Reply to D. Adkins et al.

Adkins et al claim that the Radiation Therapy Oncology Group (RTOG) should not have proceeded to a large randomized phase III trial until phase I/II studies establishing the safety, feasibility, and activity of cetuximab-cisplatin-radiotherapy had been carried out. In particular, the authors suggest that RTOG conducted a large phase III study, RTOG 0522 (Radiation Therapy and Cisplatin With or Without Cetuximab in Treating Patients With Stage III or Stage IV Head and Neck Cancer), on the basis of the results of a single-institution phase II trial that had already demonstrated activity similar to that of conventional cisplatin chemoradiotherapy at the cost of substantial toxicity and that wasted patient and financial resources. Pfister et al conducted the first study to evaluate feasibility and efficacy of the cetuximab-cisplatin-radiotherapy triplet for patients with locally advanced head and neck squamous cell carcinoma (HNSCC) in an attempt to generate a new treatment paradigm for a disease in which cisplatin chemoradiotherapy had already been the standard of care for more than two decades. This phase II study was fully accrued in 2000, and it reported 3-year survival outcomes of 56% for progression-free survival (PFS) and 76% for overall survival (OS). RTOG deemed these results promising enough to proceed to a phase III study that evaluated the cetuximab-cisplatin-radiotherapy triplet. Let’s first examine whether the evidence on efficacy is supportive of the decision to embark on a large randomized controlled trial (RCT). Indeed, at the time RTOG 0522 was designed, the outcomes observed with standard RTOG regimens were below 40% and 50% for the 3-year PFS and the 3-year OS, respectively. The Pfister et al study outcome compared favorably to outcomes of major RCTs of chemoradiotherapy reported before its publication. In particular, the outcome of the study by Pfister et al is comparable to the outcome of the much more recent RTOG 0129 study (Chemotherapy and Radiation Therapy With or Without Surgery in Treating Patients With Head and Neck Cancer), referenced by Adkins et al in their letter, despite the shifting epidemiology of the disease toward better prognosis as a result of the human papillomavirus (HPV) epidemic. In particular, the prevalence of p16-positive cancers was 39.5% among patients with oropharyngeal cancer in RTOG-9003 (Fractionated Radiation Therapy in Treating Advanced Squamous Cell Carcinoma of the Head and Neck) versus 68.0% among patients in RTOG 0129. Taken together, the results of the two pivotal cetuximab registration studies in HNSCC combined with the promising efficacy results of the Pfister study, justify RTOG’s decision to proceed with an RCT exploring the potential of the cetuximab-cisplatin-radiotherapy triplet as a new treatment paradigm in locally advanced HNSCC. Of note, in RTOG 0522, interim analyses were planned allowing for early stopping in case of futility. This provides the legitimate approach in an RCT, to not waste patient and financial resources in case the benefit of the experimental therapy is unlikely to be significant. The negative results of a phase III trial such as the RTOG 0522 study cannot and should not be used retrospectively against the decision of embarking on such a trial. As stated in the conclusions of the meta-analysis of RTOG studies conducted from 1968 to 2002 that explored the success rate of innovative treatments in RCTs, the results of an individual trial cannot be foreseen and, in addition, in most phase III trials, important benefits of an innovative treatment are not always revealed. Nevertheless, the only way to show superiority of a novel over a standard treatment is through an RCT. Let’s next examine whether the evidence on safety should have raised concerns about embarking on a large RCT. The single-center phase II study of 22 patients, which prompted the development of RTOG 0522, had been closed early because of five serious adverse events, including one myocardial infarction, one bacteremia, and one atrial fibrillation, and two deaths (one as a result of pneumonia and one as a result of an unknown cause). However, these events were attributed to comorbidities of the trial population rather than to cetuximab itself because grade 3 and 4 cardiovascular events were extremely rare (2.6%) in the clinical trial database of cetuximab (2,174 patients). Indeed, the main grade 3 to 4 toxicities in the cetuximab arm of RTOG 0522 that differed significantly from the standard arm were skin reactions, radiation mucositis, fatigue, anorexia, and hypokalemia up to 90 days from treatment initiation whereas cardiovascular toxicity and infections were not reported. The serious adverse events reported by Pfister et al did not occur in RTOG 0522. The Data Safety Monitoring Board regularly monitored safety and other data related to this phase III study. Because safety signals leading to study discontinuation did not emerge in RTOG 0522, it appears unlikely that conducting an additional small study, as suggested by Adkins et al, would have predicted the high percentage of patients who developed severe radiation mucositis in the experimental arm. A huge effort is necessary to advance the standard of care through a novel treatment, and RCTs are essential in this effort. As emphasized in the meta-analysis by Soares et al, “there is no substitute to this painstaking process of continuing testing of new treatments in the clinical trial setting. ”