Safety Of Temozolomide Research Articles

Radiotherapy and concomitant temozolomide during the first and last weeks in high grade gliomas: long-term analysis of a phase II study

We tested the efficacy and safety of temozolomide (TMZ) when given concomitantly to radiotherapy only in the first and last weeks of treatment to patients affected by high grade gliomas. Conformal radiotherapy (CTV1: tumor bed + residual tumor if present + 1.5 cm, 5,940 cGy, 180 cGy/day; CTV2: oedema, 3,960 cGy, 180 cGy/day) was associated with TMZ, 75 mg/m(2) x 5 days, the first and last weeks of radiotherapy. Adjuvant chemotherapy with TMZ (150 mg/mq daily x 5 days, q28 on the first cycle, 200 mg/mq daily x 5 days, q28 for the following cycles) was given, after chemoradiation, until disease progression or up to 6 cycles. From October 2000 to December 2003, 29 patients (25 GBL, 86.2%; 4 AA, 13.8%) were enrolled in this study. Twenty-two patients (75.8%) received a median 6 cycles of adjuvant chemotherapy with TMZ (range 1-20). Hematological toxicity was absent during concomitant chemoradiation and mild in adjuvant therapy, while neurological toxicity (seizures) was observed only in one case. At a median follow-up of 66 months (range 3-96), median progression-free survival (PFS) was 8 months, with a 1- and 2-year PFS of 46.7 and 28.7%, respectively; median overall survival (OS) time was 21 months, with a 1- and 2-year OS of 69.2 and 42.3%, respectively. In our experience, TMZ proved to be effective even when given only during the first and the last week of radiotherapy, with lower hematological toxicity.

Evaluation of the exposure equivalence of oral versus intravenous temozolomide

PurposeOral temozolomide is approved in many countries for malignant glioma and for melanoma in some countries outside the USA. This study evaluated the exposure equivalence and safety of temozolomide by intravenous infusion and oral administration.MethodsSubjects with primary central nervous system malignancies (excluding central nervous system lymphoma) received 200 mg/m2 of oral temozolomide on days 1, 2 and 5. On days 3 and 4, subjects received 150 mg/m2 temozolomide either as a 90-min intravenous infusion on one day or by oral administration on an alternate day.ResultsRatio of log-transformed means (intravenous:oral) of area under the concentration–time curve and maximum concentration of drug after dosing for temozolomide and 5-(3-methyltriazen-1-yl)imidazole-4-carboxamide (MTIC) met exposure equivalence criteria (90% confidence interval = 0.8–1.25). Treatment-emergent adverse events were consistent with those reported previously in subjects with recurrent glioma treated with oral temozolomide, except for mostly mild and transient injection site reactions with intravenous administration.ConclusionsThis study demonstrated an exposure equivalence of a 90-min intravenous infusion of temozolomide and an equivalent oral dose.

Phase II trial of temozolomide (TMZ) plus irinotecan (CPT-11) in adults with newly diagnosed glioblastoma multiforme before radiotherapy

This phase II trial evaluated efficacy and safety of temozolomide (TMZ) in combination with irinotecan (CPT-11) before radiotherapy in patients with newly diagnosed glioblastoma multiforme (GBM). Prior to radiotherapy, patients were treated with a maximum of three 6-week cycles of TMZ and CPT-11. Patients received TMZ at a dose of 200 mg/m(2)/day on days 1-5 and CPT-11 on days 1, 8, 22, and 29, with a dose adjustment for enzyme-inducing antiepileptic drug use. The primary end point was objective response rate (ORR). Secondary end points included progression-free survival (PFS), overall survival (OS), safety, and tumor O(6)-methylguanine-DNA methyltransferase (MGMT) expression. Of the 42 patients treated, 8 (19%) patients achieved a partial response. Median PFS and median OS were 3.1 and 13.8 months, respectively. Grade 3 or 4 AEs were documented in 36% of patients, most of which were hematologic (29%). Twenty-four percent of patients had grade 3 or 4 non-hematologic AEs, with gastrointestinal AEs being the most common (12%) Two patients died, one of intracranial hemorrhage and one of treatment-related renal failure. Low MGMT expression, compared with high MGMT expression, showed no significant difference in ORR (25 vs. 8%), median PFS (14 vs. 5 months) or OS (21 vs. 15 months). Although TMZ plus CPT-11 is at least comparable in efficacy to TMZ alone, this combination appears more toxic and poorly tolerated. The lack of correlation of activity with MGMT expression is intriguing, but needs further evaluation in subsequent trials.

Temozolomide: A Safe and Effective Treatment for Malignant Digestive Endocrine Tumors

Background: Systemic chemotherapies are associated with limited response rates and significant toxicity in patients with malignant digestive endocrine tumors (DET). Preliminary studies have reported interesting results with temozolomide in patients with DET. Aim: It was the aim of this study to assess the efficacy and safety of temozolomide in patients with malignant DET. Patients and Methods: Twenty-one patients, median age 61 years (range 56–77), with metastatic well-differentiated DET were retrospectively studied. All patients except 1 had received prior treatment (hepatic resection, chemotherapy). All patients had progressive disease in the 3 months prior to entry into the study. Temozolomide was administered at doses of 200 mg/m² daily for 5 days, every 28 days. Treatment was assessed for safety, progression-free and overall survival. Results: The median number of temozolomide cycles was 5 (range 2–15). Grade 3 hematological toxicity occurred in 5 patients. There were no toxic deaths. According to the Response Evaluation Criteria in Solid Tumors criteria, partial response and stabilization were obtained in 1 (5%) and 17 patients (81%), respectively. The median time to progression was 9 months (range 3–26). The 1-year progression-free survival and overall survival were 42 and 77%, respectively. Conclusion: Temozolomide is a well-tolerated oral chemotherapy in patients with malignant DET, including those who have already received treatment. In patients with progressive disease, temozolomide controls tumor progression in 86% of cases.

The safety of temozolomide in the treatment of malignancies

Background: Temozolomide (TMZ) has demonstrated clinical antitumor activity. In the US and the EU, TMZ is licensed for the treatment of glioblastoma multiforme concurrently with radiation followed by a maintenance treatment, and for refractory anaplastic astrocytoma or glioblastoma multiforme. TMZ is also approved for metastatic melanoma in > 20 countries worldwide. Objectives: To ascertain the safety profile of TMZ. Methods: Synthesis of evidence from published clinical trials and the investigator's brochure of the manufacture. Conclusion: For a cytotoxic cancer-treatment agent, TMZ has an acceptable safety profile. Lymphopenia is common in patients treated with all doses and schedules of TMZ. All patients receiving TMZ should be observed for lymphopenia and potential opportunistic infections, particularly when it is combined with other immune suppressive therapies.

Continuous Administration of Daily Low-Dose Temozolomide in Pretreated Patients with Advanced Non-Small Cell Lung Cancer: A Phase II Study

Purpose: Temozolomide, a novel triazene derivative, has shown activity in vitro against lung cancer as well as against brain metastases from a variety of solid tumors including non-small cell lung cancer (NSCLC). The aim of the study was to evaluate the efficacy and safety of temozolomide in pretreated patients with NSCLC. Patients and Methods: Thirty-one pretreated patients (median age 60 years) with histologically confirmed NSCLC were enrolled. Sixteen (52%) patients had a performance status (ECOG) of 0–1, 12 (39%) had pretreated brain metastases and 28 (90.3%) had received >2 lines of treatment. Temozolomide was administered at a dose of 75 mg/m² daily for 21 days every 28 days. A total of 73 chemotherapy cycles were administered. Results: In an intention-to-treat analysis, 2 patients (6.5%; 95% CI: –2.2 to 15.1%) achieved a partial response and 3 (10%) stable disease. The median time to progression was 2.4 months, the median survival time 3.3 months and the 1-year survival rate 22.5%. There was a toxic death due to grade 4 neutropenia. Grade 3 and 4 lymphopenia occurred in 4 (13%) and 2 (6%) patients, respectively. Nonhematological toxicity was mild, consisting of grade 2–3 asthenia (n = 14 patients) and grade 3 diarrhea (n = 1 patient). Conclusion: Prolonged low daily doses of temozolomide demonstrate minimal activity as salvage therapy in patients with advanced NSCLC. The combination of low daily doses of temozolomide with other anticancer drugs probably merits further evaluation.

Efficacy and safety of long-term administration of temozolomide monotherapy in patients with anaplastic astrocytoma at first relapse

13017 Background: Efficacy and safety of temozolomide (TMZ) were examined in a multicenter phase II study in 32 patients with anaplastic astrocytoma at first relapse. Methods: 32 pts were enrolled. After completing 6 cycles of TMZ (Step 1), the pts experiencing “no change” or better effect were allowed to continue to receive treatment in Step 2. TMZ was administered for 5 consecutive days in a 28-day cycle. The dose for the first cycle was 150 mg/m2/day. From the second cycle, the dose was 100, 150, or 200 mg/m2/day based on a dose adjustment criteria. Results: The response rate up through Cycle 6 was 34%, including 3 pts with “complete response” (CR), and the response rate at the end of the study was 44%, with the number of CR pts increased to 6. All of the additional 3 CR pts achieved CR in Step 2 from “partial response”. Pts were also observed who had transient “progressive disease” in Step 1 who had a reduction in tumor in Step 2. Fourteen pts discontinued treatment during Step 1. The reason for discontinuation was the onset of an adverse event in 2 pts, disease exacerbation in 11, and change in hospital in 1. Eighteen pts progressed to Step 2, and 1 pt received 7 cycles, 8 received 4, 1 received 9, 2 received 11, 1 each received 12, 13, 14, 16, and 23, 3 received 24, and 1 each received 27 and 35 cycles. The reason for discontinuation in Step 2 was disease exacerbation in 9, market availability of TMZ in 3, duration of treatment exceeding 2 years in 3, and for other reasons such as partner’s pregnancy in 3. No pt discontinued due to an adverse event. Adverse events judged to be CTC Grade 4 were observed in 9% (3 pts), all of which were observed in Step 1. One pt had pancytopenia, respiratory failure, septicemia, and renal failure, the second pt had intracranial hemorrhage, and the third pt had blood glucose and calcium decrease. The pt who developed decreased blood glucose and calcium discontinued treatment due to PD response and not to these adverse events. Conclusions: There are pts with anaplastic astrocytoma at first relapse for whom long-term treatment with TMZ beyond 6 cycles (with the duration of treatment at times exceeding one year) is clinically meaningful. No accumulation-type adverse events were observed, and the long-term administration of TMZ was considered possible. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Schering-Plough K.K.

Pharmacokinetic study of temozolomide on a daily-for-5-days schedule in Japanese patients with relapsed malignant gliomas: first study in Asians

Temozolomide (TMZ) is widely used in Europe and the United States. For the safe use of TMZ in the Japanese, as representative of Asians, the pharmacokinetics of TMZ was investigated in Japanese patients and compared to that in Caucasians. The pharmacokinetics and safety of TMZ following oral administration of 150 and 200 mg/m2 per day for the first 5 days of a 28-day treatment cycle were investigated in six Japanese patients with relapsed gliomas. The time-to-maximum plasma concentration (tmax) of TMZ was about 1 h and the elimination half-life of terminal excretion phase (t 1/2lambda z) was about 2 h. A dose-dependent increase was observed in maximum plasma concentration (Cmax) and AUC, while values for t 1/2lambda z, apparent total body clearance (CL/F), and apparent distribution volume (Vz/F) were independent of dose. After administration for 5 days, changes in pharmacokinetics and accumulation were not observed. The plasma 5-(3-methyl)1-triazen-1-yl-imidazole-4-carboxamide (MTIC) concentration changed in parallel with the TMZ plasma concentration, and the Cmax and AUC of MTIC were about 2% of those of TMZ. The pharmacokinetic parameters of TMZ and MTIC in Japanese patients in this study were comparable to those previously determined in Caucasian subjects. Adverse events occurred in all patients, but toxicities were mostly mild or moderate, and continuation of administration was possible by adjusting the dose and by delaying the start of the next treatment cycle. The pharmacokinetic and safety profile of TMZ in Japanese patients was comparable to that in Caucasians. The treatment regimen used in Europe and the United States will be suitable for Asian patients, including Japanese.

Phase II study of temozolomide plus pegylated interferon‐α‐2b for metastatic melanoma

Temozolomide and interferon-alpha-2b (IFN-alpha-2b) are both active in melanoma. Therefore, the efficacy and safety of temozolomide in combination with pegylated IFN-alpha-2b in patients with metastatic melanoma without brain metastases was investigated. Patients with histologically confirmed, unresectable, American Joint Committee on Cancer Stage IV melanoma were enrolled in an open-label, Phase II study. The primary endpoints were tumor response and safety. Patients received temozolomide (75 mg/m2/dayx6 weeks with a 2-week break between cycles) plus concomitant subcutaneous pegylated IFN-alpha-2b (0.5 microg/kg/wk, continuously). Treatment was continued until unacceptable toxicity or disease progression occurred. Thirty-five patients (median age, 55 years) with Stage IV melanoma and a median of 3 metastatic sites were enrolled and received a median of 1 cycle (i.e., 8 weeks) of therapy (range, 0-6 cycles). Eleven patients (31%) (95% confidence interval, 16% to 47%) had an objective tumor response, including 3 with clinical complete response durations of 6 months, 20 months, and 32+ months and 8 with partial responses. Three patients with a partial or mixed response were subsequently rendered free of clinically detectable disease with surgery. The median survival was 12 months with a median follow-up among survivors of 16 months. No patient developed brain metastases while receiving study treatment. Treatment was generally well tolerated. Hematologic toxicity consisted mainly of lymphopenia and leukopenia (National Cancer Institute Common Toxicity Criteria Grades 1-3); no Grade 4 hematologic toxicity was observed. The combination of temozolomide plus pegylated IFN-alpha-2b had antitumor activity and was well tolerated in patients with metastatic melanoma. Therefore, further study is warranted.

Surgery, radiotherapy and temozolomide in treating high-grade gliomas

Temozolomide (TMZ) a recent, oral, second generation alkylating agent is a chemotherapeutic with demonstrated efficacy for the treatment of high-grade gliomas. The efficacy of TMZ has been demonstrated in both pre-clinical and phase I and II studies. The goal of this study is to determine the activity and safety of temozolomide in improving overall survival (OS), progression-free survival (PFS) and health-related quality of life (HQL) in patient with malignant gliomas treated by surgery, radiotherapy and temozolomide. Twelve patients with newly diagnosed glioblastoma (GBM), and anaplastic astrocytoma (AA) were studied. The mean follow-up period was 12 months. The overall response rate for all histological groups was 33% (4 patients), 6 patients (50%) showed a stabilization of disease. The median progression-free survival (PFS) and overall survival (OS) was respectively 8.35 and 14.1 months; time to progression was 36 week ranging from 20 to 46 In all patients, treatment with temozolomide was associated with improvement of performance status including the patient showing disease progression; Karnofski score improved in all patients by a minimum of 10, with a median of 20 at 6 months. No patient stopped the treatment due to side-effects, no major adverse events were recorded. In two cases of glioblastoma, we observed complete response and after three years, the quality of life is optimal. Surgery allows to establish a histopathological diagnosis, to improve signs and symptoms which are attributable to intracranial hypertension or tumour topography, and to reduce the number of target cells for adjunctive therapies. Radiotherapy improves survival and TMZ chemotherapy that is given after radiotherapy adds survival benefit for patients. Because of its favourable pharmacokinetic and pharmacodynamic properties and improved tolerability. Temozolomide appears to be an ideal, first-line, single-agent, with a safe profile and demonstrated HQL benefits in patients with high-grade gliomas.

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

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

Temozolomide for the Treatment of Recurrent Supratentorial Glioma: Results of a Compassionate use Program in Belgium

Temozolomide (TMZ) has demonstrated activity and acceptable toxicity for the treatment of recurrent high-grade gliomas in prospective phase II studies. Limited information is available on TMZ when prescribed outside a clinical trial. We conducted a retrospective study to evaluate the activity and safety of TMZ that was prescribed for the treatment of recurrent glioma in the context of a compassionate use program in Belgium. Data were obtained on 117 adult patients (from five hospitals) who received TMZ as first or second line chemotherapy. The recommended starting dose of TMZ was 200 mg/m2 x5d q28d for chemonaive patients and 150 mg/m2 x5d q28d for pre-treated patients. Toxicity was generally mild. Thrombocytopenia was the most frequent treatment related adverse event (grade 3/4 in 17% of patients). Its occurrence was correlated with a starting dose of 200 mg/m2/d and stresses the need to monitor toxicity. The overall objective response rate (complete and partial response) was 29 and 34% of patients achieved an objective disease stabilization. The median progression-free survival was 104 days (95% CI: 85-123) and the median overall survival was 215 days (95% CI: 161 269). In multivariate analysis a 'deep localization' of the glioma (as opposed to a cortico-subcortical localization) and 'the preceding history of a low-grade glioma' were respectively identified as a negative and positive independent prognostic variable for survival. No significant difference in terms of response or median survival was observed between patients with anaplastic astrocytoma or oligo-astrocytoma and chemonaive glioblastoma multiforme. This retrospective study indicates that the reported activity and toxicity profile of TMZ for the treatment of patients with recurrent glioma is reproducible outside the setting of a prospective clinical trial.

Temozolomide for the treatment of recurrent glioma: Results of a compassionate use program in Belgium

1541 Background: Temozolomide (TMZ) is an oral alkylating agent that has demonstrated objective activity and an acceptable toxicity profile for the treatment of recurrent high-grade gliomas in phase II trials. Only limited information is available on the activity and toxicity of TMZ when prescribed outside a clinical trial. Methods: We conducted a retrospective study to evaluate the activity and safety of TMZ that was prescribed for the treatment of recurrent glioma in the context of a compassionate use program in Belgium. Data were obtained on 117 adult patients (from 5 hospitals) who received TMZ as first or second line chemotherapy. The recommended starting dose of TMZ was 200 mg/m2 x5d q28d for chemonaïve patients and 150 mg/m2 x5d q28d for pretreated patients. Results: Toxicity was generally mild although grade 3/4 toxicity was observed in 22 % of patients. Thrombocytopenia was the most frequent encountered toxicity (grade 3/4 in 17% of patients) and its occurrence was correlated with a starting dose of 200 mg/m2/d. The overall RR (CR + PR) was 29% and 34 % of patients achieved a SD. The median PFS was 104 days (95% CI 85–123) and the median OS was 215 days (95% CI 161–269). In multivariate analysis a “deep localization” of the glioma (as opposed to a cortico-subcortical localization) and the preceding history of a low-grade glioma were identified as independent prognostic variables with regard to TTP & OS. Administration of TMZ as first line chemotherapy was an independent prognostic variable for TTP only. Absence of disease progression at the end of TMZ cycle 3 was significantly correlated with a superior overall survival (landmark analysis, P<0.0001). Conclusions: This retrospective study indicates that the reported activity and toxicity profile of TMZ for the treatment of patients with recurrent glioma is reproducible outside the setting of a prospective clinical trial. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Schering-Plough (Benelux)

Temozolomide for the treatment of recurrent glioma: Results of a compassionate use program in Belgium

1541 Background: Temozolomide (TMZ) is an oral alkylating agent that has demonstrated objective activity and an acceptable toxicity profile for the treatment of recurrent high-grade gliomas in phase II trials. Only limited information is available on the activity and toxicity of TMZ when prescribed outside a clinical trial. Methods: We conducted a retrospective study to evaluate the activity and safety of TMZ that was prescribed for the treatment of recurrent glioma in the context of a compassionate use program in Belgium. Data were obtained on 117 adult patients (from 5 hospitals) who received TMZ as first or second line chemotherapy. The recommended starting dose of TMZ was 200 mg/m2 x5d q28d for chemonaïve patients and 150 mg/m2 x5d q28d for pretreated patients. Results: Toxicity was generally mild although grade 3/4 toxicity was observed in 22 % of patients. Thrombocytopenia was the most frequent encountered toxicity (grade 3/4 in 17% of patients) and its occurrence was correlated with a starting dose of 200 mg/m2/d. The overall RR (CR + PR) was 29% and 34 % of patients achieved a SD. The median PFS was 104 days (95% CI 85–123) and the median OS was 215 days (95% CI 161–269). In multivariate analysis a “deep localization” of the glioma (as opposed to a cortico-subcortical localization) and the preceding history of a low-grade glioma were identified as independent prognostic variables with regard to TTP & OS. Administration of TMZ as first line chemotherapy was an independent prognostic variable for TTP only. Absence of disease progression at the end of TMZ cycle 3 was significantly correlated with a superior overall survival (landmark analysis, P<0.0001). Conclusions: This retrospective study indicates that the reported activity and toxicity profile of TMZ for the treatment of patients with recurrent glioma is reproducible outside the setting of a prospective clinical trial. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Schering-Plough (Benelux)

Future directions for temozolomide therapy

Although the initial indications of temozolomide (Temodar in the United States, Temodal globally; Schering Corporation, Kenilworth, NJ) therapy are for refractory central nervous system malignancies (anaplastic astrocytoma in the United States and Europe, glioblastoma multiforme in Europe), a number of clinical trials are planned or ongoing to evaluate the efficacy and safety of temozolomide in newly diagnosed glioma, oligodendroglioma, pediatric glioma, brain metastases, metastatic melanoma, and other systemic tumors. Also under investigation are modifications to the temozolomide dosing schedule, other routes of administration, and treatment regimens that include temozolomide in combination with other chemotherapeutic and biologic agents. Temozolomide has the potential to be a useful agent in the treatment of a variety of cancers.

Phase II study of temozolomide in heavily pretreated cancer patients with brain metastases

To determine the efficacy, tolerability, and safety of temozolomide in heavily pretreated patients with solid tumors and brain metastases. 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. 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. Temozolomide demonstrated encouraging activity in the treatment of brain metastases in heavily pretreated patients with solid tumors, and was safe and well tolerated.