Introduction: Head and neck squamous cell carcinoma (HNSCC) is the seventh most common cancer worldwide. Conventional chemoradiotherapy remains the standard of care, but prolonged courses present challenges, especially in low-resource settings. Hypofractionated radiotherapy may offer an effective and resource-efficient alternative. Methods: An IAEA phase III randomized controlled clinical trial (HYPNO trial) involving the Oncology Institute of Havana, Cuba, enrolled patients from 2014 to 2018. Seventy-five patients with locally advanced HNSCC were randomized to receive conventional normofractionated radiotherapy or hypofractionated IMRT, both with concurrent low-dose chemotherapy. Outcomes included tumor response, locoregional control, survival, and toxicity. Results: The median age was 56.8 years, 88% were men, 59.5% reported being smokers and alcohol drinkers, and the oropharynx was the site of the highest incidence (78.7%). One month after treatment, a complete response was achieved in 91.4% of normofractionated patients versus 74.3% of hypofractionated patients. An improvement in tumor and lymph node response was observed at three months in the hypofractionated group, suggesting late but favorable tumor regression. Locoregional control at three years was 62.9% for the normofractionated arm versus 69.2% for the normofractionated arm. Overall survival at five years was 54.1% and at nine years was 48%. Late toxicity was lower in the hypofractionated group (12.8% versus 37.1%; p = 0.03). Conclusion: Hypofractionated radiotherapy concomitant with chemotherapy is a safe and effective option.
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