Abstract
Although treatment modalities for head and neck cancer have evolved considerably over the past decades, survival rates have plateaued. The treatment options remained limited to definitive surgery, surgery followed by fractionated radiotherapy with optional chemotherapy, and a definitive combination of fractionated radiotherapy and chemotherapy. Lately, immunotherapy has been introduced as the fourth modality of treatment, mainly administered as a single checkpoint inhibitor for recurrent or metastatic disease. While other regimens and combinations of immunotherapy and targeted therapy are being tested in clinical trials, adapting the appropriate regimens to patients and predicting their outcomes have yet to reach the clinical setting. Radiotherapy is mainly regarded as a means to target cancer cells while minimizing the unwanted peripheral effect. Radiotherapy regimens and fractionation are designed to serve this purpose, while the systemic effect of radiation on the immune response is rarely considered a factor while designing treatment. To bridge this gap, this review will highlight the effect of radiotherapy on the tumor microenvironment locally, and the immune response systemically. We will review the methodology to identify potential targets for therapy in the tumor microenvironment and the scientific basis for combining targeted therapy and radiotherapy. We will describe a current experience in preclinical models to test these combinations and propose how challenges in this realm may be faced. We will review new players in targeted therapy and their utilization to drive immunogenic response against head and neck cancer. We will outline the factors contributing to head and neck cancer heterogeneity and their effect on the response to radiotherapy. We will review in-silico methods to decipher intertumoral and intratumoral heterogeneity and how these algorithms can predict treatment outcomes. We propose that (a) the sequence of surgery, radiotherapy, chemotherapy, and targeted therapy should be designed not only to annul cancer directly, but to prime the immune response. (b) Fractionation of radiotherapy and the extent of the irradiated field should facilitate systemic immunity to develop. (c) New players in targeted therapy should be evaluated in translational studies toward clinical trials. (d) Head and neck cancer treatment should be personalized according to patients and tumor-specific factors.