Head and neck squamous cell carcinoma: Optimizing the therapeutic index

The four recent noteworthy strategies aimed at improving therapeutic outcomes for the curative treatment of head and neck squamous cancers include the development of altered fractionation regimens, integration of chemotherapy, incorporation of intensity-modulated radiation therapy and introduction of targeted biologic therapy. Clinical investigations during the last 30 years have demonstrated the benefits of biologically sound altered fractionation and concurrent chemoradiation regimens in improving locoregional control and overall survival. These results have contributed to redefining the standard of care, with the caveat that proper patient selection for those who will benefit from potentially toxic combined modality treatment regimens remains controversial. These benefits have come at the expense of increased acute toxicity (i.e., mucositis) and sometimes at the expense of late toxicity (i.e., fibrosis and dysphagia). There are two additional developments that may help to further widen the therapeutic ratio. Intensity-modulated radiation therapy allows for the delivery of a highly conformal 3D radiation dose distribution around intended targets, thereby limiting the volumes of mucosa receiving a high dose per fraction and high total doses. The technical basis for intensity-modulated radiation therapy delivery reopens many fractionation questions that are still being addressed and challenges us to determine which of these is optimal for use with intensity-modulated radiation therapy alone or in combination with concurrent sensitizers. Finally, combined radiation therapy and biologic therapies directed at targets expressed predominately or exclusively by tumor cells have the promise to help increase tumor cell kill, while at least not substantially increasing normal tissue toxicity. These strategies are reviewed in a clinical context.