Dose-dense regimen of temozolomide given every other week in patients with primary central nervous system tumors

K. Vera1, L. Djafari2, S. Faivre1, J.-S. Guillamo1, K. Djazouli2, M. Osorio1, F. Parker3, C. Cioloca4, B. Abdulkarim1, J.-P. Armand1 and E. Raymond1,*

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


    ABSTRACT
 Top
 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
Background:

Temozolomide has shown activity and limited toxicity in patients with primary brain tumors at doses of 150–200 mg/m2/day on days 1–5 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 1–3 and 14–16 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. McDonald’s 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 1–3). 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 3–4 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 3–4 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 2–3 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 I–II


    Introduction
 Top
 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
Temozolomide belongs to a new class of oral imidazotetrazines that enter the cerebrospinal fluid and do not require hepatic metabolism for activation [13]. Temozolomide spontaneously decomposes in aqueous solution to form 5-(3-methyltriazen-1-y1)-imidazole-4-carboxamide, which is a potent methylating agent. Thus, the cytotoxicity of temozolomide appears to be mediated principally through adduction of a methyl group to the O6 position of guanine (O6mG) in genomic DNA [4]. This adduct may be repaired in a single step reaction by O6-alkyl-guanine-DNA transferase (AGT). However, saturation of AGT by an excess of adducts results in residual DNA adducts that are cytotoxic. Cytotoxicity results from the recognition of this adduct by components of the mismatch repair (MMR) system, a multiple protein complex that recognizes O6mG–thymine base pairs, excises thymine and the surrounding bases, resulting in DNA strand breaks [4]. Under normal circumstances, a thymine is preferentially reincorporated opposite the persisting O6mG, further triggering MMR function. A repetitive aberrant repair process increases DNA double strand breaks and ultimately triggers apoptosis. In AGT-deficient and MMR-proficient cells, GT mispairs and futile cycles of MMR result in growth arrest, induction of p53 and apoptosis. In AGT- and MMR-deficient cells, GT mispairs are tolerated, do not lead to futile cycles of MMR or accumulation of p53 and cytotoxicity.

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 G2–M 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 G2–M 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 G2–M 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 1–3 and 14–16, every 28 days.


    Patients and methods
 Top
 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
Inclusion criteria
Patients included in this study met the following criteria: patients with primary central nervous system tumors that exhibited evidence of recurrent or progressive primary disease on contrast enhanced magnetic resonance imaging (MRI) obtained before study initiation; patients with adequate hematological, renal and hepatic functions defined by neutrophils >2 x 109/l, platelets >100 x 109/l, hemoglobin >10 g/dl, total bilirubin <1.25 x the institutional upper normal limit (UNL), alkaline phosphatases 2.5 x UNL, aspartate aminotransferase (ASAT) 2.5 x UNL; prothrombine time >50% and serum creatinine 120 µmol/l; moderate MRC <2 neurological symptoms; and performance status ranging from 0 to 3. A minimum interval of 3 or 6 weeks between prior surgery or radiotherapy, respectively, and the first intake of temozolomide must have elapsed. Exclusion criteria were current uncontrolled infection, other investigational drugs, pregnancy and lactation. Women of child bearing age had to take contraceptive measures. Informed consent was obtained and the protocol was reviewed by an internal review board.

Drug administration
Temozolomide was supplied by Schering-Plough (Levallois-Perret, France) in the form of a 100–250 mg tablet taken orally. Patients were instructed to take the doses 2 h before dinner on days 1–3 and 14–16 every 28 days (one cycle), until unacceptable toxicity or tumor progression occurred. To prevent nausea and vomiting, oral ondansetron 8 mg was given 30–60 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 Institute–common toxicity criteria (NCI–CTC) 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.


    Results
 Top
 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
Patient characteristics
A total of 70 patients with primary central nervous system tumors were enrolled in this study and assigned to one of four groups: groups I, II, III and IV received temozolomide 200, 250, 300 and 350 mg/m2/day, respectively (Table 1). At enrolment, patients (male/female: 48/22) had a median age of 50 years (range 18–78). World Health Organization (WHO) performance status was 0 or 1 in 61 patients. Patients had a variety of pathological diagnosis including 21 glioblastomas, 23 oligodendrogliomas, 11 anaplastic astrocytomas (two spinal), 10 mixed tumors, one ganglioglioma, one pineoblastoma, one malignant meningioma and two brain tumors that were considered as primary gliomas although surgical biopsy was impossible. Forty-six (66%) patients had prior surgery with curative intent, including 14 complete resections and 32 partial resections; 21 patients had only stereotaxic biopsies. Sixty-three patients had prior conformational radiotherapy [median dose, 56.9 Gy (range 45–72)]. Twenty-four patients had prior chemotherapy (including nitrosourea in 19 patients) with a median number of prior chemotherapy treatments of two (range 1–3).


View this table:
[in this window]
[in a new window]
 
Table 1. Patient characteristics
 
Definition of MTD and RD
Seventy patients completed at least one course of therapy and were evaluable for acute toxicity. The absence of DLT at cycle 1 prevented us from defining the MTD using classical phase I criteria. Moreover, occurrence of hematological toxicity after cycle 1 required us to refine the definitions of MTD and RD based on toxicity in the overall population after repeated cycles.

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 II–III 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 1–3 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).



View larger version (34K):
[in this window]
[in a new window]
 
Figure 1. Overall evaluation of delayed toxicity (cycle delay and/or decrease dose due to hematological toxicity) across four groups of patients treated with temozolomide at doses of 200–250 mg/m2 (groups I–II), 300 mg/m2 (group III) and 350 mg/m2 (group IV).

 
Treatment delivery and drug exposure
A total of 370 cycles were administered to 70 patients including 23, 72, 192 and 83 cycles in groups I, II, III and IV, respectively (Table 2). In 54 patients, no dose modification was performed. Fifty per cent of treated patients (five, five, 16 and one patients in groups I, II, III and IV, respectively) completed at least three cycles and the other half (two, five, 16 and four patients, respectively, in each group) more than four cycles at the planned dose. Median dose effectively administered daily, after consideration of delays and dose reductions, was 200, 261, 292 and 210 mg/m2/day in groups I, II, III and IV, respectively.


View this table:
[in this window]
[in a new window]
 
Table 2. Treatment delivery and drug exposure
 
Hematological toxicity
Mild to moderate grade 1–2 hematological toxicity was observed in every group. Hematological toxicity per patient and cycle is summarized across the four dose levels in Table 3. At the recommended dose of 300 mg/m2, grade 3 neutropenia was observed in three patients (7.9%) and in three cycles (1.6%), lasting 1 week. Grade 3 lymphopenia occurred in six patients (15.8%) in 27 cycles (14.1%) and grade 3 thrombocytopenia in five patients (13.1%) in five cycles (2.6%). Grade 3 neutropenia was observed at cycle 1 in a 47 year-old patient with a glioblastoma and a previous history of two cycles of 9-nitrocamptothecin 1 month prior to inclusion in this study.


View this table:
[in this window]
[in a new window]
 
Table 3. Hemato-toxicity of temozolomide per evaluable patient and cycle
 
Two other episodes of neutropenia were observed at cycles three and four in chemotherapy-naïve patients. Grade 3 thrombocytopenia (lasting 1 week) was reported at cycle 1 in a 31 year-old woman with glioblastoma who previously received four cycles of carboplatin/VP-16, 9 months prior to inclusion in this study. The other episodes of grade 3 thrombocytopenia were observed at cycle two in a man 62 years of age with a glioblastoma and concomitant treatment with low-molecular weight heparin. Three other patients 70, 54 and 51 years of age experienced a grade 3 thrombocytopenia at cycles three, one and 10, respectively.

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 dose–effect 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 1–2 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).


View this table:
[in this window]
[in a new window]
 
Table 4. Non hemato-toxicity of temozolomide per evaluable patient and cyclea
 
Efficacy evaluation
All patients were evaluated for response (Table 5). Complete responses were observed in three patients: one anaplastic oligodendroglioma and one oligoastrocytoma in group III; and one oligodendroglioma in group I. Ten partial responses were observed: one, seven and two patients in groups II, III and IV, respectively. Objective responses were observed in six chemotherapy-naïve patients and four patients previously exposed to nitrosoureas.


View this table:
[in this window]
[in a new window]
 
Table 5. Efficacy evaluation
 
Tumor control including responses (complete, partial and minor) plus tumor stabilization was observed in two, nine, 24 and 10 patients in groups I, II, III and IV, respectively (64% overall tumor control).

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).



View larger version (19K):
[in this window]
[in a new window]
 
Figure 2. Progression-free survival (Kaplan–Meier) of patients with glioblastoma, anaplastic astrocytoma, oligodendrogliomas and oligoastrocytoma treated with temozolomide 200–350 mg/m2.

 

    Discussion
 Top
 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
Temozolomide was developed in the 1980s, through rational drug design [2127], by the UK Cancer Research Campaign [21]. The daily times 5 day schedule of temozolomide was developed initially based on a phase I dose escalation at doses ranging from 150 to 240 mg/m2 every 4 weeks. With this schedule, DLTs consisted of mild to moderate neutropenia and thrombocytopenia, and the MTD was 200 mg/m2/day for 5 days [2830]. Prior treatment with chemotherapy was associated with more frequent toxicity that led to a recommended dose of 150 mg/m2/day for patients previously exposed to chemotherapy [11, 17].

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 3–4 neutropenia in 33% of patients and severe grade 3–4 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 3.7–6.7 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.


View this table:
[in this window]
[in a new window]
 
Table 6. Activity of temozolomide using several 5-day schedules
 
Compared with other schedules of temozolomide, the increase in the overall dose intensity obtained with our dose-dense regimen deserves further clinical investigation. High doses of temozolomide, thought to translate into high drug concentrations at the tumor in contact with cancer cells, might impact on the activity of temozolomide, especially for the most resistant tumor types. Very high doses of temozolomide are currently under investigation but will require bone marrow transplantation to rescue patients from drug-induced hematological toxicity. Our schedule attractively compromises between low/standard dose regimens and very high-dose chemotherapy. The simplicity of drug administration was easy to memorize by patients with impaired brain function and was fully given on an outpatient basis. This regimen has become the standard treatment at our institution for patients with malignant gliomas that have relapsed after radiation therapy. Based on the data presented here, we believe that our schedule deserves further comparison with the classical 5-day intermediate dose and protracted daily low dose administration schedule of temozolomide in patients with brain tumors. Furthermore, since the increased dose intensity was associated with manageable toxicity, this regimen could be attractive for further combination phase II studies with drugs known to induce hematological toxicity, such as other alkylating agents (including nitrosourea and cisplatin) and topoisomerase I inhibitors. In addition, considering the synergy between temozolomide and radiation therapy, our schedule can easily be incorporated during the weekend every other week without compromising the radiation program and toxicity, while optimizing the dose intensity of chemotherapy.

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.


    Acknowledgements
 
Karina Vera was a recipient of an ESMO Fellowship Award. We gratefully acknowledge the participation of Patricia Pritzbil and Claudine Mazoyer for their contribution to this study.


    FOOTNOTES
 
* Correspondence to: Dr Eric Raymond, Department of Medicine, Institute Gustave-Roussy; 39 rue Camille Desmoulins, 94815 Villejuif, France. Tel: +33-1-4211-4289; Fax: +33-1-4211-5217; E-mail: raymond{at}igr.fr Back


    REFERENCES
 Top
 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
1. Raymond E, Izbicka E, Soda H et al. Activity of temozolomide against human tumor colony-forming units. Clin Cancer Res 1997; 3: 1769–1774.[Abstract]

2. Stevens M, Hickman J, Langdon S et al. Antitumor activity and pharmacokinetics in mice of 8-carbamoyl-3-methylimidazo[5,1-D]-1,2,3,5-tetrazin-4(3H)-one (CCRG 81045: M&B39831), a novel drug with potential as an alternative to dacarbazine. Cancer Res 1987; 47: 5846–5852.[Abstract]

3. Friedman H, Kerby T, Calvert H. Temozolomide and treatment of malignant glioma. Clin Cancer Res 2000; 6: 2585–2597.[Abstract/Free Full Text]

4. Bocangel DB, Finkelstein S, Schold SC et al. Multifaceted resistance of gliomas to temozolomide. Clin Cancer Res 2002; 8: 2725–2734.[Abstract/Free Full Text]

5. Liu L, Taverna P, Whitacre CM et al. Pharmacologic disruption of base excision repair sensitises mismatch repair-deficient and -proficient colon cancer cells to methylating agents. Clin Cancer Res 1999; 5: 2908–2917.[Abstract/Free Full Text]

6. Hirose Y, Berger MS, Pieper RO. Abrogation of Chk1-mediated G2 checkpoint pathway potentiates temozolomide-induced toxicity in a p53 independent manner in human glioblastoma cells. Cancer Res 2001; 61: 5843–5849.[Abstract/Free Full Text]

7. Newlands ES, Blackledge GR, Slack JA et al. Phase I trial of temozolomide (CCRG 81045: M&B 39831: NSC 362856). Br J Cancer 1992; 65: 287–291.[ISI][Medline]

8. Bleehen NM, Newlands ES, Lee SM et al. Cancer Research Campaign phase II trial of temozolomide in metastatic melanoma. J Clin Oncol 1995; 13: 910–913.[Abstract]

9. O’Reilly SM, Newlands ES, Glaser MG et al. Temozolomide: a new oral cytotoxic chemotherapeutic agent with promising activity against primary brain tumours [published erratum appears in Eur J Cancer 1993; 29A: 1500]. Eur J Cancer 1993; 29A: 940–942.[ISI][Medline]

10. Hammond LA, Eckardt JR, Baker SD et al. Phase I and pharmacokinetic study of temozolomide on a daily-for-5-days schedule in patients with advanced solid malignancies. J Clin Oncol 1999; 17: 2604–2613.[Abstract/Free Full Text]

11. Dhodapkar M, Rubin J, Reid JM et al. Phase I trial of temozolomide (NSC 362856) in patients with advanced cancer. Clin Cancer Res 1997; 3: 1093–1100.[Abstract]

12. Tolcher AW, Gerson SL, Denis L et al. Marked inactivation of O6-alkylguanine-DNA alkyltransferase activity with protracted temozolomide schedules. Br J Cancer 2003; 88: 1004–1011.[CrossRef][ISI][Medline]

13. Brock CS, Newlands ES, Wedge SR et al. Phase I trial of temozolomide using an extended continuous oral schedule. Cancer Res 1998; 58: 4363–4367.[Abstract]

14. Denis L, Tolcher A, Figueroa J et al. Protracted daily administration of temozolomide is feasible: a phase I and pharmacokinetic–pharmacodynamic study. Proc Am Soc Clin Oncol 2000; 222a (Abstr 786).

15. Figueroa J, Tolcher A, Denis L et al. Protracted cyclic administration of temozolomide is feasible; a phase I, pharmacokinetic and pharmacodynamic study. Proc Am Soc Clin Oncol 2000; 222a (Abstr 868).

16. Brock CS, Matthews JC, Brown G et al. Response to temozolomide in recurrent high grade gliomas is related to tumour drug concentration. Ann Oncol 1998; 9: 667.[Abstract]

17. Hammond LA, Eckardt JR, Baker SD et al. Phase I and pharmacokinetic study of temozolomide on a daily-for-5-days schedule in patients with advanced solid malignancies. J Clin Oncol 1999; 17: 2604–2613.[Abstract/Free Full Text]

18. Brada M, Judson I, Beale P et al. Phase I dose-escalation and pharmacokinetic study of temozolomide (SCH 52365) for refractory or relapsing malignancies. Br J Cancer 1999; 81: 1022–1030.[CrossRef][ISI][Medline]

19. Patel M, McCully C, Godwin K, Balis FM. Plasma and cerebrospinal fluid pharmacokinetics of intravenous temozolomide in non-human primates. J Neurooncol 2003; 61: 203–207.[CrossRef][ISI][Medline]

20. MacDonald DR, Cascino TL, Schold SC et al. Response criteria for phase II studies of supratentorial malignant glioma. J Clin Oncol 1990; 8: 1277–1280.[Abstract]

21. Newlands ES, Stevens MF, Wedge SR et al. Temozolomide: a review of its discovery, chemical properties, pre-clinical development and clinical trials. Cancer Treat Rev 1997; 23: 35–61.[ISI][Medline]

22. Loo T. Triazenoimidazole derivatives. In Sartorelli and Johns (eds): Antineoplastic and Immunosuppressive Agents. Berlin, Germany: Springer Verlag 1975; 553–554.

23. Denny BJ, Wheelhouse RT, Stevens MFG et al. NMR and molecular modeling investigation of the mechanism of activation of the antitumor drug temozolomide and its interaction with DNA. Biochemistry 1994; 33: 9045–9051.[ISI][Medline]

24. Belanich M, Randall T, Pastor MA et al. Intracellular localization and intercellular heterogeneity of the human DNA repair protein O6-methylguanine-DNA methyltransferase. Cancer Chemother Pharmacol 1996; 37: 547–555.[CrossRef][ISI][Medline]

25. Friedman H, McLendon R, Kerby T et al. DNA mismatch repair and O6-aklylguanine-DNA alkyltransferase analysis and response to temodal in newly diagnosed malignant glioma. J Clin Oncol 1998; 16: 3851–3857.[Abstract]

26. Esteller M, Garcia-Foncillas J, Andion E et al. Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents. N Engl J Med 2000; 343: 1350–1354.[Abstract/Free Full Text]

27. Wedge R, Porteous JK, May BL, Newlands ES. Potentiation of temozolomide and BCNU cytotoxicity by O6-benzylguanine: a comparative study in vitro. Br J Cancer 1996; 73: 482–490.[ISI][Medline]

28. Newlands ES, Blackledge GRP, Slack JA et al. Phase I trial of temozolomide (CCRG 81045: M&B 39831: NSC 362856). Br J Cancer 1992; 65: 287–291.[ISI][Medline]

29. Bleehen NM, Newlands ES, Lee SM et al. Cancer Research Campaign phase II trial of temozolomide in metastatic melanoma. J Clin Oncol 1995; 13: 910–913.[Abstract]

30. O’Reilly SM, Newlands ES, Glaser MG et al. Temozolomide: a new oral cytotoxic chemotherapeutic agent with promising activity against primary brain tumours [published erratum appears in Eur J Cancer 1993; 29A: 1500]. Eur J Cancer 1993; 29A: 940–942.[ISI][Medline]

31. Bower M, Newlands ES, Bleehen NM et al. Multicentre CRC phase II trial of temozolomide in recurrent or progressive high-grade glioma. Cancer Chemother Pharmacol 1997; 40: 484–488.[CrossRef][ISI][Medline]

32. Levin V, Yung A, Prados M et al. Phase II study of temodal (temozolomide) at first relapse in anaplastic astrocytoma (AA) patients. Proc Am Soc Clin Oncol 1997; 16: (Abstr 1370).

33. Brandes AA, Ermani M, Pasetto L et al. Temozolomide in high grade gliomas at second relapse: a phase II study. Proc Am Soc Clin Oncol 2000; 19: (Abstr 646).

34. Chinot OL, Honore S, Barrie MF et al. Safety and efficacy of Temozolomide in patients with recurrent anaplastic oligodendrogliomas after standard radiotherapy and chemotherapy. J Clin Oncol 2001; 19: 2449–2455.[Abstract/Free Full Text]

35. Newlands ES, O’Reilly SM, Glaser MG et al. The Charing Cross Hospital experience with temozolomide in patients with gliomas. Eur J Cancer 1996; 32A: 2236–2241.[CrossRef][ISI][Medline]

36. Yung WK, Prados MD, Yaya-Tur R et al. Multicenter phase II trial of temozolomide in patients with anaplastic astrocytoma or anaplastic oligoastrocytoma at first relapse. Temodal Brain Tumor Group [published erratum appears in J Clin Oncol 1999; 17: 3693]. J Clin Oncol 1999; 17: 2762–2771.[Abstract/Free Full Text]

37. Friedman HS, McLendon RE, Kerby T et al. DNA mismatch repair and O6-alkylguanine-DNA alkyltransferase analysis and response to temodal in newly diagnosed malignant glioma. J Clin Oncol 1998; 16: 3851–3857.[Abstract]

38. Brada M, Hoang-Xuan K, Rampling R. Multicentre phase II trial of temozolomide in patients with GBM at first relapse. Ann Oncol 2001; 12: 259–266.[Abstract]

39. Yung WK, Albright RE, Olson J et al. A phase II study of temozolomide vs procarbazine in patients with glioblastoma multiforme at first relapse. Br J Cancer 2000; 83: 588–593.[CrossRef][ISI][Medline]

40. Gilbert M, Olson J, Yung W et al. Preradiation treatment of newly diagnosed anaplastic astrocytomas and glioblastoma multiforme using temozolomide. Neurooncol 2000; 2: 264 (Abstr 77).

41. Van den Bent MJ, Chinot O, Boogerd W et al. Second-line chemotherapy with temozolomide in recurrent oligodendroglioma after PCV (procarbazine, lomustine and vincristine) chemotherapy: EORTC Brain Tumor Group phase II study 26972. Ann Oncol 2003; 14: 599–602.[Abstract/Free Full Text]