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

doi:10.1016/S1470-2045(14)71207-0

The Lancet Oncology

Volume 16, Issue 2, February 2015, Pages 187-199

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Summary

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/m² 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/m²) 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/m² cetuximab was given on day 1 followed by weekly doses of 250 mg/m², 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.

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.

Section snippets

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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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

Summary

Background

Methods

Findings

Interpretation

Funding

Introduction

Section snippets

Study design and participants

Results

Discussion

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

J Thorac Oncol

Int J Radiat Oncol Biol Phys

Cancer Cell

J Chronic Dis

Lancet Oncol

Control Clin Trials

A prospective randomized study of various irradiation doses and fractionation schedules in the treatment of inoperable non-oat-cell carcinoma of the lung. Preliminary report by the Radiation Therapy Oncology Group

Cancer

Primary analysis of the phase II component of a phase I/II dose intensification study using three-dimensional conformal radiation therapy and concurrent chemotherapy for patients with inoperable non-small-cell lung cancer: RTOG 0117

J Clin Oncol

Randomized phase II trial of induction chemotherapy followed by concurrent chemotherapy and dose-escalated thoracic conformal radiotherapy (74 Gy) in stage III non-small-cell lung cancer: CALGB 30105

J Clin Oncol

Articles
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