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Cetuximab plus radiation, cisplatin yielded little benefit in advanced head and neck cancers
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The addition of cetuximab to cisplatin-based radiation therapy conferred no significant benefit with regard to PFS, OS, locoregional failure or distant metastasis in patients with stage III or stage IV head and neck carcinoma, according to results of a randomized phase 3 trial.
Rita S. Axelrod, MD, co-director of the Thoracic Oncology Program at Jefferson University Hospitals, and colleagues hypothesized that the addition of the epidermal growth factor receptor (EGFR) antagonist cetuximab (Erbitux, Eli Lilly) to accelerated radiation plus cisplatin would extend PFS in that patient population.
Rita S. Axelrod
The analysis included 891 patients. Researchers randomly assigned 444 patients to concurrent accelerated radiation plus cisplatin with cetuximab. The other 447 patients received radiation plus cisplatin alone. The cisplatin dose was comparable between arms (191.1 mg/m2 vs. 185.7 mg/m2).
Median follow-up was 3.8 years.
The cisplatin regimen was associated with more frequent interruptions in radiation therapy (26.9% vs. 15.1%), as well as higher rates of grade 3 or grade 4 events, such as radiation mucositis (43.2% vs. 33.3%), fatigue (14% vs. 9%), anorexia (16% vs. 11%), inside-portal skin reaction (25% vs. 15%) and hypokalemia (10% vs. 5%).
Axelrod and colleagues reported similar rates of 30-day mortality between those who received cetuximab and those who did not (2% vs. 1.8%; P=.81). Results also suggested similar rates of 3-year PFS (58.9% vs. 61.2%; P=.76); 3-year OS (75.8% vs. 72.9%; P=.32); locoregional failure (25.9% vs. 19.9%; P=.97) and distant metastasis (9.7% vs. 13%; P=.08) between those who received cetuximab and those who did not.
Patients with p16-positive oropharyngeal carcinoma demonstrated higher 3-year rates of PFS (72.8% vs. 49.2%; P<.001) and OS (85.6% vs. 60.1%; P<.001) than those with p16-negative oropharyngeal carcinoma. Probability of locoregional failure (17.3% vs. 32.5%; P<.001) and distant metastasis (6.5% vs. 17%; P=.005) also were lower among those with p16-positive disease. However, tumor EGFR expression did not distinguish outcome, according to researchers.
Results of multivariable analysis suggested several factors were associated with shorter PFS and OS. Those factors were primary laryngeal-hypopharyngeal carcinoma, p16-negative oropharyngeal carcinoma, N2b-3 category, T4 tumor, a history of >10 pack-year history of cigarette smoking, age older than 50 years, and a Zubrod performance status of 1.
The RGOG 1016 trial — a phase 3 trial designed to evaluate radiotherapy plus cetuximab vs. chemoradiotherapy in patients with HPV-associated oropharynx cancer — “represents this new paradigm,” Axelrod and colleagues wrote. Trial enrollment is open to patients with T1-2N2a-3 or T3-4, any N category, p16-positive oropharyngeal carcinoma.
“It is anticipated that future trials will further refine study populations based on smoking status and other biologic tumor features,” Axelrod and colleagues wrote. “This means, however, that the number of patients eligible for a given trial will decrease progressively. Therefore, international collaborations are imperative to complete patient accrual in a timely fashion. Hence, it is desirable to commence discussions of funding for and logistics of establishing international cooperative group alliances.”
Disclosure: The researchers report advisory or consultant roles with, stock ownership in, and research funding or other remuneration from Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, ImClone Systems and Merck Serono.
Perspective
Back to TopDavid J. Adelstein, MD, FACP
RTOG 0522 was a negative trial. No outcome improvement was achieved by adding cetuximab to radiation and concurrent cisplatin chemotherapy in the definitive management of patients with locoregionally advanced, non-metastatic squamous cell head and neck cancers. This clearly was a disappointing result, particularly given the benefit achieved from adding cetuximab to radiation in the same patient population, and to platinum-based chemotherapy in patients with metastatic disease.
However, several important observations emerge from this report
First, it should be pointed out how well these patients did. Researchers reported 3-year PFS rates of 59% to 61% and 3-year OS rates of 73% to 76% in an unselected patient population, which — historically — achieved cure rates of less than 40%. Although it is tempting to conclude that this reflects the impact of modern therapeutics, the importance of a rapidly changing disease epidemiology must be acknowledged. HPV — identified in this trial by immunohistochemical p16-positivity — is considered the causative agent in an increasingly large fraction of patients with oropharynx cancer, and patients with HPV-initiated disease are well recognized to have a markedly better prognosis. In this trial, 70% of analyzed patients had oropharyngeal cancers, 73% of these oropharynx cancer patients were felt to be p16-positive, and the 3-year overall survival in this patient subset was 86%. As demonstrated in this trial, cure should now be considered a reasonable expectation for most patients with this malignancy.
Secondly, this study accrued almost 1,000 patients in only 3.5 years, a remarkable achievement in a relatively uncommon malignancy. High-quality treatment was delivered and high-quality data was generated from 151 participating centers. The investigators and the RTOG should be congratulated for this successful effort.
Most importantly, however, this study should point out the need for a more nuanced approach to future clinical trial design. Much of our therapeutic success in the past has been built on the assumption that combining independently active treatments or treatment modalities will improve treatment outcomes. Such an approach, however, ignores the marked clinical and biologic heterogeneity that exists among patients with these malignancies. When using a targeted treatment like cetuximab, it would seem important to understand and identify the patient subset most likely to benefit. In this trial, EGFR expression was studied and did not prove to be a useful marker. In the large unselected patient population entered on RTOG 0522, it should then not be entirely surprising that the addition of cetuximab to standard chemoradiotherapy produced only additional toxicity, and compromised treatment delivery. This trial should reinforce for us the importance of identifying validated biomarkers that then can allow for rational study design in more homogeneous patient populations.
Finally, it is appropriate to mention the lead author of this report — K. Kian Ang, MD, PhD — who died last year. During his lifetime, Dr. Ang was responsible for extraordinary contributions to radiation oncology, to the management of head and neck cancers, and to the RTOG. We continue to benefit from his vision.
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