1. The role of simultaneous resection of synchronous liver metastasis and primary colorectal cancer
Samuel Lo
Department of Surgery

2. Synchronous Colorectal Liver Metastasis
Definition:
Detected at or before diagnosis of primary tumour
Metachronous colorectal liver metastasis
Early: detected <12 months after primary tumour
Late: detected >12 months after primary tumour
The definition of synchronous colorectal liver metastasis is the detection of which is at or before the diagnosis of the primary tumor.
This is opposed to metachronous colorectal liver metastasis;
Defined as development of liver metastasis after the diagnosis of primary tumor.
It can be divided into early or late; earlier or later than 12 months after primary tumor is known.
(synchronous has worse prognosis compared to metachronous)
EGOSLIM consensus 2015

3. Classical 3 2
Classically, the management of operable synchronous disease was first to have surgery for the primary colorectal tumor followed by adjuvant chemo before liver metastasis resection
Only about 10% of patients ever eventually made it to liver resection.
Silberhumer 1

4. Liver first 2 1
There is even a liver first approach in patients who have unresectable colorectal liver mets, who first have conversion chemotherapy to convert the unresectable liver tumor to resectable, and undergo surgery for the liver, followed by resection of the primary tumor 3

5. + Simultaneous Resection
In the last 20 years or so, experienced centers have selected patients to undergo simultaneous resection of colorectal liver metastasis and colorectal primary. There are more and more small case series on simultaneous resection with acceptable perioperative outcomes
the role of simultaneous resection of colorectal primary and liver metastasis:
Silberhumer

6. The aim of simultaneous resection is
CURE
The sole aim of simultaneous resection of colorectal primary and liver met is to achieve cure. It has been demonstrated that in patients who undergo resection enjoy a 5 year survival rate of 30-50%; far exceeding that of systemic treatment alone, for which the median survival is only months.

7. Synchronous Liver Metastasis and Colorectal Primary
Symptomatic primary
Intervention for primary
Synchronous liver metastasis and colorectal cancer
Unresectable liver metastasis
Asymptomatic Primary
Resectable liver metastasis
First we must understand which group of patients can potentially benefit from from simultaneous resection?
In patients with synchronous liver metastasis and colorectal cancer, they can be divided into asymptomatic and those who have a symptomatic primary; i.e. bleeding, obstruction, perforation, and it is obvious that these patients must undergo intervention for primary tumor first and simultaneous resection should not be attempted
However, in asymptomatic patients, the liver metastasis can be classified as resectable, unresectable or potentially resectable. This means that after conversion chemotherapy, a proportion of these unresectable liver metastasis will become resectable.
Also, in patients with clearly resectable liver metastasis, these are two potential groups that simultaneous resection may benefit.
Let’s look at some evidence and expert consensus.
Potentially Resectable liver metastasis

8. Meta-analysis of 22 retrospective studies with 4494 patients with correction of selection bias.
Simultaneous resection of primary tumor and liver metastasis vs Primary first and staged resection of liver metastasis
Outcomes: Postoperative mortality, morbidity, overall survival, disease-free survival
This is a meta-analysis done in Shanghai of several retrospective studies comparing simultaneous resection of primary tumor and liver metastasis vs staged resection
Included 22 studies and 4494 patients, looking at the postoperative mortality, morbidity, overall survival and disease-free survival.

9. There were significant baseline imbalances between the simultaneous and staged groups in most of the studies included.
In A, the number of metastases was less in the simultaneous group
in B, size of metastases was also smaller in simultaneous group

10. C, the Distribution of metastases was more frequently unilobar in the simultaneous group,
E Primary tumor location was more frequently right colon in simultaneous group
Obviously there are strong selection bias in many of these studies, which the authors tried to correct for.
(baseline imbalances mainly came from 9 studies, and the other 7 studies which had no significant baseline imbalance were summarized respectively and re-pooled
outcomes were looked at and compared)
Strong selection bias

11. Outcomes all similar: Postoperative mortality (RR = 1.14, P = 0.52)
Morbidity (RR = 1.02, P = 0.85)
Overall survival (HR = 0.96, P = 0.50)
Disease Free survival (HR = 0.97, P = 0.87)
Less pulmonary complications in simultaneous (RR = 0.23, P = )
Outcomes were similar between simultaneous resection and staged resection: postop morbidity, mortality, overall survival and disease free survival.
(even after subgroup analysis to correct the pooled postoperative mortality and overall survival, the major imbalance factors shown in the previous slides did not interfere with the two outcomes)
The only finding was that there were less pulmonary complications in simultaneous compared to staged (this is attributed to requiring a second intubation with mechanical ventilation)

12. 43,408 patients from American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database
Synchronous resection N = 922
Stratification of hepatectomy into ‘major’ and ‘minor’
Stratification of colorectal resection into ‘high risk’ and ‘low risk’

13. Low and High Risk Colectomy Minor and Major Hepatectomy
They divided colectomy into high risk and low risk and hepatectomy into minor and major.

14. Major hepatectomy has higher morbidity and mortality
So they looked at the major morbidity and mortality after the simultaneous resection.
There is low risk colectomy and minor hepatectomy,
High risk colectomy and minor hepatectomy,
Low risk colectomy and major hepatectomy,
High risk colectomy and major hepatectomy
And you can see that the morbidity and mortality increases with major hepatectomy.

15. They estimated the cumulative asynchronous probabilities of major morbidity and mortality of two independent events isolated hepatectomy and isolated colectomy and used the addition law of probability method to come up with a predicted mortality rate for simultaneous resection.
What they found was that the actual observed rate of simultaneous resection for minor hepatectomy was lower than the estimated cumulative mortality from similar isolated resections and reached statistical significance.
But regarding major hepatectomy; the number of patients undergoing synchronous major hepatic resection and CRR was insufficient
Observed mortality of simultaneous resection with minor hepatectomy is lower than estimated

16. EGOSLIM 2015 Consensus
“Simultaneous resection can be performed in selected patients undergoing limited hepatectomy with similar outcomes to sequential surgery.”
One of the recommendations in the expert group on oncosurgery management of liver metastases in 2015 was that simultaneous resection can be performed in selected patients undergoing limited hepatectomy with similar outcomes to sequential surgery.
From the previous two studies I think this is reasonable.
Adam et al 2015

17. EGOSLIM 2015 Consensus
For primary tumours (with resectable synchronous liver metastasis), one-stage surgery is not advocated for:
Mid and low rectal tumors
complex colonic tumours
high-risk patients
Major hepatectomy (3 or more adjacent segments)
They also advised that simultaneous resection is not advocated for mid and low rectal tumors, complex colonic tumors, high risk patients or those undergoing major hepatectomy
Mostly worried about the higher complication rate or increased morbidity/mortality rate
These are popularly held opinions and even from the previous NSQIP study just mentioned, (out of >43,000 patients identified/922 patients undergoing simultaneous resection, only 168 patients underwent major hepatectomy); the number of patients undergoing hepatectomy was insufficient
Adam et al 2015

18. 103 patients; simultaneous n = 55, staged n = 48 2004-2015
Outcomes: perioperative and postoperative outcomes, complications, mortality
This is a study done in South Korea looking at major hepatectomy in simultaneous resection
Had 55 simultaneous and 48 staged operations
Postop complication rate was slightly higher in simultaneous group but P value was not significant
Mortality was zero in both arms
Hospital stay was similar in both
Major liver resection in Simultaneous Resection

19. Baseline characteristics comparable
Baseline characteristics are quite similar in the two groups of patients
Baseline characteristics comparable

20. Complication rate similar
Postop complication rate was higher in the simultaneous group but not reaching statistical significance
Hospital stay also similar
They concluded that Simultaneous major liver resections are feasible and safe
Complication rate similar

21. 198 patients with Ca rectum and synchronous liver metastasis;
145 (73.2%) simultaneous resection
53 (26.8%) with staged resection
69 patients (34.8%) underwent major liver resection (30 simultaneous)
Outcomes: complications, mortality, hospitalisation
This is another study by MSKCC with subgroup of 69 patients undergoing major liver resection for rectal liver metastasis; 30 are simultaneous and 39 are staged
Major liver resection in Simultaneous Resection

22. Significant difference between two groups
Again, the selection bias is evident in the tumor characteristics
The morbidity and mortality was similar and
They found that the operating time was shorter and the hospitalisation was also shorter for simultaneous
Significant difference between two groups

23. Difference in operations over time
The use of staged and simultaneous resections differs with time period.
For the patients in this study, before 2000, 51% of patients had a staged procedure. Since 2000, only 6% of patients had been treated with a staged procedure.
So there are major limitations with this study.
Difference in operations over time

24. Synchronous Liver Metastasis and colorectal primary
Symptomatic primary
Intervention for primary
Synchronous liver metastasis and colorectal cancer
Unresectable liver metastasis
Asymptomatic Primary
Resectable liver metastasis
The other group that could possibly benefit from simultaneous resection was those with potentially resectable liver metastasis who underwent successful conversion chemotherapy.
Potentially Resectable liver metastasis

25. EGOSLIM 2015 Consensus
(In patients with potentially resectable liver metastasis undergoing conversion chemotherapy)
“If colorectal liver metastasis become resectable… recommend the liver first approach to surgery”
The expert consensus in 2015 recommended that in the group with asymptomatic
Adam et al 2015

26. EGOSLIM 2015 LiverMetSurvey
LiverMetSurvey, although not significantly different between strategies, support this approach; 5-year survival rates were 42% for the reverse approach compared with 33% for colon first surgery and 28% for one-stage surgery (Fig. 5)
LiverMetSurvey

27. The Role of Simultaneous Resection
Synchronous liver metastasis and colorectal cancer
Symptomatic primary
Intervention for Primary
Asymptomatic Primary
Unresectable liver metastasis
Resectable liver metastasis
Minor hepatectomy
?Major hepatectomy
Potentially Resectable
Currently no role
So finally, is there really a role for simultaneous resection?
There is evidence that in asymptomatic patients with clearly resectable liver metastasis requiring only a minor hepatectomy, simultaneous resection can be performed with low morbidity and mortality.
However, in patients requiring major hepatectomy or ca rectum, the current evidence still has strong bias and cannot be recommended at the moment.

28. Conclusion
Many studies have strong selection bias
Simultaneous resection is feasible in patients with minor hepatectomy
Controversy surrounding major hepatectomy and rectal tumors
Randomised control trials are required

29. The role of simultaneous resection of synchronous liver metastasis and primary colorectal cancer
Department of Surgery

30. Department of Surgery

31. 2016 ESMO Guidelines