To review radiation fractionation and chemotherapy trials for patients undergoing organ preservation therapy for locally advanced head and neck squamous cell carcinoma.

Radiation therapy fractionation and chemotherapy trial results as well as historical evidence are systematically reviewed.

Trial results, which involve nearly 30,000 patients, have been interpreted, compared, and presented in a structured manner to demonstrate the changing approaches in treatment over the years from the 1960s to the present. The review includes data from the split-course radiation therapy era, meta-analyses of chemotherapy and radiation therapy fractionation trials, cetuximab trials, "triple-drug trials," and modern trials of induction chemotherapy followed by concomitant chemotherapy and radiation therapy.

This summary will be useful to clinicians making treatment decisions today and to investigators designing trials in the future.