Bevacizumab, irinotecan combination effective in children with recurrent, low-grade glioma

Roger J. Packer, MD

Pediatric brain tumors are the second most common form of cancer and the leading cause of cancer-related morbidity and mortality in pediatrics. Until recently, the majority of research in pediatric brain tumors was focused on the highly aggressive embryonal tumors, such as medulloblastoma, and there have been recent dramatic advances in the understanding of this subset of tumors.

However, more than half of childhood primary central nervous system tumors are gliomas and, unlike the situation in adulthood, low-grade gliomas constitute most pediatric gliomas. Pediatric low-grade gliomas arise throughout the nervous system and, despite their often indolent nature — dependent on their location in the nervous system — they may not be amenable to safe, extensive resections and can result in significant morbidity and, at times, mortality.

Radiation has been a conventional second step in therapy when surgery is not deemed feasible. In many children, this can result in excellent long-term control, but it also may result in long-term sequelae. These sequelae include acute deterioration due to radiation-induced necrosis and swelling, but radiation-associated intellectual deteriorations over time, hormonal deficiencies, cerebral vascular injury and secondary brain tumors are more frequent.

Because of these complications, alternative means have been sought to treat aggressive, nonsurgically resectable low-grade gliomas. During the past 2 decades, chemotherapy has been found to be surprisingly effective, despite the apparent slow growth pattern of these tumors. Chemotherapy was initially used to primarily delay the need for radiation therapy and, in up to one-third of patients, it may obviate the need for radiotherapy.

Children with neurofibromatosis type-1 have a propensity to develop low-grade gliomas and are at a higher risk than the general population for radiation-induced sequelae, especially cerebrovascular accidents and secondary tumors. In this population, chemotherapy is often used in attempts to permanently avoid the need for radiation therapy.

The paper by Gururangan and colleagues for the Pediatric Brain Tumor Consortium confirms that bevacizumab (Avastin, Genentech) plus irinotecan is an effective treatment alternative for aggressive pediatric low-grade gliomas. In the study, 80% of patients were at least stable on treatment. Although this an excellent overall stability rate, it should be noted that pediatric low-grade gliomas may have a variable natural history, even once they are noted to be progressive, and the use of stability as a measure of outcome is problematic.

This experience is a follow-up to the experience published by other authors, suggesting that such treatment can be well tolerated and results not only in radiographic objective responses but also — in some children — clinical improvement. As noted in this paper and in other publications using this combination of treatment, some patients with significant long-term neurologic and/or visual impairment will improve on treatment. This was a pleasant part of the findings of this experience, as in the past, chemotherapy usually resulted in clinical stabilization at best. A major concern of the use of bevacizumab for low-grade gliomas remains that combination is too toxic, especially for an indolent disease.

The experience from the Pediatric Brain Tumor Consortium study is reassuring in that there were few, if any, significant side effects. The relative contribution of irinotecan is speculative. As a single agent, irinotecan has not been found to be particularly effective in pediatric low-grade gliomas. The authors note the theoretic reasons why the irinotecan may have better efficacy if coupled with the bevacizumab, but it is certainly possible that the benefit seen was primarily related to the bevacizumab. Also encouraging was that the 2-year PFS in this heavily pretreated group of patients was nearly 50%, and six of the 29 patients who benefited from therapy had stable disease without receiving any additional treatment for a median of 40 months from initiation of treatment; thus, some patients maintain their response after treatment was stopped.

This study demonstrates the potential utility of biologic-based therapy for pediatric low-grade gliomas. Although bevacizumab was not truly molecularly targeted to the condition, it does show the potential benefits of biologic therapy, not only to control disease but to improve neurologic function.

Currently, there is tremendous interest in utilizing other biologic approaches for pediatric low-grade gliomas. Probably more than three-fourths of pediatric low-grade gliomas are pilocytic astrocytomas. The vast majority, if not all, of pilocytic astrocytomas have been shown to have abnormalities in the RAS-MAPK signaling pathway. Abnormalities in BRAF ( a component of the pathway), either activating fusion protein abnormalities or point mutations, have been shown to be present in most cases, and these abnormalities are molecular targets.

Studies are underway to evaluate drugs that inhibit the effects of BRAF-point mutations and other studies attempting to block RAS-MAPK kinase signaling with the use of MEK inhibitors (MEK being a component of the signaling pathway one step after BRAF). Other studies are attempting to turn off aberrant cellular signaling of pediatric low-grade gliomas further downstream by interfering with mTOR.

These exciting new approaches will need to be carefully evaluated, not only regarding efficacy in tumor control but also their ability to improve neurologic and/or visual function without causing short- and long-term unacceptable sequelae.

However, as the paper by Gururangan and colleagues has shown, there is reason to be tremendously optimistic about the future of treatment for pediatric low-grade gliomas and the ability of molecularly targeted therapies to change the way patients with recurrent disease — and, in time, those with newly diagnosed disease — will be treated in the near future.