Chronic Toxicity Rates With De-escalated vs Standard Adjuvant Radiotherapy in HPV-Associated Oropharyngeal Squamous Cell Carcinoma

In a U.S. two-center phase III trial (MC1675) reported in The Lancet Oncology, Ma et al found that de-escalated adjuvant radiotherapy was associated with a reduced cumulative, chronic grade ≥ 3 toxicity rate at 3 to 24 months after radiotherapy compared with standard adjuvant treatment in patients with newly diagnosed human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma.

Study Details

In the open-label trial, 194 patients from two U.S. Mayo Clinic sites were randomly assigned 2:1 between October 2016 and August 2020 to receive de-escalated adjuvant radiotherapy with 30 to 36 Gy in 1.5- to 1.8-Gy fractions twice per day over 2 weeks plus docetaxel at 15 mg/m² on days 1 and 8 (n = 130) or standard of care with 60 Gy in 2-Gy fractions once daily over 6 weeks plus cisplatin at 40 mg/m² once a week (n = 64). Patients had pathologic stage III to IV HPV-associated oropharyngeal squamous cell carcinoma and more than 70% p16-immunoreactivity on immunohistochemistry evaluation of the surgical specimen. The primary outcome measure was cumulative, chronic grade ≥ 3 toxicity rate at 3 to 24 months after radiotherapy.

Key Findings

Median follow-up was 37.3 months (interquartile range = 27.6–49.2 months).

A total of five patients in the de-escalated group and two in the standard group were excluded from analysis of the primary outcome measure.

The cumulative chronic grade ≥ 3 toxicity rate at 3 to 24 months was 3% (4 of 125 patients) in the de-escalated group vs 11% (7 of 62 patients) in the standard group (P = .042); the cumulative chronic percutaneous endoscopic gastric tube rate was 2% vs 8% (P = .039).

The most common grade ≥ 3 toxic effects in the de-escalated adjuvant radiotherapy group were dysphagia (n = 2, 2%), esophagitis (n = 1, 1%), and hearing impairment (n = 1, 1%). Those in the standard group consisted of dysphagia (n = 5, 8%), esophagitis (n = 1, 2%), fatigue (n = 1, 2%), pain (n = 1, 2%), and osteonecrosis of the jaw (n = 1, 2%).

The investigators concluded: “De-escalated adjuvant radiotherapy was a more tolerable treatment in terms of chronic toxicities, demonstrating less cumulative grade 3 or higher toxicity compared with standard of care. Further clinical trials exploring indications for the DART [de-escalated adjuvant radiotherapy] regimen are warranted.”

Daniel Ma, MD, of the Department of Clinical Oncology, Mayo Clinic, Rochester, Minnesota, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by the Department of Radiation Oncology, Mayo Clinic, Minnesota and Arizona, the Braillier Family Research Fund, and the Matteson Family Research Fund. For full disclosures of all study authors, visit thelancet.com.