Older adult participation in cancer clinical trials: A systematic review of barriers and interventions.

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.

The influence of anatomic stage and receptor status on first recurrence for breast cancer within 5 years (AFT-01).

BACKGROUND: Risk-stratified follow-up guidelines that account for the absolute risk and timing of recurrence may improve the quality and efficiency of breast cancer follow-up. The objective of this study was to assess the relationship of anatomic stage and receptor status with timing of the first recurrence for patients with local-regional breast cancer and generate risk-stratified follow-up recommendations. METHODS: The authors conducted a secondary analysis of 8007 patients with stage I-III breast cancer who enrolled in nine Alliance legacy clinical trials from 1997 to 2013 (ClinicalTrials.gov identifier NCT02171078). Patients who received standard-of-care therapy were included. Patients who were missing stage or receptor status were excluded. The primary outcome was days from the earliest treatment start date to the date of first recurrence. The primary explanatory variable was anatomic stage. The analysis was stratified by receptor type. Cox proportional-hazards regression models produced cumulative probabilities of recurrence. A dynamic programming algorithm approach was used to optimize the timing of follow-up intervals based on the timing of recurrence events. RESULTS: The time to first recurrence varied significantly between receptor types (p < .0001). Within each receptor type, stage influenced the time to recurrence (p < .0001). The risk of recurrence was highest and occurred earliest for estrogen receptor (ER)-negative/progesterone receptor (PR)-negative/Her2neu-negative tumors (stage III; 5-year probability of recurrence, 45.5%). The risk of recurrence was lower for ER-positive/PR-positive/Her2neu-positive tumors (stage III; 5-year probability of recurrence, 15.3%), with recurrences distributed over time. Model-generated follow-up recommendations by stage and receptor type were created. CONCLUSIONS: This study supports considering both anatomic stage and receptor status in follow-up recommendations. The implementation of risk-stratified guidelines based on these data has the potential to improve the quality and efficiency of follow-up.

Local/Regional Recurrence Rates After Breast-Conserving Therapy in Patients Enrolled in Legacy Trials of the Alliance for Clinical Trials in Oncology (AFT-01).

OBJECTIVE: We sought to evaluate local/regional recurrence rates after breast-conserving surgery in a cohort of patients enrolled in legacy trials of the Alliance for Clinical Trials in Oncology and to evaluate variation in recurrence rates by receptor subtype. BACKGROUND: Multiple randomized controlled trials have demonstrated equivalent survival between breast conservation and mastectomy, albeit with higher local/regional recurrence rates after breast conservation. However, absolute rates of local/regional recurrence have been declining with multi-modality treatment. METHODS: Data from 5 Alliance for Clinical Trials in Oncology legacy trials that enrolled women diagnosed with breast cancer between 1997 and 2010 were included. Women who underwent breast-conserving surgery and standard systemic therapies (n=4,404) were included. Five-year rates of local/regional recurrence were estimated from Kaplan-Meier curves. Patients were censored at the time of distant recurrence (if recorded as the first recurrence), death, or last follow-up. Multivariable Cox proportional hazards models were used to identify factors associated with time to local/regional recurrence, including patient age, tumor size, lymph node status, and receptor subtype. RESULTS: Overall 5-year recurrence was 4.6% (95% CI=4.0-5.4%). Five-year recurrence rates were lowest in those with ER+ or PR+ tumors (Her2+ 3.4% [95% CI 2.0-5.7%], Her2- 4.0% [95% CI 3.2-4.9%]) and highest in the triple-negative subtype (7.1% [95% CI 5.4-9.3%]). On multivariable analysis, increasing nodal involvement and triple-negative subtype were positively associated with recurrence ( P <0.0001). CONCLUSIONS: Rates of local/regional recurrence after breast conservation in women with breast cancer enrolled in legacy trials of the Alliance for Clinical Trials in Oncology are significantly lower than historic estimates. This data can better inform patient discussions and surgical decision-making.

Statistical Considerations and Software for Designing Sequential, Multiple Assignment, Randomized Trials (SMART) with a Survival Final Endpoint.

Sequential, multiple assignment, randomized trial (SMART) designs are appropriate for comparing adaptive treatment interventions, in which intermediate outcomes (called tailoring variables) guide subsequent treatment decisions for individual patients. Within a SMART design, patients may be re-randomized to subsequent treatments following the outcomes of their intermediate assessments. In this paper, we provide an overview of statistical considerations necessary to design and implement a two-stage SMART design with a binary tailoring variable and a survival final endpoint. A chronic lymphocytic leukemia trial with a final endpoint of progression-free survival is used as an example for the simulations to assess how design parameters, including, choice of randomization ratios for each stage of randomization, and response rates of the tailoring variable affect the statistical power. We assess the choice of weights from restricted re-randomization on data analyses and appropriate hazard rate assumptions. Specifically, for a given first-stage therapy and prior to the tailoring variable assessment, we assume equal hazard rates for all patients randomized to a treatment arm. After the tailoring variable assessment, individual hazard rates are assumed for each intervention path. Simulation studies demonstrate that the response rate of the binary tailoring variable impacts power as it directly impacts the distribution of patients. We also confirm that when the first stage randomization is 1:1, it is not necessary to consider the first stage randomization ratio when applying the weights. We provide an R-shiny application for obtaining power for a given sample size for SMART designs.

Hiccups in patients with cancer: a multi-site, single-institution study of etiology, severity, complications, interventions, and outcomes.

BACKGROUND: To our knowledge, previous studies have not investigated hiccups in patients with cancer with detailed patient-level data with the goal of capturing a broad spectrum of hiccup symptomatology. METHODS: This multi-site, single institution study examined consecutive medical records to better understand hiccups in patients with cancer. RESULTS: A total of 320 patients are the focus of this report. The median age of patients when hiccups were first reported in the medical record was 63 years (range: 21, 97 years) with 284 (89%) men and 36 (11%) women. The most common diagnose was gastrointestinal cancer. Hiccups most frequently occurred daily, as seen in 194 patients (62%), and the most common duration was less than 1 week, as seen in 146 patients (47%). However, nine patients had had daily hiccups for greater than 6 weeks, and 5 had symptoms for years. Cited etiology was non-chemotherapy medications in 36 (11%) and cancer chemotherapy in 19 (6%). Complications occurred in approximately a third and included insomnia in 51 patients (16%); hospitalization or emergency department visit in 34 (11%); and musculoskeletal pain in 23 (7%). Baclofen was the single most prescribed agent for hiccup palliation, but 100 patients received more than one medication. Medical procedures, which included acupuncture, paracentesis, or phrenic nerve block, were performed in 5 patients. In 234 patients (73%), the medical record documented hiccup cessation. CONCLUSIONS: Hiccups appear to be highly problematic in a small subset of patients with cancer with no well-defined palliative approaches.

Preemptive Versus Reactive Topical Clobetasol for Regorafenib-Induced Hand-Foot Reactions: A Preplanned Analysis of the ReDOS Trial.

BACKGROUND: Hand-foot skin reaction (HFSR) is the most common regorafenib-induced adverse event and is in need of effective prevention and palliation. MATERIALS AND METHODS: The Regorafenib Dose Optimization Study (ReDOS), a four-arm, previously published trial with a 1:1:1:1 randomization scheme, was analyzed in a manner in keeping with the original protocol to assess whether clobetasol 0.05% cream (a corticosteroid) applied to the palms and soles twice per day for 8 weeks was more effective when prescribed preemptively (before the development of HFSR) versus reactively (after the development of HFSR). Patients were assessed during the first two cycles of regorafenib. RESULTS: Sixty-one patients received preemptive clobetasol, and 55 received reactive clobetasol. Groups were balanced on demographics. Over the first two cycles, no evidence of HFSR occurred in 30% with preemptive clobetasol versus 13% with reactive clobetasol (p = .03). During the first cycle, 54% and 45% of patients had no HFSR with preemptive and reactive clobetasol, respectively (p = .35). During the second cycle, 33% and 15% had no HFSR with preemptive and reactive clobetasol, respectively (p = .02). During the second cycle, rates of grade 1, 2, and 3 HFSR were 30%, 8%, and 3%, respectively, with preemptive clobetasol and 43%, 18%, and 7%, respectively, with reactive clobetasol (p = .12). Patient-reported outcomes showed HFSR compromised nearly all activities of daily living with worse quality of life in patients who received reactive versus preemptive clobetasol. No clobetasol-induced adverse events were reported. CONCLUSION: Preemptive clobetasol might lessen regorafenib-induced hand-foot reactions compared with reactive therapy. Further confirmatory studies are needed in a larger patient cohort. IMPLICATIONS FOR PRACTICE: Regorafenib causes hand-foot skin reactions. Preemptive clobetasol, a high-potency topical corticosteroid, appears to lessen the severity of this adverse event. Although further study is needed, the favorable adverse event profile of this intervention might prompt clinicians to discuss this option with their patients.

Observations with alpelisib in older patients (≥ 65 year of age) with breast cancer in a non-clinical trial setting.

PURPOSE: Alpelisib is newly-available breast cancer agent that targets PIK3 mutations and confers a somewhat unusual adverse event profile. This study focused on older patients (≥ 65 years of age) treated outside a clinical trial to gain further experience on how these under-studied patients do with this new agent. METHODS: This descriptive, multi-site study relied on medical record review. RESULTS: Fifty-one older breast cancer patients were started on alpelisib between May 2019 and September 2020. The median age and number of comorbidities at alpelisib initiation was 71 years and 4, respectively. Thirty-five patients had stopped alpelisib (median time on drug 2.6 months (range: < 1, 9.5 months)) for the following reasons: alpelisib adverse events (n = 15), cancer progression (n = 13), and other/unknown (n = 7). Alpelisib adverse events included hyperglycemia (n = 37), diarrhea (n = 23), rash (n = 19), fatigue (n = 12), and mouth sores (n = 7); (numbers in parentheses indicate the number of patients with at least one such event). Five patients were hospitalized for hyperglycemia. At the time of report, 14 patients were deceased, and median survival had not been reached. CONCLUSION: Older patients might derive further benefit from alpelisib if the adverse event profile of this agent, particularly the hyperglycemia, were able to be better managed.

Understanding Verbosity: Funding Source and the Length of Consent Forms for Cancer Clinical Trials.

Consent forms are an important educational tool that helps cancer patients decide on whether or not to enroll on a clinical trial, but wordiness potentially detracts from their educational value. This single-institution study examined word counts of consent forms for all phase I, II, and III solid tumor clinical trials between 2004 and 2010. Consent forms were categorized by trial funding source: (1) pharmaceutical company; (2) National Clinical Trials Network (NCTN); (3) R01- or other non-government grants; and (4) mixed (funding from multiple sources). Three hundred fifteen consent forms were studied; these included 106 (34%) pharmaceutical company; 145 (46%) NCTN; 44 (14%) R01 type; and 20 (6%) mixed. The overall median word count was 5129 words per consent form (interquartile range (IQR) range, 4226 to 6695). The median word counts per consent form (IQR) were 5648 (4814, 6803), 5243 (4139, 6932), 4365 (3806, 5124), and 4319 (3862, 5944), respectively, based on the above funding sources, showing that pharmaceutical company trial consent forms had the highest median word count. Of note, phase of trial was associated with consent form length (phase III were wordier), and consent forms manifested a consistent increase in wordiness over time. These observations underscore a timely need to find ways to limit the verbosity of consent forms, particularly in those from pharmaceutical company trials.

Extending venous thromboembolism secondary prevention with apixaban in cancer patients: The EVE trial.

BACKGROUND: Cancer-associated venous thromboembolism (VTE) carries a high rate of recurrence and death. Guidelines recommend continued anticoagulation therapy as long as active cancer persists. Apixaban 2.5 mg twice daily is the FDA-approved dose for secondary prevention regardless of VTE causation. Whether this apixaban dose is appropriate for secondary VTE prevention in cancer patients is not clear. The rationale and design of this investigator initiated phase III, multicenter, randomized, double-blind, trial assessing apixaban 2.5 mg vs 5 mg twice daily for 12 months for the secondary VTE prevention in cancer patients (n = 370) who have completed 6 months (but no more than 12 months) of anticoagulation is provided (NCT03080883). METHODS/DESIGN: The primary study objective is to estimate differences in the combined rate of major plus clinically relevant non-major bleeding for apixaban 2.5 mg vs 5 mg twice daily. Secondary efficacy outcome is to assess rates of venous or arterial thromboembolism. Participating centers are chosen from the Academic and Community Cancer Research United (ACCRU) consortium. CONCLUSION: We anticipate these trial results to provide evidence supporting low-dose apixaban as a safe agent for secondary prevention of cancer-associated VTE for patients who have already completed 6-12 months of anticoagulation.

Impact of MYD88L265P mutation status on histological transformation of Waldenström Macroglobulinemia.

Histological transformation in Waldenström macroglobulinemia (WM) is an uncommon complication, with limited data, particularly regarding the impact of MYD88 L265P mutation on transformation. We examined risk factors and outcomes associated with transformation in WM, highlighting the role of MYD88 L265P mutation. Patients with WM seen at Mayo Clinic, Rochester, USA and University Hospital of Reims, France, between 01/01/1996 and December 31, 2017 were included; 50 (4.3%) of 1147 patients transformed to a high-grade lymphoma, with median time-to-transformation of 4.5 (range 0-21) years in the transformed cohort. The MYD88 L265P mutation status was known in 435/1147 (38%) patients (406 with non-transformed WM and 29 patients in transformed cohort). On multivariate analysis, MYD88 WT status alone was an independent predictor of transformation (odds ratio, 7[95%CI: 2.1-23]; P = .003). Additionally, the MYD88 WT status was independently associated with shorter time-to-transformation (HR 7.9 [95%CI: 2.3-27; P = .001]), with a 5-year transformation rate of 16% for MYD88 WT vs 2.8% with MYD88 L265P mutated patients. Patients with transformation demonstrated a significant increase in risk of death compared to patients who did not transform (HR 5.075; 95%CI: 3.8-6.8; P < .001). In conclusion, the MYD88 WT status is an independent predictor of transformation and associated with a shorter time-to-transformation. Additionally, transformation conferred an inferior overall survival in patients with WM.

A qualitative study of healthcare-related experiences of non-smoking women with lung cancer.

PURPOSE: Lung cancer in non-smoking women is a distinct entity, but few studies have examined these patients' healthcare-related experiences. METHODS: Women with lung cancer and with no smoking history underwent a face-to-face semi-structured, audio-recorded interview that was analyzed with a qualitative inductive approach. RESULTS: Twenty-three patients were interviewed, and three themes emerged. The first theme centered on a delay in cancer diagnosis. One patient described, "The whole initial diagnostic process just fills me with rage… I didn't actually get my Tarceva® until the last week in April." Second, the diagnosis of lung cancer seemed especially challenging in view of patients' non-smoking history and otherwise good health; these factors seem to have contributed to the diagnostic delay. One patient explained, "Well, I was just so adamant that I didn't like smoking… maybe if I had been a smoker, they [the healthcare providers] would've been more resourceful." Finally, the stigma of a smoking-induced malignancy was clearly articulated, "Yeah. Because it's a stigma, and I had read that, too -- people go, 'Well, it's your own damn fault because you were a smoker.'" CONCLUSIONS: Non-smoking women with lung cancer appear to endure a long trajectory from symptoms to cancer diagnosis to the initiation of cancer therapy. An awareness and acknowledgement of this long trajectory might help healthcare providers render more compassionate cancer care to these patients.

Scrambler therapy for chemotherapy neuropathy: a randomized phase II pilot trial.

INTRODUCTION: Chemotherapy-induced peripheral neuropathy (CIPN) is a prominent clinical problem, with limited effective therapies. Preliminary non-randomized clinical trial data support that Scrambler Therapy is helpful in this situation. METHODS: Patients were eligible if they had CIPN symptoms for at least 3 months and CIPN-related tingling or pain at least 4/10 in severity during the week prior to registration. They were randomized to receive Scrambler Therapy versus transcutaneous electrical nerve stimulation (TENS) for 2 weeks. Patient-reported outcomes (PROs) were utilized to measure efficacy and toxicity daily for 2 weeks during therapy and then weekly for 8 additional weeks. RESULTS: This study accrued 50 patients, 25 to each of the 2 study arms; 46 patients were evaluable. There were twice as many Scrambler-treated patients who had at least a 50% documented improvement during the 2 treatment weeks, from their baseline pain, tingling, and numbness scores, when compared with the TENS-treated patients (from 36 to 56% compared with 16-28% for each symptom). Global Impression of Change scores for "neuropathy symptoms," pain, and quality of life were similarly improved during the treatment weeks. Patients in the Scrambler group were more likely than those in the TENS group to recommend their treatment to other patients, during both the 2-week treatment period and the 8-week follow-up period (p < 0.0001). Minimal toxicity was observed. CONCLUSIONS: The results from this pilot trial were positive, supporting the conduct of further investigations regarding the use of Scrambler Therapy for treating CIPN.

Numbers Have Life: A Commentary on "Predictors of Survival in Patients with Advanced Gastrointestinal Malignancies Admitted to the Intensive Care Unit".

The commentary remarks on a recently published article on a study that examined predictors of poor outcomes in cancer patients using the SOFA score, answering to the question of whether the results of the study can completely inform decisions about terminal care management.

Age and the Risk of Paclitaxel-Induced Neuropathy in Women with Early-Stage Breast Cancer (Alliance A151411): Results from 1,881 Patients from Cancer and Leukemia Group B (CALGB) 40101.

PURPOSE: A few previous studies report a direct relationship between older age and chemotherapy-induced neuropathy. This study further evaluated this adverse event's age-based risk. METHODS: CALGB 40101 investigated adjuvant paclitaxel (80 mg/m2 once per week or 175 mg/m2 every 2 weeks) in patients with breast cancer and served as a platform for the current study that investigated age-based differences in neuropathy. Grade 2 or worse neuropathy, as per Common Terminology Criteria for Adverse Events version 4, was the primary endpoint; patients were assessed at baseline, every 6 months for 2 years, and then annually for 15 years. RESULTS: Among these 1,881 patients, 230 were 65 years of age or older, 556 were 55-64 years, and 1,095 were younger than 55; 1,226 neuropathy events (commonly grade 1 or 2) were reported in 65% of the cohort. The number of grade 2 or worse events was 63 (27%), 155 (28%), and 266 (24%) within respective age groups (p = .14). In univariate analysis, only motor neuropathy had a higher age-based incidence: 19 (8%), 43 (8%), and 60 (5%), respectively (p = .04); in multivariate analyses, this association was no longer statistically significant. Other endpoints, such as time to onset of neuropathy (time from trial enrollment to neuropathy development) and time to improvement (time from maximal grade sensory neuropathy to a one-category improvement), showed no statistically significant age-based differences. In contrast, obesity was associated with neuropathy, and every 2-week paclitaxel was associated with trends toward neuropathy. CONCLUSION: Although paclitaxel-induced neuropathy is common, older age is not an independent risk factor. Clinical trial identification number. NCT00041119 (CALGB 40101). IMPLICATIONS FOR PRACTICE: Age alone is not an independent risk factor for paclitaxel-induced neuropathy.

Older-Patient-Specific Cancer Trials: A Pooled Analysis of 2,277 Patients (A151715).

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.

Comparative Age-Based Prospective Multi-Institutional Observations of 12,367 Patients Enrolled to the American College of Surgeons Oncology Group (ACOSOG) Z901101 Trials (Alliance).

BACKGROUND: The risk of surgery, particularly for older cancer patients with serious, extensive comorbidities, can make this otherwise curative modality precarious. Leveraging data from the American College of Surgeons Oncology Group, this study sought to characterize age-based comparative demographics, adverse event rates, and study completion rates to define how best to conduct research in older cancer patients. METHODS: This study relied on clinical data from 21 completed studies to assess whether older patients experienced more grade 3 or worse adverse events and were more likely to discontinue study participation prematurely than their younger counterparts. RESULTS: The study enrolled 12,367 patients. The median age was 60 years, and 36% of the patients were 65 years of age or older. Among 4008 patients with adverse event data, 1067 (27%) had experienced a grade 3 or worse event. The patients 65 years or older had higher rates of grade 3 or worse adverse events compared to younger patients [32% vs. 24%; odds ratio (OR), 1.5; 95% confidence interval (CI), 1.3-1.7; p < 0.0001]. This association was not observed in multivariate analyses. The study protocol was completed by 97% of the patients. No association was observed between age and trial completion (OR 0.8; 95% CI 0.7-1.1; p = 0.14). Only the older gastrointestinal cancer trial patients were less likely to complete their studies compared to younger patients (OR 0.50; 95% CI 0.30-0.70; p < 0.0001). CONCLUSION: Despite higher rates of adverse events, the older patients typically completed the study protocol, thereby contributing relevant data on how best to render care to older cancer patients and affirming the important role of enrolling these patients to surgical trials.

Effect of Doxepin Mouthwash or Diphenhydramine-Lidocaine-Antacid Mouthwash vs Placebo on Radiotherapy-Related Oral Mucositis Pain: The Alliance A221304 Randomized Clinical Trial.

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.

Application of multi-state models in cancer clinical trials.

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 three-state 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.

Comparative "nocebo effects" in older patients enrolled in cancer therapeutic trials: Observations from a 446-patient cohort.

BACKGROUND: A nocebo is an inert substance associated with adverse events. Although previous studies have examined the positive (placebo) effects of such inert substances, few have examined negative (nocebo) adverse event profiles, particularly in older patients who have higher morbidity and can experience frequent and severe adverse events from cancer therapy. METHODS: This study focused on placebo/nocebo-exposed patients who participated in 2 double-blind, placebo-controlled, cancer therapeutic studies, namely, North Central Cancer Therapy Group trial NCCTG 97-24-51 and American College of Surgeons Oncology Group trial Z9001, with the goal of reporting the comparative, age-based adverse event rates, as reported during the conduct of these trials. RESULTS: Among the 446 patients who received only placebo/nocebo and who were the focus of the current report, 161 were aged ≥65 years at the time of respective trial entry, and 5234 adverse events occurred. Unadjusted adverse event rates did not differ significantly between patients aged ≥65 years and younger patients (rate ratio, 1.01; 99% confidence interval, 0.47-2.02), and the findings were similar findings for grade 2 or worse adverse events and for all symptom-driven adverse events (for example, pain, loss of appetite, anxiety). Adjustment for sex, ethnicity, baseline performance score, and individual trial resulted in no significant age-based differences in adverse event rates. Similar findings were observed with an age threshold of 70 years. CONCLUSIONS: Adverse events are equally common in older and younger cancer patients who are exposed to nocebo and thus require the same degree of clinical consideration regardless of age. Cancer 2017;123:4193-4198. © 2017 American Cancer Society.

Stem cell transplantation compared with melphalan plus dexamethasone in the treatment of immunoglobulin light-chain amyloidosis.

BACKGROUND: Autologous stem cell transplantation (SCT) is a common management strategy for select patients with immunoglobulin light-chain amyloidosis, but no trials have documented improved overall survival. METHODS: Eighty-nine patients with biopsy-proven immunoglobulin light-chain amyloidosis were allowed to select treatment with melphalan plus dexamethasone (n = 34) or SCT (n = 55); all patients were transplant eligible. Treatment preference resulted in imbalanced study arms. Patients who selected SCT were younger, more frequently had an Eastern Cooperative Oncology Group performance status score less than 2, had lower-stage amyloidosis, and had a lower incidence of cardiac amyloidosis. RESULTS: Patients receiving melphalan plus dexamethasone had a 3-year progression-free survival rate of 29.1% and an overall survival rate of 58.8%. Patients undergoing SCT had a 3-year progression-free survival rate of 51.7% and an overall survival rate of 83.6%. An attempt to match patients between the 2 arms in terms of risk produced 24 matched triplet sets (2 SCT patients for each melphalan-dexamethasone patient); there was no difference in hematologic response, but there was better survival after autologous SCT. A propensity score-matched analysis of the cohorts (melphalan plus dexamethasone vs SCT) showed an overall mortality hazard ratio of 2.56 (P < .01). CONCLUSIONS: Although the study had limitations, similar hematologic responses and improved survival were observed after SCT versus melphalan plus dexamethasone. Cancer 2016;122:2197-205. © 2016 American Cancer Society.