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Medical and Targeted Therapies of GIST

Anatomical Sites of GIST


Esophagus (1<%) Stomach (60%)

Duodenum (5%) Colorectum (4%) Appendix <1%)

Jejunum & ileum 30%

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

CLINICAL PRESENTATION
Varies depending on: anatomic location of tumor tumor size aggressiveness most common presentation: GI bleeding (acute) Chronic anemia

CLINICAL PRESENTATION
GIST patients may also present with: acute abdomen (tumor rupture) GI obstruction appendicitis-like pain others: fatigue, dysphagia, satiety

PATHOGENESIS:

GIST: express CD 117 antigen* (95%)

Evolution in stromal cell neoplasms of GI tract: classification, diagnosis, management

CD117 molecule: part of KIT (c-kit) tirosinekinase receptor, produced by KIT-oncogen Express by ICC (interstitial cell of Cajal)

Other spindle cell neoplasms of GI tract :


(lipoma, schwannoma, hemangioma, leiomyoma dan leiomyosarcoma)

5% GIST CD 117 negative

CD117-negative

Diagram of KIT and PDGFRA receptor tyrosine kinases with location and relative frequencies of mutations.

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

Tyrosine kinases and cancer


Enzyme Tyrosine kinases Tyrosine phosphatases

Tyrosine phosphorylation A central mechanism for controlling cell signaling, leading to:

Proliferation

Migration

Differentation

Normal KIT Signaling


1. 2. 3. SCF ligand binding induces 2 KIT protein1,2 homodimerization Activation of the KIT kinase domain1,2 ATP binding allows binding of a substrate that can now be phosphorylated and activated1,2 Activated substrate initiates a signaling cascade thought to be crucial for1,2 Proliferation Adhesion Apoptosis Differentiation
Duensing A et al. Cancer Invest. 2004;22:106-116. Rubin BP et al. Lancet. 2007;369(9574):1731-1741.

KIT kinase domain


ATP

Substrate

4.

P P P ADP

P
SIGNALING

PP
Proliferation and survival

1. 2.

Targeted Therapies:

a new generation of cancer drugs, designed to interfere with specific proteins, that have a critical role in tumor growth and progression

Inhibition of KIT Signaling by Imatinib


1. 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 inhibits proliferation and survival1,2
1. 2. Rubin BP et al. Lancet. 2007;369(9574):1731-1741. Savage DG et al. N Engl J Med. 2002;346:683-693.

Substrate

KIT kinase domain

X
Imatinib

ATP
P P P
SIGNALING

Proliferation and survival

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.

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.

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.

TREATMENT
Multidisciplinary treatment planning involving: pathologist radiologist surgeons (digestive) medical oncologist

ADJUVANT THERAPY

Relapse can be substantial. Risk classification and mutational analysis is critical to making a clinical decision about adjuvant therapy.

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

Rate of metastases or tumor-related death in GIST


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 Size Mitotic rate 2 cm >2 5 cm a >5 10 cm >10 cm 2 cm >2 5 cm >5 10 cm >10 cm 5 per 50 HPFs 5 per 50 HPFs 5 per 50 HPFs 5 per 50 HPFs >5 per 50 HPFs >5 per 50 HPFs >5 per 50 HPFs >5 per 50 HPFs Percentage of patients due to relapse Gastric GISTs Jejunal and ileal GISTs 0 none 1.9 very low 3.6 low 12 moderate 0c 16 moderate 55 high 86 high 0 none 4.3 low 24 moderate 52 high 50c 73 high 85 high 90 high Duodenal GISTs 0 none 8.3 low 34 higha
d

Rectal GISTs 0 no ne 8.5 % low 57c highb 54 high 52 high 71 highb

1 2 3 3b 4 5 6a 6b
a

50 high 86 highb

Based on previously published long-term follow-up studies on 1055 gastric, 629 small intestinal, 144 duodenal and 111 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 Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology 23 (Supplement 7): vii49vii55, 2012

NCCN Guidelines

1.

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

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

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

IMATINIB

Dose of imatinib 400mg/d. Patients with KIT exon 9 mutations fare better in PFS on dose 800mg/d. Treatment should be continued indefinitely.

Imatinib
Patients should be alerted to the importance of compliance with therapy. Interactions with concomitant medications /foods. proper handling side effects.

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)
Authors: Joensuu H et al. Reviewed By: Dr. Vincent Tam Abstract: ASCO 2011 Abstract 1 Date posted: June 2011

www.OncologyEducation.ca

Study Design
N= 400 (1:1 randomization)
Stratification:
1) R0 resection, no tumor rupture 2) R1 resection, tumor rupture

Treatment A:
IMATINIB 400mg daily x 12 months

R
Treatment B:
IMATINIB 400mg daily x 36 months
Primary Outcome: RFS

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

RESULTS*

IMATINIB X 12 Months

IMATINIB X 36 Months

Hazard Ratio

p-value

5Y-RFS (%)

47.9%

65.6%

0.46

p<0.0001

5Y-OS (%)

81.7%

92.0%

0.45

p=0.019

* Intention-to-treat analysis

TOXICITY
IMATINIB X 12 Months (n = 194) Any adverse event 99% IMATINIB X 36 Months (n = 198) 100% P

0.24

Any grade 3/4 event

20%

33%

0.006

Grade 3/4 periorbital edema


Grade 3/4 fatigue

1%
1%

1%
1%

1.00
0.62

Grade 3/4 diarrhea Discontinued imatinib, no GIST recurrence

1%

2%

0.37

13%

26%

0.001

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

Second line : Sunitinib Third line: Regorafenib After failing on Regorafenib: participated in clinical trial Anecdotal evidence: patients who have already progressed on imatinib may occasionally benefit when rechallenged with the same drug.

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 years from 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 yrs on cessation adjuvant T/), then every 6 mo until 5 yrs, then annually. (MRI prefer than CT)
The ESMO / European Sarcoma Network Working Group. Clinical Practice Guidelines. Gastrointestinal Stromal Tumors: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology 23 (Supplement 7): vii49vii55, 2012

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

TERIMAKASIH

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 400mg to increase dose of 800mg