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© 2000 American Society for Clinical Oncology Randomized Phase III Study of Temozolomide Versus Dacarbazine in the Treatment of Patients With Advanced Metastatic Malignant MelanomaFrom the Christie Hospital, Manchester, and Royal Marsden Hospital, London, United Kingdom; Hôpital Sainte Marguerite, Marseilles, and Clinique Dermatologique, Nantes, France; Netherlands Cancer Institute, Amsterdam, the Netherlands; Eberhard-Karls Universität, Tübingen, Universitäts-Hautklinik and Poliklinik der Universität des Saarlandes, Homburg/Saar, Virchow-Klinikum der Humboldt-Universität, Berlin, and Dermatologische Klinik und Poliklinik der Medizinischen Hochschule, Hannover, Germany; Norwegian Radium Hospital, Montebello, Norway; Oncology Unit, Ludwig Institute, Austin and Repatriation Medical Centre, Heidelberg, and Royal Prince Alfred Hospital, Camperdown, Australia; and Schering-Plough Research Institute, Kenilworth, NJ. Address reprint requests to M.R. Middleton, MD, Department of Medical Oncology, Christie Hospital NHS Trust, Wilmslow Rd, Manchester M20 4BX, United Kingdom; email mmiddleton@ picr.man.ac.uk.
PURPOSE: : To compare, in 305 patients with advanced metastatic melanoma, temozolomide and dacarbazine (DTIC) in terms of overall survival, progression-free survival (PFS), objective response, and safety, and to assess health-related quality of life (QOL) and pharmacokinetics of both drugs and their metabolite, 5-(3-methyltriazen-1-yl)imidazole-4-carboximide (MTIC). PATIENTS AND METHODS: Patients were randomized to receive either oral temozolomide at a starting dosage of 200 mg/m2/d for 5 days every 28 days or intravenous (IV) DTIC at a starting dosage of 250 mg/m2/d for 5 days every 21 days. RESULTS: In the intent-to-treat population, median survival time was 7.7 months for patients treated with temozolomide and 6.4 months for those treated with DTIC (hazards ratio, 1.18; 95% confidence interval [CI], 0.92 to 1.52). Median PFS time was significantly longer in the temozolomide-treated group (1.9 months) than in the DTIC-treated group (1.5 months) (P = .012; hazards ratio, 1.37; 95% CI, 1.07 to 1.75). No major difference in drug safety was observed. Temozolomide was well tolerated and produced a noncumulative, transient myelosuppression late in the 28-day cycle. The most common nonhematologic toxicities were mild to moderate nausea and vomiting, which were easily managed. Temozolomide therapy improved health-related QOL; more patients showed improvement or maintenance of physical functioning at week 12. Systemic exposure (area under the curve) to the parent drug and the active metabolite, MTIC, was higher after treatment with oral temozolomide than after IV administration of DTIC. CONCLUSION: Temozolomide demonstrates efficacy equal to that of DTIC and is an oral alternative for patients with advanced metastatic melanoma.
THE INCIDENCE OF melanoma has increased approximately three-fold during the last 40 years, although this rate of increase has begun to slow.1 Despite recent important developments in adjuvant treatment for stage III tumors, little has changed in the management of advanced metastatic disease. A number of chemotherapeutic agents have activity in patients with metastatic melanoma, including dacarbazine (DTIC), the nitrosoureas, platinum analogs, vinca alkaloids, and the taxanes. Of these, DTIC has been the standard chemotherapeutic agent for melanoma.2 In clinical studies, the response rate observed with single-agent DTIC chemotherapy ranges from 15% to 25%. Complete responses are rare (5% of cases) and short in duration (3 to 6 months). No multiagent chemotherapy, such as the Dartmouth regimen, has yet proved superior to single-agent DTIC chemotherapy in phase III clinical studies.2-4 The combination of chemotherapy with biologic response modifiers has increased the response rate, but this has not resulted in improved survival, although a number of promising regimens are now being tested in phase III studies.5 The number of agents that are active in patients with metastatic disease is limited; currently, cure is not a realistic objective for treatment at this stage.6,7 Median survival time for patients with stage IV disease is approximately 6 months, and the estimated 5-year survival rate is only 6%. Novel treatments for this disease are urgently needed. Because chemotherapy remains palliative, any improvement in tolerability of treatment or ease of treatment delivery is welcome. Temozolomide is a novel oral alkylating agent with a broad spectrum of antitumor activity and relatively little toxicity. Both temozolomide and DTIC are prodrugs of the active alkylating agent 5-(3-methyltriazen-1-yl)imidazole-4-carboximide (MTIC). Unlike DTIC, which requires metabolic activation, temozolomide spontaneously converts to MTIC under physiologic conditions.8 Cytotoxicity of temozolomide seems to be mediated principally through methylation of DNA at the O6 position of guanine,9-11 although other mechanisms have been proposed.12 Temozolomide has demonstrated 100% oral bioavailability13 and extensive tissue distribution, including penetration of the blood-brain barrier and the CSF.14-16 In clinical studies, temozolomide was well tolerated and demonstrated rapidly reversible, mild to moderate myelosuppression. Notable activity was observed against recurrent glioblastoma multiforme, recurrent anaplastic astrocytoma, advanced malignant melanoma, and other refractory cancers.13,17-19 In a phase II study of temozolomide therapy in advanced metastatic melanoma conducted by the Cancer Research Campaign, the objective response rate was 21% (12 of 56 patients) and median survival time was 5.5 months.20 The study population included many patients with adverse prognostic indicators, such as disease progression while receiving prior therapy or CNS metastases. This study suggested that temozolomide was likely to have efficacy at least equivalent to that of DTIC. The primary objective of the current study was to compare overall survival of patients with advanced melanoma treated with either temozolomide or DTIC and to confirm the safety and tolerability of temozolomide. Secondary objectives included comparisons of progression-free survival (PFS), health-related quality of life (QOL), and response rates with either treatment.
Patients Patients at least 18 years of age with histologically confirmed, surgically incurable or unresectable, advanced metastatic melanoma were eligible for the study. Either a diagnosis of metastatic malignant melanoma had to have been made within 3 months of initiation of treatment with one of the study drugs or patients had to have symptomatic metastatic malignant melanoma or documented evidence of disease progression. Patients were required to have measurable disease. Also required were adequate performance status (World Health Organization status 0, 1, or 2) and renal (creatinine level < 1.5 times the upper limit of normal [ULN]), hepatic (total bilirubin level < 1.5 times ULN, AST level < three times ULN, alkaline phosphatase level  three times ULN), and bone-marrow (absolute neutrophil count  1,500/mm3, platelet count 100,000/mm3, hemoglobin level 10 x g/dL) functions. Patients who had received previous treatment for metastatic disease other than local radiation therapy were not enrolled. Patients with relapsing disease requiring systemic chemotherapy after isolated limb perfusion (but not with DTIC) were eligible. A single regimen of adjuvant biologic therapy was also acceptable. Prior treatment had to have been completed at least 4 weeks before administration of a study drug. Excluded from the study were pregnant or nursing patients; patients with nonmeasurable disease, ocular melanoma, or CNS metastases (observed on a magnetic resonance image); those who had not recovered from previous treatment or who had previous or concurrent malignancies at other sites; patients with disorders that would interfere with oral intake of the study drug; and patients with infections requiring systemic antibiotic therapy or with other indications of poor medical risk. Local ethical review committees approved the study.
Treatment
Evaluations
Health-Related QOL
Pharmacokinetics
Statistical Methods
Patients Between July 16, 1995, and February 25, 1997, 305 patients were enrolled at 34 centers worldwide. Of those, 156 patients were randomized to receive temozolomide and 149 to receive DTIC. Ten patients assigned to temozolomide therapy and eight to DTIC treatment proved ineligible. Of these patients, five had CNS metastases, four had no evidence of metastatic disease, four had previously undergone therapy for metastatic disease, two had concurrent malignancies, one had a second presentation of metastatic melanoma, one had an inadequate performance status, and one patient had insufficient diagnostic data. The remaining 287 patients (146 in the temozolomide treatment group and 141 in the DTIC treatment group) made up the eligible patient population, defined as those patients with untreated, advanced metastatic melanoma and no CNS involvement. Of these patients, 280 (144 in the temozolomide-treated group and 136 in the DTIC-treated group) received one dose of a study drug and made up the treated eligible population. Of the seven patients who did not receive a study drug, the condition of four deteriorated unexpectedly after randomization and three withdrew their consent. Patient demographics were similar for each treatment group (Table 1). There were no significant differences in age, sex, performance status, or disease site at baseline between the treatment groups. The median time from initial diagnosis to development of metastatic disease was 22.4 months for the temozolomide treatment group and 20.8 months for the DTIC treatment group (P = .67).
Survival In the ITT population, median overall survival time among patients assigned temozolomide was 1.3 months longer than among those assigned DTIC (7.7 months versus 6.4 months), with a hazards ratio of 1.18 (95% confidence interval, 0.92 to 1.52) (Fig 1). Although the difference between the treatment groups was not significant (P = .20), the 95% confidence interval for the hazards ratio indicates that in terms of overall survival, the efficacy of temozolomide was, statistically, at least equivalent to that of DTIC. The trend favoring temozolomide was also observed in subpopulation analysis. Median survival time was 2 months longer for temozolomide-treated patients than for DTIC-treated patients in the treated eligible population (7.9 v 5.7 months; P = .054). The maximum survival difference (hazards ratio, > 1.3) was observed between 3 and 6 months, and there was a trend in favor of a better 6-month overall survival rate with temozolomide (61% v 51%; P = .063).
Median PFS time was significantly improved with temozolomide therapy (1.9 v 1.5 months; hazards ratio, 1.37; P = .012) (Fig 2). The difference in PFS favoring temozolomide was observed at as early as 4 weeks, with a maximum difference observed at 6 weeks. At this time, 34% of the patients receiving temozolomide and 48% of those receiving DTIC had disease progression. However, DTIC-treated patients underwent the first formal assessment for disease progression 2 weeks earlier than did temozolomide-treated patients, which may have contributed to the difference observed in PFS.
A Cox regression analysis was performed to identify possible prognostic factors for overall survival and PFS. Significantly longer (P .05) overall survival and PFS were associated with two variables: site of metastatic disease (P < .01) and baseline performance status (P < .01). The magnitude of the effect associated with treatment remained virtually unchanged for both efficacy measures for age, sex, time from initial diagnosis to development of metastatic disease, and time from development of metastatic disease to randomization. This demonstrates that the treatment effect in the primary analysis of overall survival and PFS was not influenced by other prognostic factors. Subgroup analysis based on prognostic and demographic criteria supports the trend favoring temozolomide, as indicated by a hazards ratio of more than 1 in most subgroups (Table 2).
Response to Treatment The response rates to the two drugs were similar (Table 3). Assessment of objective response in the ITT population showed that a complete response was achieved by 3% of both the temozolomide-treated (four of 156) and the DTIC-treated (four of 149) groups. Of the patients who were assigned temozolomide, 13.5% (21 of 156) showed an objective response to treatment, compared with 12.1% (18 of 149) of those assigned DTIC. Rates of disease stabilization were also similar between the two groups.
Among the responding patients (complete responders and partial responders), median overall survival time was 20 months in the DTIC treatment group but had not been reached at the conclusion of the study for the temozolomide treatment group. Duration of response was longer in the temozolomide treatment group; 18 of the 21 temozolomide-treatment responders survived longer than 12 months, compared with only 11 of the 18 DTIC-treatment responders. At the time we ceased collecting clinical data, 62% (13 of 21) of temozolomide-treated patients remained alive, compared with 39% (seven of 18) of DTIC-treated patients.
Safety Both treatments were well tolerated, with most adverse events being mild to moderate in severity. For all cycles, the percentage of patients reporting any treatment-emergent adverse event, regardless of severity, was similar (92% in the temozolomide treatment arm and 87% in the DTIC treatment arm). The percentage of patients reporting grade 3 or 4 adverse events was also similar (38% in the temozolomide-treated group and 36% in the DTIC-treated group). The only exception was the percentage of patients reporting pain, which was higher in the DTIC treatment group (13% v 7%) (Table 4).
The most frequent adverse events observed with temozolomide therapy were nausea (52%), vomiting (34%), pain (34%), and constipation (30%) (Table 4). In the DTIC-treated patients, pain (39%), nausea (38%), constipation (29%), and vomiting (24%) were most common. Nausea and vomiting were easily controlled with standard antiemetics. Treatment-emergent hematologic toxicity (ie, events leading to study drug discontinuation, hospitalization, or transfusion) was also similar for each treatment group and included thrombocytopenia, leukopenia or neutropenia, and anemia. Thrombocytopenia occurred in 9% of both treatment groups. Leukopenia occurred in 2% of temozolomide-treated patients and 1% of DTIC-treated patients, whereas anemia occurred in 8% of temozolomide-treated patients and 11% of DTIC-treated patients (Table 5).
The percentage of cycles resulting in grade 3 or 4 thrombocytopenia (NCI-CTC) was 11% in the temozolomide treatment group and 7% in the DTIC treatment group, and the percentage of cycles resulting in grade 3 or 4 neutropenia (NCI-CTC) was 11% in the temozolomide treatment group and 13% in the DTIC treatment group. Myelosuppression was not cumulative and occurred in the first three cycles of treatment, with nadir platelet and neutrophil counts occurring late in the 28-day cycle. Recovery from the nadir occurred rapidly, usually within 9 days. Subgroup analysis revealed that sex and age had no clinical effect on the incidence of patients reporting at least one adverse event or grade 3 or 4 adverse events. There were few nonhematologic grade 3 or 4 adverse events. The percentage of patients who discontinued the study because of adverse events was small in each group (3% of the temozolomide-treated group and 5% of the DTIC-treated group). There were 24 deaths during treatment, of which 18 were due to disease progression. Three patients taking temozolomide died from adverse events: one from a cerebral hemorrhage while thrombocytopenic, another from cerebral hemorrhage in the absence of thrombocytopenia, and the third from coma, in which a relationship to the drug could not be excluded. In the DTIC treatment group, one patient died from intestinal perforation with peritonitis, a second died from bowel ischemia, and a third died at home from unknown causes. None of these deaths were attributed to the chemotherapy.
Health-Related QOL
Pharmacokinetics Pharmacokinetic evaluation of each parent drug and the metabolite, MTIC, was performed in 17 patients in each treatment group. Temozolomide was rapidly absorbed and eliminated after oral administration, and DTIC was rapidly absorbed after IV administration. Similarly, the formation of MTIC from either temozolomide or DTIC was rapid; maximum plasma MTIC concentrations were noted at approximately the same time for both drugs. Although DTIC was given at a higher dose, the mean systemic exposure to MTIC was twice as high for oral temozolomide–treated patients as for IV DTIC–treated patients (Fig 3 and Table 7).
Chemotherapy for advanced melanoma remains largely palliative, and survival times after diagnosis are short. Numerous trials of single agents and combinations of chemotherapy have been performed, but DTIC remains the standard regimen. Our study confirms findings of phase II trials that temozolomide is at least as effective against melanoma as DTIC. The response rates seen with both drugs are at the lower end of the range previously reported, but this reflects the scrutiny of response in this trial. All potential responses (complete or partial) were reviewed centrally, resulting in the downgrading of some conditions to stable disease. In addition, all treated eligible patients were evaluated for response; in some studies in which higher rates were found, fewer than 70% of patients randomized were evaluated, compared with 92% of patients in our study.26 The overall survival and PFS noted are in keeping with previously published results for both drugs.3,20,27 Median survival time for patients receiving temozolomide for advanced metastatic melanoma was 1.3 months longer than for those receiving DTIC. This study, though large by melanoma trial standards, was designed to detect a 50% increase in survival longer than the 6 months expected with DTIC therapy. Such a large difference in outcome may be unexpected or unlikely, given that both drugs exert their cytotoxic effect via the same intermediary, MTIC. Nevertheless, the exposure to MTIC differed according to the parent drug administered. Although DTIC was administered IV at a higher dose than that of temozolomide, the mean systemic exposure to MTIC was twice as high for temozolomide-treated patients as for the DTIC treatment group. This might explain any difference in outcome between the treatments, if the trend toward improved survival seen with temozolomide therapy is supported by further experience and based on exposure to MTIC. Retrospective analysis of various DTIC regimens suggests that prolonged administration may be slightly more effective than shorter schedules, and it is possible that this relates to increased exposure to MTIC.2 However, there are no data to help elucidate whether mean systemic MTIC exposure is important in determining response to these chemotherapies. A statistically significant difference was observed in PFS, but the difference in the time to the first formal disease assessment between arms may have contributed to this discrepancy. However, when analysis was performed by subgroups based on demographics and disease-related criteria, overall survival and PFS were consistently better among patients treated with temozolomide than among those treated with DTIC. This trend was also observed in the treated eligible subpopulation. In addition, patients with metastatic malignant melanoma who achieved either a complete or partial response with temozolomide therapy survived longer. No major differences were seen in the adverse events experienced by each treatment group, although more grade 1 or 2 nausea and vomiting occurred in the temozolomide-treated group. Similar levels of nausea and vomiting were seen in phase II trials of this drug, but, as in this study, the symptoms were usually mild and readily controlled.19,27 No patient discontinued treatment because of these side effects. The difference in frequencies of nausea and vomiting between the two arms was apparent after only one cycle of treatment and is likely explained by the less frequent use of prophylactic serotonin (5-HT3) antagonists in patients receiving temozolomide (69% v 79% in DTIC-treated patients). In later cycles of treatment, when 5-HT3 antagonist use was similar with both chemotherapies, the incidences of nausea and vomiting were also similar. At the 12-week assessment point, patients who received temozolomide reported average improvements in physical functioning, fatigue, and insomnia. More temozolomide-treated patients (86%) than DTIC-treated patients (68%) had maintained or improved physical function scale scores. Additionally, patients who achieved a clinical response in the temozolomide treatment group showed greater improvements in health-related QOL scale scores for physical functioning and insomnia than did responders in the DTIC treatment group. Temozolomide, which is 100% orally bioavailable,13 allows for outpatient treatment. This is particularly desirable for patients with advanced melanoma, a group with a short life expectancy and a low rate of response to treatment. The oral formulation of temozolomide also makes prolonged schedules a possibility, as has recently been reported.28 Six- and 7-week regimens have been shown to be feasible, and further studies are planned involving this agent in conjunction with radiation therapy in patients with glioma. Temozolomide is schedule dependent, and the 5-day regimen used in this study is standard. However, given our knowledge of the mechanisms of resistance to temozolomide, the opportunity of improving the drug’s efficacy exists. The DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) is the principal mediator of resistance to O6-alkylating agents such as temozolomide.29 MGMT levels decrease after dosing with temozolomide as consequent DNA damage is repaired. By compressing the schedule, it may be possible to give subsequent doses of the drug when levels of MGMT are low, thereby prolonging exposure to the drug and MTIC to improve cytotoxicity and response rate. A 12-hour regimen has been tested, though not in melanoma patients, and clinical trials involving 4- and 8-hour schedules are under way.30 Patients with CNS metastases were specifically excluded from this study, but there is evidence that temozolomide penetrates the CNS.15,16 The Cancer Research Campaign phase II study involving melanoma patients included four patients with intracerebral metastases, one of whom had a partial response to treatment.20 This finding may point to an additional advantage of temozolomide over DTIC, and the treatment of CNS melanoma with temozolomide was the focus of a recently completed phase II trial. Its acceptable safety profile and predictable pharmacokinetics make temozolomide an excellent candidate for inclusion in combination therapies for advanced metastatic melanoma. In a phase I study, the combination of oral temozolomide and subcutaneous interferon alfa-2b was evaluated in patients with histologically confirmed, surgically incurable metastatic melanoma.31 In that study, temozolomide 150 mg/m2/d in combination with interferon alfa-2b 7.5 MU/m2 three times a week was well tolerated, and complete or partial remissions occurred in three of 12 patients. Temozolomide is now being tested in multidrug biochemotherapy regimens. In conclusion, this study shows that in patients with advanced melanoma, treatment with temozolomide is associated with greater improvements in overall survival, PFS, and some QOL domains than is treatment with DTIC. The acceptable safety profile, QOL benefits, ability to penetrate the CNS, and ease of administration suggest that temozolomide could play an important role in the future management of this disease.
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D’Atri S, Piccioni D, Castellano A, et al: Chemosensitivity to triazene compounds and O6-alkylguanine-DNA alkyltransferase levels: Studies with blasts of leukaemic patients. Ann Oncol 6:389-393, 1995 11. Tisdale MJ: Antitumour imidazotetrazines: XV. Role of guanine O6 alkylation in the mechanism of cytotoxicity of imidazotetrazinones. Pharmacol 36:457-462, 1987 12. Wedge SR, Porteous JK, Newlands ES: 3-Aminobenzamide and/or O6-benzylguanine evaluated as an adjuvant to temozolomide or BCNU treatment in cell lines of variable mismatch repair status and O6-alkylguanine–DNA alkyltransferase activity. Br J Cancer 74:1030-1036, 1996[Medline] 13. Newlands ES, Blackledge GRP, Slack JA, et al: Phase I trial of temozolomide (CCRG 81045: M&B 39831: NSC 362856). Br J Cancer 65:287-291, 1992[Medline] 14. Agarwala SS, Reyderman L, Statkevich P: Pharmacokinetic study of temozolomide penetration into CSF in a patient with dural melanoma. Ann Oncol 9:138 (abstr 659) 15. Patel M, McCully C, Godwin K, et al: Plasma and cerebrospinal fluid pharmacokinetics of temozolomide. Clin Oncol 14:461, 1995 (abstr 1485) 16. Brock CS, Matthews JC, Brown G, et al: In vivo demonstration of 11C-temozolomide uptake by human recurrent high grade astrocytomas. Br J Cancer 75:1241, 1997 (abstr) 17. O’Reilly SM, Newlands ES, Glaser MG, et al: Temozolomide: A new oral cytotoxic chemotherapeutic agent with promising activity against primary brain tumours. Eur J Cancer 29A:940-942, 1993 18. Newlands ES, O’Reilly SM, Glaser MG, et al: The Charing Cross Hospital experience with temozolomide in patients with gliomas. Cancer 32A:2236-2241, 1996 19. 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 40:484-488, 1997[Medline] 20. Bleehen NM, Newlands ES, Lee SM, et al: Cancer Research Campaign phase II trial of temozolomide in metastatic melanoma. Oncol 13:910-913, 1995 21. National Cancer Institute: Investigator’s Handbook: A Manual for Participants in Clinical Trials of Investigational Agents Sponsored by DCTD, NCI. Bethesda, MD, National Cancer Institute, 1993 22. World Health Organization: Handbook for Reporting Results of Cancer Treatment. WHO publication no. 48. Geneva, Switzerland, World Health Organization, 1979
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Aaronson NK, Ahmedzai S, Bergman B, et al: The European Organization for Research and Treatment of Cancer QLQ-C30: A quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 85:365-376, 1993 24. Estlin EJ, Lashford L, Ablett S: Phase I study of temozolomide in paediatric patients with advanced cancer. Br J Cancer 78:652-666, 1988 25. Kim LH, Lin CC, Parker D, et al: High-performance liquid chromatographic determination and stability of 5-(3-methyltriazen-1-yl)-imidazo-4-carboximide, the biologically active product of the antitumor agent temolozolomide, in human plasma. J Chromatogr B Biomed Sci Appl 703:225-233, 1997[Medline] 26. Pyrhönen S, Hahka-Kemppinen M, Muhonen T: A promising interferon plus four-drug chemotherapy regimen for metastatic melanoma. J Clin Oncol 10:1919-1926, 1992[Abstract] 27. Middleton MR, Lunn JM, Morris C, et al: O6-methylguanine-DNA methyltransferase in pretreatment tumour biopsies as a predictor of response to temozolomide in melanoma. Br J Cancer 78:1199-1202, 1998[Medline] 28. Brock CS, Newlands ES, Wedge SR, et al: Phase I trial of temozolomide using an extended continuous oral schedule. Cancer Res 38:4363-4367, 1998 29. Margison GP, O’Connor PJ: Biological consequences of reactions with DNA: Role of specific lesions, in Cooper C, Groves P (eds): Handbook of Experimental Pharmacology. Berlin, Germany,Springer-Verlag, 1990, pp 547-566 30. Gerson SL, Spiro TP, Reidenberg P, et al: Rapid depletion of O6–alkylguanine DNA alkyltransferase with twice daily oral temozolomide (SCH 52365) in patients with advanced cancer. Proc Am Soc Clin Oncol 15:178, 1996 (abstr 366) 31. Kirkwood JM, Agarwala SS, Diaz B, et al: Phase I study of temozolomide in combination with interferon alfa-2b in metastatic malignant melanoma. Proc Am Soc Clin Oncol 16:491a, 1997 (abstr 1767) Submitted March 18, 1999; accepted August 26, 1999. This article has been cited by other articles:
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TOP
ABSTRACT
INTRODUCTION
2 test was used to compare the maintenance of or improvement in QOL scores from baseline to 12 weeks. 
), DTIC (
), MTIC after temozolomide administration (•), and MTIC after DTIC administration (
), all after dosing on day 4 of the first treatment cycle.
