Temozolomide for the Treatment of Metastatic Melanoma: A Systematic Review Ian Quirt, Shailendra Verma, Teresa Petrella, Kate Bak and Manya Charette

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1 Temozolomide for the Treatment of Metastatic Melanoma: A Systematic Review Ian Quirt, Shailendra Verma, Teresa Petrella, Kate Bak and Manya Charette The Oncologist 2007, 12: doi: /theoncologist The online version of this article, along with updated information and services, is located on the World Wide Web at: Downloaded from by guest on March 3, 2014

2 The Oncologist Melanoma and Cutaneous Malignancies Temozolomide for the Treatment of Metastatic Melanoma: A Systematic Review IAN QUIRT, a SHAILENDRA VERMA, b TERESA PETRELLA, c KATE BAK, d MANYA CHARETTE d a Princess Margaret Hospital, Toronto, Canada; b Ottawa Hospital, Ottawa, Canada; c Toronto Sunnybrook Regional Cancer Centre, Toronto, Canada; d Cancer Care Ontario Program in Evidence-Based Care, McMaster University, Hamilton, Canada Key Words. Melanoma Temozolomide Temodal Chemotherapy Systematic review Disclosure: No potential conflicts of interest were reported by the authors, planners, reviewers, or staff managers of this article. ABSTRACT Background. This systematic review examines the role of temozolomide in patients with metastatic melanoma. Outcomes of interest include response rate, progression-free survival, overall survival, quality of life, and adverse effects. Methods. The MEDLINE, EMBASE, and Cochrane Library databases were searched from 1980 through to 2005 using variations on the search terms: melanoma, clinical trial, random, temozolomide, temodal, and temodar. The American Society of Clinical Oncology Annual Meeting proceedings were searched from 1996 to Relevant articles and abstracts were selected and reviewed by two reviewers, and the reference lists from these sources were searched for additional trials. Results. Two randomized phase III trials and three randomized phase II trials were located. In addition, 21 phase I or II trials investigating single-agent temozolomide, temozolomide plus interferon-, and temozolomide plus thalidomide were reviewed. A direct comparison of temozolomide and dacarbazine demonstrated equal efficacy for response rates and overall survival; however, no significant difference was reported. A second phase III study comparing single-agent temozolomide with temozolomide combined with interferon- indicated a significantly higher response rate for the combination treatment arm, but no difference in overall survival was noted. Further phase III studies are required to confirm whether there is a benefit associated with the combination of temozolomide and interferon- or thalidomide. Conclusion. Our review of the available literature suggests that temozolomide demonstrates comparable activity to the current standard treatment, dacarbazine, with the additional benefit of being a convenient oral treatment that penetrates the blood brain barrier. The Oncologist 2007;12: INTRODUCTION The past five decades have witnessed a steady increase in the incidence of malignant melanoma. An estimated 4,400 new cases will have been diagnosed in Canada in 2005, and 880 patients will have died from this disease [1]. The majority of patients diagnosed with early-stage malignant melanoma are cured by primary surgical treatment. However, individuals with deeply invasive melanoma have a high probability of developing distant metastases. Adjuvant therapy is only partially effective in reducing the frequency Correspondence: Ian Quirt, M.D., c/o Denise Stys-Norman, Cancer Care Ontario Program in Evidence-Based Care, McMaster University, 1280 Main Street West, DTC 3rd Floor, Hamilton, Ontario, Canada L8S 4L8. Telephone: , ext ; Fax: ; stysnor@mcmaster.ca Received January 26, 2007; accepted for publication June 25, AlphaMed Press /2007/$30.00/0 doi: /theoncologist The Oncologist 2007;12:

3 Quirt, Verma, Petrella et al of metastatic disease, and metastatic malignant melanoma cannot be cured with the currently available systemic treatments. Therefore, treatments being investigated in clinical trials are an appropriate recommendation to the patient. If clinical trials are not available or appropriate for an individual patient, treatments that have the least deleterious impact on quality of life are preferable. Temozolomide is a potentially attractive chemotherapeutic agent because of the oral route of administration. It also has the ability to cross the blood brain barrier, and, therefore, may play a role in treating patients with metastases to the brain, a frequent metastatic site of melanoma. The Melanoma Disease Site Group (DSG) decided to review the available literature on singleagent temozolomide, or temozolomide in combination with interferon (IFN)- or thalidomide, in order to provide treatment recommendations for this agent. METHODS This systematic review was developed by Cancer Care Ontario s Program in Evidence-based Care, using the methods of the Practice Guidelines Development Cycle [2], and will serve as the basis for a clinical practice guideline on the use of temozolomide in the treatment of metastatic melanoma to be posted on the Cancer Care Ontario website ( The MEDLINE, EMBASE, and Cochrane Library databases were searched from 1980 through to 2005 using variations on the search terms: melanoma, clinical trial, random, temozolomide, temodal, and temodar. The American Society of Clinical Oncology Annual Meeting proceedings were searched from 1996 to 2005 for reports of new or ongoing trials. A search was also conducted for published practice guidelines, meta-analyses, and systematic reviews. Relevant articles and abstracts were selected and reviewed by two reviewers, and the reference lists from these sources were searched for additional trials, as were the reference lists from relevant review articles. Articles were selected for inclusion in this systematic review of the evidence if they were fully published reports or published abstracts of randomized controlled trials or meta-analyses of randomized controlled trials comparing single-agent temozolomide with another treatment for metastatic melanoma. Randomized phase II trials, single-arm phase II trials, or phase I trials investigating single-agent temozolomide, temozolomide combined with IFN- or temozolomide combined with thalidomide were also eligible for inclusion, as were evidence-based clinical practice guidelines and systematic reviews. Articles were required to report on any of the following specified outcomes of interest: response rates, progression-free survival, overall survival, quality of life, or adverse effects. Trials published in a language other than English were excluded because of limited translation resources. Literature Search Results Two randomized, phase III trials were available for review and considered for pooling. Temozolomide was compared with dacarbazine (DTIC) in the first trial [3] and a combination of temozolomide and IFN in the second [4]. Pooling the data was judged inappropriate because of the large differences in comparison arms. Three randomized phase II trials were also located. The first trial compared temozolomide with cisplatin [5], and, in the second trial [6], patients were randomized to receive single-agent temozolomide or a combination of temozolomide and IFN or thalidomide. The third trial [7] compared temozolomide in two different doses. All five trials were published as full reports. Trial descriptions and patient characteristics are shown in Table 1. In addition, phase I or II trials investigating singleagent temozolomide (n 9) [8 16], temozolomide plus IFN- (n 6) [17 22], and temozolomide plus thalidomide (n 6) [23 28] were reviewed. Eleven of the trials were published as full reports [8, 10, 12, 13, 15, 16, 19, 20, 24, 26, 28], while 10 were available only in abstract form [9, 11, 14, 17, 18, 21 23, 25, 27]. Patient characteristics and trial descriptions for those trials are shown in Table 2. The majority of the trials reported outcomes on similar patient groups. In most studies, patients were excluded if they were pregnant or nursing, experienced uncontrollable vomiting, showed clinically significant comorbidity, received previous chemotherapy treatment, or had brain metastases. Temozolomide was most commonly administered orally in doses of mg/m 2 for 5 days every 4 weeks. RESULTS Randomized Phase III Trials The first randomized, phase III trial, reported by Middleton et al. [3], compared temozolomide with single-agent i.v. DTIC in 305 patients. Results from that trial demonstrate that progression-free survival was significantly longer in patients treated with temozolomide (Table 3), with a reported hazard ratio (HR) of 1.37 (95% confidence interval [CI], ; p.012). The difference in the time to the first formal disease assessment between arms may have contributed to this statistically significant difference, because DTIC patients underwent the first formal assessment for disease progression 2 weeks earlier than temozolomide patients. The median survival

4 1116 Temozolomide Treatment for Melanoma Table 1. Temozolomide in metastatic melanoma randomized trial descriptions n of patients included Study (evaluable) Treatment description Description of patient population Randomized phase III trials (n 2) Middleton et al. (2000) [3] 156 (146) TMZ, 200 mg/m 2 per day, days 1 5 every 28 days 149 (141) DTIC, 250 mg/m 2 i.v., days 1 5 every 21 days Kaufmann et al. (2005) [4] 146 (134) TMZ, 200 mg/m 2, days 1 5 every 28 days 148 (137) TMZ, as above; IFN, 5 MIU/m 2 per day s.c., days 1, 3, and 5 every wk Randomized phase II trials (n 3) Bafaloukos et al. (2005) [5] 66 (62) TMZ, 200 mg/m 2 per day, days 1 5 every 28 days 66 (65) TMZ, 200 mg/m 2 per day, days 1 5; CDDP, 75 mg/m 2 i.v., day 1, every 28 days Danson et al. (2003) [6] 59 (55) TMZ, 200 mg/m 2 every 8 hours for 5 doses every 28 days 62 (62) TMZ, 200 mg/m 2 per day, days 1 5; IFN, 5 MIU s.c., 3 /wk 60 (60) TMZ, 150 mg/m 2 per day, days 1 5; THAL, 100 mg/day for 28 days Richtig et al. (2004) [7] 20 (20) TMZ, 150 mg m 2, days 1 5 every 28 days; IFN, 10 MIU/m 2 s.c. every other day 27 (27) TMZ, 150 mg m 2, days 1 5 every 28 days; IFN, 10 MIU every other day (fixed dose) time for patients treated with temozolomide was 7.7 months, versus 6.4 months for those treated with DTIC; however, the difference between the two treatment groups was not statistically significant (HR, 1.18; 95% CI, ; p.20). Twenty-one patients (14%) in the temozolomide arm showed an objective response to treatment, compared with 18 patients (12%) in the DTIC arm. Both treatment arms had four patients (3% in each group) who achieved a complete response. Grade 3 and 4 hematological toxicities were similar in the two treatment arms. It should be noted that this study, although large by melanoma trial standards, was not designed as an equivalence trial. Health-related quality of life data were reported for this patient population by both Middleton et al. [3] and Kiebert et al. [29]. Quality of life was assessed using the European Organization for Research and Treatment of Metastatic melanoma; WHO PS 0 2; no prior treatment for metastatic disease; brain metastases excluded Metastatic melanoma; brain metastases excluded; Karnofsky PS score 60 Advanced melanoma; no previous chemotherapy; brain metastases included; WHO PS score 0 2 Metastatic melanoma; no previous chemotherapy; brain metastases included (n 21); Karnofsky PS score 60 Metastatic melanoma; ECOG PS score 0 2; brain metastases included Abbreviations: CDDP, cisplatin; DTIC, dacarbazine; ECOG, Eastern Cooperative Oncology Group; IFN, interferon; MIU, million international units; PS, performance status; THAL, thalidomide; TMZ, temozolomide; WHO, World Health Organization. Cancer QLQ-C30 questionnaire. Measurements were taken at baseline and after completion of each 3-week (DTIC) or 4-week (temozolomide) cycle. The analysis did not detect statistically significant differences between the groups at baseline and after the first cycle. At 12 weeks, statistically significant improvements favoring temozolomide were reported for physical functioning, fatigue, and insomnia (p.05). However, it should be noted that quality of life data were available on only 50 patients receiving temozolomide and 31 patients receiving DTIC at 12 weeks, and DTIC was given on five consecutive days every 3 weeks rather than the more conventional schedule of once every 3 weeks. Those conditions may have potentially biased the quality of life results in favor of temozolomide. Therefore, definitive statements about quality of life are not possible. The second randomized phase III trial, published by

5 Quirt, Verma, Petrella et al Table 2. Temozolomide in metastatic melanoma single-arm trial descriptions Study n of patients included Treatment description Description of patient population Phase I and II trials (n 21) Single-agent temozolomide (n 9) Agarwala et al. (2004) [8] 155 (151) TMZ, mg/m 2 per day, days 1 5 every 28 days Serrone et al. (2004) [9] 27 (15) WBRT, 6 Gy/fraction 4 over 2 wks; TMZ, 150 mg/m 2 per day for 5 days every 28 days (5 wks after WBRT) Bedikian et al. (2003) [10] 14 (14) TMZ, 75 mg/m 2 per day for 21 days every 28 days a Berrocal et al. (2003) [11] 15 TMZ, 200 mg/m 2 per day for 5 days every 28 days Middleton et al. (2000) [12] 30 (25) TMZ, 1,000 mg/m 2 or 750 mg/m 2 split into 5 doses at 4-hour intervals, day 1 every 28 days Middleton et al. (1998) [13] 61 (50) TMZ, 150 or 200 mg/m 2 per day for 5 days every 28 days Lunn et al. (1997) [14] Bleehen et al. (1995) [15] 60 (56) TMZ, 150 or 200 mg/m 2 per day for 5 days every 28 days Metastatic melanoma to the brain; WHO PS score 0 1; adequate hepatic and renal function; no prior treatment for brain metastases Metastatic melanoma to the brain; not eligible for surgery and/or stereotactic radiosurgery; no prior treatment for brain metastases Metastatic choroidal melanoma; Zubrod PS score 2; measurable disease; no prior DTIC; no symptomatic brain metastases Metastatic melanoma; Karnofsky PS score 60; no previous chemotherapy; brain metastases excluded Metastatic melanoma; WHO PS score of 3 or better; two patients with brain metastases included Patients with progressive advanced malignant melanoma; WHO PS score 3; no chemotherapy or radiotherapy in 4 wks prior; brain metastases excluded NR (24) TMZ, dose NR Advanced malignant melanoma Patients with advanced malignant melanoma with progressive disease; WHO PS score 2; no prior chemotherapy Newlands et al. (1992) [16] b 23 (23) TMZ, 750 1,000 mg/m 2 over 5 days Advanced cancer refractory to standard forms of therapy Temozolomide plus IFN- (n 6) Dereure et al. (2004) [17] Krown et al. (2004) [18] 31 (31) TMZ, mg/m 2 per day, days 1 5 every 28 days; peg-ifn, g/wk 30 (30) TMZ, 75 mg/m 2 per day for 6 wks, every 8 wks; peg-ifn, 0.5 g/kg per wk Ridolfi et al. (2004) [19] 41 (40) TMZ, 200 mg/m 2 per day, days 1 5 every 28 days; IFN, 5 MIU s.c. 3 /wk Agarwala and Kirkwood (2003) [20] Delva et al. (2003) [21] Garcia Martin et al. (2002) [22] 23 (23) TMZ, 150 or 200 mg/m 2 per day for 5 days every 28 days; IFN-a2b, 5.0, 7.5, or 10 MIU/m 2 per day s.c. 3 /wk 34 (33) TMZ, 150 mg/m 2 per day for 5 days every 28 days; IFN-a, 20 MIU/m 2 per day i.v., days 1 5 for 4 wks, then 10 MIU s.c. 3 /wk for 4 wks 25 (25) TMZ, 150 mg/m 2 per day for 5 days every 28 days; IFN, 10 MIU/m 2 s.c. 3 /wk Metastatic melanoma; prior therapy allowed; brain metastases excluded Unresectable stage III or IV melanoma; measurable disease; brain metastases excluded; Karnofsky PS score 70 Metastatic melanoma; ECOG PS score 2; prior adjuvant therapy allowed; brain metastases excluded Stage IV malignant melanoma; ECOG PS score 0 1; no prior chemotherapy or biologic therapy for stage IV disease; brain metastases excluded Metastatic melanoma; no prior therapy for stage IV disease; PS score 2 Metastatic melanoma; no prior therapy for metastatic disease; PS score 0 2. (continued)

6 1118 Temozolomide Treatment for Melanoma Table 2. (Continued) Study n of patients included Treatment description Description of patient population Temozolomide plus thalidomide (n 6) Okeke et al. (2005) [23] 30 (9) TMZ, 75 mg/m 2 per day for 6 wks of 8-wk cycle; THAL, 200 mg/day for 2 c Hwu et al. (2005) [24] 26 TMZ, 75 mg/m 2 per day for 6 wks; THAL, mg/day Atkins et al. (2005) [25] 40 (39) TMZ, 75 mg/m 2 per day for 6 wks; THAL, 100 mg/day for 4 wks; d WBRT, 30 Gy in 10 fractions, days 1 5 and 8 12 Hwu et al. (2003) [26] 38 (38) TMZ, 75 mg/m 2 per day for 6 wks; THAL, 100 or 200 mg/day Mehta et al. (2003) [27] 14 (9) TMZ, 75 mg/m 2 per day for 6 wks; THAL, mg/day Hwu et al. (2002) [28] 12 (12) TMZ, 50 mg/m 2 per day for 6 wks every 10 wks or 75 mg/m 2 per day for 6 wks with breaks of 4, 3, or 2 wks; THAL, mg/day Kaufmann et al. [4], compared single-agent temozolomide with temozolomide combined with IFN- 2b in 294 patients (Table 3). Kaufmann et al. [4] reported a significantly higher response rate for temozolomide combined with IFN than for single-agent temozolomide (24% versus 13%; p.036) [4]. In the combination arm, complete response was achieved by 11 patients (8%) and partial response was evident in 22 patients (16%), compared with three patients (2%) and 15 patients (11%), respectively, in the temozolomide group. The median overall survival time was reported as 8.4 months for the temozolomide group (95% CI, ) and 9.7 months for the temozolomide plus IFN group (95% CI, ); no statistical significance was detected. Grades 3 and 4 hematological toxicities were significantly higher in patients receiving the combination treatment. Thrombocytopenia occurred in 23% of the temozolomide plus IFN-treated patients compared with only 4% of temozolomide-treated patients (p.0001). In the combination group, 21% of the patients developed leukopenia, whereas only 4% of patients suffered from Metastatic melanoma; 4 patients with brain metastases; prior therapy allowed; PS score 0 2 All patients had brain metastases; Karnofsky PS score 70; no prior chemotherapy, radiotherapy, or biologic therapy All patients had brain metastases; patients with prior cytotoxic chemotherapy, WBRT, or THAL were excluded; ECOG PS score 0 1 Unresectable melanoma; Karnofsky PS score 70; brain metastases excluded Metastatic melanoma; 3 patients with brain metastases included; prior therapy allowed; WHO PS score 0 2 Stage III or IV unresectable metastatic melanoma; no prior systemic chemotherapy; Karnofsky PS score 70; brain metastases excluded a The first five patients received 75 mg/m² per day, the subsequent nine received 85 mg/m² per day. b Trial included 42 patients total, 23 patients with melanoma. c Following the first 2 weeks, increased by 100 mg/day weekly up to a maximum of 400 mg/day without interruption. d Following the first 4 weeks, increased by 100 mg/day at weeks 5, 7, and 9, as tolerated, to a maximum dose of 400 mg/day; patients without central nervous system or clinically significant systemic progression received additional cycles of TMZ (same dose) and THAL (maximum-tolerated dose from cycle 1) at 10-week intervals. Abbreviations: DTIC, dacarbazine; ECOG, Eastern Cooperative Oncology Group; IFN, interferon; MIU, million international units; NR, not reported; peg, pegylated; PS, performance status; THAL, thalidomide; TMZ, temozolomide; WBRT, whole-brain radiation therapy; WHO, World Health Organization. this adverse effect in the temozolomide group (p.0001). Randomized Phase II Trials In a phase II trial, reported by Bafaloukos et al. [5], 132 patients were randomized to receive temozolomide alone or in combination with cisplatin (Table 3). There were no statistically significant differences in the overall median survival time, time to disease progression, or objective response rate between the two arms. Toxicity was comparable between the two treatments, except that grade 3 or 4 emesis was significantly higher in the combination treatment arm (p.002). The trial detected some evidence of antitumor activity in the central nervous system (CNS), including three partial responses in brain metastases (one in the temozolomide arm and two in the combination arm). Only 16% of patients receiving temozolomide alone and 18% of patients receiving temozolomide with cisplatin developed CNS metastases (median follow-up of 39.9 and 37 months, respectively), further

7 Quirt, Verma, Petrella et al Table 3. Temozolomide in metastatic melanoma randomized trial outcomes Study Treatment Randomized phase III trials (n 2) Middleton et al. (2000) [3] Kaufmann et al. (2005) [4] Randomized phase II trials (n 3) Bafaloukos et al. (2005) [5] Danson et al. (2003) [6] Richtig et al. (2004) [7] Response rate (%) suggesting that treatment with temozolomide may prevent the occurrence of brain metastases. A phase II trial, reported by Danson et al. [6], randomized 181 patients to receive either temozolomide alone or combined with either IFN or thalidomide (Table 3). Twenty-one patients with brain metastases were included in that trial. Only one of those patients, receiving temozolomide plus thalidomide, achieved a partial response. Eleven additional patients developed brain metastases (two, singleagent temozolomide; four, temozolomide plus IFN; and five, temozolomide plus thalidomide). The study was not designed or powered to make statistical comparisons among the different treatment regimens. Richtig et al. [7] randomized 47 patients to a treatment combination of temozolomide and IFN; the latter was administered in two different dosages (Table 3); however, no PFS or TTP (median months) Overall survival (median months) statistically significant differences in overall survival, response rate, or time to progression were reported. Single-Arm Phase I and II Trials Grade 3 or 4 adverse effects TMZ OR, 14; CR, 3 PFS, Anemia, 2%; neutropenia, 3%; thrombocytopenia, 7% DTIC OR, 12; CR, 3 PFS, 1.5 (p.012) 6.4 (p.20) Anemia, 1%; neutropenia, 2%; thrombocytopenia, 8% TMZ OR, 13; CR, 2 PFS, Thrombocytopenia, 4%; nausea/vomiting, 4%; Leukopenia, 4% TMZ IFN OR, 24; CR, 8; p.036 PFS, Thrombocytopenia, 23%; nausea/vomiting, 4%; Leukopenia, 21%; constitutional/fever, 3% TMZ OR, 26; CR, 8 TTP, Nausea/vomiting, 0%; thrombocytopenia, 14%; leukopenia, 3%; anemia, 3%; neutropenia, 8% TMZ CDDP OR, 29; CR, 11 TTP, Nausea/vomiting, 15%; thrombocytopenia, 14%; leukopenia, 5%; anemia, 2%; neutropenia, 5% TMZ OR, 9 PFS, 11.7; a CR, Anemia, 8% versus 2% versus 0%; neutropenia, TMZ IFN OR, 18; CR, 3 PFS 9.0 a % versus 21% versus TMZ THAL OR, 15; CR, 3 PFS, 7.5 a 7.3 2%; thrombocytopenia, 34% versus 23% versus 0% TMZ IFN OR, 35; CR, 5 TTP, 4.1 b 14.5 b Thrombopenia, 15%; TMZ IFN OR, 23; CR, leukopenia, 6% fixed dose 15 a Progression-free survival reported only for patients demonstrating a response to treatment (n 39). b Mean. Abbreviations: CDDP, cisplatin; CR, complete response; DTIC, dacarbazine; IFN, interferon; OR, objective response; PFS, progression-free survival; THAL, thalidomide; TMZ, temozolomide; TTP, time to progression. Single-Agent Temozolomide Temozolomide was investigated in various doses and schedules (Table 2) in nine single-arm phase I or II trials [8 16]. The response rates observed in those trials ranged from 0% 29%, with complete responses observed in 0% 17% of patients. The median overall survival time ranged from months (Table 4). Quality of life was not assessed in any of the trials. Temozolomide plus IFN- Six single-arm phase I or II trials were located investigating temozolomide plus IFN- [17 22]. Four were available

8 1120 Temozolomide Treatment for Melanoma Table 4. Temozolomide in metastatic melanoma single-arm trial outcomes Study Treatment Response rate (%) PFS or TTP (median months) Phase I and II trials (n 21) Overall survival (median months) Grade 3 or 4 adverse effects Single-agent temozolomide (n 9) Agarwala et al. (2004) [8] Serrone et al. (2004) [9] Bedikian et al. (2003) [10] Berrocal et al. (2003) [11] Middleton et al. (2000) [12] Middleton et al. (1998) [13] Lunn et al. (1997) [14] Bleehen et al. (1995) [15] TMZ OR, 6; CR, 1 PFS: Prior CT, 1.0; no prior CT, Headache, 9%; nausea/vomiting, 14%; asthenia, 7%; pain, 7%; thrombocytopenia, 3%; neutropenia, 2% TMZ OR, 20; CR, 0 NR 5.9 NR TMZ OR, 0; CR, 0 TTP, Fatigue, 19%; pain, 26%; constipation, 26%; anorexia, 4%; fever, 4% a TMZ OR, 13 NR 13.1 Platelet, 7% TMZ OR, 23; CR, 3; MDR, 6.6 months TTP, Thrombocytopenia, 63%; leukopenia, 50%; anemia, 20% TMZ OR, 14; CR, 6 TTP, Neutropenia, 4%; thrombocytopenia, 5% TMZ OR, 29; CR, 17 NR NR NR TMZ OR, 21; CR, 5; MDR, 6 months NR 5.5 (14.5 for responders) Leukopenia, 27%; thrombocytopenia, 5%; neutropenia, 4%; fever, 2%; infection, 2% Newlands et al. (1992) [16] TMZ OR, 17; CR, 9 NR NR NR separately for melanoma Temozolomide plus interferon- (n 6) Dereure et al. (2004) [17] TMZ IFN OR, 13; CR, 7 NR 12.0 Thrombocytopenia, 13% Krown et al. (2004) [18] Ridolfi et al. (2004) [19] Agarwala and Kirkwood (2003) [20] Delva et al. (2003) [21] Garcia Martin et al. (2002) [22] Temozolomide plus thalidomide (n 6) Okeke et al. (2005) TMZ THAL [23] TMZ IFN OR, 23; CR, 3 NR 8.5 Lymphopenia, 37%; leukopenia, 3% TMZ IFN OR, 13; CR, 5; MDR, 2.5 months TTP, Hematologic, 17%; nausea/ vomiting, 5%; cardiac, 1%; respiratory, 1% TMZ IFN OR, 17; CR, 4 NR 9.0 Fatigue, 26%; nausea/vomiting, 26%; leukopenia, 4%; thrombocytopenia, 17% TMZ IFN OR, 21; CR, 6 TTP, Fatigue, 15%; neutropenia, 12%; cytolysis, 24% TMZ IFN OR, 20; CR, 4; MDR, 7 months OR, 22; CR, 11 TTP, Neutropenia, 16%; thrombocytopenia, 8%; anemia, 8%; hepatotoxicity, 16% NR NR Thrombocytopenia, 17%; anemia, 5%; thrombosis, 5%; shingles, 5% Hwu et al. (2005) [24] TMZ THAL OR, 12; CR, 8 NR 5.0 Lymphopenia, 35%; CNS hemorrhage, 27%; thrombosis, 16%; neurosensory, 8%; nausea, 8% Atkins et al. (2005) [25] TMZ THAL WBRT OR, 8; CR, 3 TTP, Deep vein thrombosis, 8%; pulmonary embolism, 3%; myelosuppression, 5%; CNS events, 21%; cardiac, 8% (continued)

9 Quirt, Verma, Petrella et al Table 4. (Continued) Study Treatment Response rate (%) only in abstract form [17, 18, 21, 22]. All but one of the trials investigated temozolomide at a dose of mg/m 2 per day for 5 days every 28 days (Table 2). The response rates observed in those trials ranged from 13% 23%, with complete responses observed in 3% 7% of patients. The median overall survival time ranged from months (Table 4). Quality of life was not assessed in any of the trials. Temozolomide plus Thalidomide The literature search located six single-arm phase I or II trials investigating temozolomide plus thalidomide [23 28]. Three were available only in abstract form [23, 25, 27]. All trials used a prolonged dosing schedule for temozolomide (daily for 6 weeks) (Table 2). The response rates observed in those trials ranged from 8% 42%, with complete responses observed in 0% 11% of patients. Median survival in the six studies ranged from four to 12.3 months (Table 4). Hwu et al. [24] investigated the combination therapy in patients with brain metastases and observed a 12% objective response rate, with an 8% complete response rate. Quality of life was not assessed in any of the trials. DISCUSSION Treatment options for patients with unresectable metastatic malignant melanoma are limited. Despite the promising results sometimes observed in small cohort studies of singleagent or combination chemotherapy, in larger cohort studies or in randomized controlled trials, systemic chemotherapy has produced low rates of partial responses of brief duration. DTIC is currently regarded by many oncologists as the standard of care, despite the fact that this agent consistently elicits objective response rates well below 20% [3, 30, 31] and rarely results in complete responses. To date, no PFS or TTP (median months) Overall survival (median months) Grade 3 or 4 adverse effects Hwu et al. (2003) [26] TMZ THAL OR, 32; CR, 3 NR 9.5 Lymphopenia, 37%; leukopenia, 11%; neutropenia, 5%; anemia, 3%; thrombocytopenia, 3% Mehta et al. (2003) [27] TMZ THAL OR, 11; CR, 0 NR NR Constipation, 11% Hwu et al. (2002) [28] TMZ THAL OR, 42; CR, 8 NR 12.3 Deep vein thrombosis, 8%; pulmonary embolism, 8% a Percent of total courses. Abbreviations: CNS, central nervous system; CR, complete response; CT, chemotherapy; IFN, interferon; MDR, Median duration of response; NR, not reported; OR, objective response; PFS, progression-free survival; THAL, thalidomide; TMZ, temozolomide; TTP, time to progression; WBRT, whole-brain radiation therapy. systemic approach has demonstrated an overall survival benefit in a randomized clinical trial. Numerous biologic therapies have been evaluated in metastatic melanoma. The results of treatment with interleukin-2 generated much interest after demonstrating the potential to produce durable complete remissions in a small percentage of patients. A combination of chemotherapy with IFN and interleukin-2 (biochemotherapy) initially appeared to produce a high response rate with a substantial number of durable complete remissions. However, a recent large randomized study has yielded the disappointing result that this approach is no better than chemotherapy alone [32]. The use of interleukin-2 and biochemotherapy are the subjects of other reviews and practice guidelines under development by the Melanoma DSG. Temozolomide is a novel, oral, alkylating agent that has demonstrated antitumor activity along with relatively modest toxicity. Furthermore, temozolomide represents a systemic treatment that produces the least inconvenience for the patient while still having comparable activity to DTIC. In a direct comparison of the two agents, Middleton et al. [3] reported equal efficacy for response rate (13.5% temozolomide, 12.1% DTIC) and overall survival (7.7 versus 6.4 months, respectively). In contrast to DTIC and other standard agents such as cisplatin and interleukin-2, temozolomide is the only treatment to penetrate the blood brain barrier demonstrating antitumor activity. In patients with advanced melanoma, high CNS penetration is imperative because most cases of brain metastases lead directly to death. Recent clinical studies have demonstrated that the incidence of brain metastases in patients with melanoma ranges from 10% 40%, and autopsy studies identify CNS involvement in approximately two thirds of melanoma patients [33 35]. In addition, a large retro-

10 1122 Temozolomide Treatment for Melanoma spective review on 702 melanoma patients with brain metastases reported a median overall survival time of 3.8 months [33]. Because responses in brain tumors have rarely been achieved with other chemotherapy agents, the temozolomide results hold promising possibilities for melanoma patients. In a recent study by Hwu et al. [24], temozolomide appeared to have superior activity in the CNS and produced objective responses in the brain. Likewise, Bafaloukos et al. [5] reported antitumor activity in the CNS and a regression in brain metastases. In a retrospective study [36], where 20 patients responded to treatment with temozolomide and 21 to treatment with DTIC, only two patients (10%) treated with temozolomide developed brain metastases compared with nine patients (43%) treated with DTIC. That result was found to be statistically significant (p.03) despite the small number of patients used in the study. Although either surgery or radiation is the preferred treatment modality for patients with brain metastases from melanoma, temozolomide is the preferred chemotherapy if patients with brain metastases require systemic treatment. The management of brain metastases in melanoma patients is the subject of a separate review and practice guideline currently under development by the Melanoma DSG. Single-agent temozolomide was compared with temozolomide combined with INF- in one randomized, controlled trial [4]. The results indicate a significantly higher response rate with the combination treatment but no difference in overall survival, at the cost of greater hematological toxicity. Based on that limited evidence, this combination is not recommended for patients with metastatic melanoma at this time. REFERENCES The evidence on temozolomide combined with thalidomide is still preliminary. The combination was included as a treatment arm in one randomized phase II study [6] and has been investigated in six single-arm phase I or II studies. Although the initial response rates that have been reported are encouraging, further evidence from randomized trials is required before a recommendation for or against this combination treatment can be made. CONCLUSION There are few treatment options for patients with metastatic melanoma. Evidence from a randomized, phase III trial indicates that single-agent temozolomide has a similar efficacy and toxicity profile to DTIC, which is considered the current standard of care. Results of single-arm trials of temozolomide suggest this agent is a promising treatment option for this patient population. The addition of IFN to temozolomide resulted in higher response rates; however, survival was similar for both treatments and the combination was associated with higher toxicity. Therefore, this combination is not indicated for metastatic melanoma. Temozolomide has shown promising results in the treatment of brain metastases from melanoma and may be a reasonable option if surgery or radiation is not appropriate. ACKNOWLEDGMENTS A complete list of Melanoma Disease Site Group members is available at The Program in Evidence-based Care is supported by, but editorially independent of, Cancer Care Ontario and the Ontario Ministry of Health and Long-Term Care. 1 National Cancer Institute of Canada. Canadian Cancer Statistics Toronto, Canada: National Cancer Institute of Canada, 2005: Browman GP, Levine MN, Mohide EA et al. The practice guidelines development cycle: A conceptual tool for practice guidelines development and implementation. J Clin Oncol 1995;13: 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 2000;18: Kaufmann R, Spieth K, Leiter U et al. 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. J Clin Oncol 2005;23: Bafaloukos D, Tsoutsos D, Kalofonos H et al. Temozolomide and cisplatin versus temozolomide in patients with advanced melanoma: A randomized phase II study of the Hellenic Cooperative Oncology Group. Ann Oncol 2005;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 2003;21: Richtig E, Hofmann-Wellenhof R, Pehamberger H et al. Temozolomide and interferon alpha 2b in metastatic melanoma stage IV. Br J Dermatol 2004;151: 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 2004;22: Serrone L, Freschi A, Chiarion-Sileni V et al. Radiotherapy followed by temozolomide in the treatment of patients with melanoma metastatic to the brain: An Italian multicentre study. J Clin Oncol (Meeting Abstracts) 2004; 22(14 suppl): Bedikian AY, Papadopoulos N, Plager C et al. Phase II evaluation of temozolomide in metastatic choroidal melanoma. Melanoma Res 2003;13: Berrocal A, Blasco A, Camps C et al. Phase II trial of long term temozolomide administration in metastatic melanoma. Preliminary results. Proc Am Soc Clin Oncol 2003;22: Middleton MR, Lee SM, Arance A et al. O6-methylguanine formation, repair protein depletion and clinical outcome with a 4 hr schedule of temo-

11 Quirt, Verma, Petrella et al zolomide in the treatment of advanced melanoma: Results of a phase II study. Int J Cancer 2000;88: 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 1998;78: Lunn JM, Wedge SR, Rustin G et al. Measurement of pretreatment levels of O6-methylguanine-DNA methyltransferase (MGMT) in tumor biopsies as an indication of the clinical response of malignant melanoma to temozolomide [Abstract]. Proc Am Assoc Cancer Res 1997;38: Bleehen NM, Newlands ES, Lee SM et al. Cancer Research Campaign phase II trial of temozolomide in metastatic melanoma. J Clin Oncol 1995; 13: Newlands ES, Blackledge GR, Slack JA et al. Phase I trial of temozolomide (CCRG 81045: M&B 39831: NSC ). Br J Cancer 1992;65: Dereure O, Khamari A, Cupissol D et al. Multicenter phase I/II study evaluating maximal tolerated dosage and clinical efficacy of an association of temozolomide with Peg-Intron in patients with metastatic melanoma. J Clin Oncol (Meeting Abstracts) 2004;22(14 suppl):722s. 18 Krown SE, Hwu WJ, Menell JH et al. A phase II study of temozolomide (TMZ) and pegylated interferon alpha-2b (PGI) in the treatment of advanced melanoma. J Clin Oncol (Meeting Abstracts) 2004;22(14 suppl): 718s. 19 Ridolfi R, Romanini A, Sileni VC et al. Temozolomide and interferonalpha in metastatic melanoma: A phase II study of the Italian Melanoma Intergroup. Melanoma Res 2004;14: Agarwala SS, Kirkwood JM. Temozolomide in combination with interferon alpha-2b in patients with metastatic melanoma. A phase I doseescalation study. Cancer 2003;97: Delva R, Lesimple T, Delcambre C et al. A phase II study of sub-cutaneous (sc) interferon alpha (IFN) and oral temozolomide (TMZ) combination after chemo-sensibilisation by high doses intravenous (iv) IFN as first-line treatment in patients with metastatic malignant melanoma. Proc Am Soc Clin Oncol 2003;22: Garcia Martin M, 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 2002;21: Okeke I, Laber D, Bev T et al. Temozolomide and thalidomide in the treatment of advanced melanoma, a phase II study. J Clin Oncol (Meeting Abstracts) 2005;23(16 suppl):718s. 24 Hwu WJ, Lis E, Menell JH et al. Temozolomide plus thalidomide in patients with brain metastases from melanoma: A phase II study. Cancer 2005;103: Atkins MB, Sosman J, Agarwala S et al. A Cytokine Working Group phase II study of temozolomide (TMZ), thalidomide (THAL) and whole brain radiation therapy (WBRT) for patients with brain metastases from melanoma. J Clin Oncol (Meeting Abstracts) 2005;23(16 suppl):723s. 26 Hwu WJ, Krown SE, Menell JH et al. Phase II study of temozolomide plus thalidomide for the treatment of metastatic melanoma. J Clin Oncol 2003; 21: Mehta AC, Laber DA, McMasters KM et al. A phase II study of temozolomide and thalidomide in the treatment of advanced melanoma. Proc Am Soc Clin Oncol 2003;22: Hwu WJ, Krown SE, Panageas KS et al. Temozolomide plus thalidomide in patients with advanced melanoma: Results of a dose-finding trial. J Clin Oncol 2002;20: 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 2003; 21: 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 1999;17: Millward MJ, Bedikian AY, Vonry RM et al. Randomized multinational phase III trial of dacarbazine with or without BCL-2 antisense in patients with advanced malignant melanoma: Analysis of long term survival. Proc Am Soc Clin Oncol 2004;22:711s. 32 Atkins MB, Lee S, Flaherty LE et al. A prospective randomized phase III trial of concurrent biochemotherapy (BCT) with cisplatin, vinblastine, dacarbazine (CVD), IL-2 and interferon alpha-2b (IFN) versus CVD alone in patients with metastatic melanoma (E3695): An ECOG-coordinated intergroup trial. Proc Am Soc Clin Oncol 2003;22: Sampson JH, Carter JH Jr, Friedman AH et al. Demographics, prognosis, and therapy in 702 patients with brain metastases from malignant melanoma. J Neurosurg 1998;88: Amer MH, Al-Sarraf M, Vaitkevicus VK. Clinical presentation, natural history and prognostic factors in advanced malignant melanoma. Surg Gynecol Obstet 1979;149: Budman DR, Camacho E, Wittes RE. The current causes of death in patients with malignant melanoma. Eur J Cancer 1978;14: Paul MJ, Summers Y, Calvert AH et al. Effect of temozolomide on central nervous system relapse in patients with advanced melanoma. Melanoma Res 2002;12:

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