1 Department of Medicine, Institute Gustave-Roussy, Villejuif; 2 Schering Plough, Levallois-Perret; 3 Department of Neurological Surgery, Hôpital Kremlin Bicetre; 4 Department of Neurological Surgery, Hôpital Saint-Anne, Paris, France
Received 22 May 2003; revised 28 July 2003; accepted 12 August 2003
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ABSTRACT |
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Temozolomide has shown activity and limited toxicity in patients with primary brain tumors at doses of 150200 mg/m2/day on days 15 every 4 weeks. In this study, a new alternative dose-dense regimen of temozolomide was explored in patients with recurrent brain tumors.
Patients and methods:
In this study, we evaluated the safety, dose-limiting toxicity, maximum tolerated dose, recommended dose and activity of temozolomide given on days 13 and 1416 every 28 days (one cycle). The starting daily dose was 200 mg/m2 in a group of at least six patients, with subsequent increments of 50 mg/m2 in groups of at least 12 patients until unacceptable toxicity was reached. Oral ondansetron (8 mg) was given 1 h prior to temozolomide administration. McDonalds criteria were used to evaluate antitumor activity.
Results:
Seventy patients with brain tumors entered this study. The median number of prior chemotherapy treatments was two (range 13). Patients were assigned to one of four groups to receive temozolomide at daily doses of 200 (seven patients), 250 (13 patients), 300 (38 patients) and 350 mg/m2/day (12 patients). The absence of dose-limiting toxicity at cycle 1 led us to establish dose recommendations based on toxicity after repeated cycles. A total of 23, 72, 192 and 83 cycles were given at daily doses of 200, 250, 300 and 350 mg/m2, respectively. Grade 34 thrombocytopenia was observed in 0/7, 1/13, 5/38 and 4/12 patients treated at doses of 200, 250, 300 and 350 mg/m2/day, respectively. Grade 34 neutropenia was observed in 1/7, 0/13, 3/38 and 4/12 patients treated with 200, 250, 300 and 350 mg/m2/day temozolomide, respectively. At a dose of 350 mg/m2, sustained grade 23 thrombocytopenia did not allow treatment to be resumed at day 14 in >40% of patients, and this dose was considered to be the maximum tolerated dose. Thus, a dose of 300 mg/m2/day that was associated with <20% treatment delay due to sustained hematological toxicity was considered as the recommended dose. Objective responses were reported in 13 patients.
Conclusions:
Temozolomide can be given safely using a dose-dense regimen of 300 mg/m2/day for 3 consecutive days every 2 weeks in patients with recurrent brain tumors.
Key words: astrocytoma, glioblastoma, high-dose chemotherapy, oligodendroglioma, phases III
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Introduction |
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Although O6mG adducts have been extensively studied, they represent only a small part of the adducts generated by temozolomide. Temozolomide also forms other DNA adducts (N7mG and N3mA) that are removed by the base excision repair (BER) mechanism and might partially contribute to cytotoxicity [5]. Under normal circumstances, temozolomide produces strand breaks during BER-mediated repair of N7mG and N3mA adducts that are repaired efficiently and might contribute to cytotoxicity only when a high concentration of adducts are achieved. Short- and long-patch BER further requires a number of enzymes including poly-ADP ribose polymerase (PARP) and XRCC1, to sensor the DNA strand breaks, DNA polymerase ß (a low fidelity DNA polymerase) to fill the gap, and DNA ligase to seal the nick. Failure to accurately repair such DNA strand breaks either by dysfunction of BER or lack of proper recognition by PARP, XRCC1 and DNA polymerase ß would contribute towards the initiation of both apoptotic and non-apoptotic cell death cascades. This repair mechanism might be important in MMR-deficient cells, which are resistant to temozolomide because of its failure to recognize O6mG DNA adducts.
Temozolomide also induces transient arrest of proliferation with the accumulation of cells in the G2M phase of the cell cycle, a process dependent on p53 status [6]. In gliomas, p53 wild-type cells underwent prolonged cell cycle arrest associated with elevation of p53 levels, and although the cells are non-proliferative, they remain viable. Conversely, p53-deficient cells underwent a more transient cell cycle arrest and within 12 days lost viability by mitotic catastrophe and/or apoptosis. Preclinical models have demonstrated a schedule-dependent antitumor activity against high-grade glioma suggesting increased activity with repeated exposure to temozolomide [1,2].
In clinical studies, temozolomide showed good oral bioavailability with mild non-cumulative myelosuppression [3]. The schedule of daily treatment for 5 days was developed and temozolomide was given orally at the starting daily dose of 150 mg/m2, which was then escalated to 240 mg/m2 every 4 weeks. With this schedule, the dose-limiting toxicity (DLT) of temozolomide consisted of mild to moderate neutropenia and thrombocytopenia and maximum tolerated dose (MTD) was 200 mg/m2/day for 5 days [79]. Prior treatment with chemotherapy was shown to have a significant impact on the tolerability of temozolomide. A study by Hammond et al. [10] showed that the MTD of temozolomide was 150 mg/m2/day for patients previously exposed to chemotherapy. A similar phase I study, reported by the National Cancer Institute, evaluated the safety of temozolomide in patients who were stratified on the basis of prior exposure to nitrosourea [11]. As a result, temozolomide was registered in several countries on a daily times 5 schedule every 4 weeks at doses of 200 mg/m2 in chemotherapy-naïve patients and 150 mg/m2 in patients previously exposed to chemotherapy.
Laboratory data showed that temozolomide cytotoxicity was more pronounced using protracted exposures. Furthermore, in vitro and pharmacodynamic studies showed a marked decrease of AGT activity in cells exposed to temozolomide [12]. As AGT inactivation is thought to decrease the repair capacity and increase the sensitivity of cancer cells to temozolomide, protracted schedules aimed at taking advantage of this potential autoenhancement were explored in patients with malignant gliomas. Several schedules consisting of protracted daily administration of temozolomide have been explored in phase I/II clinical trials with the aim of optimizing dose-intensity and activity [1318]. From these studies, it was concluded that an extended low-dose schedule of temozolomide was well tolerated, especially in heavily pre-treated patients, but was associated with limited improvements in rate of response and survival.
Although AGT plays a role in the repair of several alkylating agents, including nitrosourea, other DNA repair mechanisms may also participate in the sensitivity to temozolomide. For instance, AGT expression levels appear to be low in gliomas and are further depressed by exposure to temozolomide; MMR deficiency is thought to be low among glial tumors, and only about 40% of gliomas lack functional p53 [46]. Therefore, at typical concentrations of temozolomide, GT mispair will most likely result in G2M arrest, and given enough time, those lesions could be reversed or bypassed, leaving viable cells that may re-enter the cell cycle. In that sense, the bypass of G2M and a lack of p53 might appear desirable to force cells to undergo fatal replication. Based on the current knowledge of temozolomide-induced cytotoxicity, standard concentrations of the drug leading to a number of DNA lesions that can easily be recognized or repaired by the DNA quality control machinery would only lead to cytostatic effects, except for in a small proportion of tumors that lack one or several components of the above mentioned system. In addition, although the penetration of temozolomide in cerebrospinal fluid was shown to be better than that of several other anticancer agents, the concentration of the drug in the brain remains limited [19]. To overcome this issue, we speculated that higher doses (i.e. increasing the drug concentration into the tumor) and more frequent temozolomide administration would result in a higher number of DNA adducts that could saturate the capacity of the tumor cell to properly repair DNA strand breaks. Based on preclinical studies, temozolomide appears to exert its antiproliferative effects in a concentration- and time-dependent fashion. Thus, we have attempted to combine, in an unique setting, high-dose temozolomide, prolonged duration of exposure (>48 h) and high frequency of drug administration to optimize the chance of inducing non-reparable DNA lesions that would finally result in glioma cell death.
Given that drug concentration at the tumor site, duration of exposure and frequency of drug administration could all have an impact on the activity of temozolomide in brain tumors, we attempted to define a schedule and dose regimen that would optimize these three parameters. In this study, we explored the feasibility of a dose-dense regimen of temozolomide that would increase the daily dose of temozolomide and the dose intensity by reducing the duration of exposure from 5 to 3 days and increasing the frequency of drug administration in an every other week schedule. We first defined the safety, MTD, DLT, recommended dose (RD) and activity of this dose-dense regimen of temozolomide given orally at escalated doses on days 13 and 1416, every 28 days.
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Patients and methods |
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Drug administration
Temozolomide was supplied by Schering-Plough (Levallois-Perret, France) in the form of a 100250 mg tablet taken orally. Patients were instructed to take the doses 2 h before dinner on days 13 and 1416 every 28 days (one cycle), until unacceptable toxicity or tumor progression occurred. To prevent nausea and vomiting, oral ondansetron 8 mg was given 3060 min before each temozolomide intake. Most of the patients were taking anticonvulsants upon enrolment onto this study. They continued those medications as prescribed at study entry during the course of the trial. Chronic oral administration of corticosteroids was used as needed to minimize tumor symptoms.
Dose escalation procedure
The starting daily dose of temozolomide was 200 mg/m2. This dose was initially given to a group of at least six patients, with subsequent dose increments of 50 mg/m2. Subsequent groups (doses >200 mg/m2/day) included at least 12 patients who were treated until unacceptable toxicity. In anticipation that at least half of the patients would stop treatment due to early tumor progression before receiving three cycles, the inclusion of 12 patients per group was expected to leave a sufficient number of patients receiving three cycles for an accurate appraisal of delayed toxicity. All patients at a given dose level were observed for toxicity for at least 4 weeks before additional patients could be entered at a higher dose level.
DLTs were defined as hematological toxicity grade 4, non-hematological toxicity grade 3, and treatment delay for >1 week attributable to the study drug. At doses >200 mg/m2, in the absence of DLT, doses were escalated according to the following scheme: if no DLT was observed in 12 patients at any given dose level (any cycle), the dose was escalated to the next dose level in a new cohort of 12 patients. If DLT was observed in >4/12 patients entered at a specific dose level (any cycle), then the dose escalation was stopped and this dose was considered to be the MTD. RD was defined as the dose level immediately inferior to the MTD. Twenty-five additional patients were treated at this RD for complementary assessment of toxicity and for preliminary evaluation of anti-tumor activity.
Dose adjustments of temozolomide were based on the worst toxicity observed during the previous cycle. Dose reduction to the immediately lower dose level was requested in case of DLT. In case of sustained hematological toxicity at the time of subsequent drug administration, treatment was delayed until the neutrophil and platelet counts reached >1000/µl and >100 000/µl, respectively.
Baseline and follow-up examinations
A comprehensive neurological examination was performed at each study visit. Clinical evaluation was based on changes in signs and symptoms from the previous examination. Complete blood cell with differential and platelet counts, serum biochemistry and hepatic parameters were assessed weekly.
Response determination was based on comparison of the baseline brain contrast-enhanced MRI performed every three cycles (18 intakes) of temozolomide along with any clinical changes in physical findings upon neurological examination.
Treatment was discontinued in case of tumor progression, unacceptable toxicity or patient refusal. Patients were followed-up clinically and using contrast-enhanced MRI at least every 3 months after the completion of the study until death.
Toxicity was graded according to National Cancer Institutecommon toxicity criteria (NCICTC) for every group and cycle. Antitumor activity was assessed according to the criteria of MacDonald [20]. Briefly, a complete response was defined as a complete disappearance of all contrast-enhancing tumors from baseline on consecutive scans at least 4 weeks apart, combined with discontinuation of corticosteroids and neurological stability or improvement. A partial response was defined as >50% reduction from baseline in the size (measured as the product of the largest perpendicular diameters) of contrast-enhancing tumor maintained for 4 weeks, corticosteroid treatment at a stable or reduced level, and neurological stability or improvement. Tumor control was defined as the sum of complete, partial and minor responses and tumor stabilizations.
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Results |
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Seven (instead of the six planned) patients were entered in group I without any evidence of toxicity. At least 12 patients were then subsequently entered in groups II and III. A total of three patients had cycle delays in groups IIIII because of sustained mild to moderate gastrointestinal toxicity or thrombocytopenia. Subsequently, 12 patients were entered in group IV. In group IV, 7/12 patients had cycle delays due to sustained hematological toxicity. In addition, two patients entered in group IV experienced severe grade 4 hematological toxicity. Thus, a dose of 350 mg/m2 was considered as the MTD and the dose escalation was stopped. As a consequence, the 300 mg/m2 dose (dose level III) which appeared to be better tolerated, was expanded by including 25 additional patients (up to 38 patients) to better define its safety and determine any evidence of activity. At this dose level, a total of 7/38 patients required treatment delays for sustained grade 13 thrombocytopenia and neutropenia. This rate of toxicity was considered acceptable and a dose of 300 mg/m2 was selected as the RD for this schedule. Longer follow-up at this dose level in a total of six patients who received up to six cycles demonstrated no cumulative toxicity (Figure 1).
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No difference in the levels of hematological toxicity were observed in patients pretreated with nitrosoureas compared to those who were not.
Non-hematological toxicity
Non-hematological toxicity was restricted to grades 1 and 2 with no clear doseeffect relationship. These toxicities were evaluated per patient and per cycle across the four dose levels and are summarized in Table 4. At an RD of 300 mg/m2, asthenia was the most frequently reported non-hematological toxicity in nine patients (23.7%) and 18 cycles (9.4%). Grades 12 nausea was observed in eight patients (21%) in 15 cycles (7.8%). Other toxicities reported were mild to moderate constipation, vomiting, diarrhea and fever with infection (no fungal or opportunistic infections were observed).
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Median progression-free survival (PFS) was 6.2 months for anaplastic oligodendroglioma, 5.9 months for glioblastoma and 9.2 months for anaplastic astrocytoma (Figure 2).
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Discussion |
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Subsequently, Brock et al. [13] have tried to increase the dose intensity and optimize the schedule dependent activity of temozolomide using a protracted oral administration over a 6- to 7-week period with dosages ranging from 50 to 100 mg/m2/day. This phase I study evaluated 24 patients with recurrent tumors, including 17 malignant gliomas. This schedule allowed the administration of higher cumulative doses of temozolomide than that of the 5-day schedule without increasing the hematological toxicity. No severe toxicity was observed at the recommended dose of 75 mg/m2/day with evidence of antitumor activity. This demonstrated that protracted administration of temozolomide could be well tolerated with sustained activity.
In our study, we aimed to optimize the dose intensity of temozolomide by both increasing the daily dose and increasing the frequency of drug administration. Therefore, temozolomide was administered at doses ranging from 150 to 350 mg/m2/day for 3 days every other week. In our study, as well as in other previously published trials, temozolomide was well tolerated [31, 32]. A dose level of 300 mg/m2 proved to be well tolerated after repeated cycles with grade 3 neutropenia and thrombocytopenia observed in only 8% and 13% of patients, respectively. At this dose level, the actual dose intensity received by the patient was of 292 mg/m2/day. At the RD of 300 mg/m2/day, the dose intensity was about 1.8 times higher than that of the 5-day schedule and was not associated with higher toxicity [31, 3338]. Non-hematological toxicity consisted of nausea and vomiting which were easily managed with oral ondansetron prophylaxis. The low rate of acute hematological toxicity allowed us to increase the dose up to 350 mg/m2. However, at this dose level, we observed evidence of severe toxicity occurring beyond cycle one, including grade 34 neutropenia in 33% of patients and severe grade 34 thrombocytopenia in 42% of patients. Since 58% of this group had cycle delays with or without dose reduction due to sustained mild to minor thrombocytopenia, the dose of 350 mg/m2 was not further explored and was considered far too toxic to be recommended in phase II studies. Therefore, a daily dose of 300 mg/m2 was considered to be the recommended dose for temozolomide using our schedule.
Different studies assessed standard doses of temozolomide in terms of efficacy in pretreated patients (Table 6). In these studies, overall response rates ranged from 5% to 52% for glioblastoma, with a 6-month progression free survival (PFS) rate ranging from 18% to 21% and a median PFS between 2.1 and 2.8 months [3740]. For malignant oligodendroglioma, oligoastrocytoma and anaplastic astrocytoma, overall response rates ranging from 22% to 44% were reported, with 6-month PFS rates ranging from 29% to 50% and median PFS of 3.76.7 months [34, 36, 41]. In our study, although the activity was not the primary end point, similar results have been reported with an overall response rate of 14% and median PFS of 5.9 months in patients with glioblastoma. Complete and partial responses were observed in 26% of patients with oligodendroglioma with a median PFS of 6.2 months.
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In summary, this alternative dose-dense schedule demonstrated simplicity of administration, good tolerability, low and manageable toxicity at the recommended dose of 300 mg/m2/day for 3 consecutive days every 2 weeks and activity in a broad range of primary brain tumors. The increase in dose intensity was about 1.8 times that of the daily times 5 schedule. Temozolomide confirmed its potential for the treatment of brain tumors using this schedule and remains an attractive drug for further combination chemotherapy.
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Acknowledgements |
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FOOTNOTES |
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