Results of this study demonstrated no apparent survival benefit associated with the addition of TMZ to conventional radiation therapy among children with DIPG. In this study and in CCG-9941, the majority of children died with disease progression within 1 year of diagnosis. This finding is particularly disappointing given the encouraging results seen with a similar chemoradiotherapy and maintenance regimen using TMZ in adult patients with supratentorial HGG.26
Two smaller pediatric trials27,28
recently reported similarly poor outcomes, albeit with slightly reduced doses of TMZ. The addition of chemoradiotherapy in the current study appeared to offer no therapeutic advantage, with a dismal outcome similar to that seen using maintenance TMZ following radiation therapy alone.29
Seven children progressed following chemoradiotherapy prior to any courses of maintenance therapy. One explanation could have been pseudoprogression, although all 7 children were dead of disease wtihin 1 year after diagnosis, suggesting that this phenomenon, if present, did not alter the natural history of this tumor.
It is unclear why TMZ was ineffective in this patient population. One possible explanation is that DIPG contains an active, presumably unmethylated, O6-methylguanine DNA methyltransferase (MGMT) promoter, as is often seen in supratentorial HGGs. MGMT activity would be anticipated to rapidly remove methyl and alkyl groups from the O6 position of guanine abrogating the cytotoxic impact of TMZ. This hypothesis is speculative, because a biopsy of the pons was not required for enrollment on this stratum. A small number of children underwent biopy, presumably when the treating physician felt that the imaging features at the time of presentation were not classic for a diagnosis of DIPG. However, these specimens were not tested for MGMT expression. Agents that inhibit MGMT activity, such as O6-benzylguanine,30
are being studied as potential therapeutic strategies to enhance the sensitivity of tumor cells to TMZ exposure.31
A major concern with this approach has been marked bone marrow suppression caused by the alkylating agent.32
A second possible explanation is that, despite the central nervous system penetration of TMZ, it fails to adequately reach the target tissue. At presentation, most DIPGs show limited or no contrast enhancement after the administration of gadolinium, raising the possibility that the blood-brain barrier is relatively intact in that region. Whether TMZ effectively penetrates the pons is unknown.
Many practitioners have suggested that improvements in the outcome for children diagnosed with a DIPG will require tissue acquisition so that appropriate molecular analyses can be undertaken in an effort to better understand the biology of this tumor. Central to this perspective is the presumption that the biology of DIPG is fundamentally different from that of other infiltrating astrocytomas, such as supratentorial AA and GBM, for which numerous specimens are available for analysis. Small series have recently suggested that there are fundamental biological differences in DIPG versus HGG.33, 34
However, biopsy of the brain stem is a contentious issue because such a procedure poses some surgical risk to the child, although in capable hands, this appears to be a relatively low-risk procedure35, 36
with limited, or no likelihood of direct benefit.37
In selected cases, an upfront biopsy is justified for clinical purposes when imaging features are not typical for the diagnosis. One recent study reported that, if biopsies are obtained from newly diagnosed children with presumed DIPG, an alternate histology will occasionally be identified. Whether this finding justifies the routine use of biopsies in all children is doubtful. Currently, if a biopsy is clinically indicated, every effort should be made by the practitioner to bank such specimens after histologic confirmation of the diagnosis, provided appropriate regulatory requirements are met for such banking. Alternatively, if the specimen were used to influence the plan of care for the child undergoing a biopsy, then the prospect of direct benefit could be argued, allowing for classification of the research as more than minimal risk but with the prospect of direct benefit. Alternatives have been recently reported, including the use of so-called “warm autopsy” specimens, in which pontine tissue is acquired as soon after the death of the child as possible. Whether such tissue reflects the pretreatment biology of a DIPG is unclear, but potential molecular targets are being identified by these methods. Another possibility would be to use specimens obtained from children who present with a classic bithalamic infiltrating astrocytoma, a lesion type that is commonly biopsied. These lesions tend to image in a manner quite similar to that of a DIPG, and their natural history is equally unfavorable.38
Numerous strategies for the treatment of DIPG are being studied in both the preclinical and early clinical setting. Chemotherapeutics that show promise against supratentorial AA and GBM are often proposed as rational candidates for study in children with DIPG. Exploiting this approach has been ineffective in the past, but perhaps newer agents will provide greater benefit. Molecularly targeted therapies hold some conceptual promise, but the utility of these agents is, as yet, unproven in the setting of a DIPG, in part because of the lack of available tissue to analyze. Local delivery strategies (eg, convection-enhanced delivery) are being explored on the presumption that the current failure of systemic therapy is related to inefficient delivery of drug to the target tissue.
Despite anecdotal reports of efficacy, the data are sufficiently poor that there appears to be little justification for the continued use of TMZ in this patient population, even in combination therapy. Currently, the only therapy remains palliative up-front XRT. Other treatments are best explored in the setting of early phase clinical trials.