Precision Radiotherapy: Reduction in Radiation for Oropharyngeal Cancer in the 30 ROC Trial

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.

Value of PET imaging for radiation therapy

“…Several prospective clinical trials have assessed the value of [ 18 F]FMISO-PET for patient stratification. A recently published prospective clinical phase II study suggests that radiation dose may be deescalated from K 70 Gy to 30 Gy in oropharyngeal cancer patients with no hypoxia on [ 18 F]FMISO-PET prior to or with a re-oxygenating tumour during radiation treatment [51]. [ 18 F]FLT-PET, an imaging biomarker of tumour cell proliferation in HNSCC, also holds high prognostic value regarding locoregional control [52][53][54].…”

“…Imaging biomarkers measured with hypoxia tracers such as [ 18 F]FMISO and [ 18 F]FAZA but also with routine [ 18 F]FDG have been shown to be prognostic for outcome after radiotherapy [43,46,48,209,[252][253][254][255][256]. Consequently, radiation treatment adaptation by means of PET-guided dose escalation or de-escalation to account for individual radiation sensitivities in tumour sub-regions, so-called dose painting, seems attractive and might enable for increased tumour control rates and/or reduced toxicity [51,252,257]. Final results from randomized studies are necessary to estimate the full potential of PET-based dose painting RT [51,252,258,259].…”

Value of PET imaging for radiation therapy

“…Several prospective clinical trials have assessed the value of [ 18 F]FMISO-PET for patient stratification. A recently published prospective clinical phase II study suggests that radiation dose may be deescalated from 70 Gy to 30 Gy in oropharyngeal cancer patients with no hypoxia on [ 18 F]FMISO-PET prior to or with a re-oxygenating tumour during radiation treatment [51]. [ 18 F]FLT-PET, an imaging biomarker of tumour cell proliferation in HNSCC, also holds high prognostic value regarding locoregional control [52][53][54].…”

“…Imaging biomarkers measured with hypoxia tracers such as [ 18 F]FMISO and [ 18 F]FAZA but also with routine [ 18 F]FDG have been shown to be prognostic for outcome after radiotherapy [43,46,48,209,[252][253][254][255][256]. Consequently, radiation treatment adaptation by means of PET-guided dose escalation or de-escalation to account for individual radiation sensitivities in tumour sub-regions, so-called dose painting, seems attractive and might enable for increased tumour control rates and/or reduced toxicity [51,252,257]. Final results from randomized studies are necessary to estimate the full potential of PET-based dose painting RT [51,252,258,259].…”

“…Consequently, radiation treatment adaptation by means of PET-guided dose escalation or de-escalation to account for individual radiation sensitivities in tumour sub-regions, so-called dose painting, seems attractive and might enable for increased tumour control rates and/or reduced toxicity [51,252,257]. Final results from randomized studies are necessary to estimate the full potential of PET-based dose painting RT [51,252,258,259].…”