Abstract
Recurrent high grade glioma patients face a poor prognosis for which no curative treatment option currently exists. In contrast to prescribing high dose hypofractionated stereotactic radiotherapy (HFSRT, ge 6 Gy times 5 in daily fractions) with debulking intent, we suggest a personalized treatment strategy to improve tumor control by delivering high dose intermittent radiation treatment (iRT, ge 6 Gy times 1 every 6 weeks). We performed a simulation analysis to compare HFSRT, iRT and iRT plus boost (ge 6 Gy times 3 in daily fractions at time of progression) based on a mathematical model of tumor growth, radiation response and patient-specific evolution of resistance to additional treatments (pembrolizumab and bevacizumab). Model parameters were fitted from tumor growth curves of 16 patients enrolled in the phase 1 NCT02313272 trial that combined HFSRT with bevacizumab and pembrolizumab. Then, iRT +/− boost treatments were simulated and compared to HFSRT based on time to tumor regrowth. The modeling results demonstrated that iRT + boost(− boost) treatment was equal or superior to HFSRT in 15(11) out of 16 cases and that patients that remained responsive to pembrolizumab and bevacizumab would benefit most from iRT. Time to progression could be prolonged through the application of additional, intermittently delivered fractions. iRT hence provides a promising treatment option for recurrent high grade glioma patients for prospective clinical evaluation.
Highlights
Recurrent high grade glioma patients face a poor prognosis for which no curative treatment option currently exists
In our recent phase 1 clinical trial (NCT02313272, 05/12/2014) recurrent high-grade glioma (rHGG) patients were treated with a combination of hypofractionated stereotactic radiotherapy (HFSRT; ≥ 6 Gy × 5 fractions), bevacizumab [antibody against vascular endothelial growth factor (VEGF)] and pembrolizumab17
Glazar et al developed a mathematical model describing the dynamic growth response of rHGG to a combination of bevacizumab and pembrolizumab aiming to predict the onset of treatment resistance12
Summary
Recurrent high grade glioma patients face a poor prognosis for which no curative treatment option currently exists. We performed a simulation analysis to compare HFSRT, iRT and iRT plus boost (≥ 6 Gy×3 in daily fractions at time of progression) based on a mathematical model of tumor growth, radiation response and patient-specific evolution of resistance to additional treatments (pembrolizumab and bevacizumab). Efficacy was not the primary endpoint, the response results were promising; yet median time to progression remained below 1 year17 In this trial, HFSRT was given in doses with maximum log cell kill intent over 1 week (consistent with current practice and trials for rHGG re-irradiation studies). Glazar et al developed a mathematical model describing the dynamic growth response of rHGG to a combination of bevacizumab and pembrolizumab aiming to predict the onset of treatment resistance12 Their approach did not account for the effects of radiotherapy and how adaptation to the fractionation schedule may improve patient outcome
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