International Journal of Radiation Oncology*Biology*Physics
Clinical InvestigationA Phase 2 Study of Dose-intensified Chemoradiation Using Biologically Based Target Volume Definition in Patients With Newly Diagnosed Glioblastoma
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
References (60)
- et al.
Survival prediction in high-grade gliomas by MRI perfusion before and during early stage of RT [corrected]
Int J Radiat Oncol Biol Phys
(2006) - et al.
Glioblastoma treated with postoperative radio-chemotherapy: Prognostic value of apparent diffusion coefficient at MR imaging
Eur J Radiol
(2010) - et al.
Hypercellularity components of glioblastoma identified by high b-value diffusion-weighted imaging
Int J Radiat Oncol Biol Phys
(2015) - et al.
Combining perfusion and high b-value diffusion MRI to inform prognosis and predict failure patterns in glioblastoma
Int J Radiat Oncol Biol Phys
(2018) - et al.
Association of 11C-methionine PET uptake with site of failure after concurrent temozolomide and radiation for primary glioblastoma multiforme
Int J Radiat Oncol Biol Phys
(2009) - et al.
Health related quality of life assessment methodology and reported outcomes in randomised controlled trials of primary brain cancer patients
Eur J Cancer
(2002) - et al.
An international validation study of the EORTC brain cancer module (EORTC QLQ-BN20) for assessing health-related quality of life and symptoms in brain cancer patients
Eur J Cancer
(2010) - et al.
Increasing feasibility and utility of (18)F-FDOPA PET for the management of glioma
Nucl Med Biol
(2015) The promise of dynamic contrast-enhanced imaging in radiation therapy
Semin Radiat Oncol
(2011)- et al.
Dynamic contrast-enhanced magnetic resonance imaging: Applications in oncology
Clin Oncol (R Coll Radiol)
(2014)
Perfusion imaging in neuro-oncology: Basic techniques and clinical applications
Radiol Clin North Am
Clinical features, mechanisms, and management of pseudoprogression in malignant gliomas
Lancet Oncol
MR-guided radiation therapy: Transformative technology and its role in the central nervous system
Neuro Oncol
The extent and severity of vascular leakage as evidence of tumor aggressiveness in high-grade gliomas
Cancer Res
The added prognostic value of preoperative dynamic contrast-enhanced MRI histogram analysis in patients with glioblastoma: Analysis of overall and progression-free survival
AJNR Am J Neuroradiol
Prognostic value of perfusion MR imaging of high-grade astrocytomas: Long-term follow-up study
AJNR Am J Neuroradiol
Gliomas: Predicting time to progression or survival with cerebral blood volume measurements at dynamic susceptibility-weighted contrast-enhanced perfusion MR imaging
Radiology
Usefulness of diffusion-weighted MRI with echo-planar technique in the evaluation of cellularity in gliomas
J Magn Reson Imaging
Malignant supratentorial astrocytoma treated with postoperative radiation therapy: Prognostic value of pretreatment quantitative diffusion-weighted MR imaging
Radiology
Predicting survival in glioblastomas using diffusion tensor imaging metrics
J Magn Reson Imaging
Concurrent temozolomide and dose-escalated intensity-modulated radiation therapy in newly diagnosed glioblastoma
Clin Cancer Res
Developing a pipeline for multiparametric MRI-guided radiation therapy: Initial results from a phase II clinical trial in newly diagnosed glioblastoma
Tomography
SU-FF-J-117: Integrated software tools for multimodality functional images in cancer clinical trials
Med Phys
The Neurologic Assessment in Neuro-Oncology (NANO) scale: A tool to assess neurologic function for integration into the Response Assessment in Neuro-Oncology (RANO) criteria
Neuro Oncol
Validation of the M.D. Anderson Symptom Inventory Brain Tumor Module (MDASI-BT)
J Neurooncol
Hopkins Verbal Learning Test–Revised: Normative data and analysis of inter-form and test-retest reliability
Clin Neuropsychol
The Halstead–Reitan Neuropsychological Test Battery: Therapy and clinical interpretation
Multilingual aphasia examination
Updated response assessment criteria for high-grade gliomas: Response Assessment in Neuro-Oncology working group
J Clin Oncol
Dose-dense temozolomide for newly diagnosed glioblastoma: A randomized phase III clinical trial
J Clin Oncol
Cited by (23)
Dosimetric feasibility analysis and presentation of an isotoxic dose-escalated radiation therapy concept for glioblastoma used in the PRIDE trial (NOA-28; ARO-2022-12)
2024, Clinical and Translational Radiation OncologyTreatment Planning Expansions in Glioblastoma: How Less Can Be More
2023, International Journal of Radiation Oncology Biology PhysicsThe role and potential of using quantitative MRI biomarkers for imaging guidance in brain cancer radiotherapy treatment planning: A systematic review
2023, Physics and Imaging in Radiation OncologyImpact of EGFR<sup>A289T/V</sup> mutation on relapse pattern in glioblastoma
2023, ESMO OpenCitation Excerpt :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.
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.