Clinical Investigation
A Phase 2 Study of Dose-intensified Chemoradiation Using Biologically Based Target Volume Definition in Patients With Newly Diagnosed Glioblastoma

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Purpose

We hypothesized that dose-intensified chemoradiation therapy targeting adversely prognostic hypercellular (TVHCV) and hyperperfused (TVCBV) tumor volumes would improve outcomes in patients with glioblastoma.

Methods and Materials

This single-arm, phase 2 trial enrolled adult patients with newly diagnosed glioblastoma. Patients with a TVHCV/TVCBV >1 cm3, identified using high b-value diffusion-weighted magnetic resonance imaging (MRI) and dynamic contrast-enhanced perfusion MRI, were treated over 30 fractions to 75 Gy to the TVHCV/TVCBV with temozolomide. The primary objective was to estimate improvement in 12-month overall survival (OS) versus historical control. Secondary objectives included evaluating the effect of 3-month TVHCV/TVCBV reduction on OS using Cox proportional-hazard regression and characterizing coverage (95% isodose line) of metabolic tumor volumes identified using correlative 11C-methionine positron emission tomography. Clinically meaningful change was assessed for quality of life by the European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire C30, for symptom burden by the MD Anderson Symptom Inventory for brain tumor, and for neurocognitive function (NCF) by the Controlled Oral Word Association Test, the Trail Making Test, parts A and B, and the Hopkins Verbal Learning Test–Revised.

Results

Between 2016 and 2018, 26 patients were enrolled. Initial patients were boosted to TVHCV alone, and 13 patients were boosted to both TVHCV/TVCBV. Gross or subtotal resection was performed in 87% of patients; 22% were O6-methylguanine-DNA methyltransferase (MGMT) methylated. With 26-month follow-up (95% CI, 19-not reached), the 12-month OS rate among patients boosted to the combined TVHCV/TVCBV was 92% (95% CI, 78%-100%; P = .03) and the median OS was 20 months (95% CI, 18-not reached); the median OS for the whole study cohort was 20 months (95% CI, 14-29 months). Patients whose 3-month TVHCV/TVCBV decreased to less than the median volume (3 cm3) had superior OS (29 vs 12 months; P = .02). Only 5 patients had central or in-field failures, and 93% (interquartile range, 59%-100%) of the 11C-methionine metabolic tumor volumes received high-dose coverage. Late grade 3 neurologic toxicity occurred in 2 patients. Among non-progressing patients, 1-month and 7-month deterioration in quality of life, symptoms, and NCF were similar in incidence to standard therapy.

Conclusions

Dose intensification against hypercellular/hyperperfused tumor regions in glioblastoma yields promising OS with favorable outcomes for NCF, symptom burden, and quality of life, particularly among patients with greater tumor reduction 3 months after radiation therapy.

Introduction

For patients with glioblastoma (GBM), key biologic properties identified by advanced imaging techniques predict outcome better than anatomic magnetic resonance imaging (MRI), but no such imaging biomarker has been integrated into standard treatment for this lethal disease.1 The development of imaging biomarkers that enable spatial identification and temporal monitoring of a therapy-resistant phenotype before, during, and after treatment is an important first step toward improving outcomes in patients with GBM. However, efforts to seamlessly incorporate advanced imaging modalities into radiation treatment planning have thus far been limited to centers with robust technical expertise.

In contrast to more specialized studies, most centers routinely perform perfusion MRI as well as diffusion-weighted MRI (DW-MRI) for the assessment of patients with brain tumors. Perfusion, quantified from dynamic susceptibility contrast MRI and dynamic contrast enhanced (DCE) MRI, can assess elevation of cerebral blood volume (CBV) and cerebral blood flow associated with neovascularization and tumor growth that predict worse progression-free survival (PFS) and overall survival (OS).2, 3, 4, 5, 6 Diffusion MRI (b = 0-1000 s/mm2) estimates water mobility in the tissue microenvironment as an indicator of tumor cellularity.7, 8, 9, 10 By extending the degree of diffusion weighting to a high b-value (b = 3000 s/mm2), it distinguishes high-density cellular tumor regions from normal brain tissue, edema, and micronecrosis and predicts recurrence and PFS.11 Using these widely available techniques, we showed that combining DCE-MRI with high b-value DW-MRI identifies largely unique, nonoverlapping hyperperfused (TVCBV) and hypercellular (TVHCV) tumor volumes that spatially predict patterns of failure better than either technique alone, and nearly always contain treatment-resistant disease that will progress.11,12

In a prior institutional phase 1/2 study,13 we showed that dose-intensified targeting of tumor regions using conventional, anatomic imaging and conformal planning techniques with concurrent temozolomide was safe and potentially effective. Consistent with other studies, tumor was identified outside of the standard enhancing boost target using 11C-methionine (11C-MET) positron emission tomography (PET), which was associated with an increased risk of noncentral tumor failure.13 Recognizing the limitations of conventional, anatomic MRI to adequately define biologically relevant tumor, we sought to implement a potentially generalizable advanced imaging technique using DCE-MRI and high b-value DW-MRI that was prognostic for tumor recurrence and that could be feasibly integrated into the radiation treatment planning process.14 Because standard-of-care tumor volumes often do not include part of the adversely prognostic tumor regions identified by DCE-MRI and high b-value DW-MRI,11,12 we hypothesized that specifically targeting these tumor regions with dose-intensified chemoradiation would improve patient outcomes. We report the results of a phase 2 study implementing an advanced, multiparametric MRI technique enabling selective targeting of hyperperfused and hypercellular tumor with dose-escalated radiation therapy (RT) in patients with GBM.

Section snippets

Methods

This phase 2, single-institution, single-arm trial was approved by the University of Michigan institutional review board and registered at ClinicalTrials.gov (NCT02805179). Informed consent was required and obtained from all patients.

Enrollment, patient population, and treatment delivery

Between September 2016 and December 2018, 26 patients were enrolled. One patient had insufficient (<1 cm3) TVCBV and TVHCV for radiation therapy targeting, and 2 patients were ineligible based on the presence of multifocal enhancing disease. For the primary endpoint, 23 eligible patients treated with dose-intensified chemoradiation were analyzable.

The median age of the patients was 61 years (interquartile range [IQR], 56-66 years), and 70% were male. Eighty-seven percent of patients had tumors

Discussion

We demonstrate evidence of the potential benefit and safety of a dose-intensification strategy using a biologically informed advanced MRI technique to identify and target adversely prognostic hypercellular and hyperperfused tumor regions in patients with newly diagnosed GBM. Early response assessment using this advanced imaging approach enabled stratification of patient outcomes that superceded conventional response assessment after treatment, underscoring the more widespread diagnostic

Conclusion

An ongoing cooperative group dose-escalation trial (NRG BN001) will further elucidate the safety and efficacy of dose-intensified RT using anatomically defined tumor targets based on conventional MRI. Although initial results have not shown a survival benefit to dose-escalated photon therapy using conventional MRI to target enhancing regions, the benefit of biologically informed tumor targeting capable of identifying the presence and evolution of both enhancing and nonenhancing disease will

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      There was an improvement in OS in patients treated with dose-escalated radiotherapy in the MGMTp-methylated group compared to the MGMTp-unmethylated patients in the control group (35.5 versus 23.3 months). Another recent study proposed delivering a higher radiation dose to abnormally higher perfused zones based on multiparametric MRI.25 The 12-month OS was significantly higher in the group of patients who received boosted radiotherapy.

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    This research has been supported in part by the National Institutes of Health (P01 CA059827), Cancer Center Support Grant (P30 CA046592), Michigan Memorial Phoenix Project Grant, and Michigan Medicine Nuclear Medicine Seed Grant.

    Disclosures: none.

    Research data are stored in an institutional repository and will be shared upon request to the corresponding author.

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