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Hepatic Colorectal Metastasis: How Much Progress Have We Made?

William R. Jarnagin, MD, FACS

Curable Metastatic Colorectal Cancer

•cure \’kyùr\ n [ME, fr. OF, fr. ML &L; ML cura, fr. L, care](14c)…a complete or permanent solution or

remedy…vb…to restore to health or normality; to free from something harmful…

Definition

Curable Metastatic Colorectal Cancer

•Treatment of metastatic colorectal cancer:•How is cure achieved?

�Complete resection of all disease♦Imperfect: recurrence in 80%

�Chemotherapy may improve results of resections

•Surgery for metastatic colorectal cancer (liver):•What are the real long-term results?

�Is cure a realistic objective?�Are we curing patients or deferring recurrence?

Definition

‘While several series have reported 5-year survival ratesof 25%, comparison has been made only with has been made only with retrospective data, an invalid control. Thus, it is not known if resection of these lesions is appropriate...The morbidity and mortality of resection come close to offsetting any advantage of resection…’

Arch Surg 1989;124:1021

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“Before you can prove that an operation is valuable,

you must be able to do it without killing people”

Leslie H. Blumgart

Hepatic ResectionResults of contemporary series

de Jong, 2009 1669* 47

Study n 5-yr Surv (%)Hughes, 1986 607* 33

Scheele, 1991 219 39

Rosen, 1992 280 25

Scheele, 1995 469 39

House, 2010 1600 43

Nordlinger, 1995 1568* 28

Jamison, 1997 280 27

1001 37

Choti, 2002 226 40

Fong, 1999

* - Multicenter study

Tomlinson et al JCO 2007;25:4575

Years

% S

urvi

ving

151050

1.0

.8

.6

.4

.2

0

1985 – 94612 Patients with follow-up ≥ 10 yrsMedian Survival = 44mos

>10 yrsn=101

5-10 yrs

2-5yrs

5 cm• CEA > 200 ng/mL

1 point for each criterionClinical risk score = sum

Fong et al Ann Surg 1999;230:309

3

0 60 1 2 0 1 8 0 2 40

0 .0

0 .2

0 .4

0 .6

0 .8

1 .0

CRS012

345

Months

Pro

port

ion

Sur

vivi

ng

Low CRSn = 359

High CRSn = 161

Hepatic Resection: Patient Selection10-year survival stratified by CRS

Tomlinson et al JCO 2007;25:4575

Survival

< 2 Years > 10 years

Node (+) Primary 63% 50%

> 1 Hepatic Tumor 59% 39%

Disease-Free Interval < 1Year 51% 36%

Largest Tumor Size > 5cm 53% 35%

Resection extent (≥ Lobe) 63% 68%

≥ 4 Hepatic Tumors 23% 5%

Margin (+) Hepatic Resection 20% 0%

Hepatic Resection: Patient Selection

What precludes long-term survival?

Tomlinson et al JCO 2007;25:4575

PLoS 2012;8(12)

•Gene expression profile•19 genes identify low/high risk groups•Molecular risk score (MRS)

•MRS combined with CRS•Effective stratification of survival after resection

Metastatic Colorectal Cancer

•Definition of resectable is a moving target

•1970’s – Noone

•1980’s –≤ 3 unilobar tumors

•1990’s – Multiple bilobar tumors

•2000 and beyond…�Major impact of contemporary systemic agents�Redefined traditional definition of resectability

Resectability

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•Dramatic improvement in efficacy•Progressive increase in survival

More active agents for patients with incurable disease

Systemic Chemotherapy

This patient underwent a complete resection of all disease

February2009

November2013

Metastatic Colorectal Cancer

Systemic Chemotherapy

Impact on patients with resectable disease

•What are the benefits in patients with potentially resectable tumors?•Is the same improvement in outcome being realized?

•Perception that chemotherapy is greatly improving survival•Is this valid?•Resulting in cure or delayed time to recurrence?

Improvement in outcome over time

Metastatic Colorectal Cancer

•Retrospective review of 279 Taiwanese patients•Era I: pre-2003•Era II: post-2003•Median FU: 27 months•Recurrence: 75% (median 9 months)

Recurrence-Free Survival

Overall Survival

Era 2

Era 1

Era 2

Era 1

VariableEra I

(n=128)Era II

(n=151) p

Age 59 y 63 y 0.009

Multiple tumors 24% 44%

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Kianmanesh et al. JACS 2003 197:164

Before

After

PVE

Two-Stage Hepatic Resection

Two-stage hepatic resection for advanced liver diseaseHepatic resection in the face of extrahepatic disease

Elias et al Ann Surg Onc 2004;11(3):274

• 75 patients• R0 resection of liver metastases plus

extrahepatic disease

• Extrahepatic sites: peritoneum, lymph nodes, lung, ovary

• Extensive use of chemotherapy

• 29% NED, median FU = 5 years

Metastatic Colorectal Cancer

•107 Patients with liver and peritoneal dz•1995 – 2006•Hepatic resection•Cytoreduction•IP Chemotherapy•Extensive systemic chemotherapy

•Overall Survival•5-year = 35%•10-year = 15%

Ann Surg 2013;257:1065

‘Neo-adjuvant’ chemotherapy

•Chemotherapy prior to hepatic resection•With 1o in situ if asymptomatic

•Rationale•No delay in starting treatment•‘In vivo’ assessment of response•Better patient selection/improved results of resection

�? Improved survival with response�? No benefit of resection with no response

Allen P et al. J Gastrointest Surg 2003;7:109

Metastatic Colorectal Cancer

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Before

After

•Potential to improve resectability

‘Neo-adjuvant’ chemotherapy

Metastatic Colorectal Cancer

•196 patients with initially unresectable disease•FOLFOXIRI – 11 cycles, median = 5.5 months

•Response rate = 70%•Complete resection = 20% (37 patients)

�5-year overall survival = 42%�Disease recurrence in 31 of 37 (84%)

Masi et al. Ann Surg 2009;249:420

•Analysis of published studies (n = 503)•Patients with initially unresectable disease•Treated with systemic chemotherapy

•Strong correlation between treatment responseand overall resection rate

•Analysis of patients treated with preoperative chemotherapy•Resectable disease•Irinotecan- or oxaliplatin-based

•5-year survival correlated with treatment response•Complete (n = 25) - 75%•Major (n = 97) - 56%•Minor (n = 149) - 33%

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Optimism meets reality

Hepatic Resection: SafetyStudy n Mortality (%)

Hughes, 1986 607* NS

Scheele, 1991 219 6

Rosen, 1992 280 4

Scheele, 1995 469 4Nordlinger, 1995 1568* 2

Jamison, 1997 280 4

1001 3Choti, 2002 226 1Fong, 1999

de Jong, 2009 1669* NS

House, 2010 1600 2†

* - Multicenter study. † - 90 day mortality

Hepatic Resection: Safety

Operative mortality (n = 1010)

0

1

2

3

4

5

6

1992-97(n=550)

1998-99(n=245)

2000-01(n=215)

%

Jarnagin et al. Ann Surg 2002;236:397

‘Neo-Adjuvant’ Chemotherapy

The other side of the sword: Liver injury

Steatosis/steatohepatitis Sinusoidal congestion

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•Major hepatectomy in 89 patients•Resectable disease•Preoperative chemotherapy

•Chemotherapy•Increased operative morbidity

�38% vs. 14%, p =0.03•Correlation between morbidity and

# cycles

Karoui et al. Ann Surg 2006;243:1

Steatosis/steatohepatitis and operative morbidity

•406 patients treated with pre-operative chemotherapy•5-FU, FOLFOX or FOLFIRI

•Steatohepatitis (34 patients)•Associated with preoperative irinotecan

�20% vs. 4% for no chemotherapy (p < 0.001)•Higher 90-day mortality

�15% vs. 2% for no steatohepatitisVauthey et al. JCO 2006;24:2065

‘Neo-Adjuvant’ Chemotherapy

0

25

50

75

%

Normal MildSteatosis

MarkedSteatosis

■ Morbidity (p

9

Neo-adjuvant Therapy toImprove Results of Resection

↑ Liver Damage

↑ Peri-operative Morbidity

↑ Risk of Recurrence↓ Disease-specific Survival

?

Morbidity after Hepatic ResectionImpact on long-term outcome

Lancet 2008;371:1007

Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial

Bernard Nordlinger, Halfdan Sorbye, Bengt Glimelius, Graeme J Poston, Peter M Schlag, Philippe Rougier, Wolf O Bechstein, John N Primrose, Euan T Walpole, Meg Finch-Jones, Daniel Jaeck, Darius Mirza, Rowan W Parks, Laurence Collette, Michel Praet, Ullrich Bethe, Eric Van Cutsem, Werner Scheithauer, Thomas Gruenberger for the EORTC Gastro-Intestinal Tract Cancer Group,* Cancer Research UK,* Arbeitsgruppe Lebermetastasen und–tumoren in der Chirurgischen Arbeitsgemeinschaft Onkologie (ALM-CAO),* Australasian Gastro-Intestinal Trials Group (AGITG),* and Fédération Francophone de Cancérologie Digestive (FFCD)*

Systemic Chemotherapy: Impact on Resection

•364 patients with up to 4 liver metastases, randomized to:•Arm 1: FOLFOX4 (6 cycles) → Resection → FOLFOX4 (6 Cycles)•Arm 2: Resection only

•Progression-free survival at 3 years•Median follow-up = 3.9 years

•364 randomized to each arm•342 eligible

�303 resected

•PeriOp Chemotx increased PFS:•7% for all randomized patients

�28% → 35% (p = 0.058)•9% for all resected patients

�33% → 42% (p = 0.025)•Increased postoperative morbidity

�25% vs. 16% (p = 0.04)

Systemic Chemotherapy: Impact on Resection

InterpretationWe found no difference in overall survival with the addition of perioperative chemotherapy with FOLFOX4 compared with surgery alone for patients with resectable liver metastases from colorectal cancer.

Nordlinger et al. Lancet Oncol 2013

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•1669 patients submitted to resection at 4 centers (USA, Milan, Turin, Geneva)•Curative intent procedures

�Resection only in 90%�Resection + ablation in 8%�R0 in 83%

•Disease specific survival = 36 months•Recurrence-free survival = 23 months•>50% of patients recurred within 2 years of resection

�Median time = 17 monthsde Jong et al. Ann Surg 2009;250:440

MSKCC data: 1600 patients

•Review of consecutive hepatic resections•1985 - 2004•First time resections only

�No ablations•Clinical risk score (CRS) calculated for each patient

�Low CRS = 0 - 2 High CRS = 3 - 5

•Divided into 2 time periods based on chemotherapy availability•Era I: 1985 - 1998 (5-FU/LV)•Era II: 1999 - 2004 (Irinotecan, oxaliplatin)

House et al. J Am Coll Surg 2010

Systemic Chemotherapy: Impact on Resection

MSKCC Results

Era I (1985-98) Era II (1999-04)n = 1037 n = 563 p

High CRS (3 - 5) 32% 29% 0.25

Extrahepatic disease 12% 19% < 0.01

R1 Resection 8% 6% 0.3

Major hepatectomy (≥3 seg) 63% 58% 0.05

RBC transfusion 42% 27% < 0.01

Morbidity 44% 44% 0.9

90-day mortality 3% 1% 0.04

Chemotherapy

Preoperative 62% 70% 0.05

Adjuvant systemic 57% 77% < 0.01

Pump chemotherapy (HAI) 12% 36% < 0.01

Operative variables

Era 1 = 1985-1998Era II = 1999-2004

0 48 96 144 192 240

0.0

0.2

0.4

0.6

0.8

1.0

p < 0.01

Era II64 months (n=563)

Era I43 months (n=1037)

Stratified by Era

MSKCC Results Overall survival

0 48 96 144 192 240

0.0

0.2

0.4

0.6

0.8

1.0

p = 0.09

p < 0.01Era II, CRS ≤ 2

Era I, CRS ≤ 2

Era II, CRS > 2

Era I, CRS > 2

Stratified by Era and CRS

Era I: CRS ≤ 2 (n=691), CRS > 2 (n=347)Era II: CRS ≤ 2 (n=403), CRS > 2 (n=159)

Time (months)

Pro

port

ion

surv

ivin

g

11

TheNew England

Journal of Medicine

Volume 341 December 30, 1999 Number 27

Original Articles

Hepatic Arterial Infusion of Chemotherapyafter Resection of Hepatic Metastases fromColorectal Cancer……………….……………………………….……378

Established in 1812 as The New England Journal of Medicine and Surgery

Nancy Kemeny, M.D. et al

HAI Chemotherapy: Pump Placement

Continuous infusion of FUDR

GDA

SQPump

HAI Chemotherapy: Advantages

•High dose chemotherapy directly to the hepatic arterial system•Tumor blood supply•Little systemic toxicity•Continuous infusion•Effective control of liver disease

•Between 2000 –2005•595 first time hepatic resections

� 125 had HAI pump placement (FUDR)� Plus systemic FOLFOX or FOLFIRI

•Comparison group•125 consecutive resections

� Adjuvant systemic therapy only (FOLFOX or FOLFIRI)

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VariablePump + Sys

(n = 125)Sys

(n = 125) p

Age ≥ 60 years 55 61 0.05

Gender (female) 35% 32% 0.59

Synchronous 50% 59% 0.39

Bilobar 30% 47% 0.01

Multiple Tumors 61% 54% 0.31

Tumor Size > 5cm 22% 14% 0.14

Clinical Risk Score > 2 40% 49% 0.12

•Median followup = 43 months•Pump chemotherapy was an independent predictor of DSS

DSSp = 0.001

Hepatic RFS p < 0.001

Overall RFS P = 0.009

Summary

•Treatment of hepatic colorectal metastases:•Resection remains the single most effective treatment

�Now practiced in an era of more effective chemotherapy•Chemotherapy has changed operative approach

�More advanced disease� Extrahepatic disease � More segmental and 2-stage resections

•Not perfect�Potential for harm�Disease-free survival has changed little

� ?Delaying recurrence vs. increasing cure rate?