Phase II Randomized Trial of Transoral Surgery and Low-Dose Intensity Modulated Radiation Therapy in Resectable p16+ Locally Advanced Oropharynx Cancer: An ECOG-ACRIN Cancer Research Group Trial (E3311)

Abstract

Purpose: Definitive or postoperative chemoradiation (CRT) is curative for human papillomavirus-associated (HPV+) oropharynx cancer (OPC) but induces significant toxicity. As a deintensification strategy, we studied primary transoral surgery (TOS) and reduced postoperative radiation therapy (RT) in intermediate-risk HPV+ OPC.

Methods: E3311 is a phase II randomized trial of reduced- or standard-dose postoperative RT for resected stage III-IVa (American Joint Committee on Cancer-seventh edition) HPV+ OPC, determined by pathologic parameters. Primary goals were feasibility of prospective multi-institutional study of TOS for HPV+ OPC, and oncologic efficacy (2-year progression-free survival) of TOS and adjuvant therapy in intermediate-risk patients after resection. TOS plus 50 Gy was considered promising if the lower limit of the exact 90% binomial confidence intervals exceeded 85%. Quality of life and swallowing were measured by functional assessment of cancer therapy-head and neck and MD Anderson Dysphagia Index.

Results: Credentialed surgeons performed TOS for 495 patients. Eligible and treated patients were assigned as follows: arm A (low risk, n = 38) enrolled 11%, intermediate risk arms B (50 Gy, n = 100) or C (60 Gy, n = 108) randomly allocated 58%, and arm D (high risk, n = 113) enrolled 31%. With a median 35.2-month follow-up for 359 evaluable (eligible and treated) patients, 2-year progression-free survival Kaplan-Meier estimate is 96.9% (90% CI, 91.9 to 100) for arm A (observation), 94.9% (90% CI, 91.3 to 98.6]) for arm B (50 Gy), 96.0% (90% CI, 92.8 to 99.3) for arm C (60 Gy), and 90.7% (90% CI, 86.2 to 95.4) for arm D (66 Gy plus weekly cisplatin). Treatment arm distribution and oncologic outcome for ineligible or step 2 untreated patients (n = 136) mirrored the 359 evaluable patients. Exploratory comparison of functional assessment of cancer therapy-head and neck total scores between arms B and C is presented.

Conclusion: Primary TOS and reduced postoperative RT result in outstanding oncologic outcome and favorable functional outcomes in intermediate-risk HPV+ OPC.

Conflict of interest statement

Robert L. FerrisThis author is a member of the Journal of Clinical Oncology Editorial Board. Journal policy recused the author from having any role in the peer review of this manuscript.Stock and Other Ownership Interests: NovasentaConsulting or Advisory Role: Merck, Pfizer, EMD Serono, Numab, Macrogenics, Aduro Biotech, Novasenta, Sanofi, Zymeworks, Bristol Myers SquibbResearch Funding: Bristol Myers Squibb, AstraZeneca/MedImmune, Merck, Tesaro, Novasenta Gregory S. WeinsteinPatents, Royalties, Other Intellectual Property: Olympus Shuli LiEmployment: TakedaStock and Other Ownership Interests: Takeda Harry QuonEmployment: Johns Hopkins HospitalLeadership: Pistevo HealthStock and Other Ownership Interests: Oncospace, Pistevo HealthHonoraria: Sanofi/RegeneronConsulting or Advisory Role: Pinnacle Biologics, Tactile MedicalResearch Funding: Toshiba, Vibrent HealthPatents, Royalties, Other Intellectual Property: Filed under Hopkins, we have several patents related to mobile informatics solutionsOther Relationship: EPIC Ranee MehraStock and Other Ownership Interests: GlaxoSmithKline (I)Consulting or Advisory Role: Bayer, Rakuten MedicalResearch Funding: AstraZeneca, Merck Christine H. ChungConsulting or Advisory Role: Bristol Myers Squibb, CUE Biopharma, Mirati Therapeutics, Sanofi/Regeneron, ExelixisResearch Funding: AstraZeneca, Bristol Myers Squibb, Lilly, Merck, Regeneron, Ignyta, Pfizer, Brooklyn ImmunoTherapeutics, Iovance BiotherapeuticsTravel, Accommodations, Expenses: AstraZeneca, Mirati Therapeutics Maura L. GillisonConsulting or Advisory Role: Bristol Myers Squibb, Merck, EMD Serono, Kura Oncology, BioNTech, Shattuck Labs, Bayer, Debiopharm Group¸ Ipsen, Gilead Sciences¸ Bicara Therapeutics, Nektar¸ Istari, LLX Solutions, OncLive, Seagen, Kura Oncology, Mirati Therapeutics, Sensei BiotherapeuticsResearch Funding: Bristol Myers Squibb, Genocea Biosciences, Cullinan Oncology, Genentech, Agenus, Kura Oncology Umamaheswar DuvvuriConsulting or Advisory Role: ACTIVARTIS BiotechResearch Funding: Kolltan Pharmaceuticals, Medrobotics Bert W. O'Malley JrPatents, Royalties, Other Intellectual Property: Receive royalties from University of Pennsylvania via a licensed technology to Olympus Inc Neil D. GrossHonoraria: Intuitive SurgicalConsulting or Advisory Role: PDS Biotechnology, Verb Surgical, Sanofi/Regeneron, Shattuck LabsResearch Funding: Regeneron, MedImmune, GenentechPatents, Royalties, Other Intellectual Property: UpToDate R. Bryan BellHonoraria: Merck, RegeneronConsulting or Advisory Role: MacrogenicsSpeakers' Bureau: Merck, RegeneronResearch Funding: Bristol Myers Squibb/Celgene Nabil F. SabaHonoraria: Merck, CUE Biopharma, BioNTech AG, GlaxoSmithKlineResearch Funding: Bristol-Myers Squibb, ExelixisTravel, Accommodations, Expenses: Merck, Pfizer, Blueprint Medicines Barbara BurtnessConsulting or Advisory Role: Merck, Debiopharm Group, CUE Biopharma, Maverick Therapeutics, Rakuten Medical, Nanobiotix, Macrogenics, ALX Oncology, IO Biotech, Ipsen, Genentech/Roche, Kura Oncology, Merck KGaA, PPD Global, ExelixisResearch Funding: Merck (Inst), Aduro Biotech (Inst), Formation Biologics (Inst), Bristol Myers (Inst), CUE Biopharma (Inst)Travel, Accommodations, Expenses: Merck, Debiopharm GroupNo other potential conflicts of interest were reported.

Figures

FIG 1.

CONSORT diagram.

FIG 2.

Kaplan-Meier estimates of PFS by arm for 359 evaluable patients. PFS, progression-free survival.

FIG 3.

Kaplan-Meier estimates of OS by arm for 359 evaluable patients. OS, overall survival.

FIG 4.

(A) Swallowing and (B) QOL. QOL, quality of life; Trt and/or Obs, treatment and/or observation; Tx, treatment.

FIG A1.

Kaplan-Meier estimates of PFS for 71 ineligible and step 2 treated patients. PFS, progression-free survival.

FIG A2.

Kaplan-Meier estimates of OS for 71 ineligible and step 2 treated patients. OS, overall survival.

FIG A3.

Kaplan-Meier estimates of PFS for 430 step 2 treated patients (eligible and ineligible combined). PFS, progression-free survival.

FIG A4.

Kaplan-Meier estimates of OS for 430 step 2 treated patients (eligible and ineligible combined). OS, overall survival.