OPTIMA: A Phase II Dose and Volume De-Escalation Trial for Human Papillomavirus-Positive Oropharyngeal Cancer.

Background: Patients with HPV+ oropharyngeal squamous cell carcinoma (OPSCC) were assigned to dose and volume de-escalated radiotherapy (RT) or chemoradiotherapy (CRT) based on response to induction chemotherapy in an effort to limit treatment-related toxicity while preserving efficacy.

Patients and Methods: Patients were classified as low-risk (≤T3, ≤N2B, ≤10 pack-year history [PYH]) or high-risk (T4 or ≥N2C or > 10 PYH). After 3 cycles of carboplatin/nab-paclitaxel, response was assessed using Response Evaluation Criteria in Solid Tumors 1.1. Low-risk patients with ≥50% response received 50 Gray (Gy) RT (RT50) while low-risk patients with 30-50% response or high-risk patients with ≥50% response received 45Gy CRT (CRT45). Patients with lesser response received standard-of-care 75Gy CRT (CRT75). RT/CRT was limited to the first echelon of uninvolved nodes. The primary endpoint was 2-year progression-free survival (PFS) compared to a historic control of 85%. Secondary endpoints included overall survival (OS) and toxicity.

Results: Sixty-two patients (28 low-risk/34 high-risk) were enrolled. Of low-risk patients, 71% received RT50 while 21% received CRT45. Of high-risk patients, 71% received CRT45. With a median follow-up of 29 months, 2-year PFS and OS were 95% and 100% for low-risk patients and 94% and 97% for high-risk patients, respectively. The overall 2-year PFS was 94.5% and within the 11% non-inferiority margin for the historic control. Grade 3+ mucositis occurred in 30%, 63%, and 91% of the RT50, CRT45, and CRT75 groups, respectively (p=0.004). Rates of any PEG-tube use were 0%, 31%, and 82% for RT50, CRT45, and CRT75 groups, respectively (p<0.0001).

Conclusions: Induction chemotherapy with response and risk-stratified dose and volume de-escalated RT/CRT for HPV+ OPSCC is associated with favorable oncologic outcomes and reduced acute and chronic toxicity. Further evaluation of induction-based de-escalation in large multicenter studies is justified.

Trial Registration: Clinical trials.gov identifier: NCT02258659.