Gastrointestinale stromacel tumoren (GIST): incidentie, diagnostiek, behandeling en prognose Hans Gelderblom 18 november 2014

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1 Gastrointestinale stromacel tumoren (GIST): incidentie, diagnostiek, behandeling en prognose Hans Gelderblom 18 november 2014

2 Gastrointestinale Stromacel Tumoren Infrequent type of sarcoma, a tumour of mesenchymal (connective tissue) origin 0.2% of gastrointestinal (GI) tumours Incidence: 3000 to 5000 cases in the US and Europe Similar male-to-female ratio Highest incidence in 5th to 7th decades of life Around 2000 described as a distinct clinical and histopathological entity

3 Klinische Presentatie Symptomen gerelateerd aan locatie Vage GI klachten GI bloeding Vaak asymptomatisch

4 Komt vaker voor dan aanvankelijk gedacht

5 Histologie Primary GIST with predominantly spindle-cell morphology Aggressive ( high grade ) GIST with mixed morphology (spindle cell and epitheloid)

6 Immuunhistochemie GISTs positive for CD117 (c-kit receptor tyrosine kinase) Positive in >95% Dog-1 positive CD34 (mesenchymal/haematopoietic precursor cell marker) Positive in 60% to 70% Vimentin and smooth muscle actin Positive in 15% to 60% GISTs do not express Desmin S-100 CD117 (c-kit) positive staining GIST

7 Structure of c-kit Receptor

8 The Biology of c-kit: Normal Functions c-kit is found in many normal tissues and is essential for Haematopoiesis Melanogenesis Gametogenesis Interstitial cells of Cajal (ICCs) development Activation of c-kit plays a critical role in different cell functions Proliferation Differentiation Apoptosis/survival Adhesion/chemotaxis

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10 GIST: Involved Sites Occur anywhere in GI tract/abdomen Site Incidence Gastric 60% 70% Small Intestine 20% 30% Colon <5% Other (omentum, mesentery, oesophagus) <5%

11 Signal Transduction Pathways Activated c-kit Receptor Werkingsmechanisme imatinib Pre-imatinib Imatinib ATP binds to kinase portion of receptor Cell membrane Blocks ATP binding Signal Transduction Pathways Inhibited Nucleus

12 Imatinib and GIST: de eerste patient Multiple liver and upper abdominal 18 FDG-accumulating metastases Joensuu et al. N Engl J Med. 2001;344: A marked decrease in 18 FDG uptake 4 weeks after starting imatinib

13 Fase 1 studie > 80% Clinical benefit! June 27, 2000 October 4, 2000 Before imatinib After imatinib

14 Fase III studie

15 Mutatie status en response (Heinrich JCO 2003) 88% KIT mutaties 76% exon 11: 84% PR 21% exon 9: 48% PR 1.6% exon 13: 100%PR 1.6% exon 17: 50% PR 4.7% PDGFRA mutaties: 0-67% PR Overig: 0% PR, 35% SD

16 Sunitinib

17 SU11248 fase III studie bij Glivec-resistente GIST 2:1 Randomisatie SU mg/d 4 wk op, 2 wk af Placebo Crossover naar SU11248 bij progressie doel: N = 357 Primair eindpunt: TTP

18 Resultaat fase III

19 Regorafenib (Stivarga) Percent control 0% 0.1% 0.1-1% 1-5% 5-10% 10-35% Biochemical activity IC 50 (nmol/l) KIT 7 VEGFR-1 13 Murine VEGFR-2 4 PDGFR-β 22 RET 1.5 B-RAF 28 FGFR1 202 Wilhelm SM et al. Int J Cancer 2011; 129:

20 Regorafenib In Progressive Disease (GRID): studie design Metastatic/ unresectable GIST patients progressing despite at least prior imatinib and sunitinib (n=236 screened; n=199 randomized) Multicenter, randomized, double-blind, R A N D O M I Z A T I O N 2 : 1 placebo-controlled phase III study Global trial: 17 countries across Europe, North America, and Asia-Pacific Regorafenib + best supportive care (BSC) 160 mg once daily 3 weeks on, 1 week off (n=133) Placebo + BSC 3 weeks on, 1 week off (n=66) Stratification: treatment line (2 vs >2 prior lines), geographical location (Asia vs Rest of World ) Disease progression per independent blinded central review Unblinding Crossover offered for placebo arm or continued regorafenib for treatment arm Regorafenib (unblinded) until next progression O F F T R E A T M E N T

21 Progressie-vrije overleving (primair eindpunt) Regorafenib significantly improved PFS vs placebo (p<0.0001)

22 Na chirurgie:

23 JAMA. 2012;307(12): doi: /jama Date of download: 11/18/2014 Copyright 2014 American Medical Association. All rights reserved.

24 Bijwerkingen Vwb imatinib meestal mild Geringe rash, periorbitaal oedeem, diarree, vermoeidheid en spierkrampen Scala aan zeer zeldzame bijwerkingen bv neutropenie, LF stoornissen, etc Volgende dia s gaan over sunitinib en regorafenib

25 Cardiotoxiciteit (from Girardi et al, the Oncologist 2010) 25

26 Wond complicaties Gerelateerd aan vasoconstrictie? Tijdens bevacizumab therapie (3 13% in spoed chirurgie in CRC) Scappaticci J Surg Oncol 2005 Advies Stop 1 week bij TKI voor geplande ok. Herstart na 2-4 weken Dosis aanpassingen bij niet helende wonden 26

27 Hypertensie Dosis afhankelijk Eerdere hypertensie Monitoren Vroeg behandelen 27

28 Huid reacties Rash and gele kleur, periunguaal erytheem, bulleuze lesies, hyperacanthosis Locale therapie Dosis aanpassingen Depigmentaties Faivre et al, JCO

29 Huid en haar

30 Bloeding Directe vasculaire effecten/antitumor effect Risico factoren Cavitatie Peritoneale localisaties 30

31 Chronische behandeling? Reproductieve functie Mucositis Compliance! Schema 31

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33 Onderzoek in centra: Genetische predispositie (van Erp JCO 2009) RET Sunitinib 738T/C Metabolic pathway -604T/C -92G/A 54T/C 11C/T 1718T/A 1501A/G In this exploratory study a relation was found between polymorphisms in the genes CYP1A1, ABCB1, ABCG2, NR1I3, VEGFR-2 and FLT3 and development of sunitinib toxicity 33

34 Trombopenie (van Erp BJC 2010) 34

35 Mutaties in cel vrij DNA (GALLOP studie) Beads, Emulsions, Amplification, Magnetics (done with Inostics): Laboratory steps: pre-amplification, emulsion PCR, hybridization, flow cytometry Detection of tumor-associated mutations using circulating free DNA from plasma Exquisitely sensitive detection: 1 mutant allele in 10,000 normal alleles Richardson AL, Iglehart JD. Clin Cancer Res 2012; 18: Ideal concept to detect emergence of multiple gene mutations which can make GIST resistant

36 Conclusies Incidentie van GIST laag Sinds 15 jaar is prognose drastisch verbeterd In palliatieve setting achtereenvolgens imatinib, sunitinib en regorafenib Chronische therapie is uitdaging Na hoog risico chirurgie is 3 jaar adjuvant imatinib standaard Neoadjuvant is geslecteerde gevallen PA review en mutatieanalyse noodzakelijk Behandeling van locally advanced, gemetastaseerd en adjuvant in centra

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