A Prospective Phase 2 Study of Chlorophyllin for the Management of Brain Radionecrosis in Patients With Diffuse Glioma

Radiotherapy (RT) forms an integral role in the multi modality management of diffuse gliomas. Radiation is indicated in low-grade gliomas with high-risk features or high-grade gliomas following maximal safe resection. Higher doses of RT can lead to symptomatic radio-necrosis (RN) in approximately 5-15% of patients, typically within the first 2-3 years of RT completion. Development of RN can lead to significant morbidity with new-onset or worsening of pre-existing neurodeficit with substantial implications on quality of life, and in extreme situations, can lead to mortality as well. The pathogenesis of RN is multi factorial, with a complex interplay of vascular-mediated damage and injury to glial cells primarily postulated through the activation of several inflammatory markers like tumor necrosis factor, interleukins, and vascular endothelial growth factor. Corticosteroids, preferably dexamethasone, form the first line of management of RN, with variable response rates ranging from 25-60%, impacted by several factors like a dose of RT and response evaluation methods (neurological/ radiographic). The response rate in our practice concurs with the reported literature with combined clinical and radiological responses seen in approximately 50% of patients from institutional experience and audit. It is important to note the long-standing use of corticosteroids comes at the cost of complications like hyperglycemia, myopathy, and increased risk of infections precluding prolonged use. Also, a proportion of patients remain refractory to steroids or turn out to be dependent on steroids, where bevacizumab (anti-angiogenic agent) can be used as second-line therapy in appropriately selected patients. However, the major disadvantages of bevacizumab remain intravenous administration requiring regular hospital visits, treatment costs, and concerns for related toxicities like hypertension, and intracranial or extracranial haemorrhage. Other agents like hyperbaric oxygen therapy, pentoxifylline, and tocopherol have been suggested in refractory radionecrosis, with questionable benefits. Sodium-copper-Chlorophyllin is a phytopharmaceutical drug obtained from the green plant pigment chlorophyll. It is a semi-synthetic mixture of sodium copper salts derived from chlorophyll. Chlorophyllin scavenges RT-induced free radicals and reactive oxygen species. It is used as a food colorant and over-the-counter in the USA, Japan, Australia, and China for many years for a variety of health benefits, including prevention of body odor in geriatric patients, enhanced wound healing, antibacterial action, prevention of cancer in the high-risk population exposed to hepatocarcinogen aflatoxin B1, treatment of fecal incontinence, etc. Studies have shown that Chlorophyllin has immunostimulatory, anti-inflammatory, and antiviral effects in addition to antioxidant and radioprotective properties. It increases the expression of a transcription factor (protein) Nrf2, improving lymphocyte survival and enabling efficient detoxification after RT exposure. Chlorophyllin also delays microtubule polymerization and slows cell division in normal cells.