Resection of Liver Metastases: State of the Art

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.[1] 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.

Surgical Approach to Hepatic Metastases

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.[5] 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 type.

Liver Metastases From Colorectal Cancer

Epidemiology

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.[9] 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 given year.

Natural History of Colorectal Cancer

"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."
—Herodotus

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 2).[12-22] The 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%.[12]

Comparison of Treatment Modalities

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 discussion.

Systemic Chemotherapy

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(Drug information on 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 unresectable disease.

Other systemic agents shown to have significant antitumor effects against colorectal cancer are the topoisomerase I inhibitor irinotecan(Drug information on irinotecan) (CPT-11, Camptosar) and the platinum-based guanine alkylator oxaliplatin(Drug information on 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 4).[25-27]

Regional Chemotherapy 

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.[28] 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 venous controls.[29]

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.[25] 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.[25] 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.[25]

Surgical Ablation

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 disease—cryoablation 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 death.

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.[48] 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.

Surgical Resection

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 disseminated disease.

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.[59] 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 42 months.

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[55] 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.