Bernard NORDLINGER M.D.

Hôpital Ambroise Paré – BoulogneAssistance Publique Hôpitaux de Paris

The multimodal treatment of liver metastases:

FREQUENTLY ASKED QUESTIONS

Questions

What is resectable?Chemotherapy before or after resection?Indications for immediate surgery?How to manage metastases which disappear from imaging?Does neoadjuvant chemotherapy increase the risks of surgery?Targeted agents before surgery for liver metastases ? Should all patients with liver metastases be considered for resection?

What is a resectable metastasis?

Question

A resectable metastasis: a principle

Complete resection of tumor is feasible Free resection clearance: R0 Preservation of hepatic vein(s) and portal pedicle to remnant

liver Remnant liver parenchyma 25 % Resectability does not depend on the number of metastases

Resectable metastases

Categories: - Easily resectable

- More difficult to resect; need for specific skills

- Resectable + RFA

- Potentially resectable after response to chemotherapy

- Unresectable and unlikely to ever be resected Do not deny the potential benefit of major liver resection; if local surgeon does not have the expertise,refer to an expert institution

Bilobar disease right lobectomy + RFA

Complete local treatment with resection and radio frequency ablation

Message:

Discuss all cases in multidisciplinary meetings

Question:

Chemotherapy combined with surgery for resectable metastases: before or after?

Aim and designDemonstrate that chemotherapy combined with surgery is a better

treatment than surgery alone

Randomize

SurgeryFOLFOX4

Surgery

6 cycles (3months)

N=364 patients

6 cycles(3 months)

FOLFOX4

Main Eligibility criteria• Potentially resectable liver

metastases of colorectal cancer• Up to 4 deposits (on CT-scan, at

randomization)

(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 : Treatment125 171 83 57 37 22 8115 171 115 74 43 21 5

SurgeryPre&Postop CT

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

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

LV5FU + Oxaliplatin Periop CT

28.1%

36.2%

+8.1%At 3 years

Surgery only

(years)

0 2 4 6 8 10 12

0

10

20

30

40

50

60

70

80

90

100

O N Number of patients at risk : Treatment109 171 133 91 69 35 4101 171 139 103 70 44 5

SurgeryPre&Postop CT

Overall survival in eligible patientsNordlinger et al. ASCO 2012

HR= 0.87; CI: 0.66 -1.14, p=0.303

LV5FU + Oxaliplatin Periop CT median OS: +8.7 months

5 years OS:+4.1 %

Surgery only

63.7M55M

52.4.%

48.3%

5

Message:

Peri-operative chemotherapy with FOLFOX considered the treatment of reference in patients with resectable metastases

Question:

• Are there indications for immediate surgery of resectable metastases?

Is this « good risk »case an indication for surgery only?

Metastasis is easily resectable with adequat margin

Risk of cancer relapse is

50%: surgery alone is not sufficient

Post-operative chemotherapypooled-analysis of two 5-FU studies

Months0 20 40 60 80

Surv

ival

Adjuvant chemotherapySurgery alone

0.0

0.2

0.4

0.6

0.8

1.0

Time (months)

0 20 40 60 80

Sur

viva

l

0,0

0,2

0,4

0,6

0,8

1,0

Adjuvant chemotherapySurgery alone

Mitry E, et al. J Clin Oncol 2008;26:4906-11.

p=0.058

Post-operative chemotherapy only?

- No sufficient evidence to be standard treatment at the moment

- 1/3 patients do not receive planned post-op treatment, although almost all can receive pre-op treatment ( EORTC study )

- No trials available comparing pre vs post- Post-operative chemotherapy is an option in patients who

did not receive peri-operative chemotherapy:

- Small and poorly located metastasis which may disappear after chemotherapy

- Small synchronous metastasis with indication to resect the primary

Question:

How to manage metastases which disappear from imaging during chemotherapy?

« Complete response » on imaging

Complete response does not mean cure in up to 80% of cases

It is preferable to resect liver metastases before complete response when surgeons can see them, and not overtreat patients with chemotherapy

1Benoist et al. JCO 20062Tan et al. J GastroIntest Surg 20073Adam et al. JCO 20084Elias et al. Ann Surg Oncol 2007

« Complete response » on imaging: looking for lost metastases

Try other imaging methods: - MRI - FDG Pet scan probably unhelpful ( Tan, J Gastrointest Surg 2007 Covas ASCO 2008) - Contrast Enhanced US

If they are no longer visible - resect the site

- hepatic artery infusion

- follow up for recurrence

Localisation of small lesions which may be lost

Evaluate patients every 3-4 cycles and resect before metastases disappear

Localisation is not a problem if an indication for anatomical resection

Percutaneous radiofrequency ablation and resection of scar Coils before chemotherapy to mark small lesions Zalinski et al, Ann Surg Oncol 2009

Question:

Does neoadjuvant chemotherapy increase the morbidity or mortality of surgery?

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, 2006 : Morbidity increased after 12 cycles • Nakano Jaeck et al, 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

Risks of surgery depend on the number of cycles

Message:

Optimal duration of pre-operative chemotherapy?

Question:

Different

- when metastases are resectable - when metastases are not resectable

Optimal duration of pre-operative chemotherapy

- 6 cycles according to EORTC 40983

- Could fewer cycles be sufficient?

Duration of pre-operative chemotherapy in resectable metastases

Duration of pre-operative chemotherapy in initially unresectable metastases?

• Aim: convert patients to resection with a hope for cure

• Chemotherapy should be discontinued when metastases have become resectable and not given until best response is observed

• Overtreatment can damage the liver and preclude surgery

Question:

If resectable metastases progress during pre-operative chemotherapy?

Progression during pre-operative CT

A biological marker for poor prognosis No surgery if metastases progress Change chemotherapy,

Question:

Targeted agents before liver surgery for metastases ?

Cetuximab:1st-line mCRC treatment in KRAS wild-type

OxFp, Oxaliplatin + fluoropyrimidine; p-value for primary endpoint onlyThe methodologies applied in the studies shown are not identical and studies should therefore not be compared

1Van Cutsem E, et al. J Clin Oncol 2010; 28(15s):3570; 2Bokemeyer C, et al. ASCO-GI 2010, #428; 3Maughan TS, et al. J Clin Oncol 2010; 28(15s):3502.

CRYSTAL1 Phase 3 n PFS(months) ORR OS

(months)FOLFIRI 350 8.4 39.7% 20.0

FOLFIRI + cmab 316 9.9HR: 0.70; p=0.0012

57.3% 23.5

OPUS2 Phase 2 n PFS ORR OSFOLFOX 97 7.2 34% 18.5

FOLFOX + cmab 82 8.3 57%OR: 2.5512; p=0.0027

22.8

COIN3 Phase 3 n PFS ORR OSOxFp CT 367 8.6 57% 17.9

OxFp CT + cmab 362 8.6 64% 17.0HR: 1.038; p=0.68

Panitumumab:1st-line mCRC treatment in KRAS wild-type

PRIME1

Phase 3 n PFS(months) ORR OS

(months)

FOLFOX4 331 8.0 48% 19.7

FOLFOX4 + pmab 325 9.6HR: 0.80; p=0.02

55% 23.9

1Siena S, et al. ASCO-GI 2010, #283;.

Bevacizumab:1st-line mCRC treatment

NO169661

Phase 3 n PFS(months) ORR OS

(months)FOLFOX4/XELOX + placebo 701 8.0 38% 19.9

FOLFOX4/XELOX + bevacizumab 699 9.4

HR: 0.83; p=0.002338% 21.3

1Saltz LB, et al. J Clin Oncol 2008; 26:2013-9; 2Hurwitz H, et al. N Engl J Med 2004; 350:2335-42.

p-value for primary endpoint onlyThe methodologies applied in the studies shown are not identical and studies should therefore not be compared

AVF21072

Phase 3 n PFS ORR OS

IFL + placebo 411 6.2 35% 15.6

IFL + bevacizumab 402 10.6 45% 20.3HR: 0.66 p<0.001

RECIST criteria may not fully evaluate the efficacy of bevacizumab in CLM

Major response

Interobserver variation: κ=0.78 Chun & Vauthey. JAMA 2009

Response and resection; phase 2 trials:Cetuximab and Bevacizumab

CELIM *: Phase 2 Non-resectable or ≥ 5 liver metastases KRAS wt

ORR Resection R0

FOLFOX or FOLFIRI + cetuximab 79% 33%

* Bechstein WO, et al. J Clin Oncol 2009;27(Suppl. 15): Abstract No. 4091** Garufi C, et al. ASCO GI 2008. Abstract No. 367; ***Wong R. ESMO34th-ECCO15th

POCHER**: Phase 2 ORR Resection R0

FOLFIRINOX + cetuximab 79% 58%

BOXER ***: Phase 2 ORR Resection R0

CAPOX + bevacizumab n=46 78% 31%

Targeted therapies and risk of surgical complications

- EGFR blockers: no interference with surgery

- VEGF inhibitors: surgery delayed 6 – 8 weeks

Targeted agents in resectable metastases

Standard treatment is FOLFOX4 Should we extrapolate that « the most effective

regimen » is the best? Which reference? Metastatic or adjuvant

treatment?

Ongoing and future trials in resectable metastasis

CRUK 06/031: FOLFOX ± cetuximab in KRAS WT

EORTC: 2 trials

FOLFOX + Panitumu

mabRResectable

Liver Metastases

from CRC n < 8

FOLFOX

FOLFOX + Panitumu

mab

FOLFOX Follow

up

Follow up

SUR

GER

YSU

RG

ERY

FOLFOX+Bevacizum

ab

SUR

GER

Y

FOLFOX + Bevacizu

mabFollow

up

KR

AS

WT

EORTC 40091: BOS2 (Biologics, Oxaliplatin, Surgery) KRAS Wild type

Endpoints: PFS; Pathological Response

EORTC 1207: BOS3 (Biologics, Oxaliplatin, Surgery) KRAS Mutated

Ran

dom

izat

ion

Resectableliver

metastases (n° ≤ 8)from CRC

KRAS mutant

mFOLFOX6 Follow up

SUR

GER

Y

mFOLFOX6

mFOLFOX6+ Aflibercept SU

RG

ERY

mFOLFOX6+ Aflibercept

Follow up

Targeted agents in unresectable metastases

Aim is resection Regimen with high response rate - intensified chemotherapy - addition of biologics to chemotherapy

Question:

Should all patients presenting with liver metastases be considered for resection?

Patients usually divided in 3 groups:- Resectable- Never resectable- Potentially resectable in case of good response

to chemotherapy

Some patients have such a major response to chemotherapy that it allows to consider surgery although not expected initially

Falcone, et al. Ann Surg 2009

GONO study: FOLFOXIRI – PFS in R0 patients

Median PFS: 17.8 months

5-years PFS: 16%

Time (months)0 12 24 36 48 60

1.0

0.8

0.6

0.4

0.2

0

R0 patients

OS

estim

ate

n=37

Events (n)=31

Median Follow up: 60.5 months

Resection after chemotherapy

Resection after chemotherapy: Never say never; keep eyes open Be aware that resection does not solve all the

problems Discuss all patients in multidisciplinary meetings

Any other question?