Introduction: Head and Neck Cancer

Article Outline

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Four years ago, Seminars in Oncology published a volume on head and neck cancer highlighting the state of the art in diagnostics, prevention, and therapeutics. At a time when targeted therapy was being explored, chemoradiotherapeutic standards were being established, and traditional management was being challenged, the December 2004 issue served as a comprehensive review for the field. This issue of Seminars in Oncology returns to the same subject matter but with a different goal. Each of the authors was asked to update readers on the recent progress made in their respective area allowing one to take stock and appreciate the velocity with which changes occurred. Thus, this issue defines where we traveled in the last 4 years.

In the last 4 years, a new disease entity has been elucidated that has distinct clinical features, including younger median age, oropharyngeal primary site, lack of typical risk factors, and better prognosis with the human papillomavirus (HPV) as a likely etiologic agent. The molecular and clinical epidemiology surrounding HPV-associated head and neck cancer has led us to re-evaluate management of these patients and clinical trial outcomes.

Epidermal growth factor receptor inhibition has yielded meaningful results as monoclonal antibodies and small molecules entered and completed clinical evaluation. Cetuximab became the first targeted therapy approved in head and neck cancer and the first drug to ever be approved in conjunction with radiotherapy. It also was the first drug in the era of prospective clinical trials to be shown to increase survival when added to chemotherapy for recurrent or metastatic disease. Currently, other targets are being intensively explored, including angiogenesis, hypoxia, c-Met, and protein kinase C.

New technologies have emerged and entered widespread use, including intensity-modulated radiotherapy and positron emission tomography. The former has allowed reduction of long-term toxicity, while the latter has improved disease staging. Utilization of both of these advances is still in its infancy with the full potential yet to be realized.

An induction chemotherapy regimen has been defined that has led to re-examination of neoadjuvant therapy in locally or regionally advanced disease. Moreover, the addition of chemotherapy to adjuvant radiotherapy has demonstrated improved efficacy changing the standard for patients who undergo surgery and have high-risk pathological features.

Finally, activity in diseases that were long considered refractory to cytotoxic chemotherapy has been observed. Clinical trials of novel agents in recurrent differentiated thyroid cancers, medullary thyroid cancers, and salivary gland cancers have demonstrated efficacy, providing hope for meaningful treatments in the near term.

These advances have been met with excitement; nonetheless, as medical practitioners and scientists we must set the research directions that will maximally serve our future patients. Our mandate continues to be improving survival, decreasing long-term morbidity, and managing acute toxicity, but the natural question is where do we need to be another 4 years from now. This issue of Seminars in Oncology, therefore, should also serve as a directive in this disease.

Evidence supports a stepwise process of carcinogenesis in head and neck cancer, with many of the molecular alterations having been defined. The genotypic and phenotypic features of this process from normal cells to malignancy can be detected and reversed. We can identify high-risk patients and must now apply chemoprevention and screening programs in these individuals.

Despite the evolution of standards, therapy is still largely based on anatomic and gross disease parameters. However, it is clear that tumor-node-metastasis (TNM) stage is an unsatisfactory system for predicting survival let alone pattern of failure. It is time to define molecular markers of chemoradiotherapy resistance, targeted therapy sensitivity, and long-term toxicities to select which patients would be ideally served by specific treatments. Empiric trials enrolling unselected populations will not be acceptable in the future.

In addition, as cure rates increase, the specter of long-term complications becomes pronounced. The situation of a clinic patient who is free of disease but whose quality of life is tremendously impacted can no longer be considered a positive outcome. The therapeutic window for treating locally advanced head and neck cancer has narrowed with more intensive regimens. The valid justification for this has been the paramount objective of survival. However, we may be over-treating some patients while rehabilitation and post-treatment therapy remain an afterthought. We must discover the determinants of long-term morbidity, develop technologies to reduce their incidence, and institute wide scale standards for speech, swallowing, and psychologic and physical rehabilitation.

On behalf of all the contributors, we hope you enjoy this issue of Seminars and that it will bring us closer to the visions expressed in the collected articles.