Role of chemotherapy and radiotherapy in Ca gall bladder

Role of chemotherapy and radiotherapy in Ca gall bladder

• 1.
  ROLE OF RADIOTHERAPY AND CHEMOTHERAPYIN CARCINOMA GALL BLADDER Presented By- Dr. Rashmi JR-II Department Of Radiation Oncology
• 2.
  BURDEN OF DISEASE- GLOBOCAN2018 DATA • New Cases: 25,999 • Deaths: 19,676 • No. of people living with the disease (5 year prevalence for all ages): 31,357
• 3.
  EPIDEMIOLOGYAND RISK FACTORS • Age>45 years • Gender women • Ethnicity – Globally: more in India, Pakistan, Eastern Europe, South American countries, East Asia and the lowest in Africa . – India : north and North-east • Gallstones and Chronic Inflammation of Gall bladder- – Only about 1% patients with gall stones develop GBC . – ‘porcelain gall bladder’- 25% (range 12% to 61%) association. – A study from North India revealed that the prevalence of gallstones was more in females (5.59%) than males (1.99%)
• 4.
  • Genetic Factors a.Pancreas and bile duct abnormalities b. Choledochal cysts • Gall bladder polyps • Family History – first degree relatives- five times increased risk. – Mutations in BRCA2 ,APOB
• 5.
  • Lifestyle Factors a.Obesity b. Infection – Approximately 6% of carriers of Salmonella typhi developed gall bladder cancer and the association showed a 12-fold increase in risk for developing GBC Helicobacter pylori bacteria may also increase the risk c. Diet – increased quantities of proteins, fats and cholesterol and low in fibre, vegetables and fruits • Chemicals- nitrosoamines (found in some industrial products) strong correlation with heavy metal pollutants in drinking water. Studies also show that people who smoke or work in the metal or rubber industry more likely to develop GB Ca. • Smoking
• 6.
  CLINICAL PRESENTATION The presentationof GBC has three situations: 1. as a mass lesion in the gallbladder. 2. incidental, upon histopathological examination of resected gallbladder 3. advanced, inoperable form (most common presentation)
• 7.
  Anorexia Cachexia Icterus a palpable hardlump in the right hypochondrium, Ascites and left supraclavicular lymphadenopathy Poor performance status
• 8.
  WORKUP • Hemogram • LiverFunction Tests: Elevated alkaline phosphatase and bilirubin levels - more advanced disease. • Imaging tests: 1. USG Whole abdomen 2. CECT Abdomen: shows tumour infiltration into adjacent viscera or vessels,lymph node and distant metastase. 3. MRCP/ERCP: validity in detection of biliary invasion, vascular invasion, hepatic invasion and lymph node involvement. Indicated in patients with jaundice 4. FNAC is not indicated in resectable GBC because the tumor has propensity for seeding the biopsy tracts and resection should be performed even if FNAC is negative. A tissue diagnosis should be obtained (FNAC, fluid cytology) from the metastasis.
• 9.
  • In aJaundiced patient a. Coagulation profile (PT,APTT,INR) b. MRCP c. ERCP/Percutaneous Transhepatic Cholangiography (PTC) if a therapeutic intervention (biliary stenting) is planned • Optional Investigations a. Positron Emission Tomography (PET) scan b. Tumor markers: Serum Ca 19-9, CEA : not very specific
• 10.
  AJCC STAGING TX- Primarytumor cannot be asseesed T0- No evidence of primary tumor Tis- Carcinoma in situ T1- Tumor invades the lamina propria or muscular layer T1a- tumor invades lamina propria T1b- tumor invades muscular layer T2 - Tumor invades the perimuscular connectivetissue on the peritoneal side, without involvement of the serosa (visceral peritoneum) Or tumor invades the perimuscular connective tissue on the hepatic side, with no extensión into the liver T2a- tumor invades peri muscular connective tissue on peritoneal side, without serosa involvement (visceral peritoneum) T2b- tumor invades peri muscular connective tissue on hepatic side, with no extension into liver. T3- Tumor proliferates serosa (visceral peritoneum) and/or directly invades liver and/or one other adjacent organ or structure such as stomach, duodenum, colon, pancreas, omentum or extrahepatic bile ducts T4- Tumor invades main portal vein or hepatic artery or two or more extrahepatic organs
• 11.
  NX- Regional nodescannot be assesed N0- No regional lymph node metastasis N1- metastasis to 1-3 regional lymph nodes N2- metastasis to 4 or more regional lymph nodes M0- No distant metastasis M1- Distant metastasis
• 12.
  When Tis AndNis AndM is Then stage group is Tis N0 M0 0 T1 N0 M0 I T2a N0 M0 IIA T2b N0 M0 IIB T3 N0 M0 IIIA T1-3 N1 M0 IIIB T4 N0-N1 M0 IVA Any T N2 M0 IVB Any T Any N M1 IVB
• 13.
  TREATMENT OPTIONS  Surgery •Simplecholecystectomy : T1a •Radical cholecystectomy : T1b,T2,T3 & T4  Radiotherapy  Chemotherapy  Combined modality treatment  Palliative therapy •Surgical Palliation •Non-surgical palliation
• 15.
  RADIOTHERAPY INDICATIONS 1. Advancedisease 2. High T stage 3. Lymph Node involvement 4. Margin positivity 5. Loco-regional recurrence 6. Palliation of jaundice
• 16.
  ADJUVANT CHEMORADIATION INGBC • Retrospective study : n = 21 (Mayo Clinic) • Protocol : EBRT (45-54Gy) + concurrent 5 FU 500mg/m2 D1-D3 on week 1 & week 5 • Median Follow Up = 5yr (range - 2.6-11yr) • Maintenance CT may be considered - as risk of distant failure was high i.e 67% • 5yr OS 65% (Stage I-III)-superior to historical control(Sx alone- 33%) • Retrospective study : n= 73, Adjuvant CTRT(n=24)-Mayo Clinic • By CTRT: Improvement in survival with 30% decrease in death rate
• 17.
  ADJUVANT CHEMORADIATIONTHERAPY 23 yearsresult • Retrospective study from Dukes University 1980-2003, n=22, 91 % incidental (Stage II-III,III/IV) • RT : 45 + 5.4-10.8 Gy boost • CT : 5FU 500mg/m2 day 1-3 & day 29-31 concurrently • MS : 1.9yr • 5yr OS : 37%
• 18.
  ADJUVANT CHEMORADIOTHERAPY/RADIOTHERAPY INDICATIONS High risk patients Node positive  T2 and above  Margin positive Adjuvant Chemoradiotherapy vs Radiotherapy  Gall bladder cancer is not a very chemosensitive disease  Chemoradiotherapy has shown benefit concurrent regimen:5FU /oral capecitabine
• 20.
  • 20 studiesbetween 1960 to 2010, n=6712, GBC & biliary (Sx=4915, Sx+RT= 1797) • GBC (Sx=3553; Sx+RT=897) • Non-significant improvement in survival in GBC by adjuvant therapy(odds ratio 0.81, i.e. 19% death reduction;p=0.06) • Node +, margin + and R1 disease shown larger benefit with adjuvant therapy • 5yr OS 26% v 14% with adjuvant CT vs surgery alone in GBC
• 21.
  TREATMENT PROTOCOL  Surgery(simple/extended cholecystectomy) +  External Beam Radiation Therapy (45-50.4 Gy / 25- 28 fractions / 5-5½ wks) +  Chemotherapy (5 Fluorouracil / Capecitabine) during and after RT x 6 cycles
• 22.
  RADIATION THERAPY PLANNING Radiation portals GB fossa + lymphatic drainage area including cystic, portal, pericholedochal, hepatico- duodenal, posterio-pancreaticoduodenal, celiac, sup. mesentric and para-aortic LN  Radiation portal after Lap. Cholecystectomy should include the trocar site/ tract & port of GB delivery otherwise incidence of trocar site recurrence
• 23.
  PRE-OPERATIVE CT SCAN 
• 24.
  RADIATION THERAPY PLANNING
• 25.
  RADIATION THERAPY PLANNING
• 26.
  Conformal Radiation Therapy: 3 D-CRT
• 27.
  Dose colour washshowing Gallbladder fossa and lymph node drainage area covered in 95% Isodose
• 28.
  CHEMOTHERAPY IN UNRESECTABLEGBC  GEMOX: Inj Oxaliplatin 80 mg/m2, 2 hours infusion in Dextrose 5% Day 1 and 8, Inj Gemcitabine 900 mg/m2 IV 30 minutes infusion day1 and 8 Cycles to be repeated every 3 weeks for maximum of 6 cycles  GEMCIS: Inj Cisplatin 25 mg/m2 PO Days 1 and 8; Inj Gemcitabine 1000 mg/m2 IV 30 minutes infusion day1 and 8 Cycles to be repeated every 3 weeks for maximum of 8 cycles  GemCap: Inj Gemcitabine 1000 mg/m2 IV 30 minutes infusion day1 and 8; Capecitabine 650mg/m2 twice a day PO Days 1-14 Cycles to be repeated every 3 weeks. Treatment should be continued until progression, unacceptable toxicity, or withdrawal of patient
• 29.
  Primary Treatment ofUnresectable Disease All recommendations are Category 2A unless otherwise indicated. REGIMEN DOSING Gemcitabine + cisplatin (Category 1) Days 1 and 8: Cisplatin 25mg/m2 IV (1-hour infusion) followed by gemcitabine 1,000mg/m2 IV (0.5-hour infusion). Repeat every 21 days initially for 4 cycles then re-evaluate and continue for an additional 4 cycles if warranted. Fluoropyrimidine- based or other gemcitabine-based chemotherapy regimen The collected clinical experience and a comprehensive meta-analysis imply that gemcitabine and gemcitabine- based platinum regimens are slightly advantageous compared with fluoropyrimidine regimens. Fluoropyrimidine chemoradiation There are limited clinical trial data to define a standard regimen or definitive benefit.
• 30.
  PALLIATIVE SETTINGS • Reliefof jaundice and pruritis – ERCP and stenting (metallic/plastic stent) • For pain relief – Medicines as per the WHO step-ladder or celiac plexus block in refractory cases • For relief of gastric outlet obstruction – Gastrojejunostomy in patients with good performance status
• 31.
  FOLLOW UP • Every6months for 2 yearsbyimaging. • Re-stagingaccordingto initial work-upshould be considered in the event of diseaserelapse or progression
• 32.
  Overall survival asper AJCC-TNM stage 1201089636 48 60 72 84 Overall survival (months) 24120 1.2 1.0 .8 .6 .4 .2 0.0 5 yr OS stage I, II, III = 50, 26.7, 18.7%
• 33.
  CONCLUSION • Primary modality- Surgery • Radical/curative surgical procedure limited due to advance nature of disease at presentation • Surgery alone : High loco-regional recurrence • Adjuvant chemoradiation therapy improves local control as well as survival in retrospective series, randomized evidence needed • High dose precise RT (IORT / Conformal RT/ IMRT with image guidance) may further improve loco-regional control • Role of CT – adjuvant to RT & metastatic GBC (level I) • Adjuvant approach is favoured and used in upto 70% of centers worldwide • Benefit of radiotherapy indicated in node positive, positive margins and >T2 tumors
• 34.
  THANK YOU