TMZ did not seem to result in an improved outcome in children with HGG compared with the therapy provided in CCG-945. This observation may lead some to question TMZ's role in the treatment of these patients22
and is in stark contrast to the consensus opinion in adults. However, it is important to put the results into a larger context before indiscriminately abandoning TMZ in childhood HGG.
First, major differences exist between the Stupp TMZ trial8
and this study. This study was a comparison with a historical control cohort and lacks the rigor of a randomized controlled comparison, making definitive conclusions about efficacy more challenging. The Stupp trial was a randomized trial between XRT alone versus XRT plus TMZ and is fundamentally different in design than this single-arm phase II trial. The last cooperative group study in the United States that randomly assigned children to XRT ± chemotherapy was CCG-943, which used adjuvant prednisone/lomustine-CCNU/vincristine (pCV).23
The 5-year EFS for children receiving XRT alone was 18% compared with 46% for those receiving combination therapy. Subsequently, adjuvant chemotherapy became the standard of practice for children with HGG, and all future trials have included XRT and chemotherapy in every study arm.
Second, prior to the Stupp trial, the benefits of chemoradiotherapy and adjuvant chemotherapy had not been well established in adults with newly diagnosed HGG. Some have suggested that this was partly because of the difficulty adults have in tolerating protracted exposure to nitrosoureas. TMZ appears to be the first alkylating agent that is well tolerated in adults, allowing for the completion of protocol-prescribed therapy. Of note, the 1-year progression-free survival rate for adults receiving TMZ chemoradiotherapy in the Stupp trial was 26.9%; the rate was 38% in children in our study. A direct statistical comparison between these results is not possible, but they suggest that the initial response and outcome of children with HGG treated with TMZ chemoradiotherapy are not inferior to those in adults.
As always, the most common reason for stopping therapy was for progressive disease. However, some children may have been removed for presumed progressive disease when the findings reflected pseudoprogression. However, time from progression to death was relatively short, suggesting that even if pseudoprogression was incorrectly coded as progressive disease in some cases, “true” progressive disease followed shortly thereafter. The current study showed no improvement in survival for children with newly diagnosed HGG who were treated with TMZ, but it did demonstrate similar survival, with less toxicity than in studies using prior nitrosourea-based regimens.1
The toxicity profile for TMZ was relatively mild. Hematologic toxicity was the most common adverse event and was generally self-limited. No life-threatening acute toxic events occurred. This has led many to argue that TMZ is a good backbone agent to use in further combination regimens.
An interesting finding in this trial is that the outcomes in children diagnosed with AA and to a lesser extent GBM were poorer than those in CCG-945. Similarly, children treated with pCV in CCG-945 had an inferior outcome to that of children treated with pCV in CCG-943. One explanation for this observation is the evolving rigor of histopathologic criteria. Nowhere is this more evident than in the review of subjects in CCG-945: among the 250 diagnoses of HGG, almost 30% were reclassified as low-grade tumors on central neuropathology review.2
While such a review was never undertaken to confirm pathologic diagnoses in CCG-943, one can reasonably presume that a similar, if not higher, number of misdiagnoses may have occurred in the earlier era of the CCG-943 study.
The above findings suggest a change in the way astrocytic tumors are being diagnosed. If neuropathologists use low thresholds for diagnosing borderline specimens as AA versus LGG, therapeutic trials will be likely to result in more AA survivors. Conversely, if more stringency is used in borderline cases, fewer AAs will be “contaminated” by LGGs and the result will be fewer AA survivors than in earlier studies. Many have speculated that this is the primary explanation for the reduction in survival seen in each subsequent trial in the COG since the results of CCG-943 were reported. One mechanism to address this apparent change in stringency is to use randomized phase II designs that would allow contemporaneous comparisons of outcome as opposed to using historic control cohorts. This strategy is being proposed by the COG for future HGG trials.
A third observation is that MGMT expression data support the finding that high levels of MGMT expression are adversely associated with outcome, which is analogous to the results of prior adult analyses in methylguanine9,24,25
and pediatric series.18,26
A strong association with outcome was particularly apparent when attention was focused on 2-year EFS. This fits with the fact that the effect of MGMT status on the response to TMZ is most likely to manifest during and several months after the time that this alkylating agent is administered. The survival curves between the MGMT-overexpressing and non-MGMT-overexpressing subsets diverged the most between 18 and 24 months after diagnosis, which is consistent with the observations of Hegi et al.9
in a series of adult GBM patients. In agreement with our previous observations, the effect of MGMT status on outcome was more apparent in tumors centrally classified as GBM, rather than those classified as AA,18
despite the lack of an association between MGMT status and histologic findings. This observation supports the prospective evaluation of MGMT expression status in future studies of childhood gliomas as a potential correlate of outcome. It remains to be determined whether MGMT overexpression constitutes an adverse prognostic factor, independent of alkylator usage; this will be addressed in subsequent studies in which the effect of MGMT expression is assessed in parallel in patients receiving alkylator-based and non-alkylator-based treatment regimens.
Where TMZ ultimately fits in the treatment of children with HGG remains unclear. Those in favor of its continued use cite the compelling adult data and the potential for similar efficacy to prior regimens with less toxicity, allowing for the development of further combinatorial therapies. Those opposed cite the results from this trial as evidence supporting the abandonment of TMZ in future trials. Given the limitation of the historical control cohort design of this trial, randomized phase II trials are being designed that will compare TMZ-based chemoradiotherapy with alternative regimens in an effort to more definitively determine the utility of TMZ in children with HGG.