Annals of Oncology 11: 409^113, 2O00. © 2000 Kluwer Academic Publishers. Printed in the Netherlands. Original article A phase II study of paclitaxel in chemonai've patients with recurrent high-grade glioma T. J. Postma, 1 J. J. Heimans, 1 S. A. Luykx, 2 C. J. van Groeningen, 2 L. F. M. Beenen, 3 O. S. Hoekstra, 4 M. J. B. Taphoorn, 5 B. A. Zonnenberg, 6 M. Klein 7 & J. B. Vermorken 2 ' 8 Departments of 'Neurology, 2 Medical Oncology, 3 Neurosurgery, ^Nuclear Medicine, 7 Medical Psychology, University Hospital Vrije Universiteh Amsterdam; Departments of ^Neurology, 6 Medical Oncology, University Hospital Utrecht, The Netherlands; % Present address: Department of Medical Oncology, University Hospital Antwerp, Belgium Summary Background: The prognosis of malignant gliomas remains poor. In recurrent disease, chemotherapy can be considered. Patients and methods: In this phase II study we determined the anti-tumour efficacy of paclitaxel 200 mg/m 2 in a three-hour intravenous infusion every three weeks in chemonai've patients with recurrent high-grade glioma in terms of response, survival, and quality of life. Results: In 17 patients (14 glioblastoma multiforme, 3 ana- plastic astrocytoma) 69 paclitaxel cycles were administered. Partial or complete responses were not observed. Stable dis- ease for four to six months was observed in five patients (29%). Median time to progression and median survival were two and 10 months, respectively. Toxicity due to paclitaxel was as to be expected and minor in most cases. Quality of life and mood estimates appeared rather stable over time. Conclusions: We conclude that three-weekly 200 mg/m 2 paclitaxel chemotherapy for patients with recurrent high-grade gliomas did not lead to major complications or adverse effects on quality of life and mood. However, this therapy is of only very limited value in terms of response and survival in such patients. Key words: paclitaxel, quality-of-life, recurrent high-grade glioma Introduction The prognosis of malignant gliomas remains poor despite attempts to optimize multimodality treatment with surgery, radiotherapy and chemotherapy with a median survival for glioblastoma multiforme and ana- plastic astrocytoma approaching one and two to three years, respectively [1]. Although variables like tumour grade, age and Kar- nofsky performance status are more important than any treatment in itself, radiotherapy and, to a smaller de- gree, extent of neurosurgical resection, prolong survival when performed in newly diagnosed high-grade glioma [2-4]. Adjuvant chemotherapy only leads to minor pro- longation of survival, especially in glioblastoma multi- forme [5, 6]. The most widely used chemotherapeutic agents are BCNU or a combination of procarbazine, CCNU, and vincristine (PCV). This latter combination chemotherapy produced better results in the adjuvant setting compared to single-agent treatment, particularly in anaplastic astrocytoma [7]. In the US, standard therapy for newly diagnosed high-grade glioma consists of neurosurgery, followed by radiotherapy and nitrosourea-based chemotherapy. In many European centres, adjuvant nitrosourea chemo- therapy is not prescribed routinely in newly diagnosed high-grade glioma. The advantages of chemotherapy are not felt to outweigh its disadvantages with possible negative impact on quality of life. Moreover, a recently performed large randomized trial showed no benefit of adjuvant PCV chemotherapy in high-grade glioma [8]. Chemotherapy is usually considered at recurrence, with or without preceding reoperation, depending primarily on the clinical condition of the patient. Paclitaxel (Taxol®) is a unique antineoplastic agent derived from the bark of the Pacific Yew (Taxus brevi- folia). The drug inhibits cell mitosis by binding to the beta subunit of tubulin, causing polymerization of microtubules [9]. In clinical studies, paclitaxel has sig- nificant antitumour activity against a variety of tumours including ovarian, head and neck, lung, and breast cancer [10]. Paclitaxel is cytotoxic to glial cell lines [11], and can act as a radiation sensitizing agent, blocking cells in the G2 and M phase, which are the most radiosensi- tive phases of the cell cycle [12, 13]. In experimental animal glioma models, paclitaxel, either free, liposome- encapsulated, interstitially delivered from a biodegrad- able polymer, or delivered as lipid-coated microbubbles can produce a significant delay in tumour growth [14, 15], and significant prolongation of survival in tumour bearing rats [16]. The drug also has anti-angiogenic properties [17]. In a rat model, paclitaxel was not detect- able in normal or malignant central nervous system tissue [18], although it could be detected in tumour tissue in three patients with recurrent glioma [19]. The objectives of the present study were: (1) to deter-
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