Le-Rademacher, Jennifer G

PURPOSE Patients with breast cancer requiring postmastectomy radiation therapy (PMRT) often desire breast reconstruction. Reconstructions can be adversely affected by PMRT, and fear of reconstruction complications has discouraged adoption of short-course radiation therapy used after lumpectomy. To fill the evidence gap, we conducted a noninferiority trial of hypofractionated versus conventional PMRT in patients undergoing breast reconstruction. The primary outcome was reconstruction complication rate, a composite of wound healing, readmission, capsular contracture, unplanned reoperation, and reconstruction failure. METHODS Women with unilateral invasive breast cancer with planned immediate or delayed reconstruction and PMRT were randomly assigned (1:1) to 50 Gy (25 fractions/5 weeks) or 42.56 Gy (16 fractions/3 weeks). This study was designed with a noninferiority margin of 10%, assuming a 2-year reconstruction complication rate of 25% with conventional PMRT. Randomization was stratified by immediate versus delayed and autologous versus implant-only reconstruction. RESULTS Between 2018 and 2021, 898 patients enrolled with a median follow-up of 3.9 years; 825 patients were evaluable for the primary end point. The 24-month reconstruction complication rates were 12.3% (52/422) with hypofractionated PMRT and 10.2% (41/403) with conventional PMRT, corresponding to an estimated difference of -2.1% (95% CI, -6.5 to 2.2). The complication rate was higher (regardless of arm) with implant-only versus autologous reconstruction (odds ratio = 1.65). There was no statistically significant difference in 36-month locoregional recurrence rates: 1.5% (95% CI, 0.7 to 3.2) with hypofractionated and 2.2% (95% CI, 1.1 to 4.3) with conventional PMRT. Acute and late toxicity rates were not statistically different. CONCLUSION A 16-fraction course of hypofractionated PMRT is safe and noninferior to conventional PMRT in women undergoing breast reconstruction after mastectomy.

Abstract Background Older adults remain underrepresented in prospective trials of immunotherapy for advanced lung cancer. To estimate pembrolizumab adverse events, we conducted a multicenter, nonrandomized, open-label phase 2 trial of oncologist-choice first-line pembrolizumab with or without chemotherapy for older adults with advanced lung adenocarcinoma. Methods Alliance for Clinical Trials in Oncology A171901 enrolled patients aged 70 years and older with stage IV or recurrent lung adenocarcinoma starting oncologist’s choice of first-line pembrolizumab with or without carboplatin and pemetrexed. The primary endpoint was the proportion of patients experiencing a solicited grade 3 or greater adverse event within 6 months. Secondary endpoints included overall survival, quality of life, and association of a geriatric assessment toxicity risk score with severe adverse events. Results Among 95 evaluable patients, 43 (45.3%) received pembrolizumab and 52 (54.7%) received pembrolizumab plus chemotherapy. Median age was 77 years (range = 70-92 years); 11.6% had an E Performance Status of 2 or higher. During 6 months of treatment, 25.6% (95% CI = 13.5% to 41.2%) experienced a solicited grade 3 or greater adverse event in the monotherapy group and 42.3% (95% CI = 28.7% to 56.8%) in the combination group. Median overall survival was 16.4 months (95% CI = 10.1 to not estimable) with monotherapy and 29.9 months (95% CI = 16.4 to not estimable) with combination therapy. Quality of life worsened during treatment. The geriatric assessment toxicity risk score was not associated with severe adverse events with pembrolizumab with or without chemotherapy. Conclusions Older adults with advanced lung adenocarcinoma receiving pembrolizumab with or without chemotherapy had comparable adverse event rates to those in prior registration trials that excluded medically frail patients. These findings can inform shared decision making and support inclusion of older adults in future trials. Clinical Trial NCT04533451 (https://clinicaltrials.gov/study/NCT04533451)

Background/Objectives. Decades of research have failed to uncover effective approaches to prevent chemotherapy-induced peripheral neuropathy (CIPN), a common side effect of neurotoxic chemotherapy. Increased interest in placebo response as a potentially under-recognized confounder in CIPN trials was recently sparked by the results of a multisite NCI-funded phase II-III CIPN prevention study of duloxetine, a promising serotonin–norepinephrine reuptake inhibitor that enhances pain-inhibitory mechanisms within the central nervous system. Study findings revealed high and nearly equivalent response rates in three randomized treatment groups—little to no CIPN was reported by 65.2%, 66.0%, and 68.0% of study participants who received duloxetine 30 mg, 60 mg, or placebo treatment, respectively. Methods. We performed a meta-analysis of placebo response rates from seven randomized, double-blinded, placebo-controlled trials conducted over the past 20 years and comprising 191 placebo participants that were specifically testing interventions for oxaliplatin- and paclitaxel-induced peripheral neuropathy and that serially collected patient responses on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Chemotherapy-Induced Neuropathy questionnaire. Additionally, we sought to identify trial- and patient-specific factors that predicted higher placebo response rates from a participant-level pooled analysis. Results. The placebo response rate was 10.0% [95% CI: 5.8%, 16.6%] when response was defined more conservatively as patients reporting no neuropathy at all. When the placebo response was defined more broadly based on patients reporting no or a little neuropathy, the placebo response rate was higher (39.6% [95% CI: 27.4%, 53.2%]). Male participants, receipt of oxaliplatin, and a 2:1 randomization ratio favoring the intervention arm were individually associated with a higher placebo response. Conclusions. High placebo response rates can threaten scientific progress toward identifying effective treatments for cancer treatment-associated side effects, like CIPN. Careful attention to study design factors, participant eligibility, and patient and research staff expectations may help to minimize placebo response rates in future CIPN intervention studies.

PURPOSE This national study was undertaken to determine screening mammography rates among transgender and gender diverse (TGD) individuals. METHODS TGD individuals and cisgender women who qualified to receive screening mammography based on American College of Radiology guidelines were identified in the longitudinal OptumLabs Data Warehouse. The primary end point was the percentage of patients who had high rates of screening (>75% recommended screenings). Multivariable analyses were conducted in a matched population of transgender men to cisgender women to identify and adjust for factors associated with high adherence. Individuals were matched at a 1:4 ratio (transgender men: cisgender women) on age, race/ethnicity, year of enrollment in their health care plan, and duration of follow-up. RESULTS This study focused on 10,478 TGD individuals (3,778 transgender men; 1,294 transgender women; 5,406 with gender dysphoria not meeting other TGD criteria, NMOT) and 6,218,369 cisgender women. For transgender men, transgender women, individuals with gender dysphoria NMOT, and cisgender women, high mammography rates were observed in 41.1% (95% CI, 39.5 to 42.6), 7.4% (95% CI, 6.0 to 8.8), 11.9% (95% CI, 11.0 to 12.7), and 38.3% (95% CI, 38.3 to 38.4), respectively ( P < .0001). When transgender men were compared with 15,112 matched cisgender women, an age-based differential association was observed between sex and high mammography rates (interaction P = .0003); compared with cisgender women, transgender men appeared more likely to manifest high rates of screening at age 40-49 years (odds ratios [ORs], 1.38 [95% CI, 1.28 to 1.50]; P < .0001) and 50-59 years (OR, 1.57 [95% CI, 1.35 to 1.81]; P < .0001) but not in the older age groups. CONCLUSION The relatively high rates of screening mammography in cisgender women and transgender men suggest clinicians are offering mammography to individuals who are at average or high breast cancer risk, as compared with cisgender women, and not to transgender women at low risk.

Background/Objectives: Results from a well-designed trial provide evidence to support approval of truly effective treatments or discontinuation of ineffective treatments. However, the information available at the time of trial design may be limited which may lead to underpowered trials. This work aims to evaluate the impact of design assumption misspecifications on the statistical power of randomized trials with survival outcomes. Methods: The impact of the design assumption misspecifications on statistical power of four different statistical methods was investigated in a simulation study. The methods include the log-rank test, MaxCombo test, the test of difference in survival probability, and test of difference in restricted mean survival time (RMST). The deviations considered include the survival rate in the control arm, the expected treatment effect in terms of magnitude and pattern, accrual rate, and drop-out rate. Results: Deviations in the control arm’s survival distribution have no impact on the power of the log-rank and MaxCombo tests but it affects the trial duration since trials designed with these tests require the total number of events to be met before the final analysis can be conducted. Misspecified treatment effect has similar effect on the statistical power of all four methods. When the proportional hazards assumption is misspecified, the RMST is more robust with a larger early treatment effect, while the survival probability and the MaxCombo tests are more robust with a larger late treatment effect and crossing hazards. Conclusions: Selecting the appropriate statistical tests to design a trial depends on the goal of the trial, the mechanism of action of the experimental treatment, the survival quantity of clinical interest, and the pattern of the expected treatment effect. The final design should be based on assumptions that are as accurate as possible, and the potential impacts of deviations from these assumptions on the trial’s statistical power should be carefully considered.

PURPOSE Patients with Waldenström macroglobulinemia (WM) have disparate outcomes. Newer therapies have emerged since the development of International Prognostic Scoring System, and MYD88 L265P mutation is now frequently assessed at diagnosis, warranting reexamination of the prognostic parameters. PATIENTS AND METHODS We reviewed records of 889 treatment-naïve patients with active WM, consecutively seen between January 01, 1996, and December 31, 2017, to identify clinical predictors of overall survival (OS) in univariate analyses. Patients with complete data for the parameters significant on the univariate analyses (n = 341) were included in a multivariable analysis to derive a prognostic model, subsequently validated in a multi-institutional cohort. RESULTS In the derivation cohort (n = 341), age (hazard ratio [HR], 1.9 [95% CI, 1.2 to 2.1]; P = .0009), serum lactate dehydrogenase (LDH) above upper limit of normal (HR, 2.3 [95% CI, 1.3 to 4.5]; P = .007), and serum albumin <3.5 g/dL (HR, 1.5 [95% CI, 0.99 to 2.3]; P = .056) were independently prognostic. By assigning a score of 1 point each to albumin <3.5 g/dL (HR, 1.5) and age 66-75 years (HR 1.4) and 2 points for age >75 years (HR, 2.6) or elevated LDH (HR, 2.3), four groups with distinct outcomes were observed on the basis of the composite scores. Five-year OS was 93% for the low-risk (score 0), 82% for low-intermediate risk (score 1), 69% for intermediate-risk (score 2), and 55% for the high-risk (score ≥3; P < .0001) groups. In the validation cohort (N = 335), the model maintained its prognostic value, with a 5-year OS of 93%, 90%, 75%, and 57% for the four groups, respectively ( P < .0001). CONCLUSION Modified Staging System for WM (MSS-WM), utilizing age, albumin, and LDH is a simple, clinically useful, and externally validated prognostic model that reliably risk-stratifies patients with symptomatic WM into four groups with distinct prognosis.

Background: Knowing the predictive factors of the variation in a center-level continuous outcome of interest is valuable in the design and analysis of parallel-arm cluster randomized trials. The symbolic two-step method for sample size planning that we present incorporates this knowledge while simultaneously accounting for patient-level characteristics. Our approach is illustrated through application to cluster randomized trials in cancer care delivery research. The required number of centers (clusters) depends on the between- and within-center variance; the within-center variance is a function of estimates obtained by regressing the log within-center variance on predictive factors. Obtaining accurate estimates of the components needed to characterize the within-center variation is challenging. Methods: Using our previously derived sample size formula, our objective in the current research is to directly account for the imprecision in these estimates, using a Bayesian approach, to safeguard against designing an underpowered study when using the symbolic two-step method. Using estimates of the required components, including the number of centers that contribute to those estimates, we make formal allowance for the imprecision in these estimates on which a sample size will be based. Results: The mean of the distribution for power is consistently smaller than the single point estimate that the sample size formula yields. The reduction in power is more pronounced in the presence of increased uncertainty about the estimates with the reduction becoming more attenuated with increased numbers of centers that contribute to the estimates. Conclusions: Accounting for imprecision in the estimates of the components required for sample size estimation using the symbolic two-step method in the design of a cluster randomized trial yields conservative estimates of power.

PURPOSE: Clinical trials are important for managing older patients with AML. We investigated differences in outcomes of older patients with AML on the basis of whether patients participated in intensive chemotherapy trials at community versus academic cancer centers. METHODS: We used data from the Alliance for Clinical Trials in Oncology phase III trials that enrolled patients age ≥ 60 years with newly diagnosed AML between 1998 and 2002 in the Cancer and Leukemia Group B (CALGB) 9720 trial and between 2004 and 2006 in the CALGB 10201 trial. Centers funded by the NCI Community Oncology Research Program were identified as community cancer centers; others were designated as academic cancer centers. Logistic regression models and Cox proportional hazards models were used to compare 1-month mortality and overall survival (OS) by center type. RESULTS: Seventeen percent of the 1,170 patients were enrolled in clinical trials in community cancer centers. The study results demonstrated comparable rates of grade ≥3 adverse events (97% v 93%), 1-month mortality (19.1% v 16.1%), and OS (43.9% v 35.7% at 1 year) between community versus academic cancer centers, respectively. After adjusting for covariates, 1-month mortality (odds ratio, 1.40; 95% CI, 0.92 to 2.12; P = .11) and OS (hazard ratio, 1.04; 95% CI, 0.88 to 1.22; P = .67) were not statistically different among patients treated in community versus academic cancer centers. CONCLUSION: An older patient population, who have complex health care needs, can be successfully treated on intensive chemotherapy trials in select community cancer centers with outcomes comparable with that achieved at academic cancer centers.

AbstractBackgroundRisk‐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.MethodsThe 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.ResultsThe 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.ConclusionsThis 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.