No Benefit of High- vs Standard-Dose Radiotherapy or for Addition of Cetuximab to Chemoradiation in Stage IIIA or IIIB NSCLC
As reported in The Lancet Oncology by Bradley and colleagues, the phase III Radiation Therapy Oncology Group 0617 trial showed no survival benefit of high- vs standard-dose radiotherapy or for addition of cetuximab (Erbitux) to concurrent paclitaxel-carboplatin chemoradiation in patients with inoperable stage IIIA or IIIB non–small cell lung cancer (NSCLC).
Study Details
In the open-label 2×2 factorial trial, patients from the United States and Canada were randomly assigned 1:1:1:1 between November 2007 and November 2011 to receive 60 Gy radiotherapy (n = 166), 74 Gy radiotherapy (n = 121), 60 Gy radiotherapy and cetuximab (n = 147), or 74 Gy radiotherapy and cetuximab (n = 110) with all patients receiving concurrent once-weekly chemotherapy with paclitaxel at 45 mg/m2 and carboplatin at area under the curve (AUC) 2. Two weeks after chemoradiation, patients received two cycles of consolidation paclitaxel at 200 mg/m2 and carboplatin at AUC 6 separated by 3 weeks. Radiation was given in 2-Gy daily fractions with either intensity-modulated or three-dimensional conformal radiation therapy. Cetuximab was given at 400 mg/m2 on day 1 followed by 250 mg/m2 weekly continued through consolidation therapy. The primary endpoint was overall survival.
Patients had a median age of 64 years, and most were male (55%–64%), white (82%–89%), had Zubrod performance status of 0 (55%–59%), were current smokers (43%–51%), received three-dimensional conformal radiotherapy (47%–54%), underwent positron-emission tomography (PET) staging (89%–91%), had squamous histology (42%–47%), and had stage IIIA disease (63%–66%).
No Improvement in Survival
Median follow-up for the radiotherapy comparison was 22.9 months. Median overall survival was 20.3 months (95% confidence interval [CI] =17.7–25.0 months) in the high-dose group vs 28.7 months (95% CI = 24.1–36.9 months) in the standard-dose group (hazard ratio [HR] = 1.38, P = .004).
Median follow-up for the cetuximab comparison was 21.3 months. Median overall survival was 25.0 months (95% CI = 20.2–30.5 months) in the cetuximab group vs 24.0 months (95% CI = 19.8–28.6 months) in the no cetuximab group (HR = 1.07, P = .29).
Both the radiation and cetuximab comparisons crossed prespecified futility boundaries.
Toxicity
There were no significant differences in grade ≥ 3 adverse events between high-dose and standard-dose radiotherapy, but severe esophagitis was more common with high-dose radiotherapy (21% vs 7%, P < .0001). Cetuximab was associated with an increased frequency of grade ≥ 3 adverse events vs no cetuximab (86% vs 70%, P < .0001). There were more treatment-related deaths with high-dose vs standard-dose radiotherapy (eight vs three patients) and with vs without cetuximab (10 vs 5 patients). No differences in incidence of severe pulmonary events were observed in the radiation and cetuximab comparisons.
The investigators noted that the median overall survival achieved with standard-dose radiotherapy and weekly concurrent followed by consolidation paclitaxel-carboplatin was higher than expected and appeared to constitute a new benchmark with chemoradiation in this setting. However, they also noted that the use of staging PET in the majority of patients may have resulted in stage migration that contributed to the better-than-expected outcomes.
They concluded: “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.”
Jeffrey D. Bradley, MD, of Washington University, is the corresponding author for the Lancet Oncology article.
The study was funded by the National Cancer Institute and Bristol-Myers Squibb. For full disclosures of the study authors, visit www.thelancet.com.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
