Gist Bedah Digestif

7/29/2019 Gist Bedah Digestif

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Medical and Targeted Therapies

of GIST


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Foo WC, Liegl-Atzwanger B, Lazar AJ. Pathology of Gastrointestinal Stromal Tumors.Pathology 2012;5:23-33

Anatomical Sites of GIST

Stomach

(60%)

Jejunum & ileum

30%

Duodenum

(5%)

Colorectum

(4%)

Appendix


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CLINICAL PRESENTATION

Varies depending on:

anatomic location of tumor

tumor size

aggressiveness

most common presentation:

GI bleeding (acute)

Chronic anemia


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CLINICAL PRESENTATION

GIST patients may also present with:

acute abdomen (tumor rupture)

GI obstruction

appendicitis-like pain

others: fatigue, dysphagia, satiety


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PATHOGENESIS:


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GIST: express CD 117 antigen*

(95%)

Evolution in stromal cell neoplasms

of GI tract: classification,

diagnosis, management

CD117 molecule: part of KIT (c-kit) tirosine-

kinase receptor, produced by KIT-oncogen

Express by ICC (interstitial cell of Cajal)


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Other spindle cell neoplasms of GI tract :

(lipoma, schwannoma, hemangioma,

leiomyoma dan leiomyosarcoma)

CD117-negative5% GIST CD 117

negative


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Foo WC, Liegl-Atzwanger B, Lazar AJ. Pathology of Gastrointestinal Stromal Tumors.Pathology 2012;5:23-33

Diagram of KIT and PDGFRA receptor tyrosine kinases with

location and relative frequencies of mutations.


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Tyrosine kinases and cancer

Tyrosine phosphorylation

A central mechanism for controlling cell signaling, leading to:

DifferentationMigrationProliferation

Enzyme Tyrosine kinases Tyrosine phosphatases


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Normal KIT Signaling

1. SCF ligand binding induces

2 KIT protein1,2

homodimerization2. Activation of the KIT

kinase domain1,2

3. ATP binding allows

binding of a substrate that

can now be

phosphorylated andactivated1,2

4. Activated substrate

initiates a signaling

cascade thought to be

crucial for1,2

Proliferation

Adhesion

Apoptosis

Differentiation PP P

ADP

PP PP

ATP

SIGNALING

KIT kinase

domain

Substrate

P

1 . D ue ns ing A e t a l. Cancer Invest. 2004;22:106-116.2. Rubin BP et al. Lancet. 2007;369(9574):1731-1741.

Proliferation

and survival


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Targeted Therapies:

a new generation of cancer drugs,

designed to interfere with specific proteins,

that have a critical role in tumor growth

andprogression


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Inhibition of KIT Signaling by Imatinib1. Imatinib binds to

the ATP-binding

pocket of the KIT

kinase domain1,2

2. This prevents

substrate

phosphorylation

and

signaling1,2

3. A lack of signaling

inhibitsproliferation

and survival1,2

SIGNALING

KIT kinase

domain

Imatinib

ATP

P P P

X

Substrate

Proliferation and survivalX1. Rubin BP et al. Lancet. 2007;369(9574):1731-1741.

2. Sav age DG et al. N Engl J Med. 2002;346:683-693.


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Targeting KIT

Imatinib and other TKIs in the treatment of

GIST has dramatically improve the outcome.

Especially in metastatic phase (no effective

treatment before TKI).

Imatinib was the first TKI to be approved for

the treatment of GIST.


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Targeting KIT

Imatinib-treated patients tend to relapse

because of secondary KIT mutation.

Dasatinib (second generation) are being

tested for their efficacy against KIT mutant

forms.


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Targeting KIT

Dasatinib is currently under investigation in

patientswith imatinib/sunitinib-refractory

GIST.

Nilotinib is inphase III first-line therapy in

inoperable/unresectable, metastatic disease.


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TREATMENT

Multidisciplinary treatment planning

involving:

pathologist

radiologist

surgeons (digestive)

medical oncologist


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ADJUVANT THERAPY

Relapse can be substantial. Risk classification and mutational analysis is

critical to making a clinical decision about

adjuvant therapy.


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Stage Classification and Risk

Assessment

TNM classification is not recommended (ESMO)

Prognostic factors:

Mitotic rate

Tumor size

Tumor site: gaster better than small bowel or

rectal GIST

Surgical margins

Tumor rupture


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Table : Rates of metastases or tumor-related death in GISTs of the stomach and small intestine by tumors grouped by

the mitotic rate and tumor size.

Group Tumor parameters Percentage of patients due to relapse

Size Mitotic rate Gastric GISTs Jejunal and ileal GISTs Duodenal GISTs Rectal GISTs

1 2 cm 5 per 50 HPFs 0 none 0 none 0 none 0 no ne

2 >2 5 cm 5 per 50 HPFs 1.9 very low 4.3 low 8.3 low 8.5 % low

3 a >5 10 cm 5 per 50 HPFs 3.6 low 24 moderate3b >10 cm 5 per 50 HPFs 12 moderate 52 high 34 higha 57c highb

4 2 cm >5 per 50 HPFs 0c 50c d 54 high

5 >2 5 cm >5 per 50 HPFs 16 moderate 73 high 50 high 52 high

6a >5 10 cm >5 per 50 HPFs 55 high 85 high

6b >10 cm >5 per 50 HPFs 86 high 90 high 86 highb 71 highb

a

Based on previously published long-term follow-up studies on 1055 gastric, 629 small intestinal, 144 duodenal and111 rectal GISTs [12, 15, 18, 30].bGroups 3a and 3b or 6a and 6b are combined in duodenal and rectal GISTs because of the small number of cases.c Denotes the tumor categories with very small numbers of cases.dNo tumors of such category were included in the study. Note that small intestinal and other intestinal GISTs show a

markedly worse prognosis in many mitotic rate and size categories than gastric GISTs.

GIST: Gastrointestinal stromal tumor; HPF: high-power field.

The ESMO / European Sarcoma Network Working Group. Clinical Practice Guidelines. Gastrointestinal Stromal Tumors: ESMO Clinical PracticeGuidelines for diagnosis, treatment and follow-up. Annals of Oncology 23 (Supplement 7): vii49vii55, 2012

Rate of metastases or tumor-related

death in GIST


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NCCN Guidelines

1. NCCN Clinical Practice Guidelines in Oncology. Soft Tissue Sarcoma. V.2.2011.


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Adjuvant imatinib therapy is safe and compared to placebo treatments

appears to prolong RFS following the resection of primary GIST.OS is not different at this time


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Preoperative imatinib can decrease tumor volume and is associatedwith complete surgical resection in locally advanced GISTs.


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IMATINIB

Dose of imatinib 400mg/d.

Patients with KIT exon 9

mutations fare better in

PFS on dose 800mg/d.

Treatment should becontinued indefinitely.


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Imatinib

Patients should be alerted to the importance

of compliance with therapy.

Interactions with concomitant medications

/foods.

proper handling side effects.


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www.OncologyEducation.ca

Authors: Joensuu H et al.Reviewed By: Dr. Vincent Tam

Abstract: ASCO 2011 Abstract 1

Date posted: June 2011

Twelve versus 36 months of adjuvant imatinib as

treatment of operable GIST with a high risk of

recurrence: Final results of a randomized trial

(SSGXVIII/AIO)


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N= 400 (1:1 randomization)

Stratification:1) R0 resection, no tumor rupture

2) R1 resection, tumor rupture

Primary Outcome: RFS

R

Treatment A:

IMATINIB 400mg daily x 12 months

Treatment B:IMATINIB 400mg daily x 36 months

Study Design


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Inclusion Criteria

- Diagnosis histology: GIST, KIT-positive

- High Risk for recurrence according Modified

Consensus Criteria:

Diameter tumor > 10cm or

Tumor mitotic count>10/50 HPF or

Tumor >5cm and mitosis count>5/50 HPF or

Spontaneous tumor rupture during surgical

procedure


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RESULTS*

IMATINIB

X 12

Months

IMATINIB

X 36

Months

Hazard

Ratiop-value

5Y-RFS

(%)47.9% 65.6% 0.46 p


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TOXICITY

IMATINIB

X 12 Mon ths

(n = 194)

IMATINIB

X 36 Mon ths

(n = 198)

P

Any adverse event 99% 100% 0.24

Any grade 3/4 event 20% 33% 0.006

Grade 3/4 periorbital

edema1% 1% 1.00

Grade 3/4 fatigue 1% 1% 0.62

Grade 3/4 diarrhea 1% 2% 0.37

Discontinued imatinib,

no GIST recurrence13% 26% 0.001


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Drug side effects and other

consideration:

Fluid retention (periorbital or peripheral edema)

Diarrhea

Nausea (diminished if taken with food)

fatigue

Muscle cramps

Abdominal pain

Rash

Mild macrocytic anemia


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Second line : Sunitinib

Third line: Regorafenib

After failing on Regorafenib: participated in

clinical trial

Anecdotal evidence:

patients who have already progressed onimatinib may occasionally benefit when

rechallenged with the same drug.


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FOLLOW UP

Relapses most often: liver and/or peritoneum.

Risk assessment: mitotic count, tumor size,tumor site useful in choosing FU policy.

High risk patients: relapse within 1-2 yearsfrom the end of adjuvant therapy.

HR pats., FU with CT/MRI every 3-6 mo (for 3

yrs during adjuvant T/), every 3 mo. (for 2 yrson cessation adjuvant T/), then every 6 mountil 5 yrs, then annually. (MRI prefer than CT)

The ESMO / European Sarcoma Network Working Group. Clinical Practice Guidelines. Gastrointestinal Stromal Tumors: ESMO Clinical PracticeGuidelines for diagnosis, treatment and follow-up. Annals of Oncology 23 (Supplement 7): vii49vii55, 2012


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ELGEKA

Komunitas Masyarakat Peduli Leukemia

Granulositik Kronik dan GIST di Jawa Tengah.

Berdiri sejak 2009

Obat didapat lewat NOA/NOA+ASKES

Sekretariat: Sub HEMON IPD FK UNDIP/RSDK


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TERIMAKASIH


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Imatinib

Suboptimal plasma levels of imatinib: worse

outcome.

Plasma levels assessment may be useful in:

pats. receiving concomitant medication (risk

major interaction)

unexpected observed toxicities

progression on 400mgto increase dose of

800mg

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Gist Bedah Digestif