Bernard NORDLINGER M.D.

Hôpital Ambroise Paré – BoulogneAssistance Publique Hôpitaux de Paris

Treatment should start with Treatment should start with Chemotherapy before Surgery: Chemotherapy before Surgery:

Answer no 3 Answer no 3

Case no 1

56-year old male had

resection of a T3N0M0

sigmoid colon cancer CT scan 12 months :

4 cm metachronous solitary

metastasis in left liver

Metastasis is resectable with adequat margin

Survival after surgery of CR liver metastases

22%35%25%25%33%39%25%26%32%37%38% 34%58%41%58%

5%0%5%3%-

5%4%2%0%

2.8%0%

0.8%-

1%-

2596080

141859219280

1818204

1001235257133615190

198119861987198719881991199219921994199920002002200220032004

Foster Iwatsuki Nordlinger Adson Hughes Scheele Rosen Nordlinger - Jaeck Gayowski Fong Minigawa Ercolani Choti Adam Abdalla

5yr SurvivalOp. Mort.PatientsYearAuthors

This patient has a « good risk » metastasis

Fong et al, Ann Surg 1999

With surgery only

- Cancer relapses in 2/3 of patients Nordlinger et al Cancer 1994

- Life expectancy

Treatment options

Surgery first +/- post-operative chemotherapy

Chemotherapy before surgery

Postoperative chemotherapy after resection of liver metastasis?

Very few trials available

Hepatic arterial infusion (M. Lorenz 1998, N. Kemeny 1999, M. Kemeny 2002)

Systemic chemotherapy (Langer 2002, Portier 2006)

Most studies are underpowered ,show a trend toward a survival benefit of 5 FU based chemotherapy, combined with surgery

Post-operative chemotherapy

Meta-analysis of the two 5FU studies

Time (months)

0 20 40 60 80

Su

rviv

al

0,0

0,2

0,4

0,6

0,8

1,0

Adjuvant chemotherapySurgery alone

DFS P=0,058

Mitry, JCO 2008

In multivariable analysis, adjuvant chemotherapy was independently associated with both progression-free survival and overall survival.

CPT-GMA 301 Phase III study

R0 resection of liver metastases

5-FU / FA (6 months)

FOLFIRI (6 months)

R

Adjuvant chemotherapy with more active regimen than 5FU only

Ychou et al.ASCO 2008

N=324,

1-year DFS: 63% vs. 77%2-year DFS: 46% vs. 51%

Disease-Free Survival

0.00

0.25

0.50

0.75

1.00

Pro

bab

ility

153 114 70 41 22LV5FUs+IRI153 95 65 44 25LV5FUs

Number at risk

0 12 24 36 48Months

LV5FUs LV5FUs+IRI

adjusted Logrank p=0.43

HR=0.89: 95%CI [0.66-1.19]Treatment

Post-operative chemotherapy

No sufficient data to be the standard of care at the moment

We need clear results from future trials

30 to 40% of patients do not, or can not receive chemotherapy within a few weeks after surgery

Nordlinger et al. Lancet 2008

Perioperative chemotherapy(before and after)

EORTC 40983: Peri-operative chemotherapy

RandomiZed

SurgeryFOLFOX4 FOLFOX4

Surgery

6 cycles

(3 months)

N=364 patients

6 cycles

(3 months)

With CR UK, ALM CAO, AGITG, FFCD

Aim of this study

To demonstrate that chemotherapy combined with surgery is a better treatment than surgery alone,

but not to compare pre vs post-operative chemotherapy

Size of lesions after pre-operative chemotherapy *

Before 50 mm (20-255)

After 33 mm (0-230)

Relative reduction - 25.6 %

* SUM of the largest diameters

Case no 1

- 4 cm metachronous solitary

metastasis in left liver

- Easily resectable with

adequat margin

Progression-free survival in resected patients Nordlinger et al. Lancet 2008

HR= 0.73; CI: 0.55-0.97, p=0.025

Surgery only

Periop CT

33.2%

42.4%

+9.2%At 3 years

(years)

0 1 2 3 4 5 6

0

10

20

30

40

50

60

70

80

90

100

O N Number of patients at risk :104 152 85 59 39 24 10

93 151 118 76 45 23 6

Results Nordlinger et al. Lancet 2008

N ptsCT

N pts Surgery

% absolute difference

in 3-year PFS

HazardRatio

(Confidence Interval)

P-value

All patients 182 182 +7.2% (28.1% to 35.4%)

0.79(0.62-1.02)

P=0.058

All eligiblePatients

171 171 +8.1% (28.1% to 36.2%)

0.77 (0.60-1.00)

P=0.041

All resectedPatients

151 152 +9.2% (33.2% to 42.4%)

0.73(0.55-0.97)

P=0.025

EORTC 40983: progression free survival, all patients: update May25, 2009

Progression-free survival

TreatmentPatients

(N)

ObservedEvents

(O)

Hazard Ratio

(95% CI)

P-Value(Log-Rank)

Median(95% CI)(Months)

% at 3 Year(s)(95% CI)

Surgery

182 134 1.00

0.0473

11.73 (9.63, 18.23)

29.58 (22.96, 36.48)

Pre&Postop CT

182 126 0.79 (0.62, 1.01)

18.66 (15.41, 25.76)

36.37 (29.34, 43.42)

EORTC 40983: progression free survival, all patients: update May25, 2009

(years)

0 1 2 3 4 5 6 7 8

0

10

20

30

40

50

60

70

80

90

100

O N Number of patients at risk : Treatment134 182 86 62 47 34 21 9 4

126 182 118 78 59 47 28 13 4

Surgery

Pre&Postop CT

Progression-free survival

26 May 2009 11:25

Overall Logrank test: p=0.047

EORTC 40983: PFS irrespective of resection (usual definition), all patients, update May25, 2009

Progression free survival / irrespective of resection

TreatmentPatients

(N)

Observed

Events(O)

Hazard Ratio

(95% CI)

P-Value(Log-Rank)

Median (95% CI)(Months)

% at 3 Year(s)(95% CI)

Surgery

182 133 1.00

0.0259 14.32 (11.04, 18.76)

30.07 (23.41, 36.99)

Pre&Postop CT

182 123 0.76 (0.59,

0.97)

20.11 (16.46, 28.94)

38.50 (31.31, 45.63)

EORTC 40983: PFS irrespective of resection (usual definition), all patients, update May25, 2009

(years)

0 1 2 3 4 5 6 7 8

0

10

20

30

40

50

60

70

80

90

100

O N Number of patients at risk : Treatment133 182 92 63 48 35 22 9 4

123 182 123 81 62 49 29 14 4

Surgery

Pre&Postop CT

Time to first prog/irrespective of resection

26 May 2009 11:25

Overall Logrank test: p=0.026

EORTC 40983

Peri-operative chemotherapy with FOLFOX4 reduces the risk of relapse of cancer after surgery by one quarter.

Potential negative impacts

Risk that metastases progress during chemotherapy

Liver damage induced by chemotherapy

Progressive disease 12/182 pts (7%) 4 were resected 8 were not resected

4: appearance of new lesions: preoperative chemotherapy permitted to avoid unnecessary surgery

4: progression of known metastases (2%)…

Risk of progression during pre-operative chemotherapy: EORTC 40983

Outcome after resection when metastases

progress during chemotherapy

30%37%

Stabilization: 39

Progression: 34

Downstaging: 58

Log–rank: p<0.000120

40

60

80

100

0 1 2 3 4 5

63%

12%8%

44%

95%

55%

Years

92%

Updated from: Adam R, et al. Ann Surg 2004;240:644–658

Su

rviv

al (

%)

Survival according to response to neoadjuvant CT (multiple metastases)

Risk of progression during pre-operative CT

Risk is low ( total: 7%; known metastases: 2%)

It is better to know before surgery because this is a biological marker for poor prognosis

Indication for second line chemotherapy,

Before surgery

Evaluate every 3 cycles

Risk of liver damage induced by chemotherapy

The type of liver injury depends on the drug administered

Vascular lesions : Oxaliplatin

(Rubbia-Brandt et al, 2004)

Steatosis : 5FU, Irinotecan ?

(Parikh et al, 2003)

Steatohepatitis : Irinotecan

(Vauthey et al, 2006)

Clinical significance: impact on surgery

•Karoui Nordlinger et al, Ann.Surg. 2006

0

10

20

30

40

50

60

70

Mor

bidi

ty

No CT =<5 cycles 6-9 cycles =>10 cycles

•Aloia Adam et al, Ann.Surg. 2006 : Morbidity increased after 12 cycles •Nakano Jaeck et al, Ann.Surg. 2008 : Morbidity increased after 6 cycles

Mortality rate not increased

Morbidity rate related to the number of cycles of CT

EORTC 40983 : complications of surgery

Peri-op CT Surgery

Reversible complications (pts) *

40 /159 (25%)

27 / 170 (16%)

Cardio-pulmonary failure 3 2

Bleeding 3 3

Biliary Fistula 13 7

(Incl Output > 100ml/d, >10d) (9) (2)

Hepatic Failure 11 8

(Incl. Bilirubin>10mg/dl, >3d) (10) (5)

Wound infection 5 4

Intra-abdominal infection 11 4

Need for reoperation 5 3

Other (lung, urinary, ascites, etc…) 20

10

Post-operative deaths 1 patient 2 patients

*P=0.04 Nordlinger et al., Lancet 2008

Liver damage

• Damage induced to liver by neoadjuvant chemotherapy is limited and has few clinical consequences if patients are not overtreated

• Damage induced to tumor has a major impact on survival

Complete pathological response after preoperative chemotherapy

Tumor is replaced by fibrosis

Impact of pathological response after chemotherapy on survival

Complete response : 29/738 (4%)Adam et al, JCO 2008

Complete response : 25/271 (9%)Blazer et al, JCO 2008

75%

56%

33%

Preoperative treatment of GI cancers in general: the present and the future

- Benefits outweigh potential disadvantages

- Has become the standard of care for most patients with cancers of the rectum

- Prolongs survival in patients with stomach cancer Cunningham,NEJM,2006.

- Reduces the risk of relapse after resection of colorectal cancer liver metastases.

The patient

Received FOLFOX4 6 cycles before surgery and 6 cycles after surgery

Post-operative course was uneventful

Pathologic examination showed:

- major response : 15% residual cancer cells

- large part of tumor was replaced by major fibrosis reflecting the effect of chemotherapy

Future trials can go two ways

1- Simplify treatment: make it easier for patients - Compare preop CT to postop CT

- Reduce the number of cycles of CT given before surgery

2- Intensify treatment to further reduce the risk of relapse of cancer

- Combine cytotoxics and targeted agents - Combine several cytotoxics

-

Perspectives

FOLFOX + EGFR blocker

R

ResectableLiver

Metastases from CRC n < 10

KRAS WT

+/-Lung Mets

< 2

FOLFOX+ VEGF inhibitor

FOLFOX

+ EGFR blocker

FOLFOX

+ VEGF inhibitor

follow up

follow up

SU

RG

ER

YS

UR

GE

RY

EORTC 40091:BOS2 (Biologics,Oxaliplatin,Surgery)

Previously untreated patients with resectable mCRC KRAS WT

2 weeks preoperative

12 weeks postoperative

CRUK phase III study: CRC liver metastases:

Randomized

(expected n=340)

Oxaliplatin +

fluoropyrimidine

Oxaliplatin +

fluoropyrimidine

+ CetuximabPFS