Gastrointestinal stromal tumor (GIST) dr ridu kumar sharma

GASTROINTESTINAL STROMAL TUMOURS

DR RIDU KUMAR SHARMAREGIONAL CANCER CENTRE,

INDIRA GANDHI INSTITUTE OF MEDICAL SCIENCES ,PATNA

Introduction Most common mesenchymal tumours of GI tract

Previously grouped with sarcomas of smooth muscle origin i.e. leiomyomas, leiomyoblastomas or leiomyosarcomas

Recently recognized as a distinct pathological entity after introduction of c-kit testing

Median age of presentation- ~58 years Slightly more common in men than women

Represent 1-3 % of all GI malignancies Incidence ~ 10-15 cases/million /year worldwide

Distribution Stomach 50-60% Small bowel 20-30% Large bowel 10% Esophagus 5% Else where in abdomen 5%

Most common site of metastasis: Liver/Dissemination within abdominal cavity

LN Mets- extremely rare

Symptoms Symptoms depend on the site and size of the tumor

Include: Abdominal pain Dysphagia Gastrointestinal bleeding Symptoms of bowel obstruction Small tumors may be asymptomatic

INVESTIGATIVE WORKUP Detailed clinical history General & physical examination Lab tests- CBC,KFT, LFT CXR-PA CECT ABDOMEN & PELVIS BIOPSY- - may not be necessary if tumor is easily resectable & preoperative therapy is not

needed

-should be done if preoperative therapy is considered for unresectable or marginally resectable tumors

-Endoscopic USG guided biopsy is preferred

-IHC-KIT, PDGFR

-DOG 1 testing

Pathology

Expression of c-Kit (CD 117) characteristic (~ 95% patients); 60-70% patients CD34 positive

c-Kit (Tyrosine Kinase) detected by IHC as CD117 antigen, is protein product of c-kit oncogene

Abnormal, continous c-Kit signaling involved in development of GIST

KIT Negative GIST- 5%

Imatinib mesylate (Formerly ST-571) targets & inhibits c-Kit similar to its activity against Bcr-Abl tyrosine kinase in CML

Staging

T-PRIMARY TUMOR Tx-primary tumor cannot be assessed To-no e/o primary disease T1-Tumor 2cm or less T2- >2cm but not >5cm in greatest dimension T3- >5cm but not >10cm T4- >10cm in greatest dimension N-REGIONAL LYMPH NODES Nx-cannot be assessed No-no e/o of LN mets N1-regional LN mets M-DISTANT METASTASIS Mo-no distant mets M1-distant mets

Prognostic factors Tumor size- 2cm or less Mitotic rate-mitotic index 5 or less per 50 HPF Location of primary tumor-Gastric GIST more

favourable prognosis than intestinal Completeness of resection Tumor rupture Cellular proliferation index (Ki67) Diffuse mucosal invasion Aneuploidy Telomerase expression Extent of disease

Risk stratification

Size Mitotic count

Very Low risk <2 cm <5/50 HPF

Low risk 2-5 cm <5/50 HPF

Intermediate risk <5 cm

5-10 cm

6-10/50 HPF

<5/50 HPF

High risk >5 cm>10 cmAny size

>5/50 HPF Any count>10/50 HPF

Treatment modalities Surgery

Chemotherapy

Surgical resection: mainstay of treatment in localized disease

Gross total resection with negative margins is the goal, with intact pseudocapsule.

No need of lymphadenectomy 40-90% patients have recurrence or metastasis 50% patients have locally advanced, unresectable disease

or metastatic

Treatment approach Localized disease Sx ± Imatinib

Advanced disease Sx + Imatinib

Preop Imatinib f/b Sx

Metastatic disease Imatinib

Molecular Targeted TherapyImatinib- selective tyrosine kinase inhibitor of–c-kit–bcr/abl – PDGFR α

Imatinib therapy Indications

Adjuvant – intermediate / high risk

Neoadjuvant – locally advanced

Therapeutic – metastatic disease

Adjuvant: Phase II ACOSOG Z9001

RFS 83 % 97 %

DeMatteo R, Owzar K, Maki R, et al.

Neoadjuvant Therapy• Single center study of 126 pts. at MD Anderson deemed 16/17 unresectable tumors resectable after on average 10 months of Gleevec Radiographic Evidence• – 4% CR• – 35% PR• – 37% Stable• – 18% Progression– 2% Died

(Scaife, C. etal. Am J Surg, 2003).

Dose and schedule of Imatinib

(Rankin, C et al. Proc AmSoc Clin Oncol, 2004).

(Verweij J. et al Lancet, 2004).

No significant difference in Response 400 mg vs 800 mgEORTC 62005/CALGB 150105

Duration of therapy

Advanced GIST and no evidence of progressive disease after one year of Gleevec

continuous therapy Interruption of therapy until disease progression.

Following one, three, or five years of benefit from imatinib, patients who discontinued imatinib were considerably more likely to progress than patients who were on continuous

dosing.

French Sarcoma Group designed a Phase III trial (BFR-14)

Blay JY et al. Proc Am Soc Clin Oncol, 2004. Le Cesne A et al Lancet Oncol, 2010.

Toxicities • Fluid retention or edema (60-70%)• Diarrhea(45%)• Myalgia or Musculoskeletal pain(40%)• Skin rashes (30%)• Headache (25%)• Myelotoxicity –less common

Other approaches TKI

Sunitinib Sorafenib Nilotinib Regorafenib Others

HACE (hepatic artery chemoembolization) RFA (radiofrequency ablation) Radiation therapy- only palliative role

Summary & Conclusion C-Kit mutations found in vast majority of GISTs

Imatinib is an effective systemic therapy for patients of GIST with good response rates & an acceptable toxicity profile

Tumour size & Mitotic Index (no. of mitosis/50 HPF) are two recommended Prognostic factors

Future directions: Many agents with novel mechanisms of action and targeting different pathways will be studied for GIST therapy.

Thanks