Pancreatic Adenocarcinoma

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1 Pancreatic Adenocarcinoma AProf Lara Lipton 28 April 2018

2 Percentage alive 5 years after diagnosis for men and women

3 Epidemiology 6% of cancer related deaths worldwide 4 th highest cause of cancer death At diagnosis, 50% have metastatic disease, 30% locally advanced disease and 20% operable disease 1 year survival overall is 24% and 5 year is 5% Median age at diagnosis is 69 in men and 65 in women

4 Risk factors for pancreatic adenocarcinoma Genetic syndromes BRCA2 (Up to 10% in Ashkenazi Jews with pancreas ca) Lynch Syndrome (MSI-H) PALB2 Familial pancreatic adenocarcinoma Peutz Jeghers Syndrome p16ink4 (melanoma and pancreas ca) CF and SPINK1 mutations (familial pancreatitis and pancreatic adenocarcinoma) Smoking Chronic pancreatitis (GS and ETOH) Pancreatic Cystadenoma (mucinous and serous) IPMN. Intrapanctreatic mucinous neoplasia

5 BRCAish and high levels of neo-antigen do better, studies ongoing with PARP inhibitors Nature February 26; 518(7540):

6 Presentation of pancreas adenocarcinoma Painless obstructive jaundice Most common (75% of adenocarcinomas are in head of pancreas) Due to obstruction of common bile duct Diabetes (often insulin dependent) or worsening/brittle diabetes Lipid malabsorption Metastatic disease symptoms Loss of weight Nausea Pain: Often poorly localized, epigastric back. May take a long time to make diagnosis.

7 Dilatation of the common bile duct PCPA Advanced Trainee Program 2018

8 Double duct sign PCPA Advanced Trainee Program 2018

9 Investigation imaging Pancreatic protocol CT (+staging CT) Most accurate way to stage pancreatic adenocarcinoma Double duct sign MRCP to delineate duct anatomy Not always necessary If unsure about stenting or site of obstruction Endoscopic ultrasound Allows staging as well as biopsy FNA only Increasingly commonly used for inoperable disease for biopsy or operable disease to stage Biopsy Increasingly EUS Not necessary if surgery is planned and CT highly suggestive

10 Other Investigation LFTs, if bilirubin not too high immediate surgery is favourable CA19.9 Definitions of operability vary widely Borderline operable no standard definition

11 Post-operative complications Anastomotic/bile leak Malabsorption Brittle diabetes Pancreatitis Failure to thrive May lead to long delays prior to adjuvant therapy and preclude some from receiving it.

12 Adjuvant therapy PCPA Advanced Trainee Program 2018

13 Adjuvant therapies in pancreatic adenocarcinoma Chemotherapy ESPAC 1 Chemotherapy vs chemoradiotherapy vs nil CONKO1 Gemcitabine vs nil ESPAC 3 Gemcitabine vs 5FU ESPAC 4 Gemcitabine vs Gemcitabine plus capecitabine Radiotherapy GITSG RTOG 9704 EORTC

14 20.1 vs 15.5 mo Final ESPAC1 results Original 2 x 2 randomisation only Chemoradiotherapy detrimental Lancet Nov 10;358(9293): JAMA Sep 8;304(10):

15 CONKO1 Oettle et al, JAMA, Vol. 297 No. 3, January 17, 2007

16 CONKO DFS Gemcitabine Observation Node months 11.2 months Node months 7.0 months R0 resection 14.0 months 7.9 months R1 resection 14.5 months 5.5 months Oettle et al, JAMA, Vol. 297 No. 3, January 17, 2007

17 ESPAC 3 Results Received no chemotherapy Completed chemotherapy Grade 3/4 diarrhoea Grade 3/4 stomatitis Grade 3/4 neutropenia Gemcitabine 5FU P value 10% 11% 60% 55% 2% 13% 0% 10% 22% 22% PFS 14.3 months 14.1 months 0.44 Median OS 23.6 months 23 months 0.39 JAMA Jul 11;308(2):147-56

18 ESPAC 3 PCPA Advanced Trainee Program 2018

19 106 sites, Not a highly selected population: 60% R1, 80% node +ve

20 2 drugs better than 1 PCPA Advanced Trainee Program year OS 28.8 v 16.3 months

21 ESPAC 4

22 ESPAC trials 5 year OS 8% => 17% => 29% PCPA Advanced Trainee Program 2018

23 Toxicity only moderately increased PCPA Advanced Trainee Program 2018

24 Chemoradiotherapy PCPA Advanced Trainee Program 2018 Trial GITSG 1985 Pt no. RT Chemotx Median OS P value 43 2 x 20Gy Bolus 5FU during and after RT 20 vs 11 months EORTC 1999 RTOG * x 20Gy CI 5FU only during RT Gy continuous CI 5FU during RT (all) 4 mo of gem vs 4 mo of CI 5FU 17.1 vs 12.6 months 18.8 vs.16.9 months Ann Surg Oncol May;18(5):

25 Is there a role for chemoradiotherapy post surgery for pancreatic adenocarcinoma today? Controversial No large randomised studies supporting the approach Study of National Cancer Data Base showed advantage in N+ and R1 resection Will not generally be curative in such patients (some anecdotes) Reduces local recurrence but not distant recurrence Increases toxicity compared to Chemotherapy alone? Save RT for treatment of symptoms due to local relapse Cancer Dec 1;121(23):4141-9

26 Neoadjuvant therapy PCPA Advanced Trainee Program 2018 Gillen et al PLoS Med April; 7(4)

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28 Neo-adjuvant chemotherapy for operable pancreatic adenocarcinoma No randomised trials CT and CRT approaches in retrospective and small prospective series Not to be confused with downstaging to operability (operable vs borderline) May spare some major surgery Risks of sepsis/blockage due to stent

29 ASCO 2017 Recommendations Recommendation 2.1: Primary surgical resection of the primary tumor and regional lymph nodes is recommended for patients who meet all of the following criteria: no clinical evidence for metastatic disease, performance status and comorbidity profile appropriate for a major abdominal operation, no radiographic interface between primary tumor and mesenteric vasculature on high-definition cross-sectional imaging, and a CA 19-9 level (in absence of jaundice) suggestive of potentially curable disease (Type: evidence based, benefits outweigh harms; Evidence quality: intermediate; Strength of recommendation: strong). Recommendation 3.1: Preoperative therapy is recommended for patients with pancreatic cancer who meet any of the following criteria: radiographic findings suspicious but not diagnostic for extrapancreatic disease, a performance status or comorbidity profile not currently appropriate (but potentially reversible) for a major abdominal operation, a radiographic interface between primary tumor and mesenteric vasculature on cross-sectional imaging that does not meet appropriate criteria for primary resection or a CA 19-9 level (in absence of jaundice) suggestive of disseminated disease (Type: evidence based, benefits outweigh harms; Evidence quality: low; Strength of recommendation: strong). Recommendation 3.2: Preoperative therapy should be offered as an alternative treatment strategy for any patient who meets all criteria in Recommendation 2.1 (Type: evidence based, benefits outweigh harms; Evidence quality: low; Strength of recommendation: strong). JCO VOLUME 35 NUMBER 20 JULY 10, 2017

30 Locally Advanced/Inoperable pancreatic adenocarcinoma Heterogeneous presentations to the oncologist Failed resection ± surgical bypass Obviously inoperable on CT ± stent inserted Too old/infirm for surgery Symptomatic pain, LOW Completely asymptomatic and bypassed/stented One approach does not fit all

31 Locally advanced disease Chemotherapy Gemcitabine Paclitaxel NAB FOLFIRINOX and derivatives Chemoradiotherapy with 5FU, capecitabine or gemcitabine Both Currently chemotherapy is standard, use of radiotherapy decreasing Radiotherapy still used for pain control

32 LAP07 Study PCPA Advanced Trainee Program 2018

33 LAP 07 chemotherapy vs chemotherapy then chemoradiotherapy PCPA Advanced Trainee Program 2018

34 Metastatic pancreas ca For 10 years standard of care = gemcitabine FOLFIRINOX Oxaliplatin, irinotecan, 5FU. 5 months increased median overall survival Increased rate of sepsis (stents = cholangitis) 2013 Gemcitabine plus Paclitaxel NAB 3 month OS advantage compared to gemcitabine Need to balance toxicity/qol vs survival. In Australia Paclitaxel NAB only on the PBS for first line use Conroy T et al. NEJM 2011;;364: Von Hoff DD, et al. N Engl J Med Oct 16

35 Biologicals? PCPA Advanced Trainee Program 2018 = p>0.05 for biological

36 Overall Survival for All Patients HR = 0.81* 95%CI P=0.025 Gemcitabine + Erlotinib Median = 6.37 months 1 year survival = 24% Gemcitabine + Placebo Median = 5.91 months 1 year survival = 17% * Adjusted for PS, pain and disease extent at randomization

37 New Targets PARPi CD4/6 inhibitors CSFR1 inhibitors Pegylated recombinant Human hyaluronidase Immunotherapies

38 NAPOLI-1 study, liposomal irinotecan Ther Adv Gastroenterol 2017, Vol. 10(7)

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40 Suggestion For ECOG 0-1 Clinical trial First line gemcitabine and paclitaxel NAB Second line FOLFOX or FOLFIRI 3 rd line (after FOLFOX) irinotecan BUT no data and likely very low RR For ECOG 2+ First line gemcitabine Second line capecitabine