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Indikationen zur prä- und postoperativen Therapie mit Imatinib bei gastrointestinalen Stromatumoren

Indications for pre- and postoperative treatment with imatinib for gastrointestinal stromal tumors

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Zusammenfassung

Imatinib ist ein gegen KIT- und PDGF- („platelet-derived growth factor“) α-Rezeptor gerichteter Tyrosinkinaseinhibitor mit nachgewiesener Wirksamkeit bei metastasiertem gastrointestinalem Stromatumor (GIST). Bei lokal fortgeschrittenem GIST erwies sich eine primäre Therapie mit Imatinib als durchführbar. Die Ansprechraten lagen bei bis zu 70%. Die Behandlung mit Imatinib alleine ist allerdings nicht kurativ. Das mediane progressionsfreie Überleben liegt bei 2 Jahren.

Bei lokalisiertem GIST ist die R0-Resektion das Ziel jeder kurativ intendierten chirurgischen Therapie. Daher empfiehlt sich bei fraglicher R0-Resektablität die neoadjuvante Therapie mit Imatinib, in der Regel für eine Dauer von 4–6 Monaten.

Nach R0-Resektion von GIST mit intermediärem und hohem Rezidivrisiko deuten erste Daten darauf hin, dass die Einnahme von Imatinib für mindestens ein Jahr das Rezidivrisiko mindert und die Prognose verbessert. Reife Überlebensdaten aus randomisierten Studien fehlen aber bislang, so dass die adjuvante Therapie mit Imatinib außerhalb klinischer Studien aktuell kein Therapiestandard ist. Der Einschluss von Patienten in laufende klinische Studien ist bei intermediärem und hohem Rezidivrisiko dringend anzuraten.

Abstract

Imatinib is a tyrosine kinase inhibitor directed against the KIT and the PDGF-α receptors. Imatinib has proven efficacy in the treatment of metastatic GIST with a response rate achieving 70%, but treatment with imatinib alone is not curative. The median progression-free survival is about 2 years. In locally advanced GIST, primary treatment with imatinib proved to be safe and feasible in several cohort studies. The goal of any curatively intended surgical treatment for GIST is R0 resection. Therefore, neoadjuvant treatment with imatinib can be recommended if tumor-free margin resection is doubtful. After R0 resection of GISTs with intermediate or high risk of relapse, preliminary data indicate that imatinib administered for at least 1 year reduces the risk of relapse and may improve the prognosis. However, no mature survival data from randomized studies have been published thus far. Therefore adjuvant treatment with imatinib is not yet approved nor is it a standard of care at this stage. The inclusion of patients with intermediate- and high-risk resected GIST into clinical studies is strongly recommended.

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Literatur

  1. Antonescu CR, Besmer P, Guo T et al. (2005) Acquired resistance to imatinib in gastrointestinal stromal tumor occurs through secondary gene mutation. Clin Cancer Res 11: 4182–4190

    Article  PubMed  CAS  Google Scholar 

  2. Benjamin RS, Choi H, Macapinlac HA et al. (2007) We should desist using RECIST, at least in GIST. J Clin Oncol 25: 1760–1764

    Article  PubMed  Google Scholar 

  3. Blanke C, Rankin C, Demetri RG et al. (2008) Phase III randomized, intergroup trial assessing imatinib mesylate at two dose levels in patients with unresectable or metastatic gastrointestinal stromal tumors expressing the kit receptor tyrosine kinase: S0033. J Clin Oncol 26: 626–632

    Article  PubMed  CAS  Google Scholar 

  4. Blay JY, Le Cesne A, Ray-Coquard I et al. (2007) Prospective multicentric randomized phase III study of imatinib in patients with advanced gastrointestinal stromal tumors comparing interruption versus continuation of treatment beyond 1 year: the French Sarcoma Group. J Clin Oncol 25: 1107–1113

    Article  PubMed  CAS  Google Scholar 

  5. Choi H, Charnsangavej C, Faria SC et al. (2007) Correlation of computed tomography and positron emission tomography in patients with metastatic gastrointestinal stromal tumor treated at a single institution with imatinib mesylate: proposal of new computed tomography response criteria. J Clin Oncol 25: 1753–1759

    Article  PubMed  Google Scholar 

  6. Corless CL, Fletcher JA, Heinrich MC (2004) Biology of gastrointestinal stromal tumors. J Clin Oncol 22: 3813–3825

    Article  PubMed  CAS  Google Scholar 

  7. Debiec-Rychter M, Dumez H, Judson I et al. (2004) Use of c-KIT/PDGFRA mutational analysis to predict the clinical response to imatinib in patients with advanced gastrointestinal stromal tumours entered on phase I and II studies of the EORTC soft tissue and bone sarcoma group. Eur J Cancer 40: 689–695

    Article  PubMed  CAS  Google Scholar 

  8. DeMatteo RP, Antonescu CR, Chadaram V et al. (2005) Adjuvant imatinib mesylate in pazients with primary high risk gastrointestinal sromal tumors (GIST) following complete resection: safety results from the U.S. Intergroup phase II trial ACOSOG Z9000. J Clin Oncol 23 [Suppl 1]: 9009 (abstr)

  9. DeMatteo RP, Gold JS, Saran L et al. (2008) Tumor mitotic rate, size, and location independently predict recurrence after resection of primary gastrointestinal stromal tumor (GIST) Cancer 112: 608–615

    Google Scholar 

  10. DeMatteo RP, Lewis JJ, Leung D et al. (2000) Two hundred gastrointestinal stromal tumors: recurrence patterns and prognostic factors for survival 231: 51–58

  11. DeMatteo RP, Maki RG, Singer S et al. (2007) Results of tyrosine kinase inhibitor therapy followed by surgical resection for metastatic gastrointestinal stromal tumor 245: 347–52

  12. DeMatteo RP, Owzar K, Antonescu CR et al. (2008) Efficacy of adjuvant imatinib mesylate following complete resection of localized, primary gastrointestinal stromal tumor (GIST) at high risk of recurrence: The U.S. Intergroup phase II trial ACOSOG Z9000. 2008 Gastrointestinal Cancers Symposoium, abstr 8

  13. DeMatteo RP, Owzar K, Maki R et al. (2007) Adjuvant imatinib mesylate increases recurrence free survival (RFS) in patients with completely resected localized primary gastrointestinal stromal tumor (GIST): North American Intergroup Phase III trial ACOSOG Z9001. J Clin Oncol 25 [Suppl 18]: 10079 (abstr)

  14. Demetri GD, Benjamin RS, Blanke CD et al. (2007) NCCN Task force report: optimal management of patients with Gastrointestinal Stromal Tumor (GIST) – update of the NCCN clinical practice guidelines. J Natl Compr Canc Netw 5 [Suppl 2]: 1–29

  15. Demetri GD, von Mehren M, Blanke CD et al. (2002) Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 347: 472–480

    Article  PubMed  CAS  Google Scholar 

  16. Emory TS, Sobin LH, Lukes L et al. (1999) Prognosis of gastrointestinal smooth-muscle (stromal) tumors: dependence on anatomic site 23: 82–87

  17. Fletcher CD, Berman JJ, Corless C et al. (2002) Diagnosis of gastrointestinal stromal tumors: A consensus approach. Hum Pathol 33: 459–465

    Article  PubMed  Google Scholar 

  18. Hassan I, You YN, Shyyan R et al. (2008) Surgically managed gastrointestinal stromal tumors: a comparative and prognostic analysis 15: 52–59

  19. Heinrich MC, Corless CL, Blanke CD et al. (2006) Molecular correlates of imatinib resistance in gastrointestinal stromal tumors. J Clin Oncol 24: 4764–4774

    Article  PubMed  CAS  Google Scholar 

  20. Heinrich MC, Corless CL, Demetri GD et al. (2003) Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol 21: 4342–4349

    Article  PubMed  CAS  Google Scholar 

  21. Hirota S, Isozaki K, Moriyama Y et al (1998) Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science 279: 577–580

    Article  PubMed  CAS  Google Scholar 

  22. Katz SC, DeMatteo RP (2008) Gastrointestinal stromal tumors and leiomyosarcomas 97: 350–359

    Google Scholar 

  23. Kindblom LG, Remotti HE, Aldenborg F et al. (1998) Gastrointestinal pacemaker cell tumor (GIPACT): gastrointestinal stromal tumors show phenotypic characteristics of the interstitial cells of cajal 152: 1259–1269

  24. Loughrey MB, Mitchell C, Mann GB et al. (2005) Gastrointestinal stromal tumour treated with neoadjuvant imatinib. J Clin Pathol 58: 779–781

    Article  PubMed  CAS  Google Scholar 

  25. Maki RG, Fletcher JA, Heinrich CM et al. (2005) Results from a continuation trial of SU11248 in patients (pts) with imatinib (IM)-resistant gastrointestinal stromal tumor (GIST). J Clin Oncol ASCO Ann Meet Proc Vol 23, 16S, Part I: 9011 (abstr)

  26. Miettinen M, Lasota J (2003) Gastrointestinal stromal tumors (GISTs): definition, occurrence, pathology, differential diagnosis and molecular genetics. Pol J Pathol 54: 3–24

    PubMed  Google Scholar 

  27. Miettinen M, Lasota J (2006) Gastrointestinal stromal tumors: pathology and prognosis at different sites. Semin Diagn Pathol 23: 70–83

    Article  PubMed  Google Scholar 

  28. Savage DG, Antman KH (2002) Imatinib mesylate–a new oral targeted therapy. N Engl J Med 346: 683–693

    Article  PubMed  CAS  Google Scholar 

  29. Stroobants S, Goeminne J, Seegers M et al. (2003) 18FDG-Positron emission tomography for the early prediction of response in advanced soft tissue sarcoma treated with imatinib mesylate (Glivec). Eur J Cancer 39: 2012–2020

    Article  PubMed  CAS  Google Scholar 

  30. Tornillo L, Terracciano LM (2005) An update on molecular genetics of gastrointestinal stromal tumours. J Clin Pathol 59: 557–563

    Article  Google Scholar 

  31. Tran T, Davila JA, El-Serag HB (2005) The epidemiology of malignant gastrointestinal stromal tumors: an analysis of 1,458 cases from 1992 to 2000 100: 162–168

  32. Van Glabbeke M, Verweij J, Casali PG et al. (2005) Initial and late resistance to imatinib in advanced gastrointestinal stromal tumors are predicted by different prognostic factors: a european organisation for research and treatment of cancer-italian sarcoma group-australasian gastrointestinal. Trials Group study 23: 5795-5804

    Google Scholar 

  33. Van Glabbeke MM, Owzar K, Rankin C et al. (2007) Comparison of two doses of imatinib for the treatment of unresectable or metastatic gastrointestinal stromal tumors (GIST): A meta-analyis based on 1,640 patients (pts). J Clin Oncol 25 [Suppl 18]: 10004 (abstr)

  34. van Oosterom AT, Judson I, Verweij J et al. (2001) Safety and efficacy of imatinib (STI571) in metastatic gastrointestinal stromal tumours: a phase I study. Lancet 358: 1421–1423

    Article  Google Scholar 

  35. Verweij J, Casali PG, Zalcberg J et al. (2004) Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial. Lancet 364: 1127–1134

    Article  PubMed  CAS  Google Scholar 

  36. Verweij J, van Oosterom A, Blay JY et al. (2003) Imatinib mesylate (STI-571 Glivec, Gleevec) is an active agent for gastrointestinal stromal tumours, but does not yield responses in other soft-tissue sarcomas that are unselected for a molecular target. Results from an EORTC soft tissue and bone sarcoma group phase II study. Eur J Cancer 39: 2006–2011

    Article  PubMed  CAS  Google Scholar 

  37. Wardelmann E, Merkelbach-Bruse S, Pauls K et al. (2006) Polyclonal evolution of multiple secondary KIT mutations in gastrointestinal stromal tumors under treatment with imatinib mesylate. Clin Cancer Res 12: 1743–1749

    Article  PubMed  CAS  Google Scholar 

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  1. Klinik für Chirurgie, Universitätsklinikum, Heidelberg, Deutschland

    U. Heger & J. Weitz

  2. Nationales Centrum für Tumorerkrankungen, Medizinische Onkologie, Universitätsklinikum, Im Neuenheimer Feld 350, 69120, Heidelberg, Deutschland

    F. Lordick

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  1. U. Heger
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Correspondence to F. Lordick.

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Heger, U., Weitz, J. & Lordick, F. Indikationen zur prä- und postoperativen Therapie mit Imatinib bei gastrointestinalen Stromatumoren. Chirurg 79, 630–637 (2008). https://doi.org/10.1007/s00104-008-1526-6

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