A risk-adjusted treatment strategy for human papillomavirus-positive (HPV+) oropharyngeal cancer led to a 2-year progression-free survival (PFS) rate approaching 100% in both high- and low-risk patients, a small nonrandomized trial showed.
Patients classified as low risk by disease status and smoking history had a 2-year PFS rate of 95%, declining only to 94% for high-risk patients. Two-year overall survival was 100% and 97% in low- and high-risk patients, respectively, treated with a radiotherapy protocol adapted to patients’ response to induction chemotherapy.
The treatment approach also resulted in less acute and chronic toxicity, as compared with historical results with standard chemoradiation protocols, as reported online in Annals of Oncology.
“As you can see from the data, we’ve had very few recurrences,” said senior author Everett E. Vokes, MD, of the University of Chicago. “It’s not from a randomized trial, so that still needs to be done, but it’s very good evidence. We’ve had very good survival. It allows, in about two thirds of patients, to give significantly less radiation.”
HPV infection accounts for 60-70% of all new cases of oropharyngeal cancer in the U.S. In contrast to HPV- disease, HPV+ oropharyngeal squamous cell carcinoma (OPSCC) has a more favorable prognosis, associated with long-term survival exceeding 70%, even in advanced-stage (III/IV) disease, as compared with about 30% for HPV- tumors.
The more favorable outlook for HPV+ OPSCC provided impetus for investigation of less intensive treatment strategies that have the goal of reducing treatment-related toxicity without sacrificing effective disease control. Results of two large randomized trials illustrated the potential risks of de-escalation, as patients who received the targeted agent cetuximab (Erbitux) instead of platinum-based chemotherapy had higher recurrence rates and worse survival.
In contrast, de-escalation strategies focusing on reducing the radiation dose have shown promise for attaining a balance between safety and efficacy. Results of a small phase II trial showed a high PFS and favorable safety profile when the radiation therapy dose was adjusted according to patients’ response to induction chemotherapy. Two other studies reported at the American Society for Radiation Oncology meeting showed reduced toxicity, quicker recovery, and lower costs associated with de-escalation of radiotherapy.
“You have to be very careful [with de-escalation strategies] because every patient who has treatment failure is a patient who potentially could have been cured,” said Vokes.
Further honing the approach to de-escalation, investigators adjusted the radiation dose on the basis of pretreatment risk stratification and response to induction chemotherapy. Low-risk patients had disease stage ≤T3, nodal status ≤N2B, and smoking history ≤10 pack year history (PYH). High risk was defined as T4 or ≥N2C or >10 PYH.
All patients started treatment with three cycles of carboplatin/nab-paclitaxel (Abraxane) induction therapy. Low-risk patients who attained at least a 50% response received a 50-Gy dose of radiotherapy (as opposed to the standard 70-75 Gy). Low-risk patients who had responses of 30-50% and high-risk patients who had ≥50% response received additional chemotherapy plus a radiotherapy dose of 45 Gy (CRT). All other patients received CRT with 75 Gy of radiation.
The trial had a primary endpoint of PFS at 2 years and had statistical power within a range of ±11% to demonstrate noninferiority of the risk-adjusted approach versus 85% for a historical control group. The study population consisted of 28 low-risk patients and 34 with high-risk disease. On the basis of their response to induction therapy, 71% of low-risk patients received a 50-Gy radiation dose and 21% received 45 Gy. In the high-risk subgroup, 71% received the 45-Gy dose.
Overall, 89% of patients responded to induction chemotherapy, including 71% who had ≥50% reduction in tumor size. Response rates were similar in low- and high-risk patients.
After a median follow-up for the patients of 29 months, the 2-year PFS for the entire cohort was 94.5%, which met statistical criteria for noninferiority. The entire study population had a 2-year overall survival of 98%.
Acute grade 3+ toxicity included mucositis rates that increased from 30% with a 50-Gy radiation dose to 63% with 45-Gy CRT to 91% with 75-Gy CRT (P=0.004) and dermatitis that occurred in 0-55% across the three treatment groups (P<0.0001). Use of a feeding tube increased with treatment intensity from 0% to 82% (P<0.0001).
“I do think this is something that the cooperative groups should pick up and do a randomized trial,” said Vokes. “In the meantime, we continue to use this approach. We can’t go back to 70 Gray when we have these kinds of results.”
The study was supported by Celgene.
Vokes disclosed relationships with AbbVie, Amgen, AstraZeneca, Biolumina, Bristol-Myers Squibb, Celgene, Eli Lilly, EMD Serono, Genentech, Merck, Novartis, and Regeneron.