Sequential vs. concurrent chemoradiation for stage III non-small cell lung cancer: randomized phase III trial RTOG 9410

Abstract

Background: The combination of chemotherapy with thoracic radiotherapy (TRT) compared with TRT alone has been shown to confer a survival advantage for good performance status patients with stage III non-small cell lung cancer. However, it is not known whether sequential or concurrent delivery of these therapies is the optimal combination strategy.

Methods: A total of 610 patients were randomly assigned to two concurrent regimens and one sequential chemotherapy and TRT regimen in a three-arm phase III trial. The sequential arm included cisplatin at 100 mg/m2 on days 1 and 29 and vinblastine at 5 mg/m2 per week for 5 weeks with 63 Gy TRT delivered as once-daily fractions beginning on day 50. Arm 2 used the same chemotherapy regimen as arm 1 with 63 Gy TRT delivered as once-daily fractions beginning on day 1 [corrected]. Arm 3 used cisplatin at 50 mg/m2 on days 1, 8, 29, and 36 with oral etoposide at 50 mg twice daily for 10 weeks on days 1, 2, 5, and 6 with 69.6 Gy delivered as 1.2 Gy twice-daily fractions beginning on day 1. The primary endpoint was overall survival, and secondary endpoints included tumor response and time to tumor progression. Kaplan-Meier analyses were used to assess survival, and toxic effects were examined using the Wilcoxon rank sum test. All statistical tests were two-sided.

Results: Median survival times were 14.6, 17.0, and 15.6 months for arms 1-3, respectively. Five-year survival was statistically significantly higher for patients treated with the concurrent regimen with once-daily TRT compared with the sequential treatment (5-year survival: sequential, arm 1, 10% [20 patients], 95% confidence interval [CI] = 7% to 15%; concurrent, arm 2, 16% [31 patients], 95% CI = 11% to 22%, P = .046; concurrent, arm 3, 13% [22 patients], 95% CI = 9% to 18%). With a median follow-up time of 11 years, the rates of acute grade 3-5 nonhematologic toxic effects were higher with concurrent than sequential therapy, but late toxic effects were similar.

Conclusion: Concurrent delivery of cisplatin-based chemotherapy with TRT confers a long-term survival benefit compared with the sequential delivery of these therapies.

Figure 1

CONSORT diagram for Radiation Therapy Oncology Group (RTOG) 9410 clinical trial. RT = radiotherapy.

Figure 2

Flow diagram of treatment arms. Patients were stratified by Karnofsky performance status and stage before being randomly assigned to one of three treatment arms, a control arm of sequential chemotherapy followed by standard radiation and two experimental arms in which chemotherapy was delivered concurrently with radiation. fx = fraction; IV = intravenous; RT = Radiotherapy.

Figure 3

Five-year survival results for patients assigned to receive standard radiation with concurrent chemotherapy compared with patients assigned to receive sequential chemotherapy and radiotherapy. Hazard ratio for death = 0.812, 95% confidence interval = 0.663 to 0.996, P = .046, two-sided log-rank test. Total dead at any time: Arm 1 = 189 and Arm 2 = 185. Slash marks indicate censored observations.

Figure 4

Five-year survival results for patients assigned to receive standard radiation with concurrent chemotherapy (arm 2) compared with patients assigned to receive hyperfractionated radiation with concurrent chemotherapy (arm 3). Hazard ratio for death = 0.925, 95% confidence interval = 0.752 to 1.138, P = .46, two-sided log-rank test. Total dead at any time: Arm 2 = 185 and Arm 3 = 175. Slash marks indicate a censored observation.