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MEDULLOBLASTOMA-CAUTION REGARDING NEW TREATMENT APPROACHES

LARRY E. KUN, M.D. AND LOUIS S. CONSTINE, M.D.

Department of Radiation Oncology, St. Jude Children’s Research Hospital, 332 North Lauderdale, P.O. Box 3 18, Memphis, TN 38 101; Departments of Radiation Oncology and Pediatrics, University of Rochester Medical Center, Rochester, NY 14642

Medulloblastoma, Radiation therapy, Low-dose craniospinal treatment.

Recently reported series from major centers indicate 5- year disease-free survival in childhood medulloblastoma of 60-65% following surgery and radiation therapy (5,6). Multi-institutional trials conducted between 1975 and 1980 have shown nearly comparable data: 50-55% dis- ease-free at 5 years (3, 11).

Factors correlating with favorable treatment outcome include local disease extent (generally defined by the Chang system (1) as T,_z or T1_ja), complete or subtotal resection, absence of neuraxis dissemination, and age over 2-4 years at diagnosis (3, 5, 6, 11). Most recent reports document the significance of subtotal or total resection (5,6, 12). Radiation therapy has, in general, included cra- niospinal irradiation (CSI) to 35-36 Gy and local posterior fossa doses of 54-55 Gy. The impact of posterior fossa control and dose-response analyses establishing local treatment levels of 54-55 Gy have been well documented (5, 10).

Halberg and coworkers at the University of California, San Francisco, present their experience in 39 children with medulloblastoma treated with reduced neuraxis dose (24 Gy) and chemotherapy (procarbazine and hydroxyurea) (4). The rationale for testing more limited doses to the cranium and spine is based upon anticipated reduction in neuropsychologic, endocrine, and spinal growth deficits known to occur following conventional management. In updating the previous UCSF report, Halberg et al. doc- ument 5-year disease-free survival of 56%, a figure com- parable to most recent series quoted above, if less im- pressive on the surface than the 78% 5-year disease-free survival Halberg notes among the 26 “historical controls” who received conventional doses of CSI beginning in 1966 (4, 8).

The rate of disease-free survivors amongst Halberg’s “better risk” patients treated with reduced neuraxis ir- radiation is 77%. The more favorable cases are defined

by limited tumor extent (i.e., Chang TI_~Mo, following postoperative neuraxis staging), nearly complete surgical resection, and age over 2 years. The excellent results in this subgroup are comparable to Tomita and coworkers’ initial description of reduced-dose neuraxis irradiation following totally resected medulloblastoma: 12 of 13 re- ported disease-free at 2 to 5+ years after 24 Gy to the neuraxis without chemotherapy (12). Hughes et al. re- ported 69% 5-year disease-free survival in a similar “fa- vorable group”; cases treated with spinal doses less than 27 Gy (median 24 Gy) showed disease control equivalent to that noted following more conventional levels (>27 Gy) without a reported difference in neuraxis failures (5). Included within Halberg’s 39 “low dose patients” are 6 treated with 36 Gy CSI, although it is unlikely that the overall results would differ significantly if reported as ac- tually treated.

Incumbent upon a decision to reduce treatment for a subset of children with medulloblastoma is the demon- stration of a parallel or significant decrease in late effects related to CSI. A trial mounted to test such a hypothesis must scrupulously gather and report data on toxicity, which does not appear to be the case in Halberg’s study. To date, none of the three institutions reporting less than conventional doses of cranial and/or spinal irradiation has demonstrated relative improvement in functional or somatic outcome (4, 5, 12). A prospective trial jointly conducted by the Pediatric Oncology Group (POG) and Children’s Cancer Study Group (CCSG) began in 1986 to test the efficacy and relative toxicities of reduced-dose neuraxis irradiation (23.4 Gy/2 1 fractions) compared to 36 Gy standard CSI in children with “favorable” medul- loblastoma. The study was halted in December 1990, fol- lowing an interim analysis which showed an excess of both isolated neuraxis failures and overall treatment fail- ures in the reduced-dose arm. Problematic, in addition,

Reprint requests to: Larry E. Km, M.D.

897

Accepted for publication 25 January 199 1.

898 1. J. Radiation Oncology 0 Biology 0 Physics April 199 I. Volume 20. Number 4

was apparent difficulty interpreting the criteria for “fa- vorable” disease: fully one-third of cases entered as TrTj,MO post-resection had more advanced disease upon central review. The data will be presented in 1991 (M. Deutsch, P. Thomas, J. Krischer, J. Boyett, J. Finlay, L. Kun, personal communication, 1990). The final analysis of the controlled POG-CCSG study should provide an answer regarding the relative rate of disease control and the difference in the risk/benefit ratio attendant to di- minished treatment in the “favorable” subset of children now estimated at 25-30s of all newly diagnosed medul- loblastoma. As with Halberg’s report, it is important to await long-term follow-up before conclusions regarding lower neuraxis doses can be drawn; the finding of late disease recurrence 5 to 10 years post-irradiation in 25% of children who have survived 5 years is humbling to all clinician-investigators managing this disease in the 1990’s (5, 6, 7).

fore, appropriate with respect to combined modality treatment, especially in the “favorable” medulloblastoma subset if chemotherapy is necessary as a “substitute” for the eliminated dose of craniospinal irradiation as in Hal- berg’s rationale. A comparison of toxicities attendant to combined modality therapy is critical.

The question of chemotherapy is unanswered in Hal- berg’s report and others (3, 4, 5, 1 1). The results of re- duced-dose irradiation and chemotherapy for “favorable” medulloblastoma do not appear to differ from those of Tomita and Hughes reporting irradiation alone. One can only speculate whether chemotherapy contributes to an apparent difference between the UCSF experience and that in the POG-CCSG trial. On the contrary. the results of reduced-dose irradiation and chemotherapy are un- impressive for the group identified as “high risk.” Halberg seems to confirm Tomita’s initial documentation of poor outcome for high risk medulloblastoma cases treated with more limited neuraxis irradiation (12). Possibly excepting those categorized as “high risk” by young age alone, there seems little impetus to diminish radiation therapy in the “high risk” subset which comprises the majority of me- dulloblastoma cases in Halberg’s series as in others.

A troublesome issue raised by this report involves the dilemma inherent in what can be termed a “negative” or “equivalence” clinical trial. The objective of such trials is to prove that a more conservative or less toxic therapy is at least as effective as a standard treatment. Large patient samples are necessary to avoid reaching a false-negative result, making such trials difficult for a single institution ( 13). When is a treatment strategy considered so successful that large numbers of patients and years of study can be invested toward this end? Halberg’s historical, high-dose irradiation group, though small in numbers, did have ex- cellent disease-free survival. Moreover, data existed sug- gesting that the use of reduced neuraxis radiation doses did not compromise outcome. One can argue whether the 79% 5-year survival in the historical group is satisfactory in an absolute sense. Both UCSF and the pediatric co- operative groups chose to study a decrease in toxicity rather than increasing efficacy: the danger is a potentially inferior outcome for the patients tested. This result appears to be the case in particular, for the high-risk patients in Halberg’s study, who had a 5-year disease-free survival of 39%. The future direction which the UCSF investigators are taking is intensification of therapy. using hyperfrac- tionated posterior fossa radiation therapy and more ag- gressive chemotherapy. in the high-risk patients. To echo the above statements, one may question whether the “fa- vorable risk” patients should be excluded from such a trial. That is, should a 23%) rate of disease recurrence be acceptable?

It is in the “high risk” or “less favorable” group with medulloblastoma that one can demonstrate a benefit from chemotherapy in multi-institutional trials reported by CCSG and SIOP (3, 11). Packer has reported excellent early results using vincristine, CCNU, and cisplatin in conjunction with conventional doses of CSI for a similar if not identical “high risk” population (9). With >90%1 disease-free survival at 3 years in Packer’s series. the ques- tion of chemotherapy for patients with high risk features seems more appropriate than a test of diminished irra- diation (9). Yet to be answered are the toxicities of com- bining chemotherapy and irradiation. Caution is, there-

A randomized test of limited neuraxis doses in favorably selected medulloblastoma has had a negative result in short-term analysis in the trial from POG and CCSG. Although it is possible that laboratory parameters will soon add to our ability to clinically define patients as “favor- able” medulloblastoma (2). it appears that current staging criteria may be inadequate to universally identify the “fa- vorable” subset of children with medulloblastoma. Long- term follow-up of Halberg’s series and the results of the prospective POG/CCSG trial are yet awaited before one can recommend more limited radiation therapy.

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