In the phase II NRG Oncology HN002 trial reported in the Journal of Clinical Oncology, Sue S. Yom, MD, PhD, and colleagues found that a reduced-dose intensity-modulated radiation therapy (IMRT) regimen for human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma satisfied predetermined criteria for advancement to phase III evaluation.
As noted by the investigators, the current standard therapy for locoregionally advanced oropharyngeal squamous cell carcinoma—consisting of 70 Gy of radiation therapy with concurrent platinum chemotherapy—can be associated with severe short- and long-term toxicities.
Sue S. Yom, MD, PhD
Study Details
The trial included 306 eligible patients from sites in four countries with p16-positive, T1–T2 N1–N2b M0, or T3 N0–N2b M0 oropharyngeal squamous cell carcinoma and ≤ 10 pack-years of smoking. Patients were randomly assigned between October 2014 and February 2017 to receive 60 Gy of IMRT in 30 fractions at 5 fractions per week over 6 weeks, plus weekly cisplatin at 40 mg/m2 (IMRT+C group, n = 157) or 60 Gy of IMRT alone at 6 fractions per week over 5 weeks (IMRT group, n = 149).
To be considered for a phase III study, a group had to achieve 2-year progression-free survival superior to a historical control rate of 85% and a 1-year mean composite score of ≥ 60 on the MD Anderson Dysphagia Inventory (MDADI). The binomial 2-year progression-free survival estimates and exact 90% lower confidence bound (LCB) were calculated, with the null hypothesis of a rate ≤ 85% being tested against the alternative of > 85% with a one-sided binomial exact test at the 0.10 level.
Treatment Outcomes
Two-year progression-free survival in the IMRT+C group was 90.5% (90% LCB = 86.6%, P =.04), rejecting the null hypothesis. In the IMRT group, 2-year progression-free survival was 87.6% (90% LCB = 83.3%, P = .23). The hazard ratio (HR) for comparison between groups was 0.67 (P = .20). One-year MDADI mean scores were 85.30 vs 81.76. The 1-year mean changes from baseline were −5.62 vs −6.22 (P = .78).
Two-year rates were 3.3% vs 9.5% for locoregional failure (HR = 0.39, P = .02), 4.0% vs 2.1% for distant metastasis (HR = 1.43, P = .58), and 96.7% vs 97.3% for overall survival (HR = 0.95, P = .93).
KEY POINTS
- A regimen of IMRT 60 Gy in 30 fractions at 5 fractions per week over 6 weeks plus weekly cisplatin met criteria for testing in a phase III trial.
- Progression-free survival at 2 years was 90.5% with IMRT plus cisplatin vs 87.6% with IMRT alone at 60 Gy in 30 fractions at 6 fractions per week over 5 weeks.
Toxicity
Grade 3 or 4 acute toxicity (occurring within 180 days from end of treatment) occurred in 79.6% of patients in the IMRT+C group vs 52.4% of patients in the IMRT group (P < .001), including grade 4 toxicity in 15.1% vs 2.0%. The most common in the IMRT+C group were grade 3 or 4 lymphocyte decrease (54.6% vs 23.8%), grade 3 oral mucositis (23.1% vs 23.1%), and grade 3 dysphagia (17.8% vs 7.5%). Late grade 3 or 4 toxicity occurred in 21.3% vs 18.1% of patients (P = .56; lymphocyte decrease in 10.7% vs 4.9%), including grade 4 toxicity in 1.3% vs 1.4%.
The investigators concluded: “The IMRT+C arm met both prespecified endpoints, justifying advancement to a phase III study. Higher rates of grade ≥ 3 acute adverse events were reported in the IMRT+C arm.”
They stated: “The next step as determined within NRG Oncology is a randomized phase II and III trial (ClinicalTrials.gov identifier NCT03952585) that directly compares 70 Gy against 60 Gy given with the same bolus cisplatin regimen and against 60 Gy with nivolumab, with co-primary endpoints of progression-free survival and swallowing quality of life.”
Dr. Yom, of the Department of Radiation Oncology, University of California San Francisco, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was supported by grants from the National Cancer Institute. For full disclosures of the study authors, visit ascopubs.org.
