Diffusion MR Characteristics Following Concurrent Radiochemotherapy Predicts Progression-Free and Overall Survival in Newly Diagnosed Glioblastoma.

Warren Chang,Phioanh L Nghiemphu,Albert Lai,Anthony J Hardy,Robert J Harris,Kevin Leu,Whitney B Pope,Reema R Mody,Benjamin M Ellingson,Timothy F Cloughesy

doi:10.18383/j.tom.2015.00115

Abstract

The standard of care for newly diagnosed glioblastoma (GBM) is surgery first, radiotherapy (RT) with concurrent temozolomide (TMZ) second, and adjuvant TMZ last. We hypothesized patients with low diffusivity measured using apparent diffusion coefficient (ADC) histogram analysis evaluated after RT + TMZ and before adjuvant TMZ would have a significantly shorter progression-free survival (PFS) and overall survival (OS). To test this hypothesis, we evaluated 120 patients with newly diagnosed GBM receiving RT + TMZ followed by adjuvant TMZ. Magnetic resonance imaging was performed after completing RT + TMZ and before initiating adjuvant TMZ. A double Gaussian mixed model was used to describe the ADC histograms within the enhancing tumor, where ADCL and ADCH were defined as the mean ADC value of the lower and higher Gaussian distribution, respectively. An ADCL value of 1.0 μm2/ms and ADCH value of 1.6 μm2/ms were used to stratify patients into high- and low-risk categories. Results suggested that patients with a low ADCL had a significantly shorter PFS (Cox hazard ratio = 0.12, P = .0006). OS was significantly shorter with low ADCL tumors, showing a median OS of 407 versus 644 days (Cox hazard ratio = 0.31, P = .047). ADCH did not predict PFS or OS when accounting for age and ADCL. In summary, after completing RT + TMZ, newly diagnosed glioblastoma patients with a low ADCL are likely to progress and die earlier than patients with a higher ADCL. ADC histogram analysis may be useful for patient-risk stratification after completing RT + TMZ.

Highlights

Glioblastoma (GBM) is the most common and deadly form of primary brain tumors in adults
Receiver operating characteristic (ROC) Analysis Results suggest ADCL is a significant predictor of patients that will progress within 6 months of starting adjuvant TMZ (Figure 3A; ROC area under the ROC curve (AUC) ϭ 0.68 Ϯ 0.053 SEM, P ϭ .0011); ADCH was not a significant predictor of progression by 6 months (Figure 2A; ROC AUC ϭ 0.5768 Ϯ 0.057 SEM, P ϭ .2187)
A threshold of ADCL Ͻ 1.0 ␮m2/ms had a low sensitivity (34%) and high specificity (90%) for identifying patients that would progress within 6 months, meaning a high proportion of patients with low ADCL after RT ϩ TMZ will progress early after starting adjuvant TMZ (Figure 3B; t test, P ϭ .027). (For reference, an ADCL Ͻ 1.2 ␮m2/ms used in previous studies showed a sensitivity of 71% and specificity of 57% for PFS6.)

Summary

Introduction

Glioblastoma (GBM) is the most common and deadly form of primary brain tumors in adults. There is great interest in identifying risk factors and biomarkers for predicting response to therapy beforehand. Neurological performance status, extent of surgical resection, radiographic composition of the tumor, tumor volume and location, isocitrate dehydrogenase 1 mutation status, gene expression subtype, and O6-methylguanine methyltransferase promoter methylation are commonly assessed prognostic characteristics for GBM [4,5,6,7,8,9,10,11,12]. The use of imaging features to phenotype tumors and to predict therapeutic response is an attractive option compared with more invasive approaches based on tissue-derived biomarkers. By noninvasively characterizing the composition of the tumor microenvironment, features associated with particular response patterns can be identified that lead to the potential for patient cohort enrichment for use in clinical trials. We recently showed that the apparent diffusion coefficient (ADC) characteristics measured using diffusion magnetic resonance imaging (MRI) techniques can be used to predict both progres-

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Conclusion