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            Limits: All Adult: 19+ years, only items with abstracts, Human
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                  Items 1-65 of 65One 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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