advances in panceratic cancer management christophe louvet hôpital saint-antoine paris, france....

Advances in panceratic cancer Advances in panceratic cancer

management management

Christophe LouvetHôpital Saint-Antoine

Paris, France.

Beyrouth, 14/11/08

Landscape of Pancreatic Cancer

• More than 210 000 new cases per year around the world (2000)

• 2.1% of all cancers• 10% of GI cancers• + 1.7% / yr (men) ; + 2.1% / yr (women)

• 6th cause of cancer-related death• Pancreatic cancer mortality almost equal to incidence• 5-yr overall survival : 4%

Landscape of Pancreatic Cancer

• p53 mutation (70%)• K-ras mutation (90%)• p16 mutation (80%)

• EGF-r overexpression (> 60%)• VEGF overexpression• Loss of somatostatin antiproliferative effect (loss of

SSTR2 receptor)

Pancreatic mass : sometimes different from pancreatic tumor

Pancreatic tumor : sometimes different from pancreatic adenocarcinoma

Definitive need for a pathological diagnosis

Pancreatic cancer: current treatment options

• Symptomatic treatment: – pain– jaundice

• Resectable (stage I-II, 10 – 20%) : surgery followed by chemotherapy (chemoradiation ?)

• Locally-advanced disease (stage III-IVA, 40%): chemoradiation ? chemotherapy ?

• Metastatic disease (stage IVB, 40 – 50%):chemotherapy (gemcitabine)

Aims of the initial work-up

1- diagnosis

- if accessible met, biopsy of met

- if no met US endoscopyCT-scan guided biopsylaparoscopy / laparotomyresection


2- guide for treatment strategy

Resectable disease

Surgery

Resection of disease

Adjuvant treatment ?

No resection

Go to LA

MDA criteria

“ Potentially resectable disease:

1) no extrapancreatic disease,

2) a patent SMV-PV confluence (assuming the technical ability to resect and reconstruct this venous confluence), and

3) a definable tissue plane between the tumor and regional arterial structures including the celiac axis, common hepatic artery and SMA. “

MDA criteria

N median survival p (months)

GITSG, Arch Surg 1985

- Surgery 21 11 - RT (20 Gy x 2) + 5 FU D1-D3 < 0,02 then 5 FU weekly / 2 yrs 22 20

EORTC, Ann Surg 1999

- Surgery 54 12,6 0,09 NS

- RT (20 Gy x 2) + 5 FU PC 60 17,1

Adjuvant CTRT phase III studies

ESPAC 1

99008800770066005500440033002200110000

0 12 84

110000

24 36 48 60 72

p<0.001

CONKO-001:

DFS99008800770066005500440033002200110000

0 12 84

110000

24 36 48 60 72

OS

p = 0.06

Surgery vs surgery followed by gemcitabine

Ongoing Adjuvant Trials in Resected Pancreatic Cancer

Trial Target N Treatment Arms Primary Endpoint

ESPAC-3 (Phase III)

990 5-FU-LV vs

Gemcitabine

2-y OS

EORTC 40013-22012 (Phase II-III)

538 Gemcitabine vs Gemcitabine → Gem + RT

Phase III: DFS/OS


2- guide for treatment strategy

Locally-advanced disease« No met, no resection »

« never resectable » « border-line resectable »

Chemotherapy ?Chemoradiation ?

Chemotherapy ?Chemoradiation ?

Secondary surgery ?

Treatment of metastatic pancreatic cancerChemotherapy or BSC ?

Study Regimen npatients

Med. Surv.(mo)

Qol

Mallinson1980

5-FU+Mtx+Vcr+ cyclo + MMCBSC

21

19

10.5

2.2*Frey1981

5-FU + CCNUBSC

6587

3.03.9

Andersen1981

5-FU + BCNUBSC

2020

3.23.4

Palmer1994

FAMBSC

2320

8.23.8*

Glimelius1996

5-FU + LV +EtoposideBSC

29

24

6.0

2.5*

benefitin chemogroup

* p < 0.05

Treatment of metastatic pancreatic cancerThe Burris Study

R

Gemcitabine

5-Fluorouracil

1000 mg/m2 30 min infusion

Weekly for 7 w , 1 w rest, then 3w /4w

600 mg/m2 30 min infusion

weekly

Primary Objective :

Clinical Benefit

n=129

Treatment of metastatic pancreatic cancer

The Burris Study

• Clinical Benefit– PS improvement (>20% in Karnofsky index)– and / or Pain decrease (> 20%)– and / or Antalgics consumption decrease (> 50%)– and / or Weight increase (> 7%)

– For at least 1 month


Clinical Benefit

Gemcitabine 23.8% p = 0.0022

5-Fluorouracil 4.8%

Treatment


Gemcitabinen=63

5-Fluorouraciln=63

Median Survival 5.65 months * 4.41 months

6-months survival 46% 31%



* p = 0.0025

Burris H A, et al.: JCO 15: 2403, 1997

Gemcitabine: activation and mechanism of action

• Gemcitabine: a deoxycytidine analogue

• Requires intracellular uptake followed by sequential phosphorylation to active metabolite form

Gem Gem Gem-MP Gem-DP Gem-TP

• Blocks DNA synthesis/replication at several steps

incorporation into DNA*

deoxycytidine kinase

inhibition of RR

NT

Treatment of metastatic pancreatic cancer

• Gemcitabine 30’ infusion or 10 mg/m²/mn fixed dose rate ?

R

Gemcitabine1500 mg/m²10mg/m²/min

Gemcitabine2200mg/m²

30 minN=80

RR 16.6%PFS 3.4 monthsOS 8 months1-yr survival : 23%

RR 2.7%PFS 1.9 monthsOS 5 months1-yr survival : 0%

Tempero, JCO 2004

Randomized phases III in Pancreatic Cancer

Gem ± Marimasmat (Bramhall, 2002) 5.5 5.5

Gem ± Pemetrexed (Richards, 2004) 6.3 6.2Gem ± CPT-11 (Rocha-Lima, 2004) 6.6 6.3Gem ± Exatecan (O’Reilly, 2004) 6.2 6.7

Study OS gem (m) OS gem + drug X (m)

Gem vs Gem-Cap study (Cunningham)

Median survival 12-month (months, 95%CI) survival

GEM 6.0 (5.4, 7.1) 19%GEM-CAP 7.4 (6.5, 8.5) 26%

Hazard Ratio:0.80 (95% CI: 0.65, 0.98)Log rank p=0.026; χ2

LR=4.93





Gem ± 5FU bolus (Berlin, 2002) 5.4 6.7

Gem ± Capecitabine (Cunningham, 2005) 6.0 7.4

Gem ± Capecitabine (Herrmann, 2005) 7.3 8.4Gem ± 5FU/LV (Riess, 2005) 6.2 5.9

GEM-GEMOX Study : Overall survival

Gem Gemox

median 7.1 m 9.0 m

6-mth 60.4% 68.0%8-mth 45.3% 56.5%9-mth 40.0% 48.1%1-yr 27.8% 34.7%

Overall Survival

0 26 52 78 104 130 1560.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0GemGemox

weeks

% s

urv

ival

p

0.13

Louvet C, et al. J Clin Oncol, 2005

GEM FDR GEMOX

Gem : median = 4.9 monthsGemox : median = 5.9 monthsGem FDR : median = 6.0 months

Gem vs Gemox : NSGem vs Gem FDR : NS




Gem ± Cisplatin (Heinemann, 2003) 6.0 7.5Gem ± Oxaliplatin (Louvet, 2004) 7.1 9.0Gem vs Gem FDR vs Gemox (Poplin, 2006) 4.9 6.0 5.9





Nucleus

AntireceptorAntibodies± Toxins

TyrosineKinase

Inhibitors

FarnesylTransferase

Inhibitors

Hormone Agonists/Antagonists

ApoptosisAgonists

Antisense

Angiogenesis Inhibitors(Angiostatin, Endostatin

& Anti-VEGF)

MetalloproteinaseInhibitors

Matrix Degradation(Collagenases,Gelatinases &Stromelysins)

Immune SystemActivation (Vaccines,

Monoclonal antibodies)

Tumor CellGrowthFactorReceptors

IntracellularSignalingMolecules

Overview: Targeted Therapies

AntimetabolitesMicrotubule inhibitors

K-ras and farnesyltransferase inhibitors

No positive results in clinical trials

to date

GEMCITABINE ± ERLOTINIB Phase III Study

Overall Survival by Treatment Arm

0%

20%

40%

60%

80%

100%

0 12 24 36Months After Registration

GemcitabineGemcitabine and Cetuximab

N369366

Events338331

Medianin Months

66

P = 0.14

5.96.4

S0205: Primary EndpointS0205: Primary EndpointSurvival of All PatientsSurvival of All Patients

HR = 1.09 (95% CI: 0.93, 1.27)

CALGB 80303: Overall Survival by Treatment Arm

Bevacizumab 5.8 mo

Placebo 6.1 mo

HR = 1.03

P = 0.78

0 5 10 15 20 25

Months from Study Entry

0.0

0.2

0.4

0.6

0.8

1.0

Pro

po

rtio

n S

urv

ivin

g

BevacizumabPlacebo




Gem ± Cisplatin (Heinemann, 2003) 6.0 7.5Gem ± Oxaliplatin (Louvet, 2004) 7.1 9.0Gem vs Gem FDR vs Gemox (Poplin, 2006) 4.9 6.0 5.9





Gem ± Tifarbinib (Van Cutsem, 2004) 6.0 6.4Gem ± Erlotinib (Moore, 2005) 5.9 6.4Gem ± Bevacizumab (Kindler, 2007) 6.1 5.8Gem ± Cetiximab (Philip, 2007) 5.9 6.4

How to move on ?

1- Better knowledege on :

pancreatic cancer cellsrelationships between tumoral, endothelial and stromal cellspancreatic cancer patients

hopefully resulting in new drugs and new strategies

EGFR1IGFRIMC-A12CP-751CP-871 EGFR1

Ub

Ub

Ub

Ub

Ub

UbUb

Ub

UbUb

Cell cycle prog.Cellular adhesionProliferationAnti- apoptosis

Pro

teas

om

e

20S

19S

Bortezomib

NF?B

TNF-?IL6Bcl2

VEGFCyclin D1D2MYC

survival proliferation angiogenesis metastasis

antisense oligonucleotide

Grb2

MEK

ERK

PDK

p70S6K

STAT

STAT5

STAT5

STAT

STAT

SrcRasRasSOS

FTFTIFTISorafenib

c-Junc-mycc-Fos

FT

CetuximabPanitumumabEMD-72000Matuzumab

Raf

PI3K

AKt

mTOR

GefitinibErlotinibLapatinibCI-1033EKB-569AEE788 EXEL 7647BIBW2992

PIP2 PIP3

NF-B

PTEN

RapamycineTsemsirolimus/CCI-779Everolimus/RAD001AP23573

STAT3

elF

-4E

4E-B

P

4E-B

Pel

F-4

E

proliferationsurvival

pRb

p53

Abl

STAT STAT

MAP

K

Jak

p53

Gene transcription

R

G protein

PKC

GSK3β

CI-1040

Enzastaurin

How to move on ?




2- Optimize the available tools :

Definitively separate strategies and studies in metastatic and in locally-advanced pancreatic cancer patients

0.0

00.2

50.5

00.7

51.0

0

Surv

ival p

rob

ab

ilitie

s

0 3 6 9 12 15 18 21 24 27 30 33 36 39Time in Months

Gemcitabine CHRT

Overall Survival according to treatment arm

109 patients included, median f.u. : 16 months [1 – 60]

Median survival : CRT = 8 months vs gemcitabine = 14 months

1-year survival : CRT= 24 % vs gemcitabine = 51 %

First-intention CRT : FFCD-SFRO trialChauffert. ASCO 2006, # 4008

selection CT

CRT may increase survival

in patients with LA disease stable

after 3 months chemotherapy

compared to CT continuation

10.8 months vs 7,4 months (p = 0.005)

15 months vs 11,7 months (p = 0.0009)

Arm A1 :

Arm A2 :

Arm B1 :

Arm B2 : CRT

CRTE

VA

LU

AT

ION

: n

on

pro

gre

ssiv

e

EV

AL

UA

TIO

N :

no

n p

rog

ress

ive

3 perfusions of gemcitabine (1000 mg/m2)

Untilprogression

Erlotinib 100 mg/d when combined to Gem150 mg/d as single agent

capecitabine

irradiation

EV

AL

UA

TIO

N

EV

AL

UA

TIO

N

EV

AL

UA

TIO

N

Secondary surgery allowed in each arm at any time

R1 R2

Locally Advanced cancer of Pancreas study LAP 07

Conventional No Nodal RT

How to move on ?






Prophylactic anticoagulation ?

How to move on ?







Methods and endpoints

ENDPOINTS AND METHODS

Response rate : NO (particularly in LAPC)

Clinical Benefit : NO (not commonly used)

PFS : NO (no impact of 2nd line)

OS : YES





OS : YES

Phase II studies ???





OS : YES

Phase II studies ???

Meta-analysis ???


Study PFS/TTP(m) OS (m) N pts

Gem ± 5FU bolus (Berlin, 2002) 3.4 6.7 362

Gem ± Cisplatin (Heinemann, 2003) 5.3 7.5 190Gem ± Oxaliplatin (Louvet, 2004) 5.8 9.0 313

Gem ± Capecitabine (Herrmann, 2005) 4.8 8.4 319Gem ± 5FU/LV (Riess, 2005) 4.9 5.9 466

Gem ± Erlotinib (Moore, 2005) 3.7 6.4 530

Gem ± Capecitabine (Cunningham, 2005) NA 7.4 533

Gem ± 5FU/Capecitabine

Gem ± Platinum-analogs

Gem ± erlotinib

Need more than 500 pts to demonstrate survival advantage

Regimen nOR

(%)

PFS

(mo)

Survival

(mo)

GemOx vs Gem

GemPlat vs Gem

313

190

28* vs 16

12 vs 10

5.7* vs 3.7

5.3* vs 3.1

9.0 vs 7.1

7.5 vs 6.0

Gem + Capecitabine vs Gem

53314*

7 -

7.4*

6.0

Gem + Erlotinib vs Gem

5308

8.6

3.75*

3.55

6.4*

5.9

Gemcitabine-based Combinationsevidence from randomised trials

*significant

Regimen nOR

(%)

PFS

(mo)

Survival

(mo)

Gem + Platinum-Analog vs Gem

50322*

14

5.5*

3.45

8.3*

6.7*


53314

7 -

7.4*

6.0


5308

8.6

3.75*

3.55

6.4*

5.9


*significant

Regimen nSurvival

(mo)HR p

Gem + Platinum-Analog vs Gem

5038.3*

6.7* 0.77 0.031*


5337.4*

6.0 0.80 0.026


5306.4*

5.9 0.81 0.034


*significant

How to move on ?








Gemcitabine-free regimens ?

Phase II trial of irinotecan/docetaxel for advanced pancreatic cancer with randomization between

irinotecan/docetaxel and irinotecan/docetaxel plus C225, a monoclonal antibody to the epidermal growth factor

receptor (EGF-r) : an Eastern Cooperative Oncology Group

Study (E8200)

B. A. Burtness, M. Powell, J. Berlin, D. Liles, A. Chapman, E. Mitchell, A. B. Benson, Eastern Cooperative Oncology Group

Fox Chase Cancer Center, Philadelphia; Dana-Farber Cancer Institute, Boston; Vanderbilt University, Nashville; East Carolina University School of Medicine , Greenville; Thomas

Jefferson University, Philadelphia; Northwestern University, Chicago

#4519

Treatment Arm ALIVEDEAD MEDIANTOTAL

A 43 37 6 6.5B 43 40 3 5.3

Sur

viva

l Pro

babi

lity

Overall Survival by Treatment Arm - E8200

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Overall Survival Time in Months

0 5 10 15 20 25 30 35

RANDOMIZED PHASE II TRIAL COMPARING FOLFIRINOX (5FU/LEUCOVORIN, IRINOTECAN

AND OXALIPLATIN) VS GEMCITABINEAS FIRST-LINE TREATMENT FOR METASTATIC PANCREATIC

ADENOCARCINOMA

FIRST RESULTS OF THE ACCORD 11/0402 TRIAL M. Ychou1, F. Desseigne2, R. Guimbaud3, M. Ducreux4, O. Bouché5,

Y. Bécouarn6, A. Adenis7, C. Montoto-Grillot8, E. Luporsi9, T. Conroy9

1. Centre Val d'Aurelle, Montpellier 2. Centre Léon Bérard, Lyon

3. Institut Claudius Regaud, Toulouse 4. Institut Gustave Roussy, Villejuif

5. Centre Hospitalier R. Debré, Reims 6. Institut Bergonié, Bordeaux

7. Centre Oscar Lambret, Lille 8. FNCLCC, Paris

9. Centre Alexis Vautrin, Nancy, FRANCE

#4516

Results – Efficacy

FOLFIRINOX (A)n = 44

Gemcitabine (B)n = 44

Complete Response (CR) 0 0

Partial Response (PR)[ 95 % IC ]

14 (31.8 %)[18.6-47.6 %]

5 (11.4 %) [3.8-24.6 %]

Stable Disease (SD)

Progressive Disease (PD)

Non Evaluable (NE)**

* Panel confirmed 15 PR in arm A and 2 in arm B** 2 non treated and 4 ineligible

12 (27.3 %)

15 (34.1 %)

3 (6.8 %)

9 (20.4 %)

27 (61.4 %)

3 (6.8 %)

Investigators Response Rate* (ITT Population)

How to move on ?


pancreatic cancer cellsrelationship between tumoral, endothelial and stroma cellspancreatic cancer patients






Gemcitabine-free regimens ?

Genomics and proteomics for individualized strategies ?

ASCO 07, June 3rd.

K-ras mutation and EGF-r expression(Moore and coll, # 4521)

Samples from 117 pts (out of the 569 included in the PA3 study)

Only « trends » on survival, since sample size limits the conclusions.

K-ras mutant (79% of pts) better than K-ras WT unexpected

Among K-ras mutant : gem > or = to gem + T expected

Fish neg (53% of pts) better than Fish pos expected

Among Fish pos, gem + T = gem unexpected

#4521

Among K-ras WT: gem + T > or = to gem expected

Among Fish neg, gem + T > gem unexpected

Pancreatic cancer: new management• Symptomatic treatment:

– pain– jaundice

• Resectable (R0 resection) : surgery followed by chemotherapy (± biotherapy) (± chemoradiation) neoadjuvant treatment ?

• Resectable (R1 resection) :surgery followed by chemotherapy (± biotherapy) followed by chemoradiationneoadjuvant treatment ?

• Locally-advanced disease : chemotherapy (± biotherapy) followed by chemoradiationsecondary resection ?

• Metastatic disease :chemotherapy (doublets ?) (± biotherapy ?)investigational new drugs ; gemcitabine-free regimens ? ; tailored choice of treatment according to molecular issues ?

advances in panceratic cancer management christophe louvet hôpital saint-antoine paris, france....

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