COMMENTS

In the earlier publication based on the same study, there was significant improvement in locoregional control with addition of cetuximab to RT[1]. The median duration of the locoregional control was 24.4 months with combined treatment, compared to 14.9 months with RT alone. Locoregional control with RT alone was 55, 41, and 34% at one, two, and three years. Locoregional control with combined therapy was 63, 50, and 47% at one, two. and three years. There was a 32% reduction in the risk of locoregional progression with addition of cetuximab. Survival at two years and three years was 55 and 45% with RT alone and 62 and 55% with RT plus cetuximab. Distant metastases were noticed in 17 and 16% patients of RT alone and combined therapy arms at two years follow up. Second primary cancers were noted in 5% of RT arm and 8% of combined therapy arm at two years follow up.

Overall, the two publications document the significant benefit that can be achieved with addition of cetuximab to radiation therapy, in terms of locoregional control, progression-free survival, and overall survival. Furthermore, the survival benefit becomes noticeable in the second year of follow up and persists without any decrease up to at least five years of follow up. It is quite reasonable to assume that this survival benefit is a sustained benefit, as the incidence of locoregional recurrences after five years of follow up is negligible in head and neck cancers. More important in this group of patients is the relatively high incidence of second malignancies. These facts are supported by the relatively low rate of distant metastases and the significant incidence of second malignancies at two years of follow up.

There are some important considerations yet. One is that the control arm in this study was radiation therapy alone. Currently, a majority of patients with locally advanced squamous cancers of the oropharynx, hypopharynx, and larynx are treated with concomitant radiotherapy and chemotherapy. Radiotherapy alone is used only in patients with poor performance status or other factors, such as, old age, significant co-existing medical problems, palliative therapy, and so on. Concomitant chemoradiotherapy has been shown to confer a significant advantage in locoregional control as well as survival and it has been confirmed in the most recent meta-analysis reported in 2008.[2] The meta-analysis has been referred to by the authors as well. It included 87 trials and 16485 patients. Based on 50 trials that used concomitant chemoradiotherapy, there was a 6.5% gain in overall survival at five years for patients treated with combined modality treatment.

The authors of the current study also raise the issue of significant toxicity seen with concurrent chemoradiotherapy. The current study showed that radiation-related toxicity in the group of patients receiving cetuximab was not higher than in the group treated with radiation alone. It would be reasonable to propose that a three-arm trial that compares concurrent chemoradiotherapy, RT with cetuximab and RT with chemotherapy and cetuximab could be useful in answering various questions that exist currently as well as show if combining the two concurrent strategies (cytotoxic chemotherapy and targeted therapy) would provide additional benefit to these patients.

Although cetuximab may find easy acceptance in USA and Europe, in resource-poor countries of Asia and Africa, it is important to consider the cost-benefit equation also in relation to concurrent chemotherapy and concurrent cetuximab. The most popular regimen for concurrent chemotherapy today is weekly administration of cisplatin. This regimen is highly effective and very cheap. In contrast, cetuximab will cost more than six lakh rupees for the total course of treatment. Unless the efficacy and toxicity profile of a cetuximab-based combined therapy shows significant benefit in direct comparison to Cisplatin-based combined therapy, it would be difficult to recommend cetuximab usage as concurrent therapy in Indian patients.

It would be important to explore if there are any patient groups that do not benefit or if there are any subgroups that show a higher-than-average benefit (from addition of cetuximab). The epidermal growth factor receptor (EGFR) expression was studied by the authors of the current study in nearly 80% of the patients and almost all the patients had documented expression of EGFR in the tumor cells. The proportion of cells expressing EGFR was more than 50% in nearly half of the patients studied. It might be necessary to look for other biological markers in the EGFR pathway to see if they showed a correlation with the benefit derived from concomitant usage of cetuximab.

There are many targeted agents against EGFR and it will be interesting to speculate about the relative efficacy of different agents in the setting of radiosensitization. Nimotuzumab is another monoclonal antibody targeted against EGFR. Early data from phase IIb studies in India have been reported recently and show benefit from addition of nimotuzumab to radiation alone or to radiation with concurrent chemotherapy.[3] Furthermore, phase III studies are necessary to document these benefits in a larger group. It may be preferable to have concurrent chemoradiation as the control arm and addition of nimotuzumab must be the study variable.