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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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