High – dose chemotherapy for medulloblastoma treatment in children older than 3 years old

1. High – dose chemotherapy for medulloblastoma treatment in children older than 3 years old

2. Medulloblastoma is the most common malignant brain tumor in childhood • During last two decades survival rate have been improved in average risk patients • However survival in high risk patients is still poorand remains near 50%

3. In our study we used multiple high – dose chemotherapy with autologous peripheral blood stem cells rescue after risk adapted craniospinal radiotherapy with boos to posterior fossa

4. Risk group stratification

5. Risk – adapted radiotherapy Average Risk High Risk 23,4 Gy CSI 36 Gy CSI + boost to posterior fossa (total dose 54 Gy)

6. After 6 weeks of radiotherapy completion all patients receive 4 cycles of cyclophosphamide – based high dose chemotherapy Day– 4: vincristine 1 mg/m2 День – 4: cisplatin75 mg/m2 День – 3: cyclophosphamide 2000 mg/m2 День – 2: cyclophosphamide 2000 mg/m2 День – 1: Hydration День 0: Infusion of peripheral blood stem cells День + 1: GCSF – 5 μg/kg until ANC> 2*109/L День + 6:vincristine 1 mg/m2

7. Between 2008 and 2012 we have enrolled 30 patients in our trial • Surgical excision of tumor was performed in Burdenko Neurosurgery Institute • Radiotherapy course patients received in our clinic and in Institute of rentgenoradiology • Courses of high dose chemotherapyperformed in our clinic

8. Clinical characteristics of enrolled patients

9. Toxicity of chemotherapy regimen • All patients had hematopoietic toxicity and requires blood and platelet transfusion • Other main type of toxicity was infection, almost all patients had febrile neutropenia. • Hepatic toxicity (grade II – III) was observed in 5 patients (16,7%) • Two patients receiving chemotherapy have died of sepsis and organ failure. • 25% of enrolled patients requiredparenteral nutrition.

10. Peripheral blood stem cell rescue • The number of PBSCs infused per cycle ranged from 0,2*106/kg to 2,8*106/kg • Median CD 34+ cells number – 1,27*106/kg • Median bone marrow recovery time ranged from 8 to 29 days • There was significant correlation between bone marrow recovery and CD 34+ number. (p = 0,001) • Duration of neutropenia in patient group who received CD 34+ cells less than 1*106/kg was longer compared with those who received more than 1*106/kg CD 34+ cells. Neutropenia duration was 10,2 days in first group and 14,3 days in second group.

11. Results 3 – year PFS in all patients was 72,2%±9,0% Median follow up was 57,9±4 months (5 – 68)

12. 3 – year PFS for High risk and Average risk patients 3 – year PFS for High risk patients was – 66,1±11,4% (median follow up - 39,4±4,7 months) 3 – year PFS for Average risk patients was - 77,4±11,5% (median follow up - 56,8±5,6 months)

13. 3 – year PFS based on extent of resection 3 – year PFS in group with residual tumorwas 63,5±16,9% (median follow up 38,1±5,3 months) 3 - year PFS in group without residual tumorwas 77,5±9,0% (median follow up 56,5±5)

14. 3 – year PFS based on extent of metastases 3 – year PFS in patient with M+ stage (M1, M2 and M3) was 62,2±17,8% (median follow up 38,6±6,6 months) 3 – year PFS in patients with M0 stage was 77,2±10,1% (median follow up – 54,9±4,9 months)

15. Conclusion • Our study demonstrates that an intensive chemotherapy regimen is feasible and effective after tumor resection and craniospinal radiotherapy in treatment of newly diagnosed medulloblastoma • Main type of toxicity was hematopoietic toxicity and requires blood and platelet transfusion. • Treatment mortality was 6,7%, caused by sepsis (multiresistantPseudomonas aeruginosa) • As a result we have reached better survival in high group risk patients (3 – year PFS - 77,4%) • However, recent studies have shown that medulloblastomais biologically heterogeneous tumor and requires new approaches in diagnostic and treatment.

16. Thank you foryour attention!