Pancreatic Ductal Adenocarcinoma. Razvan Popescu Tumor Center Aarau Switzerland

Pancreatic Ductal Adenocarcinoma Razvan Popescu Tumor Center Aarau Switzerland

Teaching aims Discuss role of palliative care in PDAC Metastatic or locally advanced irresectable disease First line Therapies Second line Therapies Novel approaches (Borderline) Resectable disease

Epidemiology In Europe fourth most common fatal cancer in men (after lung, colorectal, and prostate) and women (after breast, colorectal and lung) Death due to PC increasing, projected to become second most common fatal cancer by 2030 Life expectancy overall of 5% at 5 years

Importance of Supportive and Palliative Care Median Survival of Patients With Pancreatic Cancer Localized/ Resectable 15-24 months 10% Locally Advanced 6-15 months 30% Metastatic/ Advanced 3-12 months 60%

Pancreatic cancer symptom burden Asthenia 85% Weight loss Anorexia Abdominal / epigastric pain Dark urine Jaundice Nausea Back pain Diarrhea Vomiting Steatorrhea Abdominal fullness Thrombophlebitis 2-3%

Recent guidelines call for early palliative care as a new standard Potentially Curable Pancreatic Cancer: American Society of Clinical Oncology Clinical Practice Guideline 2016: Patients should have full assessment of symptoms, psychological status, and social supports and should receive palliative care early www.asco.org/guidelines/pcpc

Supportive and Palliative Care Start supportive and palliative care as soon as diagnosis is suspected pancreatic cancer is an EMERGENCY Assess symptoms and their speed of development Consider pain, weight loss, exocrine pancreatic insufficiency, jaundice*, delayed gastric emptying*, VTE, depression, etc. * Biliary obstruction: endoscopic stent placement * Duodenal obstruction: endoscopic metal stent placement

Many patients assume they can be cured with palliative measures 1193 patients participating in the Cancer Care Outcomes Research and Surveillance (CanCORS) study receiving chemotherapy for stage IV lung or colorectal cancers 69% lung and 81% colorectal cancer patients did not understand that their treatment was not at all likely to cure their cancer. Inaccurate beliefs were higher among patients who rated their communication with physicians very favorably! Educational level, functional status, and the patient's role in decision making were not associated with such inaccurate beliefs about chemotherapy Weeks JC, et al. Patients' expectations about effects of chemotherapy for advanced cancer. N Engl J Med. 2012 Oct 25;367(17):1616-25.

Recent Randomized Trials document Impact of EARLY Palliative Care Benefits of OUTPATIENT concurrent palliative care: Avoided admissions and readmissions, increase referral to hospice, Better communication and satisfaction Equal or lowered costs to the health system Equal or better symptom management Equal or improved quality of life Equal or LONGER survival Not a single trial showed harm, added cost, or burden

How about systematic early palliative care integration in pancreatic cancer? Many principles can be extrapolated from other trials Metastatic pancreatic cancer patients were randomized between early vs. on-demand palliative care in an Early Palliative Care Italian Study Group (EPCISG) multicenter trial. The early palliative care group had significantly improved QoL, there was no difference in survival Maltoni M et al, Eur J Cancer. 2016 Sep;65:61-8. doi: 10.1016/j.ejca.2016.06.007

Pancreatic cancer symptoms Pain Assess at every visit including response to analgesics May be neuropathic and require co-analgesics RT or Celiac Plexus Block VTE Four- to seven-fold higher in pancreatic cancer than in other common adenocarcinomas, risk highest in first months after diagnosis and increased by chemotherapy Prophylaxis with LMWH reduces VTE but does not improve OS in outpatients- those with previous VT/E - lifelong LMWH Anxiety and Depression 1/3-2/3 of patients Use validated instruments or Are you depressed? Duloxetine or Venlafaxine co-treat neuropathic pain

GI problems in Pancreatic Ca Patients Anorexia Early satiety Weight loss Fatigue, weakness Nausea Constipation Ascites Malabsorption Early involvement of nutritionist / dietitian Assess nutritional intake Assess malabsorption Supplement pancreatic enzymes Treat reversible causes like constipation, ascites, delayed gastric emptying /gastroparesis Cachexia

GI Problems - Transit Constipation can be due to opioid intake, peritoneal carcinomatosis, ascites, delayed gastric emptying Ascites May be caused by peritoneal carcinomatosis or portal vein thrombosis / obstruction Patients with portal hypertension may respond to diuretics Paracentesis, if repeatedly necessary insert long term catheter Delayed gastric emptying often without obstruction, gastrographin image series may help discriminate If obstruction is not predominant, prokinetics may help NG tube in recurrently vomiting patients,? PEG / PEJ tube

Jaundice from biliary tree obstruction Leads to pruritus, risk of cholangitis Best treatment (least invasive) is placement of a stent preferably a metal stent if permanent stent is intended (fewer recurrent obstructions) Plastic stents are cheaper and can be easier removed or exchanged If the tumor is potentially removable, speak to the surgeon as to their preferences re plastic vs. metal stent If endoscopic placement fails percutaneous placement may be an option If cholangitis occurs, emergency antibiotics and stent change may be life saving Surgical bypass is an option

Exocrine pancreatic insufficiency Leads to maldigestion, fat malabsorption, and steatorrhea Typically symptoms include abdominal cramping, flatulence, urgency to defecate, weight loss and steatorrhea (greasy, foul-smelling, soft stools that are difficult to flush- may be less prominent if patients limit fat ingestion) Treat patients empirically with adequate doses of oral pancreatic enzyme replacements best ingested with meals 30 000 IU Lipase Microencapsulated variants better with gastric acid secretion if not efficacious, consider PPI Frequent smaller meals may be preferable

Anorexia - Cachexia Weight loss and Anorexia loss of appetite is common and multifactorial, but in many cases reversible Dysgeusia, xerostomia Poor appetite Poor GI transit/ motility or absorption Early satietey (ascites, hepatomegaly) Weight loss > 5% correlates with worse mortality Cachexia is characterized by Excessive loss of lean body (skeletal muscle) mass Cytokine activation and chronic inflammatory response Increased basal metabolic rate / hypermetabolic state Far more than poor caloric intake Correlates with poor prognosis, directly linked to severity

Cachexia management Established Cachexia syndrome difficult to manage supportive care, psychological assistance, discouraging relatives to force feed Pre-cachexia more likely to respond to therapy ideally managed by teams including pall care specialists, psychologists and nutritionalists Small meals, supplements Physical exercise Trials of dexamethasone or medroxyprogesteroneacetate (short term, VTE risk!) may be warranted Clinical trial participation warranted

Locally advanced inoperable / metastatic Pancreatic Cancer

Predicting Prognosis in advanced PDAC The MSKCC Prognostic Score (MPS) A modification of the Glasgow Prognostic Score (CRP >10 and Albumin < 3.5 g/dl) Neutrophil / Lymphocyte Ratio (NLR) >4 and Albumin < 4 g/dl) get each 1 point Andrew Cheung Yang, Abstract 4105, ASCO 2017

Advanced inoperable/ metastatic Pancreatic Cancer Gemcitabine has been standard of care for over a decade various trials adding other cytotoxics have shown a (marginal) survival benefit with increased toxicity* Two recent trials however showed clear superiority of novel regimens: FOLFIRINOX in the French PRODIGE 4 / ACCORD 11 Gem/ nab-paclitaxel in MPACT Trial *Ciliberto D et al. Role of gemcitabine-based combination therapy in the management of advanced pancreatic cancer: a meta-analysis of randomised trials. Eur J Cancer 2013; 49: 593 603

Gemcitabine Established as Treatment Standard for PDAC over 20 Years Ago First-line gemcitabine vs 5- FU in advanced pancreatic cancer Median OS: 5.7 vs 4.4 mos (P =.0025); 1-yr OS: 18% vs 2% Clinical benefit (pain + KPS + weight): 23.8% vs 4.8% (P =.0022) OS (%) 100 80 60 40 20 Gemcitabine 5-FU 0 0 2 4 6 8 10 12 14 16 18 20 Mos Burris HA, et al. J Clin Oncol. 1997;15:2403-2413

FOLFIRINOX Trial Trial Schema Patient Characteristics

FOLFIRINOX Trial - Toxicity

OS 11.1 vs. 6.8 months HR 0.55, p< 0.001 No PD at FOLFIRINOX Gem 6 months 52.8% 17.2% 12 months 12.1% 3.5% 18 months 3.3% 0 %

Time until definitive deterioration of QoL FOLFIRINOX Gemcitabine

MPACT Trial Median OS 8.5 vs. 6.7 months Median PFS 5.5 vs. 3.7 months Survival Response Rate 23% vs. 7%

Sequential nab-pacli followed by gem 24 hours later might be superior PDAC mouse model suggested that nabp potentiates GEM activity by reducing cytidine deaminase levels and scheduling may be important 146 patients randomized to concurrent vs. sequential nabp and Gem Sequential Concomitant 6 m PFS 47% 33% Median PFS 5.8 4 months HR 0.66, CI.46-.95 Median OS 10.1 months 7.9 months HR.88, CI 0.61-1.29 More side effects (hematological, fatigue, QoL deterioration) in SEQ group Philippa Corrie, Abs 4100 ASCO 2017

Comparative Effectiveness of nab-paclitaxel Plus Gemcitabine vs FOLFIRINOX in Metastatic Pancreatic Cancer: A Nationwide Chart Review in the United States Sunnie Kim et al, ASCO GI Cancers Symposium 2018

Comparative Effectiveness of nab-paclitaxel Plus Gemcitabine vs FOLFIRINOX in Metastatic Pancreatic Cancer: A Nationwide Chart Review in the United States Sunnie Kim et al, ASCO GI Cancers Symposium 2018

Comparative Effectiveness of nab-paclitaxel Plus Gemcitabine vs FOLFIRINOX in Metastatic Pancreatic Cancer: A Nationwide Chart Review in the United States Sunnie Kim et al, ASCO GI Cancers Symposium 2018

UpToDate 2018

Second Line Therapy

Meta-analysis on 2 nd line Therapy for PDAC 5 Studies with 895 patients receiving monofluoropyrimidine(fp) chemo or combinations of FP and Irinotecan or Oxaliplatin HR FP+Iri vs. FP 0.64 (0.47-0.87, p=0.005) for PFS and 0.7 (0.55-0.89, p=0.004) for OS HR FP+Ox modest improvement for PFS and none for OS Sunbol et al, Cancer, 2017; 123: 4680-4686

Second Line Therapy after Gemcitabine based Therapy CONKO-003 Study: 168 patients age 18 years or older who experienced disease progression during first-line gemcitabine therapy were randomly assigned to folinic acid and fluorouracil (FF) or oxaliplatin and FF (OFF) Median OS in the OFF group (5.9 months) versus the FF group (3.3 months) significantly improved (HR 0.66; 95% CI, 0.48 to 0.91; log-rank P =.010). Similar AEs except neuropathy Oettle et al. J Clin Oncol. 2014 Aug 10;32(23):2423-9. doi: 10.1200/JCO.2013.53.6995

Phase III Experience: Second-line Chemotherapy With Oxaliplatin CONKO-003 [1] PANCREOX [2] Pts (N = 268) PD on Gem(n = 160) Previous Gem (n = 108) Treatment OFF 5-FU/LV mfolfox6 5-FU/LV (n = 76) (n = 84) (n = 54) (n = 54) OS, median 5.9 mos 3.3 mos 6.1 mos 9.9 mos HR: 0.66 (95% CI: 0.48-0.91) P =.01 HR: 1.78 (95% CI: 1.08-2.93) P =.02 PFS, median 2.9 mos 2.0 mos 3.1 mos 2.9 mos HR: 0.68 (95% CI: 0.50-0.94) P =.02 HR: 1.00 (95% CI: 0.66-1.53) P =.99 ORR, median NR 13.2% 8.5% P =.36 1. Oettle H, et al. J Clin Oncol. 2014;32:2423-2429. 2. Gill S, et al. J Clin Oncol. 2016 Sep 12.

NAPOLI-1: Nanoliposomal Irinotecan With 5-FU/LV After Previous Gemcitabine-Based Treatment Study design: Phase 3, open-label RCT; mpdac progress on Gem-based treatment Randomization: nal-iri (MM-398) (n = 151) 5-FU + LV (n = 119) or nal-iri + 5-FU + LV (n = 117) Primary endpoint: OS Secondary endpoints: PFS, TTF, ORR, and safety Nanoliposomal irinotecan: Enhanced tumor penetration and retention - EPR. Wang-Gillam A et al;. Lancet. 2016;387:545 557.

What after FOLFIRINOX? Second-Line Therapy in the ACCORD / Prodige Trial FOLFIRINOX group: n= 80 patients Gemcitabine group n= 85 patients mos both groups: 4.4 months in each group 2 nd line: after FOLFIRINOX gemcitabine: 82.5% gemcitabine-based combination: 12.5% After gemcitabine: FOLFOX: 49.4% Gemcitabine plus oxaliplatin: 17.6% 5-FU/LV plus cisplatin: 16.5% FOLFIRINOX: 4.7% Conroy et al., 2011

Cave: Not randomized cohort trial N = 57 Median 4 cycles Gem + nab-pac 17.5% ORR mpfs: 5.1 mo mos: 8.8 (18) mo G 3/4 AEs: 40% Neutropenia 12.5% Neurotoxicity 12.5% Asthenia 9% Thrombopenia 6.5% OS and PFS PFS: 5.1 mo OS and PFS since first-line chemotherapy Nab-paclitaxel plus gemcitabine for metastatic pancreatic adenocarcinoma after FOLFIRINOX failure: an AGEO prospective multicentre cohort. Portal A et al, Br J Cancer. 2015 Sep;113(7):989-95

Optimal therapeutic sequence? First-line FOLFIRINOX Gem Gem + Nab-P Second-line Gemcitabine Gem + Nab-P? Nal-IRI + 5-FU FOLFIRI Ox + FP? FOLFIRINOX? Nal-IRI + 5-FU? FOLFIRI? Ox + FP? FOLFIRINOX? Quality of life is paramount in this setting we need data!

Novel Approaches to PDAC Systemic Treatment

Hyaluronan: Major Component of the Extracellular Matrix PEGPH20: recombinant human hyaluronidase Hyaluronan degradation can Normalize tumor interstitial pressure Improve drug delivery

Phase II HALO-109-202: Addition of PEGPH20 to Gem/Nab-Pac in Metastatic Pancreatic Cancer Pts with stage IV pancreatic cancer, no prior treatment for metastatic disease, KPS 70% (planned N = 279) Gemcitabine 1000 mg/m 2 + Nab-Paclitaxel 125 mg/m 2 1 x/wk for 3/4 wks/cycle PEGPH20 3 µg/kg IV 2x/wk in cycle 1 then weekly + Gemcitabine 1000 mg/m 2 + Nab-Paclitaxel 125 mg/m 2 1 x/wk for 3/4 wks/cycle Treat until progression, intolerable toxicity, death, or choice to discontinue Primary endpoint: PFS Secondary endpoints: ORR, OS, safety, PK

Phase II HALO-109-202: Preliminary Results Outcome by Population Gem + Nab-P + PEGPH20 Gem + Nab-P P Value HR Total Median PFS, mos ORR, % (n/n) 5.7 41 (30/74) 5.2 34 (21/61).11.48 0.69 HA-high Median PFS, mos ORR, % (n/n) 9.2 52 (12/23) 4.3 24 (5/21).05.04 0.39 HA-low Median PFS, mos ORR, % (n/n) 5.3 37 (14/38) 5.6 38 (9/24).74.96 0.89 Higher rate of thromboembolic events on PEGPH20-containing arm during first stage of enrollment (42% vs 25%); mitigated during second stage with addition of prophylactic enoxaparin [1] Phase III HALO-109-301 study of gem/nab-p PEGPH20 limited to HA-high pts currently enrolling [2]

Immune Checkpoint Inhibitors in PDAC Minimal to no activity in advanced PDAC 1% of pancreatic cancers associated with defective mismatch repair (dmmr/msi-high) I 2 of 4 dmmr/msi-high pts on pembrolizumab had objective responses Change From Baseline SLD (%) 10 0 50 0-50 - 100 Target Lesion Measurements P P P Gastric Ampullary Small bowel Pancreatic Cholangio P

BRCA- or PALB2-mutation carriers Objective responses in early trials: Rucaparib: 3/19 (16%) Olaparib: 5/23 pts (22%) Veliparib: 0/16 pts

Molecular classification and transcriptional networks 32 mutated genes 10 signaling pathways Kras, TGFb, WNT, Notch, ROBO/SLIT, G1/S transition, SW1-SNF, chromatin modification, DNA repair, RNA processing 4 subtypes Squamous Mutations in P53 and KDM6A (lysin demethylase), p63dn Worst prognosis ADEK (aberrantly differentiated endocrine exocrine) Kras activation Endocrine (NEUROD1, NKX2-2) und exocrine (NR5A2, RBPJL) differentiation Pancreatic progenitor FOX2/3, PDX1, MNX1 Immunogenic P Bailey et al. Nature 1-6 (2016)

Conclusions Improving frontline and second-line treatment options 2 frontline regimens, FOLFIRINOX and gemcitabine/nab-paclitaxel, have demonstrated survival benefit (vs gemcitabine alone) in phase III studies Evidence for second-line/salvage treatment in this disease with (nanoliposomal) irinotecan plus 5-FU/LV following gemcitabine-based therapy Novel therapeutics under investigation may one day complement, but are unlikely to replace, standard cytotoxic agents Include stromal-depleting agents, immunotherapies, and signal transduction inhibitors New approaches to molecularly subclassify pancreatic cancer may one day allow us to make smarter treatment decisions

Non-metastatic Pancreatic Cancer

Pancreatic Cancer Resection Categories Resectable Borderline resectable A distinct category Neoadjuvant therapy may increase likelihood of R0 resection Unresectable (eg, locally advanced or metastatic) Ryan, David et al, New England Journal of Medicine. 371(11):1039-1049, 2014 Cancer of the pancreas: ESMO Clinical Practice Guidelines, Ducreux M et al, 2015 https://doi.org/10.1093/annonc/mdv295

Resectability in Pancreatic Adenocarcinoma Pancreatic Adenocarcinoma. Ryan, David; Hong, Theodore; Bardeesy, Nabeel New England Journal of Medicine. 371(11):1039-1049, 2014. DOI: 10.1056/NEJMra1404198

Management of localized resectable disease Upfront surgery (Whipple procedure) recommended neoadjuvant chemotherapy may lead to fewer resections due to PD - newer regimens may be more effective but as yet untested

en bloc removal of: Distal stomach Duodenum Head of pancreas Distal bile duct Gallbladder Proximal jejunum Whipple Procedure (Pancreatoduodenectomy)

Adjuvant Therapy for Pancreatic Cancer Adjuvant chemotherapy is standard Role of adjuvant RT is debated, even in R1 resected patients Old trials showed benefit of chemotherapy vs. observation (ESPAC 1) and Gemcitabine vs. Bolus 5-FU Integration of more active regimens is attractive and off label use is increasing, no clinical trial evidence

ESPAC 1 Bolus 5FU/FA vs. No Chemotherapy MS 20.1 vs. 15.5 months (p = 0.009) 2 y OS 40% vs. 30% BOLUS 5FU/ FA N Engl J Med. 2004 Mar 18;350(12):1200-10

CONKO-001 (2007 data) Gemcitabine vs. No Chemotherapy R0 13.1 vs 7.3 months R1 15.8 vs 5.5 months JAMA. 2007;297: 267-277

CONKO-001 (2013 update) Gemcitabine vs. No Chemotherapy Median DFS 13.4 months vs. 6.7 months (HR 0.55) OS Benefit from Gemcitabine (HR 0.76, p = 0.01) 5 y Survival 20.7 vs. 10.4 % 10 y Survival 12.2 vs. 7.7 % JAMA. 2013;310(14):1473-1481

Cunningham D et al. JCO 27: 5513, 2009 Neoptolemos J et al. ASCO 2016

ASCO 2016

53 resectable PDAC trials on clinicaltrials.gov

Upfront Resectable Pancreatic Cancer Primary Surgery versus Neoadjuvant Chemo Database of 15,237 patients, stage I or II resected pancreatic head Adenocarcinoma 2,005 patients (95%) receiving Neoadjuvant Chemo matched with 6,015 patients with primary surgery Chemo first group had improved survival compared with Surgery first group: median survival: 26 months versus 21 month, P < 0.01; HR 0.72 Surgery first patients vs. Chemo first patients: higher pathologic T stage (pt3 and T4: 86% v 73%; P <.01) higher positive lymph nodes (73% v 48%; P <.01) higher positive resection margin (24% v 17%; P <.01) Mokdad AA et al. J Clin Oncol 2016, Sept

Many ongoing trials looking at best strategy ESPAC-5F: randomised patients to 4 approaches

Borderline Resectable Disease Potential benefits of primary chemotherapy Better diffusion of chemotherapy in wellvascularized tissues (before surgery and radiotherapy) Better tolerance and feasibility in patients before surgery (50% of adjuvant postoperative treatment not done or uncompleted) Decrease of the delay to the first treatment Downstaging effect Exclusion of patients with rapidly progressive tumours

Recent meta-analysis of primary chemotherapy with FOLFIRINOX 13 studies with FOLFIRINOX 689 patients 355 Locally advanced 63.5% received RT-CT after FOLFIRINOX Suker M et al. Lancet Oncol 2016;17:801-10

Localised Primarily Unresectable Disease Much controversy Primary chemotherapy standard Possibly followed by radiochemotherapy * (LAP07 trial was negative but a retrospective analysis of 13 004 pts in the National Cancer Database showed that patients receiving (SB)RT did better than those only on chemo ASCO 2017, Abs 4103) Radiological reassessment is poor in identifying patients who are likely resectable -If some response documented resubmit to MDT discussion and consider exploratory surgery

Current Chemotherapy Sequencing for Metastatic PDAC First Line Gemcitabine based (eg, gem/nab-paclitaxel) Poor PS: Gemcitabine FOLFIRINOX; fluoropyrimidinebased therapy + oxaliplatin Second Line (PS 0/1): Nanoliposomal irinotecan + 5-FU; fluoropyrimidine-based therapy PS 2: Fluoropyrimidine alone or BSC PS 0/1: Gemcitabine-based (eg, gem/nab-paclitaxel, gemcitabine) PS 2 or less: Gemcitabine monotherapy or BSC Third line PS 0/1: Platinum (??)-based regimen if no prior exposure or BSC??