Childhood brain tumors: Is the future now?
Brain tumors remain a highly problematic form of childhood cancer, representing in total the second-most common form of neoplasm and the one with the highest morbidity of those occurring in patients younger than 18. With some notable exceptions, which will be discussed, prognosis for childhood brain tumors has not changed dramatically over the past quarter century. Neuroimaging has greatly advanced; neurosurgery has become more technologically driven and possibly safer, radiation therapy has become more precise, and chemotherapy has been more judiciously employed; yet, outcomes have not kept pace with these advances.
The good news
Three decades ago, the reported survival rates for children with medulloblastoma were in the 40% to 50% range at five years. Due to the use of more aggressive surgery and the routine utilization of chemotherapy during and after radiotherapy, our group in Washington, DC, leading the study for the Children’s Oncology Group, has reported an 85% five-year survival rate and likely cure in children with nondisseminated medulloblastoma.
Other groups, such as the researchers at St. Jude and colleagues in Europe, utilizing somewhat different chemotherapeutic regimens, have reported similar survival rates. Even for patients with disseminated disease, preliminary reports from the Children’s Oncology Group, as well as others, suggest survival rates in the 50% to 60% range. These improvements in outcome have been accomplished despite the reduction in the dose of craniospinal irradiation. This has allowed the study of further reductions in the dose of craniospinal radiation in nondisseminated patients, as is being pursued in the current Children’s Oncology Group study assessing the feasibility of reducing radiation from 2,340 cGy to 1,800 cGy (in the past, the dose of cranial radiation was as high as 3,600 cGy to 4,000 cGy). This is of crucial importance given the long-term intellectual and hormonal problems survivors of medulloblastoma face, believed to be due in great part to the radiotherapy required for disease control.
Management of younger children with low-grade tumors has also changed in the recent past. In those patients with nonresectable progressive lesions, our group at the Children’s National Medical Center (and earlier at Children’s Hospital of Philadelphia) demonstrated that chemotherapy could be an effective alternative treatment to delay, if not obviate, the need for radiotherapy or more aggressive potentially damaging surgery. This has since been confirmed by the Children’s Oncology Group and study groups working in Europe, including the French Pediatric Oncology Study Group and Italian study groups.
For infants with malignant brain tumors, there is some reason for cautious optimism. Reported survival rates in studies performed by the International Society of Pediatric Oncology and, to a lesser extent, by the Children’s Oncology Group, the Societe Francaise Oncologie Pediatrique and groups working in Italy have demonstrated that a subset of
children aged younger than 3 years with medulloblastoma can be successfully treated with chemotherapy alone. This is probably due to the use of more aggressive chemotherapy, although the exclusion of young children with atypical teratoid rhabdoid tumors from medulloblastoma studies no doubt has made survival figures look better. It has been known since the late 1970s, from studies performed by Van Eyes and colleagues at M.D. Anderson, that some infants with medulloblastoma, as well as other malignant tumors, can be cured with chemotherapy alone.
The bad news
Not all advances have resulted in better outcomes. In a recent Children’s Oncology Group review, Robertson and colleagues found an extremely high rate of neurosurgically-related sequelae — namely the posterior fossa syndrome — in up to one-quarter of all children entered on Children’s Oncology Group prospective national/international trials performed in the past two decades. Of those children affected by this postoperative constellation of mutism, supranuclear palsies, ataxia, and emotional lability, approximately one-half will have permanent neurologic sequelae and probably enhanced neurocognitive impairment, dramatically impairing their quality of lives. Furthermore, for many brain tumor subtypes, including childhood brain stem gliomas, malignant gliomas, pineoblastomas, primitive neuroectodermal tumors and atypical teratoid rhabdoid tumors, prognosis has not improved over the past decade.
The challenge and future
Even notable advances have been made without the incorporation of innovative neurobiologic insights into factors controlling tumor development and progression into ongoing therapeutic studies. The molecular/biologic understanding of childhood brain tumors is advancing, but lags behind that of other types of childhood cancer and adult malignant gliomas. Work by many groups, including that of Pomeroy’s at Boston Children’s Hospital, Groetzer’s from the Children’s Hospital of Philadelphia, Gilbertson’s at St. Jude Children’s Research Hospital, Olson’s at Seattle Regional Children’s Hospital, Pollack’s at Pittsburgh Children’s, Lamont’s from the United Kingdom, and MacDonald’s from our group at the Children’s National Medical Center have discovered important new aspects of childhood brain tumors.
Histologically, similar tumors have different neurobiologic signatures, and we know that the same histologic type of tumor in children may differ molecularly from those arising in adults. Growth factors have been identified that seem to be important in tumor development and progression. Molecular pathways have been identified that are upregulated in growing tumors, both in vivo and in vitro. Although multiple molecular targets have been identified, few have been fully validated and there remains little evidence to date that treatment with the specific biologic agents that are now in clinical use have affected tumor growth and changed the prognosis.
However, without the incorporation of molecularly-targeted therapy, it is unlikely that prognosis will significantly improve for childhood brain tumors. The benefits from advances in surgery, radiation and conventional chemotherapy may have reached their maximum. The question remains whether the care of childhood brain tumors is ready for a paradigm switch. Clearly, for determination of tumor type and the likelihood of tumor progression or dissemination, molecular techniques are available which have been able, in retrospect, to be predictive of outcome. These techniques have to be used prospectively, in real time, to better stratify patients and identify those children who require more aggressive therapy, while also determining which patients may receive somewhat less aggressive treatment in order to reduce long-term sequelae without sacrificing the likelihood of cure. This is of utmost importance in tumors arising in infants and in children harboring lesions which require craniospinal radiation. With present means of treatment, quality of life for children surviving infantile malignant tumor and children with medulloblastoma who are younger than 7 years of age is far from optimal, with the majority being learning disabled at best.
With the biologic agents presently available, it seems unlikely that one agent alone hitting one pathway or blocking one growth factor receptor will make a major impact on survival. It has become increasingly clear that childhood brain tumors, like other forms of cancer, often have redundant pathways and multiple means to escape targeted therapy. For the foreseeable future, biologic agents will likely have to be used in combination with other biologic agents and/or probably with chemotherapy and radiotherapy. However, without their selective but rapid incorporation, the goal of personalized therapy for children with brain tumors, resulting not only in cure but reasonable quality of lives, will not be reached. Another line of investigation that requires more attention and exploitation is how insights into developmental neurobiology, especially factors controlling early brain growth and development, can inform researchers on directions for future treatment. These innovative approaches must be the charge of groups such as the Children’s Oncology Group, the SIOP working groups, the Pediatric Brain Tumor Consortium in the United States, and multiple study groups in Europe, if improved survival rates and better qualities of life are to be a reality.
Roger J. Packer, MD, is Executive Director of Neuroscience and Behavioral Medicine, Chairman of the Department of Neurology and Director of The Gilbert Neurofibromatosis Institute and The Brain Tumor Institute at Children’s National Medical Center in Washington, DC. He is also a member of the HemOnc Today Editorial Board.
For more information:
- Ellison DW, Onilude OE, Lindsey JC, et al. Beta-catenin status predicts a favorable outcome in childhood medulloblastoma: the United Kingdom Children’s Cancer Study Group Brain Tumour Committee. J Clin Oncol. 2005; 23:7951-7957.
- Gajjar A, Chintagumpala M, Ashley D, et al. Risk-adapted craniospinal radiotherapy followed by high-dose chemotherapy and stem-cell rescue in children with newly diagnosed medulloblastoma (St. Jude Medulloblastoma-96): long-term results from a prospective, multicentre trial. Lancet. 2006;7:813-820.
- Geyer JR, Sposto R, Jennings M, et al. Multiagent chemotherapy and deferred radiotherapy in infants with malignant brain tumors: a report from the Children’s Cancer Group. J Clin Oncol. 2005;23:721-7631.
- Gilbertson S, Wickramasinghe C, Hernan R, et al. Clinical and molecular stratification of disease risk in medulloblastoma. Br J Cancer. 2001;85:705-712.
- Grotzer MA, Hogarty MD, Janss AJ, et al. MYC messenger RNA expression predicts survival outcome in childhood primitive neuroectodermal tumor/medulloblastoma. Clin Cancer Res. 2001;7:2425-2433.
- Grotzer MA, Janss AJ, Fung K, et al. TrkC expression predicts good clinical outcome in primitive neuroectodermal brain tumors. J Clin Oncol. 2000;18:1027-1035.
- Kuhl J, Muller HL, Berthold F, et al. Preradiation chemotherapy of children and young adults with malignant brain tumors: results of the German pilot trial HIT 88//89. Klin Padiatr. 1998;210:227-233.
- MacDonald TJ, Brown KM, LaFleur B, et al. Expression profiling of medulloblastoma: PDGFRA and the RAS/MAPK pathway as therapeutic targets for metastatic disease. Nat Genet. 2001;29:143-152.
- Neglia JP, Robison LL, Stovall M, et al. New primary neoplasms of the central nervous system in survivors of childhood cancer: A report from the Childhood Cancer Survivor Study. J Natl Cancer Inst. 2006;98:1528-1537.
- Packer RJ, Gajjar A, Vezina G, et al. Phase III study of craniospinal radiation therapy followed by adjuvant chemotherapy for newly diagnosed average-risk medulloblastoma. J Clin Oncol. 2006;24:4202-4208.
- Pollack IF, Finkelstein SD, woods J, et al. Expression of p53 and prognosis in children with malignant gliomas. N Engl J Med. 2002;346:420-427.
- Pomeroy S, Tamayo P, Gaasenbeek M, et al. Prediction of central nervous system embryonal tumour outcome based on gene expression. Nature. 2002;415:436-442.
- Read T-!, Hegedus B, Wechsler-Reya R, Gutmann DH. The neurobiology of neuro-oncology. Ann Neurol. 2006;6:3-11.
- Ris MD, Packer R, Goldwein J, et al. Intellectual outcome after reduced-dose radiation therapy plus adjuvant chemotherapy for medulloblastoma: a Children’s Cancer Group study. J Clin Oncol. 2001;19:3470-3476.
- Robertson PL, Muraszko KM, Holmes EJ, et al. Incidence and severity of postoperative cerebellar mutism syndrome in children with medulloblastoma: a prospective study by the Children’s Oncology Group. J Neurosurg. 2006;105(S6 Pediatrics):444-451.
- Rutkowski S, Bode U, Deinlein F, et al. Treatment of early childhood medulloblastoma by postoperative chemotherapy alone. N Engl J Med. 2005;352:978-986.
- Taylor RE, Bailey CC, Robinson K, et al. Results of a randomized study of Preradiation chemotherapy versus radiotherapy alone for nonmetastatic medulloblastoma: The International Society of Paediatric Oncology/United Kingdom Children’s Cancer Study Group PNET-3 Study. J Clin Oncol. 2003;21:1582-1591.