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Carcinoma pancreas and gastrointestinal stromal tumors- overview
Carcinoma pancreas and gastrointestinal stromal tumors- overview
Carcinoma pancreas and gastrointestinal stromal tumors- overview
Carcinoma pancreas and gastrointestinal stromal tumors- overview
Carcinoma pancreas and gastrointestinal stromal tumors- overview
Carcinoma pancreas and gastrointestinal stromal tumors- overview
Carcinoma pancreas and gastrointestinal stromal tumors- overview
Carcinoma pancreas and gastrointestinal stromal tumors- overview
Carcinoma pancreas and gastrointestinal stromal tumors- overview
Carcinoma pancreas and gastrointestinal stromal tumors- overview
Carcinoma pancreas and gastrointestinal stromal tumors- overview
Carcinoma pancreas and gastrointestinal stromal tumors- overview
Carcinoma pancreas and gastrointestinal stromal tumors- overview
Carcinoma pancreas and gastrointestinal stromal tumors- overview
Carcinoma pancreas and gastrointestinal stromal tumors- overview
Carcinoma pancreas and gastrointestinal stromal tumors- overview
Carcinoma pancreas and gastrointestinal stromal tumors- overview
Carcinoma pancreas and gastrointestinal stromal tumors- overview
Carcinoma pancreas and gastrointestinal stromal tumors- overview
Carcinoma pancreas and gastrointestinal stromal tumors- overview
Carcinoma pancreas and gastrointestinal stromal tumors- overview
Carcinoma pancreas and gastrointestinal stromal tumors- overview
Carcinoma pancreas and gastrointestinal stromal tumors- overview
Carcinoma pancreas and gastrointestinal stromal tumors- overview
Carcinoma pancreas and gastrointestinal stromal tumors- overview
Carcinoma pancreas and gastrointestinal stromal tumors- overview
Carcinoma pancreas and gastrointestinal stromal tumors- overview
Carcinoma pancreas and gastrointestinal stromal tumors- overview
Carcinoma pancreas and gastrointestinal stromal tumors- overview
Carcinoma pancreas and gastrointestinal stromal tumors- overview
Carcinoma pancreas and gastrointestinal stromal tumors- overview
Carcinoma pancreas and gastrointestinal stromal tumors- overview
Carcinoma pancreas and gastrointestinal stromal tumors- overview
Carcinoma pancreas and gastrointestinal stromal tumors- overview
Carcinoma pancreas and gastrointestinal stromal tumors- overview
Carcinoma pancreas and gastrointestinal stromal tumors- overview
Carcinoma pancreas and gastrointestinal stromal tumors- overview
Carcinoma pancreas and gastrointestinal stromal tumors- overview
Carcinoma pancreas and gastrointestinal stromal tumors- overview
Carcinoma pancreas and gastrointestinal stromal tumors- overview
Carcinoma pancreas and gastrointestinal stromal tumors- overview
Carcinoma pancreas and gastrointestinal stromal tumors- overview
Carcinoma pancreas and gastrointestinal stromal tumors- overview
Carcinoma pancreas and gastrointestinal stromal tumors- overview
Carcinoma pancreas and gastrointestinal stromal tumors- overview
Carcinoma pancreas and gastrointestinal stromal tumors- overview
Carcinoma pancreas and gastrointestinal stromal tumors- overview
Carcinoma pancreas and gastrointestinal stromal tumors- overview
Carcinoma pancreas and gastrointestinal stromal tumors- overview
Carcinoma pancreas and gastrointestinal stromal tumors- overview
Carcinoma pancreas and gastrointestinal stromal tumors- overview
Carcinoma pancreas and gastrointestinal stromal tumors- overview
Carcinoma pancreas and gastrointestinal stromal tumors- overview
Carcinoma pancreas and gastrointestinal stromal tumors- overview
Carcinoma pancreas and gastrointestinal stromal tumors- overview
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Carcinoma pancreas and gastrointestinal stromal tumors- overview

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radiotherapy, oncology, carcinoma pancreas, GIST

radiotherapy, oncology, carcinoma pancreas, GIST

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  • 1. CARCINOMA PANCREAS DR. NIKHIL SEBASTIAN
  • 2. Embryologic devt. • Dorsal and ventral pancreatic buds. dorsal ventral larger Smaller Arise from foregut destined to be duodenum Buds off from CBD as hepatic evagination Develops into head, body and tail of pancreas Develop into uncinate process.
  • 3. Anatomy
  • 4. CA pancreas • 13th MC cancer worldwide • 8th MC cause of cancer death • 23% live after 12 months • 5% live after 5 years • <10% presents with local disease • 25% has regional disease • >50% metastatic • Median age of diagnosis- 72 years.
  • 5. Aetiology • Tobacco • Infectious diseases- H. Pylori, Hep-B • Occupation- Organochlorine compounds • Demographic and host risk factors- older age, African American, Low SES, Jewish. • Diabetes mellitus • Obesity, physical inactivity and metabolic syndrome • Pancreatitis • Genetic predisposition • Inherited syndromes
  • 6. Genetics • K-ras- 95% • p16- 90% • p53- 55 to 75% • DPC4 50% • BRCA2-70% Syndrome Gene alteration Hereditary pancreatitis PRSS1 HNPCC(LynchII variant) hMSH2, hMLH1 Hereditary breast and ovarian CA BRCA2 Familial Atypical Multiple Mole melanoma syndrome (FAMMM) P16 Peutz Jegher’s LKB1/STK11 Ataxia Telangiectasia ATM
  • 7. Pathology Intraepithelial Neoplasm Microscopy Genetic mutations PanIN 1 A Columnar transition Retention of apical nuclei Intracellular mucin near the luminal aspect K ras and Her-2-neu PanIN 1 B Micro papillary or papillary transition -do- PanIN 2 Nuclear atypia/ crowding/ enlargement Loss of nuclear polarity P16 PanIN 3 Apical mitosis Prominent nucleoli Dystrophic goblet cells Cribriform architecture Luminal necrosis P53, DPC4, BRCA2
  • 8. Screening • Incidence is low for using screening in general population. • High Risk 1. Family history 2. Genetic syndromes 3. Obese with new onset DM >60yrs. • Endoscopic Ultrasound (EUS) is the Ix of choice. • Multi detector dynamic Phase CT. • EUS: 1. Excellent visualization of gland. 2. Detect small <1cm lesions 3. Can get EUS guided FNA.
  • 9. Presenting complaints • Initial symptoms vague, non- specific • Jaundice • Preceded by episodes of biliary colic, anorexia and GI distress. • Pain – s/o unresectable, metastatic and worse survival. • Steatorrhoea • a/c pancreatitis • Glucose intolerance/ overt DM- 70% • Superficial or DVT • Weight loss- MC in some studies. • Late: GOO, Ascites, skin manifestations.
  • 10. Physical Exam and Lab. • Usually unremarkable • Icterus • Cutaneous excoriations • Muscle wasting • Hepatomegaly/ nodular liver • Virchow s node • Sr mary Joseph’s nodes • Blumer’s shelf • Mild to mod. Hyperglycemia • Deranged LFT • Amylase, Lipase (IPMN) • Anaemia- NCNC • Hypoalbuminemia • Coagulation profile: prolonged PT.
  • 11. Evaluation • Confirm the diagnosis of pancreatic mass • Re establish biliary patency. • Determine the extent of disease • Resectability? • Histological diagnosis • In past combined diagnostic and therapeutic laparotomy. • Separate diagnostic evaluation advantages: 1. laparotomy required for only resectable. 2. Objective criteria to decide on resectability 3. Pre-op plan for venous reconstruction 4. NACT
  • 12. Diagnostic Imaging • Multi phase multi detector helical CT • Coordinating IV contrast administration with subsequent rapid thin cut CT through pancreas during arterial, portal venous and parenchymal phases. • SMA, celiac axis, SMV-PV, contiguous structures, mets. • MRI • Not widely used • Longer scanning times • Artefact d/t organ motion. • Dynamic MRI with rapid scanning sequence has sens. and spec. similar to CT.
  • 13. • USG • High sens and spec although lower than helical CT • Better in identifying primary lesion, but CT better for defining resectability. • EUS • Non contributory when CT has characterized the tumor as resectable. • Used when a tumor not seen on CT • And to obtain FNA in unresectable tumors before chemo or borderline resectable before NACT. • Endobiliary stent can be placed.
  • 14. • ERCP • Delineates CBD & PD anatomy • Brushings and ductal lavage (low yield). • Reserved for: 1. Endoscopic stenting 2. Equivocal findings on std. evaluation 3. Tissue diagnosis required Complications- pancreatitis, Hrg., Perforation. • CT guided FNAC • Per cutaneous • Operator dependent • Cannot be done for lesions not visible on CT • Complications: 1. Hrg. 2. Pancreatitis 3. Fistula, Abscess 4. Tumor seeding along the needle tract.
  • 15. • Staging laparoscopy: • Few(8%) adnl. tumors than detected by CT. • No routine use 1. >3cm primary tumor 2. CA 19-9 > 100 U/L 3. In body or tail. 4. Equivocal findings of mets on CT • STAGING • T1: <2cm; limited to pancreas. • T2: >2cm; limited to pancreas. • T3: Extend beyond pancreas; No involvt. Of coeliac axis or SMA. • T4: involves coeliac axis or SMA.
  • 16. • Resectable Locally advanced Metastatic T1,T2,T3 --- Resectable T4 -------Locally advanced • Resectability Definition: 1. Absence of mets outside pancreas and nodal basin. 2. Patency of SMV-PV 3. Presence of definable fat plane btw SMA, celiac A. and pancreatic mass. 4. “SMV-PV invasion”
  • 17. Treatment of Resectable disease • 5 year survival 18% • Justified to prolong survival: No cure. • Whipple- 1934. • Earlier days: 2 stage procedure- biliary bypass ---pancreatectomy. • Vitamin K in pre-op regimen to treat coagulopathy. • Evans et al: 6 steps of resection. • foll by 4 steps of reconstruction. • Post surgery use of IP drains is decreasing. • Studies show more chance of sepsis, fluid collection or fistula.
  • 18. Whipple’s surgery • 6 Steps of resection: 1. Exposing SMV 2. Extended kocher’s maneuvre. 3. Portal dissection 4. Transect stomach 5. Transect jejunum and dissect ligt of treitz, rotating duodenum under mesenteric vessels. 6. Transect pancreas.
  • 19. • 4 steps of reconstruction: 1. End to side pancreatico jejunostomy 2. End to side choledochojejunostomy 3. End to side gastrojejunostomy 4. Gastrostomy tube, jejunostomy tube, drains.
  • 20. • Biliary stents • 70% cases indicated • 2 types: 1. Metallic: durable 2. Soft silastic: do not last full course of NACT. • 2 methods: 1. percutaneous transhepatic 2. endoscopic • Older studies show increased morbidity and mortality. • But in recent studies, only increased chance of wound infection • Relatively safe procedure. • Not to be avoided to palliate patients or while referral to higher center.
  • 21. Extended Lymphadenectomy • Adnl nodes removed are: hepatic hilar, periaortic from diaphragm to inf mesenteric, incld renal hilar, coeliac and SMA. • No benefit except in node positive cases--- improved survival.
  • 22. Adjuvant therapy • Chemotherapy alone better than observation. • 5FU/ Leucovorin Ca (ESPAC-1 2004) • Gemcitabine(CONKO-001) • Gemcitabine slightly better than 5FU(p>0.05)[RTOG9704 and ESPAC3] • ChemoRT • Did worse than control(ESPAC-1) • Gem > 5FU in ChemoRT (RTOG-9704)(p=0.033). • The current standard is Adjuvant Chemo with Gemcitabine 1000mg/m2 weekly x 3 every 4 weeks x 6 cycles.
  • 23. Indications of RT 1. Adjuvant CRT in resectable disease. 2. Pre-operative CRT 3. For locally advanced lesions with good PS 4. In metastatic disease for palliation of pain and obstructive symptoms. 5. For recurrence after resection, if previous RT has not been given.
  • 24. RT techniques • Four field technique • Weighted: AP twice as lateral. • Lat fields restricted to 20 Gy [limit dose to liver and kidney] • Coeliac axis at T12 • 2 cm margin sup • 2cm margin inferiorly • 2 cm margin to the L vertebral edge • 2 cm margin from R vertebral edge. • Pre op location of duodenum defines the right border and ant extent of lateral fields.
  • 25. Pre-op Chemo RT • Advantage: 1. Initiation of Rx shortly after Δsis 2. Rx of relatively well perfused tumor bed. 3. Time to assess aggressive tumor biology. 4. Assess pt’s potential to undergo rigors of Sx. • Against: 1. Local progression (No proof for significant risk.)
  • 26. BORDERLINE RESECTABLE 1. Confined to pancreatic bed and nodes without distant mets. 2. Tumor involvt of SMV- PV incld. Abutment, constriction of lumen or encasement. 3. Arterial Involvt.- gastroduodenal and hepatic without coeliac axis. SMA with <180o • Gem chemo 50.4/28F CCRT with Gem 400mg/m2 weekly  resection. • Survival 40 months. • 40% cases after CCRT could undergo resection • 90% R0 resection. • Response to therapy: Decrease in mass size, CA- 19-9, decraese in pain.
  • 27. LOCALLY ADVANCED DISEASE • Defn: >180o SMA or coeliac axis invasion without gross disease outside the pancreatic primary. • FOLFIRINOX • CCRT with 5FU is a recommended Rx. • Gemcitabine or capecitabine also used as radiosensitizers. • CCRT – more fatigue • More GI toxicity • Novel radiosensitizers: mCCNU+ 5FU +/- testolactone • Hycanthone.
  • 28. RT techniques • LA disease pt do not benefit from LN irradiation • Would only lead to more GI toxicity • RT fields confined to gross tumour. • Respiratory motion: axial motion negligible. • So Cranio caudal 1cm extra. • 3 or 4 field technique • Equally weighted ant, post and opposed lat fields. • 2cm block margin in radial directions • 3 cm block margin in CC directions. • Delivery >50.4 Gy requires IMRT or ABC to spare duodenum, stoamch and jejunum.
  • 29. • Incidence of converting a LA disease to resectable is 1 in 25. • For them survival is similar to resectable disease. • Palliative surgeries: 1. Hepaticojejunostomy 2. Choledochojejunostomy or choledochoduodenostomy 3. Gastrojejunostomy. • Antecolic- MC used • Retrocolic • Less morbid techniques: 1. Endoscopically placed metal stent. 2. Percutaneous endoscopic gastrostomy.
  • 30. • Initial chemo for 2 to 4 months • re assess by CA19-9 and radiological assessment. • then 5FU based chemoRT • If progressive Palliative chemoRT to 30 Gy. • If no Progression, Then CCRT 50.4 Gy/5.5week. • After chemo RT: • If good PS- Chemo alone with 5FU/ Gem. • If poor PS- Best Supportive care.
  • 31. Metastatic disease • Bolus 5FU: RR 0% • Infusional 5FU: 8.6% • 5Fu+MMC- 17.1%(No diff in OS) • Gemcitabine: RR 5.4% Survival 5.65 months vs Bolus 5 FU 4.1 months. • Peak ICF accumulation when given at 10 mg/m.sq./min.(FDR) • FDR(Fixed dose rate) 1500mg/m.sq. over 150 min. vs standard Gemcitabine 2200mg/m.sq over 30 min. • OS was 8 months against 5 months.
  • 32. • Gem-Ox vs Std. Gem. • RR and PFS significant, but not OS. • Gem-Ox and FDR Gem had similar RR 0f 9 to 10% vs Std Gem has only 6%. • With Molecular agents: • Marimastat • Tipifarnib • Erlotinib [RR and OS- p 0.025] • Cetuximab • Bevacizumab
  • 33. • Gemcitabine effective at lower dose 300 to 700 mg/msq [MDACC trial] • Max tolerated dose 790mg/msq.
  • 34. THANK YOU 
  • 35. GIST Dr. Nikhil S.
  • 36. • Comprises several different molecular distinct subtypes that collectively represent the MC form of sarcomas of the GIT. • 1 to 3% of all malignant GI tumors. • Neural crest antigens NSE and S-100 Positive • CD34 Positive • Also it was proposed that GIST cells differentiate from: • 1. smooth muscle lineage • 2. neurogenic • 3. “Null” Phenotype.
  • 37. • Older eponyms: 1. Leiomyoblastoma 2. GI leiomyosarcoma 3. GI autonomic nerve tumor 4. GI pacemaker cell tumor 5. Plexosarcoma 6. GI neurofibrosarcoma • Ultra structural similarities with ICC(Interstitial Cells of Cajal) combining neural and myogenic differentiation. • Both arise from mesenchymal precursor cells. • Both express KIT RTK.
  • 38. • ICCs are unique pace maker cells in the myenteric plexus, that link the smooth muscle of the gut with the ANS • Origin of neoplastic GIST cells are believed be from CD34+ stem cells, which can differentiate to ICC phenotype. • KIT exon-9 mutant GIST found in small bowel primary • PDGFRA mutant found in gastric primary • Due to differential migration and distribution of these cells along the length of the GI tract.
  • 39. Molecular mechanisms • KIT protein normally serves as a transmembrane receptor tyrosine kinase. • CD117 is marker for KIT
  • 40. • Normal cell signalling: 1. KIT binds its ligand- stem cell (steel) factor. 2. 2 molecules of KIT together forms a homodimer. 3. Activate signal transductoin pathways downstream. 4. Cell proliferation and survival. • Mutation in KIT protooncogene • Uncontrolled activation of KIT signaling enzyme
  • 41. Clinical features • Median age 58 years. • More in males • Stomach 60 to 70% • Small intestine 20 to 30% • Esophagus, colon and rectum <10%. • Non specific symptoms • Occur only when tumor is large or in critical location e.g. GOO • Abdominal pain, mass, N, V, Anorexia, wt loss. • A/c hrg into peritoneal cavity d/t rupture of tumor • Metastasis- liver, omentum or peritoneal cavity. • Extra abd mets very rare.
  • 42. INVESTIGATIONS • CT essential for evaluating primary and for staging. • MRI may be used. • OGD- smooth mucosa lined protrusion of the bowl wall+/- ulceration. • Submucosal, endophytic growth. • Hence visual OGD very challenging. • EUS is an ideal tool for localized GIST for assessment of lesion size and guided FNA.
  • 43. • FDG PET- TKI therapy show rapid changes in PET scan • Can detect lesion of 1cm size without difficulty • This is because neither normal bowel nor omentum takes up FDG tracer with excess avidity.
  • 44. Differential diagnosis • CD117+ 1. Normal ICC s and mast ells 2. Desmoid tumors 3. Ewing’s and angiosarcoma 4. Rarely SCLC, melanoma, seminoma, ovarian,adenoid cystic CA, AML • CD34+ 1. Desmoid tumors 2. Other vascular and myoepithelial tumors. • Leiomyosarcomas CD117 neg ; SMA and desmin+ • S100+ in schwannomas but CD117 – • 5% of GIST are CD117 neg. they’re driven by PDGFRA kinase.
  • 45. Prognostic features Risk level size Mitoses/50 hpf Very low <2cm <5 Low 2 -5 cm <5 Intermediate >5 to 10cm <5 <5cm 6 to 10 high >10cm Any >5cm >5 any >10
  • 46. • Size • Mitotic rate • Small bowel and rectal primary GIST worse. • Gastric GIST good. • KIT mutations found in exon 11,9,13,17. • Exon 11 worse prognosis • PDGFRA mutations favorable prognosis.
  • 47. Management of metastatic GIST • Chemoresistance • RR 0 to <5% • Anti apoptotic impact of aberrant KIT signalling. • Increased PGP, product of MDR-1 gene. • RT-rarely any role- liver toxicity • IMRT or proton may be used for palliation 1. Focal bleeding 2. Pain control 3. Bony involvement 4. Fixed to the wall of abdomen or pelvis • Surgery also minimal role due to peritoneal and liver mets- unresectable.
  • 48. IMATINIB mesylate • 1 st molecular TKI therapy • Serendipity while screening molecules for TKI function of BCR-ABL oncoprotein (CML) • STI-571Imatininb • Optimal dose is 400mg/day • Max tolerated dose is 800mg/day. • Median time to objective response is 3 months.
  • 49. • Better response when KIT mutation is in exon11. • Poor response in exon9. • Higher doses(800mg) later was found to be beneficial in Exon 9 mutations. • KIT neg pts also respond d/t action on PDGFRA mutations. • No benefit with 600 mg/d in two trials. • EORTC trial show benefit in PFS for 600 mg/d. • Life long use • Periodic pulse therapy- being evaluated. • Neo adjuvant/ preop use to make tumor operable. • E.g. rectal GIST
  • 50. • Adverse effects 1. Nausea, vomiting 2. Edema- Periorbital 3. Myalgia- calves 40% 4. Skin rashes- 30% 5. Headache- 20% 6. Diarrhoea- 45% 7. Myelotoxicity-less common 8. GI hrg. 9. Potential of cardiac impairment. • Resistance to imatinib • Occurs in <15% • Second line therapy with Sunitinib 50 mg orally daily for 4 weeks with 2 weeks gap- life long. • Also inhibits VEGFR. • Nilotinib being evaluated. • Has better pharmacodynamic and clinical inhibitory properties.
  • 51. Early GIST: Adjuvant therapy • After complete resection, the std of care is observation/ surveillance. • FDA has approved Imatinib for adjuvant use without any qualifications. • EMA- For those at high risk of recurrence. • Phase 3 trial have confirmed the benefit of using adjuvant imatinib for 1 year. • But increased recurrences on discontinuation.
  • 52. • Targets for future research: 1. MAPK(mitogen activated protein kinase) 2. m-TOR(mammalian target of rapamycin.)
  • 53. THANK YOU…

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