MRI is the principal method being used to evaluate response to therapy and tumor progression in patients with GBM. The current study examined the predictive values of an integrated anatomic and diffusion- and perfusion-weighted imaging examinations that were obtained postsurgery, pretreatment, and at posttreatment follow-ups to determine whether the information obtained could contribute to predicting PFS and OS.
The median OS for the patients in this study with GBM was 84 weeks, but as seen from Figure , there is a large range of outcome values observed. Previous studies have found several variables that are associated with worse survival, but it is not known how these relate to each other.4–11
Age did not reach significance in the population considered in this study but was adjusted for in the statistical analysis because it has previously been shown to act as a prognostic factor in studies with larger patient populations.4,7,11
Extent of resection was also tested but was not found to be a significant factor. The importance of the extent of resection is still controversia17,11,22
and may influence decisions about the treatment that is chosen.10
Other factors—such as tumor size, edema, midline shift, and location—that may affect resection and influence survival were not examined here due to the limited size of the population.
Disease progression was determined in this study based upon the size of the CEL in conjunction with neurologic function and corticosteroid use.2
Patients who progressed by 6 months or 12 months had significantly shorter median survival time than those who did not. Although there was no difference in survival between patients who progressed by 6 months and 12 months, the second-line therapies that they were given did influence OS, with the median survival of patients who received reoperation and other chemotherapy being significantly longer than that of patients who received chemotherapy alone. Reoperation in combination with other salvage therapy has been reported to show a significantly prolonged survival compared with reoperation alone,23
but the criteria for reoperation are still not standardized across institutions.24,25
Another interesting finding from our analysis was that the pre-RT contrast-enhancing volume was not related to OS. We believe that this is due to some areas of enhancing being postsurgical effects rather than tumor. Previous studies at our institution have indicated that areas showing restricted diffusion on the immediate postsurgical scan may become enhancing in follow-up scans.26
When corrected for this effect, we have shown that an increase in the true volume of contrast enhancement between surgery and pre-RT is associated with shorter survival.27
It was not possible to make an assessment of whether variations in the pre-RT enhancing lesion volume were due to this effect in the current study because not all of the patients considered received their surgery at our institution. The robustness of the relationship between the T2ALL and NEL volumes and OS observed in our study is enhancing and supports the idea that they may be used to assess the presence of residual disease.
Recent studies have shown that some patients with GBM suffer from a temporary increase in the CEL that subsides afterward without further treatment.28,29
This effect has been termed pseudoprogression, and it commonly develops within 2 to 6 months after completion of concomitant RT plus temozolomide. Of the 47 patients who progressed during our study, 51% were confirmed as having true progression by the reoperation. For patients who did not get a resection, the assessment was based upon clinical and imaging follow-up, which included a repeat MR scan at 1-month intervals to assess whether the new enhancement was persistent. This strategy was intended to minimize any confounding effects caused by pseudoprogression.
Of interest in terms of determining which time point to consider in predicting outcome is that the volumes of all 3 anatomic lesions at the post-RT examination were related to OS. As shown in Figure , patients with worse survival had a larger volume of T2 hyperintensity after surgical resection at any given time point, even though none of the volumetric parameters were associated with PFS. The latter is not that surprising because some of the patients who progress show an initial reduction in lesion volume, and the definition of progression is based upon the change of contrast enhancement between the current and previous scans.
The observed decline in nCBV and nPH that we observed following radiation suggested that there was a reduction in vascular density due to the effects of RT and concurrent chemotherapy. The presence of regions with elevated nCBV and nPH at pre-RT and post-RT time points, as well as time-dependent changes in these values in all anatomic lesions, was correlated with shorter PFS. This is consistent with previous observations.30, 31
As gliomas grow, their cellularity tends to increase, which may cause regional hypoxia due to inadequate vascular supply. Upregulation of vasoactive endothelial growth factor (VEGF) promotes the formation of new blood vessels by the process of angiogenesis.32–35
The results of this study indicate that PWI can be used to monitor these effects. The fact that these parameters are not related to OS is not surprising given that there was so much change in them after a patient progressed. It also suggests that the relationship between tumor growth and abnormal angiogenesis in GBM is more complex than has previously been appreciated.
The recirculation and recovery parameters estimated from PWI data reflect increased vascular permeability and vessel tortuosity. Our results show that the presence of higher values of the recirculation parameter in the T2ALL and NEL at the pre-RT examination is associated with shorter PFS. In other words, patients who had more leaky vessels were more initially likely to progress at an early time point. Patients with smaller changes in the recirculation parameters between pre-RT and post-RT were more likely to show early progression. This suggests that the increased vascular permeability caused by RT36,37
may facilitate more effective delivery of the chemotherapy through the BBB and hence provide time to prolong progression.
Low ADC within regions of tumor is thought to correspond to regions of higher cellularity, while increased ADC corresponds to edema or treatment effects.38–40
In practice, both of these findings are present and may therefore counteract each other, especially once the lesion has been treated. Our data showed that there was a significant increase in nADC within all anatomic lesions after RT, which is consistent with the radiation causing increased disruption of tissue architecture and a decrease in cellularity that is associated with treatment-induced necrosis.41
Unlike the change in vascular parameters, these structural and cell-based measures of treatment effect were not related to PFS but were associated with OS when looked at longitudinally in a time-dependent analysis. The differences in relationship to clinical outcome highlight the complexity of the processes associated with disease progression and treatment effects.
Although the normalized ADC values observed at pre-RT and post-RT were not significant prognostic factors, the time-dependent values were significantly correlated with OS. Interestingly, lower nADC in the CEL and higher nADC in the T2ALL and NEL were associated with worse survival in the time-dependent analysis. This may be interpreted as the ADC in the enhancing volume being dominated by increased tumor cellularity, with the changes in ADC in the nonenhancing volume being associated with infiltrative tumor causing a breakdown of the normal tissue architecture. The potential for uncoupling these effects is interesting but highlights the complexity of interpreting changes in ADC. It is for this reason that the function diffusion map has been proposed as a measure of the sum of positive and negative changes in ADC on a pixel-by-pixel basis within the enhancing region as opposed to more global parameters. Our study suggests that it may be of interest to separately examine the temporal changes in enhancing and nonenhancing volumes separately.
The relatively short median survival for GBM patients has led to the development of therapeutic agents that are designed to act either by inhibiting angiogenesis or blocking cell proliferation.42–44
Anti-angiogenic or antiproliferative therapies that suppress tumor growth, rather than directly causing cell death may cause reduction in the incidence of CELs without a concurrent decrease in the number of tumor cells. This means that increases in the spatial extent of the T2 hyperintense lesions will be critical for assessing recurrence.45
Even in our study, where the majority of patients (81%) received only temozolomide and radiation, the volume of the T2ALL was related to OS. Future studies will use similar multiparametric anatomic and diffusion- and perfusion-weighted imaging methods to follow patients participating in clinical trials using novel treatment strategies.