No Benefit of Adding Cetuximab to Cisplatin and Accelerated Radiotherapy in Stage III or IV Head and Neck Carcinoma
Use of cisplatin or cetuximab (Erbitux) with radiotherapy improves overall survival in stage III or IV head and neck carcinoma, and adding cetuximab to platinum therapy improves overall survival in metastatic disease. In the phase III Radiation Therapy Oncology Group (RTOG) 0522 trial reported in the Journal of Clinical Oncology, Ang et al found no progression-free survival or overall survival benefit of adding cetuximab to radiation/cisplatin in stage III or IV disease.
Study Details
In the trial, 891 patients with squamous cell carcinoma of the oropharynx, hypopharynx, or larynx and Zubrod performance status 0 or 1 were randomly assigned between November 2005 and May 2009 to receive accelerated radiotherapy plus cisplatin with (n = 444) or without cetuximab (n = 447). Randomization was stratified by tumor site, nodal stage, Zubrod performance status, use of intensity-modulated radiotherapy, and use of pretreatment positron-emission tomography/computed tomography scans.
Accelerated radiotherapy regimens included 72 Gy in 42 fractions over 6 weeks using twice-a-day irradiation for 12 treatment days and an intensity-modulated radiotherapy regimen consisting of 70 Gy in 35 fractions given twice-a-day once a week for 5 weeks over 6 weeks. Cisplatin was given at 100 mg/m2 on days 1 and 22 of radiotherapy, and cetuximab was given at 400 mg/m2 the week before radiotherapy and then 250 mg/m2 per week during radiotherapy. The primary endpoint was progression-free survival in the intention-to-treat population.
The cetuximab and control groups were generally balanced for age (median, 58 and 57 years), sex (90% and 87% male), race (90% and 92% white), Zubrod performance status (0 in 66% and 65%), primary tumor site (oropharynx in 70% in both, hypopharynx in 7% in both, larynx in 23% in both), T category (T2 in 40% and 39%, T3 in 36% and 38%, T4 in 24% and 23%), N category (eg, N0 in 12% and 10%, N2b in 35% and 31%, N2c in 31% and 36%), stage (IV in 85% and 87%), p16-positive primary oropharyngeal tumor (39% and 36%, unknown in 47% and 50%), and EGFR status (27% and 26% with < 80% positive tumor cells, 16% in both with ≥ 80% positive tumor cells, unknown in 57% in both).
No Survival Difference
Median follow-up was 3.8 years. There were no significant differences between the cetuximab and control groups in 30-day mortality (2.0% vs 1.8%, P = .81), 3-year progression-free survival (58.9% vs 61.2%, P = .76), 3-year overall survival (75.8% vs 72.9%, P = .32), locoregional failure (25.9% vs 19.9%, P = .97), or distant metastasis (9.7% vs 13.0%, P = .08).
Trends for an effect of p16 status in the cetuximab group were observed. Hazard ratios (HRs) were 1.57 for p16-positive disease and 0.86 for p16-negative disease for progression-free survival (P = .12 for interaction) and 1.42 and 0.69, respectively, for overall survival (P = .13 for interaction).
After imputation and adjustment for prognostic factors, hazard ratios were reduced to 1.29 and 0.92 for progression-free survival (P = .31 for interaction) and 1.10 and 0.63 for overall survival (P = .19 for interaction). Among all patients, a significant overall survival benefit of cetuximab was observed in patients aged ≤ 50 years (HR = 0.45, P = .02 for interaction).
Effect of p16 Status
Among all patients, those with p16-positive vs p16-negative oropharyngeal carcinoma had significantly better 3-year progression-free survival (72.8% vs49.2%, P < .001) and 3-year overall survival (85.6% vs60.1%, P < .001). EGFR expression was not associated with progression-free survival or overall survival.
Toxicity
The cetuximab group was more likely to have interruption of radiotherapy (26.9% vs 15.1%) and grade 3 or 4 radiation mucositis (43.2% vs 33.3%), as well as having more frequent rash, fatigue, anorexia, and hypokalemia. Late toxicity was similar in the two groups.
The investigators concluded: “Adding cetuximab to radiation-cisplatin did not improve outcome and hence should not be prescribed routinely. [Progression-free survival] and [overall survival] were higher in patients with p16-positive [oropharyngeal carcinoma], but outcomes did not differ by EGFR expression.
Rita S. Axelrod, MD, of Thomas Jefferson University Hospital, is the corresponding author for the Journal of Clinical Oncology article.
The study was supported by grants from the National Cancer Institute. For full disclosures of the study authors, visit jco.ascopubs.org.
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®.
