Prognostic Factors in Limited-Stage Small Cell Lung Cancer: A Secondary Analysis of CALGB 30610-RTOG 0538

Abstract

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.

Figure 1.. Participant Flow Diagram

Patients were registered and randomized at the same time. An Eastern Cooperative Oncology Group performance score (PS) of 2 indicates that the patient is ambulatory and capable of all self-care but unable to carry out any work activities and is up and about more than 50% of waking hours. BID-RT indicates twice-daily radio therapy (RT); PCI, prophylactic cranial irradiation; and QD-RT, once-daily RT.

Figure 2.. Multivariable Overall (OS) and Progression-Free Survival (PFS) Based on Multivariate Analysis of Patient Factors

Arm A received twice-daily radiotherapy (RT) to a total dose of 45 Gy; arm B, once-daily RT to a dose of 70 Gy (QD-RT). An Eastern Cooperative Oncology Group performance score of 0 indicates fully active, able to carry on all predisease performance without restriction; a score of 1 indicates restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature. HR indicates hazard ratio; IMRT, intensity-modulated RT; PCI, prophylactic cranial irradiation; and 3D-RT, 3-dimensional RT. ^aCalculated using type 3 likelihood ratio test. ^bCalculated using covariate Wald test.

Figure 3.. Overall Survival and Progression-Free Survival Among Patients Categorized by Treatment Arm and Age

Arm A received twice-daily radiotherapy to a total dose of 45 Gy; arm B, once-daily radiotherapy to a dose of 70 Gy. Plus signs represent censored patients. HR indicates hazard ratio; NE, nonestimable.