Oncotarget

Research Papers:

Chemosensitivity-directed therapy compared to dacarbazine in chemo-naive advanced metastatic melanoma: a multicenter randomized phase-3 DeCOG trial

Selma Ugurel _, Carmen Loquai, Patrick Terheyden, Dirk Schadendorf, Erika Richtig, Jochen Utikal, Ralf Gutzmer, Knuth Rass, Cord Sunderkötter, Annette Stein, Michael Fluck, Martin Kaatz, Uwe Trefzer, Katharina Kähler, Rudolf Stadler, Carola Berking, Christoph Höller, Laura Kerschke, Lutz Edler, Annette Kopp-Schneider and Jürgen C. Becker

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Oncotarget. 2017; 8:76029-76043. https://doi.org/10.18632/oncotarget.18635

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Abstract

Selma Ugurel1,2, Carmen Loquai3, Patrick Terheyden4, Dirk Schadendorf1,5, Erika Richtig6, Jochen Utikal7,8, Ralf Gutzmer9, Knuth Rass10, Cord Sunderkötter11, Annette Stein12, Michael Fluck13, Martin Kaatz14, Uwe Trefzer15, Katharina Kähler16, Rudolf Stadler17, Carola Berking18, Christoph Höller19, Laura Kerschke20,21, Lutz Edler20, Annette Kopp-Schneider20 and Jürgen C. Becker1,2,5,6

1Department of Dermatology, University Hospital of Essen, Essen, Germany

2Department of Dermatology, University Hospital of Würzburg, Würzburg, Germany

3Department of Dermatology, University Hospital of Mainz, Mainz, Germany

4Department of Dermatology, University Hospital of Lübeck, Lübeck, Germany

5Translational Skin Cancer Research, Deutsches Konsortium für Translationale Krebsforschung (DKTK), Essen, Germany

6Department of Dermatology, Medical University of Graz, Graz, Austria

7Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany

8Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany

9Department of Dermatology and Allergy, Skin Cancer Center Hannover, Hannover Medical School, Hannover, Germany

10Department of Dermatology, The Saarland University Hospital, Homburg/Saar, Germany

11Department of Dermatology, University Hospital of Münster, Münster, Germany

12Department of Dermatology, University Hospital of Dresden, Dresden, Germany

13Department of Internal Medicine, Fachklinik Hornheide, Hornheide, Germany

14Department of Dermatology, University Hospital of Jena, Jena, Germany

15Department of Dermatology, University Hospital Charite, Berlin, Germany

16Department of Dermatology, University Hospital of Kiel, Kiel, Germany

17Department of Dermatology, Johannes Wesling Klinikum, Minden, Germany

18Department of Dermatology, University Hospital of Munich, Munich, Germany

19Department of Dermatology, Medical University of Vienna, Vienna, Austria

20Division of Biostatistics, German Cancer Research Center, Heidelberg, Germany

21Institute of Biostatistics and Clinical Research, University of Münster, Münster, Germany

Correspondence to:

Selma Ugurel, email: [email protected]

Keywords: melanoma, chemosensitivity, individualized chemotherapy, phase-3 trial

Received: March 06, 2017     Accepted: May 10, 2017     Published: June 27, 2017

ABSTRACT

Chemotherapy still plays an important role in metastatic melanoma, particularly for patients who are not suitable or have no access to highly efficacious new therapies. Pre-therapeutic chemosensitivity testing might be useful to identify optimal chemotherapy regimens for individual patients. This multicenter randomized phase-3 trial was aimed to test for superiority of chemosensitivity-directed combination chemotherapy compared to standard dacarbazine monochemotherapy, and to demonstrate the chemosensitivity test result as prognostic in metastatic melanoma. Chemo-naive patients with advanced melanoma were biopsied from metastatic lesions. Tumor cells were isolated and tested ex-vivo for sensitivity to chemotherapeutic agents using an ATP-based viability assay. Patients with evaluable test results were randomly assigned to receive either chemosensitivity-directed combination chemotherapy (paclitaxel+cisplatin, treosulfan+gemcitabine, treosulfan+cytarabine), or dacarbazine. The primary study endpoint was overall survival (OS). After inclusion of 287 patients and a median follow-up of 26 months, the per-protocol population (n=244) showed no difference in OS between chemosensitivity-directed therapy and dacarbazine (median 9.2 vs 9.0 months, HR=1.08, p=0.64). The disease control rate (CR+PR+SD) tended to be higher in patients treated with chemosensitivity-directed therapy (32.8% vs 23.0%, p=0.088); objective response rates (CR+PR) showed no difference between groups (10.7% vs 12.3%, p=0.90). Patients whose tumors were tested chemosensitive showed no better OS or response rate than patients with chemoresistant tumors. Severe toxicities (CTC grade 3-4) were significantly more frequently observed with chemosensitivity-directed combination chemotherapy than with dacarbazine (40.2% vs 12.3%, p<0.0001). These results indicate, that chemosensitivity-directed combination chemotherapy is not superior to dacarbazine, but leads to significantly more severe toxicities.


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