Cisplatin Versus Cetuximab With Radiotherapy in Locally Advanced Squamous Cell Carcinoma of the Head and Neck

The trial by Bonner et al demonstrated a 10% overall survival (OS) benefit when cetuximab was added to radiation in the treatment of locally advanced head and neck squamous cell carcinoma, and it led to acceptance of cetuximab-based combined modality therapy as a standard of care. Of interest, cetuximab was not shown to worsen common acute radiation toxicities such as mucositis, dysphagia, or pain. Therefore, it was considered the rare drug that improves survival without substantially increasing toxicity. These data came on the heels of several trials and a meta-analysis that demonstrated improved outcomes with chemoradiation compared with radiation alone. It remained unclear where cetuximab fit among other radiosensitizers. However, the prevailing view, as voiced in an editorial published with the initial trial, was that cisplatin remained the standard radiosensitizer and that cetuximab could be considered in patients who were ineligible for platinum therapy. The two main questions regarding cetuximab were the following: How does it compare with cisplatin head to head? And what, if anything, does it add to the cisplatinradiation backbone? The latter of these questionswas answered first, in the RTOG0522 study, which demonstrated no discernable benefit and an increase in toxicity with the addition of cetuximab to cisplatinbased chemoradiation. The more pressing question of cetuximab versus cisplatin went unanswered, although results from a few singleinstitutional studies that were subject to selection biases and that often lacked critical information regarding association with human papillomavirus (HPV) suggested that cetuximab may be inferior. Eventually, four randomized studies—RTOG 1016, TROG 12.01, De-ESCALaTE, and a phase II study from Italy—were performed to answer this question. In the article that accompanies this editorial, Magrini et al report the first results from these studies. In their study, they sought to enroll 130 patients who had locally advanced head and neck squamous cell carcinoma of the oral cavity, larynx, hypopharynx, and/or oropharynx. They randomly assigned patients to receive 70 Gy of radiation with cetuximab or cisplatin 40 mg/m once per week. The primary endpoint was compliance. The trial was designed to have 80%power to detect a 20%difference in compliance, whichwas defined broadly as a break in radiation treatmentmeasured in days, the percentage of drug dose reductions, the incidence and grade of drug-related adverse events, and the percentage of treatment discontinuations. On the basis of previous studies, the predicted compliance rate was 71% in the cisplatin arm and 90% in the cetuximab arm. Unfortunately, the trial was closed after only 70 patients were enrolled, leaving it significantly underpowered. Of note, this was a population with a significant burden of disease, with 43% T4a-b primary tumors and 17% to 23% with N2c-N3 nodal disease. There was no difference in grade 3 mucositis between cetuximab and cisplatin (59% and 53% respectively; P not stated). Oneand two-year local control rates were 64% and 53% in the cetuximab arm and 84% and 80% in the cisplatin arm. The fact that a 20% difference in local control was not significant (P5 .073) highlights the inadequate statistical power. Two-year OS rates were 75% and 78% in the cetuximab and cisplatin arms, respectively. Compliance, the primary endpoint, was far lower than anticipated in both arms. Only 28% of patients received at least seven cycles of cetuximab, compared with 94% in the trial by Bonner et al. In the cisplatin arm, only 20% of patients received all planned chemotherapy cycles, compared with the historical control of 71%. For further comparison, in the RTOG 0522 study, this rate was 94%. Nine percent of patients had infusion reactions to cetuximab, significantly higher than the 3% rate reported by the manufacturer. In addition, the incidence of treatment breaks and severe toxicity was significant. Thirteen percent of patients in the cetuximab arm had a treatment break of longer than 10 days (P , .05), and the 19% rate of severe or fatal toxicity in the cetuximab arm is startling. Four patients developed septic shock, three of whom died. One patient died from aspiration pneumonia, and one survived an intestinal perforation. The grade 5 toxicity rate in the cetuximab armwas, therefore, 12.5%, whereas no cetuximab-related deaths were reported in the trial by Bonner et al. These unexpected findings contradict the authors’ pretrial assumptions that cetuximab would be better tolerated. Although the authors should be applauded for designing a study aimed at answering this critical question in head and neck oncology, several limitations temper the utility of their findings. One of the difficulties with a compliance endpoint is the subjectivity associated with it. The decision to withhold systemic therapy or interrupt treatment is affected by toxicity, comorbidity, and nonphysiologic factors such as the motivation of the patient and the preference of the physician. The fact that compliance with cetuximab was better in another study in which cetuximab was