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Temozolomide for Treating Malignant Melanoma Rong-Hua Li1, Xiao-Yang Hou1, Chun-Sheng Yang2, Wen-Lou Liu1, Jian-Qin Tang1, Yan-Qun Liu1 and Guan Jiang1

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Temozolomide for Treating Malignant Melanoma Rong-Hua Li1, Xiao-Yang Hou1, Chun-Sheng Yang2, Wen-Lou Liu1, Jian-Qin Tang1, Yan-Qun Liu1 and Guan Jiang1 REVIEW ARTICLE Temozolomide for Treating Malignant Melanoma Rong-Hua Li1, Xiao-Yang Hou1, Chun-Sheng Yang2, Wen-Lou Liu1, Jian-Qin Tang1, Yan-Qun Liu1 and Guan Jiang1 ABSTRACT Melanoma is one of the most malignant forms of skin cancer; with a rapidly increasing prevalence. Early-stage melanoma is curable, but advanced metastatic melanoma is almost always fatal, and patients with such advanced disease have short median survival. Surgery and radiotherapy play a limited role in the treatment of metastatic melanoma. Rather, chemotherapy remains the mainstay of treatment, although other approaches, including biotherapy and gene therapy, have been attempted. The authors hereby, evaluated the use of temozolomide (TMZ) for treating metastatic melanoma compared to dacarbazine (DTIC), the effectiveness of TMZ for treating brain metastases, as well as TMZ resistance and how the efficacy of TMZ in malignant melanoma can be increased. Two chemotherapeutic regimens are commonly used for palliative treatment of malignant melanoma: intravenous administration of DTIC and oral administration of the alkylating agent temozolomide (TMZ). Compared to DTIC, TMZ is very well tolerated and has an advantage in terms of improving the quality of life of patients with metastatic melanoma. While the prognosis is currently unpromising, chemotherapy plays a palliative role for patients with metastatic melanoma. The toxicity of treatment regimens based on DTIC and TMZ do not differ significantly, although TMZ is costlier. These findings provide a reference for future researchers via a comprehensive analysis of the relevant literature. Key Words: Metastatic melanoma. Temozolomide. Dacarbazine. Nanocarriers. Cancer therapy. INTRODUCTION soureas, platinum analogs, vinca alkaloids, and the 9,10 Each year, about 200,000 cases of melanoma are taxanes. diagnosed and there are 48,000 melanoma-related TMZ is an oral agent, therefore, it has potential deaths worldwide.1 The incidence of metastatic advantages over DTIC in terms of convenience. It can melanoma increases every year, and the death rate cross the blood-brain barrier (BBB), which could continues to rise faster than that of most cancers.2,3 potentially reduce the incidence of brain metastases.11 Melanoma is surgically curable when discovered at an However, the response rate of TMZ is generally low due early stage; however, once regional and systemic to drug resistance. Several studies have focused on the spread occurs, treatment options are limited and effectiveness of TMZ in malignant melanoma. In this generally considered ineffective.4 The prognosis for review, we provide an overview of recent advances of metastatic melanoma is poorer and the 5-year survival TMZ for this disease. rate is less than 10%.5 In recent years, with the Comparison of TMZ and DTIC for treating malignant development of targeted immune therapy and melanoma: DTIC, a cell cycle-nonspecific antineo- individualized targeted therapy, the treatment of plastic agent, is the most tested single chemo- melanoma made significant progress. They include therapeutic agent.12 Hepatic metabolism is required to kinase inhibitors acting on cellular pathways, anti- yield the active metabolite 5-(3-methyl-1-triazeno) cytotoxic T-lymphocyte-associated antigen-4 mono- imidazole-4-carboxamide (MTIC) of DTIC. MTIC clonal antibody, PD-1 monoclonal antibody and so on.6 decomposes into a purine and a methyldiazonium ion, But these new medicines are very expensive. Therefore, which is the active alkylating species. The usefulness of chemotherapy for melanoma patients is still an important DTIC may, therefore, be limited in patients with liver means of treatment at this stage.7 Adjuvant therapy is metastases. Furthermore, DTIC does not cross the BBB, partially effective,8 and a number of chemotherapeutic and is therefore ineffective for treating brain metastases. agents have activity in metastatic melanoma, including DTIC also requires repeated intravenous administration, dacarbazine (DTIC), temozolomide (TMZ), the nitro- which is often less convenient for patients.13,14 TMZ is an orally active congener of DTIC with broad- 1 Department of Dermatology, Affiliated Hospital of Xuzhou spectrum anti-tumor activity. Both TMZ and DTIC Medical College, Xuzhou-221002, China. methylate the O6-guanine of DNA, generating cytotoxic 2 Department of Dermatology, Affiliated Huai'an Hospital of adducts that result in the initiation of cellular repair Xuzhou Medical College, Huai'an-223002, China. mechanisms or apoptosis. However, TMZ does not Correspondence: Dr. Guan Jiang, Department of Dermatology, require hepatic P450 and converts to the same active Affiliated Hospital of Xuzhou Medical College, Xuzhou-221002, MTIC at physiological pH. Moreover, TMZ has 100% oral Jiangsu Province, China. bioavailability with predictable pharmacokinetics and E-mail: [email protected] extensive tissue distribution, including penetration of the Received: October 15, 2014; Accepted: July 24, 2015. BBB.8,9,13,14 680 Journal of the College of Physicians and Surgeons Pakistan 2015, Vol. 25 (9): 680-688 Temozolomide for treating malignant melanoma Efficacy and safety of TMZ versus DTIC: In a phase III TMZ than DTIC ($6,902 vs. $3,697, respectively).14 The trial involving 305 patients, TMZ was not significantly incremental cost-effectiveness ratio of using TMZ was more efficacious than DTIC in terms of overall survival $36,990 per life-year or $101 per day of life gained, (OS, 7.7 vs. 6.4 months) and progression-free survival demonstrating that TMZ is more expensive than DTIC. 7 (PFS, 1.9 vs. 1.5 months). Patel et al. later conducted a TMZ for treating brain metastases in malignant large, randomized, open-label phase III study to melanoma: The BBB is a semi-permeable and selective determine whether an extended schedule of TMZ would barrier that protects the Central Nervous System (CNS) be more effective than standard single-agent DTIC for from undesirable toxic or infectious agents and at the treating patients with metastatic melanoma.15 They same time supplies the brain with the required found no difference in either OS (9.1 vs. 9.4 months) or biologically essential molecules such as glucose or PFS (2.3 vs. 2.2 months).15 Recently, Teimouri et al. hormones. A major obstacle to the management of compared the effectiveness and side effects of TMZ with malignant melanoma with brain metastases is the that of DTIC via a meta-analysis involving 1314 patients. inability to deliver therapeutic agents to the tumor They found a non-significant relative risk (RR) of 0.83 effectively.18 [95% confidence interval (CI): 0.26 - 2.64, p = 0.76] for complete response, 1.05 (95% CI: 0.85 - 1.3, p = 0.65) Temozolomide: a prodrug and an imidazotetrazine for stable disease, and 2.64 (95% CI: 0.97 - 1.36, derivative of the alkylating agent dacarbazine: Owing p = 0.11) for disease control rate.16 Compared to that of to its small size and lipophilic properties, TMZ can cross DTIC, the RR for TMZ non-hematological and the BBB. Once it has entered the CNS, TMZ is hematological side effects, such as anemia, neutro- converted spontaneously to its active metabolite. TMZ penia, and thrombocytopenia, was non-significant in all concentrations in the CNS are approximately 30% of cases, but the RR for TMZ lymphopenia was 3.79 (95% that in plasma. These pharmacological properties make CI: 1.38 - 10.39, p = 0.01), which was significant. That is it an ideal agent for CNS malignancies.8 CNS relapse is to say, the authors found no significant difference in the an important cause of treatment failure in responding efficacy and side effects of the two agents, except that patients with malignant melanoma. Up to half of these TMZ increased the prevalence of lymphopenia. patients develop CNS disease, often as the only site of 19 Health-related quality of life and cost-effectiveness relapse, and this is almost always fatal. As TMZ may analysis of TMZ versus DTIC: Given the poor be effective for preventing and treating brain prognosis and lack of curative treatments, the primary metastases, TMZ could be an exciting new alternative to aim of therapy for metastatic melanoma is palliation, DTIC, which is ineffective against CNS metastases. A maximizing symptom control while minimizing toxicity. In retrospective report provides preliminary support for this such patients, for whom a cure is currently unavailable, supposition. Paul et al. studied 40 patients with stable or improved health-related quality of life (HRQL) advanced melanoma who were treated with TMZ (n = is essential to avoid sacrificing quality of life. Following a 19) or DTIC (n = 21), and reported a reduction from 43% randomized controlled trial, Middleton and colleagues to 10% in CNS metastasis incidence in responsive TMZ- reported that patients treated with TMZ had better treated patients compared to responsive DTIC-treated physical function and less fatigue and sleep patients.20 During this period, only two patients from disturbances than DTIC-treated patients after 12 weeks the TMZ-treated group developed CNS disease of chemotherapy.7 Using a clinical trial that compared compared with nine in the DTIC-treated group. Despite TMZ and DTIC in patients with metastatic melanoma, the small number of patients, this result was statistically Kiebert et al. provided further insight into HRQL. The significant (p = 0.03). The study demonstrated that study suggested that treatment with TMZ led to patients responding to TMZ chemotherapy were less important functional improvements and decreased likely to develop CNS metastases than those treated symptoms compared to DTIC treatment.17 In addition, with DTIC-based regimens. Further work is required financial difficulties also must be addressed, which to confirm this observation, as other authors have spurred Hillner et al. to perform an economic analysis reported a similar effect for TMZ-based and DTIC- projection of this comparison.14 They found that the based combinations. Table I summarizes the results of projected average costs per patient were greater for published trials.21-25 Table I: TMZ in treatment of melanoma brain metastases.
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