<i>In vitro</i> Drug Sensitivity Predicts Response and Survival after Individualized Sensitivity-Directed Chemotherapy in Metastatic Melanoma: A Multicenter Phase II Trial of the Dermatologic Cooperative Oncology Group

Ugurel, Selma; Schadendorf, Dirk; Pföhler, Claudia; Neuber, Karsten; Thoelke, Adina; Ulrich, Jens; Hauschild, Axel; Spieth, Konstanze; Kaatz, Martin; Rittgen, Werner; Delorme, Stefan; Tilgen, Wolfgang; Reinhold, Uwe

doi:10.1158/1078-0432.ccr-05-2763

Cited by 88 publications

(85 citation statements)

References 29 publications

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“…However, recent preclinical studies on the chemosensitivity of metastatic melanoma cells to cytotoxic agents identified high sensitivity to cytotoxic single agents including cisplatin, treosulfan, gemcitabine, as well as to combinations of gemcitabine plus treosulfan and gemcitabine plus cisplatin (Cree et al, 1999;Ugurel et al, 2003Ugurel et al, , 2006.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2007

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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...

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Section: Discussionmentioning

confidence: 99%

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

et al. 2007

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“…Primary human pancreatic cancer cells were isolated and ATP-TCA was performed as described previously (Andreotti et al, 1995;Ugurel et al, 2006). Briefly, 10 000 -20 000 tumour cells per well were seeded in tumour cell-supporting growth medium in 96-well microtiter plates.…”

Section: Chemosensitivity Testing Using the Atp-tca Testmentioning

confidence: 99%

“…Various types of assays have been tested in a variety of malignancies, but none so far has been evaluated in large-scale randomised clinical trials. In this study, we used the ATP-based tumour chemosensitivity assay (ATP-TCA), which has been shown to be very sensitive and highly reproducible, at a low rate of failure (Andreotti et al, 1995;Ugurel et al, 2006).…”

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confidence: 99%

Ex vivo chemosensitivity testing and gene expression profiling predict response towards adjuvant gemcitabine treatment in pancreatic cancer

et al. 2008

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Efficacy of chemotherapy for pancreatic cancer may be improved by tailoring it to individual chemosensitivity profiles. Identification of nonresponders before initiation of treatment may help to avoid side effects. In this study, primary pancreatic cancer cells were isolated from 18 patients undergoing pancreaticoduodenectomy for pancreatic cancer. Eight commonly used pancreatic cancer cell lines were used as controls. Ex vivo chemosensitivity for gemcitabine, 5-fluorouracil, mitomycin-C, cisplatinum, oxaliplatinum, paclitaxel and a combination of gemcitabine with oxaliplatinum or mitomycin-C was determined using a cellular ATP-based tumour chemosensitivity assay (ATP-TCA). Quantitative real-time -polymerase chain reaction was performed to determine RNA expression levels of genes implicated in chemoresistance. Chemosensitivity towards cytotoxic agents was highly variable in primary pancreatic cancer cells and pancreatic cancer cell lines. ATP-TCA results for gemcitabine correlated to the tissue expression of human equilibrative nucleoside transporter-1 (hENT1). Time to relapse in patients with gemcitabine-sensitive tumours was significantly higher than in patients with chemoresistant pancreatic cancers (P ¼ 0.01; 71 vs 269 days). Furthermore, time to relapse in gemcitabine-treated patients was related to hENT1 expression (P ¼ 0.0067). Thus, chemosensitivity testing using ATP-TCA in pancreatic cancer is feasible and correlated with time to relapse in gemcitabine-treated patients. This suggests that ATP-TCA testing could be used as a decision-making tool in the adjuvant treatment of pancreatic cancer.

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“…Conventional screening of chemotherapeutics uses an established panel of cancer cell lines (18) that have been derived from bulk tumors. A recently developed clinical approach involves performing in vitro chemosensitivity testing of tumor biopsy specimens to individualize treatment (19,20). Unfortunately, benefits have been limited, with poor correlations between bulk tumor cell sensitivity and clinical efficacy.…”

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confidence: 99%

Drug-eluting microarrays to identify effective chemotherapeutic combinations targeting patient-derived cancer stem cells

Carstens

Fisher

Acharya

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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A new paradigm in oncology establishes a spectrum of tumorigenic potential across the heterogeneous phenotypes within a tumor. The cancer stem cell hypothesis postulates that a minute fraction of cells within a tumor, termed cancer stem cells (CSCs), have a tumor-initiating capacity that propels tumor growth. An application of this discovery is to target this critical cell population using chemotherapy; however, the process of isolating these cells is arduous, and the rarity of CSCs makes it difficult to test potential drug candidates in a robust fashion, particularly for individual patients. To address the challenge of screening drug libraries on patient-derived populations of rare cells, such as CSCs, we have developed a drug-eluting microarray, a miniaturized platform onto which a minimal quantity of cells can adhere and be exposed to unique treatment conditions. Hundreds of drug-loaded polymer islands acting as drug depots colocalized with adherent cells are surrounded by a nonfouling background, creating isolated culture environments on a solid substrate. Significant results can be obtained by testing <6% of the cells required for a typical 96-well plate. Reliability was demonstrated by an average coefficient of variation of 14% between all of the microarrays and 13% between identical conditions within a single microarray. Using the drug-eluting array, colorectal CSCs isolated from two patients exhibited unique responses to drug combinations when cultured on the drug-eluting microarray, highlighting the potential as a prognostic tool to identify personalized chemotherapeutic regimens targeting CSCs.personalized medicine | chemopredictive | cancer stem cell | microarray | combination therapy

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In vitro Drug Sensitivity Predicts Response and Survival after Individualized Sensitivity-Directed Chemotherapy in Metastatic Melanoma: A Multicenter Phase II Trial of the Dermatologic Cooperative Oncology Group

Cited by 88 publications

References 29 publications

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

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

Ex vivo chemosensitivity testing and gene expression profiling predict response towards adjuvant gemcitabine treatment in pancreatic cancer

Drug-eluting microarrays to identify effective chemotherapeutic combinations targeting patient-derived cancer stem cells

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