Expanding the therapeutic index of radiation therapy by normal tissue protection

Abstract

Normal tissue damages induced by radiation therapy remain dose-limiting factors in radiation oncology and this is still true despite recent advances in treatment planning and delivery of image-guided radiation therapy. Additionally, as the number of long-term cancer survivors increases, unacceptable complications emerge and dramatically reduce the patients' quality of life. This means that patients and clinicians expect discovery of new options for the therapeutic management of radiation-induced complications. Over the past four decades, research has enhanced our understanding of the pathophysiological, cellular and molecular processes governing normal tissue toxicity. Those processes are complex and involve the cross-talk between the various cells of a tissue, including fibroblasts, endothelial, immune and epithelial cells as well as soluble paracrine factors including growth factors and proteases. We will review the translatable pharmacological approaches that have been developed to prevent, mitigate, or reverse radiation injuries based upon the targeting of cellular and signalling pathways. We will summarize the different steps of the research strategy, from the definition of initial biological hypotheses to preclinical studies and clinical translation. We will also see how novel research and therapeutic hypotheses emerge along the way as well as briefly highlight innovative approaches based upon novel radiotherapy delivery procedures.

Ultra-High Dose Rate (FLASH) Radiotherapy: Silver Bullet or Fool's Gold?

“…Consequently, there is a need for novel RT strategies that maintain the anti-tumor effect whilst limiting the extent of toxicities induced in the surrounding healthy tissue. Limiting the induction of toxicities to normal tissue would subsequently increase the therapeutic index of RT regimes (7). A number of recent studies have demonstrated that irradiation at ultra-high dose rates (FLASH) diminishes the severity of toxicities in normal tissues compared to irradiation at the conventional dose rates (CONV) currently used in clinical practice (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18).…”

Dual benefit of supplementary oral 5‐aminolevulinic acid to pelvic radiotherapy in a syngenic prostate cancer model

“…Studies over the past several decades have investigated the pathophysiological and molecular mechanisms underlying RT's effects on tumors and normal tissue. [5][6][7] Although several pharmacological approaches that prevent and mitigate radiation injury in normal tissues have been examined in preclinical studies, only a few have progressed to clinical use. 5 5-aminolevulinic acid (ALA) is widely used to induce protoporphyrin IX (PPIX), a photosensitizer used in photodynamic diagnosis and therapy for non-muscle invasive bladder cancer.…”

“…[5][6][7] Although several pharmacological approaches that prevent and mitigate radiation injury in normal tissues have been examined in preclinical studies, only a few have progressed to clinical use. 5 5-aminolevulinic acid (ALA) is widely used to induce protoporphyrin IX (PPIX), a photosensitizer used in photodynamic diagnosis and therapy for non-muscle invasive bladder cancer. 8,9 ALA is distributed ubiquitously in mammalian cells and is a precursor of tetrapyrole compounds such as heme, which is essential in aerobic energy metabolism and the electron transport system.…”

“…Recent technical advances in the field of RT planning and delivery enable the administration of higher radiation doses with equal or less toxicity. Studies over the past several decades have investigated the pathophysiological and molecular mechanisms underlying RT's effects on tumors and normal tissue . Although several pharmacological approaches that prevent and mitigate radiation injury in normal tissues have been examined in preclinical studies, only a few have progressed to clinical use …”

Proton Irradiation Increases the Necessity for Homologous Recombination Repair Along with the Indispensability of Non-Homologous End Joining

“…In contrast, photons lose their energy exponentially, with higher values at the entry point and lower values at the deep-seated tissues [12][13][14]. Additionally, the rising number of particle therapy centers worldwide facilitates the use of protons or heavy ions in the clinical care of cancer patients and allows the validation of the suspected superiority of particle beams compared to photon beams in terms of normal tissue protection [15,16].…”