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Progressive disease in children with medulloblastoma/PNET during preradiation chemotherapy
A Tornesello1, S Mastrangelo, D Piciacchia
1Division of Pediatric Oncology, Catholic University, Rome, Italy.
Insights
Intensive chemotherapy for high-risk medulloblastoma (MB/PNET) showed carboplatin effectiveness but high progression rates with cyclophosphamide. Further research is needed to reduce progression and improve survival in pediatric MB/PNET patients.
Area of Science:
- Pediatric Oncology
- Neuro-oncology
- Chemotherapy Regimens
Background:
- Prognosis for pediatric medulloblastoma/primitive neuroectodermal tumors (MB/PNET) has stagnated.
- Intensive neoadjuvant chemotherapy requires further exploration for high-risk cases.
Purpose of the Study:
- To evaluate short-term clinical outcomes of an intensive chemotherapy regimen in high-risk, newly diagnosed MB/PNET children.
- To assess the efficacy and safety of a neoadjuvant chemotherapy sequence before radiation therapy.
Main Methods:
- Twelve high-risk MB/PNET patients received high-dose carboplatin followed by high-dose cyclophosphamide and vincristine.
- Treatment was administered in cycles after surgery and prior to radiation therapy.
- Disease response (CR, PR, MR, PD) was evaluated using neuroimaging of the entire neuraxis.
Main Results:
- High-dose carboplatin showed effectiveness, with 1 complete response (CR), 4 partial responses (PR), and 2 minor responses (MR) after two cycles.
- Subsequent high-dose cyclophosphamide yielded additional responses in 4 patients but also showed progressive disease (PD) in 4 patients.
- An unacceptable incidence of PD was observed during cyclophosphamide therapy, particularly when radiotherapy was delayed.
Conclusions:
- Two courses of high-dose carboplatin are effective in high-risk MB/PNET.
- High-dose cyclophosphamide in this neoadjuvant setting led to an unacceptable rate of progressive disease.
- Optimizing drug combinations for "sandwich chemotherapy" is crucial to reduce PD and improve long-term survival in pediatric MB/PNET.
Abstract:
The overall prognosis in children with medulloblastoma/PNET has not significantly improved over the past decade. Intensive neoadjuvant chemotherapy has not yet adequately explored. We evaluated the short-term clinical results of an intensive chemotherapy regimen in high risk children with newly diagnosed MB/PNET, after surgery and before radiation. Twelve previously untreated patients with high-risk medulloblastoma/PNET, according to Chang's classification, were treated with the following chemotherapy regimen: high dose carboplatin 600 mg/m2/day on days 1 and 2; the same course was administered 4 weeks later. One month later, high dose cyclophosphamide 2 g/m2/day on days 1 and 2, followed by an identical course 4 weeks later. Vincristine 1, 5 mg/m2 i.v. was given on the first day of each course. Systemic evaluation of the disease included imaging of the entire neuraxis, including MRI of the entire spine. Out of 12 enrolled, 7 patients were able to be evaluated for a residual disease after surgery. After two cycles of high dose carboplatin, we noted 1 CR, 4 PR and 2 MR. After the subsequent two cycles of high dose cyclophosphamide we observed an additional response in 4 cases. On the other hand, 4 patients clearly showed evidence of PD immediately after the first course of cyclophosphamide (2 cases) or following the second course. Three of the 4 patients had shown respectively 1 CR and 2 PR after the second course of carboplatin. Whereas it was confirmed that 2 courses of high dose carboplatin is effective in high risk MB/PNET children, we observed an unacceptable number of PD during the subsequent high dose cyclophosphamide therapy. A review from the literature also suggests that, in general, the longer radiotherapy is delayed, the higher the incidence of PD. In the search for the optimal drug combination in "sandwich chemotherapy" for children with high risk MB/PNET, PD must be reduced to an acceptable incidence, since a high number of PD may significantly lower the probability of long-term survival.