The evidence supporting this protocol comes from the randomized phase III trials RTOG 0617r and RTOG 9410.r
Bradley et alr compared overall survival after standard vs high dose radiotherapy with concurrent chemotherapy. The study was a two-by-two factorial design with patients randomized to 60Gy-standard dose (n=166), 74Gy-high dose (n=121), 60Gy with cetuximab (n=147), or 74Gy with cetuximab (n=110). The concurrent chemotherapy consisted of 45mg/m2 paclitaxel and carboplatin once a week with consolidation chemotherapy post concurrent therapy. The primary end point of the study was overall survival.
Median overall survival was 28.7 months (95% CI, 24.1-36.9) for patients that received standard dose radiotherapy and 20.3 months (95% CI, 17.7-25.0) for patients that received high dose radiotherapy (HR 1.38, 95% CI, 1.09-1.76; p=0.004). Median overall survival in patients who received cetuximab was 25.0 months (95% CI, 20.2-30.5) compared with 24.0 months (95% CI, 19.8-28.6) in those who did not (HR 1.07, 95% CI, 0.84-1.35; p=0.29). There was no statistically significant difference in grade 3 or higher toxicities between the radiotherapy groups. A higher rate of grade 3 or worse toxicity was associated with the use of cetuximab.
Increasing the radiotherapy dose to 74Gy did not improve overall survival and may be potentially harmful. The addition of concurrent cetuximab also provided no benefit in terms of overall survival.r
Figure 2. Kaplan-Meier overall survival curves for radiation dose (A)
Bradley et al, 2015r
RTOG 9410 by Curran et alr compared sequential with concurrent chemoradiation for stage III NSCLC. 610 patients were randomized between two concurrent regimens and one sequential group.
- Arm 1: sequential - cisplatin at 100mg/m2 day 1 and 29, vinblastine at 5mg/m2 weekly for 5 weeks with 60Gy radiotherapy starting at day 50.
- Arm 2: concurrent – same chemotherapy as arm 1 but with once daily radiotherapy commencing on day 1.
- Arm 3: concurrent 2 – cisplatin at 50mg/m2 on days 1, 8, 29, and 36 with oral etoposide at 50mg twice daily for 10 weeks on days 1, 2, 5 and 6 with 69.6Gy radiotherapy delivered in 1.2Gy bi-daily fractions starting on day 1.
The primary end point was overall survival with tumour response and tumour progression as secondary end points. Median survival times were 14.6, 17.0 and 15.6 months for arms 1-3 respectively. Survival at 5 years was statistically significantly higher for patients that received the concurrent regimen with once daily radiotherapy (arm 1: 10% [20 patients] 95% CI: 7%-15%, arm 2: 16% [31 patients] 95%CI: 11%-22%, p=0.46, arm 3: 13% [22 patients] 95%CI: 9%-18%). With a median follow up time of 11 years, rates of acute grade 3-5 non-haematologic toxicity were higher in the concurrent arms of the study however, late toxic effects were similar.r
Curran et al. 2011r