State of the Art in the Treatment of Medulloblastoma/Primitive Neuroectodermal Tumors with Radiation Therapy

Joel Goldwein, MD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: November 1, 2001

Innovations in the treatment of Primitive Neuroectodermal Tumors (PNET) and Medulloblastoma (MB) with Radiation Therapy (RT) have run hand-in-hand with those in the surgical, chemotherapeutic, and diagnostic spheres. Improvements in radiotherapy equipment and techniques along with the use of altered fractionation schemes, the optimization of radiation doses, and the administration of other adjuvant therapies have all contributed to improvements in outcome. Results, however, are not measured by survival alone. The long term toxicity that may arise from the administration of therapy can be considerable, and treatment must be adjusted accordingly. Thus, in the last decade, refinements in treatment have focused as much on improvements in quality of life as on survival.

Toxicity caused by craniospinal radiation therapy (CSART) can be formidable, especially in the youngest children. (17, 19) Efforts have been directed at reducing this toxicity by lowering the CSART dose. These reductions have come in the face of some series demonstrating the necessity for doses above 3000 cGy (14, 16, 18) and others demonstrating favorable outcomes in select children treated with considerably lower doses (5, 12, 15).

As a consequence of these experiences, a Pediatric Oncology Group (POG)/Children's Cancer Group (CCG) study was launched pitting reduced craniospinal radiation doses (2340 cGy) against standard radiation (3600 cGy) for patients with low stage disease. This trial closed prematurely due to an increased number of failures in the reduced-dose arm. With time, the differences between the two arms have become less significant, though improved survival is still seen in the full-dose arm (6). In parallel, an unsuccessful attempt at the complete elimination of the whole brain component of the CSART was made in the SIOP the SIOP M4 trial. Results were disappointing, with only 3 of 16 children surviving. (4).

Thus, for patients with medulloblastoma treated with RT alone, spinal and supratentorial RT is mandatory, as is the posterior fossa boost. The craniospinal dose is typically 3600 cGy in 20 fractions, and the dose to the posterior fossa 5400-5580 cGy. Survival after such treatment ranges between 40 and 90% at 5 years, depending on a variety of factors including age, stage and extent of surgical resection. (6, 8, 14, 20, 22)

Chemotherapy is now used routinely in all children with advanced disease. The justification is based on randomized trials from the U.S. and Europe comparing radiation alone with radiation plus chemotherapy. (8, 22) In both of these series, CCNU, Vincristine (and Prednisone, for the U.S. series) were shown to improve survival for children with leptomeningeal disease and advanced local disease.

Platinum-based chemotherapy regimens are now widely utilized. Platinum is highly active against recurrent MB/PNET (9) as well as newly-diagnosed cases (20) In a series from the Children's Hospital of Philadelphia (20), children with "high risk" medulloblastoma were treated with cis-platinum based chemotherapy following surgery and radiation therapy. In some of the younger children, reduced craniospinal doses were used. Survival for the "high risk" children, ordinarily reported to be less than 50% at 5 years, was is reported to be nearly 90%. A CCG pilot study utilizing 2340 cGy plus the same platinum-based chemotherapy accrued nearly 80 patients in the 2 years it was open. Thus far, actuarial survival ranges above 80% at 3 years (Personal Communications, Roger Packer, MD).

For low-stage patients, the role of chemotherapy remains complex. As a consequence of the excellent results reported for high-stage patients treated with adjuvant platinum-based chemotherapy, an effort was made to study the regimen in conjunction with reduced doses of radiation for children with low-stage disease. Indeed, a pilot study of 10 children treated with 1800 cGy to the craniospinal axis, a posterior fossa boost, and platinum-based chemotherapy achieved long term survival of 70%, without the profound neurocognitive toxicity normally associated with higher doses (11). Ultimately, a POG/CCG trial randomized low-stage patients to either standard RT alone (3600 cGy) or reduced-dose craniospinal axis RT (2340 cGy) plus chemotherapy. The trial remained open for two years but was terminated prematurely because of poor accrual. Too few patients were entered to address any of the study questions. Finally, a recently reported trial mounted by SIOP demonstrated disappointing results from the administration of chemotherapy and reduced dose radiotherapy, with a 5-year actuarial survival of 42% (3). Thus, the question as to whether low-stage medulloblastoma patients benefit from reduced-dose RT plus chemotherapy remains unanswered.

In parallel with reductions in radiation doses, radiation fields have been tailored and refined to conform better to the volumes at risk for disease. These refinements, in turn, have been based on improvements in imaging techniques which have allowed for better definition of the inferior extent of the thecal sac (13) and improved definition of the posterior fossa (21). Whether the improvements in RT techniques will result in decreased toxicity is not yet known.

Hyperfractionated radiotherapy is currently under study for children with supratentorial PNET and high stage medulloblastoma. (CCG-9931. CCG Meeting Book, November 1996). Objectives are to increase control in advanced-stage patients by increasing the radiation dose without increasing associated late toxicity. While single institutional series of children treated with hyperfractionated RT have been published (2, 23), effective comparison with conventional therapy will require larger studies performed over longer periods of time.

Babies with PNET and Medulloblastoma pose a particular challenge to the neuro-oncology team. Such patients are eminently more susceptible to the devastating side effects of radiation therapy, and may have biologically more aggressive lesions (1). Results of two prominent series of children treated with neoadjuvant chemotherapy have been reported (7, 10). Patients under the age of three were eligible for entry, and radiotherapy was delayed to the time of progression, to completion of chemotherapy, or to the age of three years depending on the circumstances for the particular patient. In the Geyer series, most children were not treated with radiotherapy as had been prescribed, while in the Duffner series, they were. Results have been discouraging, with event-free survival at 3 years of 32% or less for the children with medulloblastoma, and 19% or less for those with PNET.

Even though the last decades have seen remarkable innovations in the use of radiotherapy against these diseases, room for improvement remains. Advances will need to be directed at increasing survival and decreasing toxicity. Identifying the subgroups of children who require higher doses of radiation, or who can most benefit from altered fractionation and reduced doses will be one of our greatest challenges. Conforming our radiation beams to the volumes at risk, and minimizing doses to normal tissues will be another.

  1. Allen JC. Epstein F. Medulloblastoma and other primary malignant neuroectodermal tumors of the CNS. The effect of patients' age and extent of disease on prognosis. Journal of Neurosurgery. 57(4):446-51, 1982.

  2. Allen J, Nirenberg A, Donohue B: A phase I/II pilot study employing hyperfractionated radiotherapy and adjuvant chemotherapy for high-risk primitive neuroectodermal tumors. Ann. Neurol. 30: 457-58, 1991.

  3. Bailey CC, Gnekow A, Wellek S, Jones M et al. Prospective randomized trial of chemotherapy given before radiotherapy in childhood medulloblastoma. International Society of Pediatric Oncology (SIOP) and the German Society of Pediatric Oncology (GPO): SIOP II. Med. Ped. Onc 25: 166-78, 1995.

  4. Bouffet E, Bernard JL, Gentet JC, Roche H, Tron C et al. M4 protocol for cerebellar medulloblastoma: Supratentorial radiotherapy may not be avoided. Int J. Rad. Onc. Biol. Phys. 24: 79-85, 1992.

  5. Brand WN, Schneider PA, Tokars RP: Long term results of a pilot study of low dose craniospinal irradiation for cerebellar medulloblastoma. Int. J. Radiat. Oncol. Biol. Phys. 13:1641-1645, 1987.

  6. Deutsch M, Thomas PR, Krischer J, et al.: Results of a prospective randomized trial comparing standard dose neuraxis irradiation (3,600 cGy/20) with reduced neuraxis irradiation (2,340 cGy/13) in patients with low-stage medulloblastoma: a combined Children's Cancer Group-Pediatric Oncology Group study. Pediatric Neurosurgery 24(4): 167-177, 1996.

  7. Duffner PK, Horowitz ME, Krischer JP, et al.: Postoperative chemotherapy and delayed radiation in children less than three years of age with malignant brain tumors. New England Journal of Medicine 328(24): 1725-1731, 1993.

  8. Evans AE, Jenkin RD, Sposto R, Ortega JA, Wilson CB, Wara W, Ertel IJ, Kramer S, Chang CH, Leikin SL, et al. The treatment of medulloblastoma. Results of a prospective randomized trial of radiation therapy with and without CCNU, vincristine, and prednisone. J Neurosurg Apr;72(4):572-82, 1990.

  9. Friedman HS, Oakes WJ: The chemotherapy of posterior fossa tumors in childhood. Journal of Neuro-Oncology 5(3): 217-229, 1987.

  10. Geyer JR, Zelzer P, Boyett J, Rorke L, Stanley P, Albright L, Wisoff J, Milstein J, Allen J, Finlay J, Ayers G, Shurin S, Stevens K, Bleyer WA. Survival of Infants with primitive neuroectodermal tumors of malignant ependymomas of the CNS treated with eight drugs in 1 day: A report from the Children's Cancer Group. J. Clin Onc 12(8): 1607-15, 1994.

  11. Goldwein JW, Radcliffe J, Johnson J, Moshang T, Packer RJ, Sutton LN, Rorke LB, D'Angio GJ. Updated results of a pilot study of low dose craniospinal irradiation plus chemotherapy for children under five with cerebellar primitive neuroectodermal tumors (medulloblastoma). Int J Radiat Oncol Biol Phys 34(4):899-904, 1996.

  12. Halberg FE, Wara WM, Fippin LF, Edwards MSB, Levin VA, Davis RL, Prados MB, Wilson CB: Low-Dose craniospinal radiation for Medulloblastoma. Int. J. Rad. Oncol. Biol. Phys 20, 651-654, 1991.

  13. Halperin EC. Concerning the inferior portion of the spinal radiotherapy field for malignancies that disseminate via the cerebrospinal fluid. International Journal of Radiation Oncology, Biology, Physics. 26(2):357-62, 1993.

  14. Hershatter BW, Halperin EC, Cox EB: Medulloblastoma: The Duke University Medical Center experience. Int J Radiat Oncol Biol Phys 12(10):1771-1777, 1986

  15. Hughes E, Shillit OJ, Sallan SE et al.: Medulloblastoma at the Joint Center for Radiation Therapy between 1968 and 1984. Cancer 61: 1992-1988, 1988.

  16. Jereb B, Reid A, Rajender KA: Patterns of failure with medulloblastoma. Cancer 50:2941-2947, 1982

  17. Johnson DL, McCabe MA, Nicholson HS, et al.: Quality of long-term survival in young children with medulloblastoma. Journal of Neurosurgery 80(6): 1004-1010, 1994.

  18. Landberg TC, Lindgren ML, Cavallin-Stahl EK, Suam-Tapper GD et al: Improved radiotherapy of medulloblastoma, 1946-1975. Cancer 45:670-678, 1980.

  19. Packer RJ, Sutton LN, Atkins TE, Radcliffe J, Bunin GR, D'Angio GJ, Siegel KR, Schut L: A prospective study of cognitive function in patients receiving whole-brain radiotherapy and chemotherapy: 2-year results. J Neurosurg 70: 707-713, 1989.

  20. Packer RJ. Sutton LN. Elterman R. Lange B. Goldwein J. Nicholson HS. Mulne L. Boyett J. D'Angio G. Wechsler-Jentzsch K. et al. Outcome for children with medulloblastoma treated with radiation and cisplatin, CCNU, and vincristine chemotherapy. Journal of Neurosurgery. 81(5):690-8, 1994.

  21. Solit DB, Goldwein JW. Posterior Fossa: Analysis of a popular technique for estimating the location in children with medulloblastoma. Radiology 195: 697-8, 1995.

  22. Tait DM, Thornton-Jones H, Bloom JL, Morris-Jones P: Adjuvant chemotherapy for Medulloblastoma: the first multi-centre control trial of the International Society of Paediatric Oncology (SIOP I). Eur J Cancer 26(4): 464-469, 1990.

  23. Wara WM. Le QT. Sneed PK. Larson DA. Prados MD. Levin VA. Edwards MS. Weil MD. Pattern of recurrence of medulloblastoma after low-dose craniospinal radiotherapy. International Journal of Radiation Oncology, Biology, Physics. 30(3):551-6, 1994.