Cisplatin, gemcitabine, and treosulfan in relapsed stage IV cutaneous malignant melanoma patients

Abstract

To evaluate the efficacy of cisplatin, gemcitabine, and treosulfan (CGT) in 91 patients with pretreated relapsed AJCC stage IV cutaneous malignant melanoma. Patients in relapse after first-, second-, or third-line therapy received 40 mg m À2 intravenous (i.v.) cisplatin, 1000 mg m À2 i.v. gemcitabine, and 2500 mg m À2 i.v. treosulfan on days 1 and 8. Cisplatin, gemcitabine, and treosulfan therapy was repeated every 5 weeks until progression of disease occurred. A maximum of 11 CGT cycles (mean, two cycles) was administered per patient. Four patients (4%) showed a partial response; 15 (17%) patients had stable disease; and 72 (79%) patients progressed upon first re-evaluation. Overall survival of all 91 patients was 6 months (2-year survival rate, 7%). Patients with partial remission or stable disease exhibited a median overall survival of 11 months (2-year survival rate, 36%), while patients with disease progression upon first re-evaluation had a median overall survival of 5 months (2-year survival rate, 0%). Treatment with CGT was efficient in one-fifth of the pretreated relapsed stage IV melanoma patients achieving disease stabilisation or partial remission with prolonged but limited survival. The prognosis for malignant melanoma patients with distant metastases is poor. Even though a small proportion of patients can attain long-term survival with systemic therapy, the median survival of advanced melanoma patients is about 6 months. While interferon-a continues to be standard in the adjuvant therapy of resected high-risk melanoma (Hillner et al, 1997), dacarbazine (DTIC) has been the most widely used agent in the first-line treatment of stage IV metastatic melanoma, yielding a response rate of up to 20% (Serrone et al, 2000). Although several DTICbased chemotherapy and chemoimmunotherapy combinations have been reported with response rates between 34 and 53% (Richards et al, 1992;Huncharek et al, 2001;Atzpodien et al, 2002;Stein et al, 2002), these regimens have not yielded a significant survival advantage. Once DTIC-based therapy has failed, no standard systemic treatment has been available for relapsed IV-stage malignant melanoma patients.Preclinical studies on the chemosensitivity of metastatic melanoma cells to cytotoxic agents identified sensitivity while using combinations of gemcitabine with treosulfan and gemcitabine with cisplatin (Cree et al, 1999;Ugurel et al, 2003). First results of a phase II trial of 24 metastatic uveal melanoma patients treated with gemcitabine and treosulfan showed a prolonged progression-free survival and a slight increase in tumour responses, when compared to 24 patients treated with treosulfan alone (Schmittel et al, 2006).The goal of our present analyses was to evaluate the efficacy of combined cisplatin, gemcitabine, and treosulfan in pretreated relapsed stage IV malignant melanoma patients. PATIENTS AND METHODS PatientsBetween February 2001 and August 2006, 91 relapsed stage IV cutaneous melanoma patients received a combination treatment with cisplatin, gemcitabine, and tr...

cAMP signalling protects proximal tubular epithelial cells from cisplatin‐induced apoptosis via activation of Epac

“…Cisplatin has been widely used for clinical treatment of testicular cancer (Bosl and Motzer, 1997), ovarian carcinomas (Jandial et al ., 2009), head and neck cancer (Khuri et al ., 2000), malignant melanoma (Atzpodien et al ., 2007), lung cancer (Winton et al ., 2005) and breast cancer (Decatris et al ., 2004). However, severe adverse effects, in particular acute renal failure, limit the dose that can be given and consequently prevent more efficient treatment with higher doses (Nagai et al ., 1996; Mathe et al ., 2011).…”

Topical application of gemcitabine generates microvesicle particles in human and murine skin

“…[26][27][28] Of significance, multiple studies have reported the abilities of PAFR antagonists to control the growth of cancer cells or augment the responses of therapeutic agents. 26,29,30 Given that gemcitabine chemotherapy used against multiple human malignancies either alone or in combination with other agents, exhibits adverse effects, including skin rash/necrosis, [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21] our current studies sought to determine the potential role of MVP release in the pathologic effects of topical gemcitabine application. To that end, pharmacologic approaches using human skin explants and genetic approaches using murine skin were used as relevant models.…”

“…Given that gemcitabine chemotherapy used against multiple human malignancies either alone or in combination with other agents, exhibits adverse effects, including skin rash/necrosis, 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 our current studies sought to determine the potential role of MVP release in the pathologic effects of topical gemcitabine application. To that end, pharmacologic approaches using human skin explants and genetic approaches using murine skin were used as relevant models.…”

“…However, often these drugs are associated with adverse side effects, including localized skin eruptions and necrosis as well as systemic pathologies, including ototoxicity and neutropenia 6–11 . Gemcitabine is one of the commonly used chemotherapy drugs, which has been used either alone, or in combination with other antineoplastic agents for the treatment of malignancies, including pancreatic cancer, non‐small cell lung cancer, intrahepatic cholangiocarcinoma, colorectal cancer, ovarian cancer, breast cancer, and melanoma 12–18 . Nevertheless, the development of tumor resistance mechanisms to gemcitabine therapy remained one of the ongoing challenges in its limited therapeutic efficacy 19–21 .…”

“… 6 , 7 , 8 , 9 , 10 , 11 Gemcitabine is one of the commonly used chemotherapy drugs, which has been used either alone, or in combination with other antineoplastic agents for the treatment of malignancies, including pancreatic cancer, non‐small cell lung cancer, intrahepatic cholangiocarcinoma, colorectal cancer, ovarian cancer, breast cancer, and melanoma. 12 , 13 , 14 , 15 , 16 , 17 , 18 Nevertheless, the development of tumor resistance mechanisms to gemcitabine therapy remained one of the ongoing challenges in its limited therapeutic efficacy. 19 , 20 , 21 To that end, several applicable approaches are being explored to identify potential factors/therapeutic targets to enhance the efficacy of gemcitabine chemotherapy.…”