Heterogeneity of chemosensitivity of metastatic cutaneous melanoma

Cree, Ian A.; Neale, Michael H.; Myatt, Nyree; Takats, P.G. de; Hall, Per; Grant, Justin; Kurbacher, Christian M.; Reinhold, Uwe; Neuber, Karsten; MacKie, Rona M.; Chana, Jagdeep S.; Weaver, P. C.; Khoury, Ghassan; Sartori, C.; Andreotti, Peter E.

doi:10.1097/00001813-199906000-00002

Cited by 48 publications

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“…Additional routine histopathology analysis of the tissue samples proved as a sensible procedure to exclude secondary malignancies, as detected in one patient. As described before (23,24), melanoma tissues revealed heterogenous chemosensitivities, with drug combinations showing higher sensitivities than single agents. The most effective combinations were gemcitabine + treosulfan, paclitaxel + cisplatin, paclitaxel + doxorubicin, and gemcitabine + cisplatin.…”

Section: Discussionsupporting

confidence: 54%

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

Ugurel

Schadendorf

Pföhler

et al. 2006

Clinical Cancer Research

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Purpose: In vitro sensitivity assays are promising tools to predict the individual outcome of different chemotherapy regimens. However, a direct association between in vitro and in vivo chemosensitivity has to be shown by clinical studies. This multicenter phase II trial was aimed to investigate the efficacy of a sensitivity-directed, first-line chemotherapy in metastasized melanoma patients, and to prove an association between in vitro sensitivity and therapy outcome. Patients and Methods: The primary study end point was objective response; secondary end points were safety, overall survival, and progression-free survival.Viable tumor cells obtained from metastatic lesions were tested for chemosensitivity to seven single drugs and five drug combinations using an ATP-based luminescence viability assay. Results: Out of 82 recruited patients (intention-to-treat), 57 received assay-directed chemotherapy and 53 were evaluable for all study end points (per protocol). The drug combinations used were gemcitabine + treosulfan, paclitaxel + cisplatin, paclitaxel + doxorubicin, and gemcitabine + cisplatin. The per protocol population could be divided into 22 (42%) chemosensitive and 31 (58%) chemoresistant patients by an arbitrary chemosensitivity index. Objective response was 36.4% in chemosensitive patients compared with 16.1% in chemoresistant patients (P = 0.114); progression arrest (complete response + partial response + stable disease) was 59.1% versus 22.6% (P = 0.01). Chemosensitive patients showed an increased overall survival of 14.6 months compared with 7.4 months in chemoresistant patients (P = 0.041). Conclusion: In vitro chemosensitivity testing may be worthy of further exploration to see if it could be a useful tool to predict the outcome of melanoma patients treated with a sensitivitydirected chemotherapy. Therefore, these preliminary results will be evaluated by a planned phase III trial using a randomized, standard-regimen controlled setting.Melanoma is a cutaneous neoplasm known for its high aggressiveness, its early dissemination of metastases, and its poor prognosis once metastasized. Chemotherapy with dacarbacine (DTIC) does actually apply as the standard treatment regimen in metastasized melanoma, with reported response rates of only 10% to 18% (1). Even these might be overestimated, as recent studies using new standardized evaluation criteria (2) revealed much lower response rates of 6% to 7% (3, 4). This poor outcome does not rely on an impaired penetration of chemotherapeutics into the tumor, but has been proposed to be caused by chemoresistance mechanisms intrinsic to melanoma cells (5, 6). Moreover, biochemotherapy and immunotherapy regimens did not prove to be superior to DTIC (1, 7).Due to this unfavorable situation, a number of nonstandard chemotherapeutics were tested in small pilot studies to prove a stronger efficacy in melanoma. Although complete remissions of metastatic lesions could only be observed in few patients

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Section: Discussionsupporting

confidence: 54%

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

Ugurel

Schadendorf

Pföhler

et al. 2006

Clinical Cancer Research

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“…There is considerable heterogeneity between tumours for these two drugs, with sensitivity to MMC in 71% of the oesophagogastric tumours (15 out of 21) and 59% of the colorectal tumours (21 out of 39). For comparison between drugs and tumours, an Index SUM of o300, representing an average 50% inhibition across all concentrations tested, has been used to indicate sensitivity, as previously published (Hunter et al, 1993;Cree et al, 1999). Despite these apparently encouraging results, MMC alone achieves 495% inhibition at clinically achievable concentrations in just 14% of oesophagogastric tumours (three out of 21) and 10% of colorectal tumours (four out of 39) tested.…”

Section: Resultsmentioning

confidence: 99%

Combination chemotherapy in advanced gastrointestinal cancers: ex vivo sensitivity to gemcitabine and mitomycin C

et al. 2003

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Advanced or metastatic disease is common in both oesophagogastric and colorectal cancers, with poor 5-year survival despite palliative chemotherapy. We have investigated the sensitivity of gastrointestinal tumours to gemcitabine in combination with mitomycin C (GeM), using a modified ex vivo ATP-based tumour chemosensitivity assay (ATP-TCA). Tumour material from 41 colorectal and 22 oesophagogastric cancers were assessed. The GeM combination showed variable but definite activity in most of the samples tested. The results show that GeM achieves 495% inhibition at concentrations within the range achievable clinically in 60% of colorectal tumours (21 out of 35) and 38% of oesophagogastric tumours (five out of 13) tested. We did not identify any significant difference in sensitivity using concurrent or sequential exposure of tumour-derived cells to these two drugs. The results from this study suggest that GeM may be a useful combination in the treatment of advanced gastrointestinal malignancy.

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“…The tecnique that we have used (sulphorodamine B assay) appears to be sensitive and accurate for detecting cytotoxic drug effects in long term primary cultures of MMCs. Other techniques such as those based on soft agar cloning [35] or measurement of intracellular adenosine-5 0 -triphosphate content by chemoluminescence [16,[36][37] have obtained positive correlation between in vitro sensitivity data and clinical responsiveness, allowing speculation about the use of tumor chemosensitivity assays to tailor patient therapy. Our results appear to suggest caution in promoting assay-directed chemotherapy for cutaneous melanoma patients, as pointed out also by other authors [38].…”

Section: Discussionmentioning

confidence: 99%

“…This offers a possible explanation for the observed clinical response, often unpredictable and overall poor. Chemosensitivity assays have been recently proposed as an important tool to predict tumor responsiveness to clinical treatment [14][15][16].…”

Section: Introductionmentioning

confidence: 99%

Immunophenotypical markers, ultrastructure and chemosensitivity profile of metastatic melanoma cells

et al. 2002

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The survival of patients affected by cutaneous melanoma has improved dramatically in the last 10 years, because of earlier diagnosis. Despite this, the therapeutic results obtained in metastatic melanoma (MM) are very disappointing due to its poor responsiveness to cytotoxic agents. In this type of solid tumor, tumor chemosensitivity assays have been suggested to be an important tool to predict clinical responsiveness to therapy. Metastatic melanoma cells (MMCs) were obtained from subcutaneous melanoma metastases of five patients and cultured for several consecutive passages. An immunofluorescence and an electron microscopic study were performed in order to establish the ultrastructural and physiopathological features of MMCs. A sulphorodamine-B test was used to measure in vitro sensitivity of MMCs to temozolomide, cisplatin, vindesine, taxol and interpheron alpha-2a. Following a 72 h exposure, maximum activity was obtained with vindesine (median inhibitory concentration, IC 50 , 0.23 nM) and taxol (median IC 50 0.31 nM). Cisplatin median IC 50 values were higher (4.6 mM) than taxol and vindesine, but still in the range of clinically achievable plasma concentrations. Temozolomide inhibited cell proliferation only at very high concentrations (median IC 50 228 mM). No significant cell growth inhibitory effects (#25%) were observed with interferon alpha-2a concentrations up to 8000 IU/ml. MMCs expressed progression markers typical of cutaneous metastatic melanoma and showed poor sensitivity in vitro to most anticancer drugs tested, including temozolomide. q

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Heterogeneity of chemosensitivity of metastatic cutaneous melanoma

Cited by 48 publications

References 0 publications

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

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

Combination chemotherapy in advanced gastrointestinal cancers: ex vivo sensitivity to gemcitabine and mitomycin C

Immunophenotypical markers, ultrastructure and chemosensitivity profile of metastatic melanoma cells

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