When should we consider liver first approach in synchronous colorectal liver metastasis?

Tommy Yip Siu-manPrince of Wales Hospital

Introduction

• Colorectal cancer is the third most common cancer worldwide 1

• ~25 % of patients have synchronous liver metastases at the time of diagnosis 2

• While surgical resection of CRLM is regarded the only potential for a cure 3,4, the simultaneous presentation of primary and secondary disease provides a unique chance in deciding the optimal therapy sequence

1 - Parkin DM 2005 2 - McMillan DC 2007 3 - Tsai MS 2007 4 - Pawlik TM, 2007

Surgical strategies to Synchronous CRLM

• Resection of primary tumour first (Classical approach)

• Resection of primary tumour and CRLM (Combined approach)

• Resection of CRLM first (Liver-first approach / Reverse approach)

Resection of primary tumour first (Classical approach)

Classical approach

• Resection of primary tumour hepatectomy (if the liver metastases are resectable) subsequent adjuvant chemotherapy

• Rationale• Symptoms caused by colorectal

primary tumour (bleeding, obstruction, pain)

• Natural selection “window” to exclude from further liver resection 5,6

• ? Primary tumour as the likely source of subsequent metastasis 7

5 - Benoist S 2007 6 - Capussotti L 2006 7 - Peeters CF 2006

Limitations

• Progression of CRLM beyond resectability during treatment of primary tumour, esp if complications arise from primary resection 8 or adjuvant chemotherapy 9,10

• Postoperative immunodeficiency following primary resection increases the rate of liver metastatic growth 11,12

8 – Law WL 2007 9 – Vauthey JN 2006 10- Mentha G 2006 11- de Haas RJ 2010 12 - González HD 2007

Resection of primary tumour and CRLM (Combined approach)

Combined approach

• Resection of primary tumour and CRLM in the same operation

• Rationale:• Adjuvant therapy can be

commenced without delay 13

• Reduced total duration of surgery, total hospital stay and transfusion requirement 14,15

13 – Turrini O 2005 14 – Vassiliou I 2007 15 - Brouquet A 2010

Limitations

• Considerable morbidity of complex liver resection combined with major bowel resection

• Not for patients with • High CRLM burden who require a

major liver resection 16

• Locally advanced rectal cancer 17

• Advanced age 18

• ? Risk of leaving behind undetected occult micro-metastases in the remnant liver 19

16 - Lehmann K 2012 17 - Canberra 1999 18 - Mentha G 2008 19 - Yoshidome H 2008

Resection of CRLM first (Liver-first approach / Reverse approach)

Liver-first approach / Reverse approach

• First described by Mentha and colleagues in 35 patients who had a synchronous resectable primary tumour and advanced CRLM

• Usually preceded by neoadjuvant chemotherapy +/- radiotherapy +/- biological agents

Rationale

• Metastatic disease rather than primary colorectal tumour as the main determinant of survival 20

• Treatment of metastatic disease is not delayed by local therapy for primary tumour or by complications of surgical treatment of primary tumour

• Primary-related complications (such as bleeding, obstruction, or perforation) are rare in patients with stage IV colorectal cancer receiving combination chemotherapy21 ; may be tackled with stenting

20 - Moher D 2010 21 – Lambert LA 2000

Limitations

• Complication related to primary tumour progression (e.g obstruction, perforation, bleeding or pain)

• Inoperability during treatment (e.g disease progression, new extra-hepatic diseaseOnly few retrospective studies investigating this approach

Table 1 Setting of the studies reporting the results of the liver-first approach (LFA ) in patients with synchronous colorectal liver metastases

including the selection criteria of LFA

Reference Year of publication

Country Setting Study period Selection criteria of ‘LFA’

Mentha16 2008 Switzerland P rospective observational study

1998–2007 • Advanced synchronous colorectal liver metastasesa

• Age <70 • Performance status <2 • Non-occlusive primary tum our • At least two liver segments without metastases • No or resectable extrahepatic disease

Clinical risk score >3

Verhoef17 2009 Netherlands R etrospective 2003–2007 • Synchronous liver metastases

observational • Locally advanced rectal cancer and where it is defined as: study 1 tumour>5 cm at colonoscopy or MRI (clinically large T3); or

2 clinically fixed tumor or with ingrowth in adjacent organ on

Brouquet18 2010 United States R etrospective cohort study

MRI (T4); or 3 N + tumor (lymph node>8 mm on CT or MRI)

1992–2009 • Synchronous colorectal liver metastases • Criteria not specifically stated but liver resection is planned

as soon as the disease was considered resectable, typically after 3 to 5 cycles of preoperative chem otherapy

De Jong19 2011 Netherlands R etrospective 2005–2010 • Synchronous colorectal liver metastases

Observational • Liver remnant post resection includes at least two adjacent study liver segments as well as sufficient vascular inflow and

outflow and adequate biliary drainage • All patients with a primary rectal cancer were considered for

the liver-first approach • Patients with colorectal cancer located in the colon were

selected on a case-to-case basis

aCriteria of ‘Advanced Synchronous Colorectal Liver metastases’ was not clearly defined.

Table 1 Setting of the studies reporting the results of the liver-first approach (LFA ) in patients with synchronous colorectal liver metastases

including the selection criteria of LFA

Reference Year of publication

Country Setting Study period Selection criteria of ‘LFA’

Mentha16 2008 Switzerland P rospective observational study

1998–2007 • Advanced synchronous colorectal liver metastasesa

• Age <70 • Performance status <2 • Non-occlusive primary tum our • At least two liver segments without metastases • No or resectable extrahepatic disease

Clinical risk score >3

Verhoef17 2009 Netherlands R etrospective 2003–2007 • Synchronous liver metastases

observational • Locally advanced rectal cancer and where it is defined as: study 1 tumour>5 cm at colonoscopy or MRI (clinically large T3); or

2 clinically fixed tumor or with ingrowth in adjacent organ on

Brouquet18 2010 United States R etrospective cohort study

MRI (T4); or 3 N + tumor (lymph node>8 mm on CT or MRI)

1992–2009 • Synchronous colorectal liver metastases • Criteria not specifically stated but liver resection is planned

as soon as the disease was considered resectable, typically after 3 to 5 cycles of preoperative chem otherapy

De Jong19 2011 Netherlands R etrospective 2005–2010 • Synchronous colorectal liver metastases

Observational • Liver remnant post resection includes at least two adjacent study liver segments as well as sufficient vascular inflow and

outflow and adequate biliary drainage • All patients with a primary rectal cancer were considered for

the liver-first approach • Patients with colorectal cancer located in the colon were

selected on a case-to-case basis

aCriteria of ‘Advanced Synchronous Colorectal Liver metastases’ was not clearly defined.

Vincent W.T. Lam 2013

Santhalingam 2013

Vincent W.T. Lam 2013

Vincent W.T. Lam 2013

Vincent W.T. Lam 2013

Limitations of the studies

• No randomised controlled trials• Small sample size• Different patient selection criteria • None defined resectability for the CRLM• Only one study define anatomical site

of primary tumour• Different dosage and duration of

preoperative chemotherapy• Only one study included response rate

of CLM to chemotherapy• Lack of long-term follow-up

Liver-first approach in selected patients with CRLM is associated with low peri-operative morbidity & mortality, and acceptable survival outcomes

Patients that can be considered to “liver-first approach

• Resectable primary tumour with high liver disease burden

• Locally advanced primary tumour with low liver disease burden

• Locally advanced primary tumour with high liver disease burden

• Resectable primary tumour with high liver disease burden

• Locally advanced primary tumour with low liver disease burden

• Locally advanced primary tumour with high liver disease burden

Patients that can be considered to “liver-first approach

• Resectable primary tumour with high liver disease burden

• Locally advanced primary tumour with low liver disease burden

• Locally advanced primary tumour with high liver disease burden

Patients that can be considered to “liver-first approach

Crucial to control the disease with downstaging

chemotherapy and potentially consider

liver resection first as this can influence

patient’s long-term survival

Crucial to control the disease with downstaging

chemotherapy and potentially consider

liver resection first as this can influence

patient’s long-term survival

• Resectable primary tumour with high liver disease burden

• Locally advanced primary tumour with low liver disease burden

• Locally advanced primary tumour with high liver disease burden

Patients that can be considered to “liver-first approach

Especially for locally advanced rectal

tumour, chemoRT should be considered.

While waiting for rectal surgery, the liver tumours can be resected first

Especially for locally advanced rectal

tumour, chemoRT should be considered.

While waiting for rectal surgery, the liver tumours can be resected first

A. De Rosa 2013

Conclusion

• The “liver-first” approach may be beneficial to a selected group of patients with synchronous CRLM

• Patient selection is likely to be determined by their response to down-staging chemotherapy with or without biological agents

• Need of further prospective controlled trials to determine the correct surgical sequence

THE END

QUESTIONS & ANSWERS

Consensus conference of CLM resectability criteria

• ability to obtain a complete resection (negative margin)

• ability to preserve two contiguous liver segments, with adequate vascular inflow and outflow

• ability to preserve adequate future liver remnant (> 30% in a healthy liver, 40% in diseased liver)