MRI-informed hypoxia-based proton radiotherapy dose escalation for head-and-neck cancer-a proof-of-concept

Partially as a result of hypoxia-induced radioresistance, rates of treatment failure for head-and-neck cancer patients receiving radiotherapy can be considerable. Clinical trials utilizing positron emission tomography (PET) to image tumor hypoxia and escalate the prescription dose in hypoxic sub-volumes are being pursued in response, with current clinical prescription doses of 70 Gy generally escalated to 77-78 Gy. Instead utilizing magnetic resonance imaging (MRI) for hypoxia-based prescription dose escalation would be associated with a variety of advantages, including not requiring an additional imaging-related radiation dose to be delivered to the patient and allowing for a variety of other functional maps to be extracted from the same patient imaging session, in addition to tumor hypoxia information.

The purpose of this study is to investigate the benefits of MRI-informed hypoxia-based radiotherapy dose escalation for head-and-neck cancer patients treated with proton radiotherapy.

Ten patients with head-and-neck cancer scheduled to undergo photon therapy underwent a multi-parametric MRI protocol based on which tumor hypoxia maps were computed for every patient using a quantitative blood oxygenation level dependent (BOLD) approach. Four proton therapy treatment plans were then created for each patient, consisting of intensity-modulated proton therapy (IMPT) and proton arc therapy (PAT) treatment planning performed according to current clinical standards (IMPT_Conv and PAT_Conv) or with a 10% prescription dose escalation to the hypoxic sub-volumes of the low- and high-risk target structures (IMPT_Esc and PAT_Esc). The generated treatment plans were then analyzed with respect to target and organ-at-risk (OAR) doses and normal tissue complication probabilities (NTCPs) as well as tumor control probabilities (TCPs) calculated according to conventional models (TCP_Conv) or with consideration of hypoxia-induced radioresistance (TCP_Hyp). Statistical significance (p < 0.05) of different TCP or mean OAR dose distributions was determined using the Wilcoxon signed-rank test.

During IMPT, radiotherapy prescription dose escalation increased TCP_Conv in the nominal scenario by (5.9 ± 6.3) percentage points (pp) in the normoxic (p < 0.001) and (5.2 ± 9.0) pp in the hypoxic target volumes (p = 0.006). In the worst-case scenario, TCP_Conv was increased by (5.6 ± 4.5) pp (p < 0.001) and (5.3 ± 6.4) pp (p = 0.003). Dose escalation during PAT improved TCP_Conv by (3.1 ± 3.3) pp (p < 0.001) and (2.1 ± 5.4) pp (p = 0.015) in the nominal scenario and (3.3 ± 3.1) pp (p < 0.001) and (3.3 ± 4.4) pp (p < 0.001) in the worst-case scenario. When hypoxia-induced radioresistance was considered, dose escalation elevated TCP_Hyp in the nominal scenario by (7.6 ± 4.5) pp (p < 0.001) during IMPT and (6.4 ± 4.1) pp (p < 0.001) during PAT and TCP_Hyp in the worst-case scenario by (6.3 ± 3.8) pp (p < 0.001) during IMPT and (6.3 ± 3.1) pp (p < 0.001) during PAT. Compared to the patients' clinical photon therapy treatment plans in the nominal scenario, mean OAR doses were reduced by (13.5 ± 9.3)Gy RBE by IMPT_Conv, (14.3 ± 10.5)Gy RBE by PAT_Conv, (9.8 ± 10.5)Gy RBE by IMPT_Esc, and (10.4 ± 12.8)Gy RBE by PAT_Esc (all p = 0.002).

MRI-based hypoxia-informed radiotherapy prescription dose escalation during both IMPT and PAT significantly increased calculated TCPs while significantly reducing doses delivered to nearby healthy organs compared to the patients' clinical photon therapy treatment plans. MRI-based hypoxia-informed prescription dose escalation is therefore considered feasible and may help partially address hypoxia-induced radioresistance.