Brain radionecrosis is encountered in patients receiving high-dose cranial radiotherapy, either with fractionated radiotherapy or ablative high-dose radiosurgical treatments. Symptomatically RN can present with an entire spectrum from radiologically evident clinically silent asymptomatic to life-threatening situations refractory to treatment 21. There are limited pharmacological options for effective treatment of RN other than corticosteroids and bevacizumab, which have their limitations regarding side effects. The current study will address the gap in investigating the role of chlorophyllin, a phytopharmaceutical with potential anti-inflammatory effects in treating brain radionecrosis.
Radionecrosis is mostly seen within the first 2 years, with the most common time being 6 to 18 months post-radiation. Factors influencing the incidence and severity of RN include radiation dose (with higher rates > 60 Gy EQD2), radiotherapy technique, radiation volume, fractionation, and other biological factors, including intrinsic radiosensitivity 21,22. Diagnosis of radionecrosis can often be challenging due to similar radiological appearance with disease recurrence, which should be ruled out as prognosis and treatment implications are completely different. The use of multiparametric imaging, including advanced functional sequences like perfusion-weighted imaging and MR spectroscopy, can help differentiate radionecrosis from recurrence 23. Typically, the changes appearing within the initial few months from radiation in the high-dose region, the presence of Swiss cheese appearance on the T1-contrast sequence, hypointense to hypointense signal of T2-weighted imaging should lead to suspicion for radionecrosis. Compared to recurrence, radionecrosis is typically hypoperfused on perfusion imaging and with a lower Choline: NAA peak on MR spectroscopy. Amino acid PET with carbon-11 methionine, DOPA, and FET can add to the MRI findings in improving the diagnostic performance in differentiating between radionecrosis and disease progression with sensitivity and specificity > 95% 24,25. In the current study, the patients will undergo multiparametric MRI, including spectroscopy, perfusion, and diffusion-weighted imaging, to diagnose radionecrosis. In equivocal cases, additional imaging with FET or F-DOPA will be considered for confirmation of diagnosis. All the patients will be discussed in the multidisciplinary joint neuro-oncology meeting before accrual in the study. The interval imaging after starting intervention (starting CHL) will be considered at 1 month with both MRI and PET for assessment of both morphological and functional response for primary endpoint assessment. Further imaging will be considered at 3 months for evaluation of long-term response to CHL. Since there is always a possibility of inclusion of patients with progression, these patients will be excluded from analysis regarding the efficacy of CHL if recurrence is documented within 3 months from study accrual.
The most commonly used medication for RN is corticosteroids, which can relieve symptoms and lead to reversal or stability of radiological findings in a proportion of patients. There are no guidelines regarding the dose and duration of use of corticosteroids and also the type of steroids (with dexamethasone preferred by the majority). Typically, in symptomatic patients, at least a few weeks of steroid treatment is required for optimal clinical benefit. There are concerns of certain adverse effects both with short and long-term use of steroids, including insomnia, acute psychosis, hyperglycemia, osteoporosis, risk of infections, skin changes, myopathy, and adrenocortical insufficiency, which can itself lead to new complications affecting quality of life. Also, some patients often turn into a state of steroid dependence with relapse of symptoms upon withdrawal of steroids. In refractory cases, anti-angiogenic agent with bevacizumab can provide significant benefit, however the major challenges remain the need for frequent hospital visit for intravenous administration (typically delivered every 2–3 weeks), associated cost, and side effects including hypertension or life-threatening hemorrhages. Some agents with questionable benefits include edaravone, pentoxifylline, hyperbaric oxygen therapy 8,26. The current study will use CHL to treat radionecrosis, which has demonstrated anti-inflammatory and antioxidant properties with free radical scavenging effect in preclinical studies, with pathophysiology of radionecrosis being considered a pro-inflammatory environment15,27. In the study, we are considering patients with symptomatic and asymptomatic radionecrosis into two different strata since the burden of necrosis, tempo of disease, and clinical outcomes are expected to be different. In the symptomatic stratum, patients will be treated with CHL in addition to oral dexamethasone, which is otherwise used as the standard first-line therapy for symptomatic RN in our institution. While in other strata (asymptomatic), patients will receive CHL alone to explore the role of CHL as a steroid-sparing agent.
The primary endpoint used in the study includes combined clinical and radiological criteria at 1 month for assessment of response. Other endpoints include 3-month response and additional patient-reported outcomes, survival outcomes, toxicity, and exploratory analysis for blood markers, which can predict the response to treatment. If proven useful and the primary endpoint is met, further phase 3 randomized studies will be planned to determine the efficacy of CHL in the treatment of radionecrosis. If proven useful, this will open a new avenue for the treatment of radionecrosis as a well-tolerated oral therapy, avoiding or reducing the side effects of current standard treatment with corticosteroids.