The evidence supporting this protocol comes from the randomised phase III trials RTOG 0617 and RTOG 9410.rr
Bradley et al. compared overall survival (OS) after standard vs high dose radiotherapy with concurrent chemotherapy.r The study had a two-by-two factorial design with patients randomised to 60Gy-standard dose (n=166), 74Gy-high dose (n=121), 60Gy with cetuximab (n=147), or 74Gy with cetuximab (n=110). All patients also received concurrent chemotherapy which consisted of 45 mg/m2 paclitaxel and carboplatin once a week with consolidation chemotherapy post concurrent therapy. The primary end point of the study was OS.
Median OS 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 1. Kaplan-Meier overall survival curves for radiation dose (A)
© Lancet Oncol 2015r
RTOG 9410 by Curran et al. compared sequential with concurrent chemoradiation for stage III NSCLC.r 610 patients were randomised between two concurrent regimens and one sequential group.
- Arm 1: sequential - cisplatin at 100 mg/m2 day 1 and 29, vinblastine at 5 mg/m2 weekly for 5 weeks with 63Gy once daily radiotherapy (1.8Gy x 25 fractions, then 2Gy x 9 fractions) starting at day 50.
- Arm 2: concurrent – same chemotherapy and same radiotherapy dose fractionation as arm 1 but with radiotherapy commencing on day 1.
- Arm 3: concurrent 2 – 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 69.6Gy radiotherapy delivered in 1.2Gy bi-daily fractions starting on day 1.
The primary end point was OS 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 compared with sequential treatment (arm 1: 10% [20 patients], 95% CI: 7%-15%, arm 2: 16% [31 patients], 95% CI: 11%-22%, p=0.046, 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
Figure 2: Five year survival results
© J Natl Cancer Inst 2011r
In the PACIFIC study, stage III NSCLC patients who did not have disease progression after two or more cycles of platinum based chemotherapy were randomised to receive durvalumab or placebo.r The median progression free survival was longer with consolidation durvalumab therapy (16.8 months [95% CI: 13.0-18.1] with durvalumab versus 5.6 months [95% CI: 4.6-7.8 with placebo [HR 0.52, 95% CI: 0.42 - 0.65; P<0.001); the 12-month progression-free survival rate was 55.9% versus 35.3%, and the 18-month progression-free survival rate was 44.2% versus 27.0%. Durvalumab also significantly prolonged OS, as compared with placebo (HR for death, 0.68; 99.73% CI: 0.47-0.997, P=0.0025). The 24-month OS rate was 66.3% (95% CI: 61.7-70.4) in the durvalumab group, as compared with 55.6% (95% CI: 48.9-61.8) in the placebo group.r