Presentation on theme: "Management of pancreatic adenocarcinoma"— Presentation transcript:
1Management of pancreatic adenocarcinoma Moderator: Dr A. SarayaPresenter: Ujjwal
2EPIDEMIOLOGY13th most common cancer and 8th most common cause of cancer related deathsPancreatic cancer is the second most common gastrointestinal malignancy in the United StatesFor all stages combined, the one- and five-year relative survival rates are 24% and 5%American cancer society, facts and figures, 2004
3EPIDEMIOLOGY80% to 90% of tumors are diagnosed at an unresectable stageIn India, incidence increasing over last 2 decades in both males and femalesCancer mortality and morbidity in Mumbai, Indian cancer society,1997
4India has the lowest incidence of pancreatic cancer /100,000 males and /100,000 femalesDhir V et al, Indian J gastroenterol 1999No significant decrease in mortality over last 2 decades even in developed countriesGLOBOCON 2008 Cancer Incidence and Mortality
5RISK FACTORS ENVIRONMENTAL Cigratte smoking (most important) (OR 1.74, 95% CI 1.61–1.87),Consumption of red processed meat (OR 1.55, 95% CI 1.16–2.07)Occupational exposure to benzidine and beta-napthylamineThe risk may be particularly elevated in smokers who have homozygous deletions of the gene for glutathione S-transferase T1 (GSTT1), which is a carcinogen metabolizing enzyme.16
6BMI of more than 35 (OR 1.55, 95% CI 1.16–2.07) 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
7presence of non–type O blood antigens (OR 1. 42, 95% CI 1. 21–1 presence of non–type O blood antigens (OR 1.42, 95% CI 1.21–1.66), which display aberrant expression on pancreatic ductal cells, and affect signal transduction and cellular adhesionWolpin BM. Genotype derived ABO blood groups alleles and the risk of pancreatic cancer. Cancer Res 2010
8Chronic pancreatitis (risk: 2% per decade,independent of the type of pancreatitis) RR: 7.2Bracci PM et al, cancer 2009
9family history of pancreatic cancer (OR 2.41, 95% CI 1.04– 4.74) GENETIC FACTORSfamily history of pancreatic cancer (OR 2.41, 95% CI 1.04– 4.74)hereditary pancreatic cancer syndromeHereditary pancreatitis (RR: 50-80)Peutz-jeghers syndrome (RR: 132)HNPCC (RR: unknown)FAMMM (RR: 20-30)Familial atypical mole melanoma: Two or more blood relatives with melanoma and an underlying CDKN2A/p16 mutation.Assocation with pancreatic cancer: OR 47.8, 95% CI 28.4–74.7. Prevalence: >1/1000.
10CLINICAL 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
11CLINICAL PRESENTATION Right–upper 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.
12systemic manifestations may include: New onset or worsening of previously stable diabetes, although not usually due to the cancer, should alert the physician to the possibility of pancreatic cancersystemic manifestations may include:rapid weight loss (85%) and anorexia (83%)thromboembolic disease (3%)...Porta Mand stage. Clin Transl Oncol 2005At diagnosis, one third of tumours of the pancreas head were in stage I and another third in stage IV. None of the tumours of the body and tail were in stage I, and over 80% were in stage IV (p < 0.001) . At presentation, the most frequent symptoms were asthenia (86%), anorexia (85%), weight-loss (85%), abdominal pain (79%), and choluria (59%). Cholestatic symptoms were more common in tumours affecting only the pancreatic head (p < 0.001) . There was a clear trend toward more localized tumours with increasing numbers of cholestatic signs (p < 0.001) . Asthenia, anorexia and weight-loss were unrelated to stage. An increased symptom-to-diagnosis interval was associated with more advanced stage (p = 0.048
13PANCREATIC 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
14SURGERY/EXTENT ACCORDING TO SITE HEADN=18666BODY/TAILN=5192P-VALUECANCER DIRECTEDSURGERY563729%96016%< 0.001EXTENT OF DISEASEMETASTATIC625235%384167%
16DIAGNOSIS AND STAGINGTriphasic contrast-enhanced abdominal CT (sensitivity 89%–97%, specificity 95%)Most validated imaging study for both diagnosis and stagingUseful in assessing resectibility70-85 % of those who have resectable disease on CT undergo curative resection
17Sensitivity 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.Optimal study: NCCT plus arterial, portal venous and pancreatic protocol phase with 3 mm cuts
18Optimal study: Non-contrast plus arterial, portal venous and pancreatic protocol phase with 3 mm cuts
19ROLE OF EUSDiagnosis:For tumors < 2 cm in size which are not well visualised on CTInflammotory head mass in the setting of chronic pancreatitisTo discriminate between benign and malignant strictures
20ROLE OF EUS STAGING: Complimentary to CT and MRI Mainly in patients whose scans show doubtful vascular or lymph node involvement
21ROLE OF PET-CT Has a role in staging of disease Adjunct to multiphasic CT/MRIHas increased sensitivity for detection of distant metastasisCan prevent unnecessary pancreatic resection in upto 25 % of patients by detecting unsuspected metastasisSaif MW et al, J. gastrointestin liver disease, 2008
22ROLE OF LAPROSCOPY Role in staging: High sensitivity for peritoneal and liver capsular metastasisNot a substitute for poor quality imaging
23ROLE OF LAPROSCOPY Considered when high risk of metastatic disease: Tumor size > 2cmBorder line resectable diseaseTumor of body/tailMarkedly elevated CA 19-9
24ROLE OF BIOPSY No role in resectable disease Required in unresectable disease and metastatic disease to confirm diagnosis before starting chemotherapyEUS FNA is preferable to CT guided FNALess bleeding and infection and metastatic seeding
25BIOMARKERS Various biomarkers: CA 19-9 (best validated and most useful)CA 125CEAPancreatic oncofetal antigen
26CA 19-9:Sialylated lewis A blood group antigenGood diagnostic marker (sensitvity: 80%, specificity: 82-90%)Correlates with staging and resectibility
27Prognostic marker:Low post-operative levels and serial decrease in levels after surgery correlate with survival post curative resectionBerger AC et al J. Clin oncology 2008Pre-treatment levels are an independent prognostic factor for survival in advanced pancreatic cancersHess V et al, lancet oncology 2008
28Predictor of response: Change in CA 19-9 levels after chemotherapy in patients with advanced disease predicts response to treatment
29FALSE – ve: lewis antigen negative patients Biliary obstructionCholangitisBiliary malignanciaesPre-operative levels should be measured after biliary drainage and normalisation of blirubin levels
32STAGING stage Tumor grade Node status Distant metastasis 5yr survival, %Median Survival,moCharacteristicsIAT1NoMo1424Tumor <2cm in pancreas onlyIBT21221Tumor >2cm in pancreas onlyIIAT3715Tumor extends beyond the pancreas, but with no involvement of the celiac or SMAIIBT1-3N1513Regional lymph node metastasisIIIT4N0-1311Tumor involves the celiac or SMAIVT1-4M11
33CLASSIFICATION PANCREATIC ADENOCARCINOMA BOREDERLINE RESECTABLE PPANCREATICBOREDERLINERESECTABLERESECTABLEADVANCEDMETASTASISENCASEMENT OF ARTERIESEXTENSIVE INVOLVEMENT OF VEINSNO METASTASISNO VASCULAR INVOLVEMANTPARTIAL ABUTMENT OF PORTAL OR SMV
34Stage of diseaseSMACeliac axisCommon Hepatic ArterySMV-PVResectable(all four required)No extension; normal fat plane between the tumor and the arteryPatent (may include tumor abutment or encasement)Boderline resectable (one required)AbutmentAbutment or short segment encasement if reconstruction possibleShort segment occlusion if reconstruction possibleUnresectable (one required)EncasementExtensive encasement with no technical option for reconstructionOccluded with no technical option for reconstruction
35RESECTABLE DISEASE Only 15% -20 % of newly diagnosed cases SURGERY is the only curative treatmentProcedure depends on the location of the tumour:Pancreaticoduodenectomy (Whipple procedure): lesions of the head, neck and uncinate processDistal pancreatectomy: lesions of the body or tailTotal pancreatectomy: multifocal disease
36Overall 5-year survival after pancreatic resection is 14 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 2004Negative margin status, tumor size and lymph node status are the strongest predictors of survival
37ADJUVANT CHEMOTHERAPY Recommended for all patients who undergo curative resectionEither gemcitabine or 5 - fluorouracil (5-FU) prolongs median survival by 3 months (95% CI 0.3–5.7)Boeck S et al Oncology 2007 metaanalysis
38We performed a retrospective review 472 consecutive patients who underwent complete resection with negative margins (R0) for invasive carcinoma (T1-3N0-1M0) of the pancreasbetween 1975 and 2005 at the Mayo Clinic in Rochester, MN.
39For the 466 surviving patients, median follow-up was 32 For the 466 surviving patients, median follow-up was 32.4 months; median OS was 21.6 months. Median OS after adjuvant CT-RT was 25.2 versus 19.2months after no adjuvant therapy (P .001). Two-year OS was 50% versus 39%, and 5-year OS was 28% versus 17%.
40Adverse prognostic factors identified by univariate and multivariate analysis included positive lymph nodes (risk ratio [RR] 1.3; P .001), high histologic grade (RR 1.2; P .001), and no adjuvant therapy (RR 1.3; P .001).
41Gemcitabine has been recommended as the first-line adjuvant agent owing to its lower toxicity profile
42ROLE OF ADJUAVENT RADIATION The benefit of adjuvant radiation therapy isunclear based on the results of the ESPAC-1trial.28 Median survival with chemoradiation(13.9 mo, 95% CI 12.2–17.3) was similar to thatseen with observation alone (16.9 mo, 95% CI12.3–24.8), but was longer when chemoradiationwas followed by chemotherapy (19.9 mo, 95%CI 14.2–22.5) and longest with adjuvantchemotherapy alone (21.6 mo, 95% CI 13.5–27.3).
45ROLE OF ADJUAVENT RADIATION No clear benefit of radiation therapy in addition to adjuvant chemotherapy
46ROLE OF NEOADJUAVENT THERAPY Benefit of neoadjuvant therapy at the cost of delaying surgery is controversialNo phase III trials comparing outcomes between neoadjuvant and adjuvant therapymost centres refrain from using neoadjuvant therapy outside of research protocols
47A meta -analysis mainly consisting of heterogenous phase I and II studies found a median overall survival of 23.3 (range 12–54) months, with perioperative mortality of 5.3% (95% CI 4.1%– 6.8%).
48A total of 111 studies (n = 4,394) including 56 phase I-II trials were analyzed. A median of 31 (interquartile range [IQR] 19-46) patients per study were included.
49ROLE OF PRE-OPERATIVE DRAINAGE GoalTo alleviate symptoms of pruritisTo provide drainage in patients with cholangitisDecrease surgical morbidity by improving liver function
50Studies have failed to show decreased mortality in patients who underwent pre-operative drainage
53Recommended:CholangitisSignificant pruritis and > 1 week delay of surgeryIf patient has to receive neoadjuvant therapyPlastic stents are preferred over metal stents
54BORDERLINE RESECTABLE DISEASE Surgery is attempted only if complete resection is possibleRole of neoadjuvant therapy is debatableNo phase 3 RCTsA 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%.Müller SA, Hartel M, Mehrab A, et al. Vascular resection in pancreatic cancer surgery: survival determinants. J Gastrointest Surg 2009;13:These results suggest that major venous resection and reconstruction is safe in experienced hands and results in oncologic results equivalent to those of complete resection.
55A 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
56ADVANCED DISEASEMedian overall survival of 2–3 months without treatmentChemotherapy is advised as it improves survivalDistant organ involvement, typically that of the liver, peritoneum or lung, occurs in 50% of cases.
5751 trials involving 9,970 patients met the inclusion criteria, and 33 of these trials involving 6,026 patients were included in the meta-analyses
58N=432 mortality reduction = 36 % 51 trials involving 9,970 patients met the inclusion criteria, and 33 of these trials involving 6,026 patients were included in the meta-analyses.N=432 mortality reduction = 36 %
59Journal of clinical oncology, 1997 Gemcitabine better than 5 FUJournal of clinical oncology, 1997
61ROLE OF COMBINATION CHEMOTHERAPY No overall improved survival as compared to monotherapySurvival benefit in a subset of patient who have good performance statusIndividual clinical trials of combination gemcitabine with various cytotoxic agents53–56 have failed to show a survival benefit over gem citabine alone (Appendix 1), but significantly improved overall survival was seen when these studies were pooled (HR 0.91, 95% CI 0.85–0.97).37 Furthermore,patients with a good performance status (Karnofsky performance score > 90%) survived longer with combination gem citabine (HR 0.76, 95% CI 0.67–0.87), whereas patients with a poor performance status did not (HR 1.08, 95% CI 0.90– 1.29).
63improveMeta analysis for combination chemotherapy in advanced pancreatic cancer – overall survival with regard to combination partner (platinum analog, fluoropyrimidine or other) for gemcitabine.
64Meta-analysis for combination chemotherapy in advanced pancreatic cancer-overall survival with regard to performance status
65Reserved for patients with good performance status 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 0.85–0.97)Reserved for patients with good performance statusCombination therapy also showed higher grade 3/4 toxicity: neutropenia (risk difference [RD] 5%, 95% CI 1%–10%), thrombocytopenia(RD 5%, 95% CI 2%–8%) and nausea or vomiting (RD 3%, 95% CI 0%–5%).57 Combination chemotherapy is reserved for patients with a goodperformance status.
66GEMCITABINE + ERLOTINIB Targeted therapy in pancreatic cancer has centred on the epidermal growth factor pathwayErlotinib: tyrosine kinase inhibitor of EGFR
67Kaplan-Meier curves for (A) overall survival; (B) progression-free survival; and(C) overall survival in the 100-mg cohort.
68This phase III study of the epidermal growth factor receptor inhibitor erlotinib with gemcitabine versus gemcitabine alone showed marginally increased overall survival (6.24 v mo,vs p = 0.04)58 and 1-year survival (23% [95% CI 18%–28%] v. 17% [95% CI 12%–21%], p = 0.02).combination gem - citabine/ erlotinib is considered for patients with good performance status in the metastatic setting.
69GEMCITABINE + ERLOTINIB Recommended as an option for patients with locally advanced and metastatic diseaseBenefit more in patients who develop skin rash
70FOLFIRINOXFOLFIRINOX (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).