Temodal and Its Use in Children with Anaplastic Astrocytomas and Glioblastomas

O.G. Zheludkova, I.D. Borodina, A.G. Korshunov, S.V. Gorbatykh, M.I. Livshits, B.V. Kholodov, V.I. Ozerova, M.B. Belogurova, E.V. Kumirova, L.P. Privalova, N.I. Zelinskaya

Research Institute of Children's Hematology,
Burdenko Research Institute of Neurosurgery,
Morozovskaya Children's Clinical Hospital,
Research and Practice Center of Medical Care of Children,
Russian Research Center of Rentgenoradiology, Moscow, Russia
Hospital N 31, Saint Petersburg, Russia,
Regional Children's Clinical Hospital, Nizhny Novgorod, Russia,
Republical Clinical Children's Hospital, Kazan, Russia

 

The cooperative study, carried out in the Research Institute of Children's Hematology in December 1, 2000 - December 1, 2003, was devoted to estimation of temodal efficacy and its tolerance by children with malignant gliomas (MG). There were 34 patients with histological confirmation of diagnosis on December 1, 2003. Their distribution was as follows: anaplastic astrocytoma (AA) - 12 cases, multiform glioblastoma (MFG) - 22 cases. The disease progression or presence of residual tumor after previous operation and radiation therapy were revealed with CT/MRI examinations with enhancement.

The tumor was localized in a supratentorial area (23 cases), brain stem (5 cases), thalamus tubercle (4 cases), cerebellum (1 case) and a craniospinal region (1 case). The age varied from 3 up to 16 years (9.5 on the average).

Temodal efficacy was estimated in 20 patients with primary tumors (after previous surgical intervention and radiation therapy - 19; after previous stereotactic biopsy and radiation therapy - 1) and 14 cases with tumor relapse/progression (after previous intervention, radiation and polychemotherapy - 6; after previous intervention and radiation therapy - 8). Operation in patients with primary tumor consisted in partial removal (8), subtotal removal (9), biopsy (1). Local radiation therapy was carried out in 2-3 weeks after operation. A tumor bed was irradiated; total focal dose was 50-60 Gy (58 Gy on the average).

Previous treatment of 6 patients with disease progression lay in radiation and polychemotherapy (platinum preparations, vincristine, cyclophosphan, cisplatin, etoposide), carried out not less than 4 months before including into the present study. All the patients were in a satisfactory state by the beginning of treatment with temodal. An amount of leukocytes, neutrophils and thrombocytes was not less than 2500/ml, 1000/ml and 100000/ml respectively. Presence of AA and MFG was confirmed by the Pathomorphology Laboratory of the Burdenko Research Institute of Neurosurgery. Clinical-and-laboratory studies started a week before the beginning of treatment with temodal. CT/MRI examinations were carried out not more than 2 weeks before its use.

A dosage scheme was standard and included 10 cycles. As for patients with preceding polychemotherapy and without it, they were prescribed 150mg/m2/day and 200mg/m2/day of temodal respectively. It was taken per os during 5 days with an interval of 28 days. Hormones (I/V dexamethason in a dose of 0.15mg/kg/day) were used in 8 cases for stabilizing their neurologic state.

Direct efficacy was estimated in 30 patients with 2 and more cycles of treatment with temodal (14 cases with relapse/progression and 16 cases with primary tumor). The results were as follows: a full-value effect (FVE) - 4 cases (13%), a partial effect (PE) - 3 cases (10%), disease stabilization (DS) - 8 cases (27%), disease progression (DP) - 15 cases (50%). An objective response (FVE+PE+DS) was watched in 15 patients (50%), treated with temodal.

Total survival by the 42 month was estimated in all 34 patients. It was equal to 28±0.09% (15 months on the average). Total survival in cases with primary malignant gliomas and disease progression was 20% and 22% respectively (p=0.66). Total survival of patients with MFG and AA by the 32 month was 12% and 50% (p=0.31) respectively. Progression-free survival (PFS) by the 42 month was 210.11% in the whole group of patients (15.7 months on the average). PFS in patients with primary malignant gliomas and cases with DP was 28% and 53% respectively (p=0.56).

Chemotherapy toxicity was estimated in all patients with 253 cycles of treatment with temodal. One patient (1.6%) was excluded from the group after the first cycle because of toxicity of the IV grade. Vomiting, nausea and anorexia, myelosuppression were watched in 5.5%, 2.8%, 1.6% respectively Vomiting and nausea were treated by antiemetics (navoban, zofran).

Obtained data demonstrate certain efficacy of temodal in treatment of children with primary AA and MFG and with disease progression after preceding combined or complex therapy.

Temodal was tolerated rather well; side effects were watched mainly at the beginning of therapy. Taking into account good tolerance, temodal, combined with radiation therapy and such chemotherapeutic preparations as topoisomerase inhibitors, taxans, derivatives of nitrosourea and used in alternative doses and dosage regimens, can lead to improvement of objective response and survival.