Phase I/II fractionated stereotactic radiotherapy and weekly paclitaxel in malignant gliomas

Purpose/Objective: Management of Malignant Gliomas continues to be a challenge. We prospectively studied the role of adding weekly Paclitaxel to Stereotactic Radiation Therapy (SRT) in the treatment of Malignant Gliomas. Clinical and Pharmacokinetic (PK) results are presented. Materials/Methods: Twenty patients (fifteen males & five females) all were diagnosed with Malignant Gliomas: eighteen Glioblastoma Multiforme (GBM) & two Anaplastic Astrocytoma (AA) were enrolled in an IRB approved protocol. Patients received 46 Gy at 2 Gy/ fraction followed by a boost utilizing Fractionated streotactic Radiation therapy at a fraction of 2.5 Gy for 8 fractions. Paclitaxel (T) is delivered concomitantly at 150 mg/m2 weekly for 6 cycles. Fourteen patients had (Pk) assays of Paclitaxel levels. The ratio of serum Paclitaxel concentrations at 24 hours & 10 minutes were correlated with Phenytoin (PH) serum levels. Age ranged from 37–85 years (median 67years). Median Karnofsky Performance Status (KPS) was 70 (range 60–90). Six patients had gross total resection (GTR), nine had subtotal resection (STR) and five had biopsy only. Six patients had re-operation and/or re-treatment for recurrence. All patients were followed until death or for a maximum of 36 months. No patients were lost for follow up. Results: The overall survival of the whole group was 14.5 months. The survival rate was significantly higher (17.8 months) in patients with higher Paclitaxel ratio versus 9.5 months in those with lower Paclitaxel serum ratio (P=0.04). The ratio of Paclitaxel in serum was strongly correlated with the blood levels of Phenytoin; patients with sub-therapeutic Phenytoin levels (less than 10 mg/dl had Paclitaxel concentration ratio of 3.07% compared to 1.76% in those with therapeutic Phenytoin levels (P=0.02). All patients tolerated the regimen well, no grade IV morbidity encountered. Grade II Leucopenia was encountered in six patients & three had grade III necessitating growth factor administration. Enhanced survival was demonstrated in patients with GTR, KPS ≥80, age ≤60 years and higher Paclitaxel level. Enhanced survival was demonstrated in patients with GTR (20.8 mo.), KPS ≥80 (18.7 mo.) and age ≤60 years (22.7 mo.) as compared to STR or biopsy (12 mo.-P< 0.05), KPS ≤70 (10.8 mo.-P=0. 005) & older age > 60 (10.4 mo.- P=0.006), respectively. Conclusions: 1) The use of weekly Paclitaxel and fractionated Stereotactic radiotherapy is well tolerated active in malignant Giomas with overall survival of 14.5 months. 2) Higher Phenytoin levels result in reduced Paclitaxel concentration 3) Higher Paclitaxel concentrations are associated with enhanced survival in-patients with malignant Gliomas. 4) Modification of Paclitaxel dose may be warranted for patients on Phenytoin.