Twice-daily thoracic radiotherapy of 45 Gy in 30 fractions was so far considered the most effective regimen
In a phase II trial recently published in The Lancet Oncology, it was observed that the use of high-dose versus standard-dose 2x/day thoracic radiotherapy as part of treatment involving chemoradiotherapy at 1a line was associated with significantly better overall survival, in addition to similar toxicity rates in patients with limited stage small cell lung cancer (SCLC).
In the open clinical trial, 170 treatment-naive patients from sites in Norway, Denmark and Sweden were randomly assigned between July 2014 and June 2018 to receive radiotherapy twice a day at 60 Gy in 40 fractions (n = 89) or 45 Gy in 30 fractions (n = 81), with administration of ten fractions per week. All patients received four cycles of cisplatin 75 mg/m² or carboplatin AUC 5-6 mg/mL×min on day 1 and etoposide 100 mg/m² on days 1 to 3 every three weeks.
Radiotherapy was administered in the primary tumor and lymph node metastases identified in PET-CT, starting after 20 to 28 days of the first course of chemotherapy. Patients with response received prophylactic cranial radiotherapy of 25 to 30 Gy.
The primary endpoint was overall survival at two years, assessed after all patients were followed up for this minimum period. The study is still ongoing.
The average follow-up for primary analysis was 49 months. In total, 85% of the patients in each group received prophylactic cranial radiotherapy.
After two years, 66 patients (74.2%) in the 60 Gy group were alive versus 39 patients (48.1%) in the 45 Gy group (OR = 3.09; CI 95% = 1.62-5.89; P = 0.0005). Median overall survival was 37.2 versus 22.6 months (HR = 0.61; CI 95% = 0.41–0.90; P = 0.012).
Median progression-free survival was 18.6 versus 10.9 months (HR = 0.75; CI 95% = 0.52–1.09; P = 0.13). In a post hoc analysis, the median time from progression to death was 14.0 versus 8.2 months (P = 0.0009).
Objective response was observed in 77.5% versus 76.5% of patients (P = 0.88), with complete response in 18.0% versus 21.0%. A total of 21% versus 35% patients relapsed in the radiotherapy field (P = 0.054). In the post hoc analysis, distant metastases occurred in 42% versus 46% of patients (P = 0.59).
The most common grade three to four adverse events in the 60 Gy versus 45 Gy groups were neutropenia (81% vs 81%, P = 0.25), neutropenic infections (27% vs 39%, P = 0.30), thrombocytopenia (24% vs 25%, P = 0.96), anemia (16% vs 20%, P = 0.85) and esophagitis (21% vs 18%, P = 0.83). A total of 55 severe adverse events were observed in 38 patients in the 60 Gy group versus 56 events in 44 individuals in the 45 Gy group. Treatment-related death occurred in three patients in the 60 Gy group (due to febrile neutropenia, aortic dissection, and pneumonitis) and in three patients in the 45 Gy group (bleeding from thrombocytopenia, stroke, and myocardial infarction).
The researchers concluded that the higher dose of radiotherapy led to survival gain compared to 45 Gy, with no increase in toxicity, suggesting that twice-daily 60 Gy thoracic radiotherapy is an alternative to existing regimens.