Table 4.
Conventional and experimental therapeutic opportunities for radiation fibrosis.
| Conventional therapeutics | Clinical significance | Reference(s) |
|---|---|---|
| Anti-inflammatory agents | Both steroidal and non-steroidal anti-inflammatory agents have been administered in studies conducted in vitro and in vivo to ameliorate the acute inflammatory stage preceding fibrosis. Their ability to mitigate established fibrosis has yet to be conclusively documented. These agents may also be constrained by early administration to prophylactically prevent fibrosis onset, and their use could be limited by potential toxicities after prolonged administration. | 1,3,136 |
| Antioxidant agents | Antioxidants mitigate oxidative stress and the profibrotic effects of ROS generated after radiation. Superoxide dismutases (SODs) and other antioxidants like tocopherol/vitamin E demonstrated radioprotective effects and attenuation of profibrotic activities in vitro and in vivo; however, results from clinical studies have been mixed. | 1,136, 137, 138, 139, 140 |
| Vascular therapies | Hyperbaric oxygen is administered in pathologies associated with ischemia, hypoxia, and impaired oxygen delivery to promote wound healing and vessel regrowth. Few studies have examined its success in the clinical treatment of radiation fibrosis, and its efficacy as a standalone therapeutic agent remains controversial. Novel findings from the “HONEY” randomized controlled trial suggest that completion of a hyperbaric oxygen therapy regimen (30–40 therapeutic sessions over 6–8 weeks) may reduce pain and fibrosis in breast cancer patients with late radiation toxicities. | 54,141,142 |
| Pentoxifylline (PTX) is an anti-inflammatory, anti-fibrotic, and anti-coagulating agent that increases blood flow. Among its various effects, PTX is known to interfere with the production and signalling of inflammatory cytokines, such as TNF-α, and has also been associated with alterations in fibrotic gene expression, and improved outcomes in studies of radiation fibrosis patients. | 43,143 | |
| Experimental therapeutics | ||
| TGF-β-related therapeutics | Neutralizing antibodies, gene therapies, and the administration of recombinant soluble TGFBR2 receptors targeting TGF-β signalling have all been examined in fibrosis models and demonstrated success in limiting the amount of active TGF-β in situ or reducing downstream signal transduction; however, given the pleiotropic role of TGF-β, novel systemic therapies must be well-tolerated with respect to off-target side-effects. | 1,144, 145, 146, 147 |
| CTGF-related therapeutics | CTGF blockade using the Pamrevlumab monoclonal antibody attenuated pulmonary remodelling and improved median survival in an animal model. In a Phase 2 randomized trial for IPF, it also decelerated the decline of lung function and disease progression, while being relatively well-tolerated. | 148,149 |
| Statins | Statin-mediated inhibition of Rho/ROCK signalling reduced histopathological changes post-irradiation, including reductions in collagen synthesis, CTGF deposition, and overall fibrosis development. The “PRAVACUR” Phase 2 trial investigated the efficacy of Pravastatin in HNC patients, which demonstrated the potential to reduce the thickness and severity of fibrotic tissues. | 150, 151, 152 |
| RTKI | RTKIs target PDGFR-dependent signalling, thus reducing the proliferation of fibroblasts as well as downstream profibrotic signalling. Imatinib mesylate was found to attenuate radiation fibrosis in animal models. Similar findings were observed using Nintedanib in a pulmonary radiation fibrosis animal model. | 102,153,154 |
| ACE inhibitors | ACE inhibitors suppress the effects of the renin-angiotensin-aldosterone system, including matrix remodelling events. In an animal model, Captopril reduced matrix remodelling and preserved organ function, however radiation toxicities still occurred. Enalapril was well-tolerated in a Phase 2 clinical trial, though patients demonstrated an increased incidence of fibrosis. The clinical role of ACE inhibitors, if any, requires further investigation. | 155, 156, 157 |
| Stem cell therapies | ADSCs are a source of antifibrotic HGF and have been tested for their ability to mitigate cutaneous, muscular, and skeletal fibrosis. Their extracellular vesicles reduce profibrotic gene expression. Stem cells may also be pertinent in regenerating fibrotic tissues affected by atrophy or necrosis, though future studies are necessary. | 158,159 |
| Cellular reprogramming | Cellular reprogramming provides a modality through which abnormal cells, such as myofibroblasts, may be ushered back to a normal phenotype to drive the regression of fibrotic tissue. In a murine liver fibrosis model, viral vector-mediated reprogramming converted myofibroblasts to a hepatocyte-like state and was associated with a decrease in fibrosis. In addition, cellular reprogramming may be utilized to preferentially drive myofibroblast FAO metabolism in conjunction with ECM catabolism to counteract fibrosis. | 160,161 |