1 Department of Oncology, Metropolitan Hospital, Faliro; 2 Department of Plastic Surgery and Microsurgery, General Hospital of Athens G. Gennimatas, Athens; 3 'Rio' Hospital, University of Patras, Patras; 4 Hellenic Cooperative Oncology Group, Data Office, Athens; 5 University of Ioannina, Ioannina; 6 Alexandra Hospital, Department of Clinical Therapeutics, University of Athens, Athens; 7 First Department of Medicine, University of Athens, Athens; 8 AHEPA Hospital, Aristotle University of Thessaloniki, Thessaloniki; 9 Henry Dunan Hospital, Athens; 10 General University Hospital of Heraklion, Crete, Greece
* Correspondence to: Dr H. Gogas, 1st Department of Internal Medicine, PO Box 14120, 115 10 Athens, Greece. Tel: +30-6944-68-11-59; Fax: +30-210-77-81-517; Email: hgogas{at}hol.gr
Dr D. Bafaloukos. Email: dimmp{at}otenet.gr
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Abstract |
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Patients and methods:: From January 2000 to April 2002, 132 patients were enrolled on the study. Patient and tumor characteristics were well balanced between the two arms. Patients with cerebral metastases were included. Patients received TMZ 200 mg/m2/day orally for five consecutive days every 4 weeks or TMZ + CDDP 200 mg/m2 daily on days 15 and 75 mg/m2 of CDDP on day 1.
Results:: Tumor responses (complete and partial responses) were seen in 16 patients (26%) in arm A and 19 patients (29%) in arm B. The median time to progression (TTP) was 3.8 months in arm A and 5.8 months in arm B. The median overall survival (OS) was 11.5 months in arm A and 12 months in arm B. The difference between treatment arms regarding objective response rates, TTP and OS were not statistically significant. Toxicity was comparable between the two arms for anemia, leukopenia, neutropenia, thrombocytopenia, fatigue, constipation and arthralgias/myalgias. There was significantly more grade 3 and 4 emesis in the combination arm.
Conclusions:: No clear benefit in terms of response rates, median TTP or OS was shown with the combination of TMZ + CDDP. Additionally, the combination was associated with higher incidence of grade 3 and 4 emesis.
Key words: cisplatin, metastatic melanoma, temozolomide
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Introduction |
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Dacarbazine has become the standard chemotherapy for metastatic melanoma, with a response rate of 15% [2
]. Responses are usually partial and last only for a few months. Other agents are administered, including platinum analogues, vinca alkalloids, nitrosoureas and taxanes, but none has a better response rate than dacarbazine [2
, 3
]. Combination chemotherapy results in higher response rates but with increased toxicity and no prolongation of response duration or survival benefit [3
5
].
Temozolomide (TMZ) is an oral imidazotetrazine with activity in advanced melanoma and primary brain tumors. TMZ and dacarbazine share the active intermediary 5-(3-methyltriazen-1-yl)imidazole-4-carboximide (MTIC). However, unlike dacarbazine, which requires metabolic activation, TMZ spontaneously converts to MTIC under physiological conditions [6]. It has high oral bioavailability [7
] and extensive tissue distribution, including penetration through the bloodbrain barrier. This is of particular interest in metastatic melanoma, because brain metastases are a common cause of treatment failure, possibly because of poor central nervous system (CNS) penetration by conventional treatments [8
10
].
A randomized phase III trial showed equivalent overall survival and toxicity with increased progression-free survival and better quality of life with TMZ [11]. In addition, there is evidence to indicate that patients treated successfully with TMZ have a lower incidence of intracranial disease relapse than those responding to dacarbazine. A retrospective study looked at 41 patients with advanced melanoma who had responded to their initial treatment. Of those treated with TMZ, 10% subsequently developed brain metastases compared with 43% of dacarbazine responders [12
].
In addition, TMZ produces methyl adducts at the O6 position of guanine. The methyl adducts are removed by the DNA repair enzyme AGAT. As demonstrated by in vitro studies, cisplatin (CDDP) is able to down-regulate the AGAT activity, so enhancing the antitumor activity of TMZ [13, 14
]. From previous phase I study the recommended doses of TMZ + CDDP were 200 mg/m2 daily on days 15 and 75 mg/m2 of CDDP on day 1, respectively, every 4 weeks [15
].
We designed a randomized phase II study to compare the activity and safety profile of single-agent TMZ with the combination of CDDP and TMZ.
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Patients and methods |
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Patients were excluded from the study if they were pregnant or nursing (pregnancy tests were performed within 24 h before starting the study drugs); if they had uncontrolled vomiting that would interfere with the administration of oral medications; or if they had clinically significant comorbidity that would interfere with the study evaluation. Prior treatment had to have been completed at least 4 weeks before administration of a study drug. Local ethics review committees approved the protocol. All patients gave written informed consent before randomization, according to institutional guidelines.
Treatment
Patients were randomized to receive either TMZ (group A) or the combination of TMZ and CDDP (group B). TMZ was administered orally (p.o.) under fasting conditions once a day for five consecutive days at a starting dose of 200 mg/m2 (total dose per cycle 1000 mg/m2). CDDP was administered at a dose of 75 mg/m2 intravenously diluted in 500 ml of normal saline containing 12.5 g of mannitol on the first day of each cycle 4 h before TMZ. One liter of normal saline with 20 mEq KCI/l, and 1 g of magnesium sulfate was administered both before and after the CDDP infusion. The following antiemetic medications were administered prophylactically on day 1 of each cycle: 8 mg ondansetron p.o. prior to TMZ, and both 32 mg of ondansetron i.v. and 16 mg of dexamethasone i.v. 30 min before CDDP. On day 2 all patients received 8 mg of ondansetron p.o. before TMZ. The prophylactic use of ondansetron before treatment with TMZ on days 35 was optional. Treatment cycles were repeated every 28 days in the absence of disease progression or toxicity. The dose was reduced by 25% of the starting when grade 3 or 4 hematological toxicity [National Cancer Institute Common Toxicity Criteria (NCI CTC)] occurred. A 50% dose reduction was required in cases of grade 3 or 4 non-hematological toxicity (NCI CTC). Patients requiring more than two dose reductions were removed from the study.
Evaluations
A pre-study evaluation was completed within 2 weeks of a patient receiving the study drug. Computed tomography (CT) of the brain was performed in every patient prior to initiation of the treatment. Patients underwent clinical examination, determination of complete blood count and biochemical analysis during every treatment cycle. A formal radiological evaluation of disease, with CT or magnetic resonance imaging of the brain included, was performed every second cycle. Patients were assessable for response if they received two or more cycles of treatment. If there was no disease progression after one cycle, at least two cycles were administered, with continuation for a maximum of six cycles if a response occurred. Responses were assessed using World Health Organization response criteria. Patients were assessable for toxicity if they had received at least one cycle of treatment. The severity of adverse events was assessed using NCI CTC.
Statistical methods
The primary objective of the study was to compare response rates of patients in the intention-to-treat (ITT) population who were assigned to either TMZ or CDDP + TMZ. Secondary objectives were to assess the time to progression (TTP), overall survival (OS) and toxicity for the two treatments. The sample size was chosen to allow a detection of a 25% difference between the two arms with an 80% power to detect this difference at the 5% level of significance.
TTP was calculated from the date of initiation of treatment to the first progression of the disease. However, patients who died due to disease-related factors without having previously documentation of disease progression were considered as an event at the estimation of TTP. Survival time was calculated from the date of initiation of treatment to the date of death or day of last follow-up.
Pearson's 2-test and Fisher's exact test [16
] were applied to compare patients' characteristics, response and toxicity. The KaplanMeier method [17
] was used to calculate TTP, median follow-up and OS curves, while the log-rank test was used to compare time to event distributions. Exact confidence intervals (CI) were used to determine the 95% upper and lower confidence limits of a response rate [18
]. The analysis was made on an ITT basis.
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Results |
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Duration of response for both groups was 8 months (range 1.345+; 95% CI 5.610.3), for the TMZ group 5.7 months (range 1.345+; 95% CI 4.66.9) and for the combination group 9.4 months (range 2.136.3+; 95% CI 6.712.1) (P=0.35; when adjusting for AJCC M classification, P=0.0814). Five patients have so far not progressed (three from the TMZ group and two from the combination group). Out of the five patients that responded to chemotherapy and have not yet progressed, two had only soft tissue metastasis (one from group A and one from group B), one had only lymph nodes metastasis (group B) and two patients had both skin and lymph node metastases (both from group A).
Seven patients in the TMZ-treated group were not evaluable for response, two due to early tumor death, one changed hospital, one discontinued due to toxicity, one withdrew consent, one never started chemotherapy and one for unknown reasons. Five patients in the combination-treated group were not evaluable for response, one due to change of hospital, one due to sudden death due to heart failure, one withdrew consent, one never started chemotherapy and one for unknown reasons.
TTP and OS
With a median follow up of 39.9 months in the TMZ-treated group (range 0.247.1; 95% CI 35.049.9) and a median follow up of 37 months in the combination treated group (range 0.751; 95% CI 34.839.2), in the ITT population the median OS was 11.5 months in patients assigned to TMZ (range 0.247.1+; 95% CI 7.615.4) compared with 12 months (range 0.751+; 95% CI 8.215.7) in patients assigned to the combination (P=0.8980; when adjusting for AJCC M classification, P=0.4696) (Figure 2). Twenty-nine patients in the TMZ-treated group survived >12 months, as did 32 in the combination-treated group (P=0.7). Nine of the 16 TMZ treatment responders survived >12 months, compared with 15 of the 19 combination treatment responders (P=0.15). At the time we ceased collecting clinical data, 25% (four of 16) TMZ-treated patients remained alive, compared with 21% (four of 19) of combination-treated patients (P=1.000). No imbalances were found among the number of patients that survived >12 months between the two groups (survived <12 months, P=0.317; survived 12 months, P=0.081). In addition, no imbalances were found among the number of responders that survived >12 months between the two groups (survived <12 months, P=0.576; survived
12 months, P=0.293), as well as the number of responders that were still alive at the time we ceased collecting data (responders that are still alive, P=1.000; responders that died, P=0.481).
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Treatment characteristics are shown in Table 5Table 5. Both treatments were well tolerated, with most adverse events being mild to moderate in severity. The percentage of patients reporting grade 3 or 4 adverse events was similar. The only exception was the percentage of patients reporting nausea and vomiting, which was higher in the combination treatment group (P=0.002).
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Discussion |
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TMZ is approved in the USA for treatment of refractory anaplastic astrocytoma; it is a prodrug that hydrolyzes to MTIC at physiological pH [19]. Its complete oral bioavailability and its ability to cross the bloodbrain barrier [20
] make it an attractive alternative to dacarbazine, which possesses neither of these properties. TMZ has shown activity against CNS metastases in melanoma and other malignancies [21
]. This could be an advantage in melanoma, as CNS metastases are a frequent cause of death. In phase I and II trials with single-agent TMZ, overall response rates of 17% to 21% were achieved [7
, 22
]. Combining TMZ with other drugs in several phase II/III in melanoma has demonstrated satisfactory activity and tolerability with these regimens [1
, 23
26
].
The rationale for designing a phase II trial to compare single-agent TMZ with the combination of TMZ + CDDP was based on the potential for improved antitumor activity. Both TMZ and CDDP are active against melanoma, and target DNA with disparate mechanisms of cytotoxic action. TMZ produces methyl adducts at the O6 position of guanine via the MTIC intermediate [6, 27
30
], whereas CDDP produces DNA cross-links preferentially at the N7 positions of guanine and adenine [31
]. The methyl adducts produced by TMZ are removed by the DNA repair enzyme AGAT and TMZ activity correlates inversely with AGAT activity [29
32
]. Depletion of AGAT by the alkylthansferase inhibitors O6-methylguanine and O6-benzylguanine [32
36
] potentiates TMZ activity in vitro and in vivo, suggesting that AGAT activity confers resistance to the TMZ.
CDDP may affect AGAT activity. A dose-dependent inactivation of AGAT activity has been demonstrated in HeLa human cervical carcinoma cells exposed to CDDP [13]. The ability of CDDP to down-regulate AGAT is supported by the increased sensitivity of leukemia blasts to TMZ, with concurrent CDDP administration [13
]. Simultaneous treatment of leukemia blasts with TMZ and non-cytotoxic concentrations of CDDP produces significantly greater growth inhibition than treatment with TMZ alone [14
]. This preclinical evidence suggests that CDDP may enhance the antitumor activity of TMZ.
In this randomized phase II study, we failed to confirm superiority with the combination of TMZ and CDDP. No significant differences were seen in terms of response rates, TTP, OS or 1-year survival. This can be attributed to the small sample, size since the study was sufficiently powered for a difference of 25% in overall objective response rate in favor of the combination arm, while a difference of a 3% magnitude was observed. The overall objective response rates of 26% and 29% achieved in this study compare favorably with rates reported for single-agent TMZ (13% to 21%) [6, 10
, 21
] or single-agent CDDP (16%) [37
]. A similar response rate has been demonstrated with dacarbazine plus CDDP [38
, 39
]. As we felt that the response rate was high in the TMZ arm, we retrospectively analyzed our patients according to the new AJCC M classification [40
] and we found that there was a statistical significant difference between the two groups (M1a 43.5%, M1b 19.4%, M1c 37.1%; versus M1a 26.2%, M1b 13.8%, M1c 56.9%) (P=0.039). This might explain our findings, since we did not stratify our patients at randomization according to site of metastases. Moreover, the population in this study has a high proportion of patients with one site of disease and a lower proportion with hepatic involvement. Additionally, in this study, the duration of response achieved with the combination of TMZ + CDDP and the OS in both groups seems to be better than that of either agent alone [7
, 22
, 38
].
As patients with brain metastases were included in our study, antitumor activity in the CNS was seen, including regression of brain metastases.
The demonstration of three partial responses in brain metastases in this study reconfirms the results of previous studies [22, 23
, 41
] and verifies the promising activity of TMZ as single agent or in combination with other active drugs. Responses in brain metastases have rarely been achieved with other chemotherapy agents. As it has already been reported by our group [23
] and others [12
, 42
, 43
], few patients in this study developed CNS involvement, further suggesting that TMZ may prevent the occurrence of metastasis to the brain. In the current study only 16% of the TMZ-treated and 18% of the combination-treated patients developed CNS metastases with a median follow-up of 39.9 and 37 months, respectively.
Both regimens were also found to be safe and well tolerated, and adverse events were mild to moderate in the majority of patients. Myelosuppression, the predominant toxicity associated with TMZ therapy, was reversible an non-cumulative. Nausea and vomiting was experienced by half of the patients in both groups, with significantly more grade 3 and 4 toxicity in the combination group. Three patients discontinued treatment due to toxicity and one sudden death due to cardiac condition was reported, but it is not clear whether it was treatment related. Therefore, TMZ can be safety combined with CDDP the doses used in this study based on the phase I data.
In conclusion, the combination of TMZ and CDDP is safe and effective in the treatment of metastatic melanoma with satisfactory duration of response, but did not prove to be superior to single-agent TMZ in terms of response rate, TTP or OS. The responses achieved in the brain and the small number of patients who developed CNS metastases after the completion of treatment justifies the use of TMZ in patients with brain metastases.
Received for publication November 9, 2004. Revision received January 24, 2005. Accepted for publication January 26, 2005.
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