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Cancer Therapy: Clinical

Neoadjuvant Imatinib in Advanced Primary or Locally Recurrent Dermatofibrosarcoma Protuberans: A Multicenter Phase II DeCOG Trial with Long-term Follow-up

Selma Ugurel, Thomas Mentzel, Jochen Utikal, Peter Helmbold, Peter Mohr, Claudia Pföhler, Meinhard Schiller, Axel Hauschild, Rüdiger Hein, Eckhardt Kämpgen, Ivonne Kellner, Martin Leverkus, Jürgen C. Becker, Philip Ströbel and Dirk Schadendorf
Selma Ugurel
1Department of Dermatology, University of Würzburg, Würzburg; 2Dermatopathology Bodensee, Friedrichshafen; 3Skin Cancer Unit, German Cancer Research Center, Heidelberg; 4Department of Dermatology, University Hospital Heidelberg, Heidelberg; 5Department of Dermatology, University Medical Center Mannheim, University of Heidelberg, Mannheim; 6Department of Dermatology, Martin Luther University, Halle/Saale; 7Department of Dermatology, Elbe Klinikum Buxtehude, Buxtehude; 8Department of Dermatology, Saarland University Hospital, Homburg, Saarland; 9Department of Dermatology, University Hospital of Münster, Münster; 10Department of Dermatology, University of Kiel, Kiel; 11Department of Dermatology, Technical University Munich, Munich; 12Department of Dermatology, University Hospital Erlangen, Erlangen; 13Department of Dermatology, Helios Klinikum Erfurt, Erfurt; 14Department of Pathology, University of Göttingen, Göttingen; 15Department of Dermatology, University of Essen, Essen, Germany; and 16Department of Dermatology, Medical University Graz, Graz, Austria
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Thomas Mentzel
1Department of Dermatology, University of Würzburg, Würzburg; 2Dermatopathology Bodensee, Friedrichshafen; 3Skin Cancer Unit, German Cancer Research Center, Heidelberg; 4Department of Dermatology, University Hospital Heidelberg, Heidelberg; 5Department of Dermatology, University Medical Center Mannheim, University of Heidelberg, Mannheim; 6Department of Dermatology, Martin Luther University, Halle/Saale; 7Department of Dermatology, Elbe Klinikum Buxtehude, Buxtehude; 8Department of Dermatology, Saarland University Hospital, Homburg, Saarland; 9Department of Dermatology, University Hospital of Münster, Münster; 10Department of Dermatology, University of Kiel, Kiel; 11Department of Dermatology, Technical University Munich, Munich; 12Department of Dermatology, University Hospital Erlangen, Erlangen; 13Department of Dermatology, Helios Klinikum Erfurt, Erfurt; 14Department of Pathology, University of Göttingen, Göttingen; 15Department of Dermatology, University of Essen, Essen, Germany; and 16Department of Dermatology, Medical University Graz, Graz, Austria
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Jochen Utikal
1Department of Dermatology, University of Würzburg, Würzburg; 2Dermatopathology Bodensee, Friedrichshafen; 3Skin Cancer Unit, German Cancer Research Center, Heidelberg; 4Department of Dermatology, University Hospital Heidelberg, Heidelberg; 5Department of Dermatology, University Medical Center Mannheim, University of Heidelberg, Mannheim; 6Department of Dermatology, Martin Luther University, Halle/Saale; 7Department of Dermatology, Elbe Klinikum Buxtehude, Buxtehude; 8Department of Dermatology, Saarland University Hospital, Homburg, Saarland; 9Department of Dermatology, University Hospital of Münster, Münster; 10Department of Dermatology, University of Kiel, Kiel; 11Department of Dermatology, Technical University Munich, Munich; 12Department of Dermatology, University Hospital Erlangen, Erlangen; 13Department of Dermatology, Helios Klinikum Erfurt, Erfurt; 14Department of Pathology, University of Göttingen, Göttingen; 15Department of Dermatology, University of Essen, Essen, Germany; and 16Department of Dermatology, Medical University Graz, Graz, Austria
1Department of Dermatology, University of Würzburg, Würzburg; 2Dermatopathology Bodensee, Friedrichshafen; 3Skin Cancer Unit, German Cancer Research Center, Heidelberg; 4Department of Dermatology, University Hospital Heidelberg, Heidelberg; 5Department of Dermatology, University Medical Center Mannheim, University of Heidelberg, Mannheim; 6Department of Dermatology, Martin Luther University, Halle/Saale; 7Department of Dermatology, Elbe Klinikum Buxtehude, Buxtehude; 8Department of Dermatology, Saarland University Hospital, Homburg, Saarland; 9Department of Dermatology, University Hospital of Münster, Münster; 10Department of Dermatology, University of Kiel, Kiel; 11Department of Dermatology, Technical University Munich, Munich; 12Department of Dermatology, University Hospital Erlangen, Erlangen; 13Department of Dermatology, Helios Klinikum Erfurt, Erfurt; 14Department of Pathology, University of Göttingen, Göttingen; 15Department of Dermatology, University of Essen, Essen, Germany; and 16Department of Dermatology, Medical University Graz, Graz, Austria
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Peter Helmbold
1Department of Dermatology, University of Würzburg, Würzburg; 2Dermatopathology Bodensee, Friedrichshafen; 3Skin Cancer Unit, German Cancer Research Center, Heidelberg; 4Department of Dermatology, University Hospital Heidelberg, Heidelberg; 5Department of Dermatology, University Medical Center Mannheim, University of Heidelberg, Mannheim; 6Department of Dermatology, Martin Luther University, Halle/Saale; 7Department of Dermatology, Elbe Klinikum Buxtehude, Buxtehude; 8Department of Dermatology, Saarland University Hospital, Homburg, Saarland; 9Department of Dermatology, University Hospital of Münster, Münster; 10Department of Dermatology, University of Kiel, Kiel; 11Department of Dermatology, Technical University Munich, Munich; 12Department of Dermatology, University Hospital Erlangen, Erlangen; 13Department of Dermatology, Helios Klinikum Erfurt, Erfurt; 14Department of Pathology, University of Göttingen, Göttingen; 15Department of Dermatology, University of Essen, Essen, Germany; and 16Department of Dermatology, Medical University Graz, Graz, Austria
1Department of Dermatology, University of Würzburg, Würzburg; 2Dermatopathology Bodensee, Friedrichshafen; 3Skin Cancer Unit, German Cancer Research Center, Heidelberg; 4Department of Dermatology, University Hospital Heidelberg, Heidelberg; 5Department of Dermatology, University Medical Center Mannheim, University of Heidelberg, Mannheim; 6Department of Dermatology, Martin Luther University, Halle/Saale; 7Department of Dermatology, Elbe Klinikum Buxtehude, Buxtehude; 8Department of Dermatology, Saarland University Hospital, Homburg, Saarland; 9Department of Dermatology, University Hospital of Münster, Münster; 10Department of Dermatology, University of Kiel, Kiel; 11Department of Dermatology, Technical University Munich, Munich; 12Department of Dermatology, University Hospital Erlangen, Erlangen; 13Department of Dermatology, Helios Klinikum Erfurt, Erfurt; 14Department of Pathology, University of Göttingen, Göttingen; 15Department of Dermatology, University of Essen, Essen, Germany; and 16Department of Dermatology, Medical University Graz, Graz, Austria
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Peter Mohr
1Department of Dermatology, University of Würzburg, Würzburg; 2Dermatopathology Bodensee, Friedrichshafen; 3Skin Cancer Unit, German Cancer Research Center, Heidelberg; 4Department of Dermatology, University Hospital Heidelberg, Heidelberg; 5Department of Dermatology, University Medical Center Mannheim, University of Heidelberg, Mannheim; 6Department of Dermatology, Martin Luther University, Halle/Saale; 7Department of Dermatology, Elbe Klinikum Buxtehude, Buxtehude; 8Department of Dermatology, Saarland University Hospital, Homburg, Saarland; 9Department of Dermatology, University Hospital of Münster, Münster; 10Department of Dermatology, University of Kiel, Kiel; 11Department of Dermatology, Technical University Munich, Munich; 12Department of Dermatology, University Hospital Erlangen, Erlangen; 13Department of Dermatology, Helios Klinikum Erfurt, Erfurt; 14Department of Pathology, University of Göttingen, Göttingen; 15Department of Dermatology, University of Essen, Essen, Germany; and 16Department of Dermatology, Medical University Graz, Graz, Austria
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Claudia Pföhler
1Department of Dermatology, University of Würzburg, Würzburg; 2Dermatopathology Bodensee, Friedrichshafen; 3Skin Cancer Unit, German Cancer Research Center, Heidelberg; 4Department of Dermatology, University Hospital Heidelberg, Heidelberg; 5Department of Dermatology, University Medical Center Mannheim, University of Heidelberg, Mannheim; 6Department of Dermatology, Martin Luther University, Halle/Saale; 7Department of Dermatology, Elbe Klinikum Buxtehude, Buxtehude; 8Department of Dermatology, Saarland University Hospital, Homburg, Saarland; 9Department of Dermatology, University Hospital of Münster, Münster; 10Department of Dermatology, University of Kiel, Kiel; 11Department of Dermatology, Technical University Munich, Munich; 12Department of Dermatology, University Hospital Erlangen, Erlangen; 13Department of Dermatology, Helios Klinikum Erfurt, Erfurt; 14Department of Pathology, University of Göttingen, Göttingen; 15Department of Dermatology, University of Essen, Essen, Germany; and 16Department of Dermatology, Medical University Graz, Graz, Austria
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Meinhard Schiller
1Department of Dermatology, University of Würzburg, Würzburg; 2Dermatopathology Bodensee, Friedrichshafen; 3Skin Cancer Unit, German Cancer Research Center, Heidelberg; 4Department of Dermatology, University Hospital Heidelberg, Heidelberg; 5Department of Dermatology, University Medical Center Mannheim, University of Heidelberg, Mannheim; 6Department of Dermatology, Martin Luther University, Halle/Saale; 7Department of Dermatology, Elbe Klinikum Buxtehude, Buxtehude; 8Department of Dermatology, Saarland University Hospital, Homburg, Saarland; 9Department of Dermatology, University Hospital of Münster, Münster; 10Department of Dermatology, University of Kiel, Kiel; 11Department of Dermatology, Technical University Munich, Munich; 12Department of Dermatology, University Hospital Erlangen, Erlangen; 13Department of Dermatology, Helios Klinikum Erfurt, Erfurt; 14Department of Pathology, University of Göttingen, Göttingen; 15Department of Dermatology, University of Essen, Essen, Germany; and 16Department of Dermatology, Medical University Graz, Graz, Austria
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Axel Hauschild
1Department of Dermatology, University of Würzburg, Würzburg; 2Dermatopathology Bodensee, Friedrichshafen; 3Skin Cancer Unit, German Cancer Research Center, Heidelberg; 4Department of Dermatology, University Hospital Heidelberg, Heidelberg; 5Department of Dermatology, University Medical Center Mannheim, University of Heidelberg, Mannheim; 6Department of Dermatology, Martin Luther University, Halle/Saale; 7Department of Dermatology, Elbe Klinikum Buxtehude, Buxtehude; 8Department of Dermatology, Saarland University Hospital, Homburg, Saarland; 9Department of Dermatology, University Hospital of Münster, Münster; 10Department of Dermatology, University of Kiel, Kiel; 11Department of Dermatology, Technical University Munich, Munich; 12Department of Dermatology, University Hospital Erlangen, Erlangen; 13Department of Dermatology, Helios Klinikum Erfurt, Erfurt; 14Department of Pathology, University of Göttingen, Göttingen; 15Department of Dermatology, University of Essen, Essen, Germany; and 16Department of Dermatology, Medical University Graz, Graz, Austria
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Rüdiger Hein
1Department of Dermatology, University of Würzburg, Würzburg; 2Dermatopathology Bodensee, Friedrichshafen; 3Skin Cancer Unit, German Cancer Research Center, Heidelberg; 4Department of Dermatology, University Hospital Heidelberg, Heidelberg; 5Department of Dermatology, University Medical Center Mannheim, University of Heidelberg, Mannheim; 6Department of Dermatology, Martin Luther University, Halle/Saale; 7Department of Dermatology, Elbe Klinikum Buxtehude, Buxtehude; 8Department of Dermatology, Saarland University Hospital, Homburg, Saarland; 9Department of Dermatology, University Hospital of Münster, Münster; 10Department of Dermatology, University of Kiel, Kiel; 11Department of Dermatology, Technical University Munich, Munich; 12Department of Dermatology, University Hospital Erlangen, Erlangen; 13Department of Dermatology, Helios Klinikum Erfurt, Erfurt; 14Department of Pathology, University of Göttingen, Göttingen; 15Department of Dermatology, University of Essen, Essen, Germany; and 16Department of Dermatology, Medical University Graz, Graz, Austria
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Eckhardt Kämpgen
1Department of Dermatology, University of Würzburg, Würzburg; 2Dermatopathology Bodensee, Friedrichshafen; 3Skin Cancer Unit, German Cancer Research Center, Heidelberg; 4Department of Dermatology, University Hospital Heidelberg, Heidelberg; 5Department of Dermatology, University Medical Center Mannheim, University of Heidelberg, Mannheim; 6Department of Dermatology, Martin Luther University, Halle/Saale; 7Department of Dermatology, Elbe Klinikum Buxtehude, Buxtehude; 8Department of Dermatology, Saarland University Hospital, Homburg, Saarland; 9Department of Dermatology, University Hospital of Münster, Münster; 10Department of Dermatology, University of Kiel, Kiel; 11Department of Dermatology, Technical University Munich, Munich; 12Department of Dermatology, University Hospital Erlangen, Erlangen; 13Department of Dermatology, Helios Klinikum Erfurt, Erfurt; 14Department of Pathology, University of Göttingen, Göttingen; 15Department of Dermatology, University of Essen, Essen, Germany; and 16Department of Dermatology, Medical University Graz, Graz, Austria
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Ivonne Kellner
1Department of Dermatology, University of Würzburg, Würzburg; 2Dermatopathology Bodensee, Friedrichshafen; 3Skin Cancer Unit, German Cancer Research Center, Heidelberg; 4Department of Dermatology, University Hospital Heidelberg, Heidelberg; 5Department of Dermatology, University Medical Center Mannheim, University of Heidelberg, Mannheim; 6Department of Dermatology, Martin Luther University, Halle/Saale; 7Department of Dermatology, Elbe Klinikum Buxtehude, Buxtehude; 8Department of Dermatology, Saarland University Hospital, Homburg, Saarland; 9Department of Dermatology, University Hospital of Münster, Münster; 10Department of Dermatology, University of Kiel, Kiel; 11Department of Dermatology, Technical University Munich, Munich; 12Department of Dermatology, University Hospital Erlangen, Erlangen; 13Department of Dermatology, Helios Klinikum Erfurt, Erfurt; 14Department of Pathology, University of Göttingen, Göttingen; 15Department of Dermatology, University of Essen, Essen, Germany; and 16Department of Dermatology, Medical University Graz, Graz, Austria
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Martin Leverkus
1Department of Dermatology, University of Würzburg, Würzburg; 2Dermatopathology Bodensee, Friedrichshafen; 3Skin Cancer Unit, German Cancer Research Center, Heidelberg; 4Department of Dermatology, University Hospital Heidelberg, Heidelberg; 5Department of Dermatology, University Medical Center Mannheim, University of Heidelberg, Mannheim; 6Department of Dermatology, Martin Luther University, Halle/Saale; 7Department of Dermatology, Elbe Klinikum Buxtehude, Buxtehude; 8Department of Dermatology, Saarland University Hospital, Homburg, Saarland; 9Department of Dermatology, University Hospital of Münster, Münster; 10Department of Dermatology, University of Kiel, Kiel; 11Department of Dermatology, Technical University Munich, Munich; 12Department of Dermatology, University Hospital Erlangen, Erlangen; 13Department of Dermatology, Helios Klinikum Erfurt, Erfurt; 14Department of Pathology, University of Göttingen, Göttingen; 15Department of Dermatology, University of Essen, Essen, Germany; and 16Department of Dermatology, Medical University Graz, Graz, Austria
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Jürgen C. Becker
1Department of Dermatology, University of Würzburg, Würzburg; 2Dermatopathology Bodensee, Friedrichshafen; 3Skin Cancer Unit, German Cancer Research Center, Heidelberg; 4Department of Dermatology, University Hospital Heidelberg, Heidelberg; 5Department of Dermatology, University Medical Center Mannheim, University of Heidelberg, Mannheim; 6Department of Dermatology, Martin Luther University, Halle/Saale; 7Department of Dermatology, Elbe Klinikum Buxtehude, Buxtehude; 8Department of Dermatology, Saarland University Hospital, Homburg, Saarland; 9Department of Dermatology, University Hospital of Münster, Münster; 10Department of Dermatology, University of Kiel, Kiel; 11Department of Dermatology, Technical University Munich, Munich; 12Department of Dermatology, University Hospital Erlangen, Erlangen; 13Department of Dermatology, Helios Klinikum Erfurt, Erfurt; 14Department of Pathology, University of Göttingen, Göttingen; 15Department of Dermatology, University of Essen, Essen, Germany; and 16Department of Dermatology, Medical University Graz, Graz, Austria
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Philip Ströbel
1Department of Dermatology, University of Würzburg, Würzburg; 2Dermatopathology Bodensee, Friedrichshafen; 3Skin Cancer Unit, German Cancer Research Center, Heidelberg; 4Department of Dermatology, University Hospital Heidelberg, Heidelberg; 5Department of Dermatology, University Medical Center Mannheim, University of Heidelberg, Mannheim; 6Department of Dermatology, Martin Luther University, Halle/Saale; 7Department of Dermatology, Elbe Klinikum Buxtehude, Buxtehude; 8Department of Dermatology, Saarland University Hospital, Homburg, Saarland; 9Department of Dermatology, University Hospital of Münster, Münster; 10Department of Dermatology, University of Kiel, Kiel; 11Department of Dermatology, Technical University Munich, Munich; 12Department of Dermatology, University Hospital Erlangen, Erlangen; 13Department of Dermatology, Helios Klinikum Erfurt, Erfurt; 14Department of Pathology, University of Göttingen, Göttingen; 15Department of Dermatology, University of Essen, Essen, Germany; and 16Department of Dermatology, Medical University Graz, Graz, Austria
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Dirk Schadendorf
1Department of Dermatology, University of Würzburg, Würzburg; 2Dermatopathology Bodensee, Friedrichshafen; 3Skin Cancer Unit, German Cancer Research Center, Heidelberg; 4Department of Dermatology, University Hospital Heidelberg, Heidelberg; 5Department of Dermatology, University Medical Center Mannheim, University of Heidelberg, Mannheim; 6Department of Dermatology, Martin Luther University, Halle/Saale; 7Department of Dermatology, Elbe Klinikum Buxtehude, Buxtehude; 8Department of Dermatology, Saarland University Hospital, Homburg, Saarland; 9Department of Dermatology, University Hospital of Münster, Münster; 10Department of Dermatology, University of Kiel, Kiel; 11Department of Dermatology, Technical University Munich, Munich; 12Department of Dermatology, University Hospital Erlangen, Erlangen; 13Department of Dermatology, Helios Klinikum Erfurt, Erfurt; 14Department of Pathology, University of Göttingen, Göttingen; 15Department of Dermatology, University of Essen, Essen, Germany; and 16Department of Dermatology, Medical University Graz, Graz, Austria
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DOI: 10.1158/1078-0432.CCR-13-1411 Published January 2014
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Abstract

Purpose: Dermatofibrosarcoma protuberans (DFSP) is a rare cutaneous tumor. COL1A1–PDGFB gene fusion is frequent in DFSP, rendering tumor cell proliferation and survival dependent on PDGFRβ (platelet-derived growth factor receptor β) signaling. This trial investigated imatinib as neoadjuvant treatment of DFSP, including long-term follow-up.

Experimental Design: The primary endpoint of this multicenter phase II trial was response; secondary endpoints were safety, tumor relapse, and response biomarkers. Patients with advanced primary or locally recurrent DFSP and measurable disease by RECIST (response evaluation criteria in solid tumors) were eligible and received imatinib 600 mg/d until definitive surgery with histopathologic proof of tumor-free margins.

Results: Sixteen patients received imatinib, and 14 patients were evaluable for all endpoints. Median treatment duration was 3.1 months; median tumor shrinkage was 31.5%. Best overall response was 7.1% complete response (CR), 50.0% partial response (PR), 35.7% stable disease, and 7.1% progressive disease (PD). Toxicity was moderate with 25.0% grade 3 and 4 events. During a median follow-up of 6.4 years, one patient developed secondary resistance to imatinib but responded to second-line sunitinib. This patient also presented local recurrence, distant metastasis, and death from DFSP. Exploratory analysis showed that response to imatinib was associated with decreased tumor cellularity and formation of strong hyalinic fibrosis. Weak PDGFRB phosphorylation and pigmented-type DFSP were associated with nonresponse. Additional to PDGFRB, the kinases EGFR and insulin receptor were found activated in a high percentage of DFSPs.

Conclusion: The neoadjuvant use of imatinib 600 mg/d in DFSP is efficacious and well tolerated. Long-term follow-up results do not definitely support smaller surgical margins after successful imatinib pretreatment, and presume that secondary resistance to imatinib might promote accelerated disease progression. Clin Cancer Res; 20(2); 499–510. ©2013 AACR.

Footnotes

  • Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).

  • Received May 22, 2013.
  • Revision received October 16, 2013.
  • Accepted October 21, 2013.
  • ©2013 American Association for Cancer Research.
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Clinical Cancer Research: 20 (2)
January 2014
Volume 20, Issue 2
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Neoadjuvant Imatinib in Advanced Primary or Locally Recurrent Dermatofibrosarcoma Protuberans: A Multicenter Phase II DeCOG Trial with Long-term Follow-up
Selma Ugurel, Thomas Mentzel, Jochen Utikal, Peter Helmbold, Peter Mohr, Claudia Pföhler, Meinhard Schiller, Axel Hauschild, Rüdiger Hein, Eckhardt Kämpgen, Ivonne Kellner, Martin Leverkus, Jürgen C. Becker, Philip Ströbel and Dirk Schadendorf
Clin Cancer Res January 15 2014 (20) (2) 499-510; DOI: 10.1158/1078-0432.CCR-13-1411

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Neoadjuvant Imatinib in Advanced Primary or Locally Recurrent Dermatofibrosarcoma Protuberans: A Multicenter Phase II DeCOG Trial with Long-term Follow-up
Selma Ugurel, Thomas Mentzel, Jochen Utikal, Peter Helmbold, Peter Mohr, Claudia Pföhler, Meinhard Schiller, Axel Hauschild, Rüdiger Hein, Eckhardt Kämpgen, Ivonne Kellner, Martin Leverkus, Jürgen C. Becker, Philip Ströbel and Dirk Schadendorf
Clin Cancer Res January 15 2014 (20) (2) 499-510; DOI: 10.1158/1078-0432.CCR-13-1411
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