Moderator: Dr A. Saraya Presenter: Ujjwal. EPIDEMIOLOGY 13 th most common cancer and 8 th most common cause of cancer related deaths Pancreatic cancer.

• Slide 1

Moderator: Dr A. Saraya Presenter: Ujjwal Slide 2 EPIDEMIOLOGY 13 th most common cancer and 8 th most common cause of cancer related deaths Pancreatic cancer is the second most common gastrointestinal malignancy in the United States For all stages combined, the one- and five-year relative survival rates are 24% and 5% American cancer society, facts and figures, 2004 Slide 3 EPIDEMIOLOGY 80% to 90% of tumors are diagnosed at an unresectable stage In India, incidence increasing over last 2 decades in both males and females Cancer mortality and morbidity in Mumbai, Indian cancer society,1997 Slide 4 India has the lowest incidence of pancreatic cancer 0.5-2.4/100,000 males and 0.2-1.8/100,000 females Dhir V et al, Indian J gastroenterol 1999 No significant decrease in mortality over last 2 decades even in developed countries GLOBOCON 2008 Cancer Incidence and Mortality Slide 5 RISK FACTORS ENVIRONMENTAL Cigratte smoking (most important) ( OR 1.74, 95% CI 1.611.87), Consumption of red processed meat (OR 1.55, 95% CI 1.162.07) Occupational exposure to benzidine and beta- napthylamine Slide 6 BMI of more than 35 (OR 1.55, 95% CI 1.162.07) consumption of more than 6 alcoholic beverages per day (OR 1.46, 95% CI 1.16 1.83) Klein AP. Identifying people at high risk of developin pancreaticcancer. Nat Rev Cancer 2013 Slide 7 presence of nontype O blood antigens (OR 1.42, 95% CI 1.211.66), which display aberrant expression on pancreatic ductal cells, and affect signal transduction and cellular adhesion Wolpin BM. Genotype derived ABO blood groups alleles and the risk of pancreatic cancer. Cancer Res 2010 Slide 8 Chronic pancreatitis (risk: 2% per decade,independent of the type of pancreatitis) RR: 7.2 Bracci PM et al, cancer 2009 Slide 9 GENETIC FACTORS family history of pancreatic cancer (OR 2.41, 95% CI 1.04 4.74) hereditary pancreatic cancer syndrome Hereditary pancreatitis (RR: 50-80) Peutz-jeghers syndrome (RR: 132) HNPCC (RR: unknown) FAMMM (RR: 20-30) Slide 10 CLINICAL PRESENTATION The pancreas is located in the retroperitoneum, where initial growth of the cancer is silent; therefore, symptoms are usually a sign of advanced disease. Depends on the stage of disease and the location of the primary tumour Slide 11 CLINICAL PRESENTATION Rightupper quadrant or epigastric pain (79%) Jaundice (56%) Nausea or vomiting secondary to obstruction of the gastric outlet (51%) Diarrhea (43%) and steatorrhea due to pancreatic insufficiency (25%) New or worsening back pain (49%) could signal cancer in the pancreatic body or tail. Slide 12 New onset or worsening of previously stable diabetes, although not usually due to the cancer, should alert the physician to the possibility of pancreatic cancer systemic manifestations may include: rapid weight loss (85%) and anorexia (83%) thromboembolic disease (3%)...Porta Mand stage. Clin Transl Oncol 2005 Slide 13 PANCREATIC CANCER ACCORDING TO SITE pancreatic head, neck or uncinate process (70%) body or tail (20%) Multifocal disease (10%) Artinyan A et al. The anatomic location of pancreatic cancer is a prognostic factor for survival. HPB 2008 Slide 14 SURGERY/EXTENT ACCORDING TO SITE HEAD N=18666 BODY/TAIL N=5192 P-VALUE CANCER DIRECTED SURGERY 5637 29% 960 16% < 0.001 EXTENT OF DISEASE METASTATIC6252 35% 3841 67% < 0.001 Slide 15 Slide 16 DIAGNOSIS AND STAGING Triphasic contrast-enhanced abdominal CT (sensitivity 89%97%, specificity 95%) Most validated imaging study for both diagnosis and staging Useful in assessing resectibility 70-85 % of those who have resectable disease on CT undergo curative resection Slide 17 Sensitivity poor for peritoneal metastasis and tumor < 2 cm in size MRI is considered equivalent to CT (sensitivity 81% 99%, specificity 70%93%), its more limited availability has restricted its use to patients with contraindications to CT (e.g., pregnancy, nephropathy) or where resectability is unclear after CT. Slide 18 Optimal study: Non-contrast plus arterial, portal venous and pancreatic protocol phase with 3 mm cuts Slide 19 ROLE OF EUS Diagnosis: For tumors < 2 cm in size which are not well visualised on CT Inflammotory head mass in the setting of chronic pancreatitis To discriminate between benign and malignant strictures Slide 20 ROLE OF EUS STAGING: Complimentary to CT and MRI Mainly in patients whose scans show doubtful vascular or lymph node involvement Slide 21 ROLE OF PET-CT Has a role in staging of disease Adjunct to multiphasic CT/MRI Has increased sensitivity for detection of distant metastasis Can prevent unnecessary pancreatic resection in upto 25 % of patients by detecting unsuspected metastasis Saif MW et al, J. gastrointestin liver disease, 2008 Slide 22 ROLE OF LAPROSCOPY Role in staging: High sensitivity for peritoneal and liver capsular metastasis Not a substitute for poor quality imaging Slide 23 ROLE OF LAPROSCOPY Considered when high risk of metastatic disease: Tumor size > 2cm Border line resectable disease Tumor of body/tail Markedly elevated CA 19-9 Slide 24 ROLE OF BIOPSY No role in resectable disease Required in unresectable disease and metastatic disease to confirm diagnosis before starting chemotherapy EUS FNA is preferable to CT guided FNA Slide 25 BIOMARKERS Various biomarkers: CA 19-9 (best validated and most useful) CA 125 CEA Pancreatic oncofetal antigen Slide 26 CA 19-9: Sialylated lewis A blood group antigen Good diagnostic marker (sensitvity: 80%, specificity: 82-90%) Correlates with staging and resectibility Slide 27 Prognostic marker: Low post-operative levels and serial decrease in levels after surgery correlate with survival post curative resection Berger AC et al J. Clin oncology 2008 Pre-treatment levels are an independent prognostic factor for survival in advanced pancreatic cancers Hess V et al, lancet oncology 2008 Slide 28 Predictor of response: Change in CA 19-9 levels after chemotherapy in patients with advanced disease predicts response to treatment Slide 29 FALSE ve: lewis antigen negative patients FALSE +ve: Biliary obstruction Cholangitis Biliary malignanciaes Pre-operative levels should be measured after biliary drainage and normalisation of blirubin levels Slide 30 SUMMARY Slide 31 Slide 32 STAGING stageTumor grade Node status Distant metastasis 5yr survival, % Median Survival,mo Characteristics IAT1NoMo1424Tumor 2cm in pancreas only IIAT3NoMo715Tumor extends beyond the pancreas, but with no involvement of the celiac or SMA IIBT1-3N1Mo513Regional lymph node metastasis IIIT4N0-1Mo311Tumor involves the celiac or SMA IVT1-4N0-1M115Distant metastasis Slide 33 CLASSIFICATION PPANCREATIC RESECTABLE BOREDERLINE RESECTABLE ADVANCED PANCREATIC ADENOCARCINOMA NO METASTASIS NO VASCULAR INVOLVEMAN T PARTIAL ABUTMENT OF PORTAL OR SMV METASTASIS ENCASEMENT OF ARTERIES EXTENSIVE INVOLVEMENT OF VEINS Slide 34 Stage of disease SMACeliac axisCommon Hepatic Artery SMV-PV Resectable(all four required) No extension; normal fat plane between the tumor and the artery Patent (may include tumor abutment or encasement) Boderline resectable (one required) Abutment Abutment or short segment encasement if reconstruction possible Short segment occlusion if reconstruction possible Unresectable (one required) Encasement Extensive encasement with no technical option for reconstruction Occluded with no technical option for reconstruction Slide 35 RESECTABLE DISEASE Only 15% -20 % of newly diagnosed cases SURGERY is the only curative treatment Procedure depends on the location of the tumour: Pancreaticoduodenectomy (Whipple procedure): lesions of the head, neck and uncinate process Distal pancreatectomy: lesions of the body or tail Total pancreatectomy: multifocal disease Slide 36 Overall 5-year survival after pancreatic resection is 14.6%, but higher in well-differentiated disease (30% 40%) and disease that has not metastasized to the lymph nodes (25%30%) Cleary SP, et al J Am Coll Surg 2004 Negative margin status, tumor size and lymph node status are the strongest predictors of survival Slide 37 ADJUVANT CHEMOTHERAPY Recommended for all patients who undergo curative resection Either gemcitabine or 5 - fluorouracil (5-FU) prolongs median survival by 3 months (95% CI 0.35.7) Boeck S et al Oncology 2007 metaanalysis Slide 38 Slide 39 Slide 40 Slide 41 Gemcitabine has been recommended as the first-line adjuvant agent owing to its lower toxicity profile Slide 42 ROLE OF ADJUAVENT RADIATION Slide 43 Slide 44 Slide 45 No clear benefit of radiation therapy in addition to adjuvant chemotherapy Slide 46 ROLE OF NEOADJUAVENT THERAPY Benefit of neoadjuvant therapy at the cost of delaying surgery is controversial No phase III trials comparing outcomes between neoadjuvant and adjuvant therapy most centres refrain from using neoadjuvant therapy outside of research protocols Slide 47 Slide 48 Slide 49 ROLE OF PRE-OPERATIVE DRAINAGE Goal To alleviate symptoms of pruritis To provide drainage in patients with cholangitis Decrease surgical morbidity by improving liver function Slide 50 Studies have failed to show decreased mortality in patients who underwent pre-operative drainage Slide 51 Slide 52 Slide 53 Recommended: Cholangitis Significant pruritis and > 1 week delay of surgery If patient has to receive neoadjuvant therapy Plastic stents are preferred over metal stents Slide 54 BORDERLINE RESECTABLE DISEASE Surgery is attempted only if complete resection is possible Role of neoadjuvant therapy is debatable No phase 3 RCTs A 6-year prospective study involving 110 patients with resection of the hepatic portal vein, SMV or both for suspected tumour infiltration showed median overall survival of 14.5 (range 7.3 24) months, with perioperative mortality of 3.7%. Mller SA, Hartel M, Mehrab A, et al. Vascular resection in pancreatic cancer surgery: survival determinants. J Gastrointest Surg 2009;13:784-92. Slide 55 A role and optimal regimen for neoadjuvant therapy in borderline resectable disease is unclear, based on inconclusive findings regarding median survival in a retrospective study of neoadjuvant treatment versus immediate surgery (35 mo v. 27 mo; p = 0.7). Barugola G et al. Outcomes after resection of borderline resectable pancreatic cancer after neoadjuvant therapy. Am J Surg 2012 Slide 56 ADVANCED DISEASE Median overall survival of 23 months without treatment Chemotherapy is advised as it improves survival Slide 57 Slide 58 N=432 mortality reduction = 36 % Slide 59 Journal of clinical oncology, 1997 Slide 60 Slide 61 ROLE OF COMBINATION CHEMOTHERAPY No overall improved survival as compared to monotherapy Survival benefit in a subset of patient who have good performance status Slide 62 Slide 63 improve Slide 64 Meta-analysis for combination chemotherapy in advanced pancreatic cancer-overall survival with regard to performance status Slide 65 Individual clinical trials of combination gemcitabine with various cytotoxic agents have failed to show a survival benefit over gemcitabine alone but significantly improved overall survival was seen when these studies were pooled (HR 0.91, 95% CI 0.850.97) Reserved for patients with good performance status Slide 66 GEMCITABINE + ERLOTINIB Targeted therapy in pancreatic cancer has centred on the epidermal growth factor pathway Erlotinib: tyrosine kinase inhibitor of EGFR Slide 67 Kaplan-Meier curves for (A) overall survival; (B) progression-free survival; and (C) overall survival in the 100-mg cohort. Slide 68 This phase III study of the epidermal growth factor receptor inhibitor erlotinib with gemcitabine versus gemcitabine alone showed marginally increased overall survival (6.24 v. 5.91 mo,vs p = 0.04)58 and 1-year survival (23% [95% CI 18%28%] v. 17% [95% CI 12%21%], p = 0.02). Slide 69 GEMCITABINE + ERLOTINIB Recommended as an option for patients with locally advanced and metastatic disease Benefit more in patients who develop skin rash Slide 70 FOLFIRINOX FOLFIRINOX (5-FU, leuco - vorin, irinotecan and oxaliplatin) Increase in median overall survival over gemcitabine alone in metastatic pancreatic cancer (11.1 mo v. 6.8 mo; HR 0.57, 95% CI 0.45 0.73, p < 0.001). Slide 71 FOLFIRINOX Slide 72 Folfirinox: 11.1 months gemcitabine: 6.6 months Slide 73 Folfirinox: 6.4 months gemcitabine: 3.3 months Slide 74 FOLFIRINOX Slide 75 Slide 76 THANK YOU