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Der Chirurg

, Volume 90, Issue 6, pp 462–469 | Cite as

Imatinib und darüber hinaus – was ist wichtig für die Chirurgie?

  • R. Hamacher
  • J. Falkenhorst
  • J. Treckmann
  • S. BauerEmail author
Leitthema

Zusammenfassung

Die Behandlung gastrointestinaler Strumatumoren (GIST) ist seit Einführung von KIT-Inhibitoren dramatisch verbessert worden. Eine Heilung gelingt allerdings unverändert nur auf der Grundlage einer operativen Therapie des Primärtumors. Auch in der metastasierten Situation erscheint die Chance auf eine langfristige Tumorkontrolle durch Tyrosinkinaseinhibitoren (TKI) nach dem Erreichen einer ggf. chirurgischen kompletten Resektion höher zu sein. Die Entscheidung, welche Patienten am ehesten von multimodalen Konzepten profitieren, basiert inzwischen neben klinischen Faktoren auch auf einer Vielzahl molekularer Prädiktoren und verlangt eine Besprechung in multidisziplinären, erfahrenen Behandlungsteams. Neue, breiter wirksame Inhibitoren ermöglichen ein Therapieansprechen auch bei bislang refraktären GIST-Subtypen wie den PDGFR-D842V-mutierten GIST, aber scheinen auch bei KIT-mutierten GIST nach dem Versagen aller zugelassenen Therapien einen therapeutischen Nutzen aufzuweisen. Hier ist eine grundlegende Änderung der Behandlungssequenzen in naher Zukunft zu erwarten.

Schlüsselwörter

Gastrointestinale Stromatumoren Mutation Adjuvant Neoadjuvant Operation 

Abkürzungen

BRAF

Homolog B, rapidly accelerated fibrosarcoma (serine/threonine-protein kinase)

EMA

European Medicines Agency (Europäische Arzneimittel-Agentur)

GIST

Gastrointestinaler Stromatumor

HPF

High-power-field

KIT

Proto-oncogene tyrosine-protein kinase Kit (c-kit), CD117, mast/stem cell growth factor receptor precursor (SCFR)

NTRK

Neurotrophic tyrosine kinase

PDGFRA

Platelet-derived growth factor receptor A

SDH

Succinat-Dehydrogenase

TKI

Tyrosinkinaseinhibitoren

Imatinib and beyond—what is important for surgery?

Abstract

The treatment of gastrointestinal stromal tumors (GIST) has dramatically improved since the introduction of small molecule KIT proto-oncogene receptor tyrosine kinase inhibitors. Nevertheless, the cure of patients is still based on surgical treatment of the primary tumor. The chance of long-term tumor control by tyrosine kinase inhibitors (TKI) even in the metastatic setting also appears to be improved after achieving a surgical complete resection. The decision on which patients will most likely profit from multimodal treatment approaches is increasingly based on complex molecular predictors in addition to clinical factors and also a profound understanding of the biology of GIST that requires discussion in a multidisciplinary, highly experienced treatment team. Novel, more potent inhibitors enable a response to treatment in so far treatment-refractory GIST subtypes, such as the platelet-derived growth factor receptor (PDGFR) D842V mutated GIST subtype and also appear to show treatment benefits even in KIT mutated GIST after the failure of all approved treatments. These treatments are expected to profoundly change treatment algorithms in the near future.

Keywords

Gastrointestinal stromal tumor Mutation Adjuvant Neoadjuvant Surgery 

Notes

Einhaltung ethischer Richtlinien

Interessenkonflikt

R. Hamacher: Novartis (Einladung zu Kongressteilnahme). S. Bauer: Advisory Role: Blueprint Medicines, ADC Therapeutics, Lilly, Novartis, Daichii, Lilly, Plexxikon, Nanobiotix, Deciphera; CME Honoraria: Novartis, Pfizer, Bayer, Lilly, Pharmamar; Research Support: Blueprint Medicines, Incyte, Novartis. J. Falkenhorst und J. Treckmann geben an, dass kein Interessenkonflikt besteht.

Dieser Beitrag beinhaltet keine von den Autoren durchgeführten Studien an Menschen oder Tieren.

Literatur

  1. 1.
    Gastrointestinal Stromal Tumor Meta-Analysis Group (MetaGIST) (2010) Comparison of two doses of imatinib for the treatment of unresectable or metastatic gastrointestinal stromal tumors: a meta-analysis of 1,640 patients. J Clin Oncol 28:1247–1253CrossRefGoogle Scholar
  2. 2.
    An HJ, Ryu MH, Ryoo BY, Sohn BS, Kim KH, Oh ST et al (2013) The effects of surgical cytoreduction prior to imatinib therapy on the prognosis of patients with advanced GIST. Ann Surg Oncol 20:4212–4218CrossRefGoogle Scholar
  3. 3.
    Bauer S, Rutkowski P, Hohenberger P, Miceli R, Fumagalli E, Siedlecki JA et al (2014) Long-term follow-up of patients with GIST undergoing metastasectomy in the era of imatinib—analysis of prognostic factors (EORTC-STBSG collaborative study). Eur J Surg Oncol 40:412–419CrossRefGoogle Scholar
  4. 4.
    Boye K, Berner JM, Hompland I, Bruland OS, Stoldt S, Sundby Hall K et al (2018) Genotype and risk of tumour rupture in gastrointestinal stromal tumour. Br J Surg 105:e169–e175CrossRefGoogle Scholar
  5. 5.
    Casali PG, Zalcberg J, Le Cesne A, Reichardt P, Blay JY, Lindner LH et al (2017) Ten-year progression-free and overall survival in patients with Unresectable or metastatic GI stromal tumors: long-term analysis of the European Organisation for Research and Treatment of Cancer, Italian Sarcoma Group, and Australasian Gastrointestinal Trials Group intergroup phase III randomized trial on Imatinib at two dose levels. J Clin Oncol 35:1713–1720CrossRefGoogle Scholar
  6. 6.
    Casali PG, Abecassis N, Bauer S, Biagini R, Bielack S, Bonvalot S et al (2018) Gastrointestinal stromal tumours: ESMO-EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 29:iv68–iv78CrossRefGoogle Scholar
  7. 7.
    Cavnar MJ, Wang L, Balachandran VP, Antonescu CR, Tap WD, Keohan M et al (2017) Rectal gastrointestinal stromal tumor (GIST) in the era of Imatinib: organ preservation and improved oncologic outcome. Ann Surg Oncol 24:3972–3980CrossRefGoogle Scholar
  8. 8.
    Debiec-Rychter M, Sciot R, Le Cesne A, Schlemmer M, Hohenberger P, van Oosterom AT et al (2006) KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumours. Eur J Cancer 42:1093–1103CrossRefGoogle Scholar
  9. 9.
    Demetri GD, van Oosterom AT, Garrett CR, Blackstein ME, Shah MH, Verweij J et al (2006) Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet 368:1329–1338CrossRefGoogle Scholar
  10. 10.
    Demetri GD, Reichardt P, Kang YK, Blay JY, Rutkowski P, Gelderblom H et al (2013) Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 381:295–302CrossRefGoogle Scholar
  11. 11.
    Du CY, Zhou Y, Song C, Wang YP, Jie ZG, He YL et al (2014) Is there a role of surgery in patients with recurrent or metastatic gastrointestinal stromal tumours responding to imatinib: a prospective randomised trial in China. Eur J Cancer 50:1772–1778CrossRefGoogle Scholar
  12. 12.
    Fletcher CD, Berman JJ, Corless C, Gorstein F, Lasota J, Longley BJ et al (2002) Diagnosis of gastrointestinal stromal tumors: a consensus approach. Hum Pathol 33:459–465CrossRefGoogle Scholar
  13. 13.
    Ford SJ, Gronchi A (2016) Indications for surgery in advanced/metastatic GIST. Eur J Cancer 63:154–167CrossRefGoogle Scholar
  14. 14.
    Garner AP, Gozgit JM, Anjum R, Vodala S, Schrock A, Zhou T et al (2014) Ponatinib inhibits polyclonal drug-resistant KIT oncoproteins and shows therapeutic potential in heavily pretreated gastrointestinal stromal tumor (GIST) patients. Clin Cancer Res 20:5745–5755CrossRefGoogle Scholar
  15. 15.
    George S, Heinrich M, Chi P, Abdul Razak A, von Mehren M, Gordon M et al (2018) Initial Results of Phase 1 Study of DCC-2618, a Broad-spectrum KIT and PDGFRa Inhibitor, in Patients (pts) with Gastrointestinal Stromal Tumor (GIST) by number of prior regimes. Ann Oncol 29(suppl_8):viii576–viii595Google Scholar
  16. 16.
    Gunawan B, von Heydebreck A, Sander B, Schulten HJ, Haller F, Langer C et al (2007) An oncogenetic tree model in gastrointestinal stromal tumours (GISTs) identifies different pathways of cytogenetic evolution with prognostic implications. J Pathol 211:463–470CrossRefGoogle Scholar
  17. 17.
    Hawkins AT, Wells KO, Krishnamurty DM, Hunt SR, Mutch MG, Glasgow SC et al (2017) Preoperative chemotherapy and survival for large anorectal gastrointestinal stromal tumors: a national analysis of 333 cases. Ann Surg Oncol 24:1195–1201CrossRefGoogle Scholar
  18. 18.
    Heinrich M, von Mehren M, Jones RL, Bauer S, Kang Y‑K, Schöffski P et al (2018) Avapritinib is highly active and well-tolerated in patients with advanced GIST driven by a diverse. Variety of oncogenic mutations in KIT and PDGFRA. CTOS 2018 Annual Meeting. Abstract 3027631Google Scholar
  19. 19.
    Heinrich MC, Corless CL, Demetri GD, Blanke CD, von Mehren M, Joensuu H et al (2003) Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol 21:4342–4349CrossRefGoogle Scholar
  20. 20.
    Ivanyi P, Winkler T, Ganser A, Reuter C, Grunwald V (2008) Novel therapies in advanced renal cell carcinoma: management of adverse events from sorafenib and sunitinib. Dtsch Arztebl Int 105:232–237PubMedPubMedCentralGoogle Scholar
  21. 21.
    Jakob J, Mussi C, Ronellenfitsch U, Wardelmann E, Negri T, Gronchi A et al (2013) Gastrointestinal stromal tumor of the rectum: results of surgical and multimodality therapy in the era of imatinib. Ann Surg Oncol 20:586–592CrossRefGoogle Scholar
  22. 22.
    Jakob J, Hohenberger P (2018) Neoadjuvant therapy to downstage the extent of resection of gastrointestinal stromal tumors. Visc Med 34:359–365CrossRefGoogle Scholar
  23. 23.
    Joensuu H (2008) Risk stratification of patients diagnosed with gastrointestinal stromal tumor. Hum Pathol 39:1411–1419CrossRefGoogle Scholar
  24. 24.
    Joensuu H, Vehtari A, Riihimaki J, Nishida T, Steigen SE, Brabec P et al (2012) Risk of recurrence of gastrointestinal stromal tumour after surgery: an analysis of pooled population-based cohorts. Lancet Oncol 13:265–274CrossRefGoogle Scholar
  25. 25.
    Joensuu H, Eriksson M, Sundby Hall K, Reichardt A, Hartmann JT, Pink D et al (2016) Adjuvant Imatinib for high-risk GI stromal tumor: analysis of a randomized trial. J Clin Oncol 34:244–250CrossRefGoogle Scholar
  26. 26.
    Keung EZ, Fairweather M, Raut CP (2016) The role of surgery in metastatic gastrointestinal stromal tumors. Curr Treat Options Oncol 17:8CrossRefGoogle Scholar
  27. 27.
    Liu W, Zeng X, Wu X, He J, Gao J, Shuai X et al (2017) Clinicopathologic study of succinate-dehydrogenase-deficient gastrointestinal stromal tumors: A single-institutional experience in China. Medicine (Baltimore) 96:e7668CrossRefGoogle Scholar
  28. 28.
    Luber V, Wagner J, Lock JF, Dietz UA, Lichthardt S, Matthes N et al (2018) The use of tumor therapeutics in the perioperative period. Chirurg 89:108–115CrossRefGoogle Scholar
  29. 29.
    Lv A, Qian H, Qiu H, Wu J, Li Y, Li Z et al (2017) Organ-preserving surgery for locally advanced duodenal gastrointestinal stromal tumor after neoadjuvant treatment. Biosci Trends 11:483–489CrossRefGoogle Scholar
  30. 30.
    Miettinen M, Lasota J (2006) Gastrointestinal stromal tumors: pathology and prognosis at different sites. Semin Diagn Pathol 23:70–83CrossRefGoogle Scholar
  31. 31.
    Mussi C, Ronellenfitsch U, Jakob J, Tamborini E, Reichardt P, Casali PG et al (2010) Post-imatinib surgery in advanced/metastatic GIST: is it worthwhile in all patients? Ann Oncol 21:403–408CrossRefGoogle Scholar
  32. 32.
    Nannini M, Urbini M, Astolfi A, Biasco G, Pantaleo MA (2017) The progressive fragmentation of the KIT/PDGFRA wild-type (WT) gastrointestinal stromal tumors (GIST). J Transl Med 15:113CrossRefGoogle Scholar
  33. 33.
    Patrikidou A, Domont J, Chabaud S, Ray-Coquard I, Coindre JM, Bui-Nguyen B et al (2016) Long-term outcome of molecular subgroups of GIST patients treated with standard-dose imatinib in the BFR14 trial of the French Sarcoma Group. Eur J Cancer 52:173–180CrossRefGoogle Scholar
  34. 34.
    Raut CP, Posner M, Desai J, Morgan JA, George S, Zahrieh D et al (2006) Surgical management of advanced gastrointestinal stromal tumors after treatment with targeted systemic therapy using kinase inhibitors. J Clin Oncol 24:2325–2331CrossRefGoogle Scholar
  35. 35.
    Raut CP, Wang Q, Manola J, Morgan JA, George S, Wagner AJ et al (2010) Cytoreductive surgery in patients with metastatic gastrointestinal stromal tumor treated with sunitinib malate. Ann Surg Oncol 17:407–415CrossRefGoogle Scholar
  36. 36.
    Roland CL, Bednarski BK, Watson K, Torres KE, Cormier JN, Wang WL et al (2018) Identification of preoperative factors associated with outcomes following surgical management of intra-abdominal recurrent or metastatic GIST following neoadjuvant tyrosine kinase inhibitor therapy. J Surg Oncol 117:879–885CrossRefGoogle Scholar
  37. 37.
    Sato S, Tsujinaka T, Masuzawa T, Yamamoto K, Takahashi T, Yamashita Y et al (2017) Role of metastasectomy for recurrent/metastatic gastrointestinal stromal tumors based on an analysis of the Kinki GIST registry. Surg Today 47:58–64CrossRefGoogle Scholar
  38. 38.
    Tirumani SH, Shinagare AB, Jagannathan JP, Krajewski KM, Ramaiya NH, Raut CP (2014) Radiologic assessment of earliest, best, and plateau response of gastrointestinal stromal tumors to neoadjuvant imatinib prior to successful surgical resection. Eur J Surg Oncol 40:420–428CrossRefGoogle Scholar
  39. 39.
    Van Glabbeke M, Verweij J, Casali PG, Le Cesne A, Hohenberger P, Ray-Coquard I 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. J Clin Oncol 23:5795–5804CrossRefGoogle Scholar
  40. 40.
    von Mehren M, Joensuu H (2018) Gastrointestinal stromal tumors. J Clin Oncol 36:136–143CrossRefGoogle Scholar
  41. 41.
    Wardelmann E, Merkelbach-Bruse S, Pauls K, Thomas N, Schildhaus HU, Heinicke T et al (2006) Polyclonal evolution of multiple secondary KIT mutations in gastrointestinal stromal tumors under treatment with imatinib mesylate. Clin Cancer Res 12:1743–1749CrossRefGoogle Scholar
  42. 42.
    Wozniak A, Laenen A, Gutierrez A, Bylina E, Schöffski P, Blay J‑Y et al (2018) Extended conticagist analysis adds to the amended prognostication in GIST based on tumor KIT/PDGFRA genotype status. CTOS 2018 Annual Meeting. Abstract 3041764Google Scholar
  43. 43.
    Hornick JL, Fletcher CD (2007) Hum Pathol 38(5):679–687CrossRefGoogle Scholar
  44. 44.
    Corless CL, Schroeder A, Griffith D, Town A, McGreevey L, Harrell P, Shiraga S, Bainbridge T, Morich J, Heinrich MC (2005) PDGFRA mutations in gastrointestinal stromal tumors: frequency, spectrum and in vitro sensitivity to imatinib. J Clin Oncol 23(23):5357–5364CrossRefGoogle Scholar
  45. 45.
    Miettinen M, Fetsch JF, Sobin LH, Lasota J (2006) Gastrointestinal stromal tumors in patients with neurofibromatosis 1: a clinicopathologic and molecular genetic study of 45 cases. Am J Surg Pathol 30(1):90–96CrossRefGoogle Scholar
  46. 46.
    Miettinen M, Wang ZF, Sarlomo-Rikala M, Osuch C, Rutkowski P, Lasota J (2011) Succinate dehydrogenase-deficient GISTs: a clinicopathologic, immunohistochemical, and molecular genetic study of 66 gastric GISTs with predilection to young age. Am J Surg Pathol 35(11):1712–1721CrossRefGoogle Scholar

Copyright information

© Springer Medizin Verlag GmbH, ein Teil von Springer Nature 2019

Authors and Affiliations

  • R. Hamacher
    • 1
  • J. Falkenhorst
    • 1
  • J. Treckmann
    • 2
  • S. Bauer
    • 1
    Email author
  1. 1.Innere Klinik (Tumorforschung), Sarkomzentrum am Westdeutschen Tumorzentrum, Universitätsklinik EssenUniversität Duisburg-EssenEssenDeutschland
  2. 2.Sektion Viszerale/retroperitoneale Sarkome und GIST, Klinik für Allgemein‑, Viszeral- und Transplantationschirurgie, Sarkomzentrum am Westdeutschen Tumorzentrum, Universitätsklinik EssenUniversität Duisburg-EssenEssenDeutschland

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