Aside from serving as a
primary organ for the maintenance
of metabolic homeostasis, the liver is unfortunately also known for its
propensity to harbor tumor metastases. It has been noted that the liver is
surpassed only by regional lymph nodes as the most common site of metastases,
and that hepatic metastases can be found in 25% to 50% of all patients dying of
cancer. These figures, in part, reflect the wide spectrum of primary tumors
that may use the liver as a repository for their metastases. Although the
majority of hepatic metastases originate from colorectal cancer, primary tumors
from the lung, breast, kidney, pancreas, ovaries, uterus, stomach, and
esophagus, as well as neuroendocrine tumors, sarcomas, and melanoma, also
metastasize to the liver.
In this article, we present current surgical perspectives on the management
of liver metastases by critically evaluating the clinical data provided in the
medical literature. The focus of the discussion is on the current status of
patient selection, techniques, and resection of liver metastases from a select
group of primary sites wherein it is applicable. Because metastases from
colorectal cancer are the most amenable to resection when considering long-term
benefit, we highlight the evidence-based rationale for surgical resection and
provide a succinct comparison of all treatment modalities for liver metastases
from colorectal cancer. The results of surgical resection of metastases
originating from sites other than the colon and rectum are also discussed.
Although a wide variety of primary cancers are known to metastasize to the
liver, there is a paucity of reliable data to guide resection of many such
tumors. To date, colorectal cancer and neuroendocrine tumors of the
gastrointestinal tract constitute the only two histologic types for which a
liver-directed surgical approach has been well substantiated in the literature.
This discrepancy may be due to the fact that liver metastases from other
cancers typically occur in the setting of widespread systemic failure, whereas
tumors arising within the portal system possess a greater proclivity for
establishing truly isolated hepatic metastases. Currently, surgical management
of hepatic metastases primarily involves interventions that center on achieving
potential cure; therefore, patient selection is limited to those in whom the
liver is the only site of failure or the dominant site of disease.
Neuroendocrine tumors of gastrointestinal origin comprise a diverse group
that includes malignant gastrinomas, carcinoid tumors, insulinomas, glucagonomas,
somatostatinomas, and vasoactive intestinal peptide-secreting tumors (VIPomas).
When neuroendocrine liver metastases can be completely removed, aggressive
surgical resection should be undertaken, because the 5-year survival rates in
this setting are typically greater than 50%.[2-4] Unfortunately, these
metastases are most often discovered when they are diffuse and usually beyond
curative resection. At this point, they are often associated with disabling or
life-threatening symptoms, and their initial management should consist of
medical therapy aimed at alleviating such manifestations.
In contrast to the management of most hepatic metastases, surgical therapy of
neuroendocrine liver metastases can be advocated even if complete resection is
not possible. The goal in such a case becomes improvement in quality of life as
opposed to potential cure. Especially in the case of carcinoid metastases,
significant palliation of symptoms seen secondary to these functional endocrine
tumors has been achieved with 90% debulking. Moreover, the indolent nature of
neuroendocrine metastases may allow for surgical re-resection to provide
long-term symptomatic disease control and exceptionally long survival rates.
Although reports are largely anecdotal, several authors have noted variable
success using a surgical approach to "noncolorectal, nonneuroendocrine"
metastases. Many reports collectively group these tumors, making individual
analysis of the various tumor types difficult. Investigators have only begun to
elucidate which of these tumors are best treated by surgical resection.[6-8]
Table 1 compiles reported hepatic resections for a wide variety of
noncolorectal nonneuroendocrine liver metastases. As a general tenet, most
surgeons would consider resection of certain lesions if the procedure yielded a
5-year survival rate > 10%. The first eight histologic types of primary
tumors listed in the table might meet this benchmark, but the limited numbers of
cases make accurate outcome analysis difficult. At present, the lack of data on
the natural history of these subtypes makes general recommendations for
resection premature, but the trends we have begun to see are promising.
Although the surgical management of hepatic metastases may infrequently
encompass an exotic presentation from a multitude of primaries, the majority of
cases mandating resection are derived from colorectal cancer. Therefore, the
remainder of this article will focus on the management of these metastatic
cancers. It should be noted, however, that aside from colorectal cancer-specific
chemotherapy, the underlying principles and practices guiding surgical
management are applicable to most liver metastases, regardless of histologic
In the year 2002, an estimated 148,300 people will be diagnosed with
colorectal cancer and approximately 56,600 will die of the disease in the United
States alone. Despite well-promulgated screening recommendations and
improving treatment regimens, approximately 40% of all patients diagnosed with
primary colorectal cancer will develop liver metastasis. With regard to timing,
15% to 20% of colorectal cancer patients present with synchronous liver
metastases at the time of initial diagnosis and another 20% will later present
with metachronous liver metastases.[10,11] This translates roughly into more
than 50,000 patients with colorectal cancer-derived liver metastases in a
Natural History of
"I will proceed with my history, telling the story as I go along of small
cities no less than of great. For most of those which were great once are small
today; and those which used to be small were great in my own time. Knowing,
therefore, that human prosperity never abides long in the same place, I shall
pay attention to both alike."
The state of any art represents a dynamic glimpse at the ongoing spectrum of
improvement. As noted by Herodotus, in order to frame the advances to be
garnered tomorrow, one must have an accurate appraisal of the past. The state of
the art for the resection of hepatic metastasis should therefore reflect first
on the natural history of untreated disease.
Since no future clinical trial will include an untreated control arm, an
examination of the data from the 1960s through the early 1980s is necessary in
order to determine the natural history of this disease. Special attention is
paid to patient survival rates because these statistics serve as the backdrop
against which all subsequent treatment strategies must be compared. The data
from this time period can be stratified into two groups (Table
studies conducted during the 1960s and 1970s typically represent symptomatic
patients accrued during the pre-computed tomography (CT) era, and the 1980s
data reflect asymptomatic patients in the post-CT era. As a result, some debate
continues over whether the advent of CT imaging improved detection significantly
enough to produce a lead-time bias in the survival rates of the latter group.
Despite these differences, both sets of studies clearly demonstrate that
untreated disease is uniformly fatal, with a median survival ranging from 5 to
12 months. Even the cohort that had potentially resectable liver metastases
demonstrated a median survival of approximately 18 months and a 5-year survival
rate ranging from only 2% to 8%.
Table 3 compares survival rates achieved with different treatment modalities.
At present, surgical resection is associated with superior survival rates
compared to any other modality and, therefore, remains the treatment of choice
for hepatic colorectal metastases. However, in most patients, surgical resection
is not an option either due to extrahepatic disease or due to regionally
advanced tumors; in the latter group, there is a growing impetus toward
multimodality therapy. Therefore, systemic treatments merit a succinct
Chemotherapeutic approaches to the treatment of
metastatic colorectal cancer have met with only modest success, at best. Due to
poorer outcomes, chemotherapy is conventionally reserved for patients who are
not candidates for curative surgical resection. Unfortunately, approximately 80%
to 90% of colorectal cancer patients with liver metastasis comprise this group.
The origin of effective chemotherapy for colorectal cancer dates back to the
early 1950s. Following Rutman’s observation that rat hepatoma cells utilized
uracil to a greater extent than normal intestinal cells, Heidelberger’s
development of fluorouracil (5-FU) was subsequently applied to the treatment of
gastrointestinal cancers.[23,24] Nearly 20 years later, in the late 1970s/early
1980s, the use of 5-FU-based systemic chemotherapeutic regimens began, leading
to the current standard of intravenous 5-FU plus leucovorin for the treatment of
Other systemic agents shown to have significant antitumor effects against
colorectal cancer are the topoisomerase I inhibitor irinotecan (CPT-11,
Camptosar) and the platinum-based guanine alkylator oxaliplatin. Recent emphasis
has been on examining these agents in combination. The most active of these
combinations produce response rates ranging from 20% to 50% but only rare
complete responses and a median survival of 10 to 16 months (Table
Approximately 15% of patients with unresectable
colorectal liver metastases have detectable disease confined only to the liver.
In this group, regional chemotherapy represents an improved option. Current
regional chemotherapy comprises hepatic artery infusion of floxuridine, based on
a study by Breedis et al that illustrated preferential perfusion of tumor cells
by the hepatic artery in contrast to the predominantly portal supply of normal
hepatic tissue. Another benefit afforded by hepatic artery infusion includes
a high 90% first-pass extraction of floxuridine by the liver when administered
slowly. This allows for decreased systemic drug toxicity and intrahepatic drug
concentrations that are 100- to 400-fold higher than those seen in systemic
The seven randomized trials of hepatic artery infusion compared with either
systemic therapy or ad libitum controls are well analyzed in the report
published by the Meta-Analysis Group in Cancer. Their multivariate analysis
showed that hepatic artery infusion results in a three- to fourfold increase in
tumor response rates (40%-62%), compared to standard systemic chemotherapy
(15%-21%), and lengthens time to progression. However, hepatic artery
infusion demonstrated only a marginal increase in survival; ie, the overall and
progression-free survival rates were significantly longer for hepatic artery
infusion when analyzed against all studies of systemic therapy and ad libitum
controls combined, but only a handful of patients survived for 5 years
(comparable to natural history controls). In fact, in this meta-analysis report
covering several hundred patients, only two survived beyond 5 years.
Unlike surgical resection, the goal of which is en
bloc removal of tumor with clean margins, regional ablative therapy strives to
destroy colorectal cancer metastases in situ. Two forms of surgical ablation are
currently used in the treatment of unresectable diseasecryoablation and
radiofrequency ablation. Both employ destructive energy applied intratumorally
to cause cell death through thermal mechanisms.
Cryoablation entails the use of probes equipped with liquid nitrogen or argon
gas refrigerant to achieve probe tip temperatures as cold as
-160°C. Cell death is enhanced by rapidly freezing the tumor to a peripheral
tumor zone temperature of at least -50°C, followed by slow thaw, and
subsequent repetition of this freeze/thaw cycle. Radiofrequency ablation causes
cell death by application of an alternating electrical current at a frequency of
~400 kHz. This stimulus leads to frictional heating of tissues by ionic
agitation. Heating above the 50°C threshold allows for disruption of cellular
membranes and induction of protein denaturation, culminating in tumor cell
Results following cryoablation are promising for patients with unresectable
but liver-isolated metastases. Several investigators have shown survival rates
after cryotherapy to be superior to those seen in natural history controls and
systemic/regional chemotherapy cohorts (Table 5).[30-35] Long-term survival is
typically achieved in 10% to 20% of patients. Because the majority of
recurrences are limited to the liver, we have initiated a prospective phase II
trial of cryoablation followed by 12 months of adjuvant hepatic artery infusion.
This combination yields a median survival of about 34 months and a 5-year
disease-free survival rate of 17%.
Results of radiofrequency ablation for hepatic metastases are not as well
substantiated in the literature. In published series to date, most data
contain both primary and mixed metastatic tumors.[36-47] Only one series
involved more than 40 patients with metastatic tumors. Results have varied, and
most reports do not provide long-term survival statistics. One concern regarding
this treatment modality is the issue of recurrence as a function of the size of
treated tumors (Table 6).
One of the largest studies of radiofrequency ablation analyzed predictors of
failure.[47a] These include (1) lack of increased lesion size on
contrast-enhanced CT scan at 1 week, implying ineffectively treated margins, (2)
poorer outcome for colorectal cancer vs a better outcome for hepatocellular
carcinoma, neuroendocrine cancer, and other metastases, and (3) larger tumor
volume (failure if tumor size > 18 cm3; success if £ 9.2 cm3;
P = .015). Possibly contributing to treatment failure is the fact that
intraoperative (real-time) ultrasound monitoring is not as effective in
delineating ablation margins during radiofrequency ablation as for cryoablation,
making the estimation of complete tumor destruction less than optimal.
Recent evidence suggests that improved modes of radiofrequency delivery may
yield better results in the future. We have initiated a prospective
randomized multicenter phase II trial of radiofrequency ablation as part of a
multimodality regimen for unresectable liver metastasis from colon cancers. The
trial will systematically examine overall survival, quality of life, and
patterns of failure for radiofrequency ablation followed by either systemic
chemotherapy alone or hepatic artery infusion plus systemic chemotherapy.
Although liver surgery was performed as early as the
turn of the century, resection of liver metastases was not in vogue until the
1970s. Much of the early skepticism regarding a surgical approach was due to the
high morbidity and mortality associated with these procedures, as well as the
debatable therapeutic benefit of local surgery in what was considered widely
Several factors have since led to safer liver resections. These include
surgical application of the principles of liver anatomy, enhancement of
preoperative imaging, optimization of cardiopulmonary monitoring, the advent of
intraoperative staging, technical advances leading to "bloodless"
surgery, and better postoperative metabolic support. These improvements have led
to numerous publications highlighting the safety of liver resection. An
examination of the literature from major centers illustrates that mortality
typically ranges from 2% to 4% (Table 7).[49-58]
The operative mortality is usually related to the magnitude of the liver
resection and is commonly attributable to complications from hemorrhage or liver
failure. Reports from several authors illustrate that complications due to
liver failure occur in about 1% to 4% and due to hemorrhage in 1% to 3% of all
resections.[60,61] Although overall morbidity ranges from 20% to 40%, close
supervision and rapid intervention preempt most mortality. At our institution,
the low incidence of major complications from resection is best reflected by a
current perioperative mortality of well under 1% and median hospital stay of
less than 6 days.
By the 1970s, the emerging strategy of focusing on the specific subset of
patients with "liver only" metastases began to demonstrate the
possible therapeutic benefit of resection.[62-64] By the late 1970s, the number
of surgeons reporting on liver resection in colorectal cancer patients increased
dramatically, and has since led to the publication of several large series with
100 or more patients (Table 7).[49-58] These investigations have uniformly
demonstrated that surgical resection can result in long-term survival for a
substantial portion of patients. The reported 5-year survival rates in these
studies range from 25% to 37%, and the median survivals range from 24 to
Although not listed in Table 7, three studies included 10-year follow-up
statistics. Both Scheele and Jamison[53,54] documented 10-year survival rates of
20%, and Fong reported a 22% 10-year survival. Although randomized
prospective trials are lacking, these results clearly demonstrate that surgical
resection produces survival rates superior to other modalities and is the only
treatment associated with a considerable potential for cure.
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