Temozolomide: A new oral cytotoxic chemotherapeutic agent with promising activity against primary brain tumours

O'Reilly, S.M.; Newlands, E. S.; Brampton, M.; Glaser, M.G.; Rice-Edwards, J.M.; Illingworth, R; Richards, Peter G.; Kennard, Charles D.; Colquhoun, Iain; Lewis, Paul D.; Stevens, M.F.G.

doi:10.1016/s0959-8049(05)80198-4

Cited by 233 publications

(138 citation statements)

References 7 publications

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“…Temozolomide is well tolerated (Newlands et al, 1992;O'Reilly et al, 1993;Bleehen et al, 1995;Dhodapkar et al, 1997), with thrombocytopaenia as the main toxicity. This is usually self-limiting and most patients recover by day 28.…”

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confidence: 99%

Phase I study of temozolomide plus paclitaxel in patients with advanced malignant melanoma and associated in vitro investigations

et al. 2005

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The purpose of this study was to determine activity of temozolomide combined with paclitaxel or epothilone B in vitro, and to investigate the combination of temozolomide with paclitaxel in a Phase I clinical trial. Melanoma cell lines A375P and DX3 were treated with temozolomide and either paclitaxel or epothilone B. Combination indices were determined to assess the degree of synergism. In a clinical study, 21 patients with malignant melanoma were treated with increasing doses of temozolomide (orally, days 1 -5), in combination with a fixed dose of paclitaxel (i.v. infusion day 1), followed by dose escalation of the latter drug. Cycles of treatment were repeated every 3 weeks. Pharmacokinetics of both agents were determined on day 1, with temozolomide pharmacokinetics also assessed on day 5. All three compounds were active against the melanoma cell lines, with epothilone B being the most potent. There was a strong degree of synergism between temozolomide and either paclitaxel or epothilone B. In the clinical study, no pharmacokinetic interaction was observed between temozolomide and paclitaxel. Dose escalation of both drugs to clinically active doses was possible, with no dose-limiting toxicities observed at 200 mg m À2 day À1 temozolomide and 225 mg m À2 day À1 paclitaxel. There were two partial responses out of 15 evaluable patients. One patient remains alive and symptom-free at 4 years after treatment. Temozolomide and paclitaxel may be administered safely at clinically effective doses. Further evaluation of these combinations in melanoma is warranted.

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confidence: 99%

Phase I study of temozolomide plus paclitaxel in patients with advanced malignant melanoma and associated in vitro investigations

et al. 2005

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“…The promise is that the combination of surgery, radiotherapy, chemotherapy and RIT may provide, at last, a way of increasing life expectancy in high grade glioma patients (O'Reilly et al, 1993).…”

Section: Clinicalmentioning

confidence: 99%

Pretargeted adjuvant radioimmunotherapy with Yttrium-90-biotin in malignant glioma patients: A pilot study

et al. 2002

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In a previous study we applied a three-step avidin -biotin pretargeting approach to target 90 Y-biotin to the tumour in patients with recurrent high grade glioma. The encouraging results obtained in this phase I -II study prompted us to apply the same approach in an adjuvant setting, to evaluate (i) time to relapse and (ii) overall survival. We enrolled 37 high grade glioma patients, 17 with grade III glioma and 20 with glioblastoma, in a controlled open non-randomized study. All patients received surgery and radiotherapy and were disease-free by neuroradiological examinations. Nineteen patients (treated) received adjuvant treatment with radioimmunotherapy. In the treated glioblastoma patients, median disease-free interval was 28 months (range=9 -59); median survival was 33.5 months and one patient is still without evidence of disease. All 12 control glioblastoma patients died after a median survival from diagnosis of 8 months. In the treated grade III glioma patients median disease-free interval was 56 months (range=15 -60) and survival cannot be calculated as only two, within this group, died. Three-step radioimmunotherapy promises to have an important role as adjuvant treatment in high grade gliomas, particularly in glioblastoma where it impedes progression, prolonging time to relapse and overall survival. A further randomized trial is justified.

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“…Recent trials suggest that epipodophillotoxins alone or combined with cisplatin are very effective in treating NSCLCrelated BrM and ifosfamide-mitomycin-cisplatin or gemcitabine-cisplatin combinations have been evaluated with similar good responses [3][4][5][6][7][8][9]. Temozolomide (TMZ) is a novel, oral, alkylating agent with virtually 100% bioavailability [10][11][12]. It is a new class of second generation imidazotetrazine pro-drugs that undergoes spontaneous conversion under physiological conditions to the active alkylating agent-MTIC, thus not requiring hepatic metabolism to become active.…”

Section: Introductionmentioning

confidence: 99%

“…It is a new class of second generation imidazotetrazine pro-drugs that undergoes spontaneous conversion under physiological conditions to the active alkylating agent-MTIC, thus not requiring hepatic metabolism to become active. It crosses the blood-brain barrier and has showed activity in heavily pretreated patients affected by BrM from NSCLC [10][11][12]. Concentrations of the drug in the central nervous system reach approximately 30-40% of plasma concentrations and clearance of TMZ is unaffected by co-administration with anticonvulsivants, antiemetics or dexamethasone.…”

Section: Introductionmentioning

confidence: 99%

Oral temozolomide in heavily pre-treated brain metastases from non-small cell lung cancer: Phase II study

Giorgio¹,

Giuffrida²,

Pappalardo³

et al. 2005

Lung Cancer

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Summary Introduction:The primary tumour type most likely to metastasize to the brain is lung cancer. In heavily pre-treated patients, limited therapeutic option is available and the results of availability therapies reported in literature are disappointing. The present phase II study was designed to assess the efficacy and safety of temozolomide (TMZ) as palliative treatment for brain metastases (BrM) in NSCLC patients pre-treated with WBRT and at least one line of chemotherapy for metastatic brain disease. Material and methods: Temozolomide was administered orally at 150 mg/mq/day for five consecutive days for the first cycle, doses were increased to 200 mg/mq/day for 5 days every 28 days for subsequent cycles if no grade 3/4 haematological toxicity was observed. Eligibility criteria included cytological or histological confirmed NSCLC; BrM, recurrent or progressing after WBRT and at least one line of chemotherapy. A total of 30 consecutive patients entered the study and received the allocated treatment.Results: Three patients (10%) achieved an objective response (OR) of BrM with two complete remission. Stable disease and progressive disease were achieved in 3 (10%) and 24 patients (80%), respectively. A correlation between response to TMZ * Corresponding author. and sensitivity to the previous first line chemotherapy was reported. Time to progression and overall survival were examined both for responder patients and for all included patients. For long-term survivors, we considered the patients who survived >12 months after the start of TMZ. According to this definition, three patients resulted long-term survivors: 2 with OR and 1 with stable brain disease. No grades 3 or 4 toxicity occurred. The total of treatment-related adverse events were mild or moderate (G1-2) in intensity. No patients discontinued TMZ as a result of treatment-related toxicity. Discussion: The results of the present trial clearly demonstrates that TMZ is active and safe in BrM NSCLC patients previously treated with WBRT and at least one line of chemotherapy.

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Temozolomide: A new oral cytotoxic chemotherapeutic agent with promising activity against primary brain tumours

Cited by 233 publications

References 7 publications

Phase I study of temozolomide plus paclitaxel in patients with advanced malignant melanoma and associated in vitro investigations

Phase I study of temozolomide plus paclitaxel in patients with advanced malignant melanoma and associated in vitro investigations

Pretargeted adjuvant radioimmunotherapy with Yttrium-90-biotin in malignant glioma patients: A pilot study

Oral temozolomide in heavily pre-treated brain metastases from non-small cell lung cancer: Phase II study

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