GBMs are histologically, radiographically, and clinically heterogeneous. On average, 50% of these patients respond to the current standard of care, which is concurrent radiation and chemotherapy.26
As new agents that work on specific molecular and genetic targets are integrated with the standard of care, it is extremely important to assess response to treatment as early as possible in the course of treatment. This is especially true with new antiangiogenic agents that can significantly affect the contrast-enhancing volume within 24 hours, a time scale very likely affecting the integrity of the blood–brain barrier and not tumor burden. Therefore, the contrast enhancement may no longer be considered a good measure of tumor burden for these therapies.4,5
Other parameters that have recently been suggested as being relevant as early biomarkers for predicting subsequent progression are the mean, median, and histogram analysis of the ADC and the manner in which these parameters change before and during treatment.7–12,27
In this study, we evaluated the diffusion parameters in relation to 6-moPFS within the whole tumor, and the contrast enhancement and nonenhancement for pre-, mid-, and post-RT scans.
The median normalized ADC values within the contrast enhancement at the mid-RT exam showed a trend toward higher values for the nonprogressors. Prior studies that included a mix of grade III and IV gliomas along with metastatic brain tumors have suggested that an increase in the ADC preceded tumor response,7,8,10
but these studies assessed the ADC weeks post-treatment. Tomura et al.11
showed that the normalized ADC values of primarily metastatic tumors were significantly higher at 2–4 weeks after stereotactic irradiation when compared with the baseline scan. There was a significant difference in the normalized ADC values at 2–4 weeks after stereotactic irradiation between the responder and the nonresponder groups (P
< .05) when evaluated at 8–12 weeks but not at 2–4 weeks after stereotactic irradiation. We also observed significantly higher normalized ADC values from pre- to post-RT (P
< .0001) for progressors and nonprogressors. We did not observe significant differences in post-RT normalized ADC values between progressors vs nonprogressors within any of the regions. However, there was a trend toward higher mid-RT normalized ADC, EV1, and EV2 values among nonprogressors compared with progressors.
The within-patient analysis that was performed in our population indicated that progressors showed a significant change in normalized ADC from mid- to post-RT and pre- to post-RT, whereas the nonprogressors showed a significant change from pre- to mid-RT and pre- to post-RT. This could explain why the percent change in the normalized ADC from mid- to post-RT showed much clearer significant difference between progressors and nonprogressors within all the regions, with significantly higher percent changes for progressors vs nonprogressors. Previous studies have shown dynamic changes in the ADC after treatment,7,10
with ADC values increasing and then decreasing again. In this study, we noticed dynamic changes (increases, decreases, and stability) in the normalized ADC between pre- to mid-RT and mid- to post-RT, with the changes from mid- to post-RT seeming to indicate the most significant separation between progressors and nonprogressors. This suggests that an increase or decrease in the ADC alone is not sufficient to determine treatment response and that the timing of these increases and/or decreases may be very important both during and after treatment. For the treatment considered in this study, it appears that the percent changes in the ADC from mid- to post-RT are significant in assessing 6-moPFS.
The majority of patients were off steroids or tapering down. The literature suggests variable effects of high steroid dose on ADC values. Sinha et al.28
showed an increase in the ADC values within a nonenhancing lesion of a patient. Sinha et al. also showed a decrease in the ADC values within the nonenhancing lesions,29–31
whereas Minamikawa et al. showed no significant decrease within the nonenhancing lesions.32
Most studies suggest a decease in the ADC values within enhancing lesions of 6%–11%.30,31
Since the majority of patients were off steroids or tapering down, we suspect that steroid use would not have a strong impact on the ADC values in this study.
Key to the interpretation of the fDM parameters is a comparison between parameters in similar regions of tissue in the pretreatment and follow-up scans. This can be problematic when there is an extensive surgical resection that leaves a relatively small region of residual tumor, which may lead to substantial tissue shift in the follow-up examinations. In this study, most patients received sub- or gross-total resections. This translated to a median intersecting pre- and mid-RT contrast enhancement of 1.3 cc. For the majority of patients, the residual contrast enhancement appeared as a narrow region that surrounded the cavity and temporal changes led to substantial tissue shift for follow-up examinations. For cases where the region is relatively small, it is difficult to make accurate correlations between parameter values from different examinations. It is for this reason that requiring the patient to have a minimum volume of intersecting contrast enhancement of 4 cc was recently proposed as a criterion for eligibility to apply the fDM technique.25
The fact that our lesion volumes were mostly at the threshold or lower than the suggested limit means that it is not surprising that there was no significant difference in the VR
parameters between the progressors and nonprogressors.
In conclusion, this study assessed the changes in the volumes and diffusion parameters within the enhancing and nonenhancing lesions at pre-, mid-, and post-RT and how these changes may relate to the clinical outcome of 6-moPFS. The results indicated that changes from mid- to post-RT were significantly different between patients who progressed within 6 months vs those who were free of progression for 6 months after initiation of therapy. The study also showed that changes in diffusion parameters from the mid- to post-RT scan may be more significant than changes from pre- to mid-RT or from pre- to post-RT. This is important because the mid-RT scan is currently not performed as part of the standard clinical care. Although we initially intended to apply the fDM method to evaluate our patients, the fact that the median intersecting pre- and mid-RT CEL volume was 1.3 cc meant that our data did not satisfy the requirement of a minimum volume of 4 cc. Our observation of no significant differences in fDM parameters was consistent with the observation that, in its current form, the technique is unable to assess response to therapy in populations of patients with GBM who have had resections that leave behind limited or no residual contrast enhancement.