**4. Clinical Trials: Other Therapeutic Avenues, Antifibrotics**

#### *4.1. Antifibrotic or Antioxidant Pharmacological Agents*

Vitamin E has protectiveeffects against oxidative stress and also plays an important role in preventing lipid peroxidation in the cellular membrane [39]. Between April 2003 and July 2009, 53 breast cancer patients were recruited to determine if a combination of Pentoxifylline (PTX) and Vitamin E could prevent the development of radiation fibrosis after radiotherapy for the definitive management (NCT00583700). This clinical study of post-irradiation cancer patients treated with PTX/vitamin E showed a significant difference in radiation-induced fibrosis. Of importance, the combination of PTX/vitamin E did not impact local control or survival within the first 2 years of follow-up (which is still quite a short follow-up). The oral PTX/vitamin E treatment was safe and well-tolerated. After pelvic irradiation in high-risk patients, the combination of Pentoxifylline (PTX) and Vitamin E can thus be considered clinically useful in preventing fibrosis [40,41]. Orgotein copperzinc superoxide dismutase (SOD) is an enzyme found in various tissues throughout the body and has a fundamental role in the elimination of reactive oxidative species and free radicals that cause tissue damage and fibrosis [42]. SOD was found to be effective in reducing radiation-induced fibrosis by a reduced pain score and a decrease in the size of the fibrotic area in half of the cases after 6 months in 44 patients with clinical radiofibrosis following conservative treatment of breast cancer [43]. However, the role of antifibrotic agents in reducing or mitigating radiation cystitis remains unknown.

#### *4.2. Angiotensin-Converting-Enzyme Inhibitors*

An initial clinical study had revealed that angiotensin-converting-enzyme inhibitors mightdecrease the incidence of radiation pneumonitis in patients receiving thoracic radiation for lung cancer [44]. An ongoing clinical study (NCT01754909) is evaluating the efficacy of enalapril on radiation pneumonitis and fibrosis for patients undergoing radiation therapy for lung cancer or other intrathoracic cancers. A recently published phase 2 prospective study supported the notion of radio-induced fibrosis reversibility, showing that pravastatin (40 mg/d for 12 months) was an efficient antifibrotic agent in patients with grade ≥ 2 cutaneous and subcutaneous fibrosis following head and neck radiotherapy [45]. However, no data are available in the setting of radiation cystitis.
