Epidermal Growth Factor Receptor Inhibition in Head and Neck Cancer—More Insights, but More Questions

Squamous cell cancer of the head and neck (HNSCC) would seem to be the ideal malignancy for epidermal growth factor receptor (EGFR) inhibition either with antibodies or small molecule tyrosine kinase (TK) inhibitors. EGFR protein is overexpressed in more than 90% of tumors relative to normal tissue, and high expression is associated with poor disease control. Data from preclinical models show at least additive effects of the two classes of EGFR inhibitors when combined with cisplatin, providing rationale for combination therapy. To date, cetuximab has been studied in recurrent HNSCC in combination with cisplatin and platinum plus fluorouracil (FU) as first-line treatment for recurrence and in the setting of platinum refractory disease, whereas the small molecule TK inhibitors have been tested as single agents in the secondor third-line setting. The optimal timing of EGFR inhibitors in the palliation of patients with disease recurrence has not been well defined. HNSCC has the theoretical advantage of providing easily accessible tumor for biopsy, which could facilitate study of the putative effects of molecularly targeted therapies on the complex signaling pathways downstream of the EGFR. Such correlative tissue studies are needed to elucidate EGFR pathway tumor biology and identify predictive markers for better patient selection for these costly therapies. This issue of the Journal of Clinical Oncology contains five articles that provide some insights into these questions and the results of an analysis of the impact of radiotherapy (RT) plus EGFR antibody therapy on quality of life (QoL). QoL is a complex measure, particularly for those not immersed in this field, seemingly with its own terminology, variety of tools, and myriad statistical tests. However, the importance of QoL cannot be underestimated for patients with head and neck cancer. As multimodality therapies are intensified, consideration of QoL in therapeutic decision-making, and in formulating standards of care, is of paramount importance. This issue of JCO contains a report of QoL assessments that were performed as part of the prospective comparison of RT alone to RT plus concurrent cetuximab in patients with locally advanced HNSCC published by Bonner et al. Significant improvements in overall survival and local-regional recurrence-free survival were observed for patients in the cetuximab treatment group without an apparent increase in toxicity. The current paper bolsters those findings through the use of two validated questionnaires (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 and Quality of Life Questionnaire, Head and Neck Module) that address symptom burden and its effect on physical and functional well-being, emotional, and social interactions. No significant differences were found between the two treatments in QoL at baseline or during the course of treatment out to 12 months. In both groups, QoL declined during treatment, with the greatest impact on function due to fatigue, loss of appetite, swallowing difficulty, and sensory problems, and then improved by 8 to 12 months. The authors interpreted this as a positive result. This pattern of decline and then return to baseline by about 12 months confirms data from other head and neck trials as does the observed correlation between global health/QoL and survival. Because a significant difference in local-regional control was reported in the primary paper, one might have postulated that the symptom burden of uncontrolled disease would result in a worse QOL for patients in the control group. In other words, the real goal and indication of a positive outcome should be an improvement in QOL for patients receiving the treatment that afforded them significantly longer survival and disease control, in this case RT plus cetuximab. It is not clear whether the occurrence of more dropouts over time among controls (RT alone) obscured this effect or the questionnaires used were not sensitive enough to detect differences between the treatment groups (not just within treatment groups). The conclusion that QOL was not worse for patients receiving RT plus cetuximab than for those treated with RT alone is, unfortunately, not very satisfying. As advances are made in multimodality therapies, we should seek improvements in QoL that parallel improvements in survival. Two therapeutic trials are reported in this issue. Vermorken et al tested single-agent cetuximab in a multicenter phase II trial enrolling 103 patients with recurrent/metastatic HNSCC that had progressed on platinum-based chemotherapy. In a two-part design, patients were first treated with cetuximab alone until disease progression, and then they were offered continuation of cetuximab with the addition of platinum. The objective response rate (complete plus partial response) for treatment with cetuximab alone was 13% (95% CI, 7 to 21), the disease control rate (complete plus partial plus stable response) was 46% (95% CI, 36 to 56), and the median time to progression (TTP) was 70 days. Of these 103 patients, 53 proceeded to the second part of the trial and received JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 25 NUMBER 16 JUNE 1 2007