High Dose Hyperfractionated Thoracic Radiotherapy vs. Standard Dose for Limited Stage Small-Cell Lung Cancer: A Multicenter, Open-Label Randomized, Phase 3 Trial

Purpose/Objective(s)Limited stage small-cell lung cancer (LS-SCLC) is associated with poor prognosis. We aimed to assess the efficacy and safety of high-dose, hyperfractionated thoracic radiotherapy of 54 Gy in 30 fractions compared with standard dose (45 Gy in 30 fractions) as a first-line treatment for LS-SCLC.Materials/MethodsThe study was an open-label, randomized, phase 3 trial, done at 16 public hospitals in China. Key inclusion criteria were patients aged 18-70 years, with previously histologically or cytologically confirmed LS-SCLC, previously untreated or received 1-2 courses of intravenous cisplatin (75 mg/m²of body-surface area, on day 1 or divided into two days of each cycle) or carboplatin (area under the curve of 5 mg/mL per min, day 1 of each cycle)and intravenous etoposide (100 mg/m²of body-surface area, on days 1-3 of each cycle), and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.Eligible patients were randomly assigned (1:1) to receive volumetric-modulated arc radiotherapy (VMAT) of 45 Gy in 30 fractions or the simultaneous integrated boost VMAT (SIB-VMAT) of 54 Gy in 30 fractions to the primary lung tumor and lymph node metastases starting 0-42 days after the first chemotherapy course. Both groups of patients received thoracic radiotherapy twice per day and 10 fractions per week. Prophylactic cranial radiation (PCI, 25 Gy in 10 fractions) was implemented to patients with responsive disease. The primary endpoint was overall survival. Safety was analyzed in the as-treated population.ResultsBetween June 30, 2017, and April 6, 2021, 224 eligible patients were enrolled and randomly assigned to 54 Gy (n = 108) or 45 Gy (n = 116). Median follow-up for the primary analysis was 45 months (IQR 41-48). Median overall survival was significantly improved in the 54 Gy group (62.4 months) compared with the 45 Gy group (43.1 months; p = 0.001). Median progression-free survival was significantly improved in the 54 Gy group (30.5 months) compared with the 45 Gy group (16.7 months; p = 0.044). The most common grade 3-4 adverse events were neutropenia (30 [28%] of 108 patients in the 54 Gy group vs 27 [23%] of 116 patients in the 45 Gy group), neutropenic infections (6 [6%] vs 2 [2%]), thrombocytopenia (13 [12%] vs 12 [10%]), anemia (6 [6%] vs 4 [3%]), and esophagitis (1 [1%] vs 3 [3%]). Treatment-related serious adverse events occurred in 9 [8%] patients in the 54 Gy group and 16 [14%] patients in the 45 Gy group. There were one treatment-related deaths in 54 Gy group (myocardial infarction).ConclusionCompared with standard thoracic radiotherapy dose of 45 Gy, the high dose of 54 Gy improved overall survival and progression-free survival without increasing toxicities in patients with LS-SCLC, supporting twice-daily hyperfractionated thoracic radiotherapy of 54 Gy with concurrent chemotherapy is an alternative treatment option for LS-SCLC. This study is complete and registered with ClinicalTrials.gov, NCT03214003. Limited stage small-cell lung cancer (LS-SCLC) is associated with poor prognosis. We aimed to assess the efficacy and safety of high-dose, hyperfractionated thoracic radiotherapy of 54 Gy in 30 fractions compared with standard dose (45 Gy in 30 fractions) as a first-line treatment for LS-SCLC. The study was an open-label, randomized, phase 3 trial, done at 16 public hospitals in China. Key inclusion criteria were patients aged 18-70 years, with previously histologically or cytologically confirmed LS-SCLC, previously untreated or received 1-2 courses of intravenous cisplatin (75 mg/m²of body-surface area, on day 1 or divided into two days of each cycle) or carboplatin (area under the curve of 5 mg/mL per min, day 1 of each cycle)and intravenous etoposide (100 mg/m²of body-surface area, on days 1-3 of each cycle), and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.Eligible patients were randomly assigned (1:1) to receive volumetric-modulated arc radiotherapy (VMAT) of 45 Gy in 30 fractions or the simultaneous integrated boost VMAT (SIB-VMAT) of 54 Gy in 30 fractions to the primary lung tumor and lymph node metastases starting 0-42 days after the first chemotherapy course. Both groups of patients received thoracic radiotherapy twice per day and 10 fractions per week. Prophylactic cranial radiation (PCI, 25 Gy in 10 fractions) was implemented to patients with responsive disease. The primary endpoint was overall survival. Safety was analyzed in the as-treated population. Between June 30, 2017, and April 6, 2021, 224 eligible patients were enrolled and randomly assigned to 54 Gy (n = 108) or 45 Gy (n = 116). Median follow-up for the primary analysis was 45 months (IQR 41-48). Median overall survival was significantly improved in the 54 Gy group (62.4 months) compared with the 45 Gy group (43.1 months; p = 0.001). Median progression-free survival was significantly improved in the 54 Gy group (30.5 months) compared with the 45 Gy group (16.7 months; p = 0.044). The most common grade 3-4 adverse events were neutropenia (30 [28%] of 108 patients in the 54 Gy group vs 27 [23%] of 116 patients in the 45 Gy group), neutropenic infections (6 [6%] vs 2 [2%]), thrombocytopenia (13 [12%] vs 12 [10%]), anemia (6 [6%] vs 4 [3%]), and esophagitis (1 [1%] vs 3 [3%]). Treatment-related serious adverse events occurred in 9 [8%] patients in the 54 Gy group and 16 [14%] patients in the 45 Gy group. There were one treatment-related deaths in 54 Gy group (myocardial infarction). Compared with standard thoracic radiotherapy dose of 45 Gy, the high dose of 54 Gy improved overall survival and progression-free survival without increasing toxicities in patients with LS-SCLC, supporting twice-daily hyperfractionated thoracic radiotherapy of 54 Gy with concurrent chemotherapy is an alternative treatment option for LS-SCLC. This study is complete and registered with ClinicalTrials.gov, NCT03214003.