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The Oncologist, Vol. 12, No. 9, 1114-1123, September 2007; doi:10.1634/theoncologist.12-9-1114
© 2007 AlphaMed Press

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Melanoma and Cutaneous Malignancies

Temozolomide for the Treatment of Metastatic Melanoma: A Systematic Review

Ian Quirta, Shailendra Vermab, Teresa Petrellac, Kate Bakd, Manya Charetted

aPrincess Margaret Hospital, Toronto, Canada; bOttawa Hospital, Ottawa, Canada; cToronto Sunnybrook Regional Cancer Centre, Toronto, Canada; dCancer Care Ontario Program in Evidence-Based Care, McMaster University, Hamilton, Canada

Key Words. Melanoma • Temozolomide • Temodal • Chemotherapy • Systematic review

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: 905-525-9140, ext. 22115; Fax: 905-522-7681; e-mail: stysnor{at}mcmaster.ca

Received January 26, 2007; accepted for publication June 25, 2007.

Disclosure: No potential conflicts of interest were reported by the authors, planners, reviewers, or staff managers of this article.


   ABSTRACT
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Conclusion
 Acknowledgments
 References
 
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 2005. 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-{alpha}, 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-{alpha} 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-{alpha} 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.


   INTRODUCTION
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Conclusion
 Acknowledgments
 References
 
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 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 single-agent temozolomide, or temozolomide in combination with interferon (IFN)-{alpha} or thalidomide, in order to provide treatment recommendations for this agent.


   METHODS
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Conclusion
 Acknowledgments
 References
 
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 (http://www.cancercare.on.ca).

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-{alpha} 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.


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  		Table 1. Temozolomide in metastatic melanoma—randomized trial descriptions

 
In addition, phase I or II trials investigating single-agent temozolomide (n = 9) [8–16], temozolomide plus IFN-{alpha} (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 2Go.


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  		Table 2. Temozolomide in metastatic melanoma—single-arm trial descriptions

 


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  		Table 2. (Continued)

 
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 150–200 mg/m2 for 5 days every 4 weeks.


   RESULTS
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Conclusion
 Acknowledgments
 References
 
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], 1.07–1.75; 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 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, 0.92–1.52; 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.


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  		Table 3. Temozolomide in metastatic melanoma—randomized trial outcomes

 
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 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 Kaufmann et al. [4], compared single-agent temozolomide with temozolomide combined with IFN-{alpha} 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, 7.07–9.72) and 9.7 months for the temozolomide plus IFN group (95% CI, 8.26–11.18); 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 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 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, single-agent 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 statistically significant differences in overall survival, response rate, or time to progression were reported.

Single-Arm Phase I and II Trials

Single-Agent Temozolomide
Temozolomide was investigated in various doses and schedules (Table 2Go) 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 3.2–13.1 months (Table 4Go). Quality of life was not assessed in any of the trials.


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  		Table 4. Temozolomide in metastatic melanoma—single-arm trial outcomes

 


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  		Table 4. (Continued)

 

Temozolomide plus IFN-{alpha}
Six single-arm phase I or II trials were located investigating temozolomide plus IFN-{alpha} [17–22]. Four were available only in abstract form [17, 18, 21, 22]. All but one of the trials investigated temozolomide at a dose of 150–200 mg/m2 per day for 5 days every 28 days (Table 2Go). 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 8.5–12.0 months (Table 4Go). 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 2Go). 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 4Go). 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
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Conclusion
 Acknowledgments
 References
 
Treatment options for patients with unresectable metastatic malignant melanoma are limited. Despite the promising results sometimes observed in small cohort studies of single-agent 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 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 retrospective 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-{alpha} 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.

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
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
Acknowledgments
 References
 
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
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
 Acknowledgments
References
 
A complete list of Melanoma Disease Site Group members is available at http://www.cancercare.on.ca/. 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.


   REFERENCES
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
 Acknowledgments
 References
 

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Genomic and Molecular Profiling Predicts Response to Temozolomide in Melanoma
Clin. Cancer Res., January 15, 2009; 15(2): 502 - 510.
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A. M. Giammarioli, A. Maselli, A. Casagrande, L. Gambardella, A. Gallina, M. Spada, A. Giovannetti, E. Proietti, W. Malorni, and M. Pierdominici
Pyrimethamine Induces Apoptosis of Melanoma Cells via a Caspase and Cathepsin Double-Edged Mechanism
Cancer Res., July 1, 2008; 68(13): 5291 - 5300.
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C. K. Augustine, Y. Yoshimoto, M. Gupta, P. A. Zipfel, M. A. Selim, P. Febbo, A. M. Pendergast, W. P. Peters, and D. S. Tyler
Targeting N-Cadherin Enhances Antitumor Activity of Cytotoxic Therapies in Melanoma Treatment
Cancer Res., May 15, 2008; 68(10): 3777 - 3784.
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