Definitive Chemo-Radiotherapy With or Without Up-front Neck Dissection for Regionally Advanced Head and Neck Squamous Cell Carcinoma: A Phase III Multi-center Prospective Randomized Controlled Trial With Two Additional Observational Cohorts

The main objective of this project is to test the hypothesis that the addition of UFND prior to (C)RT results in a significant reduction of treatment toxicities and improvement of QoL in regionally advanced (cN2-3) HNSCC through dose de-escalation and volume reduction of RT.

The primary endpoint of this trial is to evaluate the toxicity from the beginning of radiotherapy until 90 days after the end of the treatment. The incidence of acute and subacute toxicities higher than grade ≥3 (CTCAE v.4, except for Xerostomia, for which RTOG/EORTC scale will be used) will be compared between study arms. Secondary endpoints include the survival endpoints for both treatment modalities; i.e. loco-regional control, progression-free and overall survival. Assessment of QoL (EORTC QLQ-C30 + H&N43), late toxicity, surgical complications, cost-effectiveness and the need of feeding-tube will be a part of the final analysis of this trial.

Trial design: randomized multi-center open-label comparative one-staged phase III trial with a superiority design and the primary endpoint of highest grade radiation toxicity during and until 90 days after the completion of the treatment. Interventions in both arms of the trial are considered as standard treatments. No experimental diagnostic tools will be used during the trial. In addition to the randomized arms, two identical observational arms will be opened for the patients who are diagnosed before the activation of the randomized arms, and subsequently for those who refuse to be randomized. Their aim is to prospectively acquire high quality data for patients who refuse randomization. The observational and randomized cohorts will be analyzed separately for the pre-defined endpoints.

For the calculation of the sample size, grade ≥3 acute radiation toxicity in the CRT alone (Arm A) was assumed as 70% based on literature. For the primary endpoint, a follow-up period of 90 days after the last day of (C)RT is needed after the accrual of the last patient. However, 2 years of follow-up after (C)RT is needed for the secondary endpoints (exception: oncological outcome and survival will be calculated from the day of randomization in order to avoid immortal time bias). On this basis, sample size was calculated based on the Pearson chi-squared test and performed in Stata. Assuming a toxicity fraction of 70% for any grade 3 or higher toxicity in Arm A, a relative risk of 0.5 (35% in Arm B), a two-sided alpha of 0.05, a power of 80%, a drop-out rate of 5%, and an allocation ratio of 1 we calculated an overall sample size of 65. Expected accrual time is 3 years.