Gastrointestinal Stromal TumorsGastrointestinal Stromal Tumors

(GISTs)(GISTs)

Efraim Idelevich, MD, PhD

Gastro-Intestinal Oncology Unit

Kaplan Medical Center

GISTs

Originally classified as other tumors: leiomyoma,

leiomyoblastoma, leiomyosarcoma or schwannomas

1998- the discovery of gain-of-function mutations in the

c-KIT proto-oncogene in GISTs that allowed GISTs to be

distinguished reliably from these other histopathological

subtypes of GI tumors

GISTs

The most common mesenchymal neoplasm of the GI tract.

0.1%-3% of GI malignant tumors

Recently described as a distinct clinical and histopathological entity:

Type of sarcoma, a tumor of mesenchymal (connective tissue) origin

Epidemiology

4000-6000 new cases in the USA each year with annual incidence of 11-14 per 106

Occur mostly in patients with a median age of 60 years (40-80)

No predilection for either gender

Familial GISTs- autosomal dominant Type I neurofibromatosis (7% mostly in the small intestine without

KIT mutations) Carney triad (GISTs + paraganglioma +pulmonary chondroma)

GIST: Involved Sites Occurs anywhere in GI tract/abdomen

Site Incidence %

Gastric 60-70

Small intestine 20-30

Colon <5

Other (omentum, mesentery,esophagus)

<5

Clinical Presentation Often asymptomatic, especially early in tumor

development, discovered incidentally by CT or endoscopy

Symptomatic:

Signs/symptoms related to location of tumor

– Vague GI pain or discomfort

– GI hemorrhage

– Anorexia, weight loss, nausea, anemia, and additional GI complaints

Diagnostic studies

CT – for initial evaluation and surveillance for recurrence

EUS – determines size and extent of the tumor

FDG-PET – reveals small metastases and establish baseline metabolic activity and assess therapy response

Routine use of PET for surveillance after resection is not yet recommended

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Histopathology of GIST: Biological Markers Used in Diagnosis of GIST

GISTs positive for

– CD117 (c-Kit receptor tyrosine kinase)

• Positive in >95%

– CD34 (mesenchymal/haematopoietic precursor cell marker)

• Positive in 60% to 70%

– Vimentin and smooth muscle actin

• Positive in 15% to 60%

• DOG1

– Desmin

– S-100 (rare- in small intestine 10%)

– Keratin (rare 10%) CD117 (c-Kit)–positivestaining GIST

The need for a biopsy is debatable FNA- cytologic morphology immunohistochemistry PCR analysis for KIT mutations FNA- not consistently diagnostic FNA- controversial due to risk of rupture and dissemination

Resectable lesion in the absence of metastatic disease-a preoperative diagnosis may be unnecessary

If diagnosis would impact the extent of resection or if unresectable or metastatic disease is present , biopsy is warrant

Biopsy should be open or by endoscopy and not percutaneous

Traditional Treatment Options Pre-Imatinib Mesylate (Glivec)

Surgery is primary treatment modality for GISTs

– 5-year survival 50% to 65%

– Recurrence have been reported up to 20 years after surgery

If incomplete resection/metastatic at presentation

– Median survival <1 year

– 5-year survival <35%

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Management of localized disease

Surgical resection – complete gross resection with preservation of an intact pseudocapsule without any tumor rupture

Segmental resection with negative microscopic margins is the preferred intervention

Laparoscopic resection cannot be recommended routinely yet

Routine lymphadenectomy is not recommended

Endoscopic resection of small GISTs is still controversial due to its inherent risks of positive margins and tumor spillage Is adjuvant treatment recommended?

Imatinib (Glivec)

Small molecule tyrosine kinase inhibitor with activity against ABL , BCR-ABL , KIT , PDGFRA , PDGFRB and CSF1R

Its structure mimics ATP and it binds competitively to the ATP binding site of the target kinases

Imatinib Mesylate: Mechanism of Action

Imatinib mesylate occupies the ATP binding pocket of the c KIT kinase domain

This prevents substrate phosphorylation and signaling

A lack of signaling inhibits proliferation and survival

P

PP P

ATP

SIGNALING

Imatinib mesylate

c KIT

Savage and Antman. N Engl J Med. 2002;346:683.

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Survival according to tumor size

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Neoadjuvant Imatinib in primary GISTs

Still investigational May be use to downstage primary or metastatic disease

before surgery many reports have been published of this approach to

convert an unresectable mass to one that is surgically approachable, or to reduce the morbidity of a procedure

The use of neoadjuvant imatinib, with or without adjuvant imatinib, to reduce or eradicate micrometastatic disease is also being assessed

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Conclusions

Surgery in M1 patients still an individual decision. No data from randomized or prospectively controlled

yet available Residual tumor resection is safe Resection of progressive tumor is less rewarding Multifocal resection is not recommended without

considering the patient’s personal situation Our experience with systemic therapy is: it more

often avoids emergency surgery

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Resistance to Imatinib

Primary resistance : no achievement of stable disease or progressing disease within 6 months of an initial clinical response (KIT exon 9 mutation or no detectable kinase mutation – wild-type tumors)

Secondary resistance: disease progression after more than 6 months clinical response (new acquired kinase mutation in KIT or PDGF-R that interfere with Imatinib activity)

Dose escalation of imatinib is the first step Use of other kinase inhibitors (Sunitinib) Surgery, radiofrequency ablation or hepatic artery chemoembolisation

Continuous vs. Intermittent Imatinib in Advanced GIST

Prospective multicenter phase III Imatinib treatment study: continuous vs. interrupted (46 patients randomized to two groups)

After 3 months: 0 and 5 (21%) patients had re-progression respectively

Conclusion: Advanced GIST patients stopping Glivec experience frequent re-progression at 3 months

Based on these results imatinib should not be discontinued

ASCO 2004

SUTENT (Sunitinib Malate) Capsules

Conclusions: SUTENT in GIST

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Final thoughts Neoadjuvant treatment with IM is still investigational Adjuvant treatment with IM is “standard of care” for high

(moderate) risk recurrence GIST (3 year and >) Metastatic and unresectable GIST should be treated with

IM (genotype evaluation is suggested) Retrospective studies have defined the subset of pts

most likely to potentially benefit from “adjuvant cytoreductive surgery”

Benefit of cytoreductive surgery in pts on SU is less clear

Thank you