Durable therapeutic gain despite competing mortality in long-term follow-up of a randomized hyperfractionated radiotherapy trial for locally advanced head and neck cancer

Abstract

To examine the therapeutic ratio and mortality profile over time in a radiotherapy randomized trial in stage III-IV larynx/pharynx cancer with long-term follow-up. Materials/methods: From 1988 to 1995, 331 cases were randomized to either hyperfractionated (HF) (58 Gy/40 fractions, twice daily) or conventional (CF) (51 Gy/20 fractions, once daily) radiotherapy. Overall survival (OS), locoregional (LRC), distant control (DC), Grade 3 late toxicity (LT), and relative mortality risk profile over time were compared between both arms. Results: Median follow-up was 13.6 years. HF had a 10% improved OS at 5-years (40% vs 30%, p = 0.04), but the benefit diminished to 3% at 10-years (21% vs 18%). A trend towards higher LRC with HF remained (5-year: 49% vs 40%; 10-year: 49% vs 39%, p = 0.05). DC rates were unchanged (5-year: 87% vs 85%; 10year: 87 vs 84%, p = 0.56). LT rates were similar (HF vs CF: 5-year: 9% vs 12%; 10-year: 11% vs 14%, p = 0.27). Multivariable analysis confirmed that HF reduced mortality risk by 31% [HR 0.69 (0.55-0.88), p < 0.01] and locoregional failure risk by 35% [HR 0.65 (0.48-0.89), p < 0.01]. Index cancer mortality (5-year: 46% vs 51%; 10-year: 49% vs 55%) was lower in the HF arm. Competing mortality (mostly smoking-related) was also numerically lower with HF at 5-years (14% vs 19%) but became similar at 10-years (30% vs 28%). Conclusions: This trial confirms that HF with augmented total dose has a durable 10% effect size on LRC with comparable LT. OS benefit is evident at 5-years (10%) but relative mortality risk profile changes in longer follow-up.

Hypofractionated radiotherapy alone with 2.4 Gy per fraction for head and neck cancer during the COVID‐19 pandemic: The Princess Margaret experience and proposal

“…11 Moreover, hypofractionated radiotherapy (RT-hypo) schedules have typically not been included in phase 3 randomized trials other than rarely as a control arm. [11][12][13][14] Thus, contemporary data are needed to evaluate the outcomes of RT-hypo alone in comparison with other altered-fractionation regimens or standard-fractionation CCRT. We reasoned that this analysis would identify HNSCC subgroups that could obtain similar rates of locoregional control (LRC) and distant control (DC) when managed with RT-hypo alone in comparison with CCRT and thus facilitate evidence-based HNC care in response to the COVID-19 pandemic.…”

“…However, these approaches were not addressed in the Meta‐Analysis of Radiotherapy in squamous cell Carcinomas of Head and neck of altered‐fractionation regimens, nor are there other randomized trial data from which to draw the usual inferences about efficacy 11 . Moreover, hypofractionated radiotherapy (RT‐hypo) schedules have typically not been included in phase 3 randomized trials other than rarely as a control arm 11‐14 . Thus, contemporary data are needed to evaluate the outcomes of RT‐hypo alone in comparison with other altered‐fractionation regimens or standard‐fractionation CCRT.…”