Thoracic Radiation Dose Fractionation Schedules for Limited-Stage Small Cell Lung Cancer: A Systematic Review and Network Meta-Analysis of Randomized Trials

Abstract

The Intergroup randomized controlled trial (RCT) established 45 Gy in 30 fractions (F) twice-daily (BID) as the standard thoracic radiation therapy (TRT) regimen with concurrent platinum-based chemotherapy (PBC) for limited-stage small cell lung cancer (LS-SCLC) in 1999. Since then, several RCTs were conducted to investigate novel TRT dose fractionation schedules (DoFS). However, it is unclear which is the optimal DoFS. This study aimed to compare the efficacy and safety of various DoFS of TRT in LS-SCLC using 45 Gy in 30F BID as the reference comparator. We searched biomedical databases for eligible RCTs comparing at least two DoFS of TRT in LS-SCLC. The outcomes of interest were progression-free survival (PFS), overall survival (OS), treatment-related death, grade 3-5 pneumonitis and esophagitis. We employed GRADE approach to appraise the certainty of the evidence. Meta-analyses were performed using fixed effects frequentist network model. The ESMO-Magnitude of Clinical Benefit Score (MCBS) version 1.1 was used to judge the value of the novel DoFS. This study was registered with PROSPERO (CRD42022336338). We identified six RCTs including 2,111 patients and six DoFS (45 Gy in 25F once-daily (OD), 42 Gy in 15F OD, 66 Gy in 33F OD, 60 Gy in 40F BID, 65 Gy in 26F OD and 70 Gy in 35F OD) that were compared with 45 Gy in 30F BID. There was high certainty evidence showing that 65 Gy in 26F OD (hazard ratio (HR), 0.67; 95% confidence interval (CI), 0.46-0.96) significantly improved PFS and 60 Gy in 40F BID (HR, 0.61; 95% CI, 0.41-0.91) significantly improved OS, compared to 45 Gy in 30F BID. There were no significant differences among the DoFS (42 Gy in 15F OD, 60 Gy in 40F BID, 65 Gy in 26F OD and 70 Gy in 35F OD) for PFS and OS. Both 65 Gy in 26F OD and 60 Gy in 40F BID were scored GRADE A on the ESMO-MCBS. The odds of grade 3-5 pneumonitis may be lower with 65 Gy in 26F OD (odds ratio (OR), 0.71; 95% CI, 0.12-4.32; low certainty) and higher with 60 Gy in 40F BID (OR, 6.60; 95% CI, 0.34-129.66); very low certainty). There were no significant differences among the DoFs (42 Gy in 15F OD, 66 Gy in 33F OD, 60 Gy in 40F BID, 65 Gy in 26F OD and 70 Gy in 35F OD) for treatment-related deaths or grade 3-5 esophagitis. There was no evidence to suggest that there were significant differences among the newer DoFS for PFS and OS with 45 Gy in 30F BID as the reference. Both 65 Gy in 26F OD and 60 Gy in 40F BID were judged to provide clinically meaningful benefit based on ESMO-MCBS. Treatment with 65 Gy in 26F OD may be an option if once-daily treatment is preferred. Treatment with 60 Gy in 40F BD may be considered for select patients with excellent performance status.