Gastrointestinale stromacel tumoren (GIST): incidentie, diagnostiek, behandeling en prognose Hans Gelderblom 18 november 2014
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
Klinische Presentatie Symptomen gerelateerd aan locatie – Vage GI klachten – GI bloeding
Vaak asymptomatisch
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Komt vaker voor dan aanvankelijk gedacht…
Histologie
Primary GIST with predominantly spindle-cell morphology
Aggressive (“high grade”) GIST with mixed morphology (spindle cell and epitheloid)
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
Structure of c-Kit Receptor
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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GIST: Involved Sites • Occur anywhere in GI tract/abdomen Site
Incidence
Gastric
60%–70%
Small Intestine
20%–30%
Colon
<5%
Other (omentum,
<5%
mesentery, oesophagus)
Werkingsmechanisme imatinib Imatinib
c-Kit Receptor
Pre-imatinib
Signal Transduction Pathways Activated
ATP binds to kinase portion of receptor
Cell membrane
Blocks ATP binding
Signal Transduction Pathways Inhibited
Nucleus
Imatinib and GIST: de eerste patient
Multiple liver and upper abdominal 18FDG-accumulating metastases
Joensuu et al. N Engl J Med. 2001;344:1052-1056.
A marked decrease in 18FDG uptake 4 weeks after starting imatinib
Fase 1 studie > 80% Clinical benefit! June 27, 2000
Before imatinib
October 4, 2000
After imatinib
Fase III studie
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
Sunitinib
SU11248 fase III studie bij Glivec-resistente GIST
2:1 Randomisatie
SU11248 • 50 mg/d • 4 wk op, 2 wk af Placebo
doel: N = 357 Primair eindpunt: TTP
Crossover naar SU11248 bij progressie
Resultaat fase III
Regorafenib (Stivarga)
Percent control 0% 0.1% 0.1-1% 1-5% 5-10% 10-35%
Wilhelm SM et al. Int J Cancer 2011; 129: 245-255.
Biochemical activity IC50 (nmol/l) KIT
7
VEGFR-1
13
Murine VEGFR-2
4
PDGFR-β
22
RET
1.5
B-RAF
28
FGFR1
202
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)
R A N D O M I Z A T I O N
Regorafenib + best supportive care (BSC)
2:1
160 mg once daily 3 weeks on, 1 week off (n=133)
Placebo + BSC 3 weeks on, 1 week off (n=66)
• Multicenter, randomized, double-blind, placebo-controlled phase III study • Global trial: 17 countries across Europe, North America, and Asia-Pacific • 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
Progressie-vrije overleving (primair eindpunt)
Regorafenib significantly improved PFS vs placebo (p<0.0001)
Na chirurgie:…
JAMA. 2012;307(12):1265-1272. doi:10.1001/jama.2012.347
Date of download: 11/18/2014
Copyright © 2014 American Medical Association. All rights reserved.
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
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Cardiotoxiciteit (from Girardi et al, the Oncologist 2010)
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Wond complicaties • Advies
• Gerelateerd aan vasoconstrictie? • Tijdens bevacizumab therapie (313% in spoed chirurgie in CRC) Scappaticci J Surg Oncol 2005
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• Stop 1 week bij TKI voor geplande ok. Herstart na 2-4 weken • Dosis aanpassingen bij niet helende wonden
Hypertensie • Dosis afhankelijk
• Monitoren
• Eerdere hypertensie
• Vroeg behandelen
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Huid reacties • Rash and gele kleur , periunguaal erytheem, bulleuze lesies, hyperacanthosis
• Locale therapie
• Dosis aanpassingen
• Depigmentaties
Faivre et al, JCO 2006 28
Huid en haar
Bloeding • Directe vasculaire effecten/antitumor effect • Risico factoren • Cavitatie • Peritoneale localisaties
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Chronische behandeling? • Reproductieve functie
• Compliance !
• Mucositis
• Schema
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Onderzoek in centra: Genetische predispositie (van Erp JCO 2009) RET
Sunitinib 738T/C Metabolic pathway
-604T/C
1501A/G
-92G/A 54T/C
11C/T 1718T/A
“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
Trombopenie (van Erp BJC 2010)
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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
• Ideal concept to detect emergence Richardson AL, Iglehart JD. Clin Cancer Res 2012; 18: 3209–3211
of multiple gene mutations which can make GIST resistant
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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Dank voor uw aandacht!!!....Vragen?
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