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Indian Journal of Cancer, Vol. 48, No. 2, April-June, 2011, pp. 145-147 Mini Symposium - Editorial Cetuximab in head and neck cancer PM Parikh1, GS Bhattacharyya2, A Vora3 1 Indian Cooperative Oncology Network, Mumbai, India Correspondence Address: P M Parikh Indian Cooperative Oncology Network, Mumbai India purvish1@gmail.com Code Number: cn11039 DOI: 10.4103/0019-509X.82871 Squamous cell carcinoma of head and neck (SCCHN) region is the largest group of cancers seen in India and many countries with limited resources. [1] In patients with advanced disease, outcome still remains poor. Yet, the subgroup of patients who do not have distant metastases, can be offered potentially curative therapy in the form of chemoradiotherapy. This translates into an absolute survival benefit of 6.5% at 5 years for concurrent chemoradiotherapy as per the MACH-NC collaborative group meta-analysis. [2] The best results have been with cisplatin- and carboplatin-based chemotherapy combined with radiotherapy, the survival being prolonged by 16.8 and 6.7 months, respectively. [3] Unfortunately, this benefit is not delivered to significant number of eligible patients - toxicity prevents this in as many as 30% of cases. [1] Results can be improved by one of the following approaches: (1) use of more tolerable chemotherapy combinations, (2) integration of molecular targeted drugs, and (3) application of modern radiotherapy technology. SCCHN is associated with overexpression of epidermal growth factor receptors (EGFR) and contributes to the natural history of the disease. Cetuximab is a large molecule monoclonal antibody that binds to the extracellular domain of EGFR, inhibits intracellular phosphorylation, and blocks further downstream signaling. It has been shown to block cell cycle, promote apoptosis as well as potentiate the effects of chemotherapy and radiotherapy. [4] This issue of the Indian Journal of Cancer has two original articles on the concomitant use of cetuximab with radiation therapy for patients with advanced SCCHN. [5],[6] Agarwal JP have reported the retrospective evaluation of 37 cases, whereas Dattatreya and Goswami document the outcome in 19 patients with locally advanced SCCHN treated prospectively at two centers. Before we discuss their data, let us get an understanding of the background. In the landmark Bonner trial, the median improvement in OS was 30 months (vs RT alone). [7] Such a dramatic improvement in patients with advanced SCCHN was not reported till this data was presented. The results were reaffirmed when other trials also confirmed the median OS benefit (of 25 months). In the meantime, our medical knowledge has moved on and the new standard of care for locally advanced SCCHN became chemoradiotherapy (CRT). [1] The impression is that CRT has more data. So let us understand the truth about chemotherapy (CT) in SCCHN patients. CT can have significant toxicity when combined with RT - in fair number of patients. If separated from RT and used in the neoadjuvant setting, its toxicity has the potential to compromise subsequent RT. For instance it is well documented that only 40% of the patients are able to maintain dose intensity for the concomitant segment due to toxicity of neoadjuvant CT. [8] To specify further, recent data from Tata Hospital presented at the annual American Head and Neck Society meeting (April 2011), showed that the incidence of febrile neutropenia was as high as 50%. [9] Finally if one looks at the long term (5 year) overall survival for advanced SCCHN, it remains in the range of 30 to 40 % even with the most effective chemotherapy molecule (cisplatin). [1] Hence, it is reasonable to evaluate the role of monoclonal antibodies (MoAb) like cetuximab - be it concomitant, neoadjuvant, or adjuvant setting. [10] In fact the data of benefit of cetuximab in SCCHN is so compelling that various regulatory authorities had no choice but to approve its use. Yet the path taken by various countries is interesting. We will take just two examples to make our point. With the regulatory approval of cetuximab by US FDA, its use has become widespread. [11] On the other hand, its use in UK and Canada continues to be limited. [12],[13] In these countries, the initial approval was only if cisplatin was contraindicated (later broadened to all non elderly patients - since the elderly subgroup analysis failed to show benefit in the elderly). The original data of concomitant cetuximab and RT from India is therefore crucial and needs to be understood well. Whereas Agarwal has studied this in unfit patients, Dattatreya and Goswami were able to document its benefit in fit patients. [5],[6] In fit patients, the overall response rate (ORR) was 68.42% and the overall survival at 2 year was 84%. This compares favourably with the data presented by Bonner et al (loco-regional control of 47% and overall survival of 55%). [6],[14] This was achieved with minimal toxicity, permitting good dose intensity in the majority of patients. In fact, other than the solitary patient who developed Progressive disease (PD) while on therapy, dose intensity was more than 90% in all of them. The concern that this combination leads to significant toxicity was unfounded in fit Indian patients enrolled on this study. There was no grade 3 or 4 toxicity. Among unfit patients, the median age was 59 years. [5] Cisplatin could not be used as concurrent chemotherapy due to major co-morbidities (renal impairment being the most common) or advanced age. Even in this group of 37 patients, dose intensity was maintained in 80% of cases. At the median follow-up of 16 months, the projected 2-year loco-regional control was 35.5% after initial primary treatment (increasing to 40.7% with the use of salvage surgery) and the overall survival was 44.4%. For patients not fit to receive the most successful concomitant chemotherapy, this data demonstrated the ability to combine cetuximab with RT with tolerable toxicity. In the Bonner study, at two years, the locoregional control with combined therapy was 50% and ultimately resulted in a 32% reduction in the risk of locoregional progression with addition of cetuximab. [14] Survival at two years was 62 % with RT plus cetuximab. This is not dissimilar from the two studies from India. But there is scope for improvement by personalising therapy to optimise benefit. Bonner has shown that patients with oropharyngeal cancers, early T stage, concomitant boost RT, higher N stage, higher performance status, male sex, and younger age were associated with a higher benefit from cetuximab. [14] On the other hand, we also know that cetuximab does not work in patients with EGFR mutation type III. [15] Another study has shown an overall survival advantage (24.5 vs. 14.8 months) in the post operative salvage setting without a significant increase in grade 3/4 toxicities. [16] There is also least preclinical evidence that RT induced a strong and very significant increase in tumour angiogenesis, which was reversed when combined with erlotinib and bevacizumab. [17] Finally, the triple combination of cetuximab, chemotherapy, and RT will be reported at ASCO this year. [18] We should evaluate whether these (or other) parameters can help us positively select to improve outcomes. While doing this we must also remember what is not going to change. With concomitant cetuximab and RT, the incidence of distant metastases (16%) or second primary cancers (8%) remains unchanged at two years follow-up. [14] So we should not expect cetuximab to help control distant spread and we should dispel the fear of higher risk of second malignancies. The bottom line is that in palliative setting in SCCHN, use of cetuximab is the only intervention that has improved survival in last 30 years (by almost 36% - from 7 to 10 months) and should be considered in all eligible patients. [19] References
Copyright 2011 - Indian Journal of Cancer |
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