Randomized Controlled Trial of Hypofractionated vs. Normo-fractionated Accelerated Radiation Therapy with or without Cisplatin for Locally Advanced Head and Neck Squamous Cell Carcinoma (HYPNO)

Purpose/Objective(s) HYPNO, a multi-center, two-arm, unblinded phase III trial, tested definitive hypofractionated (HFX) vs. normofractionated (NFX) accelerated RT ±cisplatin for locally advanced HNSCC. HYPNO opened in 12 centers in 10 low- and middle-income countries. We hypothesized HFX (55 Gy, 20F, 5F/wk over 4 weeks) is non-inferior to NFX (66 Gy, 33F, 6F/wk over 5.5 weeks) ± weekly cisplatin with a non-inferiority margin, Δ, chosen as an absolute difference of 10% at 3 years for the coprimary endpoints of loco-regional control (LRC) and Grade 3+ late adverse events (LAE). Chosen Δ corresponds to critical hazard ratios of 1.31 (LRC) and 1.5 (LAE). Materials/Methods 792 pts. were centrally randomized Mar 2014 to Feb 2020, 395 to HFX, 397 to NFX. Accrual closed, with all outcome data still blinded, with 792 of a planned 836 pts. (94.7%) enrolled, in part due to the emerging COVID-19 pandemic, in part due to accrual leveling off. Chemoradiation, prescribed before randomization, consisted of i.v. cisplatin 35 mg/m2 weekly during RT, 4 cycles in HFX arm, 5 in NFX arm. Stratification factors (distribution): Performance status 0-1 v. 2 (3.7%); Chemotherapy n v. y (75.8%); Tumor subsite: oral cavity (8.5%) v. oropharynx (50.5%) v. hypopharynx (13.5%) v. larynx (24.5%) v. other (3.0%), and institution. Enrollees were 86.9% males; 38.1% current and 39.3% former smokers; T3-4 (72.7%); N2-3 (49.1%). HYPNO allowed institutions to use their standard clinical RT technique: 2D (22.5%) v. 3D (7.1%) v. IMRT (70.2%). 3-year Kaplan-Meier estimates were used for time-to-event outcomes and compared with the logrank test based on full follow-up time available. Results 3-year outcomes (see table). HFX was non-inferior for the coprimary endpoints. For LRC, HR=1.098, 95% CI (0.929, 1.298), non-inferiority p=0.041. For LAE G3+, HR=0.926, 95% CI (0.684, 1.253), non-inferiority p=0.004. Regarding early adverse events, max grade of mucositis was 3+ in 190/373 (50.9%) of cases after HFX and 208/380 (54.7%) after NFX, Fisher's Exact Test p=0.307. Conclusion HYPNO shows hypofractionated accelerated RT is non-inferior to the 6-fractions-a-week schedule with respect to both loco-regional tumor control and Grade 3+ late adverse events. In addition to passing the non-inferiority test, the 3-year outcomes were remarkably similar with an absolute difference of <1.5% between the two arms. This result is potentially practice changing. Treating in 20 fractions instead of 33 is both resource sparing and more convenient to patients. HYPNO is, to the best of our knowledge, the largest randomized controlled trial with this level of complexity conducted in the setting of low- and middle-income countries. HYPNO, a multi-center, two-arm, unblinded phase III trial, tested definitive hypofractionated (HFX) vs. normofractionated (NFX) accelerated RT ±cisplatin for locally advanced HNSCC. HYPNO opened in 12 centers in 10 low- and middle-income countries. We hypothesized HFX (55 Gy, 20F, 5F/wk over 4 weeks) is non-inferior to NFX (66 Gy, 33F, 6F/wk over 5.5 weeks) ± weekly cisplatin with a non-inferiority margin, Δ, chosen as an absolute difference of 10% at 3 years for the coprimary endpoints of loco-regional control (LRC) and Grade 3+ late adverse events (LAE). Chosen Δ corresponds to critical hazard ratios of 1.31 (LRC) and 1.5 (LAE). 792 pts. were centrally randomized Mar 2014 to Feb 2020, 395 to HFX, 397 to NFX. Accrual closed, with all outcome data still blinded, with 792 of a planned 836 pts. (94.7%) enrolled, in part due to the emerging COVID-19 pandemic, in part due to accrual leveling off. Chemoradiation, prescribed before randomization, consisted of i.v. cisplatin 35 mg/m2 weekly during RT, 4 cycles in HFX arm, 5 in NFX arm. Stratification factors (distribution): Performance status 0-1 v. 2 (3.7%); Chemotherapy n v. y (75.8%); Tumor subsite: oral cavity (8.5%) v. oropharynx (50.5%) v. hypopharynx (13.5%) v. larynx (24.5%) v. other (3.0%), and institution. Enrollees were 86.9% males; 38.1% current and 39.3% former smokers; T3-4 (72.7%); N2-3 (49.1%). HYPNO allowed institutions to use their standard clinical RT technique: 2D (22.5%) v. 3D (7.1%) v. IMRT (70.2%). 3-year Kaplan-Meier estimates were used for time-to-event outcomes and compared with the logrank test based on full follow-up time available. 3-year outcomes (see table). HFX was non-inferior for the coprimary endpoints. For LRC, HR=1.098, 95% CI (0.929, 1.298), non-inferiority p=0.041. For LAE G3+, HR=0.926, 95% CI (0.684, 1.253), non-inferiority p=0.004. Regarding early adverse events, max grade of mucositis was 3+ in 190/373 (50.9%) of cases after HFX and 208/380 (54.7%) after NFX, Fisher's Exact Test p=0.307. HYPNO shows hypofractionated accelerated RT is non-inferior to the 6-fractions-a-week schedule with respect to both loco-regional tumor control and Grade 3+ late adverse events. In addition to passing the non-inferiority test, the 3-year outcomes were remarkably similar with an absolute difference of <1.5% between the two arms. This result is potentially practice changing. Treating in 20 fractions instead of 33 is both resource sparing and more convenient to patients. HYPNO is, to the best of our knowledge, the largest randomized controlled trial with this level of complexity conducted in the setting of low- and middle-income countries.