A Phase II Single Arm Trial of Elective Volume Adjusted De-Escalation Radiotherapy (EVADER) in Patients with Low-risk HPV-related Oropharyngeal Squamous Cell Carcinoma

Abstract

Purpose/Objective(s)

Human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) is effectively treated with radiotherapy (RT) with or without concurrent chemotherapy (CRT). These treatments are highly efficacious but can cause significant toxicities. Reducing the volume of elective nodal irradiation (ENI) to uninvolved cervical nodal levels is one strategy for limiting toxicity. CCTG HN.10 (NCT03822897) evaluated whether volume-reduced ENI would result in acceptable disease control and survival rates in patients with HPV-related OPSCC.

Materials/Methods

In this multi-center prospective phase II single arm trial, eligible patients had stage T1-3 N0-1 M0 (8th Ed. TNM) HPV-related OPSCC treated with definitive RT or CRT. Patients received 70 Gy over 7 weeks if eligible for concurrent cisplatin or over 6 weeks if treated with RT alone. For all patients, volume-reduced ENI was tailored to primary location, T-category, and distribution of involved nodes. RT contours underwent central quality assurance prior to treatment. Primary endpoint was 2-year event-free survival (EFS), and secondary endpoints included locoregional control (LRC), out-of-field regional control, overall survival (OS), toxicity, and quality of life. With an expected 2-year EFS of 91% in this population, 100 eligible patients would provide 80% power to detect a clinically meaningful 6% EFS decrement with one-sided alpha of 0.1. The null hypothesis would be rejected if 2-year EFS exceeded 88.85%.

Results

CCTG HN.10 accrued 103 patients from 2/2019 through 12/2021. As of the data cut-off date for this final analysis (May 31, 2024), median follow-up was 37 (0-56) months, and total person-years follow-up was 304.7. Median age was 62.8 years, 82.5% were male, 87.4% were T1-2, 89.3% were N1, 26.2% had smoked >10 pack-years. Among 100 treated patients, all completed RT, with 50 also receiving cisplatin. Grade 3 and 4 toxicities were observed in 46% and 1%, respectively. In 99 eligible patients, 2-year EFS was 91.8% (95% CI: 86.6%-97.4%), surpassing the protocol-specified threshold. In secondary analysis, there were 5 LRC events including 1 out-of-field regional control event; 2-year OS was 94.7% (95% CI: 90.2%-99.3%). Subgroup analysis showed identical 2-year EFS among patients treated with RT or CRT. By 24 months post-RT, quality of life measurements approximated baseline whereby FACT-HN overall scores and MDADI composite scores improved by mean of 0.41 (N=85, SD=14.8) and declined by mean of 3.58 (N=85, SD=16.2), respectively.

Conclusion

For patients with HPV-related OPSCC treated with radical RT, volume-reduced ENI as defined in this study can be safely performed while maintaining high efficacy with rare out-of-field regional failures. This de-escalation strategy should continue to be evaluated in rigorously conducted trials.