Wang, Xiaofei

Importance The impact of patient-specific, disease-related, and social factors on outcomes in limited-stage small cell lung cancer (LS-SCLC) is not well defined. A post hoc secondary analysis of such factors from the Cancer and Leukemia Group B (CALGB) 30610–Radiation Therapy Oncology Group (RTOG) 0538 trial may impact future trial design. Objective To assess the comprehensive demographic, disease-related, treatment-related, and social factors for potential associations with survival outcomes and understand whether specific subpopulations may benefit from radiotherapy (RT) dose escalation in LS-SCLC. Design, Setting, and Participants This post hoc secondary analysis of a randomized clinical trial included 638 adults with LS-SCLC treated at 186 unique treatment sites with at least 1 accrual for all patients from March 15, 2008, to December 1, 2019; 313 patients were randomized to receive RT twice daily to a dosage of 45 Gy for 3 weeks and 325 to receive RT once daily to a dosage of 70 Gy for 7 weeks. Data were locked February 28, 2022, and analyzed from November 28, 2022, to June 4, 2024. Interventions Twice-daily RT or once-daily RT. Main Outcomes and Measures Multivariable Cox proportional hazards models evaluated the association of treatment groups and other risk factors with progression-free survival (PFS) and overall survival (OS). Patient-specific factors included age, sex, and Eastern Cooperative Oncology Group performance status. Disease-related factors included tumor, nodal, and overall cancer stages. Treatment-related factors included type of chemotherapy, timing of concurrent RT, RT technique, and prophylactic cranial irradiation. Social factors included marital status and treatment center accrual volume. Results Among 507 patients (260 [51.3%] female and 247 [48.7%] male; mean [SD] age, 62.6 [7.9] years) included in the multivariate survival analysis, with a median follow-up of 4.7 (IQR, 3.7-7.1) years, female sex was associated with improved OS (hazard ratio [HR], 0.73 [95% CI, 0.58-0.91]; P = .006), while being 70 years or older was associated with decreased OS (HR, 1.50 [95% CI, 1.14-1.98]; P = .004). Neither age nor sex was associated with PFS. When compared with those with N1 disease, OS and PFS were worse in patients with N2 (HRs, 1.64 [95% CI, 1.19-2.26]; P = .002 and 1.36 [95% CI, 1.02-1.81]; P = .04, respectively) and N3 (HRs, 2.03 [95% CI, 1.40-2.93]; P < .001 and 1.63 [95% CI, 1.17-2.26]; P = .004) disease. Compared with stage II cancer, OS was worse for stage IIIA (HR, 1.65 [95% CI, 1.17-2.31]; P = .004) and stage IIIB (HR, 1.94 [95% CI, 1.34-2.83]; P < .001). Compared with high-volume accrual centers, treatment at low- or middle-volume accrual centers was associated with worse PFS (HRs, 1.94 [95% CI, 1.33-2.82; P < .001] and 1.44 [95% CI, 1.15-1.82; P = .002], respectively) and worse OS (HRs, 1.55 [95% CI, 1.03-2.32; P = .03] and 1.33 [95% CI, 1.04-1.70; P = .02], respectively). Conclusions and Relevance This secondary analysis of the CALGB 30610–RTOG 0538 randomized clinical trial of patients with LS-SCLC found associations between female sex or being younger than 70 years and improved overall survival and between advanced nodal stage or treatment at low- or middle-volume accrual centers and worse outcomes. These findings suggest that stratification by nodal stage, clinical stage, and age should be considered in future randomized trials. Trial Registration ClinicalTrials.gov Identifier: NCT00632853

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical trial updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. Patients with early-stage non–small-cell lung cancer (NSCLC) who undergo curative surgical resection are at risk for developing second primary lung cancer (SPLC). Cancer and Leukemia Group B 140503 (Alliance) was a multicenter, international, randomized, phase III trial in patients with stage T1aN0 NSCLC (using the TNM staging system seventh edition) and demonstrated the noninferiority for disease-free survival between sublobar resection (SLR) and lobar resection (LR). After surgery, patients underwent computed tomography surveillance as defined by the protocol. The determination of a SPLC was done by the treating physician and recorded in the study database. We performed an analysis of the rate of SPLC (per patient per year) and the 5-year cumulative incidence in the study population and within the SLR and LR arms. Median follow-up was 7 years. The rate per patient per year in the study population, in the SLR arm, and in the LR arm was 3.4% (95% CI, 2.9 to 4.1), 3.8% (95% CI, 2.9 to 4.9), and 3.1% (95% CI, 2.4 to 4.1), respectively. The estimated 5-year cumulative incidence of SPLC in the study population, SLR arm, and LR arm was 15.9% (95% CI, 12.9 to 18.9), 17.2% (95% CI, 12.7 to 21.5), and 14.7% (95% CI, 10.6 to 18.7), respectively.

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

AbstractBackgroundEligibility criteria and endpoints for cancer cachexia trials—and whether weight loss should be included—remain controversial. Although most cachexia trials enrol patients after initial cancer diagnosis, few studies have addressed whether weight loss well after a cancer diagnosis is prognostic.MethodsWe pooled data from non‐small cell lung cancer patients from prospectively conducted trials within the Alliance for Clinical Trials in Oncology (1998–2008), a nationally funded infrastructure. We examined (i) weight data availability and weight changes and (ii) survival.ResultsA total of 822 patients were examined. Of these, 659 (80%) were on treatment at the beginning of Cycle 2 of chemotherapy; weight was available for 656 (80%). By Cycles 3 and 4, weight was available for 448 (55%) and 384 (47%), respectively. From baseline to immediately prior to Cycle 2, 208 (32%) gained weight; 225 (34%) lost <2% of baseline weight; and 223 (34% of 656) lost 2% or more. Median survival from the beginning of Cycle 2 was 13.0, 10.9, and 6.9 months for patients with weight gain, weight loss of <2%, and weight loss of 2% or more, respectively. In multivariate analyses, adjusted for age, sex, performance score, type of treatment, and body mass index, weight loss of 2% or more was associated with poor overall survival compared with weight gain [hazard ratio (HR) = 1.66; 95% confidence interval (CI): 1.33–2.07; P < 0.001] and compared with weight loss of <2% (HR = 1.57; 95% CI: 1.27–1.95; P < 0.001). Although weight loss of <2% was not associated with poorer overall survival compared with weight gain, it was associated with poorer progression‐free survival (HR = 1.24; 95% CI: 1.01–1.51; P = 0.036). Similar findings were observed in a separate 255‐patient validation cohort.ConclusionsWeight should be integrated into cancer cachexia trials because of its ease of frequent measurement and sustained prognostic association.

Background Platinum and etoposide with thoracic radiation followed by prophylactic cranial irradiation constitute the standard treatment for limited‐stage small cell lung cancer (LS‐SCLC). Many patients with LS‐SCLC are elderly with comorbidities. Methods Individual patient data were collected from 11 phase 2 or 3 trials for LS‐SCLC conducted by the National Clinical Trials Network and activated from 1990 to 2010. The primary endpoint was overall survival (OS); the secondary endpoints were progression‐free survival (PFS), the rate of severe adverse events, and off‐treatment reasons. The outcomes were compared for patients 70 years old or older (elderly patients) and patients younger than 70 years (younger patients). Results Individual patient data from 1049 younger patients (81%) and 254 elderly patients (19%) were analyzed. In the multivariate model, elderly patients, in comparison with younger patients, had worse OS (hazard ratio [HR], 1.38; 95% confidence interval [CI], 1.18‐1.63; median OS for elderly patients, 17.8 months; OS for younger patients, 23.5 months) and worse PFS (HR, 1.19; 95% CI, 1.03‐1.39; median PFS for elderly patients, 10.6 months; median PFS for younger patients, 12.3 months). Elderly patients, in comparison with younger patients, experienced more grade 5 adverse events (8% vs 3%; P < .01) and more grade 3 or higher dyspnea (11% vs 7%; P = .03) but less grade 3 or higher esophagitis/dysphagia (14% vs 19%; P = .04) and less grade 3 or higher vomiting (11% vs 17%; P = .01). Elderly patients completed treatment less often, discontinued treatment because of adverse events and patient refusal more frequently, and died during treatment more frequently. Conclusions Elderly patients with LS‐SCLC have worse PFS and OS and more difficulty in tolerating therapy. Future trials should incorporate assessments of elderly patients, novel monitoring of adverse events, and more tolerable radiation and systemic therapies.

Abstract Purpose The aim of this study was to investigate whether progression-free survival (PFS) can be considered a surrogate endpoint for overall survival (OS) in malignant mesothelioma. Materials and Methods Individual data were collected from 15 Cancer and Leukemia Group B (615 patients) and 2 North Central Cancer Treatment Group (101 patients) phase II trials. The effects of 5 risk factors for OS and PFS, including age, histology, performance status (PS), white blood cell count, and European Organisation for Research and Treatment of Cancer (EORTC) risk score, were used in the analysis. Individual-level surrogacy was assessed by Kendall’s tau through a Clayton bivariate Copula survival (CBCS) model. Summary-level surrogacy was evaluated via the association between logarithms of the hazard ratio (log HR)—log HROS and log HRPFS—measured in R2 from a weighted least-square (WLS) regression model and the CBCS model. Results The median PFS for all patients was 3.0 months (95% confidence interval [CI], 2.8–3.5 months) and the median OS was 7.2 months (95% CI, 6.5–8.0 months). Moderate correlations between PFS and OS were observed across all risk factors at the individual level, with Kendall’s tau ranging from 0.46 to 0.47. The summary-level surrogacy varied among risk factors. The Copula R2 ranged from 0.51 for PS to 0.78 for histology. The WLS R2 ranged from 0.26 for EORTC and PS to 0.67 for age. Conclusions The analyses demonstrated low to moderate individual-level surrogacy between PFS and OS. At the summary level, the surrogacy between PFS and OS varied significantly across different risk factors. With a short postprogression survival and a moderate correlation between PFS and OS, there is no evidence that PFS is a valid surrogate endpoint for OS in malignant mesothelioma.