Transoral robotic surgical resection followed by randomization to low- or standard-dose IMRT in resectable p16+ locally advanced oropharynx cancer: A trial of the ECOG-ACRIN Cancer Research Group (E3311).

Abstract

6500 Background: ECOG-ACRIN 3311 examines reduced postoperative therapy in patients with “intermediate risk” p16+ oropharynx cancer (OPC) undergoing primary transoral surgical management. We report the primary endpoint of 2-year progression free survival (PFS) for patients randomized to 50Gy vs 60Gy without chemotherapy. Methods: Between December 2013 and July 2017, 82 credentialed surgeons performed transoral resection (TOS) for 519 OPC patients (cT1-2 stage III/IV AJCC7 without matted neck nodes); post-operative management was determined by pathologically assessed risk. Among 353 eligible and treated patients, Arm A enrolled 10% (N=37) for clear margins, 0-1 nodes, no extranodal extension (ENE)), Arms B (50Gy, N=102) or C (60Gy, N=104) randomized 58%, for clear/close margins, 2-4 + nodes, or ENE ≤1mm, while Arm D (N=110, 60-66Gy plus weekly cisplatin, 40 mg/m2, positive margin with any T stage, >4 + nodes, or >1mm ENE) enrolled 31%. Arm D assignment was based on >1mm ENE (76%), > 4 nodes (27%), and/or positive margins (11%). Intermediate-risk patients were stratified by smoking history (>10 pk-yr). Of the 80 pts (15%) deemed ineligible, 28 had scans/labs not done per protocol, however treatment arm distribution for all patients mirrored that for the 353 pts eligible and treated. Results: Median follow-up was 31.8 months. 2 yr PFS for Arms A, B and C were 93.9% (90% CI=87.3%, 100%), 95.0% (90% CI=91.4%, 98.6%) and 95.9% (90% CI=92.6%, 99.3%) respectively, while Arm D was 90.5% (90% CI=85.9%, 95.3%). The regimen of TOS + low-dose radiation is considered worthy of further study, since the primary endpoint of the upper bound of the 90% CI (in the intermediate risk group) exceeding 85% was met. Of 17 progression events, 7 were locoregional. There were 10 distant recurrences: Arm A=1, Arm B=2, Arm C=4, Arm D=3. Grade III/IV treatment-related AE rates were 15%/2% during surgery, 13%/2% for Arm B and 25%/0% for Arm C. There were 2 treatment-related deaths (one surgical and one Arm D). Conclusions: Transoral resection of p16+ OPC is safe and results in good oncologic outcome, presenting a promising deintensification approach. For patients with low-risk disease, 2-yr PFS is favorable without post-operative therapy. For those with uninvolved surgical margins, <5 involved nodes, and minimal (<1mm) ENE, reduced dose postoperative RT without chemotherapy appears sufficient. Transoral surgery plus 50Gy should be compared to optimal non-surgical therapy in a phase III trial. Clinical trial information: NCT01898494 .

Significance of Extranodal Extension in Surgically Treated HPV-Positive Oropharyngeal Carcinomas

“…Patients with macroscopic ENE had the worst outcome (HR = 2.50; 95% CI = 1.39-4.51; p = 0.002) (5). In addition to that, recent data even differentiate between the categories "no ENE, " "minimal ENE" (≤1 mm beyond the lymph node capsule"), and ">1 mm beyond the lymph node capsule" (6).…”

Optimization of therapeutic strategy for p16‐positive oropharyngeal squamous cell carcinoma: Multi‐institutional observational study based on the national Head and Neck Cancer Registry of Japan

“…Chera et al reported that a deintensified chemoradiotherapy regimen of 60 grays of intensity‐modulated RT with concurrent low‐dose cisplatin provides a favorable outcome in patients with AJCC eighth edition T0‐T3, N0‐N2 disease 15 . Recently, Ferris et al demonstrated that the transoral resection of p16‐positive OPSCC is safe and results in a good oncologic outcome; the authors presented a promising deintensification approach at the 2020 American Society of Clinical Oncology annual meeting 16 . However, none of these trials reduced the dose of cisplatin in the low‐intensity arm compared with the standard‐therapy arm.…”

Systematic review of postoperative therapy for resected squamous cell carcinoma of the head and neck: Executive summary of the American Radium Society appropriate use criteria

“…16 The ECOG 3311 phase II clinical trial has completed followup and will determine the efficacy of reduced-dose PORT (50 Gy) compared to standard PORT (60 Gy) for patients with intermediate-risk cancers, negative margins, and ≤1 mm extranodal extension (NCT01898494). At the time of this publication, ECOG 3311 is published in abstract form 123 with a median follow-up of 31.8 months and suggests that 50 Gy may be sufficient for such patients. The reduced dose arm will be carried forward into subsequent phase III trials.…”