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Items 1-65 of 65 | One page.
1: J Clin Oncol. 2003 Sep 1;21(17):3351-6. | Related Articles, Links
Phase II study of temozolomide plus thalidomide for the treatment of metastatic melanoma. Hwu WJ, Krown SE, Menell JH, Panageas KS, Merrell J, Lamb LA, Williams LJ, Quinn CJ, Foster T, Chapman PB, Livingston PO, Wolchok JD, Houghton AN. Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021, USA. hwuw@mskcc.org. PURPOSE: To further investigate the efficacy and safety of temozolomide plus thalidomide in patients with metastatic melanoma without brain metastases. PATIENTS AND METHODS: Patients with histologically confirmed advanced-stage metastatic melanoma were enrolled in an open-label, phase II study. The primary end point was response rate. Patients received temozolomide (75 mg/m2/d x 6 weeks with a 2-week rest between cycles) plus concomitant thalidomide (200 mg/d with dose escalation to 400 mg/d for patients < 70 years old, or 100 mg/d with dose escalation to 250 mg/d for patients >/= 70 years old). Treatment was continued until unacceptable toxicity or disease progression occurred. RESULTS: Thirty-eight patients (median age, 62 years) with stage IV (three patients with M1a, eight with M1b, and 26 with M1c) or stage IIIc (one patient) melanoma and a median of four metastatic sites were enrolled, and received a median of two cycles of therapy. Twelve patients (32%) had an objective tumor response, including one with an ongoing complete response of 25+ months' duration and 11 with partial responses. Five patients achieving partial response with a more than 90% reduction of disease were converted to a complete response with surgery. Treatment was generally well tolerated. Median survival was 9.5 months (95% confidence interval, 6.05 to 19.38 months), with a median follow-up among survivors of 24.3 months. CONCLUSION: The combination of temozolomide plus thalidomide seems to be a promising and well-tolerated oral regimen for metastatic melanoma that merits further study. Publication Types: Clinical Trial Clinical Trial, Phase II PMID: 12947072 [PubMed - indexed for MEDLINE]
2: Br J Cancer. 2003 Jul 21;89(2):248-51. | Related Articles, Links
Phase I study of temozolamide (TMZ) combined with procarbazine (PCB) in patients with gliomas. Newlands ES, Foster T, Zaknoen S. Imperial College School of Medicine, Charing Cross Hospital, Fulham Palace Road, London W6 8RF, UK. e.newlands@ic.ac.uk Temozolomide (TMZ) is an oral alkylating agent with a good safety profile and proven efficacy in the treatment of malignant glioma. Procarbazine (PCB) has been used for treating gliomas for many years and here both agents were combined in the treatment. This phase I study was designed to evaluate the efficacy and safety of TMZ alone (course 1) and TMZ in combination with PCB in subsequent courses in chemotherapy-naive patients with malignant glioma. Patients with anaplastic astrocytoma (AA), glioblastoma multiforme (GBM) and low-grade glioma were treated with TMZ 200 mg m(-2) on days 1-5 on a 28-day cycle for course 1. Beginning with course 2, cohorts of patients received TMZ at full dose with escalating doses of PCB (50/75/100/125 mg m(-2) days 1-5 given 1 h prior to TMZ). A total of 28 patients were enrolled with three patients each at dose level 1 and 2, 16 patients at dose level 3 and six patients at dose level 4 received 182+ cycles of treatment and were included in this analysis. In all, 16 patients had GBM, seven patients had AA, five had grade 1 or 2 glioma and the median age was 47 years. The patients had received prior surgery and radiotherapy. Responses were seen at all dose levels. Overall, there were 10 (36%) responses lasting from 2 to 17+ months. Treatment was generally well tolerated with few grade 3 or 4 toxicities, except at dose level 4, where four patients had grade 3/4 had thrombocytopaenia at this dose and several patients had moderate-to-severe lethargy. TMZ 200 mg m(-2) and PCB 100 mg m(-2) were well tolerated on a daily 5 x and four weekly cycle in patients with malignant glioma and clearly had antitumour activity. Publication Types: Clinical Trial Clinical Trial, Phase I PMID: 12865911 [PubMed - indexed for MEDLINE]
3: J Clin Oncol. 2003 Jul 1;21(13):2525-8. | Related Articles, Links
Phase II study of first-line chemotherapy with temozolomide in recurrent oligodendroglial tumors: the European Organization for Research and Treatment of Cancer Brain Tumor Group Study 26971. van den Bent MJ, Taphoorn MJ, Brandes AA, Menten J, Stupp R, Frenay M, Chinot O, Kros JM, van der Rijt CC, Vecht ChJ, Allgeier A, Gorlia T; European Organization for Research and Treatment of Cancer Brain Tumor Group. Department of Neuro-Oncology, University Hospital Rotterdam/Rotterdam Cancer Center, the Netherlands. m.vandenbent@erasmusmc.nl PURPOSE: Oligodendroglial tumors are chemotherapy-sensitive tumors, with two thirds of patients responding to combination chemotherapy with procarbazine, lomustine, and vincristine (PCV). Temozolomide (TMZ), a new alkylating and methylating agent, has demonstrated high response rates in patients with recurrent anaplastic astrocytoma. We investigated TMZ as first-line chemotherapy in recurrent oligodendroglial tumors (OD) and mixed oligoastrocytomas (OA) after surgery and radiation therapy. PATIENTS AND METHODS: In a prospective, nonrandomized, multicenter, phase II trial, patients were treated with 200 mg/m2 of TMZ on days 1 through 5 in 28-day cycles for 12 cycles. Patients with a recurrence after prior surgery and radiotherapy, and with measurable and enhancing disease on magnetic resonance imaging (MRI) were eligible for this study. Patients with large lesions and mass effect or with new clinical deficits were not eligible. Pathology and the MRI scans of all responding patients were centrally reviewed. RESULTS: Thirty-eight eligible patients were included. In three patients, pathology review did not confirm the presence of an OD or OA. TMZ was generally well tolerated. The most frequent side effects were hematologic; only one patient discontinued treatment for toxicity. In 20 (52.6%) of 38 patients (95% exact confidence interval, 35.8% to 69.0%), a complete (n = 10) or partial response to TMZ was observed. The median time to progression was 10.4 months for all patients and 13.2 months for responding patients. At 12 months from the start of treatment, 40% of patients were still free from progression. CONCLUSION: TMZ provides an excellent response rate with good tolerability in chemotherapy-naive patients with recurrent OD. A randomized phase III study comparing PCV with TMZ is warranted. Publication Types: Clinical Trial Clinical Trial, Phase II Multicenter Study PMID: 12829671 [PubMed - indexed for MEDLINE]
4: J Clin Oncol. 2003 Jun 15;21(12):2305-11. | Related Articles, Links
Phase II evaluation of temozolomide and 13-cis-retinoic acid for the treatment of recurrent and progressive malignant glioma: a North American Brain Tumor Consortium study. Jaeckle KA, Hess KR, Yung WK, Greenberg H, Fine H, Schiff D, Pollack IF, Kuhn J, Fink K, Mehta M, Cloughesy T, Nicholas MK, Chang S, Prados M; North American Brain Tumor Consortium. University of Texas M. D. Anderson Cancer Center, Houston, USA. jaeckle.kurt@mayo.edu. PURPOSE: Temozolomide (TMZ) and 13-cis-retinoic acid (cRA) have shown activity in prior single-agent trials of recurrent malignant gliomas (MG). This phase II trial evaluated efficacy and toxicity of combination temozolomide and cRA treatment in recurrent MG. PATIENTS AND METHODS: Adults with recurrent supratentorial MG for whom surgery, radiation, and/or chemotherapy failed were eligible. Treatment included oral TMZ 150 or 200 mg/m2/d, days 1 through 5, and cRA 100 mg/m2/d, days 1 to 21, every 28 days. Primary end point was progression-free survival at 6 months (PFS 6); secondary end points included response, survival, and PFS12. RESULTS: Eighty-eight eligible patients (glioblastoma multiforme [n = 40]; anaplastic gliomas [n = 48; astrocytoma, 28; oligodendroglioma, 14; mixed glioma, six]) received treatment. PFS 6 was 43% (95% confidence interval [CI], 33% to 54%) and PFS12 was 16% (95% CI, 10% to 26%). Median overall PFS was 19 weeks (95% CI, 16 to 27 weeks), and median overall survival (OS) was 47 weeks (95% CI, 36 to 58 weeks). OS was 46% (95% CI, 36% to 57%) at 52 weeks and 21% (95% CI, 13% to 31%) at 104 weeks. Of 84 assessable patients, there were two (3%) complete responses and eight (12%) partial responses (complete plus partial response, 15%). Among 499 treatment cycles, the most common grade 3/4 events included granulocytopenia (1.8%), thrombocytopenia (1.4%), and hypertriglyceridemia (1.2%). CONCLUSION: TMZ and cRA were active, exceeding our 20% thresholds for PFS 6 success, assuming 20% improvement over our previously reported database (glioblastoma multiforme: expected, 30%; observed, 32%; anaplastic glioma: expected, 40%; observed, 50%). Publication Types: Clinical Trial Clinical Trial, Phase II PMID: 12805331 [PubMed - indexed for MEDLINE]
5: Eur J Cancer. 2003 Jun;39(9):1271-6. | Related Articles, Links
Temozolomide in patients with advanced non-small cell lung cancer with and without brain metastases. a phase II study of the EORTC Lung Cancer Group (08965). Dziadziuszko R, Ardizzoni A, Postmus PE, Smit EF, Price A, Debruyne C, Legrand C, Giaccone G; EORTC Lung Cancer Group. Department of Oncology and Radiotherapy, Medical University of Gdansk, 7 Debinki St., 80-211, Gdansk, Poland. rafald@post.pl This study was performed to evaluate the activity of single-agent temozolomide in two groups of chemotherapy-naive non-small cell lung cancer (NSCLC) patients, with (12 patients) and without (13 patients) brain metastases (BM). Patients in both groups were treated with temozolomide 200 mg/m(2)/day, administered orally for 5 consecutive days of a 28-day cycle. Treatment was continued for up to six cycles, disease progression or unacceptable toxicity. The median number of received cycles was only one in the group with and two in the group without BM, and early disease progression was the main reason for treatment discontinuation. Toxicity was moderate-in the group of patients with BM, the most frequently observed grade 3 or 4 side-effects included thrombocytopenia (17%), granulocytopenia (17%), lethargy (17%); other neurological (17%) and other genitourinary toxicity (17%). Patients without BM experienced anaemia (15%), thrombocytopenia (23%), nausea (15%) and lethargy (15%). This trial was designed according to Simon one-sample two-stage testing procedure and both groups of patients were assessed separately. No objective response was observed in either group and the study was closed after the first step of accrual with the conclusion of a lack of therapeutic activity of single-agent temozolomide in patients with stage IV NSCLC. Publication Types: Clinical Trial Clinical Trial, Phase II Controlled Clinical Trial Multicenter Study PMID: 12763216 [PubMed - indexed for MEDLINE]
6: Cancer Res. 2003 May 15;63(10):2409-15. | Related Articles, Links
Metabolic activation of temozolomide measured in vivo using positron emission tomography. Saleem A, Brown GD, Brady F, Aboagye EO, Osman S, Luthra SK, Ranicar AS, Brock CS, Stevens MF, Newlands E, Jones T, Price P. Cancer Research United Kingdom Positron Emission Tomography Oncology Group, Imperial College London, London W12 0NN, United Kingdom. The purpose of this research was to quantitate and confirm the mechanism of in vivo metabolic activation of temozolomide. The secondary aims were to evaluate the tumor, normal tissue, and plasma pharmacokinetics of temozolomide in vivo, and to determine whether such pharmacokinetics resulted in tumor targeting. [(11)C]temozolomide kinetics were studied in men using positron emission tomography (PET). It has been postulated that temozolomide undergoes decarboxylation and ring opening in the 3-4 position to produce the highly reactive methyldiazonium ion that alkylates DNA. To investigate this, a dual radiolabeling strategy, with [(11)C]temozolomide separately radiolabelled in the 3-N-methyl and 4-carbonyl positions, was used. We hypothesized that (11)C in the C-4 position of [4-(11)C-carbonyl]temozolomide would be converted to [(11)C]CO(2) if the postulated mechanism of metabolic conversion was true resulting in lower [(11)C]temozolomide tumor exposure. Paired studies were performed with both forms of [(11)C]temozolomide in 6 patients with gliomas. Another PET scan with (11)C-radiolabelled bicarbonate was performed and used to account for the metabolites of temozolomide using a data-led analytical approach. Plasma was analyzed for [(11)C]temozolomide and [(11)C]metabolites throughout the scan duration. Exhaled air was also sampled throughout the scan for [(11)C]CO(2). The percentage ring opening of temozolomide over 90 min was also calculated to evaluate whether there was a differential in metabolic breakdown among plasma, normal tissue, and tumor. There was rapid systemic clearance of both radiolabelled forms of [(11)C]temozolomide over 90 min (0.2 liter/min/m(2)), with [(11)C]CO(2) being the primary elimination product. Plasma [(11)C]CO(2) was present in all of the studies with [4-(11)C-carbonyl]temozolomide and in half the studies with [3-N-(11)C-methyl]temozolomide. The mean contributions to total plasma activity by [(11)C]CO(2) at 10 and 90 min were 12% and 28% with [4-(11)C-carbonyl]temozolomide, and 1% and 4% with [3-N-(11)C-methyl]temozolomide, respectively. There was a 5-fold increase in exhaled [(11)C]CO(2) sampled with [4-(11)C-carbonyl]temozolomide compared with [3-N-(11)C-methyl]temozolomide (P < 0.05). A decrease in tissue exposure [area under the curve between 0 and 90 min (AUC(0-90 min))] to [(11)C]temozolomide was also observed with [4-(11)C-carbonyl] temozolomide compared with [3-N-(11)C-methyl]temozolomide. Of potential therapeutic advantage was the higher [(11)C]radiotracer and [(11)C]temozolomide exposure (AUC(0-90 min)) in tumors compared with normal tissue. [(11)C]temozolomide ring opening over 90 min was less in plasma (20.9%; P < 0.05) compared with tumor (26.8%), gray matter (29.7%), and white matter (30.1%), with no differences (P > 0.05) between tumor and normal tissues. The significantly higher amounts of [(11)C]CO(2) sampled in plasma and exhaled air, in addition to the lower normal tissue and tumor [(11)C]temozolomide AUC(0-90 min) observed with [4-(11)C-carbonyl]temozolomide, confirmed the postulated mechanism of metabolic activation of temozolomide. A higher tumor [(11)C]temozolomide AUC(0-90 min) in tumors compared with normal tissue and the tissue-directed metabolic activation of temozolomide may confer potential therapeutic advantage in the activity of this agent. This is the first report of a clinical PET study used to quantify and confirm the in vivo mechanism of metabolic activation of a drug. PMID: 12750260 [PubMed - indexed for MEDLINE]
7: Cancer. 2003 May 1;97(9 Suppl):2359-62. | Related Articles, Links
The emerging role of irinotecan (CPT-11) in the treatment of malignant glioma in brain tumors. Friedman HS, Keir ST, Houghton PJ. Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710, USA. fried003@mcduke.edu Irinotecan is a water-soluble derivative of camptothecin, an alkylator originally extracted from the Chinese tree Camptotheca acuminata. Laboratory studies have demonstrated the activity of irinotecan in a broad panel of pediatric and adult central nervous system tumor xenografts in athymic nude mice. These studies led to a Phase II trial that confirmed the activity of this agent in the treatment of recurrent malignant glioma. Subsequent laboratory studies have demonstrated that a combination of irinotecan (CPT-11) and alkylating agents, particularly 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), increases antitumor effects to a level well above the additive effects of the individual agents. These laboratory studies generated a recently completed Phase I trial of CPT-11 + BCNU, which now is being evaluated in a formal Phase II trial for adults with newly diagnosed or recurrent malignant glioma. More recent studies have demonstrated similar interaction between CPT-11 and temozolomide and have led to a Phase I trial of these agents in the treatment of adults with malignant glioma. Studies currently are addressing the role of O(6)-alkylguanine-DNA alkyltransferase (AGT) in reducing the benefits of combining CPT-11 with temozolomide and the potential therapeutic gain from utilizing an inhibitor of AGT. Copyright 2003 American Cancer Society.DOI 10.1002/cncr.11305 Publication Types: Review Review Literature PMID: 12712457 [PubMed - indexed for MEDLINE]
8: Cancer. 2003 May 1;97(9):2262-6. | Related Articles, Links
Temozolomide as an alternative to irradiation for elderly patients with newly diagnosed malignant gliomas. Glantz M, Chamberlain M, Liu Q, Litofsky NS, Recht LD. Southwestern Vermont Cancer Center, Bennington, Vermont, USA. BACKGROUND: The optimal treatment for elderly patients (defined as patients 70 years of age or older) with malignant gliomas (MG) remains controversial. Some physicians advocate withholding therapy following diagnosis based on the observation that elderly patients do not tolerate adjuvant radiotherapy. The availability of temozolomide (TMZ), a new alkylating agent with antiglioma efficacy, offers another potential therapeutic option for these patients. The drug can be administered orally at home with minimal morbidity. METHODS: The authors retrospectively reviewed a cohort of 86 consecutive elderly MG patients from three institutions, 32 of whom received monthly TMZ in lieu of radiation. RESULTS: Initial Karnofsky performance score was the only predictor of survival in this cohort. No difference in survival was noted between these two groups. Toxicity was minimal in the chemotherapy-treated group and a higher percentage of patients receiving chemotherapy died at home. CONCLUSIONS: The authors concluded that TMZ is as effective as irradiation as a treatment of elderly patients with MG. It is an alternative and, perhaps, a superior therapeutic option to irradiation, based on its ease of administration and low morbidity. Copyright 2003 American Cancer Society.DOI 10.1002/cncr.11323 Publication Types: Multicenter Study PMID: 12712481 [PubMed - indexed for MEDLINE]
9: Cancer. 2003 Apr 15;97(8):1963-8. | Related Articles, Links
Phase I study of temozolomide and escalating doses of oral etoposide for adults with recurrent malignant glioma. Korones DN, Benita-Weiss M, Coyle TE, Mechtler L, Bushunow P, Evans B, Reardon DA, Quinn JA, Friedman H. James P. Wilmot Cancer Center, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA. david_korones@urmc.rochester.edu BACKGROUND: Although temozolomide is active against recurrent malignant glioma, responses in many patients are modest and short-lived. Temozolomide may prove more effective in combination with other agents. Therefore, combination oral chemotherapy for these patients is a particularly attractive approach. METHODS: The authors conducted a Phase I study of temozolomide in combination with escalating doses of oral etoposide (VP-16) to determine the maximum tolerated doses of these two agents when given together. The temozolomide dose was fixed at 150 mg/m(2) per day on Days 1-5. The oral VP-16 was escalated in cohorts of 3 to 6 patients by numbers of days of VP-16 administered: 50 mg/m(2) per day, Days 1-5 (dose level 1), Days 1-8 (dose level 2), Days 1-12 (dose level 3), Days 1-16 (dose level 4), and Days 1-20 (dose level 5). Therapy was given in 28-day cycles. RESULTS: Of the 29 patients enrolled, 26 were fully evaluable and 3 were partially evaluable for toxicity. The 29 patients received a total of 92 cycles. The median age of the patients was 49 years (range, 28-76 years). Diagnoses included glioblastoma (n = 19), gliosarcoma (n = 3), anaplastic astrocytoma (n = 5), and anaplastic oligoastrocytoma (n = 2). The median time from diagnosis to disease recurrence was 8 months (3-188 months). Twenty patients were treated at the first disease recurrence, seven at the second, and two at the third. Twenty-four patients (83%) were receiving anticonvulsants and 24 were receiving dexamethasone. All patients had received previous radiation, and 25 of 29 had been treated with chemotherapy previously. Of the 3 patients at dose level 1, none had dose-limiting toxicity (DLT). Of the 6 patients at dose level 2, 1 patient had DLT: Grade 3 thrombocytopenia resulting in a > 2-week delay in starting the next cycle of chemotherapy. Of the 6 patients at dose level 3, 1 patient had DLT: death due to pneumonia. There were 2 DLTs in the 7 patients at dose level 4: fever, neutropenia, and herpes zoster infection in 1 patient and death due to pneumonia in another. Seven patients had been started at dose level 5 when DLT was established at dose level 4: of the 5 fully evaluable and 2 partially evaluable patients at dose level 5, there was no DLT. CONCLUSIONS: The maximum tolerated dose of temozolomide and oral VP-16 in this heavily treated group of patients with recurrent malignant glioma is temozolomide 150 mg/m(2) per day for 5 days and oral VP-16 50 mg/m(2) per day for 12 days. Copyright 2003 American Cancer Society. Publication Types: Clinical Trial Clinical Trial, Phase I PMID: 12673724 [PubMed - indexed for MEDLINE]
10: Ann Oncol. 2003 Apr;14(4):599-602. | Related Articles, Links
Second-line chemotherapy with temozolomide in recurrent oligodendroglioma after PCV (procarbazine, lomustine and vincristine) chemotherapy: EORTC Brain Tumor Group phase II study 26972. van den Bent MJ, Chinot O, Boogerd W, Bravo Marques J, Taphoorn MJ, Kros JM, van der Rijt CC, Vecht CJ, De Beule N, Baron B. Department of Neuro-Oncology, University Hospital Rotterdam/Rotterdam Cancer Center, The Netherlands. bent@neuh.azr.nl BACKGROUND: Oligodendroglial tumors are chemosensitive, with two-thirds of patients responding to PCV combination chemotherapy with procarbazine, lomustine (CCNU) and vincristine. Temozolomide (TMZ), a new alkylating and methylating agent has shown high response rates in recurrent anaplastic astrocytoma. We investigated this drug in recurrent oligodendroglial tumors (OD) and mixed oligoastrocytomas (OA) after prior PCV chemotherapy and radiation therapy. PATIENTS AND METHODS: In a prospective non-randomized multicenter phase II trial patients were treated with TMZ 150 mg/m(2) on days 1-5 in cycles of 28 days for 12 cycles. Eligible patients had a recurrence after prior PCV chemotherapy, with measurable and enhancing disease as shown by magnetic resonance imaging. Pathology and all responses were centrally reviewed. RESULTS: Thirty-two eligible patients were included. In four patients the pathology review did not confirm the presence of an OD or OA. Twelve of 24 patients [50%, 95% confidence interval (CI) 29% to 71%] evaluable for response to first-line PCV chemotherapy had responded to PCV. Temozolomide was in general well tolerated; the most frequent side-effects were hematological. One patient discontinued treatment due to toxicity. In seven of 28 patients (25%, 95% CI 11% to 45%) with histologically confirmed OD an objective response to TMZ was observed. Median time to progression for responding patients was 8.0 months. After 6 and 12 months from the start of treatment, 29% and 11% of patients, respectively, were still free from progression. CONCLUSIONS: TMZ may be regarded as the preferred second-line treatment in OD after failure of PCV chemotherapy. Further studies on TMZ in OD are indicated. Publication Types: Clinical Trial Clinical Trial, Phase II Multicenter Study PMID: 12649108 [PubMed - indexed for MEDLINE]
11: Strahlenther Onkol. 2003 Apr;179(4):219-32. | Related Articles, Links
Radiochemotherapy of malignant glioma in adults. Clinical experiences. Kortmann RD, Jeremic B, Weller M, Plasswilm L, Bamberg M. Department for Radiation Oncology, University of Tubingen, Germany. rdkortma@med.uni-tuebingen.de BACKGROUND: Standard treatment in patients with malignant glioma consists of surgery and postoperative radiotherapy. A high early recurrence rate, particularly in glioblastoma, has led to the investigation of additional chemotherapy. MATERIAL AND METHODS: Recent results of radiochemotherapy published in the literature were reviewed with respect to outcome in phase II and III trials. Based on these experiences, aspects of future strategies were discussed. RESULTS: 3 decades of intensive research had, unfortunately, little impact on the overall results. While early prospective studies established adjuvant nitrosoureas, particularly BCNU, as suitable adjuvant to surgery and postoperative radiotherapy, further studies largely concentrated on combined chemotherapeutic protocols, mostly procarbazine, CCNU and vincristine (PCV), which was shown to prolong survival in anaplastic astrocytoma. The recent MRC study, however, showed no effect for adjuvant PCV in grade III and IV malignant glioma. Only in high-grade glioma with an oligodendroglial component, additional chemotherapy may be of a decisive benefit. The introduction of newer drugs such as paclitaxel, temozolomide, or gemcitabine demonstrated no decisive advantage. Different modes of application and sequencing of radiotherapy and chemotherapy are presently actively investigated, but failed to substantially improve outcome. CONCLUSIONS: Therefore, search for newer and more effective drugs continues, as well as for "optimal" administration and sequencing, especially from the standpoint of accompanying acute and late toxicity. Finally, recent endeavors focused on basic research such as angiogenesis, migration and invasion, or induction of cell differentiation, but these strategies are still away from broader clinical investigation. Publication Types: Review Review, Tutorial PMID: 12707711 [PubMed - indexed for MEDLINE]
12: J Neurooncol. 2003 Feb;61(3):267-73. | Related Articles, Links
Impact of chromosome 1p status in response of oligodendroglioma to temozolomide: preliminary results. Chahlavi A, Kanner A, Peereboom D, Staugaitis SM, Elson P, Barnett G. Department of Neurological Surgery, Brain Tumor Institute, Cleveland Clinic Cancer Center, Cleveland Clinic, Cleveland, OH 44195, USA. In this IRB-approved retrospective study, we analyzed the efficacy of temozolomide on World Health Organization Grade II and III oligodendrogliomas, as well as mixed oligoastrocytomas, to determine if a correlation exists between the tumors' 1p status and control of growth by this new oral agent. We assessed six patients with oligodendrogliomas with 1p intact (38%) and 10 patients with 1p loss (62%), who received temozolomide. Chromosome 1p status was significantly associated with response to treatment using temozolomide. While nine of 10 patients (90%) with 1p loss responded to temozolomide, only two of six patients (33%) with 1p intact benefited from this treatment (p = 0.04). Although the number of patients evaluated was small, there was no association between 1p status and gender, age, and tumor grade. Gender, age, and tumor grade were similarly not correlated with response to chemotherapy. This report is the first to find that patients harboring oligodendrogliomas with 1p loss are more likely to be sensitive to treatment with temozolomide than those that retain this chromosomal element. Larger prospective trials are needed to confirm these findings; however, temozolomide should be considered in the management of these tumors. PMID: 12675321 [PubMed - indexed for MEDLINE]
13: Oncologist. 2003;8(1):69-75. | Related Articles, Links
Use of temozolomide with other cytotoxic chemotherapy in the treatment of patients with recurrent brain metastases from lung cancer. Ebert BL, Niemierko E, Shaffer K, Salgia R. Departments of Adult Oncology and Medicine, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Boston, Massachusetts, USA. The use of chemotherapy for the treatment of brain metastases arising from lung cancer has been limited by poor efficacy and high toxicity. Temozolomide, an orally bioavailable alkylating agent that crosses the blood-brain barrier, has activity against brain metastases from both small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) when used as a single agent, but response rates are low. Preclinical experiments and early clinical studies in other malignancies indicate that temozolomide may have additive or synergistic effects when used with other chemotherapeutic agents. We report a case of a patient with SCLC with recurrent brain metastases after treatment with multiple chemotherapeutic regimens and whole-brain radiation therapy (WBRT) who was treated with temozolomide (150 mg/m(2) for 5 days in a 28-day cycle) and oral etoposide (50 mg/m(2) for 10 days in a 28-day cycle). A second patient with NSCLC and brain metastases who progressed after treatment with chemotherapy and WBRT was treated with temozolomide (150 mg/m(2) for 5 days in a 28-day cycle) and gemcitabine (1,000 mg/m(2) weekly for 2 weeks in a 3- week cycle). In both patients, the temozolomide regimens were extremely well tolerated and resulted in dramatic and durable responses. The combination of temozolomide with other chemotherapeutic agents represents a promising strategy for treating patients with lung cancer and recurrent brain metastases and merits further study. PMID: 12604733 [PubMed - indexed for MEDLINE]
14: Curr Treat Options Oncol. 2002 Dec;3(6):509-24. | Related Articles, Links
Recurrent malignant glioma in adults. Tatter SB. Department of Neurosurgery, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1029, USA. statter@wfubmc.edu Meaningful palliation is possible for selected patients with recurrent malignant glioma (glioblastoma multiforme, anaplastic astrocytoma, anaplastic oligodendroglioma, or anaplastic mixed oligoastrocytoma) using aggressive treatment. Although long-term disease-free survival occurs in fewer than 10% of patients, most who achieve such survival have been treated for multiple recurrences. Surgical resection with the placement of lomustine-releasing wafers is the only therapy proven in randomized trials to be beneficial for recurrent malignant gliomas. Reoperation is indicated when local mass effect limits the quality of life. Reoperation may make other treatments more effective by removing treatment-resistant hypoxic cells and thereby prolonging high-quality survival. Combination chemotherapy (including procarbazine and a nitrosourea) provides dramatic benefit for many recurrent anaplastic or aggressively behaving oligodendrogliomas and anaplastic mixed oligoastrocytomas. For other recurrent malignant gliomas, single-agent cytotoxic chemotherapy (eg, intravenous lomustine or platinums, oral carmustine, temozolomide, or procarbazine) appears to provide equivalent results and better quality of life at a lower cost than do the combinations of cytotoxic drugs. A randomized phase II trial demonstrates that temozolomide provides longer progression-free survival and better quality of life than standard-dose procarbazine in patients with recurrent glioblastoma multiforme. Because benefits of available cytotoxic chemotherapy for anaplastic astrocytoma and glioblastoma are small, participation in clinical trials is appropriate for most patients. Reirradiation (using stereotactic or three-dimensional conformal techniques with or without concomitant cytotoxic chemotherapy) as radiation sensitization can prolong high-quality survival in selected patients. Specific examples include radiosurgery with the gamma knife or with linear accelerators, intracavitary radiation with the newly US Food and Drug Administration-approved GliaSite (Proxima Therapeutics, Alpharetta, GA) radiation therapy system, low dose rate permanent-seed brachytherapy, and high dose rate stereotactic brachytherapy. Dexamethasone (used for the shortest time in the lowest effective doses) can provide symptomatic benefits. Osmotic diuretics such as mannitol reduce cytotoxic edema more rapidly. Publication Types: Review Review, Tutorial PMID: 12392640 [PubMed - indexed for MEDLINE]
15: Am J Clin Oncol. 2002 Oct;25(5):513-4. | Related Articles, Links
Hemorrhagic cystitis as an unexpected adverse reaction to temozolomide: case report. Islam R, Isaacson BJ, Zickerman PM, Ratanawong C, Tipping SJ. Department of Hematology/Oncology, Marshfield Clinic-Wausau Center, 2727 Plaza Drive, Wausau, WI 54401, USA. A case is reported in which temozolomide, a promising new DNA alkylating agent, was successfully used to treat radiation refractory metastatic brain tumors arising from primary breast cancer. However, the treatment had to be terminated after the second round of treatment due to the development of hemorrhagic cystitis. This side effect was totally unexpected. Another class of alkylating agents (cyclophosphamide and related compounds) exhibits this side effect caused by a prevalent acrolein metabolite. Temozolomide and its sister compounds, dacarbazine and 5-(3-methyltriazen-1-yl)imidazole-4-caroxamide, have never been reported to have this adverse reaction. This case serves to alert physicians to the existence of a possible subpopulation of patients who may experience hemorrhagic cystitis on treatment with imidazotetrazines by a mechanism that is yet to be established. PMID: 12393995 [PubMed - indexed for MEDLINE]
16: Clin Cancer Res. 2002 Oct;8(10):3075-81. | Related Articles, Links
A phase II pilot trial of concurrent biochemotherapy with cisplatin, vinblastine, temozolomide, interleukin 2, and IFN-alpha 2B in patients with metastatic melanoma. Atkins MB, Gollob JA, Sosman JA, McDermott DF, Tutin L, Sorokin P, Parker RA, Mier JW. Department of Medicine, Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA. matkins@caregroup.harvard.edu PURPOSE: In an effort to reduce the frequency of central nervous system (CNS) progression in patients with metastatic melanoma with ongoing systemic response to biochemotherapy, we modified our standard concurrent biochemotherapy regimen by replacing dacarbazine (DTIC) with oral temozolomide. Experimental Design: Patients received cisplatin, vinblastine, and temozolomide (20 mg/m(2) cisplatin and 1.2 mg/m(2) vinblastine i.v., days 1-4; 150 mg/m(2) p.o. temozolomide, days 1-4) concurrent with interleukin 2 (9 MIU/m(2)/day) by continuous i.v. infusion on days 1-4 and IFN-alpha (5 MU/m(2)/day) on days 1-5, 8, 10, and 12. Prophylactic antibiotics and a maximum of four cycles were administered. Routine granulocyte-colony stimulating factor and aggressive antiemetics were also provided. Tumor staging included torso computed tomography scans and brain magnetic resonance imaging pretreatment, after cycle 4 and then every 3 months for 2 years. Torso computed tomography scans were also performed after cycle 2. RESULTS: A total of 147 treatment cycles were administered to 48 patients. No patients had received prior chemotherapy or interleukin 2; however, 19 (40%) had received prior adjuvant IFN-alpha. Significant toxicities included 2 deaths from cardiac events (pericarditis al tamponade and posttreatment myocardial infarction with associated ventricular arrhythmia) and 3 gastrointestinal serious adverse events (pancreatitis, appendicitis, and upper GI bleed). No other nonhematological grade 4 toxicities were observed. Tumor responses were seen in 22 of 47 evaluable patients (relative risk, 47%) with 7 complete responses (15%). Response durations ranged from 1 to 29+ months with 1 currently ongoing. Median survival was 7.5 months. The CNS was the initial site of progression in 2 responding patients. An additional 6 responding patients developed CNS progression within 3 months of systemic progression. Initial CNS progression was significantly less frequent what was seen with the prior DTIC-based biochemotherapy regimen (2 of 22 versus 12 of 19; P = 0.001). CONCLUSION: This regimen appears to be active and reasonably well tolerated in patients with metastatic melanoma. Although the substitution of temozolomide for DTIC reduced the incidence of initial CNS progression, this effect did not appear to result in an improved overall outcome. Publication Types: Clinical Trial Clinical Trial, Phase II PMID: 12374674 [PubMed - indexed for MEDLINE]
17: Hautarzt. 2002 Oct;53(10):659-65. | Related Articles, Links
[Temozolomide as therapeutic option for patients with metastatic melanoma and poor prognosis] [Article in German] Frick S, Lischner S, Rosien F, Haacke TC, Schafer F, Christophers E, Hauschild A. Klinik fur Dermatologie, Venerologie und Allergologie der Christian-Albrechts-Universitat zu Kiel, Germany. seiling@dermatology.uni-kiel.de BACKGROUND AND OBJECTIVE: Stage IV melanoma patients with a very advanced disease are usually excluded from clinical trials. We treated 25 stage IV patients with temozolomide - a cytostatic drug with 100% oral bioavailability and considerable penetration of CNS tissue. PATIENTS/METHODS: 25 patients (17 female, 8 male) between 24 and 82 years (mean: 55.5 years) were included in this retrospective study. 19 patients had received at least one and up to four previous chemotherapy regimens during the course of stage IV disease. 11 (44%) patients showed cerebral metastases prior to therapy with temozolomide. 200 mg/m2 temozolomide were given orally at home on day 1 to 5 in week 1 and in week 5, respectively. RESULTS: Out of 23 evaluable patients 2 (8.7%) showed a partial remission, 2 (8,7%) a minor response, 6 (26.1%) had stable disease, 1 (4,3%) a mixed response, and 12 (52.1%) patients experienced disease progression. Sites of remission included brain, lung, liver, lymph nodes and muscle. Two patients interrupted therapy due to severe leuko- and thrombocytopenia (WHO grade 3 and 4). All other patients tolerated treatment with temozolomide well and no dose reduction was necessary. The median overall survival was 7 months (2-28+ months) since beginning of therapy and 15 months (4-63+ months) since onset of stage IV disease. CONCLUSION: Temozolomide represents a safe treatment option in patients with metastatic melanoma and poor prognosis. PMID: 12297947 [PubMed - indexed for MEDLINE]
18: Neuro-oncol. 2002 Oct;4(4):261-7. | Related Articles, Links
A phase II study of temozolomide in patients with newly diagnosed supratentorial malignant glioma before radiation therapy. Gilbert MR, Friedman HS, Kuttesch JF, Prados MD, Olson JJ, Reaman GH, Zaknoen SL. Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA. Temozolomide is a novel second-generation oral alkylating agent with demonstrated efficacy and safety in patients with recurrent glioblastoma multiforme (GBM) and anaplastic astrocytoma (AA). A multicenter phase II trial was conducted to determine the efficacy and safety of temozolomide before radiotherapy in patients with newly diagnosed GBM and AA. Fifty-seven patients (51 adult, 6 pediatric) with newly diagnosed supratentorial GBM or AA were treated with temozolomide (200 mg/m ( 2 ) per day for 5 consecutive days every 28 days) for a maximum of 4 cycles. All patients were then treated with external beam radiotherapy. Twenty-two patients (39%) achieved objective response, including 6 (11%) with complete response (CR) and 16 (28%) with partial response (PR). Additionally, 18 (32%) patients had stable disease (SD). Of 21 patients (18 adult, 3 pediatric) with AA, 2 (10%) achieved CR, 5 (24%) achieved PR, and 8 (38%) had SD. Among adult patients with AA, the median progression-free and overall survival rates were 7.6 and 23.5 months, respectively. Among 36 patients (33 adult, 3 pediatric) with GBM, 4 (11%) had CR, 11 (31%) had PR, and 10 (28%) had SD. The median progression-free and overall survival rates among adult patients with GBM were 3.9 and 13.2 months, respectively. Temozolomide was safe and well tolerated in adult and pediatric patients. Grades 3 and 4 adverse events were reported in 16 (28%) and 7 (12%) patients, respectively. Temozolomide was safe and effective in treating newly diagnosed GBM and AA before radiotherapy. This pre-irradiation treatment approach appears promising, but will require additional evaluation in comparative studies. Publication Types: Clinical Trial Clinical Trial, Phase II PMID: 12356356 [PubMed - indexed for MEDLINE]
19: J Clin Oncol. 2002 Sep 1;20(17):3644-50. | Related Articles, Links
Phase II randomized trial of temozolomide and concurrent radiotherapy in patients with brain metastases. Antonadou D, Paraskevaidis M, Sarris G, Coliarakis N, Economou I, Karageorgis P, Throuvalas N. Metaxas Cancer Hospital, Piraeus, Greece. d_antona@hol.gr PURPOSE: To determine the efficacy, tolerability, and safety of concurrent temozolomide and radiotherapy in patients with previously untreated brain metastases. PATIENTS AND METHODS: Fifty-two patients with brain metastases from solid tumors were randomized to oral temozolomide (75 mg/m(2)/d) concurrent with 40-Gy fractionated conventional external-beam radiotherapy (2 Gy, 5 d/wk) for 4 weeks versus 40-Gy radiotherapy alone. The group receiving temozolomide and radiotherapy continued temozolomide therapy (200 mg/m(2)/d) for 5 days every 28 days for an additional six cycles. The primary end points were radiologic response and neurologic symptom evaluation. RESULTS: The objective response rate was significantly (P =.017) improved in patients receiving temozolomide and radiotherapy versus radiotherapy alone. Among 24 patients assessable for response in the temozolomide group, 23 (96%) of 24 responded, including nine (38%) patients with a complete response and 14 (58%) patients with a partial response. With radiotherapy alone, 14 (67%) of 21 assessable patients responded, including seven (33%) complete responses and seven (33%) partial responses. There was marked neurologic improvement in the group receiving temozolomide, and the proportion of patients requiring corticosteroids 2 months after treatment was lower in the temozolomide group compared with radiotherapy alone (67% v 91%, respectively). Daily temozolomide concurrent with radiotherapy was generally well tolerated; however, grade >or= 2 nausea (48% v 13%, P =.13) and vomiting (32% v 0%, P =.004) were significantly increased in the temozolomide group. Hematologic toxicity was predictable and reversible. CONCLUSION: Temozolomide is safe, and a significant improvement in response rate was observed when administered in combination with radiotherapy in patients with previously untreated brain metastases. A larger randomized trial is warranted to verify these results. Publication Types: Clinical Trial Clinical Trial, Phase II Randomized Controlled Trial PMID: 12202665 [PubMed - indexed for MEDLINE]
20: J Neurooncol. 2002 Sep;59(2):165-8. | Related Articles, Links
Case report: a patient with primary CNS lymphoma treated with temozolomide to complete response. Lerro KA, Lacy J. Department of Internal Medicine, Yale University School of Medicine, New Haven 06520, USA. We report the case of a 72-year-old woman with primary CNS lymphoma of the mid-brain and pons who had a complete response to oral temozolomide chemotherapy. She initially presented in early 2001 with several weeks of progressive memory loss and unresponsiveness. Because of her age and impaired renal function, she was a poor candidate for whole-brain radiotherapy or systemic high-dose methotrexate. After treatment with two cycles of temozolomide, restaging MRI revealed no evidence of disease. Her mental status improved significantly over this time. Temozolomide may represent a promising new drug for the treatment of primary CNS lymphoma. PMID: 12241110 [PubMed - indexed for MEDLINE]
21: Intern Med J. 2002 Jul;32(7):346-8. | Related Articles, Links
Temozolomide-induced flare in high-grade gliomas: a new clinical entity. Rosenthal MA, Ashley DL, Cher L. Department of Medical Oncology and Clinical Haematology, Royal Melbourne Hospital, Parkville, Victoria, Australia. mark.rosenthal@mh.org.au A transient deterioration in neurological status following commencement of chemotherapy for high-grade gliomas has not been previously described. We report eight cases of transient deterioration following administration of temozolomide, a relatively new cytotoxic agent used in the treatment of high-grade gliomas. We believe this represents the novel clinical entity of temozolomide-induced tumour flare. PMID: 12088355 [PubMed - indexed for MEDLINE]
22: Orv Hetil. 2002 May 26;143(21):1201-4. | Related Articles, Links
[Treatment of recidive malignant gliomas with temozolomide] [Article in Hungarian] Sipos L, Vitanovics D, Afra D. Orszagos Idegsebeszeti Tudomanyos Intezet, Budapest. INTRODUCTION: The prognosis of malignant gliomas despite of the recent advances of diagnostical and therapeutical techniques remains poor. The majority of gliomas following total removal and postoperative radiotherapy recurs. In case of recurrencies reoperation is rarely possible and chemotherapy is the last treatment modality. METHODS: Forty patients with recurrent malignant gliomas had been treated with temozolomide (Temodal). The treatment had to be stopped in four cases. RESULTS: Complete remission was observed in 3, partial in 11, progressive disease in 4 and stable disease in 50% of the cases with CT and/or MR images. The mean progress free interval was 6.25 and the mean survival time 9 months. According to the primary histology the mean survival time for glioblastoma patients was 6.8 and for anaplastic astrocytoma or mixed oligoastrocytoma patients 12.2 months. CONCLUSIONS: Due to its low toxicity and relatively long survival time after recurrency temozolomide seems to be a promising drug in the treatment of recurrent malignant gliomas. PMID: 12073541 [PubMed - indexed for MEDLINE]
23: J Neurooncol. 2002 May;57(3):247-51. | Related Articles, Links
Temozolomide as second-line chemotherapy for relapsed gliomas. Trent S, Kong A, Short SC, Traish D, Ashley S, Dowe A, Hines F, Brada M. Neuro-Oncology Unit, The Institute of Cancer Research and The Royal Marsden NHS Trust, Sutton, Surrey, UK. BACKGROUND: Temozolomide, an imidazotetrazine prodrug has shown activity in phase II studies in patients with high-grade glioma at first recurrence. We assessed the efficacy of temozolomide as second-line therapy following failure of PCV chemotherapy in patients with recurrent/progressive gliomas. PATIENTS AND METHODS: Between September 1994 and November 2000, 32 patients with high-grade gliomas at second recurrence/progression received temozolomide as salvage therapy and results were reviewed retrospectively. RESULTS: Of 32 assessable patients 7 had clinical improvement; there were no imaging responses. Median survival of the cohort was 4 months, with 28% alive at 6 months. Age, performance status, histology and previous response to PCV chemotherapy did not predict for clinical response to temozolomide. CONCLUSION: In the small cohort of patients with recurrent malignant glioma who failed PCV chemotherapy temozolomide demonstrated limited activity as second-line treatment although this remains within the confidence intervals of response seen in patients with glioblastoma. PMID: 12125988 [PubMed - indexed for MEDLINE]
24: J Cancer Res Clin Oncol. 2002 Apr;128(4):214-8. Epub 2002 Mar 12. | Related Articles, Links
Temozolomide and whole brain irradiation in melanoma metastatic to the brain: a phase II trial of the Cytokine Working Group. Margolin K, Atkins B, Thompson A, Ernstoff S, Weber J, Flaherty L, Clark I, Weiss G, Sosman J, II Smith W, Dutcher P, Gollob J, Longmate J, Johnson D. Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, 1500 E. Duarte Rd., Duarte, CA 91010, USA. kmargolin@coh.org PURPOSE: To evaluate the antitumor effects and toxicities of whole brain irradiation (WBI) with temozolomide (TMZ) administered by prolonged oral dosing in patients with melanoma metastatic to the brain. BACKGROUND: Patients with melanoma metastatic to the central nervous system (CNS) have an extremely poor prognosis and appear to benefit little from WBI. TMZ is an alkylating agent chemically similar to dacarbazine (DTIC) with good oral bioavailability and CNS penetration. TMZ has broad preclinical antitumor activity which in melanoma is comparable to that of DTIC. The combination of TMZ and WBI may provide enhanced antitumor activity against CNS metastasis from melanoma. PATIENTS AND METHODS: Patients with measurable CNS metastases with or without systemic disease were treated with WBI, 30 Gray over ten fractions (days 1-5 and 8-12). TMZ, 75 mg small middle dotm(2 small middle dot)day, was started on day 1, continued daily for 6 weeks and repeated every 10 weeks. RESULTS: Thirty-one patients were treated. There was one CNS complete response of 4.5 months and two CNS partial responses of 2 months and 7 months duration; the latter patient also had a 4-month complete remission of systemic metastases. Toxicities were limited to a single episode of grade 3 transaminase elevation and two episodes of grade 3 neutropenia, one complicated by fatal sepsis. The median progression-free interval for both CNS and extracranial sites was 2 months (range 1 week-11 months), and median survival 6 months (range 2-12 months). CONCLUSIONS: WBI has lower than expected activity in CNS metastasis of malignant melanoma. Although TMZ can be safely administered with WBI, the combination has limited anti-tumor activity. Publication Types: Clinical Trial Clinical Trial, Phase II Multicenter Study PMID: 11935312 [PubMed - indexed for MEDLINE]
25: Melanoma Res. 2002 Apr;12(2):175-8. | Related Articles, Links
Effect of temozolomide on central nervous system relapse in patients with advanced melanoma. Paul MJ, Summers Y, Calvert AH, Rustin G, Brampton MH, Thatcher N, Middleton MR. Cancer Research UK Department of Medical Oncology, Christie Hospital NHS Trust, Manchester, UK. Temozolomide has shown efficacy in the treatment of metastatic melanoma similar to that of dacarbazine (DTIC), the standard chemotherapy, but with the added benefit of penetration into the central nervous system (CNS). Isolated CNS relapse is increasingly a problem for patients who respond to biochemotherapy. By replacing DTIC with temozolomide in treatment regimens, the incidence of CNS relapse might be reduced. This hypothesis is difficult to test in a prospective randomized controlled trial because of the large number of patients that would be required. We have examined this question in a retrospective case control study, observing the rates of CNS relapse in advanced metastatic melanoma patients responding to DTIC- or temozolomide-based chemotherapy in three institutions. Twenty-one DTIC and 20 temozolomide responders were identified, and have been followed up for a median of 19.0 months (range 6.0-74.3 months). CNS relapse occurred in nine DTIC- and two temozolomide-treated patients, a statistically significant difference in favour of the new agent (P = 0.03). These results support the investigation of temozolomide as a replacement for DTIC in systemic treatment regimens for melanoma. Publication Types: Clinical Trial Clinical Trial, Phase II Multicenter Study PMID: 11930115 [PubMed - indexed for MEDLINE]
26: Neuro-oncol. 2002 Apr;4(2):102-8. | Related Articles, Links
Phase II study of irinotecan (CPT-11) in children with high-risk malignant brain tumors: the Duke experience. Turner CD, Gururangan S, Eastwood J, Bottom K, Watral M, Beason R, McLendon RE, Friedman AH, Tourt-Uhlig S, Miller LL, Friedman HS. The Brain Tumor Center at Duke, Duke University Medical Center, Durham, NC 27710, USA. A phase II study of irinotecan (CPT-11) was conducted at Duke University Medical Center, Durham, NC, to evaluate the activity of this agent in children with high-risk malignant brain tumors. A total of 22 children were enrolled in this study, including 13 with histologically verified recurrent malignant brain tumors (glioblastoma multiforme [GBM] 4, anaplastic astrocytoma 1, ependymoma 5, and medulloblastoma/primitive neuroectodermal tumor 3), 5 with recurrent diffuse pontine glioma, and 4 with newly diagnosed GBM. All patients with recurrent tumor had prior chemotherapy and/or irradiation. Each course of CPT-11 consisted of 125 mg/m ( 2 ) per week given i.v. for 4 weeks followed by a 2-week rest period. Patients with recurrent tumors received therapy until disease progression or unacceptable toxicity. Patients with newly diagnosed tumors initially received 3 cycles of treatment to assess tumor response and then were allowed radiotherapy at physician's choice; patients who demonstrated a response to CPT-11 prior to radiotherapy were allowed to continue the drug after radiation until disease progression or unacceptable toxicity. A 25% to 50% dose reduction was made for grade III-IV toxicity. Responses were assessed after every course by gadolinium-enhanced MRI of the brain and spine. Twenty-two patients received a median of 2 courses of CPT-11 (range, 1-16). Responses were seen in 4 of 9 patients with GBM or anaplastic astrocytoma (44%; 95% confidence interval, 11%-82%) (complete response in 2 patients with recurrent GBM lasting 9 months and 48+ months; partial response in one patient with a newly diagnosed midbrain GBM lasting 18 months prior to radiotherapy; and partial response lasting 11 months in 1 patient with recurrent anaplastic astrocytoma), 1 of 5 patients with recurrent ependymoma (partial response initially followed by stable disease lasting 11 months), and none of 5 patients with recurrent diffuse pontine glioma. Two of 3 patients with medulloblastoma/primitive neuroectodermal tumor had stable disease for 9 and 13 months. Toxicity was mainly myelosuppression, with 12 of 22 patients (50%) suffering grade II-IV neutropenia. Seven patients required dose reduction secondary to neutropenia. CPT-11, given in this schedule, appears to be active in children with malignant glioma, medulloblastoma, and ependymoma with acceptable toxicity. Ongoing studies will demonstrate if activity of CPT-11 can be enhanced when combined with alkylating agents, including carmustine and temozolomide. Publication Types: Clinical Trial Clinical Trial, Phase II PMID: 11916501 [PubMed - indexed for MEDLINE]
27: J Clin Oncol. 2002 Mar 1;20(5):1383-8. | Related Articles, Links
Phase II trial of temozolomide plus the matrix metalloproteinase inhibitor, marimastat, in recurrent and progressive glioblastoma multiforme. Groves MD, Puduvalli VK, Hess KR, Jaeckle KA, Peterson P, Yung WK, Levin VA. Department of Neuro-Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA. PURPOSE: Novel therapies are needed for patients with recurrent glioblastoma multiforme (GBM). Because there is evidence that temozolomide (TMZ) has some activity in GBM and is well tolerated, and because of laboratory evidence that metalloproteinases are important in glioma cell invasion, the combination of TMZ and the matrix metalloproteinase inhibitor marimastat (MRM) in patients with recurrent GBM was studied. PATIENTS AND METHODS: Forty-four patients with recurrent GBM after standard radiotherapy were enrolled. For 19 patients, this therapy was their first chemotherapy after tumor progression after irradiation; 25 others had received chemotherapy previously. TMZ 150 to 200 mg/m(2) days 1 to 5 and MRM 50 mg days 8 to 28 was administered at 28-day intervals for two cycles; then patients were reevaluated. Treatment continued until progression of tumor or toxicity developed. RESULTS: Joint and tendon pain was the major therapy-related toxicity and was reported in 47% of patients. Five patients (11%) were removed from the study because of intolerable joint pain. For all patients, the progression-free survival (PFS) at 6 months was 39%. Median PFS was 17 weeks, median overall survival was 45 weeks, and 12-month PFS was 16%. CONCLUSION: The combination of TMZ and MRM resulted in a PFS at 6 months that exceeded the literature target by 29%. This drug combination met phase II study criteria; further study in recurrent patients with GBM might be warranted. Further study of therapy-induced joint pain is necessary. Publication Types: Clinical Trial Clinical Trial, Phase II PMID: 11870183 [PubMed - indexed for MEDLINE]
28: J Clin Oncol. 2002 Mar 1;20(5):1375-82. | Related Articles, Links
Comment in: J Clin Oncol. 2002 Jul 15;20(14):3179-80; author reply 3181-2. J Clin Oncol. 2002 Jul 15;20(14):3180-1; author reply 3181. Promising survival for patients with newly diagnosed glioblastoma multiforme treated with concomitant radiation plus temozolomide followed by adjuvant temozolomide. Stupp R, Dietrich PY, Ostermann Kraljevic S, Pica A, Maillard I, Maeder P, Meuli R, Janzer R, Pizzolato G, Miralbell R, Porchet F, Regli L, de Tribolet N, Mirimanoff RO, Leyvraz S. Department of Medical Oncology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland. roger.stupp@chuv.hospvc.ch PURPOSE: Temozolomide is a novel oral alkylating agent with demonstrated efficacy as second-line therapy for patients with recurrent anaplastic astrocytoma and glioblastoma multiforme (GBM). This phase II study was performed to determine the safety, tolerability, and efficacy of concomitant radiation plus temozolomide therapy followed by adjuvant temozolomide therapy in patients with newly diagnosed GBM. PATIENTS AND METHODS: Sixty-four patients were enrolled onto this open-label, phase II trial. Temozolomide (75 mg/m(2)/d x 7 d/wk for 6 weeks) was administered orally concomitant with fractionated radiotherapy (60 Gy total dose: 2 Gy x 5 d/wk for 6 weeks) followed by temozolomide monotherapy (200 mg/m(2)/d x 5 days, every 28 days for six cycles). The primary end points were safety and tolerability, and the secondary end point was overall survival. RESULTS: Concomitant radiation plus temozolomide therapy was safe and well tolerated. Nonhematologic toxicities were rare and mild to moderate in severity. During the concomitant treatment phase, grade 3 or 4 neutropenia, thrombocytopenia, or both were observed in 6% of patients, including two severe infections with Pneumocystis carinii. During adjuvant temozolomide, 2% and 6% of cycles were associated with grade 3 and 4 neutropenia or thrombocytopenia, respectively. Median survival was 16 months, and the 1- and 2-year survival rates were 58% and 31%, respectively. Patients younger than 50 years old and patients who underwent debulking surgery had the best survival outcome. CONCLUSION: Continuous daily temozolomide and concomitant radiation is safe. This regimen of concomitant chemoradiotherapy followed by adjuvant chemotherapy may prolong the survival of patients with glioblastoma. Further investigation is warranted, and a randomized trial is ongoing. Publication Types: Clinical Trial Clinical Trial, Phase II PMID: 11870182 [PubMed - indexed for MEDLINE]
29: J Clin Oncol. 2002 Jan 15;20(2):420-5. | Related Articles, Links
Temozolomide in combination with docetaxel in patients with advanced melanoma: a phase II study of the Hellenic Cooperative Oncology Group. Bafaloukos D, Gogas H, Georgoulias V, Briassoulis E, Fountzilas G, Samantas E, Kalofonos Ch, Skarlos D, Karabelis A, Kosmidis P. Metaxa's Cancer Hospital, Piraeus, Greece. hesmo@compulink.gr PURPOSE: Temozolomide is a novel oral alkylating agent that is effective against melanoma. Moreover, temozolomide readily crosses the blood-brain barrier and may consequently be effective in patients with brain metastases. This phase II study was performed to assess the efficacy and safety of the combination regimen of temozolomide and docetaxel in patients with advanced metastatic melanoma. PATIENTS AND METHODS: Sixty-five patients with metastatic melanoma were enrolled. Treatment consisted of intravenous docetaxel (80 mg/m(2)) on day 1 and oral temozolomide (150 mg/m(2)) on days 1 to 5, every 4 weeks, for a maximum of six cycles. RESULTS: Sixty-two patients were eligible for the efficacy and safety analysis. Seventeen patients (27%) achieved an objective response, including five complete (8%) and 12 partial responses (19%). Median response duration was 9.5 months. Among responders, median time to progression (TTP) was 11.2 months and median overall survival (OS) was 16 months. For all treated patients, the median TTP was 4 months and median OS was 11 months. Three (38%) of eight patients who presented with brain metastases had a partial response for 5, 6, and 12 months. Of 52 patients who did not have brain involvement at presentation, only four (8%) developed brain metastases at a median follow-up of 14 months. Myelosuppression was the primary toxicity. CONCLUSION: The combination of temozolomide and docetaxel was effective and well tolerated as first-line treatment for patients with advanced metastatic melanoma and demonstrated encouraging antitumor activity against brain metastases. Publication Types: Clinical Trial Clinical Trial, Phase II Multicenter Study PMID: 11786569 [PubMed - indexed for MEDLINE]
30: Int J Clin Pharmacol Res. 2002;22(1):19-22. | Related Articles, Links
Temozolomide in second-line treatment after prior nitrosurea-based chemotherapy in glioblastoma multiforme: experience from a Portuguese institution. Teixeira MM, Garcia I, Portela I, Cernuda M, Oliveira C, Albano J, Lima L. Medical Oncology Department, Francisco Gentil Portuguese Institute of Oncology, Coimbra Regional Oncology Center. Temozolomide is a new cytotoxic alkylating agent that has recently been approved in Portugal for the treatment of recurrent high-grade glioma. From September 1999 to March 2001, 16 patients with recurrent glioblastoma multiforme who had prior nitrosurea-based chemotherapy [procarbazine, carmustine, vincristine (PCV)] were given temozolomide 150-200 mg/m2/day for 5 days every 28-day cycle. The estimated 1-year survival rate was 16% and the median overall survival was 6.5 months. Despite the small sample size, the overall survival achieved with temozolomide was similar to that of other reports. These promising data suggest that randomized trials should be undertaken to assess its use in first-line therapy its inclusion in combined chemotherapy regimes and its effectiveness with concurrent radiotherapy. Publication Types: Clinical Trial PMID: 12395915 [PubMed - indexed for MEDLINE]
31: Neuro-oncol. 2002 Jan;4(1):39-43. | Related Articles, Links
A phase II study of extended low-dose temozolomide in recurrent malignant gliomas. Khan RB, Raizer JJ, Malkin MG, Bazylewicz KA, Abrey LE. Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA. Temozolomide is an effective agent in the treatment of recurrent malignant gliomas. The standard dosage is 150-200 mg/m2 per day for 5 days in a 28-day cycle. A prior phase I study established a chronic daily temozolomide dose that significantly increased the total dose administered and suggested a superior response rate. In a prospective phase II trial, we treated 35 patients with recurrent malignant gliomas with temozolomide 75 mg/m2 per day for 42 consecutive days in a 70-day cycle. Median age was 55 years (range, 27-73 years) and median Karnofsky performance score was 70 (range, 60-90). Twenty-eight (79%) patients had glioblastoma multiforme, 3 (9%) anaplastic astrocytoma, 2 (6%) anaplastic oligodendroglioma, and 2 (6%) anaplastic oligoastrocytoma. All but one had prior radiotherapy, and 27 had prior chemotherapy. There were 2 partial (anaplastic astrocytoma) and 3 minor (glioblastoma multiforme) radiographic responses; 17 patients had progressive disease at the end of the first cycle. In 55 cycles of temozolomide, there were 8 episodes of asymptomatic drug-related grade 3 toxicity: 6 lymphopenia, 1 neutropenia, and 1 thrombocytopenia. Median progression-free survival and overall survival were 2.5 and 8.7 months (2.3 and 7.7 months in glioblastoma multiforme patients). At 6 months, progression-free survival and overall survival rates were 27% and 67% (19% and 60% in glioblastoma multiforme). Quality of life scores did not change significantly during treatment. We conclude that the extended low-dose schedule of temozolomide is well tolerated in heavily pre-treated patients; however, our results do not support an improved rate of response or survival. Publication Types: Clinical Trial Clinical Trial, Phase II PMID: 11772431 [PubMed - indexed for MEDLINE]
32: Tumori. 2002 Jan-Feb;88(1):28-31. | Related Articles, Links
Combined radiotherapy and temozolomide in patients with recurrent high grade glioma. Schonekaes K, Mucke R, Panke J, Rama B, Wagner W. Department of Radiotherapy and Radiooncology, Paracelsusklinik, Osnabruck, Germany. drkgs@aol.com AIMS AND BACKGROUND: There is only little preliminary information about combined-modality treatment with radiotherapy and temozolamide. The purpose of this analysis was to document the feasibility of such combined-modality treatment. METHODS: We treated 25 patients with recurrent high grade gliomas after standard therapy (surgery and radiation) with the following schedule: 400 mg temozolomide orally for five days repeated every 28 days, and radiotherapy at a dose of 20-30 Gy (2 x 1.2 Gy per day). Four of these patients underwent a second operation without complete tumor resection. RESULTS: After 125 courses of temozolomide, grade 1 (NCI-CTC) thrombocytopenia was found in four patients and grade 2 in two patients. Two patients developed grade 1 leukocytopenia and two others grade 2. CTC grade 1-2 nausea was observed in eight patients. For one patient we reduced the dose of temozolomide to 300 mg/day because of thrombocytopenia. One patient discontinued therapy after the first course because of leukocytopenia and nausea. CTC grade 3-4 side effects did not occur. Combined-modality treatment showed no more side effects than treatment with temozolomide alone. The median duration of response was seven months. CONCLUSION: The observed side effects were tolerable. Combined treatment with radiotherapy and temozolomide is feasible. Further investigation of this agent is necessary. PMID: 12004846 [PubMed - indexed for MEDLINE]
33: Curr Treat Options Oncol. 2001 Dec;2(6):495-506. | Related Articles, Links
Low-grade gliomas. Stieber VW. Department of Radiation Oncology, Wake Forest University Baptist Medical Center, Medical Center Boulevard, Winston-Salem, NC 27157-1030, USA. vstieber@wfubmc.edu Low-grade gliomas are uncommon primary brain tumors classified as histologic grades I or II in the World Health Organization (WHO) classification. The most common variants are pilocytic and low-grade astrocytomas, oligodendrogliomas, and mixed oligo-astrocytomas located in the cerebral hemispheres. Prognostic factors that predict progression-free and overall survival include young age, pilocytic histology, good Karnofsky performance status, gross total resection, lack of enhancement on imaging, and small preoperative tumor volumes. Edema and vasogenic effects are typically managed with corticosteroids. Dexamethasone is given at an initial dosage of 4 mg given four times daily. Anticonvulsants are given prophylactically after resection and for patients who present with seizures. The rationale for open craniotomy depends on the need for immediate palliation of symptoms by reduction of intracranial pressure or focal mass effect, and/or improved oncologic control. Gross total resection of tumor is generally defined as the absence of residual enhancement on contrast-enhanced postoperative MRI scan. Most retrospective studies suggest that patients who have undergone a gross total resection of tumor have improved survival. Depending upon the proximity of the tumor to eloquent brain, gross total resection may or may not be possible. In these cases a stereotactic biopsy is required to provide the histologic diagnosis. Adjuvant radiotherapy is recommended for patients with incompletely resected grade II tumors or for patients older than age 40 regardless of extent of resection. It may be considered for any pilocytic astrocytoma from which a biopsy has been performed. Phase III randomized prospective trials have shown statistically significantly improved progression-free survival at 5 years with the addition of radiotherapy, though overall survival does not appear different. Based on prospective randomized phase III trials, 50.4 Gy to 54 Gy of conventionally fractionated radiotherapy appears to be a safe and effective regimen with minimal neurotoxicity; 45 Gy may be adequate for biopsied pilocytic astrocytomas. Currently, RTOG trial 98-02 is investigating the efficacy of postradiation PCV chemotherapy (procarbazine, CCNU, and vincristine) in the treatment of newly diagnosed unfavorable low-grade gliomas. Other areas of investigation include Temozolomide chemotherapy and the association of 1p and 19q chromosomal deletions with prolonged survival in oligodendrogliomas and sensitivity to PCV chemotherapy. Radiosurgery and/or experimental chemotherapy may provide some measure of local control in the recurrent disease setting. Publication Types: Review Review, Tutorial PMID: 12057095 [PubMed - indexed for MEDLINE]
34: Curr Treat Options Oncol. 2001 Dec;2(6):507-15. | Related Articles, Links
Adults with newly diagnosed high-grade gliomas. Croteau D, Mikkelsen T. Hermelin Brain Tumor Center, Henry Ford Hospital, 2799 West Grand Boulevard, Detroit, MI 48202, USA. nsdac@neuro.hfh.edu Despite tremendous advances in brain tumor molecular biology and several emerging novel therapies, multimodality therapy that includes surgery, radiation therapy (RT), and chemotherapy is still the cornerstone of high-grade glioma treatment. The first step in high-grade glioma therapy is surgery and a maximal resection should be attempted to reduce the tumor burden before initiation of other adjuvant therapies. External beam radiation therapy (EBRT) generally follows surgery, using conventional dosage, and fractionation, and ideally a three-dimensional conformal technique. Stereotactic radiosurgery (SRS) to maximize cytoreduction may be used in selected cases. Because no curative chemotherapy exists for high-grade glioma, we always consider an investigational agent either before or concurrently with RT. However, the use of a standard cytotoxic agent, such as temozolomide alone or combined with 13-cis-retinoic acid also is a rational choice particularly for patients with relatively good prognostic factors for whom an investigational agent would not be available. The management of anaplastic oligodendroglioma does not differ significantly from other high-grade gliomas in terms of surgery, RT, or investigational or protocol agent; however, these tumors appear to respond to chemotherapy that includes a combination of procarbazine, CCNU, and vincristine (PCV) [1**]. The vincristine provides more toxicity than benefit and it is our practice to only use a combination of procarbazine and CCNU (PC). A single agent, such as temozolomide is an increasingly used and rational choice for anaplastic oligodendroglioma. It is our belief that early, aggressive multimodality treatment still provides the best chance for long-term control of high-grade gliomas, particularly in patients with good prognostic factors. However, despite best therapy and state-of-the-art technology, most patients with high-grade glioma will experience progression or recurrence and will require either a change in the ongoing therapeutic strategy or additional treatment. Better therapies are necessary and progress will only be made through investigation of promising agents in well-designed clinical trials. Publication Types: Review Review, Tutorial PMID: 12057096 [PubMed - indexed for MEDLINE]
35: J Neurooncol. 2001 Dec;55(3):179-84. | Related Articles, Links
Brain metastases from fallopian tube carcinoma responsive to intra-arterial carboplatin and intravenous etoposide: a case report. Newton HB, Stevens C, Santi M. Department of Neurology, The Ohio State University Medical Center and James Cancer Hospital and Solove Research Institute, Columbus, Ohio, USA. newton.12@osu.edu Fallopian tube carcinoma is the least common neoplasm of the female genital tract. Although rare, neurological complications such as brain metastases can develop. It remains unclear, however, what role chemotherapy has in the treatment of these patients and what route of administration is most effective. Intra-arterial (IA) regional administration of chemotherapy may increase intra-tumoral drug concentrations and improve efficacy. We report the case of a 47-year-old woman who developed bilateral fallopian tube cancer and multifocal brain metastases. After progression through radiation therapy and oral chemotherapy, she was placed on IA carboplatin (200 mg/m2/d x 2 days every 4 weeks) and intravenous etoposide (100 mg/m2/d x 2 days every 4 weeks). During treatment she had objective tumor shrinkage that has remained stable for more than 12 months. For patients with fallopian tube carcinoma that develop brain metastases and respond poorly to surgery and/or irradiation, multi-agent chemotherapy containing carboplatin should be considered. The effectiveness of carboplatin may be improved if administered by the IA route. PMID: 11859973 [PubMed - indexed for MEDLINE]
36: Neuro-oncol. 2001 Oct;3(4):246-50. | Related Articles, Links
Phase I study of Gliadel wafers plus temozolomide in adults with recurrent supratentorial high-grade gliomas. Gururangan S, Cokgor L, Rich JN, Edwards S, Affronti ML, Quinn JA, Herndon JE 2nd, Provenzale JM, McLendon RE, Tourt-Uhlig S, Sampson JH, Stafford-Fox V, Zaknoen S, Early M, Friedman AH, Friedman HS. Department of Neurosurgery, Duke University Medical Center, Durham, NC 27710, USA. Both Gliadel wafers [1,3-bis(2-chloroethyl)-1-nitrosourea] and temozolomide (TEMO) have been shown in independent studies to prolong survival of patients with recurrent malignant glioma following surgery and radiotherapy. On the basis of preclinical evidence of synergism between Gliadel wafers and TEMO, a phase I study was designed to evaluate the toxicity of combining these 2 agents in the treatment of patients with recurrent supratentorial malignant glioma. All patients had surgical resection of the tumor at relapse, and up to 8 Gliadel (3.85%) wafers were placed in the surgical cavity following resection. Two weeks after surgery, TEMO was given orally daily for 5 days. Cohorts of 3 patients received TEMO at daily doses of 100 mg/m2, 150 mg/m2, and 200 mg/m2, respectively. Patients were assessed for toxicity 4 weeks after start of the first course of TEMO. Contrast-enhanced MRI of the brain was used to assesstumor response after the first cycle of TEMO. Patients with stable disease or response after the first cycle of TEMO were allowed to continue treatment at the same dose every 4 weeks for 12 cycles or until disease progression or unacceptable toxicity. Ten patients with a median age of 47 years (range, 22-66 years) were enrolled in this study. There were 7 patients with glioblastoma multiforme and 3 patients with anaplastic astrocytoma. Three patients were treated with TEMO at the first dose level of 100 mg/m2, 4 at the second dose level of 150 mg/m2, and 3 at the third dose level of 200 mg/m2. The 10 patients received a median of 3 cycles (range, 1-12 cycles) of TEMO following placement of Gliadel wafers. The treatment was well tolerated, with only 1 patient suffering grade III thrombocytopenia at the highest dose level. Two patients at each dose level had no evidence of disease progression after treatment. Four patients suffered progressive disease on therapy. Our study demonstrates that TEMO can be given safely after placement of Gliadel (3.85%) wafers. The recommended dosage for TEMO for a phase II study of this combination is 200 mg/m2 per day for 5 days. Publication Types: Clinical Trial Clinical Trial, Phase I PMID: 11584894 [PubMed - indexed for MEDLINE]
37: Semin Oncol. 2001 Aug;28(4 Suppl 13):34-42. | Related Articles, Links
Temozolomide for treating brain metastases. Abrey LE, Christodoulou C. Department of Neurology at Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA. The metastasis of solid tumors to the brain is associated with a poor prognosis despite aggressive treatment. Available treatment options are limited, as many chemotherapeutic agents do not penetrate the blood-brain barrier. Temozolomide (Temodar in the United States, Temodal globally; Schering Corporation, Kenilworth, NJ) is a novel chemotherapeutic agent with a good safety profile that crosses the blood-brain barrier and has shown activity against many human solid tumors. In two phase II trials of temozolomide in heavily pretreated patients with various solid tumor brain metastases, temozolomide was safe and generally well tolerated and showed clinical activity, with three partial responses and 19 disease stabilizations. Results of a third randomized phase II trial of concurrent administration of temozolomide and radiation therapy followed by adjuvant temozolomide therapy compared with radiation alone showed a higher rate of complete and partial responses (objective response of 96% v 67%) and significantly more complete responses (38% v 33%, P =.017), primarily in patients with newly diagnosed brain and lung metastases. Copyright 2001 by W.B. Saunders Company. Publication Types: Review Review, Tutorial PMID: 11550137 [PubMed - indexed for MEDLINE]
38: Neurology. 2001 Jul 24;57(2):340-2. | Related Articles, Links
Temozolomide chemotherapy in recurrent oligodendroglioma. van den Bent MJ, Keime-Guibert F, Brandes AA, Taphoorn MJ, Kros JM, Eskens FA, Carpentier AF. Department of Neuro-Oncology, University Hospital Rotterdam/Rotterdam Cancer Center, the Netherlands. bent@neuh.azr.nl The authors determined the tolerance, response rate, and duration of recurrent anaplastic oligodendroglioma in 30 patients to temozolomide given orally at 150 to 200 mg/m2 on days 1 through 5 in cycles of 28 days. Nine patients responded: 7 of 27 patients (26%) treated with temozolomide after prior PCV chemotherapy and 2 of 3 chemotherapy-naive patients (both complete response). Median time to progression in responding patients was 13 months. Temozolomide shows promise and has an acceptable safety profile in recurrent anaplastic oligodendroglial tumors. Patients not responding to PCV may respond to temozolomide. PMID: 11468326 [PubMed - indexed for MEDLINE]
39: J Clin Neurosci. 2001 Jul;8(4):325-7. | Related Articles, Links
An Australian experience with temozolomide for the treatment of recurrent high grade gliomas. Harris MT, Rosenthal MA, Ashley DL, Cher L. Austin and Repatriation Medical Centre, Heidelberg, Victoria, Australia. Temozolomide has an evolving role in the treatment of high grade gliomas. Recent studies suggest that temozolomide is well tolerated and efficacious. This study retrospectively analysed the activity and toxicity associated with temozolomide at two Australian centres over a 24 month period. Fifty-six patients with recurrent high grade gliomas were treated with temozolomide. Patients received temozolomide orally at 150-200mg/m(2)daily, days 1-5, every 4 weeks. The median number of treatment cycles was 4 (1-12). Of the 56 patients, 15 (27%) achieved complete or partial response and 18 (32%) achieved minor response or stable disease. There were no episodes of febrile neutropenia and temozolomide was generally well tolerated. In conclusion, temozolomide is an active therapy in patients with recurrent high grade glioma and our results concord with published studies. Copyright 2001 Harcourt Publishers Ltd. Publication Types: Multicenter Study PMID: 11437571 [PubMed - indexed for MEDLINE]
40: J Comput Assist Tomogr. 2001 Jul-Aug;25(4):529-36. | Related Articles, Links
Mapping therapeutic response in a patient with malignant glioma. Haney SM, Thompson PM, Cloughesy TF, Alger JR, Frew AJ, Torres-Trejo A, Mazziotta JC, Toga AW. Laboratory of Neuro Imaging, Division of Brain Mapping, Department of Neurology, UCLA School of Medicine, Los Angeles, CA 90095-1769, USA. Short-interval scanning of patients offers a detailed understanding of the natural progression of tumor tissue, as revealed through imaging markers such as contrast enhancement and edema, prior to therapy. Following treatment, short-interval scanning can also provide evidence of attenuation of growth rates. We present a longitudinal imaging study of a patient with glioblastoma multiforme (GBM) scanned 15 times in 104 days on a 3 T MR scanner. Images were analyzed independently by two automated algorithms capable of creating detailed maps of tumor changes as well as volumetric analysis. The algorithms, a nearest-neighbor-based tissue segmentation and a surface-modeling algorithm, tracked the patient's response to temozolomide, showing an attenuation of growth. The need for surrogate imaging end-points, of which growth rates are an example, is discussed. Further, the strengths of these algorithms, the insight gained by short-interval scanning, and the need for a better understanding of imaging markers are also described. PMID: 11473181 [PubMed - indexed for MEDLINE]
41: J Neurooncol. 2001 Jul;53(3):259-65. | Related Articles, Links
A phase II trial of temozolomide for patients with recurrent or progressive brain metastases. Abrey LE, Olson JD, Raizer JJ, Mack M, Rodavitch A, Boutros DY, Malkin MG. Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA. abreyl@mskcc.org BACKGROUND: Treatment options for patients with recurrent brain metastases are extremely limited. This study was designed to determine the safety and efficacy of temozolomide in the treatment of recurrent or progressive brain metastases. PATIENTS AND METHODS: Forty-one patients (11 men, 30 women) with a median KPS of 80 were treated with temozolomide 150 mg/m2/day (200 mg/m3/day if no prior chemotherapy) for 5 days; treatment cycles were repeated every 28 days. Primary tumor types included 22 non-small cell lung, 10 breast, three melanoma, two small cell lung, two rectal, one ovarian and one endometrial cancer. RESULTS: There were five episodes of grade 3 thrombocytopenia and one grade 4 leukopenia. Significant non-hematologic toxicity possibly related to temozolomide included pneumonitis [21, constipation [1], and elevated liver enzymes [21. Thirty-four patients were assessed for radiographic response; two had a partial response, 15 stable disease and 17 progressed. Both objective responses were seen in patients with non-small cell lung cancer. Overall median survival was 6.6 months. CONCLUSIONS: Single agent temozolomide achieved disease control (PR or SD) in 41% of patients with recurrent brain metastases from a variety of primary malignancies with minimal toxicity. Therefore, temozolomide may be a reasonable treatment option for some patients with recurrent brain metastases. Publication Types: Clinical Trial Clinical Trial, Phase II PMID: 11718258 [PubMed - indexed for MEDLINE]
42: J Clin Oncol. 2001 May 1;19(9):2449-55. | Related Articles, Links
Safety and efficacy of temozolomide in patients with recurrent anaplastic oligodendrogliomas after standard radiotherapy and chemotherapy. Chinot OL, Honore S, Dufour H, Barrie M, Figarella-Branger D, Muracciole X, Braguer D, Martin PM, Grisoli F. Service de Neurochirurgie, Hopital de la Timone, and Faculte de Medecine, Laboratoire de Cancerologie Experimentale, Marseille, France. OCHINOT@mail.ap-hm.fr PURPOSE: Most primary oligodendrogliomas and mixed gliomas (oligoastrocytoma) respond to treatment with procarbazine, lomustine, and vincristine (PCV), with response rates of approximately 80%. However, limited data on second-line treatments are available in patients with recurrent tumors. A novel second-generation alkylating agent, temozolomide, has recently demonstrated efficacy and safety in patients with recurrent glioblastoma multiforme and anaplastic astrocytoma. This study describes the effects of temozolomide in patients with recurrent anaplastic oligodendroglioma (AO) and anaplastic mixed oligoastrocytoma (AOA). PATIENTS AND METHODS: Forty-eight patients with histologically confirmed AO or AOA who had received previous PCV chemotherapy were treated with temozolomide (150 to 200 mg/m2/d for 5 days per 28-day cycle). The primary end point was objective response. Secondary end points included progression-free survival (PFS), time to progression, overall survival (OS), safety, and tolerability. RESULTS: Eight patients (16.7%) experienced a complete response, 13 patients (27.1%) experienced a partial response (objective response rate, 43.8%), and 19 patients (39.6%) experienced stable disease. For the entire treatment group, median PFS was 6.7 months and median OS was 10 months. For objective responders, median PFS was 13.1 months and median OS was 16 months. For complete responders, PFS was more than 11. 8 months and OS was more than 26 months. Response correlated with improved survival. Temozolomide was safe and well tolerated. Twelve patients developed grade 1/2 thrombocytopenia and three patients developed grade 3/4 thrombocytopenia. CONCLUSION: Temozolomide is safe and effective in the treatment of recurrent AO and AOA. Publication Types: Clinical Trial Clinical Trial, Phase II PMID: 11331324 [PubMed - indexed for MEDLINE]
43: J Neurooncol. 2001 Mar;52(1):49-56. | Related Articles, Links
Atypical teratoid/rhabdoid tumors in adult patients: case report and review of the literature. Lutterbach J, Liegibel J, Koch D, Madlinger A, Frommhold H, Pagenstecher A. Abteilung Strahlenheilkunde, Radiologische Universitatsklinik, Freiburg, Germany. lutterba@mst1.ukl.uni-freiburg.de Atypical teratoid/rhabdoid tumors (AT/RT) of the central nervous system are rare and extremely aggressive malignancies of early childhood. We report a case of AT/RT in an adult patient. A 30-year-old woman presented with headache, vomiting and ataxia during the second trimester of pregnancy. Magnetic resonance imaging revealed a posterior fossa mass. A gross total resection was performed. Pathological examination revealed an AT/RT. Despite the dismal prognosis the patient decided not to undergo an abortion. For this reason postoperative accelerated hyperfractionated radiotherapy was limited to the tumor region. Six months later the woman delivered a healthy baby. One week postpartum, a central nervous system recurrence localized apart from the primary lesion was treated with radiosurgery. Two months later a diffuse progression was noted. Despite a 6 week course of oral temozolomide, the tumor progressed and the patient died 11 months after diagnosis. Although survival was short, surgery and involved field radiotherapy yielded a progression-free interval of 9 months. This allowed the patient to carry pregnancy to term. Radiosurgery resulted in a complete remission of the first recurrence. Oral chemotherapy was not effective in controlling diffuse tumor spread. Publication Types: Review Review of Reported Cases PMID: 11451202 [PubMed - indexed for MEDLINE]
44: Ann Oncol. 2001 Feb;12(2):259-66. | Related Articles, Links
Comment in: Ann Oncol. 2001 Feb;12(2):149-50. Multicenter phase II trial of temozolomide in patients with glioblastoma multiforme at first relapse. Brada M, Hoang-Xuan K, Rampling R, Dietrich PY, Dirix LY, Macdonald D, Heimans JJ, Zonnenberg BA, Bravo-Marques JM, Henriksson R, Stupp R, Yue N, Bruner J, Dugan M, Rao S, Zaknoen S. The Royal Marsden Hospital, Surrey, UK. mbrada@icr.ac.uk BACKGROUND: Recurrent glioblastoma multiforme (GBM) is resistant to most therapeutic endeavors, with low response rates and survival rarely exceeding six months. There are no clearly established chemotherapeutic regimens and the aim of treatment is palliation with improvement in the quality of life. PATIENTS AND METHODS: We report an open-label, uncontrolled, multicenter phase II trial of temozolomide in 138 patients (intent-to-treat [ITT] population) with glioblastoma multiforme at first relapse and a Karnofsky performance status (KPS) > or = 70. One hundred twenty-eight patients were histologically confirmed with GBM or gliosarcoma (GS) by independent central review. Chemotherapy-naive patients were treated with temozolomide 200 mg/m2/day orally for the first five days of a 28-day cycle. Patients previously treated with nitrosourea-containing adjuvant chemotherapy received 150 mg/m2/day for the first five days of a 28-day cycle. In the absence of grade 3 or 4 toxicity, patients on the 150 mg/m2 dose schedule were eligible for a 200 mg/m2 dose on the next cycle. RESULTS: The primary endpoint was six-month progression-free survival assessed with strict radiological and clinical criteria. Secondary endpoints included radiological response and Health-related Quality of Life (HQL). Progression-free survival at six months was 18% (95% confidence interval (CI): 11%-26%) for the eligible-histology population. Median progression-free survival and median overall survival were 2.1 months and 5.4 months, respectively. The six-month survival rate was 46%. The objective response rate (complete response and partial response) determined by independent central review of gadolinium-enhanced magnetic resonance imaging (MRI) scans was 8% for both the ITT and eligible-histology populations, with an additional 43% and 45% of patients, respectively, having stable disease (SD). Objectively assessed response and maintenance of a progression-free status were both associated with HQL benefits (characterized by improvements over baseline in HQL domains). Temozolomide had an acceptable safety profile, with only 9% of therapy cycles requiring a dose reduction due to thrombocytopenia. There was no evidence of cumulative hematologic toxicity. CONCLUSIONS: Temozolomide demonstrated modest clinical efficacy, with an acceptable safety profile and measurable improvement in quality of life in patients with recurrent GBM. The use of this drug should be explored further in an adjuvant setting and in combination with other agents. Publication Types: Clinical Trial Clinical Trial, Phase II Multicenter Study PMID: 11300335 [PubMed - indexed for MEDLINE]
45: Ann Oncol. 2001 Feb;12(2):255-7. | Related Articles, Links
Comment in: Ann Oncol. 2001 Feb;12(2):149-50. Temozolomide as a second-line systemic regimen in recurrent high-grade glioma: a phase II study. Brandes AA, Ermani M, Basso U, Amista P, Berti F, Scienza R, Rotilio A, Pinna G, Gardiman M, Monfardini S. Department of Medical Oncology, Azienda Ospedaliera, Padova, Italy. brandes@ux1.unipd.it BACKGROUND: To investigate the efficacy of temozolomide in relation to response rate, toxicity, time to progression. and median survival time, a phase II study was conducted in patients with recurrent high-grade glioma following surgery plus radiotherapy and first-line chemotherapy based on nitrosourea, procarbazine and vincristine. PATIENTS AND METHODS: Forty-one patients with high-grade glioma, at second recurrence or progression, of which twenty-two (54%) had glioblastoma multiforme, ten (24%) anaplastic astrocytoma, and nine (22%) anaplastic oligodendroglioma were administered temozolomide, 150 mg/m2/daily for five days every four weeks. RESULTS: Response was assessed in 40 patients. The overall response rate (complete + partial response) was 22.5% (95% confidence interval (CI): 9.5%-35%). The median time to progression for all 41 patients was 22.3 weeks; progression-free survival at 6 and 12 months was 48.5% and 34.7%, respectively. Median survival time was 37.1 weeks with 80.2% at 6 and 34.9% survival at 12 months. CONCLUSIONS: On multivariate analysis, response to previous treatment was significant (P = 0.03) for time to progression and Karnofsky performance score for overall survivall (P = 0.002). Temozolomide gave a moderate response rate with acceptable toxicity as second-line chemotherapy in patients with recurrent high-grade glioma. Publication Types: Clinical Trial Clinical Trial, Phase II PMID: 11300334 [PubMed - indexed for MEDLINE]
46: Ann Oncol. 2001 Feb;12(2):249-54. | Related Articles, Links
Comment in: Ann Oncol. 2001 Feb;12(2):149-50. Phase II study of temozolomide in heavily pretreated cancer patients with brain metastases. Christodoulou C, Bafaloukos D, Kosmidis P, Samantas E, Bamias A, Papakostas P, Karabelis A, Bacoyiannis C, Skarlos DV; Hellenic Cooperative Oncology Group. Athens Medical Center, Greece. hecogiat@otenet.gr PURPOSE: To determine the efficacy, tolerability, and safety of temozolomide in heavily pretreated patients with solid tumors and brain metastases. PATIENTS AND METHODS: Twenty-seven of twenty-eight enrolled patients with brain metastases from solid tumors received temozolomide (150 mg/m2/day for five days every 28 days). Twelve patients had non-small-cell lung cancer, five patients had small-cell lung cancer, four patients had breast cancer, and seven patients had other solid tumors. The majority of the patients had multiple metastatic sites, a poor performance status, and had been heavily pretreated. The primary end points were objective response rate, time to progression, and overall survival. Secondary end points included safety and tolerability, and neurologic performance status. RESULTS: A partial response was achieved in 1 (4%) of 24 evaluable patients. Disease stabilization was observed in four (17%) patients. Overall median survival was 4.5 months and median time to progression was 3 months. Improvements in clinical neurologic status were achieved in 10 (37%) patients. Treatment with temozolomide was well tolerated. Four patients had grade 3 nausea and vomiting. No grade 4 toxicity or treatment-related deaths were observed. CONCLUSIONS: Temozolomide demonstrated encouraging activity in the treatment of brain metastases in heavily pretreated patients with solid tumors, and was safe and well tolerated. Publication Types: Clinical Trial Clinical Trial, Phase II PMID: 11300333 [PubMed - indexed for MEDLINE]
47: J Neurooncol. 2001 Jan;51(1):41-5. | Related Articles, Links
Thalidomide as an anti-angiogenic agent in relapsed gliomas. Short SC, Traish D, Dowe A, Hines F, Gore M, Brada M. Unit of Neuro-Oncology, The Institute of Cancer Research and The Royal Marsden NHS Trust, Sutton, Surrey, UK. susan.short@rmh.nthames.nhs.uk BACKGROUND: Thalidomide (alpha-phthalimidoglutarimide), a synthetic sedative drug, has anti-angiogenic properties due to inhibition of growth-factor mediated neovascularisation and has been shown to inhibit tumour growth in experimental solid tumour models. AIM: To assess response of recurrent malignant gliomas to thalidomide. METHODS: Eighteen patients with recurrent gliomas were enrolled to an open, non-randomised phase II trial between October 1997 and December 1999. All patients had failed following treatment with radiotherapy and chemotherapy with PCV and/or temozolomide regimens. Eleven patients had high-grade gliomas de novo and 7 high-grade gliomas following transformation of low-grade gliomas. Thalidomide was prescribed at 100 mg/day p.o. continuously. Response was assessed at 4-weekly intervals. Disease progression was defined as neurological deterioration and/or radiological evidence of increased tumour size. Treatment was discontinued at the time of disease progression, or if toxicity occurred, or at patients' request. RESULTS: Thalidomide was prescribed for a median of 42 days (range 7-244). Treatment was discontinued due to toxicity (peripheral sensory neuropathy) in 1 patient. Six patients died before response could be fully assessed and are classified as non-responders. Of 12 who continued treatment for more than 4 weeks, 1 patient had clinical and radiological response (PR), 2 patients had stable disease for 2 and 4 months respectively and 9 patients had disease progression. The median survival from the start of thalidomide was 2.5 months. CONCLUSION: The efficacy of thalidomide in terms of response in recurrent gliomas is low, with a partial response rate of only 6%. Future studies should investigate thalidomide in combination with other agents and at an earlier stage of disease. Methods to assess anti-angiogenic properties such as changes in tumour vasculature could be employed as initial surrogate end-points in the investigation of efficacy. Publication Types: Clinical Trial Clinical Trial, Phase II PMID: 11349879 [PubMed - indexed for MEDLINE]
48: Oncology. 2001;61(3):189-91. | Related Articles, Links
Late recurrence of a primitive neuro-ectodermal tumor. Rao RD, Robins HI, Mehta MP. Department of Medicine, University of Wisconsin, Madison, USA. Late recurrences after therapy are rare in primitive neuro-ectodermal tumor (PNET). Most recurrences occur within the first 2 years after therapy, although a small number of recurrences may occur up to 5 years after therapy. We present a rare case of a recurrence of PNET in a 31-year-old woman 17 years after her initial presentation. The potential biological implications of this late recurrence as well as responses to subsequent therapy, including temozolomide, are discussed. Copyright 2001 S. Karger AG, Basel PMID: 11574773 [PubMed - indexed for MEDLINE]
49: Oncology. 2001;60(2):134-40. | Related Articles, Links
Combined treatment with high-dose methotrexate, vincristine and procarbazine, without intrathecal chemotherapy, followed by consolidation radiotherapy for primary central nervous system lymphoma in immunocompetent patients. Ferreri AJ, Reni M, Dell'Oro S, Ciceri F, Bernardi M, Camba L, Ponzoni M, Terreni MR, Tomirotti M, Spina M, Villa E. Department of Radiochemotherapy, San Raffaele H Scientific Institute, Milan, Italy. andres.ferreri@hsr.it OBJECTIVES: To assess the feasibility and the activity, as well as the efficacy to treat meninges, of chemotherapy (CHT) containing high-dose methotrexate (HD-MTX) followed by radiation therapy (RT), without intrathecal CHT, in patients with primary central nervous system lymphoma. Methods: Eligibility criteria were histologically proven diagnosis, disease limited to the CNS, age < or = 70, ECOG performance status < or = 3, HIV-negative and no prior treatment. Thirteen patients (1996-1999; median age 54 years) received two courses of vincristine 1.4 mg/m2 day 1, MTX 3 g/m2 days 3 and 10 and procarbazine 100 mg/m2 days 1-14 every 4 weeks. Patients who achieved a complete remission were referred to RT, those with progressive disease were excluded from further study; all the remaining patients received a third course of CHT followed by RT. RESULTS: Twelve patients responded to CHT (overall response rate = 92%, complete response rate = 77%): 9 underwent consolidation RT, 3 did not. Two patients experienced severe acute toxicity; lethal pulmonary thromboembolism and transient renal failure. Five patients relapsed: 2 after CHT and 3 after RT. Relapse was local in all cases, with a case of concomitant hepatic involvement. No cases of ocular or meningeal relapse were observed. In contrast to high-dose cytarabine-containing CHT, salvage therapy with temozolomide produced good results. Two patients died of treatment-related neurotoxicity. Six patients are alive with a median follow-up of 17 months, and a 2-year overall survival (OS) of 61%. The median survival of the 9 patients who completed the planned treatment is 25+ months with a 2-year OS of 80%. CONCLUSIONS: HD-MTX, procarbazine and vincristine followed by RT, without intrathecal therapy, produce similar results with respect to other HD-MTX-containing regimens. These results seem to suggest that adequate meningeal treatment is possible without intrathecal drug delivery, even in CSF-positive patients. Corroborating data from a larger series are, however, necessary. Temozolomide should be tested in relapsed patients in a phase II prospective trial. PMID: 11244328 [PubMed - indexed for MEDLINE]
50: Cancer Treat Rev. 2000 Dec;26(6):397-409. | Related Articles, Links
A comparison of treatment results for recurrent malignant gliomas. Nieder C, Grosu AL, Molls M. Department of Radiation Oncology, Klinikum rechts der Isar, TU Munich, Ismaninger Str. 22, Munich, 81675, Germany. Retreatment of malignant gliomas may be performed with palliative intent after careful consideration of the risks and benefits, and with special regards to iatrogenic neurotoxicity and quality of life (QOL). This review compares studies of several retreatment strategies (published between 1987 and 2000) based on the quality of their evidence. Depending on both established prognostic factors and previous treatment, individually tailored retreatment strategies are possible. In all studies that included a multivariate analysis of prognostic factors, performance status was the most important. So far, predictive factors for response, which might facilitate patient selection, have not been unequivocally defined.In terms of QOL, single-agent chemotherapy (temozolomide, nitrosoureas, platinum and taxane derivatives) may offer a better therapeutic ratio than polychemotherapy. For glioblastoma multiforme, progression-free survival and QOL were more favourable after temozolomide than procarbazine (level 1 evidence).The survival of patients after various radiotherapy techniques is broadly similar. However, considerable toxicity is associated with radiosurgery or brachytherapy. Fractionated stereotactic radiotherapy plus radio-sensitizing cytostatic agents has shown promising initial results in small groups of selected patients and awaits further evaluation. Level 2 evidence derived from non-randomized studies does not suggest a substantial prolongation of survival by re-resection as compared with chemotherapy or radiotherapy alone. Level 1 evidence derived from a randomized trial suggests that application of BCNU polymers significantly improves the outcome after re-resection. However, most studies reported median survival in the range of only 25-35 weeks, thereby emphasizing the need for the development and clinical evaluation of new innovative treatment approaches. Copyright 2000 Harcourt Publishers Ltd. Publication Types: Review Review, Tutorial PMID: 11139371 [PubMed - indexed for MEDLINE]
51: Br J Cancer. 2000 Sep;83(5):588-93. | Related Articles, Links
A phase II study of temozolomide vs. procarbazine in patients with glioblastoma multiforme at first relapse. Yung WK, Albright RE, Olson J, Fredericks R, Fink K, Prados MD, Brada M, Spence A, Hohl RJ, Shapiro W, Glantz M, Greenberg H, Selker RG, Vick NA, Rampling R, Friedman H, Phillips P, Bruner J, Yue N, Osoba D, Zaknoen S, Levin VA. Department of Neuro-Oncology, UTMD Anderson Cancer Center, Box 100, 1515 Holcombe Boulevard, Houston, Texas, 77030, USA. A randomized, multicentre, open-label, phase II study compared temozolomide (TMZ), an oral second-generation alkylating agent, and procarbazine (PCB) in 225 patients with glioblastoma multiforme at first relapse. Primary objectives were to determine progression-free survival (PFS) at 6 months and safety for TMZ and PCB in adult patients who failed conventional treatment. Secondary objectives were to assess overall survival and health-related quality of life (HRQL). TMZ was given orally at 200 mg/m(2)/day or 150 mg/m(2)/day (prior chemotherapy) for 5 days, repeated every 28 days. PCB was given orally at 150 mg/m(2)/day or 125 mg/m(2)/day (prior chemotherapy) for 28 days, repeated every 56 days. HRQL was assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30 [+3]) and the Brain Cancer Module 20 (BCM20). The 6-month PFS rate for patients who received TMZ was 21%, which met the protocol objective. The 6-month PFS rate for those who received PCB was 8% (P = 0.008, for the comparison). Overall PFS significantly improved with TMZ, with a median PFS of 12.4 weeks in the TMZ group and 8.32 weeks in the PCB group (P = 0.0063). The 6-month overall survival rate for TMZ patients was 60% vs. 44% for PCB patients (P = 0.019). Freedom from disease progression was associated with maintenance of HRQL, regardless of treatment received. TMZ had an acceptable safety profile; most adverse events were mild or moderate in severity. Copyright 2000 Cancer Research Campaign. Publication Types: Clinical Trial Clinical Trial, Phase II Multicenter Study Randomized Controlled Trial PMID: 10944597 [PubMed - indexed for MEDLINE]
52: Eur J Cancer. 2000 Sep;36(14):1788-95. | Related Articles, Links
Health-related quality of life in patients with anaplastic astrocytoma during treatment with temozolomide. Osoba D, Brada M, Yung WK, Prados MD. QOL Consulting, 4939 Edenvale Court, West, BC, V7W 3H7, Vancouver, Canada. david_osoba@telus.net One of the objectives of this phase II study was to determine whether temozolomide (TMZ) improved the health-related quality of life (HRQL) of patients with recurrent anaplastic astrocytoma (AA). HRQL was assessed at baseline (pretreatment) and every 4 weeks at each treatment cycle using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) (version 2.0) and the Brain Cancer Module (BCM20). Changes from baseline in the scores of seven preselected HRQL domains (role and social functioning, global QL, visual disorder, motor dysfunction, communication deficit and drowsiness) were determined at 6 months as well as prior to, and at the time of, disease progression. The significance of the changes was assessed by calculating statistical significance, effect sizes and the proportions of patients with improvement in their HRQL scores (changes of >/=10 points). After 6 months of treatment, patients who were free of progression of disease reported either an improvement or maintenance of all the preselected HRQL domains scores. Patients with disease progression by 6 months usually experienced improvement in HRQL before progression, but there was a sharp decline in most of the preselected domains at progression. We conclude that treatment of recurrent AA with temozolomide is associated with significant HRQL benefits. Publication Types: Clinical Trial Clinical Trial, Phase II PMID: 10974627 [PubMed - indexed for MEDLINE]
53: Clin Cancer Res. 2000 Jul;6(7):2585-97. | Related Articles, Links
Temozolomide and treatment of malignant glioma. Friedman HS, Kerby T, Calvert H. Department of Surgery, Duke University, Durham, North Carolina 27710, USA. Malignant gliomas (glioblastoma multiforme and anaplastic astrocytoma) occur more frequently than other types of primary central nervous system tumors, having a combined incidence of 5-8/100,000 population. Even with aggressive treatment using surgery, radiation, and chemotherapy, median reported survival is less than 1 year. Temozolomide, a new drug, has shown promise in treating malignant gliomas and other difficult-to-treat tumors. Temozolomide, a p.o. imidazotetrazine second-generation alkylating agent, is the leading compound in a new class of chemotherapeutic agents that enter the cerebrospinal fluid and do not require hepatic metabolism for activation. In vitro, temozolomide has demonstrated schedule-dependent antitumor activity against highly resistant malignancies, including high-grade glioma. In clinical studies, temozolomide consistently demonstrates reproducible linear pharmacokinetics with approximately 100% p.o. bioavailability, noncumulative minimal myelosuppression that is rapidly reversible, and activity against a variety of solid tumors in both children and adults. Preclinical studies have evaluated the combination of temozolomide with other alkylating agents and inhibitors of the DNA repair protein O6-alkylguanine alkyltransferase to overcome resistance to chemotherapy in malignant glioma and malignant metastatic melanoma. Temozolomide has recently been approved in the United States for the treatment of adult patients with refractory anaplastic astrocytoma and, in the European Union, for treatment of glioblastoma multiforme showing progression or recurrence after standard therapy. Predictable bioavailability and minimal toxicity make temozolomide a candidate for a wide range of clinical testing to evaluate the potential of combination treatments in different tumor types. An overview of the mechanism of action of temozolomide and a summary of results from clinical trials in malignant glioma are presented here. Publication Types: Review Review, Academic PMID: 10914698 [PubMed - indexed for MEDLINE]
54: J Clin Oncol. 2000 Apr;18(7):1481-91. | Related Articles, Links
Health-related quality of life in patients treated with temozolomide versus procarbazine for recurrent glioblastoma multiforme. Osoba D, Brada M, Yung WK, Prados M. Quality of Life Consulting, Vancouver, British Columbia, Canada. dosoba@bc.sympatico.ca PURPOSE: To determine whether chemotherapy with temozolomide (TMZ) versus procarbazine (PCB) for recurrent glioblastoma multiforme (GBM) was associated with improvement in health-related quality of life (HRQOL). PATIENTS AND METHODS: HRQOL was assessed at baseline and during treatment using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 and a Brain Cancer Module (BCM20) in two clinical trials that enrolled a total of 366 patients. Two hundred eighty-eight patients provided HRQOL data that could be used for analysis; 109 patients received TMZ in a phase II study, whereas 89 patients received TMZ and 90 received PCB in a randomized phase III study. Changes from baseline in the scores of seven preselected HRQOL domains (role and social functioning, global quality of life [QOL], visual disorders, motor dysfunction, communication deficit, and drowsiness) were calculated for all groups. Statistical significance, effect sizes, and proportions of patients with improved HRQOL scores (changes of > or = 10 points) were calculated. RESULTS: Before disease progression, patients treated with TMZ were found to have an improvement in most of the preselected HRQOL domain scores compared with their baseline (pretreatment) scores. Those who were progression-free on TMZ at 6 months had improvement in all the preselected HRQOL domains. Conversely, patients treated with PCB reported deterioration in HRQOL that was independent of whether or not the disease had progressed by 6 months. Patients with disease progression, regardless of treatment, experienced a sharp decline in all domains at the time of progression. CONCLUSION: Treatment with TMZ was associated with improvement in HRQOL scores compared with treatment with PCB. The deterioration reported by PCB-treated patients was likely because of toxicity. Delaying disease progression by treatment with TMZ is beneficial to the HRQOL status of patients with recurrent GBM. Publication Types: Clinical Trial Clinical Trial, Phase III Randomized Controlled Trial PMID: 10735896 [PubMed - indexed for MEDLINE]
55: Br J Cancer. 2000 Feb;82(3):608-15. | Related Articles, Links
Early evaluation of tumour metabolic response using [18F]fluorodeoxyglucose and positron emission tomography: a pilot study following the phase II chemotherapy schedule for temozolomide in recurrent high-grade gliomas. Brock CS, Young H, O'Reilly SM, Matthews J, Osman S, Evans H, Newlands ES, Price PM. MRC Cyclotron Unit, Hammersmith Campus, Imperial College of Science and Medicine, London, UK. Quantitation of metabolic changes in tumours may provide an objective measure of clinical and subclinical response to anticancer therapy. This pilot study assesses the value of quantitation of metabolic rate of glucose (MRGlu) measured in mmol min(-1) ml(-1) to assess early subclinical response to therapy in a relatively non-responsive tumour. Nine patients receiving the CRC Phase II study schedule of temozolomide were assessed with [18F]fluorodeoxyglucose ([18F]FDG) dynamic positron emission tomography (PET) scans prior to and 14 days after treatment with temozolomide given as 750-1000 mg m(-2) over 5 days every 28 days. Tumour MRGlu was calculated and compared with objective response at 8 weeks. Pretreatment MRGlu was higher in responders than non-responders. The responding patient group had a greater than 25% reduction in MRGlu in regions of high focal tumour uptake (HFU). Whole tumour changes in MRGlu did not correlate with response. Percentage change in HFU standardized uptake value (SUV) did discriminate the responding from the non-responding patients, but not as well as with MRGlu. Large differences also occurred in the normal brain SUV following treatment. Thus, MRGlu appeared to be a more sensitive discriminator of response than the simplified static SUV analysis. Changes in MRGlu may reflect the degree of cell kill following chemotherapy and so may provide an objective, quantitative subclinical measure of response to therapy. Publication Types: Clinical Trial Clinical Trial, Phase II PMID: 10682673 [PubMed - indexed for MEDLINE]
56: Br J Cancer. 1999 Nov;81(6):1022-30. | Related Articles, Links
Phase I dose-escalation and pharmacokinetic study of temozolomide (SCH 52365) for refractory or relapsing malignancies. Brada M, Judson I, Beale P, Moore S, Reidenberg P, Statkevich P, Dugan M, Batra V, Cutler D. The Royal Marsden NHS Trust, and the Institute of Cancer Research, Sutton, Surrey, UK. Temozolomide, an oral cytotoxic agent with approximately 100% bioavailability after one administration, has demonstrated schedule-dependent clinical activity against highly resistant cancers. Thirty patients with minimal prior chemotherapy were enrolled in this phase I trial to characterize the drug's safety, pharmacokinetics and anti-tumour activity, as well as to assess how food affects oral bioavailability. To determine dose-limiting toxicities (DLT) and the maximum tolerated dose (MTD), temozolomide 100-250 mg m(-2) was administered once daily for 5 days every 28 days. The DLT was thrombocytopenia, and the MTD was 200 mg m(-2) day(-1). Subsequently, patients received the MTD to study how food affects the oral bioavailability of temozolomide. When given orally once daily for 5 days, temozolomide was well tolerated and produced a non-cumulative, transient myelosuppression. The most common non-haematological toxicities were mild to moderate nausea and vomiting. Clinical activity was observed against several advanced cancers, including malignant glioma and metastatic melanoma. Temozolomide demonstrated linear and reproducible pharmacokinetics and was rapidly absorbed (mean Tmax approximately 1 h) and eliminated (mean t1/2 = 1.8 h). Food produced a slight reduction (9%) in absorption of temozolomide. Temozolomide 200 mg m(-2) day(-1) for 5 days, every 28 days, is recommended for phase II studies. Publication Types: Clinical Trial Clinical Trial, Phase I PMID: 10576660 [PubMed - indexed for MEDLINE]
57: J Clin Oncol. 1999 Sep;17(9):2762-71. | Related Articles, Links
Erratum in: J Clin Oncol 1999 Nov;17(11):3693. Multicenter phase II trial of temozolomide in patients with anaplastic astrocytoma or anaplastic oligoastrocytoma at first relapse. Temodal Brain Tumor Group. Yung WK, Prados MD, Yaya-Tur R, Rosenfeld SS, Brada M, Friedman HS, Albright R, Olson J, Chang SM, O'Neill AM, Friedman AH, Bruner J, Yue N, Dugan M, Zaknoen S, Levin VA. University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA. yung@manderson.org PURPOSE: To determine the antitumor efficacy and safety profile of temozolomide in patients with malignant astrocytoma at first relapse. PATIENTS AND METHODS: This open-label, multicenter, phase II trial enrolled 162 patients (intent-to-treat [ITT] population). After central histologic review, 111 patients were confirmed to have had an anaplastic astrocytoma (AA) or anaplastic mixed oligoastrocytoma. Chemotherapy-naive patients were treated with temozolomide 200 mg/m(2)/d. Patients previously treated with chemotherapy received temozolomide 150 mg/m(2)/d; the dose could be increased to 200 mg/m(2)/d in the absence of grade 3/4 toxicity. Therapy was administered orally on the first 5 days of a 28-day cycle. RESULTS: Progression-free survival (PFS) at 6 months, the primary protocol end point, was 46% (95% confidence interval, 38% to 54%). The median PFS was 5.4 months, and PFS at 12 months was 24%. The median overall survival was 13.6 months, and the 6- and 12-month survival rates were 75% and 56%, respectively. The objective response rate determined by independent central review of gadolinium-enhanced magnetic resonance imaging scans of the ITT population was 35% (8% complete response [CR], 27% partial response [PR]), with an additional 26% of patients with stable disease (SD). The median PFS for patients with SD was 4.4 months, with 33% progression-free at 6 months. Maintenance of progression-free status and objectively assessed response (CR/PR/SD) were both associated with health-related quality-of-life (HQL) benefits. Adverse events were mild to moderate, with hematologic side effects occurring in less than 10% of patients. CONCLUSION: Temozolomide demonstrated good single-agent activity, an acceptable safety profile, and documented HQL benefits in patients with recurrent AA. Publication Types: Clinical Trial Clinical Trial, Phase II Multicenter Study PMID: 10561351 [PubMed - indexed for MEDLINE]
58: Ann Oncol. 1999 Jul;10(7):831-8. | Related Articles, Links
Sequential administration of temozolomide and fotemustine: depletion of O6-alkyl guanine-DNA transferase in blood lymphocytes and in tumours. Gander M, Leyvraz S, Decosterd L, Bonfanti M, Marzolini C, Shen F, Lienard D, Perey L, Colella G, Biollaz J, Lejeune F, Yarosh D, Belanich M, D'Incalci M. Centre Pluridisciplinaire d'Oncologie, Lausanne, Switzerland. BACKGROUND: The DNA repair protein O6-alkylguanine-DNA alkyl transferase (AT) mediates resistance to chloroethylnitrosoureas. Agents depleting AT such as DTIC and its new analogue temozolomide (TMZ) can reverse resistance to chloroethylnitrosoureas. We report the results of a dose finding study of TMZ in association with fotemustine. PATIENTS AND METHODS: Twenty-four patients with metastatic melanoma or recurrent glioma were treated with escalating dose of oral or intravenous TMZ ranging from 300 to 700 mg/m2, divided over two days. Fotemustine 100 mg/m2 was given intravenously on day 2, 4 hours after TMZ. AT depletion was measured in peripheral blood mononuclear cells (PBMCs) and in selected cases in melanoma metastases and was compared to TMZ pharmacokinetics. RESULTS: The maximum tolerated dose (MTD) of TMZ was 400 mg/m2 (200 mg/m2/d) when associated with fotemustine the 2nd day with myelosuppression as dose limiting toxicity. The decrease of AT level in PBMCs was progressive and reached 34% of pretreatment values on day 2. There was however wide interindividual variability. AT reduction was neither dose nor route dependent and did not appear to be related to TMZ systemic exposure (AUC). In the same patients, AT depletion in tumour did not correlate with the decrease of AT observed in PBMCs. CONCLUSIONS: PBMCs may not be used as a surrogate of tumour for AT depletion. Further study should concentrate on the pharmacokinetic pharmacodynamic relationship in tumour to provide the basis for individually tailored therapy. Publication Types: Clinical Trial PMID: 10470431 [PubMed - indexed for MEDLINE]
59: Curr Opin Oncol. 1999 May;11(3):157-61. | Related Articles, Links
New chemotherapy options for the treatment of malignant gliomas. Burton E, Prados M. University of California, San Francisco, Department of Neurosurgery, USA. Chemotherapy remains part of the treatment triad that includes surgery and radiation therapy for the management of malignant gliomas. In recent years there has been an increased understanding of the molecular pathways of malignant transformation. Based on this research, new drugs have been evaluated, with specific cellular targets in mind that can be modified or inhibited. Many of these agents are now being tested in phase I and II clinical trials and have shown some promising results. Clearly, not all patients with malignant gliomas respond equally to chemotherapy. Recent evidence suggests that certain molecular markers may predict chemosensitivity in some tumor types, particularly anaplastic oligodendroglioma. This article reviews recent trends in the use of chemotherapy and clinical trials of new therapies for adults with malignant gliomas. Publication Types: Review Review, Tutorial PMID: 10328588 [PubMed - indexed for MEDLINE]
60: Anticancer Drugs. 1999 Feb;10(2):179-85. | Related Articles, Links
Sensitivity of short-term cultures derived from human malignant glioma to the anti-cancer drug temozolomide. Sankar A, Thomas DG, Darling JL. University Department of Neurosurgery, Institute of Neurology, University College London, National Hospital for Neurology and Neurosurgery, UK. The activity of temozolomide, which has shown clinical activity against malignant glioma, has been assessed in vitro against short-term cultures derived from these tumors using an intermediate duration microtitration assay with MTT reduction as the end-point This assay has previously been shown to correlate closely with a monolayer clonogenic assay. Sensitivity was assessed in 15 short-term cultures (passage levels 3-9) derived from WHO grade III and IV astrocytomas. These cultures had a median ID50 value of 258 microM for temozolomide and 16.13 microM for CCNU. Maximum serum concentrations of temozolomide are of the order of 75 microM but only three of 15 (20%) cultures had ID50s below this value. Fourteen of 15 (93%) cultures displayed cross-resistance between temozolomide and CCNU, although one line which was extremely resistant to CCNU retained sensitivity to temozolomide. Comparative studies of published clonogenic survival curves indicate that the short-term glioma cell lines used in this study have similar sensitivities to established glioma cell lines, whilst colon carcinoma cell lines and bladder carcinoma are often more resistant to these drugs. Cell lines from testicular teratoma cell lines may show exquisite sensitivity to temozolomide and this level of sensitivity is seen only occasionally in short-term cultures derived from malignant glioma. PMID: 10211548 [PubMed - indexed for MEDLINE]
61: J Clin Oncol. 1998 Dec;16(12):3851-7. | Related Articles, Links
DNA mismatch repair and O6-alkylguanine-DNA alkyltransferase analysis and response to Temodal in newly diagnosed malignant glioma. Friedman HS, McLendon RE, Kerby T, Dugan M, Bigner SH, Henry AJ, Ashley DM, Krischer J, Lovell S, Rasheed K, Marchev F, Seman AJ, Cokgor I, Rich J, Stewart E, Colvin OM, Provenzale JM, Bigner DD, Haglund MM, Friedman AH, Modrich PL. Department of Surgery, Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710, USA. fried003@mc.duke.edu PURPOSE: We evaluated the response to Temodal (Schering-Plough Research Institute, Kenilworth, NJ) of patients with newly diagnosed malignant glioma, as well as the predictive value of quantifying tumor DNA mismatch repair activity and O6-alkylguanine-DNA alkyltransferase (AGT). PATIENTS AND METHODS: Thirty-three patients with newly diagnosed glioblastoma multiforme (GBM) and five patients with newly diagnosed anaplastic astrocytoma (AA) were treated with Temodal at a starting dose of 200 mg/m2 daily for 5 consecutive days with repeat dosing every 28 days after the first daily dose. Immunochemistry for the detection of the human DNA mismatch repair proteins MSH2 and MLH1 and the DNA repair protein AGT was performed with monoclonal antibodies and characterized with respect to percent positive staining. RESULTS: Of the 33 patients with GBM, complete responses (CRs) occurred in three patients, partial responses (PRs) occurred in 14 patients, stable disease (SD) was seen in four patients, and 12 patients developed progressive disease (PD). Toxicity included infrequent grades 3 and 4 myelosuppression, constipation, nausea, and headache. Thirty tumors showed greater than 60% cells that stained for MSH2 and MLH1, with three CRs, 12 PRs, three SDs, and 12 PDs. Eight tumors showed 60% or less cells that stained with antibodies to MSH2 and/or MLH1, with 3 PRs, 3 SDs, and 2 PDs. Eleven tumors showed 20% or greater cells that stained with an antibody to AGT, with 1 PR, 2 SDs, and 8 PDs. Twenty-five tumors showed less than 20% cells that stained for AGT, with 3 CRs, 12 PRs, 4 SDs, and 6 PDs. CONCLUSION: These results suggest that Temodal has activity against newly diagnosed GBM and AA and warrants continued evaluation of this agent. Furthermore, pretherapy analysis of tumor DNA mismatch repair and, particularly, AGT protein expression may identify patients in whom tumors are resistant to Temodal. PMID: 9850030 [PubMed - indexed for MEDLINE]
62: Cancer Res. 1998 Oct 1;58(19):4363-7. | Related Articles, Links
Phase I trial of temozolomide using an extended continuous oral schedule. Brock CS, Newlands ES, Wedge SR, Bower M, Evans H, Colquhoun I, Roddie M, Glaser M, Brampton MH, Rustin GJ. Medical Oncology Unit, Charing Cross Hospital, London, United Kingdom. Temozolomide, a methylating imidazotetrazinone, has antitumor activity against gliomas, malignant melanoma, and mycosis fungoides and is presently administered as a 5-day oral schedule every 4 weeks. This Phase I study aimed to determine the maximum tolerated dose of temozolomide administered as a single oral daily dose for a continuous 6- or 7-week period, evaluate the plasma pharmacokinetics on this schedule, and compare total plasma exposure over 7 weeks with the conventional 5-day regimen. Twenty-four patients with varying tumor types (17 of 24 gliomas) received temozolomide. All had clinically evaluable, refractory disease; normal renal, hepatic, and bone marrow function; and WHO performance status < or = 2. Temozolomide was administered at 50 mg/m2/day, increasing by 25 mg/m2/day/cohort until at 100 mg/m2/day grade 4 myelotoxicity forced dose reductions to 85 mg/m2/day, then 75 mg/m2/day. At 75 mg/m2/day the regimen was extended to 7 weeks, allowing the future potential combination with irradiation for primary gliomas. Patient responses (standard Union International Contre Cancer criteria; for gliomas objective response) and toxicity were assessed. Temozolomide plasma pharmacokinetics were determined on day 1 and at the beginning of the final week of administration (n = 5). The most frequent toxicities were myelosuppression and grades 1 and 2 nausea and vomiting. Grade 4 leucopenia and thrombocytopenia occurred in one of four patients receiving 100 mg/m2/day temozolomide and in one of seven patients receiving 85 mg/m2/day. These hematological toxicities did not exceed grade 2 in 10 patients receiving 75 mg/m2/day temozolomide. One of 4 malignant melanoma patients and 7 of 17 glioma patients (41%) demonstrated tumor responses. The overall response rate for this prolonged schedule was 33% (objective response, 7 of 24 patients; partial response, 1 of 24 patients); also, 6 of 17 glioma patients maintained SD. Peak plasma temozolomide concentrations were obtained 30-90 min after oral administration. Elimination in plasma was best described by a monoexponential equation with an elimination half-life of 96 +/- 16 min. No plasma accumulation of temozolomide occurred. Toxicity was greatest in higher dose cohorts, with a resultant maximum tolerated dose of 85 mg/m2/day, whereas lower dose cohorts tolerated the schedule well. The area under the temozolomide plasma versus time curve was noncumulative between the first and last week of the schedule. Temozolomide administration of 75 mg/m2/day over a 7-week period permits a 2.1-fold greater drug exposure/4 weeks in comparison with the 5-day schedule of 200 mg/m2/day repeated every 28 days. The overall response rate was 33% (glioma patients, 41% and a further 25% SD). Temozolomide (75 mg/m2/day) for 7 weeks is the recommended starting dose for further assessment of this schedule. Publication Types: Clinical Trial Clinical Trial, Phase I Multicenter Study PMID: 9766665 [PubMed - indexed for MEDLINE]
63: Cancer Chemother Pharmacol. 1998;42(6):433-40. | Related Articles, Links
Erratum in: Cancer Chemother Pharmacol 1999;43(5):439-40. Pharmacokinetics of temozolomide in association with fotemustine in malignant melanoma and malignant glioma patients: comparison of oral, intravenous, and hepatic intra-arterial administration. Marzolini C, Decosterd LA, Shen F, Gander M, Leyvraz S, Bauer J, Buclin T, Biollaz J, Lejeune F. Departement de medecine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland. PURPOSE: Depletion of the DNA repair enzyme O6-alkylguanine-DNA alkyltransferase (AT) has been shown to increase tumor sensitivity to chloroethylnitrosoureas. Temozolomide (TMZ), an analogue of dacarbazine, can deplete AT, suggesting that it may be used to sensitize tumors to chloroethylnitrosoureas. However, the influence of nitrosoureas on the pharmacokinetics of TMZ is unknown, and a pilot study was performed to assess the pharmacokinetics of TMZ given via, various routes to 29 patients (27 malignant melanomas, 2 gliomas) with or without sequential administration of i.v. fotemustine. METHODS: On day 1, TMZ was given intravenously (i.v.), orally (p.o.), or by intra-hepatic arterial infusion (h.i.a.) at four ascending dose levels (150 to 350 mg/m2 per day). On day 2 the same dose of TMZ was given by the same route (or by another route in six patients for determination of its bioavailability), followed 4 h later by fotemustine infusion at 100 mg/m2. Plasma and urinary levels of TMZ were determined on days 1 and 2 by high-performance liquid chromatography after solid-phase extraction. RESULTS: The pharmacokinetics of i.v. TMZ appeared linear, with the area under the curve (AUC) increasing in proportion to the dose expressed in milligrams per square meter (r = 0.86 and 0.91 for days 1 and 2, respectively). The clearance after i.v. administration was 220 +/- 48 and 241 +/- 39 ml/min on days 1 and 2, respectively. The apparent clearance after p.o. and h.i.a. administration was 290 +/- 86 and 344 +/- 77 ml/min, respectively. The volume of distribution of TMZ after i.v., p.o., and h.i.a. administration was 0.4, 0.6, and 0.6 l/kg on day 1 and 0.5, 0.5, and 0.6 l/kg on day 2, respectively. The absolute bioavailability of TMZ was 0.96 +/- 0.1, regardless of the sequence of the i.v.-p.o. or p.o.-i.v. administration, confirming that TMZ is not subject to a marked first-pass effect. A comparison of TMZ pharmacokinetics after i.v. and h.i.a. treatment at the same infusion rate revealed little evidence of hepatic extraction of TMZ. However, the systemic exposure to TMZ (AUC) appeared to decrease at a lower infusion rate. TMZ excreted unchanged in the urine accounted for 5.9 +/- 3.4% of the dose, with low within-patient and high interpatient variability. TMZ crosses the blood-brain barrier and the concentration detected in CSF amounted to 9%, 28%, and 29% of the corresponding plasma levels (three patients). The equilibrium between plasma and ascitic fluid was reached after 2 h (assessed in one patient). CONCLUSION: The sequential administration of fotemustine at 4 h after TMZ treatment had no clinically relevant influence on the pharmacokinetics of TMZ. The potential clinical effect of TMZ given by h.i.a. or by locoregional administration has yet to be established, as has the impact of the infusion duration on patients' tolerance and response rate. Publication Types: Clinical Trial PMID: 9788568 [PubMed - indexed for MEDLINE]
64: Cancer Chemother Pharmacol. 1997;40(6):484-8. | Related Articles, Links
Multicentre CRC phase II trial of temozolomide in recurrent or progressive high-grade glioma. Bower M, Newlands ES, Bleehen NM, Brada M, Begent RJ, Calvert H, Colquhoun I, Lewis P, Brampton MH. Department of Medical Oncology, Charing Cross Hospital, London, UK. PURPOSE: Patients with progressive or recurrent supratentorial high-grade gliomas were entered into a multicentre phase II trial to evaluate the efficacy and toxicity of temozolomide. METHODS: The treatment schedule was 150-200 mg/m2 per day orally for 5 days repeated every 28 days. Response evaluation was by a combination of neurological status evaluation (MRC scale) and imaging. RESULTS: Of 103 eligible patients enrolled, 11 (11%) achieved an objective response and a further 48 (47%) had stable disease. The median response duration was 4.6 months. Response rates were similar for anaplastic astrocytomas (grade III) and glioblastoma multiforme (grade IV) tumours. Predictable myelosuppression was the major toxicity. CONCLUSIONS: The observation of objective responses and tolerable side effects in this heterogeneous population of patients supports the further investigation of this agent in high-grade gliomas. Publication Types: Clinical Trial Clinical Trial, Phase II Multicenter Study PMID: 9332462 [PubMed - indexed for MEDLINE]
65: Eur J Cancer. 1996 Dec;32A(13):2236-41. | Related Articles, Links
The Charing Cross Hospital experience with temozolomide in patients with gliomas. Newlands ES, O'Reilly SM, Glaser MG, Bower M, Evans H, Brock C, Brampton MH, Colquhoun I, Lewis P, Rice-Edwards JM, Illingworth RD, Richards PG. Department of Medical Oncology, Charing Cross Hospital, London, U.K. Temozolomide, a new oral cytotoxic agent, was given to 75 patients with malignant gliomas. The schedule used was for the first course 150 mg/m2 per day for 5 days (i.e. total dose 750 mg/m2), escalating, if no significant myelosuppression was noted on day 22, to 200 mg/m2 per day for 5 days (i.e. total dose 1000 mg/m2) for subsequent courses at 4-week intervals. There were 27 patients with primary disease treated with two courses of temozolomide prior to their radiotherapy and 8 (30%) fulfilled the criteria for an objective response. There were 48 patients whose disease recurred after their initial surgery and radiotherapy and 12 (25%) fulfilled the criteria for an objective response. This gave an overall objective response rate of 20 (27%) out of 75 patients. Temozolomide was generally well tolerated, with little subjective toxicity and predictable myelosuppression. However, the responses induced with this schedule were of short duration and had relatively little impact on overall survival. In conclusion, temozolomide given in this schedule has activity against high grade glioma. However, studies evaluating chemotherapy in primary brain tumours should include a quality-of-life/performance status evaluation in addition to CT or MRI scanning assessment. Publication Types: Clinical Trial PMID: 9038604 [PubMed - indexed for MEDLINE]
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