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PubMed2006

Optimizing a novel regional chemotherapeutic agent against melanoma: hyperthermia-induced enhancement of temozolomide cytotoxicity.

PURPOSE: Previous preclinical studies have shown that regional temozolomide therapy via isolated limb infusion is more effective than melphalan, the current drug of choice for regional chemotherapy for advanced extremity melanoma. The aim of this study was to determine whether hyperthermia could further augment the efficacy of temozolomide, an alkylating agent, against melanoma and improve its therapeutic index in a rat model of isolated limb infusion. EXPERIMENTAL DESIGN: Athymic rats bearing s.c. human melanoma xenografts (DM6) in their hind limbs were randomized to a 15-minute isolated limb infusion procedure with or without temozolomide at room temperature, normothermic (37.5 degrees C), or hyperthermic (43 degrees C) conditions. RESULTS: The concomitant administration of hyperthermia during an infusion with temozolomide led to the greatest increase in tumor growth delay, decreased proliferative index, and increased cell death. Isolated limb infusion treatment with a low dose (350 mg/kg) of temozolomide was ineffective at producing tumor growth delay (P = 0.07). Similarly, temozolomide infusion under normothermia yielded minimal tumor growth delay (P = 0.08). In contrast, the combination of hyperthermia plus temozolomide treatment produced marked tumor growth delay of 10.4 days (P = 0.02) with minimal toxicity. The addition of heat to temozolomide treatment yielded the smallest proliferative index (P = 0.001), while markedly increasing the level of apoptosis 48 hours after isolated limb infusion. CONCLUSION: This study, the first to examine the interaction between hyperthermia and temozolomide, shows a strong, synergistic antitumor effect when hyperthermia is combined with temozolomide for regional treatment of melanoma confined to an extremity. The mechanism of this synergy seems to be through an augmentation, by hyperthermia, of the antiproliferative and proapoptotic effects of temozolomide.

Animals↗
PubMed2005

Food and Drug Administration Drug approval summary: temozolomide plus radiation therapy for the treatment of newly diagnosed glioblastoma multiforme.

On March 15, 2005, the U.S. Food and Drug Administration approved temozolomide (Temodar capsules, Schering-Plough Research Institute) for the treatment of adult patients with newly diagnosed glioblastoma multiforme concomitantly with radiotherapy and then as maintenance treatment. Five hundred seventy-three glioblastoma multiforme patients were randomized to receive either temozolomide + radiotherapy (n = 287) or radiotherapy alone (n = 286). Patients in the temozolomide + radiotherapy arm received concomitant temozolomide (75 mg/m2) once daily for the duration of radiation therapy (42-49 days). This was followed, 4 weeks later, by six cycles of temozolomide, 150 or 200 mg/m2 daily for 5 days, every 4 weeks. Patients in the control arm received radiotherapy only. In both arms, radiotherapy was delivered as 60 Gy/30 fractions to the tumor site with a 2 to 3 cm margin. Pneumocystis carinii pneumonia prophylaxis was required during temozolomide + radiotherapy treatment and was continued until recovery of lymphocytopenia (Common Toxicity Criteria grade <1). At disease progression, temozolomide salvage treatment was given to 161 of 282 patients (57%) in the radiotherapy alone arm, and to 62 of 277 patients (22%) in the temozolomide + radiotherapy arm. Patients receiving concomitant and maintenance temozolomide + radiotherapy had significantly improved overall survival. The hazard ratio was 0.63 (95% confidence interval, 0.52-0.75; log-rank, P < 0.0001). Median survival was 14.6 months (temozolomide + radiotherapy) versus 12.1 months (radiotherapy alone). Adverse events during temozolomide treatment included thrombocytopenia, nausea, vomiting, anorexia, constipation, alopecia, headache, fatigue, and convulsions.

Adult↗
PubMed2002

Phase II randomized trial of temozolomide and concurrent radiotherapy in patients with brain metastases.

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.

Analysis of Variance↗
PubMed2003

Marked inactivation of O6-alkylguanine-DNA alkyltransferase activity with protracted temozolomide schedules.

Temozolomide, an oral DNA methylator that inactivates the DNA repair enzyme O(6)-alkylguanine-DNA alkyltransferase (AGAT), has demonstrated anticancer activity on protracted schedules. Protracted schedules may lead to an 'autoenhancement' of temozolomide's inherent cytotoxic potential by cumulative reduction of the cell's capacity for AGAT-mediated DNA repair and resistance. This study was undertaken to characterise AGAT inactivation and regeneration in the peripheral blood mononuclear cells (PBMCs) of patients treated on two protracted temozolomide schedules. O(6)-alkyl guanine-DNA alkyltransferase activity was measured in the PBMCs of patients treated on two phase I protracted temozolomide studies. Patients were treated daily for either 7 days every 2 weeks (Schedule A) or 21 days every 4 weeks (Schedule B). The effects of various temozolomide doses (75-175 mg m(-2)), treatment duration (7-21 days), and temozolomide plasma levels on AGAT inactivation and regeneration, as well as the relation between AGAT inactivation and toxicity, were studied. O(6)-alkyl guanine-DNA alkyltransferase activity in PBMCs was measured serially in 52 patients. Marked inactivation of AGAT occurred following 7 days of temozolomide treatment, with mean AGAT activity decreasing by 72% (P<0.0001). Similarly, mean AGAT activity decreased by 63 and 73% after 14 and 21 days of treatment, respectively (P<0.001 for both comparisons). O(6)-alkyl guanine-DNA alkyltransferase inactivation was greater after 7 days of treatment with higher doses of temozolomide than lower doses and remained markedly reduced 7 days post-treatment. However, AGAT inactivation following temozolomide treatment for 14 and 21 days was similar at all doses. On the continuous 21-day schedule, AGAT inactivation was significantly greater in patients who experienced severe thrombocytopenia than those who did not (90.3+/-5.5 vs 72.5+/-16.1%, P<0.045). In conclusion, protracted administration of temozolomide, even at relatively low daily doses, leads to significant and prolonged depletion of AGAT activity, which may enhance the antitumour activity of the agent.

Antineoplastic Agents, Alkylating↗
PubMed2004

Disposition and pharmacokinetics of temozolomide in rat.

1. Temozolomide, an imidazotetrazine derivative, is a cytotoxic alkylating agent of broad-spectrum antitumour activity. The absorption, metabolism, distribution and excretion of temozolomide have been investigated in male and female Sprague-Dawley and Long-Evans rats following single oral or intravenous dose administration of 200 mg m(-2) non-radiolabelled or (14)C-radiolabelled temozolomide. The distribution of (14)C-temozolomide was also evaluated by whole-body autoradiography in male Sprague-Dawley rats. Plasma concentrations of temozolomide and its active metabolite 3-methyl-(triazen-1-yl)imidazole-4-carboxamide (MTIC) were determined by high-performance liquid chromatography (HPLC) with ultraviolet detection. Plasma, urine and faeces were profiled by HPLC with radiochemical detection. 2. Temozolomide was rapidly and extensively (>90%) absorbed and widely distributed in tissues. The distribution pattern of radioactivity was gender independent. Penetration into the brain following oral or intravenous administration was 35-39% based on the brain/plasma AUC ratio. 3. Following intravenous or oral administration, temozolomide was primarily eliminated renally (75-85% of the dose) as either unchanged drug, a carboxylic acid analogue, AIC (a degradation product) and a highly polar unidentified peak. Biliary excretion was minimal (1.4-1.6%). The pharmacokinetics (oral versus intravenous) were similar and gender independent. The absolute oral availability was 96-100%. Temozolomide was rapidly eliminated (t(1/2) = 1.2 h) and converted to MTIC. 4. Systemic exposure to MTIC was about 2% that of temozolomide. Overall, the disposition of temozolomide in rats was similar to that observed in humans.

Administration, Oral↗
PubMedDate not supplied

Temozolomide and radiotherapy as first-line treatment of high-grade gliomas.

AIMS AND BACKGROUND: Temozolomide, a novel alkylating agent, has shown promising results in the treatment of patients with high-grade gliomas, when used as single agent as well as in combination with radiation therapy. MATERIALS AND METHODS: In this report we retrospectively reviewed the clinical outcome of 128 consecutive patients with a diagnosis of high-grade gliomas referred to our Institutions from April 1994 to November 2001. The first 64 patients were treated with radiotherapy alone and the other 64 with a combination of radiotherapy and temozolomide (31 with radiotherapy and adjuvant temozolomide and 33 with radiotherapy and concomitant temozolomide followed by adjuvant temozolomide). RESULTS: Grade 3 hematological toxicity was scored in 9% of 64 patients treated with radiotherapy and temozolomide. No grade 4 hematological toxicity was reported, and the other acute side effects observed were mild or easily controlled with medications. Age, histology and administration of temozolomide were statistically significant prognostic factors associated with better 2-year overall survival. In contrast, we did not observe a significant difference in overall survival between adjuvant and concomitant/adjuvant temozolomide administration. CONCLUSIONS: We report the favorable results of a schedule combining radiotherapy and temozolomide in the treatment of patients with high-grade gliomas. The literature data and above all the findings of the phase III EORTC-NCIC 26981 trial suggest that actually the schedule can be used routinely in clinical practice. Further clinical studies, using temozolomide in combination with other agents, are required.

Adult↗
PubMed2003

Randomized phase II study of temozolomide given every 8 hours or daily with either interferon alfa-2b or thalidomide in metastatic malignant melanoma.

PURPOSE: Temozolomide is an imidazotetrazine with a mechanism of action similar to dacarbazine and equivalent activity in melanoma. It is well tolerated and is a candidate for combination chemotherapy and schedule manipulation. In this study, we combined temozolomide with interferon alfa-2b and, separately, with thalidomide, and we administered temozolomide alone in a compressed schedule. The objectives of this randomized phase II, two-center study were to determine response rates, overall survival, and tolerability of the regimens in patients with advanced metastatic melanoma. PATIENTS AND METHODS: One hundred eighty-one patients with metastatic melanoma were randomly assigned to receive up to six 4-weekly cycles consisting of temozolomide 200 mg/m2 every 8 hours for five doses, or temozolomide 200 mg/m2 daily for days 1 to 5 plus interferon alfa-2b 5 MU (million International Units) subcutaneously three times a week, or temozolomide 150 mg/m2 (increased after one cycle to 200 mg/m2) daily on days 1 to 5 plus thalidomide 100 mg daily days 1 to 28. RESULTS: The treatment arms were well balanced for known prognostic factors. Median survival was 5.3 months for 8-hourly temozolomide, 7.7 months for temozolomide/interferon, and 7.3 months for temozolomide/thalidomide; and 1-year survivals were 18%, 26%, and 24%, respectively. Response or disease stabilization occurred in 20% of patients (95% confidence interval [CI], 10% to 33%) given 8-hourly temozolomide, 21% (95% CI, 12% to 33%) given temozolomide/interferon, and 25% (95% CI, 15% to 38%) given temozolomide/thalidomide. Grade 3 or 4 nonhematologic toxicities were similar in each arm except for infection, which was more frequent with 8-hourly temozolomide. There were fewer instances of grade 3 or 4 myelotoxicity with temozolomide/thalidomide. CONCLUSION: Of the three regimens tested, the combination of temozolomide and thalidomide seems the most promising for future study.

Adolescent↗
PubMed2000

Temozolomide delivered by intracerebral microinfusion is safe and efficacious against malignant gliomas in rats.

Intracerebral microinfusion (ICM) is an innovative technique of delivering therapeutic agents throughout large portions of the brain that circumvents the blood-brain barrier, minimizes systemic toxicity, and provides a homogeneous distribution of the infused agent. Temozolomide is a novel methylating agent with proven efficacy against malignant gliomas (MGs) after systemic administration but with dose-limiting myelotoxicity. Because MGs rarely metastasize, systemic drug delivery is unnecessary. Therefore, we evaluated the efficacy and toxicity of ICM with temozolomide in an athymic rat model of human MGs. Treatment of rats by ICM with temozolomide 3 days after intracerebral challenge with D54 human MG xenograft increased median survival by 128% compared with rats treated by ICM with saline, by 113% compared with rats treated with i.p. saline, and by 100% compared with rats treated with i.p. temozolomide (P < 0.001). Delay of treatment until 9 days after tumor challenge still resulted in a 23% increase in median survival in rats treated by ICM of temozolomide compared with rats treated with i.p. temozolomide. In addition, overall, 21.7% of rats treated by ICM with temozolomide survived for > 100 days without clinical or histological evidence of tumor. The dose of temozolomide delivered by ICM in this study was limited only by drug solubility, and no neurological or systemic toxicity could be attributed to ICM with temozolomide. Therefore, ICM of temozolomide may offer significant advantages in the treatment of MGs.

Animals↗
PubMed2005

Temozolomide in uterine leiomyosarcomas.

OBJECTIVE: Temozolomide has been studied in soft-tissue sarcomas with varying dosing schedules. We review the Memorial Sloan-Kettering Cancer Center (MSKCC) experience in women with metastatic or unresectable leiomyosarcoma treated with continuous daily dose (CDD) or bolus-dose (BD) temozolomide. We include a literature review of temozolomide activity in leiomyosarcoma patients. METHODS: After obtaining Institutional Review Board approval, we identified women with recurrent leiomyosarcoma treated with temozolomide at MSKCC from 9/2001 to 9/2004. Patients were treated daily with dosages ranging from 50 to 75 mg/m(2) for 6 out of 8 weeks or for 5 days every 4 weeks with 150-300 mg/m(2) daily. All patients were evaluated at least every month for toxicity and response. We reviewed patients' charts for age at diagnosis, stage, performance status, prior treatments, temozolomide dose and schedule, best response to treatment, and treatment delays or dose reductions due to toxicity. RESULTS: Twelve patients were treated with CDD temozolomide (median age, 54 years; range, 35-72 years). All patients had previously received doxorubicin; 11 had received >/=2 previous chemotherapy regimens. One patient achieved a prolonged partial response for 4 cycles; 4 demonstrated stabilization of disease for 2-5+ cycles. Seven patients were treated with BD temozolomide (median age, 50 years; range, 43-63 years). All patients received previous doxorubicin and received >/=2 previous chemotherapy regimens. Four patients achieved stabilization of disease for 3, 5, 6, and 16 cycles, respectively. One patient achieved a near complete response for 13 cycles and continues to be followed off therapy for 10+ months. CONCLUSIONS: Temozolomide has promising therapeutic benefit and is well tolerated in patients with metastatic unresectable leiomyosarcoma. Further investigation of temozolomide in leiomyosarcoma patients is warranted.

Adult↗
PubMed2000

Survival of human glioma cells treated with various combination of temozolomide and X-rays.

PURPOSE: To investigate the effect of temozolomide, a 3-methyl derivative of mitozolomide in combination with X-rays in human glioma-derived cell lines. METHODS AND MATERIALS: Glioma cell lines D384 and U251 were treated with temozolomide for various periods of time in combinations with X-rays. Temozolomide administration was repeated every 24 h for exposures up to 96 h. Cytotoxicity was determined with a clonogenic assay. RESULTS: Incubation of D384 cells with temozolomide during 24 h prior to or following irradiation results in a moderate enhancement of the cytotoxicity. Prolonged treatment with temozolomide, i.e., 48-96 h before X-rays, causes a stronger potentiation. In contrast, no enhancement is observed in irradiated U251 cells in combination with 24-96 h temozolomide treatment. In addition to single-dose irradiation, we investigated the effect of temozolomide in D384 cells with concomitant fractionated irradiation. A 96-h exposure to temozolomide with simultaneous doses of 2 Gy X-rays at 24-h intervals, causes a significant further reduction in cell survival as compared to fractionated irradiation only. CONCLUSION: Depending on the cell line, treatment of glioma cells with temozolomide and X-rays can have either an additional effect or potentiate cell killing.

Antineoplastic Agents, Alkylating↗
PubMed1996

Potentiation of temozolomide and BCNU cytotoxicity by O(6)-benzylguanine: a comparative study in vitro.

Depletion of the DNA repair protein O(6)-alkylguanine-DNA alkyltransferase (AGT) with O(6)-benzylguanine (O(6)-BG) has been widely shown to enhance 1,3-bis(2-chloroethyl)-nitrosourea (BCNU) activity. This study aimed to determine whether temozolomide, a methylating imidazotetrazinone, would similarly benefit from combination with O(6)-BG. Seven human cell lines were examined with AGT activities ranging from <6 fmol mg-1 protein to >700 fmol mg-1 protein. Comparisons with BCNU were made on both single and multiple dosing schedules, since temozolomide cytotoxicity is highly schedule dependent. In single-dose potentiation studies, cells were preincubated with 100 microM O(6)-BG for 1 h, a treatment found to deplete AGT activity by >90% for 24 h. No potentiation of either temozolomide or BCNU cytotoxicity was observed in two glioblastoma cell lines with <6 fmol mg-1 protein AGT. In all other cell lines studied potentiation of BCNU toxicity by O(6)-BG was between 1.6- and 2.3-fold and exceeded that of temozolomide (1.1- to 1.7-fold). The magnitude of this potentiation was unrelated to AGT activity and the relative potentiation of temozolomide and BCNU cytotoxicity was found to be highly variable between cell lines. In multiple dosing studies two colorectal cell lines (Mawi and LS174T) were treated with temozolomide or BCNU at 24 h intervals for up to 5 days, with or without either 100 microM O(6)-BG for 1 h or 1 microM O(6)-BG for 24 h, commencing 1 h before alkylating treatment. Extended treatment with 1 microM O(6)-BG produced greater potentiation than intermittent treatment with 100 microM O(6)-BG. Potentiation of temozolomide cytotoxicity increased linearly in Mawi with each subsequent dosing: from 1.4-fold (day 1) to 4.2-fold (day 5) with continuous 1 microM O(6)-BG. In contrast, no potentiation was observed in LS174T, a cell line that would appear to be 'tolerant' of methylation. Potentiation of BNCU cytotoxicity increased in both cell lines with repeat dosing, although the rate of increase was less than that observed with temozolomide and continuous 1 microM O(6)-BG in Mawi. These results suggest that repeat dosing of an AGT inhibitor and temozolomide may have a clinical role in the treatment of tumours that exhibit AGT-mediated resistance.

Antineoplastic Agents↗
PubMed2005

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

The purpose of this study was to determine activity of temozolomide combined with paclitaxel or epothilone B in vitro, and to investigate the combination of temozolomide with paclitaxel in a Phase I clinical trial. Melanoma cell lines A375P and DX3 were treated with temozolomide and either paclitaxel or epothilone B. Combination indices were determined to assess the degree of synergism. In a clinical study, 21 patients with malignant melanoma were treated with increasing doses of temozolomide (orally, days 1-5), in combination with a fixed dose of paclitaxel (i.v. infusion day 1), followed by dose escalation of the latter drug. Cycles of treatment were repeated every 3 weeks. Pharmacokinetics of both agents were determined on day 1, with temozolomide pharmacokinetics also assessed on day 5. All three compounds were active against the melanoma cell lines, with epothilone B being the most potent. There was a strong degree of synergism between temozolomide and either paclitaxel or epothilone B. In the clinical study, no pharmacokinetic interaction was observed between temozolomide and paclitaxel. Dose escalation of both drugs to clinically active doses was possible, with no dose-limiting toxicities observed at 200 mg m(-2) day(-1) temozolomide and 225 mg m(-2) day(-1) paclitaxel. There were two partial responses out of 15 evaluable patients. One patient remains alive and symptom-free at 4 years after treatment. Temozolomide and paclitaxel may be administered safely at clinically effective doses. Further evaluation of these combinations in melanoma is warranted.

Adult↗
PubMed2006

Re-evaluation of the cost effectiveness of temozolomide for malignant gliomas in British Columbia.

STUDY OBJECTIVES: To re-evaluate the cost effectiveness and median overall survival (OS) achieved in patients with recurrent malignant gliomas treated with temozolomide in British Columbia, as compared to previous lomustine use in the same patient population based on updated outcomes data. Results were also compared to temozolomide literature reports. METHODS: A retrospective medical record review was performed to identify patients who received single agent temozolomide or lomustine during successive, prespecified time periods. Data were collected on survival, duration of therapy, drug cost, labour and supplies, and successive or prior chemotherapy. RESULTS: Forty-one patients in the temozolomide group and 25 patients in the lomustine group were analysed. The median OS was 33.3 weeks (95% CI 28.4, 42.1 weeks) and 37.7 weeks (95% CI 25.0, 88.4 weeks) respectively (P = 0.783). Temozolomide patients received a mean of 5.1 cycles of drug treatment, with a mean cost per patient of 10746 dollars (CAD). In contrast, lomustine patients received a mean of 3.3 cycles of therapy, with a mean cost per patient of 129 dollars (CAD). The cost-effectiveness analysis showed that temozolomide was generally not a cost-effective strategy and that lomustine was the dominant strategy. In the sensitivity analysis, in scenarios where median OS was prolonged with temozolomide as compared to lomustine, the incremental cost-effectiveness ratio for each life year gained ranged from 32,247 dollars to 162,186 dollars. CONCLUSION: No difference in survival was observed between patients treated with single agent lomustine and temozolomide. Based on the higher cost and lack of additional clinical benefit of temozolomide, lomustine is a more cost-effective treatment strategy.

Adult↗
PubMed2000

Biochemical correlates of temozolomide sensitivity in pediatric solid tumor xenograft models.

The antitumor activity of the methylating agent temozolomide has been evaluated against a panel of 17 xenografts derived from pediatric solid tumors. Temozolomide was administered p.o. daily for five consecutive days at a dose level of 66 mg/kg. Courses of treatment were repeated every 21 days for three cycles. Tumor lines were classified as having high, intermediate, or low sensitivity, determined by complete responses, partial responses, or stable disease, respectively. Overall, temozolomide induced complete responses in five lines and partial responses in three additional tumor lines, giving objective regressions in 47% of xenograft lines. Analysis of temozolomide plasma systemic exposure indicated that this dose level was relevant to exposure achieved in patients. Tumors were analyzed by immunoblotting for levels of O6-methylguanine-DNA methyltransferase (MGMT) and two mismatch repair proteins, MLH-1 and MSH-2. Tumors classified as having high or intermediate sensitivity had low or undetectable MGMT and expressed detectable MLH-1 and MSH-2 proteins. Tumors classified as having low sensitivity had either (a) high MGMT or (b) low or undetectable MGMT but were deficient in MLH-1. The relationship between p53 and response to temozolomide was also examined. In vitro temozolomide did not induce p21cip1 in p53-competent NB-1643 neuroblastoma cells. Suppression of p53 function in NB1643 clones through stable expression of a trans dominant negative p53 (NB1643p53TDN) did not confer temozolomide resistance. Similarly, tumor sensitivity to temozolomide did not segregate with p53 genotype or p53 functional status. These results indicate that MGMT is the primary mechanism for temozolomide resistance, but in the absence of MGMT, proficient mismatch repair determines sensitivity to this agent.

Adaptor Proteins, Signal Transducing↗
PubMed2003

Phase I. Trial of irinotecan and temozolomide in patients with solid tumors.

This phase I study was conducted to determine the dose-limiting toxicity, maximum tolerated doses, and recommended phase II doses of the combination of irinotecan (CPT-11, Camptosar) and temozolomide (Temodar). Patients have received irinotecan and temozolomide on one of three different dosing schedules: (1) oral temozolomide on days 1-14 plus a single i.v. dose of irinotecan on day 8 every 28 days (arm 1); (2) weekly i.v. irinotecan on days 1, 8, 15, and 22 plus oral temozolomide on days 1-7 and 15-21 every 42 days (arm 2); and (3) every-other-week i.v. irinotecan on days 1 and 15 plus oral temozolomide on days 1-7 and 15-21 every 28 days (arm 3). A total of 49 patients have received 112+ cycles of therapy on all three dosing schedules to date. Dose-limiting toxicity consisting of diarrhea, neutropenia, and thrombocytopenia was encountered at a temozolomide dose of 125 mg/m2/d and an irinotecan dose of 250 mg/m2 on treatment arm 1. As a result, the protocol has been amended to explore lower doses of temozolomide in combination with higher doses of irinotecan, and patient accrual is currently continuing. Dose-limiting grade 3 diarrhea, nausea, and vomiting were reported in 7/12 patients enrolled on the two dose levels explored on treatment arm 2, so this dosing regimen was considered intolerable. Patient accrual currently continues at dose level 1 of treatment arm 3, so it is too early to determine dose-limiting toxicities and recommended phase II doses for this treatment schedule. Two partial responses have been reported to date in patients with glioblastoma and head and neck cancer, respectively. One evaluable response has also been observed in a patient with metastatic colorectal cancer. Irinotecan weekly x 4 plus temozolomide on days 1-7 and 15-21 is intolerable due to the development of dose-limiting gastrointestinal toxicities. The recommended phase II doses of irinotecan and temozolomide on treatment arms 1 and 3 remain to be determined as patient accrual is currently ongoing.

Adult↗
PubMed2005

[Favourable result for temozolomide in recurrent high-grade glioma].

OBJECTIVE: To describe the results of the treatment of recurrent glioma with temozolomide. DESIGN: Retrospective. METHOD: This study evaluated 77 patients with a recurrent high-grade glioma who from August 1997-December 2003 were treated with temozolomide (150-200 mg/m2/day for 5 days per 28-day cycle) following surgery and radiotherapy at the Daniel den Hoed Oncology Centre of the Erasmus MC, Rotterdam, the Netherlands. The patients were divided into 4 groups depending on histology and chemotherapy history. RESULTS: 15 patients received temozolomide for a recurrent anaplastic oligodendroglioma or mixed oligo-astrocytoma. The response in this group was 80% and after 12 months in 47% of the patients there was no disease progression. 35 patients underwent second-line chemotherapy with temozolomide after earlier chemotherapy with procarbazine, lomustine and vincristine for recurrent anaplastic oligodendroglioma or mixed oligo-astrocytoma. Response was 26% and after 12 months in 15% of patients there was still no disease progression. 14 patients were treated with temozolomide for a recurrent anaplastic astrocytoma with a response of 35% and after 12 months in 8% of these patients there was no disease progression. Of the 13 patients with a recurrent glioblastoma who were treated with temozolomide 16% responded and after 6 and 12 months 21% were still free from progression. Temozolomide was well-tolerated: 2 patients had to stop because of probable side effects. CONCLUSION. Temozolomide has an acceptable safety profile and may be regarded as the preferred treatment for recurrent anaplastic gliomas after radiotherapy. There is only a limited role for temozolomide in the treatment of recurrent glioblastoma.

Adult↗
PubMed2000

Four-hourly scheduling of temozolomide improves tumour growth delay but not therapeutic index in A375M melanoma xenografts.

PURPOSE: To establish whether temozolomide is more effective against A375M human melanoma xenografts if given every 4 h rather than every 24 h, in order to exploit depletion of the DNA repair protein O6-alkylguanine-DNA alkyltransferase (ATase) by prior doses of the drug. METHODS: ATase depletion in A375M human melanoma xenografts was determined over 24 h after a single dose of temozolomide. The effect of different drug schedules (all of total dose 500 mg/kg) in delaying the growth of the xenografts was tested, and ATase depletion and DNA methylation damage assessed in tumour and normal tissue. RESULTS: Maximal depletion of ATase in tumour, to 2.52 +/- 0.23% of pretreatment levels, occurred 4-8 h after a single 100 mg/kg i.p. dose of temozolomide, with 23.0% recovery of protein levels at 24 h. Scheduling of temozolomide every 4 h increased tumour growth delay (33.6 +/- 1.39 days with temozolomide 100 mg/kg 4-hourly x versus 23.2 +/- 1.43 days with temozolomide 100 mg/kg once daily x 5; P < 0.0001) at the expense of increased toxicity (17.4 +/- 1.55% animal weight loss versus 10.6 +/- 1.27%. respectively). Temozolomide every 4 h did not increase ATase depletion compared with the 5-day schedule, but resulted in greater DNA 06-guanine methylation (29.0% more in tumour, 20.8% in liver and 56.0% in brain, comparing areas under the methylation-time curve). CONCLUSIONS: The 4-hourly schedule of temozolomide delayed tumour growth significantly more than the once-daily and 12-hourly schedules, probably as a result of greater DNA damage inflicted, but also increased toxicity. It remains to be seen if this regimen confers a net benefit over the standard schedule.

Animals↗
PubMed2005

Phase II study of two-weekly temozolomide in patients with high-grade gliomas.

Palliative chemotherapy has an increasing role in the management of recurrent high-grade gliomas. Temozolomide is a well-tolerated agent that results in objective responses and stabilisation of disease. Theoretically, temozolomide may be more effective when given in a prolonged schedule rather than the standard 5 days-monthly schedule. This Phase II study examined the efficacy and toxicity of temozolomide when given in a two-weekly schedule. Twenty-five patients received 150 mg/m2 temozolomide daily for seven days alternating with seven days of no treatment. One cycle of temozolomide was a total of two weeks treatment in every 28 days. Of the 25 evaluable patients, there was one complete response (4%), four partial responses (16%) and 10 patients had disease stablisation (40%). The progression free survival at 6 months was 56%. Two-weekly temozolomide was well tolerated with only four episodes of Grade 3 thrombocytopenia. Overall, two-weekly temozolomide is an active and well tolerated schedule, but does not appear to improve on the activity of temozolomide using the standard 5-day schedule.

Adult↗