In 2006, cetuximab, an epidermal growth factor receptor antagonist, arrived as the first US-approved treatment of squamous cell carcinoma of the head and neck in over 4 decades. The standard of care at the time for locally advanced disease was radiotherapy plus chemotherapy, the agent usually being cisplatin. Cetuximab was approved because phase III evidence was showing that it was of greater benefit than radiotherapy alone in regional disease control, survival (progression-free and overall), and distant metastasis. By 2011 additional data from this same study confirmed sustained benefit in overall survival, and a separate study showed cetuximab to be an efficacious adjuvant to chemotherapy in first-line treatment of recurrent and metastatic disease.

There was at the time a phase III clinical trial underway, of radiotherapy plus cisplatin compared to radiotherapy plus cisplatin plus cetuximab in locally advanced disease. This was an interesting start for clinicians interested in knowing, reasonably enough, whether one of these drugs was better than the other. There was no control arm of radiotherapy plus cetuximab in this study, however, and so Adrian Levy, at Canada’s Dalhousie University, led a study to ascertain their relative effectiveness. The comparison was between radiotherapy plus cisplatin and radiotherapy plus cetuximab in locally advanced squamous cell carcinoma of the head and neck, with endpoints being locoregional control and overall survival.

The way they did it was by literature review. The idea was to use meta-analysis to estimate hazard ratios from published studies of radiotherapy and radiotherapy plus cisplatin, and compare them to those pertaining to radiotherapy and radiotherapy plus cetuximab. It was an indirect comparison, in other words, beginning with a harvest of papers from the Medline and EMBASE databases between 1998 and mid-2008. For inclusion, studies had to be randomized clinical trials of locally advanced disease, there had to be cisplatin (only) plus radiotherapy as a treatment arm, and there had to be a radiotherapy-only arm. The radiation protocol had to be comparable to the cisplatin registration trial, and cisplatin dosing had to be that currently in general use. There was only one study available of radiotherapy versus radiotherapy plus cetuximab; it did offer locoregional control and overall survival outcomes. To find more studies, the review team sorted 269 abstracts, and found 4 qualifying studies, and also a meta-analysis that compared radiotherapy with more than one radiotherapy plus chemotherapy protocol, of which they considered only cisplatin.

Initial results were hazard ratios that appeared to favor efficacy for cetuximab for overall survival and locoregional control. Updated analysis, however, using 60-month data, resulted in differences that were negligible. Hazard ratio estimates ranged from 0.92 to 1.02 for overall survival, and from 0.99 to 1.15 in disease control. There was similar effectiveness, consistently. All confidence intervals spanned the null value, and results stayed robust with sensitivity analysis. Neither drug was superior in locoregional control or overall survival, in other words.

That being so, Dr. Levy suggested that toxicity profile was probably the way to choose one over the other. Data was sparse, but cetuximab patients were more likely to respond with dermatitis, mucositis, rash, and weight loss; cisplatin patients, however, were more likely to stop treatment, though it wasn’t clear why.

This was a small study, it drew on a collection of papers that may, because of publication bias, not include negative ones, the patient cohorts may or may not have been truly comparable, some of the studies’ treatment arms were complicated with use of carboplatin, for unclear reasons, radiotherapy protocols varied quite widely, and not every head and neck cancer was necessarily the same: those driven by human papilloma virus, evidence suggests, may be atypical malignancies, with etiologies that differ from other head and neck cancers.

Dr. Levy’s team emphasized that full head-to-head trials still needed doing. But the punchline of this indirect comparison was clear at least: administered alongside radiotherapy, cetuximab and cisplatin were, on the face of it, equally efficacious.