New Approaches for Resistant Brain Tumors

by Roger Packer MD
Source: Fall 2003 CCCF Newsletter

Therapy for childhood brain tumors, the most common form of solid malignancy in pediatrics, has slowly improved and evolved. Over 75% of children with brain tumors can be expected to be alive and free of progressive disease five years from diagnosis and more than one-half are likely cured of their disease. However, tremendous challenges remain for some forms of childhood brain tumors and, in addition, significant strides need to be made in devising therapies with less long-term sequelae.

Medulloblastoma

Medulloblastoma is the most common form of childhood malignant brain tumor and comprises approximately 40% of all tumors that arise in the posterior fossa. For some subsets of patients, primarily those with localized disease at the time of diagnosis and who are older (usually greater than three years of age at diagnosis), long-term disease control and probable cure is possible in up to 85% of patients. Research into the neurobiology of these tumors promises to revolutionize stratification of patients into risk groups and to result in potentially more rational intensification of treatment for some patients and possibly reductions in therapy for others.

Children with medulloblastoma who have disseminated disease at the time of diagnosis carry a poorer prognosis. Survival in these patients five years from diagnosis is probably 50% or less. Therapeutic approaches utilizing craniospinal irradiation therapy and adjuvant chemotherapy, as used for those with localized disease, are inadequate to control disease in many patients. Attempts at altering the dose schedule of radiotherapy (such as the use of multiple uses of radiotherapy per day – hyperfractionated radiation therapy) has not improved survival. Similarly, to date, the use of pre-radiation chemotherapy has not resulted in better disease control.

One approach under study is utilization of chemotherapy, during radiation therapy, to act as both a radiosensitizer and independent anti-tumor agent. Carboplatinum is one drug being utilized in this manner. Another therapeutic avenue has been to utilize high-dose chemotherapy with peripheral stem cell rescue after radiation therapy. Although the latter approach has been feasible in infants, who did not receive initial craniospinal radiotherapy, there have been significant toxicities associated with therapy utilizing alternating doses of thiotepa/carboplatin and cyclophosphamide/ carboplatin. Other post-radiotherapy high-dose chemotherapy approaches, including the use of cyclophosphamide coupled with cisplatin supported with peripheral stem cell rescue, are under study.

More likely, the major breakthrough in the therapy of medulloblastoma will be biologic-based therapy. Molecular targeted therapy aiming at aspects of the cell cycle signaling, tumor differentiation and programmed cell death (apoptosis) carry great promise. Recent molecular genetic studies have disclosed genes, and probably, even more importantly, genes involved in cell signaling pathways that are up-regulated in medulloblastoma. Differences have been shown in gene expression between localized and disseminated medulloblastoma. Studies are already being developed evaluating the potential efficacy of cis-retinoic acid as a maturation agent and pro-apoptotic agent for children with medulloblastoma. Similarly, the use of drugs interfering with cell signaling are now being tested, and there is significant biologic rationale to believe that drugs which interfere with growth factor receptors, such as epidermal growth factor, and drugs which specifically interfere with cell cycle signaling, such as farnesyl transferase inhibitors, will play a major role in the future therapy of medulloblastoma.

A frustratingly slow developing, but possibly extremely important, approach for children with medulloblastomas is the potential use of intrathecal therapy, such as is now a standard component of the treatment for children with leukemia. There has been significant difficulty in identifying an effective and safe intrathecal drug. Furthermore, because of altered cerebrospinal fluid flow in many children with medulloblastoma due to tumor surgery, or tumor dissemination, reliable drug delivery has been an issue. Standard drugs such as methotrexate have not been extensively used because of concerns of excessive toxicity, especially when coupled with radiotherapy. New intrathecal agents are under study, including mafosfamide, a cyclophosphamide derivative, and topotecan. Similarly, radio-labeled antibodies are under investigation.

An extremely problematic subgroup of children with medulloblastoma are those less than three years of age at diagnosis. Because of the detrimental effects of radiation therapy on the developing nervous system and the need for craniospinal (including whole brain radiation) in most patients with medulloblastoma, this group of patients is extremely difficult to treat. Many of the new approaches discussed previously being utilized for patients with disseminated medulloblastoma are potentially applicable to the infant population. Studies underway include those evaluating higher-dose chemotherapy regimens with peripheral stem cell rescue and intrathecal chemotherapeutic approaches. There is also interest, although with some reservation, of re-introducing radiation therapy to the primary tumor site, early in the course of illness, in infants with localized medulloblastoma. However, the long-term sequelae of focal radiotherapy in infant

s are unknown. The subgroup of infants with disseminated medulloblastoma is even more problematic to treat. Once again, the intrathecal approaches and intensification of chemotherapy are being evaluated. However, there is significant information to suggest that the primary determinant of outcome in infants with medulloblastoma is the biology of the tumor and this is where molecular target therapy may be of extreme importance.

Cortical Primitive Neuroectodermal Tumors and Pineoblastomas

Although such tumors are relatively uncommon, they, in total, comprise approximately 5% of all pediatric brain tumors. There is now convincing molecular genetic information to conclude that these are biologically different from medulloblastoma.

For pineoblastomas, treatment approaches are complicated by the frequent occurrence of such tumors in very young children. For cortical tumors, therapy is complicated by the need to give high doses of radiation therapy to the so-called thinking part of the brain (the cerebral cortex) in very young children, often with resultant significant brain injury, long-term intellectual difficulties, and seizures. Therapy for such tumors has been conventionally the same as that used for high-risk medulloblastomas; but prognosis has been poor, especially in those with disseminated disease at diagnosis.

Atypical Teratoid/Rhabdoid Tumors

This is a highly problematic, recently identified, tumor type arising predominantly in children less than 3 years of age. Such tumors, prior to the routine use of immunohistochemistry, were likely considered a variant of medulloblastomas or cortical primitive neuroectodermal tumors. It is now thought that between 15 and 30% of tumors previously believed to be childhood medulloblastomas in younger children may actually be atypical teratoid/rhabdoid tumors. Atypical teratoid/rhabdoid tumors are biologically different and have a different molecular genetic underpinning; the majority having an abnormal 22 chromosome.

The prognosis for atypical/rhabdoid tumors has been dismal, with early series suggesting that the tumor was essentially uniformly fatal in children less than two years of age. More recent studies have suggested that some patients with these tumors do respond to therapy and therapeutic approaches have focused on utilizing intensive chemotherapy followed by relatively early radiation therapy. It is unclear whether intensification of chemotherapy will result in improved outcome in such patients. However, it has also been recently recognized that histologically identical tumors may occur in older patients and probably carry a somewhat more favorable prognosis. It is unclear whether this better prognosis is related to age-related biologic differences or to the use of earlier, more extensive radiotherapy.

A standardized therapeutic approach is presently being organized within the Children’s Oncology Group, utilizing intensified high-dose chemotherapy with the inclusion of high-dose methotrexate followed by early localized radiotherapy (for those patients without disseminated disease at the time of diagnosis) and consolidation with highdose chemotherapy with peripheral stem cell rescue.

Gliomas

Childhood gliomas are comprised of an extremely variable group of histologically different tumors. Prognosis for patients with pilocytic tumors and for many children with grade 2 tumors is relatively good. However, for patients with high-grade gliomas and those involving the brain stem, outcome is much poorer.

Brain stem gliomas remain probably the most problematic group of childhood tumors to treat. Approximately 80 to 90% of childhood brain stem gliomas are diffuse intrinsic tumors; the remain ing patient have either more focal tumors, tectal lesions, or exophytic cervicomedullary gliomas. The latter groups of tumors carry a significantly better prognosis; however, 90% or more of children with diffuse intrinsic brain stem tumors will die of progressive disease within 18 months of diagnosis.

Radiotherapy has been the only modality of treatment that has shown a consistent, at least transient, benefit for children with brain stem gliomas. The use of chemotherapy, either prior to or after radiotherapy, to date, has not resulted in improved survival. Similarly, alterations in radiation dose schedule have not improved outcome

Much of the recent clinical investigations in brain stem gliomas have centered around the use of chemotherapy or other agents concurrently with radiotherapy, to act as radiosensitizers. For this group of tumors, alternative approaches are desperately needed, and more recently molecular targeted therapy such as growth-factor receptor antagonists and drugs designed to interfere with cellular signaling have been added during and after radiotherapy in attempts to improve survival.

Similar approaches are underway for children with malignant gliomas. Although the outcome for children with malignant gliomas is not quite as dismal as it is in adults, long-term disease control for patients with diffuse tumors that cannot be easily resected remains quite poor. The use of molecular targeted therapy hopefully will usher in a new era for the management of such lesions. Another approach, about to be begun in children, is the use of infusional therapies (coupling agents that specifically bind to receptors on brain tumors to cellular poisons). This therapy will be delivered directly into the tumor via the placement of surgicallyplaced catheters. Then the drugs will be slowly infused into the brain under slow steady pressure (convection delivery). Initially, such approaches will be utilized primarily for children with malignant cortical gliomas; but it is hoped that if this approach is proved safe in pediatrics, tumors deeper in the brain, including brain stem gliomas, will be treated.

Synopsis

Although progress has been made in the management of childhood brain tumors, clearly new approaches are needed. Because of the relative rarity of individual tumor types, for progress to be made quickly there is need for multi-institutional studies and close partnership between industry (producing the new agents) and these cooperative groups. In the United States, the Children’s Oncology Group has undertaken many studies. Similar groups exist throughout Europe, Australia, and the Far-East. More recently, the formation of the Pediatric Brain Tumor Consortium (a National Cancer Institute sponsored group now consisting of 11 institutions around the United States) has been challenged to develop biologically-based approaches for children with brain tumors and to assess innovative treatment approaches which may not be initially easily performed at many sites across the country. The institutions that are part of this consortium are as listed in Table 1 below. It is hoped that such new therapy will not only be more effective but safer for children with brain tumors resulting in improved survival and better quality of life.

Pediatric Brain Tumor Consortium

Children’s National Medical Center, Washington, DC

St. Jude Children’s Research Hosp., Memphis,TN

Dana Farber Cancer Center, Boston, MA

Children’s Hospital of Philadelphia, Philadelphia, PA

Children’s Memorial Hospital, Chicago, IL

Seattle Regional Children’s Hospital, Seattle, WA

University of California at San Francisco, San Francisco, CA

Duke Medical Center, Durham, NC

Texas Children’s Hospital Houston, TX

Pittsburgh Children’s Hospital Pittsburgh, PA

NCI, Neuro-Oncology Branch, Bethesda, MD

Author: Roger J. Packer, MD
Executive Director, Neuroscience and Behavioral Medicine
Chairman, Department of Neurology
Children’s National Medical Center Professor of Neurology and Pediatrics
The George Washington University Professor of Neurology
Georgetown University Washington, DC
Professor in Neurosurgery
The University of Virginia Charlottesville, VA