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© 2003 American Society for Clinical Oncology Randomized Phase II Study of Temozolomide Given Every 8 Hours or Daily With Either Interferon Alfa-2b or Thalidomide in Metastatic Malignant MelanomaFrom the Christie Hospital, Manchester; and Weston Park Hospital, Sheffield, United Kingdom. Address reprint requests to S. Danson, MRCP, Department of Medical Oncology, Christie Hospital NHS Trust, Wilmslow Road, Manchester M20 4BX, United Kingdom; email: sdanson{at}fsmail.net.
Purpose: Temozolomide is an imidazotetrazine with a mechanism of action similar to dacarbazine and equivalent activity in melanoma. It is well tolerated and is a candidate for combination chemotherapy and schedule manipulation. In this study, we combined temozolomide with interferon alfa-2b and, separately, with thalidomide, and we administered temozolomide alone in a compressed schedule. The objectives of this randomized phase II, two-center study were to determine response rates, overall survival, and tolerability of the regimens in patients with advanced metastatic melanoma. Patients and Methods: One hundred eighty-one patients with metastatic melanoma were randomly assigned to receive up to six 4-weekly cycles consisting of temozolomide 200 mg/m2 every 8 hours for five doses, or temozolomide 200 mg/m2 daily for days 1 to 5 plus interferon alfa-2b 5 MU (million International Units) subcutaneously three times a week, or temozolomide 150 mg/m2 (increased after one cycle to 200 mg/m2) daily on days 1 to 5 plus thalidomide 100 mg daily days 1 to 28. Results: The treatment arms were well balanced for known prognostic factors. Median survival was 5.3 months for 8-hourly temozolomide, 7.7 months for temozolomide/interferon, and 7.3 months for temozolomide/thalidomide; and 1-year survivals were 18%, 26%, and 24%, respectively. Response or disease stabilization occurred in 20% of patients (95% confidence interval [CI], 10% to 33%) given 8-hourly temozolomide, 21% (95% CI, 12% to 33%) given temozolomide/interferon, and 25% (95% CI, 15% to 38%) given temozolomide/thalidomide. Grade 3 or 4 nonhematologic toxicities were similar in each arm except for infection, which was more frequent with 8-hourly temozolomide. There were fewer instances of grade 3 or 4 myelotoxicity with temozolomide/thalidomide. Conclusion: Of the three regimens tested, the combination of temozolomide and thalidomide seems the most promising for future study.
MALIGNANT MELANOMA accounts for 2% of all cancers in the United States and Europe, and its incidence is increasing.1 Wide local excision is the treatment of choice for primary tumors and for locoregional recurrence. Surgery remains the only modality where cure is a possibility, and this is achieved in the majority of patients. In contrast, metastatic disease is incurable, and median survival, at 6 to 9 months, is short. Systemic therapy with palliative intent is the mainstay of treatment. Dacarbazine has become the standard chemotherapy for metastatic melanoma, with a response rate of approximately 15%. Responses are usually incomplete and last only a few months. Other agents are administered, including platinum analogues, vinca alkaloids, nitrosoureas, and taxanes, but none has a better response rate than dacarbazine. Combination chemotherapy results in higher response rates but with increased toxicity with no prolongation of response duration or survival benefit.2–4 Temozolomide is an oral imidazotetrazine with activity in advanced melanoma and primary brain tumors. Temozolomide and dacarbazine share the active intermediary 5- (3-methyltriazen-1-yl) imidazole-4-carboximide (MTIC). However, unlike dacarbazine, which requires metabolic activation, temozolomide spontaneously converts to MTIC under physiologic conditions.5 Temozolomide has high oral bioavailability6 and extensive tissue distribution, including penetration through the blood-brain barrier. This is of particular interest in metastatic melanoma7–9 because brain metastases are a common cause of treatment failure, possibly because of poor CNS penetration by conventional treatments. A randomized phase III trial involving 305 patients with untreated metastatic melanoma has compared the efficacy of temozolomide with that of dacarbazine.10 The trial demonstrated equivalent overall survival and toxicity with increased progression-free survival and better quality of life with temozolomide. In addition, there is evidence to indicate that patients treated successfully with temozolomide have a lower incidence of intracranial disease relapse than those responding to dacarbazine. A retrospective study11 looked at 41 patients with advanced melanoma who had responded to their initial treatment. Of those treated with temozolomide, 10% subsequently developed brain metastases compared with 43% of dacarbazine responders. Conventionally, temozolomide is given once daily for 5 days,12 but work in animal models of melanoma indicates that this may not be the most effective way of giving the drug. The DNA repair protein O6-methylguanine-DNA-methyltransferase (MGMT) is known to be important in tumor resistance to temozolomide but is depleted in repairing DNA damage caused by the chemotherapy.13,14 Such resistance might be attenuated by administering temozolomide during the MGMT nadir after the previous dose. The nadir occurs after 4 to 8 hours in the peripheral-blood mononuclear cells of patients treated with temozolomide. Our group has previously tested a 4-hourly schedule in melanoma, finding an increased tumor response rate but greatly increased myelotoxicity.13 In a murine model of melanoma, we have observed a similar increase in efficacy from 8-hourly dosing with temozolomide but with a lesser effect on toxicity, indicating that this schedule is worthy of further study (unpublished observation). Interferon has been used in combination with chemotherapy in melanoma since the late 1980s.15 Improvements in response rate, disease free survival, and overall survival have been reported by some investigators, albeit inconsistently.16,17 A recent study from the Eastern Cooperative Oncology Group found no benefit from the addition of interferon to dacarbazine, although the difference would have had to be substantial to be detectable in this study of 271 patients.18 A meta-analysis of single-agent dacarbazine compared with combination therapy analyzed five randomized trials, involving 549 patients, that compared single-agent dacarbazine with dacarbazine plus interferon. The study demonstrated a 53% increase in tumor response rate when interferon was added (P = .01) but no statistically significant difference in survival, although this favored combination therapy.19 At the time that our study was conceived, few data were available on the combination of temozolomide and interferon alfa in melanoma, although a phase I study reported it to be well tolerated at the doses we selected.20 Thalidomide has antiangiogenic and biologic modulatory properties21 and has been used successfully in the treatment of Kaposi’s sarcoma, myeloma, and renal cell cancer.22,23 Thalidomide has been used in metastatic melanoma as a single agent with mixed results.23,24 In animal models of melanoma, thalidomide shows synergy with dacarbazine25 and temozolomide (unpublished data, Paterson Institute of Cancer Research, Manchester, United Kingdom), stimulating our interest in combining the drugs. The aim of this study was to determine the efficacy, in terms of response rate and overall survival, and the tolerability of these three novel temozolomide-based regimens in order to identify which, if any, merits further study.
Patients Patients at the two study centers who had histologically confirmed advanced metastatic melanoma were eligible for the study, provided they fulfilled the following criteria: no previous chemotherapy; full recovery from previous radiotherapy, adjuvant biologic therapy, or surgery; measurable disease; age 18 years or older; adequate bone marrow reserve (absolute neutrophil count ≥ 1,500/µL, platelets ≥ 100,000/µL, hemoglobin ≥ 10g/dL); urea and serum creatinine less than 1.5 times the upper limits of laboratory normal [ULN]); adequate hepatic function (total bilirubin < 1.5 x ULN, AST < 3 x ULN, and alkaline phosphatase ≤ 2 x ULN, unless disease was arising from bone); and adequate birth control measures. Patients were excluded from the study if they were pregnant or nursing (pregnancy tests were performed within 24 hours before starting the study drugs); if they had uncontrolled vomiting that would interfere with the administration of oral medications or had biologic therapy within 4 weeks of the administration of temozolomide; if they were patients known to be human immunodeficiency virus-positive; or if they had clinically significant comorbidity that would interfere with the study evaluations. Local ethical review committees approved the protocol. All patients gave written informed consent before randomization.
Treatment On the 8-hourly temozolomide arm, temozolomide was administered orally at a dose of 200 mg/m2 at 8-hour intervals, for a total of five doses. On the temozolomide/interferon arm, temozolomide 200 mg/m2 was given orally once daily for 5 days with interferon alfa-2b 5 mIU administered subcutaneously every Monday, Wednesday, and Friday. On the temozolomide/thalidomide arm, temozolomide 150 mg/m2 was given orally once daily for 5 days, with thalidomide 100 mg given orally once daily for 28 doses. Patients were required to fast for 1 hour before and after each temozolomide dose. If there was no hematologic toxicity in the first cycle of treatment, then the temozolomide dose was increased to 200 mg/m2 for subsequent cycles. There was no dose escalation of either interferon or thalidomide. The antiemetic regimen to be used was not specified, but nearly all patients received ondansetron on the days of temozolomide administration, with additional metoclopramide as needed. Treatment cycles were repeated every 28 days in the absence of disease progression or toxicity. To receive treatment, the full blood count in the preceding 72 hours needed an absolute neutrophil count of 1,500/µL or greater and a platelet count of 100,000/µL or greater. Dosing was delayed for up to 3 weeks, and patients were removed from the study at that stage if they still did not meet the criteria for re-treatment. The temozolomide dosage was reduced by 25% of the existing dose if the patient met the common toxicity criteria26 grade 3 or 4 hematologic toxicity. A 50% dosage reduction was required for grade 3 or 4 nonhematologic toxicity, at the investigators’ discretion. Patients requiring more than two dosage reductions were removed from the study. If the toxicity was considered to be caused by interferon, then the dose was halved for subsequent cycles. If symptoms persisted despite this, then interferon was discontinued. If the toxicity was considered to be caused by thalidomide, then the dose was reduced to 50 mg once daily. If the symptoms persisted, then thalidomide was discontinued. Patients came off study when they had completed six treatment cycles or were found to have progressive disease.
Evaluations Full blood count and biochemical profiles were performed on days 1 and 22 of all cycles. Before each cycle, adverse events (common toxicity criteria26), performance status (Karnofsky score), and measurement of clinically assessable disease were documented. When tumor lesions required formal radiologic evaluation, the evaluation was performed in the 14 days before the last day of cycles 3 and 6. Responses were assessed according to the standard World Health Organization response criteria.27 Complete response was defined as the disappearance of all known disease, determined by two observations not less than 4 weeks apart. Partial response was defined as at least a 50% decrease in total tumor size, determined by two observations not less than 4 weeks apart, without the appearance of new lesions or progression of any lesion.
Statistical Methods
Patients
Patient and Tumor Characteristics
Survival At final analysis in April 2002, eight patients on 8-hourly temozolomide, 10 patients on temozolomide/interferon, and 14 patients on temozolomide/thalidomide remained alive (median follow-up, 6.3 months). Median overall survival among patients assigned 8-hourly temozolomide was 5.3 months, compared with 7.7 months for temozolomide/interferon patients and 7.3 months for temozolomide/thalidomide patients (Fig 1  ). The range of survival was 0.1 to 36.5 months. Progression-free survival was similar in the three arms. In the 39 patients who responded, progression-free survival was 11.7 months with 8-hourly temozolomide, 9.0 months with temozolomide/interferon, and 7.5 months with temozolomide/thalidomide. The response duration ranged from 2.4 to 21.2 months. One-year survival rates were 18%, 26%, and 24%, and 2-year survival rates were 7%, 9%, and 17% with 8-hourly temozolomide, temozolomide/interferon, and temozolomide/thalidomide, respectively (Table 2).
Response to Treatment The response rates to the three regimens were similar (Table 3 ). A complete response was achieved by 3% of patients in each of the combination arms but in none of the 8-hourly temozolomide patients. Objective responses were observed in 9% of patients (five of 55 patients) who received 8-hourly temozolomide, 18% (11 of 62 patients) who received temozolomide/interferon, and 15% (nine of 60 patients) who received temozolomide/thalidomide. Across all three arms, the response rate was 14.1%, with 2.3% of patients achieving complete response.
Safety The mean number of cycles administered was similar in the three arms (3.5 with temozolomide/thalidomide, 3.3 with temozolomide/interferon, and 3.0 with 8-hourly temozolomide). Table 4 lists the number of patients entering each cycle and the number of patients with stable disease at the end of each cycle. Patients who did not enter the next cycle despite having nonprogressive disease did so because of intolerable toxicity or patient preference. The three arms were well-balanced, with six patients with nonprogressive disease in the 8-hourly temozolomide arm stopping treatment, compared with seven patients who did so each in the combination arms. Dose delay or reduction was less common with temozolomide/thalidomide; 6% of cycles were delayed, compared with 18% on the other two regimens. The main reasons for delay of treatment were thrombocytopenia and neutropenia. All three regimens were well tolerated, with most adverse events being grade 1 or 2 in severity.
There were two deaths in which treatment was implicated. In both cases, the patients, one on 8-hourly temozolomide and the other on temozolomide/interferon, developed bleeding into cerebral metastases. Computed tomography scan confirmed this in one patient, who was also known to be thrombocytopenic. Two other patients died as a result of acute nonmalignant pathology while on treatment. One patient on temozolomide/interferon developed an intracerebral bleed while anticoagulated for pulmonary embolism, and the other, who received temozolomide/thalidomide, developed peritonitis in the face of progressive disease.
Hematologic toxicity, although readily manageable, occurred frequently in the temozolomide/interferon and 8-hourly temozolomide arms. No grade 3 or 4 thrombocytopenia was observed with temozolomide/thalidomide, but it occurred in 34% and 23% of patients on the 8-hourly temozolomide and temozolomide/interferon arms, respectively. Grade 3 or 4 neutropenia occurred in 28% of 8-hourly temozolomide patients and 21% of temozolomide/interferon patients but in only 2% of temozolomide/thalidomide patients. Grade 3 or 4 anemia affected 8% of patients on 8-hourly temozolomide, 2% on temozolomide/interferon, and none on temozolomide/thalidomide. The hematologic toxicity in the temozolomide/thalidomide arm was significantly lower than the hematologic toxicity in the other two arms (Table 5
The most frequent nonhematologic adverse events observed were lethargy, nausea, vomiting, and constipation (Table 6 ). Nausea and vomiting were easily controlled with standard antiemetics. There were few grade 3 or 4 nonhematologic adverse events, and there was little difference between the treatment arms in this regard. Grade 3 or 4 infections and fever were more common with 8-hourly temozolomide and temozolomide/interferon, and there was significantly more constipation in the temozolomide/thalidomide arm. Modest rises in transaminases were also found more often in the 8-hourly temozolomide and temozolomide/interferon arms. We observed no difference in the patterns of toxicity from cycle to cycle in the three study arms.
Brain Metastases Twenty-one patients were known to have brain metastases at the time of treatment. In addition, one patient, who had previously received adjuvant immunotherapy, had neurosurgery and cranial radiotherapy when a brain metastasis was diagnosed and, thus, had no detectable intracranial melanoma at the start of treatment. Of the 21 patients, eight received 8-hourly temozolomide, six received temozolomide/interferon, and seven received temozolomide/thalidomide. The pattern of prior therapies is described in Table 7 . All but one of the patients with brain metastases progressed on treatment; one patient achieved a partial response on temozolomide/thalidomide. Three patients received cranial radiotherapy after temozolomide; one patient was on temozolomide/interferon, and the other two patients were on temozolomide/thalidomide. A further 11 patients, not known to have prior brain metastases, developed symptomatic brain metastases after treatment; two of these patients received 8-hourly temozolomide, four received temozolomide/interferon, and five received temozolomide/thalidomide.
Metastatic malignant melanoma remains a disease with a poor prognosis, and chemotherapy is given with palliative intent. Recently, temozolomide has offered a potential alternative to dacarbazine, the standard of care, because of its tolerability and oral administration.10 There is an urgent need to improve on existing treatment, and temozolomide is a candidate for schedule manipulation or inclusion in combination therapy. The three regimens tested might, based on limited preclinical or clinical evidence, offer a modest improvement on conventional monotherapy. We sought to identify which of these regimens, if any, merit further investigation. Slightly more than 14% of patients in the current study responded to treatment, a rate that corresponds closely with the rate observed in the phase III study of temozolomide in melanoma.10 The complete response rate of 2.3% is also similar to the previous experience with temozolomide, despite a patient population that would be expected to fare worse than the population in the pivotal trial. We did not screen asymptomatic individuals for CNS disease or exclude patients with known involvement. Performance status, sites of involvement, age, and sex distributions were similar to those described in other large studies in melanoma.18,28 The 8-hourly regimen represents an attempt to enhance the DNA damage wrought by temozolomide by administering the drug when cellular capacity to repair DNA is at its lowest. The repair protein MGMT is a significant factor in tumor resistance to O6-alkylating agents such as temozolomide.29 In animal models, it has been demonstrated that MGMT levels are lowest 4 to 8 hours after administration of temozolomide because of repair of DNA damage.30 A similar pattern of MGMT depletion is observed in the peripheral-blood mononuclear cells of patients taking the drug.31 We have previously evaluated a 4-hourly schedule of temozolomide in melanoma. The tumor response rate was higher than for conventional dosing, but there was increased grade 3 or 4 hematologic toxicity.13 With evidence for some recovery of MGMT in normal tissue at 8 hours, we wished to test whether an increased response rate could be achieved without the excessive toxicity associated with the 4-hourly schedule. The 8-hourly regimen was much less toxic than the 4-hourly regimen, with 34% grade 3 or 4 thrombocytopenia compared with 68% and 28% grade 3 or 4 leukopenia compared with 54%, respectively. However, the median survival of 5.3 months and 9% response rate we observed are worse than the outcome with conventional dosing, which is much better tolerated. Less toxic means of MGMT manipulation now exist and are being evaluated in the clinic. Pseudosubstrate inactivators, such as O6-benzylguanine and O6- (4-bromothenyl)guanine, are in phase II trials, and the European Organization for the Research and Treatment of Cancer is testing a prolonged schedule of temozolomide in a phase III study. Thus, there seems to be a limited role for compressed schedules of temozolomide in the management of melanoma patients. The temozolomide/interferon combination arm demonstrated a median survival of 7.7 months and response rate of 18%, which compares favorably with the other arms in this trial. The symptoms attributable to interferon were tolerable. Flu-like symptoms occurred, but these were of only mild or moderate intensity, and patients reported lethargy more than twice as often as with conventional temozolomide use. Hematologic toxicity was significantly increased, but further experience combining interferon and temozolomide indicates that reducing the dose of the latter to 150 mg/m2/d obviates the problem.32 Our data support the opinion that combining chemotherapy with cytokines in metastatic melanoma produces, at best, only a minimal improvement in clinical efficacy.19 However, other recent nonrandomized trials with this combination in advanced melanoma have produced superior results, with median survivals of 10.4 months32 and 14.6 months,33 so further investigation is warranted. The combination of temozolomide and thalidomide produced a median survival of 7.3 months and a response rate of 15%. It was well tolerated, with the symptoms attributable to thalidomide being manageable. At this low dose, there were only two cases of mild peripheral neuropathy and five instances of rash. There was increased lethargy and constipation, but the latter was readily controlled with laxatives. The recommended starting dose for future studies would be 200 mg/m2/d of temozolomide. It is interesting to note that one sixth of the patients assigned temozolomide/thalidomide were alive 2 years after randomization. To our knowledge, no large melanoma trial with similar eligibility criteria has reported such a result. Indeed, rates of 10% or less are commonly described.10,28,34,35 Thalidomide and temozolomide have been combined in a phase I trial involving 12 patients with advanced melanoma.36 This study used a daily low-dose regimen of temozolomide to maintain MGMT depletion. A subsequent phase II trial confirmed the safety of the regimen and demonstrated a response rate of 26%.37 The relative contributions of temozolomide schedule manipulation and the addition of thalidomide remain to be determined. Results with thalidomide as a single agent in melanoma have been disappointing, but the combination of thalidomide with temozolomide deserves further investigation. There has been much interest in temozolomide because it crosses the blood-brain barrier, unlike dacarbazine. In this study, the portion of patients known to have brain metastases at the commencement of treatment was small (12% overall); only symptomatic patients would undergo a computed tomography scan of the head. There was only one responder in this group. There were 11 relapses in the brain in patients not known to have brain metastases at the start of treatment; more of these patients were in the combination arms, but this may be because those patients lived longer. It is difficult to draw conclusions from these small numbers, but future trials should be designed to document the incidence and outcome of patients with brain metastases. In conclusion, all three regimens tested were well tolerated and had comparable efficacy, although there was an indication of better tumor response and overall survival with the combination arms. There was significantly less hematologic toxicity with temozolomide plus thalidomide, and this combination seems the most promising for future study.
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5. Stevens MFG, Hickman JA, Langdon SP, 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 & B 39831), a novel drug with potential as an alternative to dacarbazine. Cancer Res 47:5846–5852, 1987 6. 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] 7. Agarwala SS, Reyderman L, Statkevich P: Pharmacokinetic study of temozolomide penetration into CSF in a patient with dural melanoma. Ann Oncol 9:659a, 1998 (suppl 4) 8. Patel M, McCully C, Godwin K, et al: Plasma and cerebrospinal fluid pharmacokinetics of temozolomide. Proc Am Soc Clin Oncol 14:461, 1995 (abstr) 9. 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)
10. Middleton MR, Grob JJ, Aaronson N, et al: Randomized phase III study of temozolamide versus dacarbazine in the treatment of patients with advanced metastatic melanoma. J Clin Oncol 18:158–166, 2000 11. Paul MJ, Summers Y, Calvert H, et al: Effect of temozolomide on central nervous system relapse in patients with advanced melanoma. Melanoma Res 12:175–178, 2002[CrossRef][Medline] 12. 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] 13. Middleton MR, Lee SM, Arance A, et al: O6-methylguanine formation, repair protein depletion and clinical outcome with a 4 hr schedule of temozolomide in the treatment of advanced melanoma: Results of a phase II study. Int J Cancer 88:469–473, 2000[CrossRef][Medline]
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21. D’Amato RJ, Loughnan MS, Flynn E, et al: Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci 91:4082–4085, 1994 22. Saphir A: Jekyll and Hyde: A new license for thalidomide? J Natl Cancer Inst 89:1480–1481, 1997[Medline] 23. Eisen T, Boshoff C, Mak I, et al: Continuous low dose thalidomide: A phase II study in advanced melanoma, renal cell, ovarian and breast cancer. Br J Cancer 14:17–20, 2000 (suppl 13)
24. Kudva G, Collins BT, Dunphy FR: Thalidomide for malignant melanoma. N Engl J Med 345:1214–1215, 2001 25. Heere-Ress E, Boehm J, Hoeller C, et al: Thalidomide enhances the anti-tumour activity of standard chemotherapy in a human melanoma xenotransplantation model. Proc Am Assoc Cancer Res 43:523, 2002 (abstr 2595) 26. 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 27. World Health Organization: The WHO Handbook for Reporting Results of Cancer Treatment. WHO publicaton no. 48. Geneva, Switzerland, World Health Organization, 1979
28. Chapman PB, Einhorn LH, Meyers ML, et al: Phase III multicenter randomized trial of the Dartmouth regimen versus dacarbazine in patients with metastatic melanoma. J Clin Oncol 17:2745–2751, 1999 29. D’Incalci M, Citti L, Taverna P, et al: Importance of the DNA repair enzyme O6-alkylguanine alkyltransferase (AT) in cancer chemotherapy. Cancer Treat Rev 15:279–292, 1988[CrossRef][Medline] 30. Middleton MR, Kelly J, Goodger S, et al: Four-hourly scheduling of temozolomide improves tumour growth delay but not therapeutic index in A375M melanoma xenografts. Cancer Chemother Pharmacol 45:15–20, 2000[CrossRef][Medline] 31. Lee SM, Thatcher N, Crowther D, et al: Inactivation of O6-alkyltransferase-DNA-alkyltransferase in human peripheral mononuclear cells by temozolomide. Br J Cancer 69:452–456, 1994[Medline] 32. Martin MG, 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) 33. Ridolfi R, Romanini A, Sileni VC, et al: Temozolomide plus alpha interferon in metastatic melanoma: Preliminary evaluation of a multicenter phase II study of Italian Melanoma Intergroup. Proc Am Soc Clin Oncol 21:348, 2002 (abstr 1388)
34. Rusthoven JJ, Quirt IC, Iscoe NA, et al: Randomized, double-blind, placebo-controlled trial comparing the response rates of carmustine, dacarbazine and cisplatin with and without tamoxifen in patients with metastatic melanoma. National Cancer Institute of Cancer Clinical Trials Group. J Clin Oncol 14:2083–2090, 1996 35. Jungnelius U, Ringbourg U, Aamdal S, et al: Dacarbazine-vindesine versus dacarbazine-vindesine-cisplatin in disseminated malignant melanoma: A randomized phase III trial. Eur J Cancer 34:1368–1374, 1998[CrossRef][Medline]
36. Hwu W, Krown SE, Pangeas KS, et al: Temozolomide plus thalidomide in patients with advanced melanoma: Results of a dose-finding trial. J Clin Oncol 20:2610–2615, 2002 37. Hwu WJ, Krown SE, Menell JH, et al: U-temozolomide (TMZ) plus thalidomide in patients with advanced melanoma: A phase II trial. Proc Am Soc Clin Oncol 21:344, 2002 (abstr 1372) Submitted October 4, 2002; accepted April 17, 2003.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test or, when appropriate, the Fisher’s exact test or the Kruskall-Wallis test, was used to compare baseline patient characteristics in the three arms and to evaluate differences in toxicity. 
