Synchrotron radiation therapy for the treatment of cancer

Abstract

Despite advances in radiation oncology there remain numerous clinical scenarios where radiation therapy, in conjunction with other cancer therapies, is unable to significantly improve disease prognosis. Advanced lung cancer, pancreatic cancer, and aggressive paediatric brain tumours such as Diffuse Intrinsic Pontine Glioma are examples of incurable diseases with an extremely poor prognosis.

Synchrotron-based radiation therapy modalities challenge classical radiobiology paradigms and could address these unmet clinical needs. The two synchrotron radiation therapy modalities investigated in this thesis are microbeam radiation therapy (MRT) and high dose-rate synchrotron broad-beam radiation therapy (SBBR). The brilliance and minimal divergence of synchrotron-generated radiation gives MRT and SBBR physical properties that are distinctly different to conventional radiation therapy (CRT). Pre-clinical animal studies demonstrate the potential of these unique physical characteristics to both control tumours and reduce radiation-induced damage to healthy tissue.

The purpose of this thesis was to present radiobiological data that would inform future veterinary and clinical trials of MRT and/or SBBR. Specific objectives were to: 1) produce systematic toxicity data for organs of the head, thorax and abdomen, 2) characterise dose-equivalence between MRT, SBBR and CRT based on both in vitro and in vivo techniques, 3) describe the differential effects of MRT and broad-beam radiation therapy on healthy tissue at a molecular level, and, 4) identify optimal clinical scenarios were MRT could be applied, considering the limitations imposed by normal tissue toxicity.

Based on total and partial body dose-escalation studies in a murine model, MRT peak doses of approximately 120 Gy and 260 Gy were equivalent to approximately 7 Gy and 12.5 Gy, respectively. The MRT valley dose was a better predictor of normal tissue toxicity than the MRT peak dose, and for SBBR, a normal tissue sparing effect (ie. a ‘FLASH’ effect) could not be detected at a dose-rate of 35-40 Gy/s. Based on a treatment planning study using clinical datasets, small recurrent glioblastomas and head and neck tumours demonstrated the most favourable MRT dosimetry.

This thesis includes the first in vivo dose-equivalence data for synchrotron radiation therapy compared to conventional radiation therapy and the first MRT toxicity data for total body, abdominal and thoracic irradiation. These data are essential for designing safe treatment regimens for future veterinary trials and ultimately, the first human clinical trial of MRT and/or SBBR.