Originally published as JCO Early Release 10.1200/JCO.2005.01.1551 on October 31 2005

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Temozolomide in Combination With Interferon-Alfa Versus Temozolomide Alone in Patients With Advanced Metastatic Melanoma: A Randomized, Phase III, Multicenter Study from the Dermatologic Cooperative Oncology Group

Roland Kaufmann, Konstanze Spieth, Ulrike Leiter, Cornelia Mauch, Peter von den Driesch, Thomas Vogt, Ruthild Linse, Wolfgang Tilgen, Dirk Schadendorf, Jürgen C. Becker, Günther Sebastian, Sven Krengel, Lutz Kretschmer, Claus Garbe, Reinhard Dummer

From the Departments of Dermatology, J.W. Goethe-University, Frankfurt am Main; University of Tübingen, Tübingen; University of Köln, Cologne; University of Erlangen, Erlangen/Stuttgart; University of Regensburg, Regensburg; Helios Clinic Erfurt, Erfurt; Saarland University, Homburg; Skin Cancer Unit, German Cancer Research Center, Mannheim; University of Würzburg, Würzburg; University of Dresden, Dresden; University of Schleswig-Holstein Campus Lübeck, Lübeck; University of Göttingen, Göttingen, Germany; and University of Zürich, Switzerland

Please address reprint requests to Konstanze Spieth, MD, Department of Dermatology, J.W. Goethe-University, Frankfurt am Main, Germany; e-mail: konstanze.spieth{at}kgu.de.

	ABSTRACT

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PURPOSE: Temozolomide (TMZ) has shown efficacy in metastatic melanoma equal to that of dacarbazine (DTIC), the standard chemotherapeutic agent for melanoma. As the combination with interferon-alfa (IFN-) appears superior to single-agent DTIC regarding response rates, the purpose of this study was to compare TMZ alone and TMZ plus IFN- in terms of objective response (OR), overall survival, and safety in a prospective, randomized, multicenter trial.

PATIENTS AND METHODS: Two hundred ninety-four patients with untreated stage IV metastatic melanoma (American Joint Committee on Cancer staging system) were randomly assigned to receive either oral TMZ alone (200 mg/m²/day; days 1 through 5 every 28 days) or in combination with subcutaneous IFN- (5 MU/m²; days 1, 3, and 5 every week).

RESULTS: Two hundred eighty-two patients were eligible for an intent-to-treat analysis, 271 patients were treated per protocol. In the TMZ + IFN- arm, 33 (24.1%) of 137 patients responded to therapy (partial or complete remission) whereas in the monotherapy arm, in 18 (13.4%) of 134 patients, a response was evident. Thus, the response rate was significantly higher in the combination arm (P = .036). Median survival time was 8.4 months for patients treated with TMZ (95% CI, 7.07 to 9.27) and 9.7 months for those treated with the combination (95% CI, 8.26 to 11.18; P = .16). Dose modifications and interval prolongations due to hematologic toxicity were significantly more frequent in the TMZ + IFN- arm (P < .001).

CONCLUSION: In metastatic melanoma treatment with TMZ + IFN- leads to a significantly superior OR rate compared to treatment with TMZ alone, which did not translate into prolonged survival in our study population.

	INTRODUCTION

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Despite enormous efforts to diagnose melanoma at more early stages, the mortality rate continues to increase because of the significant rise in incidence. Currently, approximately two to three of 100,000 people per year die from melanoma in the northern hemisphere.^1,2 Metastatic melanoma has remained nearly refractory to systemic treatment for decades. After completion of numerous trials with different cytotoxic and immunomodulatory substances as single agent or combination, dacarbazine (DTIC) is still considered as standard monochemotherapy.³

The modern orally available agent temozolomide (TMZ) is an imidazotetrazinone with activity attributed to the formation of a reactive methyldiazonium cation and methylation of O⁶-guanine in DNA. It shares its active metabolite methyl-triazenyl imidazole carboxamide (MTIC) with DTIC. Because of its chemical structure and pharmacokinetic properties, it has distinct advantages over DTIC. It is absorbed rapidly and nearly completely after oral administration. TMZ is spontaneously activated into MTIC at physiologic pH in aqueous solution, whereas DTIC requires enzymatic demethylation in the liver to be converted into the reactive species. TMZ has an excellent penetration profile into all body tissues, including the brain. Currently TMZ is approved for refractory anaplastic astrocytoma and submitted to US Food and Drug Administration and the European Medicines Evaluation Agency for approval in first line therapy of glioblastoma multiforme.

The first trial with TMZ in patients with metastatic melanoma was conducted in 1992.⁴ This phase I trial established the schedule of the 5-day oral application on a 4-week cycle and demonstrated clinical activity in melanoma, confirmed also in a phase II study in 56 patients with advanced melanoma.⁵ Dose-limiting toxicity occurred after a single-dose of 1,000 mg/m² and after five consecutive doses of 200 mg/m², leading to the phase III trial by Middleton,⁶ in which patients were randomly assigned to receive either oral temozolomide at a dosage of 200 mg/m²/day for 5 days every 28 days or intravenous DTIC at a dosage of 250 mg/m²/day for 5 days every 21 days.

The current trial was designed to further clarify the role of interferon-alfa (IFN-) as an additive agent to TMZ in the treatment of metastatic melanoma. The primary objective of the current study was to compare the response rate and overall survival (OS) of temozolomide alone with the combination of temozolomide and IFN-. At the time the study design was being prepared (1997-1998) a controversial discussion was ongoing regarding the benefit of adding IFN- to monochemotherapy with DTIC, because several diverse results had been published.^7-9 The secondary objectives of the study were to evaluate observed toxicities and progression-free survival (PFS). The prospective randomized phase III trial was performed under the auspices of the Dermatologic Cooperative Oncology Group (DeCOG).

	PATIENTS AND METHODS

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The protocol was approved by the ethics committee of the J.W. Goethe-University (Frankfurt, Germany) and by the local committees of all participating centers. The study was performed in accord with an assurance filed with and approved by the US Department of Health and Human Services.

Patients eligible for this trial provided written informed consent and had to fulfill the following inclusion criteria: histologically confirmed melanoma stage IV (American Joint Committee on Cancer staging system) with no prior systemic therapy in stage IV; a Karnofsky performance status 60% (ranging from 0 to 100, with a higher status indicating a better ability to carry out daily activities); and age between 18 and 75 years. At the time of entrance onto the trial, patients had WBCs > 3,000/mm³, platelet counts > 100,000/mm³, serum creatinine < 2x the upper limit of normal and bilirubin < 1.5 mg/dL. Prior treatment (adjuvant; stage III) had to have been completed at least 4 weeks before study entrance.

Patients were not eligible if they had evidence of CNS metastases or had major concomitant illnesses of the cardiovascular, respiratory, or renal system, or if they were pregnant or nursing. Individuals with primary ocular or mucosal melanoma or those with nonmeasurable disease were not included.

Patient Treatment and Evaluation
Patients were randomly assigned without stratification to receive either TMZ alone or in combination with IFN-. The medication was administered in an outpatient setting and in a nonblinded fashion. TMZ was administered orally as capsules containing 5, 20, 100, or 250 mg TMZ at an initial dose of 200 mg/m² body surface over 5 consecutive days. Treatment cycles were repeated every 28 days in the absence of disease progression. In the combination arm, IFN- (5.0 MU/m² three times per week) was administered subcutaneously in addition to TMZ, which was dosed equally as in the monotherapy arm. As IFN--2b was the only approved IFN- for melanoma at initiation of the trial 1998, it was applied predominantly during the whole study duration.

TMZ doses were adjusted when grade 3 (TMZ 150 mg/m²) or grade 4 (TMZ 100 mg/m²) toxicity occurred according to the National Cancer Institute common toxicity criteria (NCI-CTC). To proceed with each cycle, the thrombocytes had to be greater 100.000/m³ and the neutrophils had to be greater 1,500/m³. The protocol suggested an antiemetic regimen comprised of a 5HT3-antagonist (ie, granisetron or ondansetron), and metoclopramide that could be altered according to local practice and patient needs. For managing constitutional symptoms of IFN- administration of prophylactic antipyretics, such as paracetamol, acetaminophen, or ibuprofen, was recommended. The severity of adverse events was classified according to NCI-CTC.

Evaluation of response was performed before treatment and repeated after every second cycle. Measurements of metastatic disease included physical examination as well as computed tomographic scans or magnetic resonance imaging of the brain, chest, abdomen and pelvis. Tumor responses were assessed using the bidimensional WHO criteria, because the response evaluation criteria in solid tumors (RECIST) were established only in 2000, when the recruitment of the study was already ongoing. Disease progression was defined as either the appearance of new lesions or an increase in disease > 25%. Stable disease was described as < 25% decrease or increase in disease bulk, partial response was defined as > 50% decrease in disease bulk. Complete response was defined by disappearance of all measurable metastatic lesions. There was no centralized review of the radiologic files provided.

Statistical Analysis
The primary objective of this study was to compare response rate and survival of patients between combination therapy of TMZ plus IFN- with TMZ alone. Secondary objectives were to evaluate toxicity, to assess the PFS and to possibly identify any relevant prognostic factors. The study was designed to have 80% power to detect a 15% difference regarding objective response rate, which required 120 eligible patients in each arm. Furthermore, a survival difference of 25% after 1 year of follow-up should be detected with a power of 80%, which required 90 eligible patients in each arm. Calculating a drop-out rate of 20%, 144 patients should be included per study arm.

The patients' characteristics, response rates, and toxicities were compared using the ² test or Wilcoxon rank sum test. OS was evaluated by descriptive analysis using Kaplan-Meier estimates of the survival curves and the log-rank test for comparisons of the OS time and time to progressive disease.

	RESULTS

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Between October 1998 and December 2001, 294 patients with histologically confirmed metastatic melanoma were included in the study at 31 centers in Germany (29) and Switzerland (2). Of these patients, 146 were randomly assigned to receive TMZ, and 148 to receive TMZ plus IFN-. Twelve patients (seven in the TMZ group and five in the TMZ + IFN- group) proved to be ineligible due to violations of inclusion criteria (n = 10) or due to missing follow-up data (n = 2). Two hundred eighty-two patients were found to be eligible for treatment (139 in the TMZ arm and 143 in the TMZ + IFN- arm) and made up the intent-to-treat (ITT) population. Treatment per protocol could not be conducted in two patients who withdrew their consent; nine more patients discontinued the study for personal reasons. Thus, 271 patients were treated per protocol (134 received TMZ and 137 patients received TMZ + IFN-; Fig 1). Patient demographics showed similar results for both treatment arms. No significant differences in sex, age, performance status, site of metastatic disease and time from diagnosis to development of metastases could be observed. The median time from initial diagnosis to development of metastatic disease was 23.86 months for the TMZ group and 23 months for the group that received TMZ plus IFN- (P = .66; Table 1).

View larger version (30K): [in this window] [in a new window]   Fig 1. Study profile. TMZ, temozolomide; IFN-, interferon-alfa.

View larger version (15K): [in this window] [in a new window]   Fig 2. Overall survival rates for patients treated with temozolomide (TMZ) alone (green) and for those treated with TMZ plus interferon-alfa (IFN-; red). The median overall survival time was 8.4 months for the TMZ group and 9.7 months for the TMZ plus IFN- group. Intent-to-treat population, n = 282.

View larger version (15K): [in this window] [in a new window]   Fig 3. Progression-free survival (PFS) rates in patients treated with TMZ alone (green) and those treated with TMZ plus interferon-alfa (IFN-; red). The median PFS was 2.4 months for the TMZ group compared with 3.3 months for the TMZ plus IFN- group.

Seven hundred seventeen cycles of TMZ plus IFN- were administered to 141 patients. Four hundred sixty-four cycles (64.7%) were performed at modified schemes; of these, 266 cycles were performed at reduced doses, 33 with prolonged intervals, and 165 with prolonged intervals and reduced doses.

Incidence of hematologic toxicity in all CTC grades, consisting primarily of thrombocytopenia and leucopenia, was significantly different between the two treatment groups (Table 3). Thrombocytopenia (grade 1 to 4) occurred in 47.1% of the patients of the TMZ plus IFN- group (grade 3,8.9%; grade 4, 13.8%), whereas only 16.3% of all patients in the TMZ group suffered from this adverse effect (grade 3, 1.7%; grade 4, 2.6%; P < .0001).

The most frequent nonhematologic adverse events were nausea and vomiting, constitutional symptoms such as fever and myalgia, constipation or diarrhea, and elevation of liver enzymes. These adverse effects were similar for both treatment groups, except for fever and constitutional symptoms (grade 1 to 4) which occurred significantly more often in the IFN- containing arm (32.2% v 7.1%; P < .0001). No patient died in direct correlation to the study treatment.

	DISCUSSION

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The alkylating agent TMZ has been administered as treatment for metastatic melanoma for more than a decade now. A randomized phase III study demonstrated an efficacy of TMZ at least equal to that of DTIC with a nonstatistical benefit of increase in survival.⁶ Until now, there have been no randomized trials comparing single-agent TMZ and combination of TMZ with other drugs, which might be superior to monotherapy. Our study is the first large prospective, randomized, multicenter phase III study to evaluate the efficacy and tolerability of adding IFN- to monochemotherapy with TMZ. Two smaller, nonrandomized trials with this combination of therapy in patients with metastatic melanoma were published recently,^10,11 as well as a trial with the identical combined regimen in patients with advanced renal cell carcinoma,¹² confirming the significant impact of this regimen at present. In retrospect, it would have been advantageous to have acquired the lactate dehydrogenase (LDH) value in our study to stratify stages according to the current staging system; however at initiation of the trial, lactate dehydrogenase was not part of the existing system (Union International Contre le Cancer system).

Our data showed no statistically significant difference in survival between treatment arms, despite a significant increase in response rate. These results are comparable with the outcome of several previously published trials for chemoimmunotherapy with mono-agent DTIC and IFN-.^9,13,14 The meta-analysis of more than 3,000 patients from multiple randomized trials by Huncharek et al¹⁴ came to the conclusion, that the combination of DTIC plus IFN- is capable of producing response rates greater than DTIC alone, although just as in our trial, the superior response rate was not associated with improved survival. Also interesting in this context is the result of a randomized study by Keilholz et al,¹⁵ published in 1997, showing that the addition of cisplatin to combination treatment with IFN- and interleukin-2 does not influence survival of patients with advanced metastatic melanoma, while almost doubling the response rate. Remissions in patients with metastatic melanoma are characteristically short-lived, irrespective of the mode of therapy. The antiproliferative, immunomodulatory, and antiangiogenic properties of IFN obviously do not have the ability to induce more persistent responses to impact OS. Therefore, PFS and OS rather than response rate seem to be appropriate surrogate end points for clinical outcome in patients with metastatic melanoma. With regard to all existing data concerning this issue, the described phenomenon of greater response rates not naturally being associated with prolonged survival today seems sufficiently verified.

At the same time one has to keep in mind that any combination of a chemotherapeutic agent with cytokines comes along with an increased toxicity, an effect we could confirm through the safety analysis in our trial as well. A considerable proportion of patients in the combination arm suffered from myelosuppression, the most frequent nonhematologic adverse effects were fever, nausea and emesis and abnormalities in hepatic enzymes. Although all treatment-related symptoms were manageable and reversible, dose reduction and interval prolongation were appropriate instruments to counteract occurrence of grade 3 and 4 myelosuppression. In previous trials, different regimen of the combination of TMZ and IFN- have been applied: TMZ 200 mg/² on days 1 to 5 plus IFN--2b 5 MU flat or per square meter subcutaneously three times a week,^11,16 TMZ 150 mg/m² on days 1 to 5 plus either IFN--2b 10 MU flat or per square meter body surface subcutaneously every other day or in combination with 7,5 MU/m² IFN--2b.^10,17,18 In their phase I dose escalation study, Agarwala and Kirkwood¹⁸ found that the maximum-tolerated dose was either TMZ 150 mg/m² plus 7.5 MU/m² IFN--2b or TMZ 200 mg/m² plus 5 MU/m² IFN--2b three times per week, which we can endorse through the results of our trial. Our data were also consistent with the response rates and OS in these preliminary trials.

Hypothesizing the efficacy of TMZ alone or in combination with IFN- to be similar to that of DTIC ± IFN-, some other favorable aspects of this novel chemotherapy agent are to be mentioned. Quality of life was not assessed our trial, but detailed health-related quality of life results of the phase III clinical trial comparing TMZ to DTIC were published recently.¹⁹ Patients treated with TMZ reported significantly better physical functioning and less fatigue or sleep disturbances than patients treated with DTIC after 12 weeks of treatment. Previous studies showed that patients clearly prefer oral versus intravenous palliative chemotherapy.^20,21

A distinct advantage of TMZ concerning pharmacokinetics is its ability to cross the blood-brain barrier, providing approximately 20% of the systemic TMZ exposure measured in the plasma in the CSF.²² From our study, no conclusion can be drawn regarding the occurrence of brain metastases because this issue was not evaluated. TMZ has demonstrated a certain activity in CNS metastases from melanoma alone or in combination with radiation or other chemotherapeutic agents.^23-26 Regarding the potential of TMZ to prevent or at least decelerate the occurrence of CNS metastases, controversial results from retrospective trials have been reported so far.^27,28 Further prospective, randomized studies to define the potency of TMZ to treat or prevent cerebral metastases are warranted and urgently needed.

The disability of the combination of TMZ with IFN- to increase OS, which is the fundamental target value of treating metastatic melanoma, has to be accepted as a result of this trial. The impact of TMZ as a novel chemotherapeutic agent in the treatment of metastatic melanoma in comparison to the established drug DTIC is defined most notably by its oral bioavailability and its ability to cross the blood-brain barrier. In addition, the possibility to easily combine TMZ with other components as antiangiogenic agents or molecular targeted drugs and the option of rescheduling TMZ in different dosing schemes, as a 1-week-on/1-week-off regimen or a daily administration, are attractive attributes to be utilized in the future.

	Appendix

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... REFERENCES

 
We would like to thank the additional investigators at different participating centers.

Germany: Mannheim—R. Figl, MD, and C. Zimpfer—Rechner, MD; Dresden—S. Eppinger, MD, and A. Stein, MD; Lübeck—J. Grabbe, MD; Erlangen—C. Balz, MD; Würzburg—P. Terheyden, MD, and A.O. Eggert, MD; Erfurt—I. Kellner, MD; Homburg—C. Pföhler, MD; Köln—A. Jöckel, MD; Regensburg—A. Glaessl, MD, and B. Coras, MD; Göttingen—E.M. Habe Nicht, MD, and S. Emmert, MD; Frankfurt—S. Hawerkamp, MD, and A. Gaul (study nurse); Tübingen—M. Kreissig (statistical evaluations); and investigators at participating centers in Aachen, Augsburg, Berlin Neukölln, Chemnitz, Dessau, Dortmung, Görlitz, Hamburg, Hameln, Hannover, Heidelberg, Jena, Leipzig, Magdeburg, Minden, Münster, Rostock, Stuttgart, Ulm, Wiesbaden, and Zwickau.

Switzerland: Zürich—T. Maier, MD; and investigators at participating centers in Bern.

	Authors' Disclosures of Potential Conflicts of Interest

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Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Authors Employment Leadership Consultant Stock Honoraria Research Funds Testimony Other Dirk Schadendorf Schering-Plough (A)

Dollar amount codes: (A) < $10,000 (B) $10,000-99,999 (C) $100,000 (N/R) Not Required

	NOTES

 
Supported by grants from Essex Pharma GmbH (Munich, Germany).

R.K. and K.S. are co-senior authors.

Presented in part at the 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 3, 2003.

Terms in blue are defined in the glossary, found at the end of this issue and online at www.jco.org.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... REFERENCES

 
1. Marks R: Epidemiology of melanoma. Clin Exp Dermatol 25:459-463, 2000[CrossRef][Medline]

2. Lens MB, Dawes M: Global perspectives of contemporary epidemiological trends of cutaneous malignant melanoma. Br J Dermatol 150:179-185, 2004[CrossRef][Medline]

3. Eggermont AM, Kirkwood JM: Re-evaluating the role of dacarbazine in metastatic melanoma: What have we learned in 30 years? Eur J Cancer 40:1825-1836, 2004

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

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

6. Middleton MR, Grob JJ, Aaronson N, et al: Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. J Clin Oncol 18:158-166, 2000[Abstract/Free Full Text]

7. Bajetta E, Di LA, Zampino MG, et al: Multicenter randomized trial of dacarbazine alone or in combination with two different doses and schedules of interferon alfa-2a in the treatment of advanced melanoma. J Clin Oncol 12:806-811, 1994[Abstract]

8. Falkson CI: Experience with interferon alpha 2b combined with dacarbazine in the treatment of metastatic malignant melanoma. Med Oncol 12:35-40, 1995[CrossRef][Medline]

9. Falkson CI, Ibrahim J, Kirkwood JM, et al: Phase III trial of dacarbazine versus dacarbazine with interferon alpha-2b versus dacarbazine with tamoxifen versus dacarbazine with interferon alpha-2b and tamoxifen in patients with metastatic malignant melanoma: an Eastern Cooperative Oncology Group study. J Clin Oncol 16:1743-1751, 1998[Abstract]

10. Richtig E, Hofmann-Wellenhof R, Pehamberger H, et al: Temozolomide and interferon alpha 2b in metastatic melanoma stage IV. Br J Dermatol 151:91-98, 2004[Medline]

11. Ridolfi R, Romanini A, Sileni VC, et al: Temozolomide and interferon-alpha in metastatic melanoma: a phase II study of the Italian Melanoma Intergroup. Melanoma Res 14:295-299, 2004[Medline]

12. Sunkara U, Walczak JR, Summerson L, et al: A phase II trial of temozolomide and IFN-alpha in patients with advanced renal cell carcinoma. J Interferon Cytokine Res 24:37-41, 2004[Medline]

13. Hauschild A, Garbe C, Stolz W, et al: Dacarbazine and interferon alpha with or without interleukin 2 in metastatic melanoma: a randomized phase III multicentre trial of the Dermatologic Cooperative Oncology Group (DeCOG). Br J Cancer 84:1036-1042, 2001[CrossRef][Medline]

14. Huncharek M, Caubet JF, McGarry R: Single-agent DTIC versus combination chemotherapy with or without immunotherapy in metastatic melanoma: a meta-analysis of 3273 patients from 20 randomized trials. Melanoma Res 11:75-81, 2001[CrossRef][Medline]

15. Keilholz U, Goey SH, Punt CJ, et al: Interferon alfa-2a and interleukin-2 with or without cisplatin in metastatic melanoma: a randomized trial of the European Organization for Research and Treatment of Cancer Melanoma Cooperative Group. J Clin Oncol 15:2579-2588, 1997[Abstract/Free Full Text]

16. Danson S, Lorigan P, Arance A, et al: Randomized phase II study of temozolomide given every 8 hours or daily with either interferon alfa-2b or thalidomide in metastatic malignant melanoma. J Clin Oncol 21:2551-2557, 2003[Abstract/Free Full Text]

17. Martin GM., Tres A, Crespo C, et al: Phase II multicenter study of temozolomide in combination with interferon alfa-2b in metastatic malignant melanoma. Proc Am Soc Clin Oncol 21:348, 2002 (abstr 1389)

18. Agarwala SS, Kirkwood JM: Temozolomide in combination with interferon alpha-2b in patients with metastatic melanoma: A phase I dose-escalation study. Cancer 97:121-127, 2003[CrossRef][Medline]

19. Kiebert GM, Jonas DL, Middleton MR: Health-related quality of life in patients with advanced metastatic melanoma: Results of a randomized phase III study comparing temozolomide with dacarbazine. Cancer Invest 21:821-829, 2003[Medline]

20. Liu G, Franssen E, Fitch MI, et al: Patient preferences for oral versus intravenous palliative chemotherapy. J Clin Oncol 15:110-115, 1997[Abstract/Free Full Text]

21. Borner MM, Schoffski P, de Wit R, et al: Patient preference and pharmacokinetics of oral modulated UFT versus intravenous fluorouracil and leucovorin: A randomised crossover trial in advanced colorectal cancer. Eur J Cancer 38:349-358, 2002

22. Ostermann S, Csajka C, Buclin T, et al: Plasma and cerebrospinal fluid population pharmacokinetics of temozolomide in malignant glioma patients. Clin Cancer Res 10:3728-3736, 2004[Abstract/Free Full Text]

23. Frick S, Lischner S, Rosien F, et al: Hautarzt 53:659-665, 2002

24. Agarwala SS, Kirkwood JM, Gore M, et al: Temozolomide for the treatment of brain metastases associated with metastatic melanoma: a phase II study. J Clin Oncol 22:2101-2107, 2004[Abstract/Free Full Text]

25. Dvorak J, Melichar B, Zizka J, et al: Complete response of multiple melanoma brain metastases after treatment with temozolomide. Onkologie 27:171-174, 2004[Medline]

26. Bafaloukos D, Tsoutsos D, Fountzilas G, et al: The effect of temozolomide-based chemotherapy in patients with cerebral metastases from melanoma. Melanoma Res 14:289-294, 2004[Medline]

27. Paul MJ, Summers Y, Calvert AH, et al: Effect of temozolomide on central nervous system relapse in patients with advanced melanoma. Melanoma Res 12:175-178, 2002[CrossRef][Medline]

28. Conill C, Gonzalez-Cao M, Jorcano S, et al: Temozolomide as prophylaxis for melanoma brain metastases. Melanoma Res 14:73-74, 2004[Medline]

Submitted March 28, 2005; accepted August 3, 2005.

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				I. Quirt, S. Verma, T. Petrella, K. Bak, and M. Charette Temozolomide for the Treatment of Metastatic Melanoma: A Systematic Review Oncologist, September 1, 2007; 12(9): 1114 - 1123. [Abstract] [Full Text] [PDF]

				H Gogas, A Polyzos, I Stavrinidis, K Frangia, D Tsoutsos, P Panagiotou, C Markopoulos, O Papadopoulos, D Pectasides, M Mantzourani, et al. Temozolomide in combination with celecoxib in patients with advanced melanoma. A phase II study of the Hellenic Cooperative Oncology Group Ann. Onc., December 1, 2006; 17(12): 1835 - 1841. [Abstract] [Full Text] [PDF]

				D Schadendorf, A Hauschild, S Ugurel, A Thoelke, F Egberts, M Kreissig, R Linse, U Trefzer, T Vogt, W Tilgen, et al. Dose-intensified bi-weekly temozolomide in patients with asymptomatic brain metastases from malignant melanoma: a phase II DeCOG/ADO study. Ann. Onc., October 1, 2006; 17(10): 1592 - 1597. [Abstract] [Full Text] [PDF]

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