTHOR]

Background/aims: The difference in mean survival time, which quantifies the treatment effect in terms most meaningful to patients and retains its interpretability regardless of the shape of the survival distribution or the proportionality of the treatment effect, is an alternative endpoint that could be used more often as the primary endpoint to design clinical trials. The underuse of this endpoint is due to investigators' lack of familiarity with the test comparing the mean survival times and the lack of tools to facilitate trial design with this endpoint. The aim of this article is to provide investigators with insights and software to design trials with restricted mean survival time as the primary endpoint. Methods: A closed-form formula for the asymptotic power of the test of restricted mean survival time difference is presented. The effects of design parameters on power were evaluated for the mean survival time test and log-rank test. An R package which calculates the power or the sample size for user-specified parameter values and provides power plots for each design parameter is provided. The R package also calculates the probability that the restricted mean survival time is estimable for user-defined trial designs. Results: Under proportional hazards and late differences in survival, the power of the mean survival time test can approach that of the log-rank test if the restriction time is late. Under early differences, the power of the restricted mean survival time test is higher than that of the log-rank test. Duration of accrual and follow-up have little influence on the power of the restricted mean survival time test. The choice of restriction time, on the other hand, has a large impact on power. Because the power depends on the interplay among the design factors, plotting the relationship between each design parameter and power allows the users to select the designs most appropriate for their trial. When modification is necessary to ensure the difference in restricted mean survival time is estimable, the three available modifications all perform adequately in the scenarios studied. Conclusion: The restricted mean survival time is a survival endpoint that is meaningful to investigators and to patients and at the same time requires less restrictive assumptions. The biggest challenge with this endpoint is selection of the restriction time. We recommend selecting a restriction time that is clinically relevant to the disease and the clinical setting of the trial of interest. The practical considerations and the R package provided in this work are readily available tools that researchers can use to design trials with restricted mean survival time as the primary endpoint. [ABSTRACT FROM AUTHOR]

Purpose: To test the psychometric properties of the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Chemotherapy-Induced Peripheral Neuropathy (QLQ-CIPN20) using Rasch-based methods.Methods: A secondary data analysis was performed using pooled QLQ-CIPN20 data from patients (N = 1008) who had participated in any of four multi-site chemotherapy-induced peripheral neuropathy (CIPN) treatment and prevention trials. QLQ-CIPN20 responses were evaluated using a polytomous Rasch partial credit model. Data were assessed for person-item fit using the chi-square statistic, item scaling based on response proportions, threshold ordering using item characteristic curves and logit threshold locations, differential item response (DIF) (i.e., response bias) using likelihood ratio tests, and unidimensionality using cluster analysis.Results: A statistically significant chi-square test indicated poor fit of the observed to the expected responses. More than 70% of the respondents reported a complete absence of six symptoms, reflecting significant floor effects and poor item scaling. Disordered/non-ordinal or narrow response thresholds were found for 11 of the 20 items. Item responses were significantly different by gender (p < 0.0001) and chemotherapy type (p < 0.0001). Cluster analysis findings suggest that the QLQ-CIPN20 is a unidimensional scale due to the absence of item clusters.Conclusions: Rasch model testing revealed psychometric weaknesses that could be addressed by revising the QLQ-CIPN20's problematic items and response options. Alternatively, perhaps the new gold standard CIPN measurement approach in future intervention trials should involve use of only the best items, which would also allow comparisons across previous trials that utilized the QLQ-CIPN20. [ABSTRACT FROM AUTHOR]

Background: Less than 3% of older patients with cancer are enrolled in clinical trials. To reverse this underrepresentation, we compared older patients enrolled with older‐patient‐specific trials, defined as those designed for older patients with cancer, with those enrolled in age‐unspecified trials. Materials and Methods: We focused on individual patient data from those ≥65 years (younger patients excluded) and included all Alliance phase III adjuvant breast cancer trials from 1985–2012. Results: Among 2,277 patients, 1,014 had been enrolled to older‐patient‐specific and 1,263 to age‐unspecified trials. The median age (range) in the older‐patient‐specific trials was 72 (65–89) years compared with 68 (65–84) years in the cohort of older patients in age‐unspecified trials; p <.0001. A greater percentage of patients 75 years or older had enrolled in older‐patient‐specific trials compared with the cohort of age‐unspecified trials: 26% versus 6% (p <.0001). Median overall survival (OS) was 12.8 years (95% confidence interval [CI], 11.9–13.7) and 13.5 years (95% CI, 12.9–14.1) for older‐patient‐specific and age‐unspecified trials, respectively. OS was comparable (hazard ratio [HR], 1.08; 95% CI, 0.92–1.28; p =.34; referent: age‐unspecified trials), after adjusting for age, estrogen receptor status, tumor size, and lymph node status. Similar findings were reached for recurrence‐free survival. A lower rate of grade 3–5 adverse events (hematologic and nonhematologic) was reported in older‐patient‐specific trials (43% vs. 58%; p <.0001). Sensitivity analysis with chemotherapy only trials and subset analysis, adjusted for performance score, yielded similar OS results. Conclusion: Older‐patient‐specific trials appear to address this underrepresentation of older patients with ostensibly comparable outcomes. Clinical trial identification numbers. NCT00003088 (CALGB 9741); NCT00024102 (CALGB 49907); NCT00068601 (CALGB 40401); NCT00005970 (NCCTG N9831) Implications for Practice: This work underscores the importance of clinical trials that focus on the recruitment of older patients with cancer. Few older cancer patients are enrolled in cancer clinical trials. This article assesses whether the development and conduct of older‐patient‐specific trials is justified, comparing outcomes of patients enrolled in trials purposely designed for older cancer patients versus age‐unspecified trials. [ABSTRACT FROM AUTHOR]

Importance: Oral mucositis causes substantial morbidity during head and neck radiotherapy. In a randomized study, doxepin mouthwash was shown to reduce oral mucositis-related pain. A common mouthwash comprising diphenhydramine-lidocaine-antacid is also widely used.Objective: To evaluate the effect of doxepin mouthwash or diphenhydramine-lidocaine-antacid mouthwash for the treatment of oral mucositis-related pain.Design, Setting, and Participants: A phase 3 randomized trial was conducted from November 1, 2014, to May 16, 2016, at 30 US institutions and included 275 patients who underwent definitive head and neck radiotherapy, had an oral mucositis pain score of 4 points or greater (scale, 0-10), and were followed up for a maximum of 28 days.Interventions: Ninety-two patients were randomized to doxepin mouthwash (25 mg/5 mL water); 91 patients to diphenhydramine-lidocaine-antacid; and 92 patients to placebo.Main Outcome and Measures: The primary end point was total oral mucositis pain reduction (defined by the area under the curve and adjusted for baseline pain score) during the 4 hours after a single dose of doxepin mouthwash or diphenhydramine-lidocaine-antacid mouthwash compared with a single dose of placebo. The minimal clinically important difference was a 3.5-point change. The secondary end points included drowsiness, unpleasant taste, and stinging or burning. All scales ranged from 0 (best) to 10 (worst).Results: Among the 275 patients randomized (median age, 61 years; 58 [21%] women), 227 (83%) completed treatment per protocol. Mucositis pain during the first 4 hours decreased by 11.6 points in the doxepin mouthwash group, by 11.7 points in the diphenhydramine-lidocaine-antacid mouthwash group, and by 8.7 points in the placebo group. The between-group difference was 2.9 points (95% CI, 0.2-6.0; P = .02) for doxepin mouthwash vs placebo and 3.0 points (95% CI, 0.1-5.9; P = .004) for diphenhydramine-lidocaine-antacid mouthwash vs placebo. More drowsiness was reported with doxepin mouthwash vs placebo (by 1.5 points [95% CI, 0-4.0]; P = .03), unpleasant taste (by 1.5 points [95% CI, 0-3.0]; P = .002), and stinging or burning (by 4.0 points [95% CI, 2.5-5.0]; P < .001). Maximum grade 3 adverse events for the doxepin mouthwash occurred in 3 patients (4%); diphenhydramine-lidocaine-antacid mouthwash, 3 (4%); and placebo, 2 (2%). Fatigue was reported by 5 patients (6%) in the doxepin mouthwash group and no patients in the diphenhydramine-lidocaine-antacid mouthwash group.Conclusions and Relevance: Among patients undergoing head and neck radiotherapy, the use of doxepin mouthwash or diphenhydramine-lidocaine-antacid mouthwash vs placebo significantly reduced oral mucositis pain during the first 4 hours after administration; however, the effect size was less than the minimal clinically important difference. Further research is needed to assess longer-term efficacy and safety for both mouthwashes.Trial Registration: ClinicalTrials.gov Identifier: NCT02229539. [ABSTRACT FROM AUTHOR]

Background/aims: The goal of this article is to illustrate the utility of multi-state models in cancer clinical trials. Our specific aims are to describe multi-state models and how they differ from standard survival methods, to illustrate how multi-state models can facilitate deeper understanding of the treatment effect on multiple paths along the disease process that patients could experience in cancer clinical trials, to explain the differences between multi-state models and time-dependent Cox models, and to briefly describe available software to conduct such analyses. Methods: Data from 717 newly diagnosed acute myeloid leukemia patients who enrolled in the CALGB 10603 trial were used as an illustrative example. The current probability-in-state was estimated using the Aalen-Johansen estimator. The restricted mean time in state was calculated as the area under the probability-in-state curves. Cox-type regression was used to evaluate the effect of midostaurin on the various clinical paths. Simulation was conducted using a newly constructed shiny application. All analyses were performed using the R software. Results: Multi-state model analyses of CALGB 10603 suggested that the overall improvement in survival with midostaurin seen in the primary analysis possibly resulted from a higher complete remission rate in combination with a lower risk of relapse and of death after complete remission in patients treated with midostaurin. Simulation results, in a threestate illness-death without recovery model, demonstrate that multi-state models and time-dependent Cox models evaluate treatment effects from different frameworks. Conclusion: Multi-state models allow detailed evaluation of treatment effects in complex clinical trial settings where patients can experience multiple paths between study enrollment and the final outcome. Multi-state models can be used as a complementary tool to standard survival analyses to provide deeper insights to the effects of treatment in trial settings with complex disease process. [ABSTRACT FROM AUTHOR]

Most advanced cancer patients suffer loss of appetite (anorexia) and loss of weight. Despite the fact that cancer anorexia and weight loss are associated with a poor prognosis and detract from quality of life, no interventions have been demonstrated to palliate this syndrome in its entirety, particularly in patients with treatment-refractory malignancies. Recently, two registration trials − one with anamorelin and another with enobosarm − failed to reach their primary endpoints, thus raising questions. Were both these agents ineffective? Alternatively, did study design issues compromise the ability of these trials to identify effective agents? Thus, this review is timely insofar it serves as an introduction to study design, offers guidance on how to test promising agents for cancer anorexia/weight loss, and provides advice for overcoming trial design obstacles. [ABSTRACT FROM AUTHOR]

The introduction of reduced-intensity conditioning (RIC) regimens made it possible to offer allogeneic hematopoietic cell transplantation (alloHCT) to older patients with myelodysplastic syndromes (MDS). However, the relative risks and benefits of alloHCT compared with novel nontransplant therapies continue to be the source of considerable uncertainty. We will perform a prospective biologic assignment trial to compare RIC alloHCT with nontransplant therapies based on donor availability. Primary outcome is 3-year overall survival. Secondary outcomes include leukemia-free survival, quality of life, and cost-effectiveness. Four hundred patients will be enrolled over roughly 3 years. Planned subgroup analyses will evaluate key biologic questions, such as the impact of age and response to hypomethylating agents on treatment effects. Findings from this study potentially may set a new standard of care for older MDS patients who are considered candidates for alloHCT. [ABSTRACT FROM AUTHOR]

Studies show that engaging patients in exercise and/or stress management techniques during hematopoietic cell transplantation (HCT) improves quality of life. The Blood and Marrow Transplant Clinical Trials Network tested the efficacy of training patients to engage in self-directed exercise and stress management during HCT. The study randomized 711 patients at 21 centers to receive 1 of 4 training interventions before HCT: a self-directed exercise program, a self-administered stress management program, both, or neither. Participants completed self-reported assessments at enrollment and up to 180 days after HCT. Randomization was stratified by center and transplant type. There were no differences in the primary endpoints of the Physical Component Summary and Mental Component Summary scales of the Medical Outcomes Study Short Form 36 at day +100 among the groups, based on an intention-to-treat analysis. There also were no differences in overall survival, days of hospitalization through day +100 post-HCT, or in other patient-reported outcomes, including treatment-related distress, sleep quality, pain, and nausea. Patients randomized to training in stress management reported more use of those techniques, but patients randomized to training in exercise did not report more physical activity. Although other studies have reported efficacy of more intensive interventions, brief training in an easy-to-disseminate format for either self-directed exercise or stress management was not effective in our trial. [ABSTRACT FROM AUTHOR]

Simple Summary: There are no known effective preventative interventions for oxaliplatin-induced peripheral neuropathy (OIPN) sensory symptoms of numbness, tingling and pain other than limiting drug exposure. With the shorter 3-month duration of oxaliplatin increasingly being used, compared to the previous 6-month standard, we were motivated to quantify the temporal, location- and symptom-specific likelihood of patient-reported sensory symptoms related to OIPN in 141 patients from the placebo arms of two multisite OIPN prevention trials exposed to oxaliplatin for 3 months. Despite a shorter duration of oxaliplatin, we show that OIPN was still pervasive, with patients experiencing considerable mild to moderate numbness and tingling in the lower and upper distal extremities. To avoid the debilitating sequelae from OIPN and to ensure that patients continue to receive the most efficacious doses of oxaliplatin, identification of effective OIPN preventative interventions is still needed, regardless of whether oxaliplatin is planned to be given for 3 versus 6 months. While oxaliplatin-induced peripheral neuropathy (OIPN) is more common and severe in patients who receive the previous standard, 6-month oxaliplatin-based treatment, we hypothesized that OIPN was still pervasive in patients who received shorter, 3-month-treatment regimens. Using six EORTC QLQ-CIPN20 questions that quantify numbness (N), tingling (T) and shooting/burning pain (P) in upper/lower distal extremities, our aim is to quantify patient-reported responses over 3 months (6 cycles) of oxaliplatin regarding symptom-specific timing, location and severity. For each question, patients were asked how each of the sensory symptoms had affected them during the preceding week, with 1 = "Not at all", 2 = "A little", 3 = "Quite a bit" and 4 = "Very much". The proportional odds model for the cumulative log odds of response that allowed symptom-specific patient heterogeneity to be obtained was applied to a pooled dataset from the placebo arms of two multisite OIPN prevention trials and fit separately to the upper/lower distal extremities. For each symptom, we report the cycle-specific marginal probabilities for each response. In 141 patients, substantial patient heterogeneity in the likelihood, at a given cycle, of a more severe response for a symptom was present. Distinct patterns in the probabilities for each response over time for N and T were observed between the upper/lower distal extremities, while the probabilities of a response >1 for P was largely negligible in both locations. Despite the decrease in exposure to oxaliplatin from 6 to 3 months, OIPN was still pervasive with patients experiencing considerable N and T in the fingers (or hands) and toes (or feet). [ABSTRACT FROM AUTHOR]

Simple Summary: In cancer clinical trials, adverse event data are collected after every treatment cycle, using the Common Terminology Criteria for adverse events, which includes 837 terms. The vast number of potentially reportable adverse events over multiple treatment cycles makes summarizing and analyzing adverse event data challenging. The current standard reporting of adverse event data includes the frequency of the maximum (worst) grade of commonly occurring adverse events. In this article, we propose a single quantitative summary measure that incorporates both the frequency and the severity of multiple adverse events over time; the adverse event burden score. This score is a well-defined measure that enables statistical comparisons analogous to other quantitative endpoints in clinical trials. The adverse event burden score can readily accommodate different trial settings, diseases, and treatments, with diverse safety profiles. This article introduces the adverse event (AE) burden score. The AE burden by treatment cycle is a weighted sum of all grades and AEs that the patient experienced in a cycle. The overall AE burden score is the total AE burden the patient experienced across all treatment cycles. AE data from two completed Alliance multi-center randomized double-blind placebo-controlled trials, with different AE profiles (NCCTG 97-24-51: 176 patients, and A091105: 83 patients), were utilized for illustration. Results of the AE burden score analyses corroborated the trials' primary results. In 97-24-51, the overall AE burden for patients on the treatment arm was 2.2 points higher than those on the placebo arm, with a higher AE burden for patients who went off treatment early due to AE. Similarly, in A091105, the overall AE burden was 1.6 points higher on the treatment arm. On the placebo arms, the AE burden in 97-24-51 remained constant over time; and increased in later cycles in A091105, likely attributable to the increase in disease morbidity. The AE burden score enables statistical comparisons analogous to other quantitative endpoints in clinical trials, and can readily accommodate different trial settings, diseases, and treatments, with diverse AE profiles. [ABSTRACT FROM AUTHOR]

Blood and Marrow Transplant Clinical Trials Network (BMT CTN) protocol 0902 evaluated whether exercise and stress management training before hematopoietic cell transplantation (HCT) improved physical and mental functioning after HCT. Neither overall survival nor other patient-reported transplantation outcomes were improved by the training intervention. In some animal studies of HCT, moderate-intensity exercise for 8 weeks before HCT has been associated with positive effects on hematopoietic progenitors, resulting in improved donor engraftment and improved survival. Accordingly, we performed a secondary analysis of data from BMT CTN 0902 to determine whether exercise engagement before HCT was associated with engraftment and survival. We found no significant associations between self-reported pre-HCT exercise levels and engraftment or survival. There was also no effect of pretransplantation exercise on either neutrophil or platelet engraftment. These findings do not support the observations in animal models but are limited by several shortcomings that do not refute the hypothesis that exercise before HCT may be beneficial. [ABSTRACT FROM AUTHOR]

This secondary analysis of a large, multicenter Blood and Marrow Transplant Clinical Trials Network randomized trial assessed whether patient-reported outcomes (PROs) and socioeconomic status (SES) before hematopoietic stem cell transplantation (HCT) are associated with each other and predictive of clinical outcomes, including time to hematopoietic recovery, acute graft-versus-host disease, hospitalization days, and overall survival (OS) among 646 allogeneic and autologous HCT recipients. Pretransplantation Cancer and Treatment Distress (CTXD), Pittsburgh Sleep Quality Index (PSQI), and mental and physical component scores of the Short-Form 36 were correlated with each other and with SES variables. PROs and SES variables were further evaluated as predictors of clinical outcomes, with the PSQI and CTXD evaluated as OS predictors ( P  < .01 considered significant given multiple testing). Lower attained education was associated with increased distress ( P  = .002), lower income was related to worse physical functioning ( P  = .005) and increased distress ( P  = .008), lack of employment before transplantation was associated with worse physical functioning ( P  < .01), and unmarried status was associated with worse sleep ( P  = .003). In this large heterogeneous cohort of HCT recipients, although PROs and SES variables were correlated at baseline, they were not associated with any clinical outcomes. Future research should focus on HCT recipients at greater psychosocial disadvantage. [ABSTRACT FROM AUTHOR]