Functional diffusion map as an early imaging biomarker for high-grade glioma: correlation with conventional radiologic response and overall survival

Abstract

Purpose: Assessment of radiologic response (RR) for brain tumors utilizes the Macdonald criteria 8 to 10 weeks from the start of treatment. Diffusion magnetic resonance imaging (MRI) using a functional diffusion map (fDM) may provide an earlier measure to predict patient survival.

Patients and methods: Sixty patients with high-grade glioma were enrolled onto a study of intratreatment MRI at 1, 3, and 10 weeks. Receiver operating characteristic curve analysis was used to evaluate imaging parameters as a function of patient survival at 1 year. Both log-rank and Cox proportional hazards models were utilized to assess overall survival.

Results: Greater increases in diffusion in response to therapy over time were observed in those patients alive at 1 year compared with those who died as a result of disease. The volume of tumor with increased diffusion by fDM at 3 weeks was the strongest predictor of patient survival at 1 year, with larger fDM predicting longer median survival (52.6 v 10.9 months; log-rank, P < .003; hazard ratio [HR] = 2.7; 95% CI, 1.5 to 5.9). Radiologic response at 10 weeks had similar prognostic value (median survival, 31.6 v 10.9 months; log-rank P < .0007; HR = 2.9; 95% CI, 1.7 to 7.2). Radiologic response and fDM differed in 25% of cases. A composite index of response including fDM and RR provided a robust predictor of patient survival and may identify patients in whom RR does not correlate with clinical outcome.

Conclusion: Compared with conventional neuroimaging, fDM provided an earlier assessment of equal predictive value, and the combination of fDM and RR provided a more accurate prediction of patient survival than either metric alone.

Figures

Fig 1.

Representative functional diffusion map (fDM) analysis over time. Functional diffusion maps at (A) 1, (B) 3, and (C) 10 weeks for two patients treated with fractionated radiation therapy. The patient on the left was scored as responsive by fDM at 3 weeks but progressive disease by radiologic response at week 10 and had overall survival (OS) of more than 33 months. The patient on the right was scored as nonresponsive by fDM at 3 weeks but stable disease by Macdonald criteria and OS of 7 months. Depicted images are single slices of the T1 postcontrast scans at each time point with a pseudocolor overlay of the fDM. Red voxels indicate regions with a significant rise in apparent diffusion coefficient (ADC) at each time point compared with pretreatment, green regions had unchanged ADC, and blue voxels indicate areas of significant decline in ADC. The scatter plots display data for the entire tumor volume and not just for the depicted slice at each time point, with the pretreatment ADC on the x-axis and post-treatment ADC on the y-axis. The central red line represents unity, and the flanking blue lines represent the 95% CIs.

Fig 2.

Overall survival as a function of functional diffusion map (fDM), radiologic response (RR), and their composite. (A) Overall survival by log-rank test based on fDM stratification at 3 weeks from the start of treatment where the yellow curve (n = 27) represents patients with VI < 4.7% and the upper blue curve (n = 28) represents those with VI ≥ 4.7%. Median survival was 10.9 versus 52.6 months, respectively (P < .003; hazard ratio [HR] = 2.7; 95% CI, 1.5 to 5.9). (B) Overall survival as a function of RR at 10 weeks from the start of treatment, where the yellow curve (n = 25) represents those patients with progressive disease and the upper blue curve represents those with stable disease (n = 27) or partial response (n = 3). Median survival was 10.9 versus 31.6 months, respectively (P < .0007, HR = 2.9; 95% CI, 1.7 to 7.2). (C) Overall survival as a function of the composite index of response. The combination of fDM stratification at 3 weeks from the start of treatment and later radiographic response at 10 weeks provides a robust predictor of patient survival (log-rank P < .0002). Both the intermediate responding population (gray line, middle curve; n = 14; median survival, 14.4 months; P < .02) and the best responding population (yellow line, top curve; n = 22; median survival, 52.6 months; P < .0001) were distinct from the worst-responding radiographic group (blue line, bottom curve; n = 19; median survival, 8.1 months). VI, areas within the tumor where apparent diffusion coefficient increased (> 55 × 10−5 mm2/sec).

Fig 3.

Correlation of functional diffusion map (fDM) mediated evaluation of response with radiologic response (RR). There was a strong correlation between increasing fDM-VI at 3 weeks and subsequent RR at 10 weeks going from worst to best (progressive disease [PD] → stable disease [SD] → partial response; Cochran-Armitage P < .001). However, RR and fDM had conflicting results for 25% (14/55 patients) including seven patients with PD who demonstrated response by fDM and seven patients with SD who did not demonstrate response by fDM. VI, areas within the tumor where apparent diffusion coefficient increased (> 55 × 10−5 mm2/sec).

Fig A1.

(A) fDM-VI and (B) fDM-VD as a function of time since start of treatment and survival status 1 year from diagnosis. fDM analysis was performed 1, 3, and 10 weeks from the start of treatment. Data plotted are the mean fDM values at each time point ± 95% CI. Values are stratified by whether patients were alive (n = 34, blue or yellow squares) or dead (n = 21, black triangles) 1 year from diagnosis. fDM-VI increased continuously over time, and the increase was greater for patients who were alive at 1 year compared with those who had died. The VI values were statistically different at both 3 and 10 weeks (P < .02 and P < .06, respectively). For fDM-VD, there was no significant change in VD over time, nor was there a difference between groups at any time point. fDM, functional diffusion map; VI, areas within the tumor where apparent diffusion coefficient increased (> 55 × 10−5 mm2/sec).

Fig A2.

Receiver operating characteristic curve analysis to predict patient survival 1 year from diagnosis. The curves depicted represent overall predictive accuracy for radiologic response at 10 weeks and fDM-VI at 3 weeks. fDM, functional diffusion map; VI, areas within the tumor where apparent diffusion coefficient increased (> 55 × 10−5 mm2/sec).