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

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

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

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

+ 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

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 12-18 months.

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

Meta-analysis of 22 retrospective studies with 4494 patients with correction of selection bias. 2000-2013 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.

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

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

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 = 0.0003) 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)

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’

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

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.

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

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

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

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

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

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

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

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

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

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

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

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

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.

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

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

Department of Surgery

2016 ESMO Guidelines