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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

Authors' Affiliations: ¹ Skin Cancer Unit, German Cancer Research Center Heidelberg and Department of Dermatology, University Hospital of Mannheim, Mannheim, Germany; ² Department of Dermatology, The Saarland University Hospital, Homburg/Saar, Germany; ³ Department of Dermatology, University Hospital Eppendorf, Hamburg, Germany; ⁴ Department of Dermatology, Otto von Guericke University, Magdeburg, Germany; ⁵ Department of Dermatology, Christian Albrechts University, Kiel, Germany; ⁶ Department of Dermatology, Johann Wolfgang Goethe University, Frankfurt/Main, Germany; ⁷ Department of Dermatology, Friedrich Schiller University, Jena, Germany; and ⁸ Central Unit of Biostatistics and ⁹ Department of Radiology, German Cancer Research Center, Heidelberg, Germany

Requests for reprints: Selma Ugurel, Skin Cancer Unit, German Cancer Research Center Heidelberg, Department of Dermatology, University Hospital of Mannheim, Theodor-Kutzer-Ufer 1, 68167 Mannheim, Germany. Phone: 49-621-383-3905; Fax: 49-621-383-2163; E-mail: s.ugurel{at}dkfz.de.

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 sensitivity-directed chemotherapy. Therefore, these preliminary results will be evaluated by a planned phase III trial using a randomized, standard-regimen controlled setting.

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