Hypoxia-Directed Treatment of Human Papillomavirus-Related Oropharyngeal Carcinoma

Abstract

Purpose: Standard curative-intent chemoradiotherapy for human papillomavirus (HPV)-related oropharyngeal carcinoma results in significant toxicity. Since hypoxic tumors are radioresistant, we posited that the aerobic state of a tumor could identify patients eligible for de-escalation of chemoradiotherapy while maintaining treatment efficacy.

Methods: We enrolled patients with HPV-related oropharyngeal carcinoma to receive de-escalated definitive chemoradiotherapy in a phase II study (ClinicalTrials.gov identifier: NCT03323463). Patients first underwent surgical removal of disease at their primary site, but not of gross disease in the neck. A baseline ¹⁸F-fluoromisonidazole positron emission tomography scan was used to measure tumor hypoxia and was repeated 1-2 weeks intratreatment. Patients with nonhypoxic tumors received 30 Gy (3 weeks) with chemotherapy, whereas those with hypoxic tumors received standard chemoradiotherapy to 70 Gy (7 weeks). The primary objective was achieving a 2-year locoregional control (LRC) of 95% with a 7% noninferiority margin.

Results: One hundred fifty-eight patients with T0-2/N1-N2c were enrolled, of which 152 patients were eligible for analyses. Of these, 128 patients met criteria for 30 Gy and 24 patients received 70 Gy. The 2-year LRC was 94.7% (95% CI, 89.8 to 97.7), meeting our primary objective. With a median follow-up time of 38.3 (range, 22.1-58.4) months, the 2-year progression-free survival (PFS) and overall survival (OS) rates were 94% and 100%, respectively, for the 30-Gy cohort. The 70-Gy cohort had similar 2-year PFS and OS rates at 96% and 96%, respectively. Acute grade 3-4 adverse events were more common in 70 Gy versus 30 Gy (58.3% v 32%; P = .02). Late grade 3-4 adverse events only occurred in the 70-Gy cohort, in which 4.5% complained of late dysphagia.

Conclusion: Tumor hypoxia is a promising approach to direct dosing of curative-intent chemoradiotherapy for HPV-related carcinomas with preserved efficacy and substantially reduced toxicity that requires further investigation.

FIG 1.

A phase II clinical trial of personalized radiotherapy for oropharyngeal cancer (30-ROC). (A) Protocol schema illustrating typical positive and negative FMISO PET scans pre- and repeated intratreatment along with which patients received 30 Gy versus 70 Gy. (B) CONSORT diagram of all enrolled patients (n = 158), illustrating excluded patients (n = 6) and aggregate statistics for FMISO PET pre- and repeated intratreatment results. (C) Radiotherapy volumes (PTVs) for a typical case on study in a patient with a T1N2c base of tongue tumor. Note that the green contour is PTV that targets microscopic disease and receives 30 Gy regardless of hypoxia status. Red contour highlighting gross nodal disease will receive 30 or 70 Gy depending on hypoxia status. FDG PET, fluorodeoxyglucose positron emission tomography; FMISO PET, 18F-fluoromisonidazole positron emission tomography; PTV, planning target volume; ROC, reduction in oropharyngeal carcinoma.

FIG 2.

Oncologic outcomes. (A) Cumulative incidence of LRR for the entire cohort using competing risk analysis. (B) PFS by treatment group. (C) OS by treatment group. LRR, locoregional recurrence; OS, overall survival; PFS, progression-free survival.

FIG 3.

Toxicity and dysphagia-related outcomes. Modified barium swallow objective assessments using DIGEST score (0 is within normal limits, and 4 denotes profound dysphagia) for the 30-Gy cohort.