ArticlesStandard-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
Introduction
The commonly accepted radiation therapy dose (60–63 Gy in 1·8–2·0 Gy fraction sizes) for patients with stage III non-small-cell lung cancer was established by the Radiation Therapy Oncology Group (RTOG) 7301 trial and has remained unchanged for more than 30 years.1 With the idea that increasing radiation dose would improve both local-regional control and overall survival, the RTOG and other investigators did separate prospective phase 1 and 2 trials to establish the safety and efficacy of increasing the total radiation dose in the setting of concurrent chemotherapy while reducing irradiated volumes by use of image guidance and either three-dimensional conformal or intensity-modulated radiation therapy for locally advanced non-small-cell lung cancer.2, 3, 4, 5, 6, 7 Findings from these trials were similar, showing that a maximum tumour dose of 74 Gy given with concurrent weekly paclitaxel and carboplatin was safe and resulted in a median overall survival of roughly 24 months3, 4, 5, 6 versus a median overall survival of around 17·1 months in patients given a 60 Gy dose in RTOG 9410.8
Our trial (RTOG 0617) was designed to establish whether a 74 Gy dose was better than a 60 Gy dose and whether adding cetuximab to concurrent chemoradiation would confer an overall survival benefit. Cetuximab is a chimerised antibody of the immunoglobulin G1 subclass that blocks binding of EGF and TGF α to EGFR.9 The use of cetuximab in this setting was tested in RTOG 0324, a phase 2 study combining chemoradiation with cetuximab in patients with unresectable stage III non-small-cell lung cancer.10 The trial enrolled 93 patients, showed a median survival of 22·7 months, and 24-month overall survival of 49·3%. On the basis of these encouraging data, we investigated cetuximab in this trial.
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Study design and participants
In this randomised phase 3 study, we recruited patients aged 18 years and older with stage IIIA/IIIB non-small cell-lung cancer from 185 institutions in the USA and Canada. Eligibility criteria included having stage IIIA or IIIB non-small-cell lung cancer, no previous invasive cancer during the previous 3 years, Zubrod performance status score of 0–1, less than 10% weight loss (in the month before study entry), and pulmonary function (before or after bronchodilation) of 1·2 L per s or higher.
Results
Between Nov 27, 2007, and Nov 22, 2011, the trial accrued 544 patients from 185 institutions (hospital and outpatient centres; median two per institution, range 1–18), 464 while the radiotherapy dose randomisation was still in effect, and 514 while the cetuximab randomisation was in effect. The radiotherapy randomisation was closed early because of futility, but the cetuximab randomisation met targeted accrual goals. This report includes all data reported as of Oct 24, 2013; median follow-up
Discussion
We noted two major findings in this study: increasing radiation therapy dose to 74 Gy with 2 Gy per fraction did not improve overall survival and might be potentially harmful, and the addition of concurrent cetuximab, an anti-EGFR antibody, did not improve overall survival. However, use of standard-dose (60 Gy) radiation therapy with concurrent weekly carboplatin and paclitaxel, followed by consolidation chemotherapy with these drugs, resulted in a median overall survival of 28·7 months and 116
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