Oropharyngeal Cancer, Human Papilloma Virus, and Clinical Trials

Abstract

As advances in our understanding of the molecular biology of cancer have evolved in recent years, cancers that were once considered to be relatively homogeneous diseases are now being recognized as comprising distinct subtypes. These subtypes may differ in etiology, molecular profile, sensitivity to treatment, and prognosis. Examples include luminal (mainly estrogen receptor–positive), human epidermal growth factor receptor 2–positive, and basal breast cancer subtypes; non–small-cell lung cancer associated with EGFR or EML4-ALK mutations; and melanoma associated with BRAF (V600E) or c-KIT mutations. In head and neck cancer, we have traditionally combined squamous cell carcinomas of the oral cavity, oropharynx, larynx, and hypopharynx in clinical trials. This has been justified on the basis of similar etiology (tobacco and alcohol) and similar sensitivity to radiotherapy and systemic therapy. However, it has also been recognized that there are differences in clinical behavior, treatment outcome, and prognosis with regard to primary site. Although surgery has remained the primary treatment for oral cavity cancers, organ preservation with primary chemoradiotherapy has been widely used over the last two decades for cancers of the oropharynx, larynx, and hypopharynx. It has become apparent over this same time period that a new subtype of oropharyngeal cancer resulting from human papilloma virus (HPV) has emerged. The proportion of HPV-associated oropharyngeal cancer has steadily increased, and in many countries, this subtype now represents the majority of new oropharyngeal cancers. HPV-associated oropharyngeal cancer differs from other oropharyngeal cancers with regard to risk factors, clinical features, sensitivity to treatment, and prognosis. Patients with HPV-associated oropharyngeal cancer have markedly superior survival after chemoradiotherapy compared with those with HPV-negative oropharyngeal cancer. Preliminary reports of the pattern of failure suggest that this is because of lower rates of locoregional failure, second malignancies, and death as a result of other causes. There does not seem to be a significant difference between the two in the rate of distant metastasis as site of first failure. Over the last 5 years, two new treatment options for squamous cell carcinomas of the head and neck—taxane-based induction chemotherapy and concomitant cetuximab and radiation administration— have emerged after widely publicized clinical trials. However, the designs of the initial randomized trials of both these approaches did not include comparisons with standard concomitant chemoradiotherapy regimens. We have learned that the regimen of docetaxel, cisplatin, and fluorouracil (TPF) improves overall survival compared with cisplatin and fluorouracil when followed by radiation alone or radiation and weekly low-dose carboplatin. Although it had been clearly established that induction chemotherapy decreases distant metastases, the improvement with TPF, surprisingly, was demonstrated to be a result of improvement in locoregional control. The pivotal trial showing that the addition of cetuximab to radiation produced superior results compared with radiation alone was first presented in 2005; however, we do not have any results from randomized trials comparing this regimen with a standard concomitant chemoradiotherapy regimen. It is clear that both of these treatment approaches are being widely used in clinical practice, but with the currently available evidence, there remains considerable uncertainty about the relative efficacy and indications of these approaches compared with standard concomitant chemoradiotherapy regimens. Ongoing and recently completed trials should better define the role of induction chemotherapy and epidermal growth factor receptor–targeted therapy concurrent with irradiation. In this issue of Journal of Clinical Oncology, Kies et al report the results of a phase II trial incorporating cetuximab into a short weekly regimen of carboplatin and paclitaxel induction followed by what the authors describe as risk-based local therapy. Although the overall results are good, it is difficult to determine the relative contributions of induction chemotherapy, cetuximab, HPV status, and risk-based local therapy. On the basis of the results of a trial involving patients with relapsed or metastatic head and neck cancer, which demonstrated that theadditionofconcurrentandmaintenancecetuximabtochemotherapy improved overall survival and response rates, it was reasonable to anticipate that the addition of cetuximab to induction chemotherapy might also be beneficial. However, Kies et al report that complete response rates achieved with their regimen did not seem to be better than those reported using the same regimen without cetuximab. Furthermore, in contrast to the TPF regimen, the weekly carboplatin and paclitaxel regimen, while clearly an active induction regimen, has not been demonstrated to be superior to the cisplatin and fluorouracil regimen. In the trial by Kies et al, the majority of patients had oropharyngeal cancer (41 of 47; 87%). We know that 12 of 26 tumors tested were HPV positive, and this group had a better prognosis than the JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 28 NUMBER 1 JANUARY 1 2010