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

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 poor and remains near 50%

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

Risk group stratification

Average risk High risk

Residual tumor < 1.5 cm2 > 1.5 cm2

Extent of metastases

M0 M+ (M1, M2, M3)

Histological type

Large cell/anaplastic

Risk – adapted radiotherapy

Average Risk High Risk

23,4 Gy CSI 36 Gy CSI

+ boost to posterior fossa

(total dose 54 Gy)

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: cisplatin 75 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

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 chemotherapy performed in our clinic

Clinical characteristics of enrolled patients

Characteristic Number of patients

Characteristic Number of patients

Sex: Male Female

17 (56,7%)13 (43,3%)

Histological characteristics: Classic

Nodular desmoplastic

Large cell/anaplastic

26 (86,7%)

1 (3,3%)

3 (10%)

Age (years) Median (range) 10,7 (3 – 18)

Extent of resection R0 R1

19 (56,7%)11 (43,3%)

Extent of metastases M0 M+ (M1 – M3)

20 (66,7%)10 (23,3%)

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 required parenteral nutrition.

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.

Results

3 – year PFS in all patients was 72,2%±9,0%

Median follow up was 57,9±4 months (5 – 68)

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)

3 – year PFS based on extent of resection

3 – year PFS in group with residual tumor was 63,5±16,9% (median follow up 38,1±5,3 months)

3 - year PFS in group without residual tumor was 77,5±9,0% (median follow up 56,5±5)

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)

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 (multiresistant Pseudomonas 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 medulloblastoma is biologically heterogeneous tumor and requires new approaches in diagnostic and treatment.

Thank you for your attention!