Peri-operative FOLFOX4 chemotherapy Peri-operative FOLFOX4 chemotherapy and surgery for resectable liver and surgery for resectable liver

metastases from colorectal cancer metastases from colorectal cancer

Final efficacy results of the EORTC Final efficacy results of the EORTC Intergroup phase III study 40983.Intergroup phase III study 40983.

B. Nordlinger, H. Sorbye, B. Glimelius, G.J. Poston, P.M. Schlag, P. Rougier, W.O. Bechstein, J. Primrose, E.T. Walpole, T. Gruenberger

Statistical analysis L. Collette

For the EORTC GI Group, CR UK, ALMCAO, AGITG and For the EORTC GI Group, CR UK, ALMCAO, AGITG and FFCDFFCD

ALMCAO AGITG

g

Aim of this study

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

Study design

Randomize

SurgeryFOLFOX4 FOLFOX4

Surgery

6 cycles

(3 months)

N=364 patients

6 cycles

(3 months)

Rationale for FOLFOX4

FOLFOX4 demonstrated a response rate above 50%, and improved PFS in metastatic colorectal cancer

De Gramont et al.JCO 2000

Rationale for timing of chemotherapy

Preoperative : tumor response to chemotherapy allows to resect smaller metastases and to test their chemoresponsivness

Postoperative: dormant cancer cells are present in remnant liver; chemotherapy is beneficial for stage III colon cancer (André et al.,NEJM 2004)

Pragmatic approach: the design is not meant to validate the value of post vs pre-operative chemotherapy

Main eligibility criteria

Potentially resectable liver metastases of colorectal cancer (metachronous or synchronous)

Up to 4 deposits (on CT-scan, at randomization)

No extra-hepatic disease

No previous chemotherapy with oxaliplatin

WHO/EGOG 0-2

Informed consent

Objectives of the trial

Primary endpoint: demonstrate an improvement in progression-free survival with peri-operative FOLFOX4 compared to surgery alone

Secondary endpoints : overall survival, tumor resectability, tumor response, safety

Statistical hypothesis and sample size

Definition of progression Recurrent or progressive disease Metastases not resectable at surgery Death of any cause if prior to progression

Objective: to demonstrate a 40% increase in median PFS (HR=0.71) with 80% power and 2-sided significance level 5%

Sample size: 330 patients (for 278 events)

364 patients (182 x 2) recruited from September ‘00 to July ‘04

Patient population (N=364)

Peri-op CT(N=182)

Surgery(N=182)

Median age (range) 62 (29-79)

64 (25-78)

Males 69.8% 62.6%

1-3 liver mets on CT-scan 93.4% 91.2%<2 years between diagnosis of primary and liver metastases

73.1% 76.4%

T1-2T3-4Tx

17.0%83.0%

-

15.4%82.4%2.2%

N0N1N2NX

44.5%37.9%17.0%0.5%

39.6%36.8%20.3%3.3%

Compliance to pre-op chemotherapy

Randomized to CT

(N=182)

N (%)

# cycles

0 11 (6.0)

<=3 15 (8.2)

4 7 (3.8)

5 6 (3.3)

6 143 (78.6)

Median 6

ReceivedCT

(N=171)

N (%)

1 dose reduction 58 (33.9)

1 delayed cycle 75 (43.9)

Median (range)

RDI 5-FU 92.3% (50-111)

RDI Folinic Acid 93.5%(50-200)

RDI Oxaliplatin 92.1%(54-106)

Tolerance to pre-operative CT (Gr 3-4 toxicities )

N (%)

Allergy Gr 3* 1 ( 0.6)

Diarrhea Gr 3* 14 ( 8.2)

Nausea Gr 3* 6 ( 3.5)

Vomiting Gr 3/4 5 (2.9)

Stomatitis/pharyngitis Gr 3* 3 ( 1.8)

Sensory neuropathy Gr 3*

4 ( 2.3)

CholinergicSyndrome Gr 3*

1 ( 0.6)

Dysesthesia Gr 3*

4 ( 2.3)

N (%)

Hepatic Gr 3* 5 (2.9)

Cardio Vascular Gr 3*

4 ( 2.3)

Febrile Neutropenia Gr 4

1 ( 0.6)

Infection w/o Neutropenia Gr 3*

5 ( 2.9)

Leukopenia Gr ¾

10 (5.9)

Neutropenia Gr ¾

31(18.1)

Thrombocytopenia Gr 3*

2 (1.1)

Hemoglobin Gr 3*

1 (0.6)

*No grade 4;

No toxic death during preop CT;

One patient not resected due to liver damage probably due to CT

Size of lesions after pre-operative CT*

Before preop CT (median) : 45 mm (5-255)

After preop CT (median) : 30 mm (0-230)

Relative change : - 29.5 %

* SUM of the largest diameters

Complete response: 7 ( 3.8%)

Partial response: 73 (40.1%)

Stable disease: 64 (35.2%)

Progressive disease: 12 ( 6.6%)8 progressed after 3-4 cycles, 3 were resected 4 progressed after 6 cycles, 1 was resected

Not evaluable 26 (14.3%)Ineligible 7Benign lesion 3<3 cycles 12 No follow-up measures 4

RECIST Response after pre-operative CT

Total: 182 pts

Surgery

Peri-op CT(N=182)

Surgery(N=182)

Operated 159 (87.4)

170 (93.4)

Resected 151 (83.0)

152 (83.5)

Not resected 8 ( 4.3) 18 ( 9.9)

Not operated more advanced disease refusal poor condition/death other reason

22 (12.1)

10 4 3 5

8 (4.4) 7 0 0 1

Unknown 1 (0.5) 4 (2.2)

Median time to surgery 16.5 w 2 w

Complications of surgery

Peri-op CT Surgery

Post-operative complications*

40 /159 (25.2%)

27 / 170 (15.9%)

Cardio-pulmonary failure 3 2

Bleeding 3 3

Biliary Fistula 12 5

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

Hepatic Failure 11 8

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

Wound infection 4 4

Intra-abdominal infection 8 2

Need for reoperation 5 3

Other 25

16

Incl. post-operative death 1 patient 2 patients

*P=0.04

Compliance to post-op chemotherapy

Randomized to CT

(N=182)

N (%)

No CT 67 (36.8)*

Post op CT 115 (63.2)

# cycles

<=3 22 (12.1)

4 5 ( 2.7)

5 8 ( 4.4)

6 80 (43.9)

Received CT (N=115)

N (%)

1 dose reduction 69 (60.0)

1 delayed cycle 73 (63.5)

Median (range)

RDI 5-FU 82.0% (36.9-112.2)

RDI Folinic Acid 86.0%(59.6-104.9)

RDI Oxaliplatin 79.1%(0.0-106.5)

* No postop protocol CT : No protocol CT at all (11), Not operated or not resected (22), refusal (9), complications (14; including 2 gr 3 neurotoxicity), progression (5), other (6)

Tolerance to post-operative CT (Gr 3-4 Toxicities )

N (%)

Allergy Gr 3/4 5 (4.4)

Diarrhea Gr 3* 6 (5.2)

Nausea Gr 3* 5 (4.3)

Vomiting Gr 3* 3 (2.6)

Hand-Foot Syndrom Gr 3* 1 (0.9)

Sensory neuropathy Gr 3*

11(9.6)

CholinergicSyndrome Gr 3*

1 (0.9)

Dysesthesia Gr 3*

5 (4.3)

N (%)

Hepatic Gr3* 6 (5.2)

Cardio Vascular Gr 3*

1 (0.9)

Febrile Neutropenia Gr 3*

4 (3.5)

Infection w/o Neutropenia Gr 3*

2 (1.7)

Catheter-related infection Gr 3* 5 (4.3)

Leucopenia Gr 3/4

14(12.2)

Neutropenia Gr 3/4

40(34.8)

Thrombocytopenia Gr 3*

8 (7.0)

Hemoglobin Gr 3*

1 (0.9)

* No grade 4

N=115

Interim analysis – Early release of results

December 2006 235/ 278 PFS events IDMC reviewed the data and authorized the present

release of the results

At the cut off date of March 2007 median follow-up of 48 months 254/278 PFS events Final analysis performed 2-sided p= 0.0434 significance level

Patient FlowPatient flow

Informed consent

Randomized: 364

Pre&Postop CT182

Surgery 182

Ineligible11 11

Started pre-op CT 171

Resected 152

Resected 151

Started post-op CT 115

Resectable on imaging

Resectable at surgery

Results

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

Results

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

Results

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

Progression-free survival in eligible patients

HR= 0.77; CI: 0.60-1.00, p=0.041

Periop CT

28.1%

36.2%

+8.1%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 :125 171 83 57 37 22 8

115 171 115 74 43 21 5

Surgery only

Progression-free survival in resected patients

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

Conclusions

Peri-operative chemotherapy with FOLFOX4 improved PFS in patients with resectable liver metastases, and even more in patients whose metastases were actually resected, and was safe.

This treatment should be proposed as the new standard for these patients, and should be delivered by a multidisciplinary team.

Perspectives

Progress in imaging with spiral CT, MRI, contrast US, PET scans … reduces the rate of patients deemed non resectable at surgery

Timing and duration of chemotherapy may be optimized

Combination with new agents will be tested

FOLFOX6 modified

+ cetuximab

6 cycles

RA

ND

OM

IZA

TIO

N

ResectableLiver

Metastases from

Colorectal Cancer

no extrahepatic

disease

WHO PS 0,1

No previous chemo for

mets

FOLFOX6 modified

+ cetuximab+ bevacizumab

6 cycles(no

bevacizumab in cycle #6)

FOLFOX6 modified

+ cetuximab

6 cycles

FOLFOX6 modified

+ cetuximab

+ bevacizumab

6 cycles

follow up

follow up

SU

RG

ER

YS

UR

GE

RY

Trial 40051 (BOS)

Acknowledgments

Patients and Participating Centers

EORTC Data Center:, M. Praet, M.A.Lentz, M.Debois, U.Bethe, P.Therasse

Sanofi-Aventis: I.Tabah-Fisch, T.Pearce

Austria 49

Belgium 19

France 60

Germany 67

UK 76

Italy 1

Norway 24Sweden 24

Netherlands 5 Australia: 35

Hong Kong: 6

EORTC GI Group, CR UK, ALMCAO, AGITG and FFCDEORTC GI Group, CR UK, ALMCAO, AGITG and FFCD

Other Participating investigators

Finch-Jones - Jaeck - Mirza - Parks - Hugh - Hohenberger - Karner - De Greve - Chan - Davidson - Iesalnieks / Jauch - Lindner - Parnis - Peeters - Diamond - Ducreux - Graeven - Paillot - Doran - Gouillat - Jagot-Lacoussiere - Jansen - Konopke / Koehne - Otto - Sherlock - Van Hazel - Ackland - Bedenne - Bories - Clavero-Fabri - Conroy - Husseini - Karapetis - Mueller - Price - Rosenberg - Schott - Tschmelitsch - Van Laethem - Wals - Weimann - Arnaud - Arsene - Auby - Bhattacharya - Cebon - Cherqui - Confente - Dousset - Frickhofen - Frilling - Ganju - Hoeffken - Lazorthes - Letoublon - Nitti - Orr - Pariente - Pector - Raoul - Rees - Ridwelski - Rouanet - Toogood – Van Cutsem - Vergauwe - Wilke - Madroszyk

Matthias Lorenz