Tumori, 94: 674-680, 2008
Carboplatin and oral cyclophosphamide combination after temozolomide failure in malignant gliomas Emel Yaman, Suleyman Buyukberber, Aytug Uner, Ugur Coskun, Deniz Yamac, Banu Ozturk, Ali Osman Kaya, Ramazan Yıldız, Mustafa Benekli for the Anatolian Society of Medical Oncology (ASMO) Department of Medical Oncology, Gazi University Faculty of Medicine, Ankara, Turkey
ABSTRACT
Background. Temozolomide is a novel cytotoxic agent for malignant gliomas. However, treatment failure occurs approximately in half of patients, and the optimal regimen in this setting has yet to be defined. In the present study, we assessed retrospectively the efficacy and toxicity of the combination of carboplatin and oral cyclophosphamide in temozolomide-resistant patients. Methods. We evaluated the medical records of 30 patients with malignant gliomas. After failure of temozolomide therapy, patients were treated with a combination of carboplatin and oral cyclophosphamide. Treatment consisted of intravenous carboplatin AUC 6 (based on the Calvert Formula) on day 1 and oral cyclophosphamide 75 mg/m2 daily on days 1 to 14, followed by 14 days of rest, with the treatment repeated every 4 weeks. Results. All patients were evaluated for response and toxicity. The objective response rate was 30%, including 9 partial responses. Median time to disease progression and median overall survival was 7 months and 8 months, respectively. Clinically responsive patients had statistically significant longer progression-free survival and overall survival than unresponsive patients. Hematological side effects were commonly observed toxicities, with neutropenia the most frequent. Conclusions. Our data suggest that carboplatin and oral cyclophosphamide therapy is a convenient regimen after failure of temozolomide therapy in patients with malignant gliomas because of its activity, feasibility and tolerability. Further prospective studies are needed in this setting.
Introduction Treatment of malignant gliomas is palliative; results are usually dismal. Median survival is usually less than 1 year1,2. Until recently, radiotherapy following optimal resection was the standard therapy, due to the chemo-resistant nature of the tumor. Nowadays, temozolomide is the most promising agent in malignant gliomas, with a 2-year survival rate of 26% in glioblastoma multiforme and 35% in anaplastic astrocytoma3-6. Unfortunately, despite the hopeful results with temozolomide, no response was observed in approximately half of the patients or progression occurred only after a short time. The optimal management of these patients is somewhat unclear, and there is no accepted therapy. A wide variety of drugs including irinotecan in combination with carmustine7, PCV (procarbazine, vincristine, CCNU)8, imatinib mesylate and hydroxyurea combination9-11, erlotinib12, gefitinib13 and bevacizumab plus irinotecan14,15 are under evaluation in this respect. Carboplatin and cyclophosphamide are both effective alkylating agents in the treatment of malignant glioma16-22. Their combination showed some activity in patients with unresectable tumors at the pre-irradiation setting in a phase II study21.
Key words: carboplatin, cyclophosphamide, malignant gliomas, temozolomide refractory. Correspondence to: Prof Dr Suleyman Buyukberber, Gazi University Faculty of Medicine, Director of Medical Oncology Department, Ankara, Turkey. Tel 00-90-312-2025830; fax 00-90-312-2158710; e-mail
[email protected] Received November 11, 2007; accepted May 28, 2008.
CARBOPLATIN AND CYCLOPHOSPHAMIDE IN TEMOZOLOMIDE-REFRACTORY GLIOMAS
This is the first report on a carboplatin and oral cyclophosphamide regimen in temozolomide-refractory malignant glioma patients.
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on MRI, and worsening of the neurological condition with corticosteroid doses remaining stable or increasing. Stable disease (SD) meant other conditions. Treatment plan
Patients and methods Patients We retrospectively evaluated the medical records of 30 patients with high-grade malignant gliomas who received intravenous carboplatin and oral cyclophosphamide combination between May 2005 and March 2007. Patients with high-grade malignant gliomas that had a recurrence after curative radiotherapy and prior temozolomide resistance were eligible for the study. Temozolomide failure was defined as clinical or radiological progression within 6 months of completion of temozolomide treatment. All patients had to have histopathologically proven high-grade malignant glioma based on The 2000 World Health Organization (WHO) scheme23 and measurable intracranial disease by contrast-enhanced magnetic resonance imaging (MRI) of the cranium. If radiation necrosis was suspected, spectroscopic MRI was performed to exclude radiation necrosis. Other inclusion criteria were: age 18-75 years, Karnofsky performance status (KPS) >50, life expectancy longer than 3 months, and a 4-week interval after the last chemotherapy cycle. Patients with prior malignancies other than basal cell carcinoma or cervical carcinoma in situ, psychiatric disorder and uncontrolled infections were excluded. Additionally, pregnant or lactating women were not allowed to participate in the study. Patients were required to have adequate bone morrow (white blood cell count >3 x 109/l, platelets >100 x 109/l, hemoglobulin >10g/dl), liver (total billirubin
