Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study

Abstract

Background: We aimed to compare overall survival after standard-dose versus high-dose conformal radiotherapy with concurrent chemotherapy and the addition of cetuximab to concurrent chemoradiation for patients with inoperable stage III non-small-cell lung cancer.

Methods: In this open-label randomised, two-by-two factorial phase 3 study in 185 institutions in the USA and Canada, we enrolled patients (aged ≥ 18 years) with unresectable stage III non-small-cell lung cancer, a Zubrod performance status of 0-1, adequate pulmonary function, and no evidence of supraclavicular or contralateral hilar adenopathy. We randomly assigned (1:1:1:1) patients to receive either 60 Gy (standard dose), 74 Gy (high dose), 60 Gy plus cetuximab, or 74 Gy plus cetuximab. All patients also received concurrent chemotherapy with 45 mg/m(2) paclitaxel and carboplatin once a week (AUC 2); 2 weeks after chemoradiation, two cycles of consolidation chemotherapy separated by 3 weeks were given consisting of paclitaxel (200 mg/m(2)) and carboplatin (AUC 6). Randomisation was done with permuted block randomisation methods, stratified by radiotherapy technique, Zubrod performance status, use of PET during staging, and histology; treatment group assignments were not masked. Radiation dose was prescribed to the planning target volume and was given in 2 Gy daily fractions with either intensity-modulated radiation therapy or three-dimensional conformal radiation therapy. The use of four-dimensional CT and image-guided radiation therapy were encouraged but not necessary. For patients assigned to receive cetuximab, 400 mg/m(2) cetuximab was given on day 1 followed by weekly doses of 250 mg/m(2), and was continued through consolidation therapy. The primary endpoint was overall survival. All analyses were done by modified intention-to-treat. The study is registered with ClinicalTrials.gov, number NCT00533949.

Findings: Between Nov 27, 2007, and Nov 22, 2011, 166 patients were randomly assigned to receive standard-dose chemoradiotherapy, 121 to high-dose chemoradiotherapy, 147 to standard-dose chemoradiotherapy and cetuximab, and 110 to high-dose chemoradiotherapy and cetuximab. Median follow-up for the radiotherapy comparison was 22.9 months (IQR 27.5-33.3). Median overall survival was 28.7 months (95% CI 24.1-36.9) for patients who received standard-dose radiotherapy and 20.3 months (17.7-25.0) for those who received high-dose radiotherapy (hazard ratio [HR] 1.38, 95% CI 1.09-1.76; p=0.004). Median follow-up for the cetuximab comparison was 21.3 months (IQR 23.5-29.8). Median overall survival in patients who received cetuximab was 25.0 months (95% CI 20.2-30.5) compared with 24.0 months (19.8-28.6) in those who did not (HR 1.07, 95% CI 0.84-1.35; p=0.29). Both the radiation-dose and cetuximab results crossed protocol-specified futility boundaries. We recorded no statistical differences in grade 3 or worse toxic effects between radiotherapy groups. By contrast, the use of cetuximab was associated with a higher rate of grade 3 or worse toxic effects (205 [86%] of 237 vs 160 [70%] of 228 patients; p<0.0001). There were more treatment-related deaths in the high-dose chemoradiotherapy and cetuximab groups (radiotherapy comparison: eight vs three patients; cetuximab comparison: ten vs five patients). There were no differences in severe pulmonary events between treatment groups. Severe oesophagitis was more common in patients who received high-dose chemoradiotherapy than in those who received standard-dose treatment (43 [21%] of 207 patients vs 16 [7%] of 217 patients; p<0.0001).

Interpretation: 74 Gy radiation given in 2 Gy fractions with concurrent chemotherapy was not better than 60 Gy plus concurrent chemotherapy for patients with stage III non-small-cell lung cancer, and might be potentially harmful. Addition of cetuximab to concurrent chemoradiation and consolidation treatment provided no benefit in overall survival for these patients.

Funding: National Cancer Institute and Bristol-Myers Squibb.

Conflict of interest statement

Declaration of interests

RP reports grants from National Cancer Institute, grants from Bristol-Myers Squibb, during the conduct of the study; GB reports personal fees and non-financial support from Bristol-Myers Squibb, during the conduct of the study, personal fees from Bayer Healthcare, Biothera Pharma, and Novartis Pharmaceuticals outside the submitted work; CH reports grants from Bristol-Myers Squibb (U10CA21661 U10CA37422) and funds for general study support (Bristol-Myers Squibb did not at any time have the right or were they permitted to effect underlying analysis or edit any portion of this manuscript); AM has a consultant or advisory role for Ventana Medical System, receives honoraria from Ventana Medical Systems and Genoptix, and received research funding from Roche and Ventana Medical Systems; HC has a consulting or advisory role for Bayer and EMD Serono, and receives research funding from Celgene (institution); JDB, RK, GM, SS, JBo, KF, VN, YIG, SN, PI, CR, RBW, CK, JM, JBe, RG, and WC declare no competing interests.

Copyright © 2015 Elsevier Ltd. All rights reserved.

Figures

Figure 1. Trial profile

The trial was initially opened only to the radiation dose groups. After the initial 30 patients were enrolled, the cetuximab groups were opened to accrual. After the 464th patient was enrolled, the 74 Gy and 74 Gy plus cetuximab groups were closed to accrual because the futility boundary relating to the radiation therapy endpoint had been crossed. We then continued to enrol to the 60 Gy and 60 Gy plus cetuximab groups. Thus the numbers of patients enrolled to the radiation therapy and cetuximab endpoints differ according to these three enrolment periods. CBC=complete blood count.

Figure 2. Kaplan-Meier overall survival curves for radiation dose (A) and the use of cetuximab (B)

(A) One-sided log-rank p=0·0042. (B) one-sided log-rank, p=0·2938.

Figure 3. Kaplan-Meier overall survival curves for patients with high EGFR expression (H score ≥200)

Two-sided log-rank, p=0·0325.