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TREATMENT OPTIONS FOR ADVANCED PANCREATIC CANCER

DR MOHD SHAFI MOONA

Pancreatic cancer is the fourth leading cause of cancer-related death in Europe and the United States.Worldwide, pancreatic cancer is the eighth most common cause of death from cancer in both sexes..

Since 1997, gemcitabine therapy has been the standard first line treatment for patients with unresectable locally advanced or metastatic pancreatic cancerAmong patients with metastatic disease, the 5-year survival rate is only 5% and 1-year survival rates of 17 to 23% have been reported with gemcitabine.

Signs and symptoms of the disease seldom appear until more advanced stages of cancer. By the time symptoms appear, cancer cells are likely to have metastasized to other parts of the body.

Pancreatic cancers can arise from both the exocrine and endocrine portions of the pancreas. Of pancreatic tumors, 95% develop from the exocrine portion of the pancreas and adenocarcinomas account for 75% of all pancreas cancers.

5-year survival rate < 5%80% have unresectable diseaseMetastatic survival 3-6 monthsLocalized unresectable survival 6-10 months.

Diagnosis Ultrasound of the abdomen Endoscopic ultrasonography (EUS) Endoscopic retrograde cholongeopancreatography ( ERCP) Computed tomography

NCCN guidelines 2015: Principles of chemotherapyMetastatic diseaseAcceptable monotherapy:Gemcitabine (category 1)Capecitabine (category 2B)Acceptable combination therapies for patients with a good PS:Gemcitabine + erlotinib (category 1, survival benefit is small)FOLFIRINOX (category 1)Gemcitabine + capecitabineGemcitabine + cisplatin (especially for patients with hereditary cancers) (category 2A)Gemcitabine + nab paclitaxel ( category 1)Fluoropyrimidine + oxaliplatin (category 2B)Category 1: The recommendation is based on high-level evidence (e.g. randomized controlled trials) and there is uniform NCCN consensus.Category 2A: The recommendation is based on lower-level evidence and there is uniform NCCN consensus.Category 2B: The recommendation is based on lower-level evidence and there is non uniform NCCN consensus (but no major disagreement).Category 3: The recommendation is based on any level of evidence but reflects major disagreement.

Prodige 4 - ACCORD 11/0402 Trial

Randomized Phase III Trial Comparing Folforinox Vs Gemcitabine As First-line Treatment For Metastatic Pancreatic Adenocarcinoma

R

Treatment A:

FOLFIRINOX Treatment B:

GEMCITABINEN=342

Primary Outcome: OS

Study Design

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INCLUSION CRITERIAHistologically/cytologically confirmed pancreatic CA.ECOG performance status of o or 1.Measurable metastases.No prior cytotoxic chemotherapy.No prior abdominal radiotherapy. Age 18-75 years.Adequate hematopoietic, hepatic and renal function.Billirubin < 1.5 UNL. No unstable angina or MI within 12 months before entry.Written informed consent.

Experimental Arm: FOLFIRINOX

Oxaliplatin 85 mg/m2 over 2 hours,Leucovorin 400 mg/m2 over 2 hours,Irinotecan 180 mg/m2 in 90 mn infusion,5-FU 400 mg/m2 bolus, 5-FU 2400 mg/m2 on 46-h infusion. 1 cycle = 14 days

1 h 30

2 h2 h46 h

Oxaliplatin85 mg/m2Irinotecan180 mg/m2Leucovorin400 mg/m2Continuous 5-FU 2.400 mg/m2

Bolus 5-FU 400 mg/m2q2wks

PFSReprinted with permission from Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364(19):1817-1825.Median PFS FOLFIRINOX: 6.4 mos Median PFS gemcitabine: 3.3 mos

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0.25

0.50

0.75

1.00Probability17112185421774110000FOLFIRINOX17188268520000000GemcitabineNumber at risk

0

3

6

9

12

15

18

21

24

27

30

33

36Months

GemcitabineFOLFIRINOXP < 0.0001HR = 0.47, 95% CI (0.37-0.59)

Hematological AEsFolfirinoxN=171GemcitabineN=171Grade 3/4Grade 3/4PNeutropenia45.721.00.001Febrile Neutropenia 1.20.03Anemia7.86.0NSThrombocytopenia9.13.60.04

5.442.5 % of the pts received G-CSF in the F arm vs 5.3% in the G armOne toxic death occurred in each arm

Main Non-Hematological AEsFolfirinox N=171Gemcitabine N=171pGrade 3/4Grade 3/4Vomiting14.58.3NSPeripheral neuropathy900.001ALT7.320.80.001

Fatigue23.217.8NSDiarrhea12.71.80.001

STUDY COMMENTARY

FOLFIRINOX improves OS and PFS in comparison to Gem for patients with MPC and good PS.Median PFS: 6.4 vs 3.3 months (HR 0.47, p < 0.0001)Risk of disease progression reduced by 53%Median OS: 11.1 VS 6.8 months (HR 0.57, p < 0.0001)FOLFIRINOX is more toxic but has a manageable toxicity profile.Grade 3/4 febrile neutropenia: 5.4 % vs 1.2 % (p = 0.009)FOLFIRINOX may be a potential new standard of care for patients with MPC and good PS.

STUDY COMMENTARY

Well designed randomized trial that demonstrated a statistically and clinically significant increase in OS However: Patients PS 0/1 only5% febrile neutropenia rate despite use of GCSF in 42% of patients Therefore : PATIENT SELECTION KEY!

What does a typical pancreatic cancer patient look like?41% are greater than 76 years old50% have biliary stents20% have co-existing heart disease30% do not receive any treatment

Issues

Toxicity is very concerning. 42.5% of patients in the experimental arm received G-CSF and almost 1/4 of the patients had grade 3/4 fatigue. 10 15% experienced grade 3/4 vomiting, diarrhea, or neuropathy.

N Engl J Med 2011; 364:1817-25FOLFIRINOX is a first-line option for patients with metastatic pancreatic cancer who are younger than 76 years and who have a good performance status (ECOG 0 or 1), no cardiac ischemia, and normal or nearly normal bilirubin levels.

Primary ObjectiveTo evaluate efficacy of the combination of nab-paclitaxel and gemcitabine versus gemcitabine alone in improving overall survival in patients with metastatic adenocarcinoma of the pancreas

Secondary ObjectivesTo evaluate the following:Objective tumor response and progression-free survival (PFS) according to RECIST criteriaSafety and tolerability Functional tumor response according to EORTC criteria

A Randomized Phase III Study of nab-Paclitaxel plus Gemcitabine versus Gemcitabine Alone in Patients with Metastatic Adenocarcinoma of the Pancreas

IMPACT - Study DesignRANDOMIZEnab-Paclitaxel 125 mg/m2(No Premedication)+Gemcitabine 1000 mg/m2Weekly, 3 of 4 WeeksGemcitabine 1000 mg/m2Weekly, 7 of 8 Weeks (Cycle 1) thenWeekly, 3 of 4 Weeks (Cycle 2 Onward)

(1:1)N = 842

IMPACT - Study DesignRANDOMIZEnab-Paclitaxel 125 mg/m2(No Premedication)+Gemcitabine 1000 mg/m2Weekly, 3 of 4 WeeksGemcitabine 1000 mg/m2Weekly, 7 of 8 Weeks (Cycle 1) thenWeekly, 3 of 4 Weeks (Cycle 2 Onward)

(1:1)N = 842 Intent-To-Treat (ITT) Stage IV No prior tx PS > 70% Measureable Dz

Nab-paclitaxel/GEM vs. FOLFIRINOX:

nab-pacli + GEM FOLFIRINOX Median OS, mos8.711.1Median PFS, mos5.56.4One year Survival 35%48%ORR (%)23.031.6 n=430171 Geography3 ContinentsFrance

TOLERABILITY:SELECTED GRADE 3+ TOXICITIES (%)nab-pacli + GEMFOLFIRINOXFatigue1724Diarrhea613Neuropathy179Neutropenia3846Neutropenic fever35Thrombocytopenia139

FOLFIRINOX vs Gem-nab-paclitaxel

Similarities in populationMedian ageGender100% stage IVSite of primary

Differences in populationMPACT allowed PS 2 (KPS 70%) patients though 75 allowed on MPACT though only 5%Median # of sites of mets 3 in MPACT2 in FOLFIRINOX

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Differences in efficacyOS for FOLFIRINOX was 11.1 months vs 8.7 months for gemcitabine + nab-paclitaxelHR was 0.57 was for FOLFIRINOX vs 0.72 for gem-nab-paclitaxelHowever control arm was the same gemcitabine for both (FOLFIRINOX 6.8 months and Gem-nab-paclitxel 6.7 monhts)Response RateReally similar:29% for gem-nab-paclitaxel vs 31.6 % for FOLFIRINOX

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NCCN guidelines 2015: Principles of chemotherapyMetastatic diseaseAcceptable monotherapy:Gemcitabine (category 1)Capecitabine (category 2B)Acceptable combination therapies for patients with a good PS:Gemcitabine + erlotinib (category 1, survival benefit is small)FOLFIRINOX (category 1)Gemcitabine + capecitabineGemcitabine + cisplatin (especially for patients with hereditary cancers) (category 2A)Gemcitabine + nab paclitaxel ( category 1)Fluoropyrimidine + oxaliplatin (category 2B)Category 1: The recommendation is based on high-level evidence (e.g. randomized controlled trials) and there is uniform NCCN consensus.Category 2A: The recommendation is based on lower-level evidence and there is uniform NCCN consensus.Category 2B: The recommendation is based on lower-level evidence and there is non uniform NCCN consensus (but no major disagreement).Category 3: The recommendation is based on any level of evidence but reflects major disagreement.

Where Do We Stand Now? Gemcitabine is no longer the standard treatment for frontline pancreatic cancer

Options for therapy in the frontline setting:Good performance status/ normal organ function: FOLFIRINOX

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