A multicenter, prospective, phase 2 trial on proton re‐irradiation for patients with previously treated head and neck cancer
Edward Christopher Dee, Christopher A. Barker, Noah S. Kalman, Yingzhi Wu, Charlie White, Zhigang Zhang, Haibo Lin, Daphna Y. Gelblum, Yao Yu, Jung Julie Kang, C. Jillian Tsai, Kaveh Zakeri, Linda Chen, Sean M. McBride, Achraf Shamseddine, Loren S. Michel, Lara A. Dunn, Alan L. Ho, Marc A. Cohen, Ian Ganly, Jennifer R. Cracchiolo, Richard J. Wong, Paul B. Romesser, Nadeem Riaz, Eric J. Sherman, Nancy Y. LeeAbstract
Background
Re‐irradiation (re‐RT) for recurrent head and neck cancer (HNC) can be potentially curative but is constrained by significant toxicity. Proton therapy may improve the therapeutic ratio. This multicenter phase 2 trial evaluated the safety and efficacy of proton re‐RT in patients with HNC.
Methods
Patients received prior HNC radiotherapy at a dose of ≥40 gray (Gy). Salvage surgery and/or systemic therapy before re‐RT were permitted. Considering clinical status, two pragmatic treatment approaches were used: fractionated re‐RT (F‐Re‐RT; 60–70 Gy) or QUAD shot re‐RT (QS‐Re‐RT; 14.8 Gy per cycle, up to four cycles; maximum total, 59.2 Gy). Primary end points were locoregional recurrence–free rates at 12 months for F‐Re‐RT and at 6 months for QS‐Re‐RT, and a fixed‐time, binary proportion analyzed using 90% Clopper–Pearson confidence intervals (CIs) and prespecified success thresholds (lower bound, >55% and >10%, respectively). Secondary end points included overall survival (OS), progression‐free survival, the cumulative incidence of distant metastasis and locoregional recurrence, clinician‐reported toxicity, and patient‐reported outcomes.
Results
From July 2017 to November 2022, 85 patients received either F‐Re‐RT ( n = 57) or QS‐Re‐RT ( n = 28), with a median follow‐up of 38 months. The locoregional recurrence–free rates were 71% (90% CI, 59%–81%) at 12 months for F‐Re‐RT and 76% (90% CI, 58%–89%) at 6 months for QS‐Re‐RT, surpassing prespecified success thresholds. The highest late toxicity attributable to re‐RT was grade 3 in 20% of patients, grade 4 in 11%, and grade 5 in 4%. The 5‐year OS rate was 29%, and the 5‐year progression‐free survival rate was 23%. Patient‐reported outcomes were stable at 1 year after F‐Re‐RT and after QS‐Re‐RT.
Conclusions
Proton re‐RT demonstrated encouraging locoregional control and survival in heavily pretreated patients, although late toxicities remain important concerns (ClinicalTrials.gov identifier: NCT03217188).