As you use this educational tool you will be driven to infer (and in sections sometimes read) what the organizing principles of therapy for hepatic metastases from colorectal cancer are. Based on your own reading of the commentaries and reference materials you will come to your own conclusions about their applicability. The following two principles seem to be the overarching principles that have driven many of the opinions. Of course implied in all of this (as it is in all medical decisions) is that the risk/benefit ratio needs to be taken into account, and that the patient should be an informed participant in decisions about their care.

Principle 1: Colorectal cancer metastatic to the liver if resectable is often a curable disease.

Although a classic dogma in oncology suggests that any metastatic disease is an early sign of widely dispersed metastatic disease, this is too simplistic a view. Specifically in a number of clinical scenarios resection of metastatic disease can lead to long term survival and apparent cure of some patients. One of the most common scenarios for which this seems to be true is that of colorectal cancer metastatic to the liver. Such disease if left unresected results in a dismal prognosis with a 5 year survival of < 5%, while 5 year survivals of ~30% are commonly reported for patients undergoing resection of hepatic metastasis, and even higher 5 year survival rates have been reported in some patient subsets. Although there have been no randomized studies of outcome with or without resection of resectable disease, the dramatic differences in outcome seen in patient series is compelling evidence for the value of resection.

Corollary 1B: Every patient with newly diagnosed colorectal cancer should have adequate staging procedures to detect the possible presence and extent of metastatic disease.

Exception 1A: Patients who have absolute medical contra-indications to surgery.

Exception 1B: Patients who have metastatic disease to multiple organ systems (although for patients with a single additional organ system involved (e.g. the lung) success for an aggressive resection strategy directed at both metastatic sites has been reported.

Practical Issue #1 Are hepatic metastases resectable? Often! Except if:

One of the crucial determinants of outcome for patients undergoing resection of hepatic metastasis is the feasibility of undergoing the resection of all hepatic tumor (an R0 resection). For example the NCCN 2009 guidelines emphasize this point stating that resection should only be attempted if an R0 resection is possible. Certainly there is no evidence that debulking surgery leaving macroscopic (R2) disease behind improves outcome. A recent European publication that contested the view that R0 resections must be achieved, suggesting that post chemotherapy surgery when only an R1 resection is prospectively planned, resulted in benefit similar to that of R0 resections, but this view is controversial and awaits additional study.

Reason for non-resectability #1. Clean macroscopic margins cannot be obtained because of the involvement of or effacement to crucial vascular structures.

A common reason that a patient with otherwise resectable disease (leaving adequate functional liver parenchyma behind) may be considered unresectable is that the metastatic disease abuts crucial vascular structures. In this scenario an attempt to reduce the extent of hepatic disease can be undertaken with pre-operative "conversion" therapy. In this situation patients are given pre-operative chemotherapy with the hope of causing tumor shrinkage allowing clean surgical margins to be obtained.

Reason for non-resectability #2. Clean macroscopic margins cannot be obtained because of extensive disease, necessitating the resection of so much hepatic tissue that residual hepatic function would be inadequate.

Estimates of the percentage of remaining liver that would be adequate depend on the state of the liver. For patients with no underlying liver disease, a generally accepted minimum amount of hepatic tissue needed is 20%. For patients with mild hepatic disease a remnant of 30% is generally thought necessary. For patients with moderate to severe hepatic parenchymal disease an even greater amount of hepatic tissue may be needed. These estimates are not absolute in that they do not guarantee adequate or inadequate hepatic reserve. There are two methods used to specifically encourage hepatic hypertrophy. One is pulmonary vein embolization. A second is staged hepatic surgery.

Reason for non-resectability #3. Presence of extrahepatic disease.

Although thought by some to be an absolute contra-indication for attempted resection of hepatic metastases, recently reported series show that favorable outcome can occur in patients with portal lymph node involvement or limited metastatic disease to the lungs.

Principle 2: Systemic therapy as part of the treatment plan improves outcome of patients with resectable colorectal cancer metastatic to the liver.

It is widely accepted that systemic therapy as part of the treatment plan improves outcome of patients with resectable colorectal cancer metastatic to the liver. This view is largely based on improvements seen in patients with colorectal cancer when such therapy is given in the initial adjuvant setting or in the setting of unresected metastatic disease.

Given the wide acceptance of this principle it is surprising to find that no single analysis of a clinical trial shows a statistically significant effect. However this is not altogether surprising given that trials in this area have been difficult to complete and have had low statistical power. The strongest of these studies of adjuvant therapy after R0 resection of hepatic metastases due to colorectal cancer is based on the combined analysis of two trials (which used 5FU based regimens) that had to close prematurely because of slow accrual, thus each lacked the planned statistical power to demonstrate the predefined difference. This small (n=278) combined analysis showed a trend (not statistically significant) for a relative ~25% reduction in the risk of relapse at 2.5 years of follow-up. This reduction is approximately the same seen for such therapy in the adjuvant and metastatic arenas.

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