Nadeem Riaz1,2, Eric Sherman3, Xin Pei1, Heiko Schöder4, Milan Grkovski5, Ramesh Paudyal5, Nora Katabi6, Pier Selenica6, Takafumi N Yamaguchi7,8,9, Daniel Ma10, Simon K Lee6, Rachna Shah1, Rahul Kumar11, Fengshen Kuo2, Abhirami Ratnakumar1, Nathan Aleynick6, David Brown11, Zhigang Zhang12, Vaios Hatzoglou4, Lydia Y Liu7,8,9,13,14, Adriana Salcedo8,13, Chiaojung J Tsai1, Sean McBride1, Luc G T Morris2,15, Jay Boyle15, Bhuvanesh Singh15, Daniel S Higginson1, Rama R Damerla1, Arnaud da Cruz Paula6, Katharine Price16, Eric J Moore17, Joaquin J Garcia18, Robert Foote10, Alan Ho3, Richard J Wong15, Timothy A Chan1,2,19, Simon N Powell1, Paul C Boutros7,8,9,13,20,21,22, John L Humm5, Amita Shukla-Dave4,5, David Pfister3, Jorge S Reis-Filho6,19, Nancy Lee1. 1. Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. 2. Immunogenomics and Precision Oncology Platform, Memorial Sloan Kettering Cancer Center, New York, NY, USA. 3. Department of Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. 4. Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. 5. Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY, USA. 6. Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. 7. UCLA, Department of Human Genetics, Los Angeles, CA, USA. 8. Informatics and Biocomputing Program, Ontario Institute for Cancer Research, Toronto, ON, USA. 9. Jonsson Comprehensive Cancer Centre, University of California, Los Angeles, CA, USA. 10. Department of Radiation Oncology, Mayo Clinic, Rochester, MN, USA. 11. Institute for Cancer Genetics, Columbia University, New York, NY, USA. 12. Departmant of Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA. 13. Department of Medical Biophysics, University of Toronto, Toronto, ON, USA. 14. Vector Institute for Artificial Intelligence, Toronto, ON, USA. 15. Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. 16. Divison of Medical Oncology, Mayo Clinic, Rochester, MN, USA. 17. Department of Otolaryngology, Mayo Clinic, Rochester, MN, USA. 18. Department of Pathology, Mayo Clinic, Rochester, MN, USA. 19. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. 20. Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, USA. 21. Department of Urology, University of California, Los Angeles, CA, USA. 22. Institute for Precision Health, University of California, Los Angeles, CA, USA.
Abstract
BACKGROUND: Patients with human papillomavirus-related oropharyngeal cancers have excellent outcomes but experience clinically significant toxicities when treated with standard chemoradiotherapy (70 Gy). We hypothesized that functional imaging could identify patients who could be safely deescalated to 30 Gy of radiotherapy. METHODS: In 19 patients, pre- and intratreatment dynamic fluorine-18-labeled fluoromisonidazole positron emission tomography (PET) was used to assess tumor hypoxia. Patients without hypoxia at baseline or intratreatment received 30 Gy; patients with persistent hypoxia received 70 Gy. Neck dissection was performed at 4 months in deescalated patients to assess pathologic response. Magnetic resonance imaging (weekly), circulating plasma cell-free DNA, RNA-sequencing, and whole-genome sequencing (WGS) were performed to identify potential molecular determinants of response. Samples from an independent prospective study were obtained to reproduce molecular findings. All statistical tests were 2-sided. RESULTS: Fifteen of 19 patients had no hypoxia on baseline PET or resolution on intratreatment PET and were deescalated to 30 Gy. Of these 15 patients, 11 had a pathologic complete response. Two-year locoregional control and overall survival were 94.4% (95% confidence interval = 84.4% to 100%) and 94.7% (95% confidence interval = 85.2% to 100%), respectively. No acute grade 3 radiation-related toxicities were observed. Microenvironmental features on serial imaging correlated better with pathologic response than tumor burden metrics or circulating plasma cell-free DNA. A WGS-based DNA repair defect was associated with response (P = .02) and was reproduced in an independent cohort (P = .03). CONCLUSIONS: Deescalation of radiotherapy to 30 Gy on the basis of intratreatment hypoxia imaging was feasible, safe, and associated with minimal toxicity. A DNA repair defect identified by WGS was predictive of response. Intratherapy personalization of chemoradiotherapy may facilitate marked deescalation of radiotherapy.
BACKGROUND: Patients with human papillomavirus-related oropharyngeal cancers have excellent outcomes but experience clinically significant toxicities when treated with standard chemoradiotherapy (70 Gy). We hypothesized that functional imaging could identify patients who could be safely deescalated to 30 Gy of radiotherapy. METHODS: In 19 patients, pre- and intratreatment dynamic fluorine-18-labeled fluoromisonidazole positron emission tomography (PET) was used to assess tumor hypoxia. Patients without hypoxia at baseline or intratreatment received 30 Gy; patients with persistent hypoxia received 70 Gy. Neck dissection was performed at 4 months in deescalated patients to assess pathologic response. Magnetic resonance imaging (weekly), circulating plasma cell-free DNA, RNA-sequencing, and whole-genome sequencing (WGS) were performed to identify potential molecular determinants of response. Samples from an independent prospective study were obtained to reproduce molecular findings. All statistical tests were 2-sided. RESULTS: Fifteen of 19 patients had no hypoxia on baseline PET or resolution on intratreatment PET and were deescalated to 30 Gy. Of these 15 patients, 11 had a pathologic complete response. Two-year locoregional control and overall survival were 94.4% (95% confidence interval = 84.4% to 100%) and 94.7% (95% confidence interval = 85.2% to 100%), respectively. No acute grade 3 radiation-related toxicities were observed. Microenvironmental features on serial imaging correlated better with pathologic response than tumor burden metrics or circulating plasma cell-free DNA. A WGS-based DNA repair defect was associated with response (P = .02) and was reproduced in an independent cohort (P = .03). CONCLUSIONS: Deescalation of radiotherapy to 30 Gy on the basis of intratreatment hypoxia imaging was feasible, safe, and associated with minimal toxicity. A DNA repair defect identified by WGS was predictive of response. Intratherapy personalization of chemoradiotherapy may facilitate marked deescalation of radiotherapy.
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