In a phase II trial reported in The Lancet Oncology, Grønberg et al found that use of high-dose vs standard-dose twice daily thoracic radiotherapy as part of first-line chemoradiotherapy was associated with significantly improved overall survival and similar toxicity in patients with limited-stage small cell lung cancer.

Study Details

In the open-label trial, 170 treatment-naive patients from sites in Norway, Denmark, and Sweden were randomly assigned between July 2014 and June 2018 to receive twice daily radiotherapy at 60 Gy in 40 fractions (n = 89) or 45 Gy in 30 fractions (n = 81) given in 10 fractions per week. All patients received four courses of cisplatin at 75 mg/m² or carboplatin at AUC 5–6 mg/mL × min on day 1 and etoposide at 100 mg/m² on days 1 to 3 every 3 weeks.

Radiotherapy was delivered to the primary lung tumor and positron-emission tomography/computed tomography–positive lymph node metastases starting 20 to 28 days after the first chemotherapy course. Patients with a response were offered prophylactic cranial irradiation at 25 to 30 Gy.

The primary endpoint was 2-year overall survival, assessed after all patients had been followed for a minimum of 2 years. The trial is ongoing.

Overall Survival

Median follow-up for the primary analysis was 49 months (interquartile range = 38–56 months). Overall, 85% of patients in each group received prophylactic cranial irradiation.

At 2 years, 66 patients (74.2%, 95% confidence interval [CI] = 63.8%–82.9%) in the 60-Gy group were alive vs 39 patients (48.1%, 95% CI = 36.9%–59.5%) in the 45-Gy group (odds ratio [OR] = 3.09, 95% CI = 1.62–5.89, P = .0005).

Median overall survival was 37.2 months (95% CI = 28.4–46.1 months) vs 22.6 months (95% CI = 17.1–28.1 months, hazard ratio [HR] = 0.61, 95% CI = 0.41–0.90, P = .012). Median progression-free survival was 18.6 months (95% CI = 7.3–30.0 months) vs 10.9 months (95% CI = 8.7–13.1 months, HR = 0.75, 95% CI = 0.52–1.09, P = .13). In a post hoc analysis, median time from progression to death was 14.0 months (95% CI = 9.5–18.6 months) vs 8.2 months (95% CI = 7.3–9.0 months, P = .0009).

Objective response was observed in 77.5% vs 76.5% of patients (P = .88), with complete response in 18.0% vs 21.0%. A total of 21% vs 35% of patients had relapse within the radiotherapy field (P = .054). In post hoc analysis, distant metastases occurred in 42% vs 46% of patients (P = .59). 

Toxicity

The most common grade 3 to 4 adverse events in the 60-Gy vs 45-Gy groups were neutropenia (81% vs 81%, P = .25), neutropenic infections (27% vs 39%, P = .30), thrombocytopenia (24% vs 25%, P = .96), anemia (16% vs 20%, P = .85), and esophagitis (21% vs 18%, P = .83). Totals of 55 serious adverse events were observed in 38 patients in the 60-Gy group vs 56 in 44 patients in the 45-Gy group. Treatment-related death occurred in three patients in the 60-Gy group (due to neutropenic fever, aortic dissection, and pneumonitis) and in three patients in the 45-Gy group (due to thrombocytopenic bleeding, cerebral infarction, and myocardial infarction).

The investigators concluded, “The higher radiotherapy dose of 60 Gy resulted in a substantial survival improvement compared with 45 Gy, without increased toxicity, suggesting that twice-daily thoracic radiotherapy of 60 Gy is an alternative to existing schedules.”

Bjørn Henning Grønberg, MD, of the Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by the Norwegian Cancer Society; Liaison Committee for Education, Research and Innovation in Central Norway; Nordic Cancer Union; and Norwegian University of Science and Technology. For full disclosures of the study authors, visit thelancet.com.