pancreatic ductal adenocarcinoma · pancreatic ductal adenocarcinoma razvan popescu tumor center...

Pancreatic Ductal Adenocarcinoma

Razvan Popescu Tumor Center Aarau

Switzerland

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Recent guidelines

• NCCN Guideline Nov 2018• ASCO metastatic pancreatic adenocarcinoma

guideline update Aug 2018• NICE Feb 2018• French intergroup guidelines update July 2018• ESMO update of adjuvant guideline Mar 2019

• https://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf• DOI: 10.1200/JCO.2018.78.9636 Journal of Clinical Oncology 36, no. 24

(August 20 2018) 2545-2556.• https://www.nice.org.uk/guidance/ng85• Dig Liver Dis. 2018 Dec;50(12):1257-1271. doi: 10.1016/j.dld.2018.08.008.

Epub 2018 Aug 18.

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https://www.nice.org.uk/guidance/ng85

https://www.ncbi.nlm.nih.gov/pubmed/30219670

• 10% Localized/ Resectable 15 - 24 months

• 30% Locally Advanced 6 - 15 months

• 60% Metastatic/ Advanced 3 - 12 months

Median Survival of Patients With Pancreatic Cancer

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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

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Pancreatic Cancer Resection Categories

• Metastatic (unresectable)

• Resectable

• Borderline resectable

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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

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Gemcitabine Established as Treatment Standard for PDAC over 20 Years Ago

• First-line gemcitabine vs bolus 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)

Gemcitabine

5-FU

100

80

60

40

20

00 2 4 6 8 10 12 14 16 18 20

Mos

OS

(%)

Burris HA, et al. J Clin Oncol. 1997;15:2403-2413

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FOLFIRINOX Trial

Trial Schema Patient Characteristics

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FOLFIRINOX Trial - Toxicity

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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 %

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Time until definitive deterioration of QoL

FOLFIRINOX

Gemcitabine

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Design of PRODIGE 35 PANOPTIMOX study

Presented By Laetitia Dahan at 2018 ASCO Annual Meeting

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PROGRESSION FREE SURVIVAL (PFS)


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OVERALL SURVIVAL (OS)


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TOLERANCE:<br />Neurotoxicity grade 3-4


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MPACT Trial

Median OS

8.5 vs. 6.7 months

Median PFS

5.5 vs. 3.7 months

Response Rate

23% vs. 7%Survival

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Palliative Care • Patients with metastatic pancreatic cancer should have a full

assessment of symptom burden, psychological status, and social supports as early as possible, preferably at the first visit.

• In most cases, this assessment will indicate a need for a formal palliative care consult and services

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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%

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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%

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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

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IT’S NOT ONLY ABOUT SYMPTOM CONTROL

• 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.

Many patients assume they can be cured with palliative therapies

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Sequencing Chemotherapy first – second line

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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

QoL maintained under Nanoliposomal Iri + 5FU/LV

Nanoliposomal irinotecan: Enhanced tumor penetration and retention - EPR ESO-E

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Metastatic Pancreatic Cancer: ASCO Clinical Practice Guideline Update DOI: 10.1200/JCO.2018.78.9636


• “For second-line therapy, gemcitabine plus nanoparticle albumin-bound paclitaxel should be offered to patients with first-line treatment with FOLFIRINOX, an ECOG PS of 0 to 1 and a favorable comorbidity profile;

• ”Fluorouracil plus nanoliposomal irinotecan can be offered to patients with first-line treatment with gemcitabine plus NAB-paclitaxel, an ECOG PS of 0 to 1, and a favorable comorbidity profile;

• fluorouracil plus irinotecan or fluorouracil plus oxaliplatin may be offered when there is a lack of availability of fluorouracil plus nanoliposomal irinotecan”

• “Gemcitabine or fluorouracil should be offered to patients with either an ECOG PS of 2 or a comorbidity profile that precludes other regimens”

FOLFIRINOX Gemcitabine plus NAB-paclitaxel

Gemcitabine plus NAB-paclitaxel 5-FU plus nanoliposomal irinotecan *

* if unavailable: FOLFIRI

PS 2 Gemcitabine 5- FU

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How about third- line therapy?

• See options for molecular drivers• SM-88 therapy in patients with advanced or

metastatic pancreatic cancer– SM-88 (tyrosine derivative, mTOR inhibitor, CYP3a4

inducer and oxidative stress catalyst) is a relatively non-toxic, targeted therapy

– Extensively pretreated patients on SM-88 – 40% (4/10) of patients achieved survival benefit of

greater than one year (mean 12.2 mo). Monotherapy patients maintained or improved ECOG PS and did not experience drug-related SAEs during treatment. 2/10 patients achieved partial responses

ASCO GI 2019 DOI: 10.1200/JCO.2018.36.4_suppl.457

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Rare drivers which may lead to uncommonly good responses

• rate of BRCA positivity is approximately 4.6% in the advanced pancreatic cancer population

• Inclusion in clinical trials with PARP-inhibitors or olaparib / rucaparib

• In patients with dMMR or MSI-H the PD-1 immune checkpoint inhibitor pembrolizumab is recommended


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• Resectable


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Whipple Procedure (Pancreatoduodenectomy)

en bloc removal of:• Distal stomach• Duodenum• Head of pancreas • Distal bile duct• Gallbladder • Proximal jejunum

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Adjuvant Chemotherapy ESMO Guideline

• mFOLFIRINOX should be the first adjuvant therapeutic option after resection of pancreatic cancer in selected and fit patients, in view of survival outcomes and associated toxicity profile [I, A; ESMO-Magnitude of Clinical Benefit Scale (MCBS) v1.1 score: A].

• In more frail patients (age > 70, Eastern Cooperative Oncology Group performance status 2, or patients who have any contraindication to the drugs used in FOLFIRINOX), gemcitabine/capecitabine could be an option [I, B; ESMO-MCBS v1.1 score A].

• Gemcitabine alone should be used only in frail patients.

eUpdate: Cancer of the Pancreas Treatment Recommendations, 15 March 2019

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CONKO-001 Gemcitabine vs. No Chemotherapy

JAMA. 2007;297: 267-277

R0 13.1 vs 7.3 monthsR1 15.8 vs 5.5 months

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ASCO 2016

ESPAC – 4 : adjuvant Gem vs. Gem+ Cape

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PRODIGE 24/CCTG PA.6, an Unicancer GI trial: a multicenter international randomized phase III trial of adjuvant mFOLFIRINOX versus gemcitabine (gem) in patients with resected pancreatic ductal adenocarcinomas.

Presented By Thierry Conroy at 2018 ASCO Annual Meeting

N Engl J Med 2018; 379:2395-2406DOI: 10.1056/NEJMoa1809775

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Presented By Thierry Conroy at 2018 ASCO Annual Meeting

N Engl J Med 2018; 379:2395-2406DOI: 10.1056/NEJMoa1809775

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pT1-2 vs pT3-4

pN0 vs. pN1

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Upfront Resectable Pancreatic CancerPrimary Surgery versus Neoadjuvant Chemo

• Database of 15,237 patients, stage I or II resected pancreatic head Adenocarcinoma

• 2,005 patients 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

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Presented By Douglas Evans at 2018 ASCO Annual Meeting

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• Resectable


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Preoperative radiochemotherapy versus immediate surgery for resectable and borderline resectable pancreatic cancer (PREOPANC) : <br />A randomized, controlled, multicenter phase III trial of the<br /> Dutch Pancreatic Cancer Group

Presented By Geertjan Van Tienhoven at 2018 ASCO Annual Meeting

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Preoperative Radiochemotherapy Versus Immediate Surgery For (Borderline) Resectable Pancreatic Cancer: <br />(PREOPANC)

Presented By Colin Weekes at 2018 ASCO Annual Meeting

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Resection Rate


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Disease-Free Survival


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Overall Survival Analyses


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• 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

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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

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French Intergroup Guidelines Update July 2018 doi: 10.1016/j.dld.2018.08.008. Epub 2018 Aug 18

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Take home messages

Advanced disease:• FOLFIRINOX – Gem Abraxane – Gem (Cape)• Palliative and supportive care early on• Second line therapies, don’t miss the rare

‘targetable alterations’

‘Early’ disease• Adjuvant FOLFIRINOX > Gem Cape > Gem• Role of neoadjuvant therapies?

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