Gastrointestinal stromal tumor (GIST) dr ridu kumar sharma

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Gastrointestinal stromal tumor (GIST) dr ridu kumar sharma

  1. 1. GASTROINTESTINAL STROMAL TUMOURS DR RIDU KUMAR SHARMA REGIONAL CANCER CENTRE, INDIRA GANDHI INSTITUTE OF MEDICAL SCIENCES ,PATNA
  2. 2. 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
  3. 3. 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
  4. 4. 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
  5. 5. 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
  6. 6. 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
  7. 7. 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
  8. 8. 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
  9. 9. 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 >5/50 HPF  Any count >10/50 HPF  >5 cm >10 cm Any size
  10. 10. 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
  11. 11. Treatment approach  Localized disease  Sx ± Imatinib  Advanced disease  Sx + Imatinib Preop Imatinib f/b Sx  Metastatic disease  Imatinib
  12. 12. Molecular Targeted Therapy  Imatinib- selective tyrosine kinase inhibitor of  –c-kit  –bcr/abl  – PDGFR α
  13. 13. Imatinib therapy  Indications  Adjuvant – intermediate / high risk  Neoadjuvant – locally advanced  Therapeutic – metastatic disease
  14. 14. Adjuvant: Phase II ACOSOG Z9001 RFS 83 % 97 % DeMatteo R, Owzar K, Maki R, et al.
  15. 15. 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).
  16. 16. Dose and schedule of Imatinib No significant difference in Response 400 mg vs 800 mg EORTC 62005/CALGB 150105 (Rankin, C et al. Proc AmSoc Clin Oncol, 2004). (Verweij J. et al Lancet, 2004).
  17. 17. Duration of therapy French Sarcoma Group designed a Phase III trial (BFR-14) Advanced GIST and no evidence of progressive disease after one year of Gleevec continuous therapy Interruption of therapy until disease progression. Blay JY et al. Proc Am Soc Clin Oncol, 2004. Le Cesne A et al Lancet Oncol, 2010. 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.
  18. 18. Toxicities • • • • • • Fluid retention or edema (60-70%) Diarrhea(45%) Myalgia or Musculoskeletal pain(40%) Skin rashes (30%) Headache (25%) Myelotoxicity –less common
  19. 19. Other approaches  TKI  Sunitinib  Sorafenib  Nilotinib  Regorafenib  Others  HACE (hepatic artery chemoembolization)  RFA (radiofrequency ablation)  Radiation therapy- only palliative role
  20. 20. 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.
  21. 21. Thanks

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