Hypoxia-Directed Treatment of Human Papillomavirus–Related Oropharyngeal Carcinoma

Author(s): Nancy Y. Lee, MD1, Eric J. Sherman, MD2, HeiKo Schöder, MD, MBA3, Rick Wray, MD3, Jay O. Boyle, MD4, Bhuvanesh Singh, MD, PhD4, Milan Grkovski, PhD5, Ramesh Paudyal, PhD5, Louise Cunningham, SLPD4, Zhigang Zhang, PhD6, Vaios Hatzoglou, MD3, Nora Katabi, MD7, Bill H. Diplas, MD, PhD1, James Han, MD1, Brandon S. Imber, MD, MA1, Khoi Pham, MBA8, Yao Yu, MD1, Kaveh Zakeri, MD, MAS1, Sean M. McBride, MD, MPH1, Jung J. Kang, MD, PhD1, C. Jillian Tsai, MD, PhD1, Linda C. Chen, MD1, Daphna Y. Gelblum, MD1, Jatin P. Shah, MD4, Ian Ganly, MD, PhD4, Marc A. Cohen, MD, MPH4, Jennifer R. Cracchiolo, MD4, Luc G.T. Morris, MD, MSc4, Lara A. Dunn, MD2, Loren S. Michel, MD2, James V. Fetten, MD2, Anuja Kripani, MD, MPH, David G. Pfister, MD2, Alan L. Ho, MD, PhD2, Amita Shukla-Dave, PhD5, John L. Humm, PhD5, Simon N. Powell, MD, PhD1, Bob T. Li, MD, PhD, MPH2, Jorge S. Reis-Filho, MD, PhD7, Luis A. Diaz, MD, MSc2, Richard J. Wong, MD4, Nadeem Riaz, MD, MSc1
Source: https://doi.org/10.1200/JCO.23.01308
Anjan J Patel MD

Dr. Anjan Patel's Thoughts

Interesting study where HPV+ head/neck cancer patients were assessed with a unique PET/CT with F-fluoromisonidazole, which assesses hypoxia in tissue. If, after two weeks of chemoradiation, the tumor became hypoxic, the patients were allowed to have chemotherapy alone while nonresponders went on to complete chemoradiation. At two years of follow-up, both arms were equivalent. There is more and more interest in how to safely de-escalate HPV+ head/neck cancer patients, but still, none have shown this can be done without compromising outcomes; this may be worth following to see if this works out.


Standard curative-intent chemoradiotherapy for human papillomavirus (HPV)–related oropharyngeal carcinoma results in significant toxicity. Since hypoxic tumors are radioresistant, we posited that the aerobic state of a tumor could identify patients eligible for de-escalation of chemoradiotherapy while maintaining treatment efficacy.


We enrolled patients with HPV-related oropharyngeal carcinoma to receive de-escalated definitive chemoradiotherapy in a phase II study (ClinicalTrials.gov identifier: NCT03323463). Patients first underwent surgical removal of disease at their primary site, but not of gross disease in the neck. A baseline 18F-fluoromisonidazole positron emission tomography scan was used to measure tumor hypoxia and was repeated 1-2 weeks intratreatment. Patients with nonhypoxic tumors received 30 Gy (3 weeks) with chemotherapy, whereas those with hypoxic tumors received standard chemoradiotherapy to 70 Gy (7 weeks). The primary objective was achieving a 2-year locoregional control (LRC) of 95% with a 7% noninferiority margin.


One hundred fifty-eight patients with T0-2/N1-N2c were enrolled, of which 152 patients were eligible for analyses. Of these, 128 patients met criteria for 30 Gy and 24 patients received 70 Gy. The 2-year LRC was 94.7% (95% CI, 89.8 to 97.7), meeting our primary objective. With a median follow-up time of 38.3 (range, 22.1-58.4) months, the 2-year progression-free survival (PFS) and overall survival (OS) rates were 94% and 100%, respectively, for the 30-Gy cohort. The 70-Gy cohort had similar 2-year PFS and OS rates at 96% and 96%, respectively. Acute grade 3-4 adverse events were more common in 70 Gy versus 30 Gy (58.3% v 32%; P = .02). Late grade 3-4 adverse events only occurred in the 70-Gy cohort, in which 4.5% complained of late dysphagia.


Tumor hypoxia is a promising approach to direct dosing of curative-intent chemoradiotherapy for HPV-related carcinomas with preserved efficacy and substantially reduced toxicity that requires further investigation.

Author Affiliations

1Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, 2Department of Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, 3Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, 4Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, 5Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY, 6Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, 7Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, 8Department of Finance, Memorial Sloan Kettering Cancer Center, New York, NY

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