Although the prognosis for children 3 years of age or older with medulloblastoma has significantly improved, approximately 20%–30% will relapse and die of their disease. Children's Hospital of Philadelphia investigators described 23 patients treated for medulloblastoma between 1980 and 1991 whose tumor recurred and noted the median survival to be 5 months, with the longest survivor living for 38 months from recurrence.4
We previously reported that 23 patients with recurrent medulloblastoma treated with this high-dose carboplatin, thiotepa, and etoposide regimen achieved 36 month EFS of 34% and concluded that this strategy may provide long-term survival for some patients with recurrent medulloblastoma.5
Limitations of our prior work included the inclusion of younger patients originally treated with chemotherapy only who may have been curable with external beam RT without high-dose chemotherapy,11
and patients with extra-neural disease who are rarely encountered in contemporary clinical practice. This current manuscript addresses only the most currently clinically relevant patients, those whose original therapy included external beam RT who subsequently developed recurrent disease in the central nervous system (CNS), and we still note that a subset may achieve long-term EFS using this aggressive salvage strategy.
Several recent papers from other groups provide relevant data. A report from a Korean group included 6 patients with recurrent medulloblastoma whose original treatment had included external beam RT. Two of the 6 were event-free following tandem high-dose chemotherapy/ASCR treatments (melphalan–cyclophosphamide, carboplatin–thiotepa–etoposide), but their follow-up was short (9+ and 12+ months).12
A report from the Mayo Clinic included 10 previously irradiated patients with recurrent CNS embryonal tumors (8 medulloblastoma and 2 cerebral neuroblastoma) treated with high-dose chemotherapy and ASCR. Nine of the 10 received high-dose thiotepa-containing regimens (with a thiotepa dose of 200 mg/m2
/day × 3 days) in addition to carmustine or carboplatin. Five of the patients were alive (4 without disease progression) with a median follow-up of 2.9 years. The authors concluded that high-dose chemotherapy with ASCR should be considered for adults with recurrent CNS embryonal tumors.13
High-dose chemotherapy regimens that do not include thiotepa appear to be less promising. St Jude investigators included 10 patients with recurrent medulloblastoma whose original treatment had included craniospinal RT in a larger series regarding a variety of high-dose chemotherapy regimens. Only 1 of their patients received a regimen that included thiotepa. Nine patients died and only 1 patient was free of disease (at 1319 days).14
POG investigators included 22 children with recurrent medulloblastoma in a report regarding the use of high-dose cyclophosphamide and melphalan with ASCR. Six were event-free at follow-up from 34 to 116 months.15
Four of the 18 patients whose initial therapy included external beam RT were event-free (R. Kadota, personal communication dated September 22, 2008).
Finally, Duke investigators included 12 previously irradiated patients in a report regarding the use of high-dose chemotherapy for recurrent medulloblastoma. Nine patients received high-dose cyclophosphamide and melphalan and 3 received high-dose busulfan and melphalan. Five patients were reirradiated as part of their salvage therapy (4 focal and 1 craniospinal). All 12 patients relapsed from 4 to 24 months post-ASCR and subsequently died of disease.16
In summary, these reports in conjunction with our data suggest that an aggressive retrieval regimen including the use of high-dose chemotherapy in conjunction with ASCR may provide long-term survival for some patients with recurrent medulloblastoma and that thiotepa may be an important component of the high-dose chemotherapy regimen. Additional RT may also be an important component of a salvage regimen (although the power to appreciate a difference was limited by the small numbers of patients), but it is noteworthy that 3 of the 6 event-free survivors in our series were not reirradiated. This supports the hypothesis that high-dose thiotepa-based chemotherapy is an important component of the retrieval strategy.
It is important to note a limitation of this study is that patients were enrolled onto the protocol just prior to the administration of high-dose chemotherapy, not at the time of first recurrence of their medulloblastoma. Therefore, the survival data that we describe are most relevant to patients who have achieved a minimal disease state following recurrence, not to the total population of patients with recurrent disease.
We continue to recommend that an aggressive salvage regimen should be considered for patients with previously irradiated recurrent medulloblastoma. We generally offer neurosurgical resection, irradiation, and/or conventional chemotherapy after detection of relapse in an attempt to achieve a very good partial or complete remission prior to high-dose chemotherapy with ASCR. Novel approaches such as intrathecal radioimmunotherapy17
or biologically targeted agents may also appropriate considerations for these patients, but since they may be most effective in the setting of minimal residual disease we recommend that they may be considered as supplemental approaches to high-dose chemotherapy rather than as mutually exclusive alternative strategies.
Conflict of interest statement. None declared.