Abstract
BackgroundA randomized trial in glioblastoma patients with methylated-MGMT (m-MGMT) found an improvement in median survival of 16.7 months for combination therapy with temozolomide (TMZ) and lomustine, however the approach remains controversial and relatively under-utilized. Therefore, we sought to determine whether comprehensive genomic analysis can predict which patients would derive large, intermediate, or negligible benefits from the combination compared to single agent chemotherapy.MethodsComprehensive genomic information from 274 newly diagnosed patients with methylated-MGMT glioblastoma (GBM) was downloaded from TCGA. Mutation and copy number changes were input into a computational biologic model to create an avatar of disease behavior and the malignant phenotypes representing hallmark behavior of cancers. In silico responses to TMZ, lomustine, and combination treatment were biosimulated. Efficacy scores representing the effect of treatment for each treatment strategy were generated and compared to each other to ascertain the differential benefit in drug response.ResultsDifferential benefits for each drug were identified, including strong, modest-intermediate, negligible, and deleterious (harmful) effects for subgroups of patients. Similarly, the benefits of combination therapy ranged from synergy, little or negligible benefit, and deleterious effects compared to single agent approaches.ConclusionsThe benefit of combination chemotherapy is predicted to vary widely in the population. Biosimulation appears to be a useful tool to address the disease heterogeneity, drug response, and the relevance of particular clinical trials observations to individual patients. Biosimulation has potential to spare some patients the experience of over-treatment while identifying patients uniquely situated to benefit from combination treatment. Validation of this new artificial intelligence tool is needed.
Highlights
A randomized trial in glioblastoma patients with methylated-methylguanine-DNA methyl-transferase (MGMT) (m-MGMT) found an improvement in median survival of 16.7 months for combination therapy with temozolomide (TMZ) and lomustine, the approach remains controversial and relatively under-utilized
Larger benefits accrued in the m-MGMT patients with a 2-year survival of 75% compared to 20% for u-MGMT patients, and median survival of not reached and 12.6 months, respectively
Aside from quoting median survival and considering clinical variables, for individual patients oncologists are at a loss to predict the magnitude of benefit of a particular chemotherapy strategy before treatment
Summary
A randomized trial in glioblastoma patients with methylated-MGMT (m-MGMT) found an improvement in median survival of 16.7 months for combination therapy with temozolomide (TMZ) and lomustine, the approach remains controversial and relatively under-utilized. A single arm, phase II trial (UKT-03) evaluated TMZ plus lomustine in newly diagnosed GBM patients revealed a median survival of 23 months, considerably better than the historical experience of 14.6 months [3]. Larger benefits accrued in the m-MGMT patients with a 2-year survival of 75% compared to 20% for u-MGMT patients, and median survival of not reached and 12.6 months, respectively This led to the Nordic phase III trial (NOA-9) in newly diagnosed, m-MGMT GBM which randomized 141 patients to standard therapy (RT-TMZ followed by adjuvant TMZ) or experimental therapy with radiation alone followed by lomustine and TMZ every 6 weeks [4]. Neurooncologists are often unwilling to prescribe combination therapy citing the small study size, delayed separation of the progression free survival curves, and increased toxicity in the combination arm [5]
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