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.
• 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
Recent Randomized Trials document Impact of EARLY Palliative Care
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
• Cachexia
• Early involvement of nutritionist / dietitian
• Assess nutritional intake• Assess malabsorption• Supplement pancreatic enzymes• Treat reversible causes like
constipation, ascites, delayed gastric emptying /gastroparesis
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 PDACThe 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/ metastaticPancreatic 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)
Gemcitabine5-FU
100
80
60
40
20
00 2 4 6 8 10 12 14 16 18 20
MosOS
(%)
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 monthsHR 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 OS8.5 vs. 6.7 months
Median PFS5.5 vs. 3.7 months
Response Rate23% vs. 7%
Survival
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
• More side effects (hematological, fatigue, QoLdeterioration) in SEQ group
Philippa Corrie, Abs 4100 ASCO 2017
Sequential Concomitant6 m PFS 47% 33%Median PFS 5.8 4 months HR 0.66, CI .46-.95Median OS 10.1 months 7.9 months HR .88, CI 0.61-1.29
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 2nd line Therapy for PDAC
Sunbol et al, Cancer, 2017; 123: 4680-4686
• 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
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
. Wang-Gillam A et al;. Lancet. 2016;387:545–557.
Study design: • Phase 3, open-label RCT;• mPDAC• progress on Gem-based
treatmentRandomization:• 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
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
2nd 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 randomizedcohort 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 GemcitabineGem + Nab-P?
Nal-IRI + 5-FUFOLFIRIOx + 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
• Primary endpoint: PFS
• Secondary endpoints: ORR, OS, safety, PK
Pts with stage IV pancreatic
cancer, no prior treatment for
metastatic disease, KPS ≥ 70%
(planned N = 279)
Gemcitabine 1000 mg/m2 +
Nab-Paclitaxel 125 mg/m2
1 x/wk for 3/4 wks/cycle
PEGPH20 3 µg/kg IV
2x/wk in cycle 1 then weekly +
Gemcitabine 1000 mg/m2 +
Nab-Paclitaxel 125 mg/m2
1 x/wk for 3/4 wks/cycle
Treat until progression,
intolerable toxicity, death, or choice to
discontinue
Phase II HALO-109-202: Preliminary Results
• 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]
Outcome by Population Gem + Nab-P + PEGPH20 Gem + Nab-P P Value HRTotal§ Median PFS, mos§ ORR, % (n/N)
5.741 (30/74)
5.234 (21/61)
.11
.480.69
HA-high§ Median PFS, mos§ ORR, % (n/N)
9.252 (12/23)
4.324 (5/21)
.05
.040.39
HA-low§ Median PFS, mos§ ORR, % (n/N)
5.337 (14/38)
5.638 (9/24)
.74
.960.89
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
Target Lesion Measurements
GastricAmpullarySmall bowelPancreatic Cholangio
100
50
0
-50
-100
Cha
nge
From
Bas
elin
e SL
D (%
)
P
PP
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 (lysindemethylase), 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, 2014Cancer of the pancreas: ESMO Clinical Practice Guidelines, Ducreux M et al, 2015 https://doi.org/10.1093/annonc/mdv295
Pancreatic Adenocarcinoma.Ryan, David; Hong, Theodore; Bardeesy, NabeelNew England Journal of Medicine. 371(11):1039-1049, 2014.DOI: 10.1056/NEJMra1404198
Resectability in Pancreatic Adenocarcinoma
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
Whipple Procedure (Pancreatoduodenectomy)
en bloc removal of:• Distal stomach• Duodenum• Head of pancreas • Distal bile duct• Gallbladder • Proximal jejunum
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 1Bolus 5FU/FA vs. No Chemotherapy
MS 20.1 vs. 15.5 months (p = 0.009)
2 y OS 40% vs. 30%
N Engl J Med. 2004 Mar 18;350(12):1200-10
BOLUS 5FU/ FA
CONKO-001 (2007 data)Gemcitabine vs. No Chemotherapy
JAMA. 2007;297: 267-277
R0 13.1 vs 7.3 monthsR1 15.8 vs 5.5 months
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, 2009Neoptolemos J et al. ASCO 2016
ASCO 2016
53 resectable PDAC trials on clinicaltrials.gov
Upfront Resectable Pancreatic CancerPrimary 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
• Better diffusion of chemotherapy in well-vascularized 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
Potential benefits of primary chemotherapy
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
FOLFIRINOX; fluoropyrimidine-
based therapy + oxaliplatin
PS 0/1: Gemcitabine-based (eg,
gem/nab-paclitaxel,
gemcitabine)
PS 2 or less: Gemcitabine
monotherapy or BSC
??
Gemcitabine based (eg,
gem/nab-paclitaxel)
Poor PS: Gemcitabine
(PS 0/1): Nanoliposomal
irinotecan + 5-FU;
fluoropyrimidine-based therapy
PS 2: Fluoropyrimidine alone or
BSC
PS 0/1: Platinum (??)-based
regimen if no prior exposure or
BSC
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