Introduction

The liver is a common site of metastatic disease. This bland statement suggests that the liver is just another place where tumor cells spread in the inevitable progression of cancer. Enormous progress in therapies for liver metastases have made this progression slower, and in some cases have eradicated metastatic disease. This chapter will focus on treatments unique to the treatment of isolated liver metastases. The interplay of surgical therapy, liver-directed therapy, and systemic therapy in persons with colorectal cancer will be emphasized.

Metastatic liver disease is common in most gastrointestinal malignancies, presumably because of hepatic portal venous drainage from the gastrointestinal tract. Disease isolated to the liver is a unique feature of colorectal carcinoma. Isolated liver metastases are less commonly associated with breast cancer, lung cancer, pancreatic cancer, gastric cancer, neuroendocrine malignancies, and melanoma. The unusual biology of colorectal cancer has made the liver a tempting target for local therapies such as surgical resection. When colorectal metastases are isolated in the liver, surgical resection affords an opportunity for cure, yielding 5-year survival rates from 20% to 50%.1,2 Indications for surgical resection have become broader as surgical techniques have improved. Surgical resection of liver metastases is, however, limited by tumor location and hepatic reserve. Despite a more aggressive approach to management of liver metastases, only 15% to 25% of patients are able to undergo curative surgical resection.

Diagnostic and Preoperative Evaluation

Evaluation of patients with liver metastases is initially focused on evaluating criteria for surgical resection. Unresectable extrahepatic metastatic disease is a contraindication to hepatic resection. However, patients with synchronous lung disease or an intact primary cancer may benefit from hepatectomy in highly selected cases. The number of metastases and location of metastatic disease are critical in surgical decision making, but hard and fast numbers (e.g., the number of lesions and their size and location) cannot easily be defined. More subtle factors such as tumor proximity to major vasculature and biliary structures, hepatic functional reserve, and the impact of prior chemotherapy also must be considered.³

Positron Emission Tomography

Combined PET and CT provides excellent anatomic localization of FDG-avid “hot spots” for further evaluation (Fig. 53-1). However, its use is limited by availability and in the detection of small liver metastases because of the heterogeneity of hepatic uptake of FDG. PET can detect extrahepatic metastatic disease that is difficult to detect on CT, such as nonenlarged lymph nodes with metastatic foci.⁴ Engledow et al.⁶ demonstrated that the addition of PET/CT led to changes in cancer stage (31% upstaged and 3% downstaged) and ultimate management in patients with colorectal liver metastases. Ruers and colleagues⁷ demonstrated that in 150 patients with colorectal liver metastases, the addition of PET/CT compared with CT alone led to a reduction in futile laparotomies from 45% to 28%. Wiering et al.,⁸ in a study of 150 patients randomly assigned to PET/CT or CT alone, also demonstrated a 38% reduction in futile laparotomies. Because chemotherapy decreases the metabolic rate of the tumor cells, patients with preoperative chemotherapy showed decreased FDG uptake and less efficient detection of metastatic lesions.⁹ The cost of preoperative evaluation, however, must be a factor in the decision to obtain additional imaging. Currently the use of PET is not standard of care, and its use should be individualized.

Evaluation of Future Liver Remnant

Evaluation of the future liver remnant (FLR) has become a more critical part of preoperative planning as the use of preoperative systemic therapy has increased. The importance of measurement of the FLR is focused on the volume of the liver remnant, but the volume is only a surrogate for estimation of the function of the FLR after resection. FLR is generally expressed in terms of the percentage of the total liver volume remaining after resection. FLR can be measured by using three-dimensional CT reconstruction and then normalized based on body surface area.¹⁸

The limits for safe liver resection depend on a variety of factors, including underlying hepatic function, the receipt of preoperative chemotherapy, and FLR volume and function (Fig. 53-2). Many persons suggest that patients with underlying hepatic disease require an FLR in excess of 40%, whereas those with chemotherapy-induced steatosis require an FLR of at least 30%. Patients with normal liver function can be left with an FLR as small as 20% provided major hepatic vessels and biliary structures can be preserved.^19–22 Figure 53-3 depicts an algorithm for approaching resectable liver metastases in the setting of normal hepatic function.

Patients with substantial chemotherapy-induced hepatoxicity require a future liver remnant of at least 30%.²⁰ Narita et al.²³ established limits on safe hepatic resections for colorectal liver metastases in a study of 101 patients with colorectal liver metastases who underwent preoperative chemotherapy. These investigators found that the safe FLR threshold for predicting overall morbidity, sepsis, and liver failure were 44.8%, 43.1%, and 37.7%, respectively. Chemotherapy-induced steatosis has been shown to impede liver regeneration, but the degree of its influence on postoperative morbidity and mortality has been debated. A review of 406 patients with colorectal liver metastases, 61% of whom had preoperative chemotherapy consisting primarily of either fluorouracil alone or in combination with irinotecan or oxaliplatin, demonstrated that irinotecan was associated with more steatohepatitis compared with no chemotherapy (18.9% vs. 1.9%, P < .001). Patients with steatohepatitis had an increased 90-day mortality rate (14.7% vs. 1.6%, P = .001).²⁴

Routine hepatic biochemical tests such as bilirubin, aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase levels are an essential component of the preoperative hepatic function assessment. A coagulation panel and platelet count also provides information on hepatic function. Hyaluronic acid concentration can provide information on the degree of hepatic fibrosis and sinusoidal endothelial damage.²⁵ Many dynamic tests have been described to evaluate hepatic functional reserve but are largely used for patients with hepatocellular carcinoma or cirrhosis.²¹ The presence of underlying hepatic dysfunction suggests that the role of surgical resection may be more limited than in patients with normal hepatic reserve. These patients either are not candidates for resection, require more limited resection, or should be allowed to recover from any insult to their liver more fully before resection.

Management of Colorectal Liver Metastases

Liver metastases develop in half of patients with colorectal cancer; unfortunately, approximately 80% of these patients have unresectable disease at the time of presentation.29,30 Untreated, the median survival for patients with unresectable liver metastasis from colorectal cancer is generally poor, with roughly a 30% 1-year survival rate and between a 0% and 5% 5-year survival rate.^30,31 Several studies have demonstrated that patients with resectable liver metastases that go untreated fare slightly better, with 1-year survival rates ranging between 20% and 80% and median survival rate ranging from 10.6 to 21 months (Table 53-1). A retrospective analysis of 484 patients with untreated colorectal liver metastases identified six independent determinants of survival rate on multivariable analysis. Although the percentage of metastatic liver tumor burden was the strongest predictive factor, primary tumor grade, extrahepatic disease, mesenteric lymph node involvement, serum carcinoembryonic antigen, and age were also independent predictors of survival.³¹ Data on cancer-specific survival rates of patients after resection are robust and should be discussed with all patients. Factors that are unknown preoperatively are risk factors for recurrence (e.g., incomplete tumor resection), but they do not assist in preoperative decision making.

Prediction of Survival Rate after Surgical Resection

Before the era of surgical resection for liver metastases, survival rates were poor. However, as the approach shifted from palliative to curative and surgery became the mainstay for treatment of liver metastases, long-term survival and even cure became possible. As surgical management of liver metastases became more aggressive, survival rates and operative mortality improved. Ten-year survival rates reported during the past two decades have ranged between 20% and 39% after resection of liver metastases, and 5-year survival rates ranged between 25% and 58% (Table 53-2).^{19,27,32–37}

Fong et al.²⁷ proposed seven independent predictors of poor long-term outcomes after resection of colorectal metastases: positive margins, extrahepatic disease, node-positive primary cancer, disease-free interval from primary cancer to metastases <12 months, number of hepatic tumors, and carcinoembryonic antigen level >200 ng/mL. When the latter five criteria were used in a preoperative scoring system in which one point was assigned for each criterion, the total score was highly predictive of survival (Table 53-3). The survival rate, stratified by clinical risk score, after liver resection is shown in Figure 53-4.

Management of Surgically Resectable Liver Metastasis

The general approach to patients with liver metastases begins with determination of surgical resectability. As shown in Figure 53-5, if the disease is resectable, no data exist that give absolute guidance to the clinician. Patients with initially resectable disease but a higher rate of recurrence after hepatic resection (Fong’s Clinical Risk Score 4 to 5) may undergo neoadjuvant chemotherapy as a means of identifying patients who experience other disease during systemic therapy and thus are less likely to benefit from surgical resection.^38–41 Other potential advantages to neoadjuvant chemotherapy include earlier treatment of micrometastases and avoidance of local therapy in patients with early disease progression.⁴² However, neoadjuvant chemotherapy is associated with liver injury and may lead to a missed opportunity for resection if disease progression occurs with chemotherapy.⁴³ All patients should be evaluated by an experienced liver surgeon before the initiation of systemic therapy for isolated liver disease.

Surgical resection clearly improves survival in patients with colorectal liver metastases. It is the treatment of choice in patients who are deemed surgical candidates. However, fewer than 25% of patients with isolated liver metastases are amenable to resection.⁴⁴ Traditional contraindications to resection of colorectal liver metastases include more than four liver metastases, extrahepatic disease, and inability to achieve 1-cm resection margins.⁴⁵ More recently, patient selection has been liberalized to include all patients for whom all metastatic disease can be resected with a negative margin, leaving adequate hepatic functional reserve. An international consensus statement defines absolute criteria for unresectability, including untreatable extrahepatic disease, unfitness for surgery, or involvement of more than 70% of the liver or six segments.⁴⁶ Resectability may also depend on hepatic artery, major bile duct, main portal vein, or celiac/paraaortic involvement.⁴⁷ Although once considered an absolute contraindication to resection of liver metastases, select patients with limited extrahepatic disease, such as pulmonary metastases, are now being considered for resection because it may improve long-term survival.^44,48 Table 53-4 summarizes the evolving indications for surgical resection of liver metastases.

Anatomic Considerations

Hepatic resection requires a detailed understanding of liver anatomy. Historically, four common liver resections were performed, including formal left or right hepatic lobectomy, lateral segmentectomy, or trisegmentectomy (extended right hepatic lobectomy).⁴⁹ As knowledge of functional anatomy has improved, liver resections have evolved. Couinaud defined eight liver segments as being related to branches of the portal and hepatic veins, where segment I is the caudate lobe, segments II to IV comprise the left lobe, and segments V to VIII comprise the right lobe (Fig. 53-6). Although these segments cannot be seen on the surface of the liver, intraoperative ultrasound allows for identification of segmental anatomy. In addition to individual segmentectomy, anatomic liver resection options therefore include right hepatectomy (segments V to VIII), left hepatectomy (segments II to IV), right anterior sectionectomy (segments V to VIII) right posterior sectionectomy (segments VI to VII), left medial sectionectomy (segment IV), left lateral sectionectomy (segments II and III), right trisectionectomy (also known as an extended right hepatectomy; segments IV to VIII), and left trisectionectomy (also known as an extended left hepatectomy; segments II to V and VIII).⁵⁰

Current Surgical Controversies

Does the Number of Tumors Matter?

Several recent studies have suggested that resection of liver metastases should not be limited by the number of liver metastases. Although Ekberg et al.⁴⁵ reported no survivors at 3 years among patients with four or more colorectal liver metastases in a small series in 1986, more recent literature has shown evidence to the contrary. In a series of 600 hepatic resections for liver metastases, no survival difference was found between patients with one to three liver metastases and patients with four or more metastases, provided R0 resection was achieved.⁵¹ Pawlik et al.⁵² reported a series of 159 patients with four or more colorectal liver metastases who underwent resection with a 22% 5-year disease-free survival rate and a 51% 5-year overall survival rate. Thus larger, more contemporary reports suggest that the number of liver metastases is less important than obtaining an R0 resection.

Does Tumor Size Matter?

The evidence regarding the importance of metastatic tumor size on prognosis is conflicting. Although some studies suggest that tumor size is an important prognostic factor,27,53 other studies suggest it is not important.^34,54 Given mixed results, large tumor size alone should not be considered a factor in the resectability of liver metastases. However, large tumors may compromise the surgeon’s ability to achieve negative margins or leave an adequate hepatic remnant, thus contributing to unresectability.⁵⁵

Is Anatomic Resection Superior to Nonanatomic Resection?

In anatomic liver resections, the lines of resection match Couinaud’s functional segments of the liver, whereas in nonanatomic resection, these lines are crossed to minimize parenchymal loss. Nonanatomic resection is increasingly used in patients with colorectal liver metastases, with results comparable to anatomic resections. In several reports of patients with colorectal liver metastases who underwent anatomic versus nonanatomic resection, no differences in positive margin rates, recurrence patterns, or overall survival were demonstrated.56,57 Thus anatomic resections are not superior, and nonanatomic resection remains an excellent strategy for minimization of liver parenchymal loss in patients with liver metastases.

Does the Surgical Margin Matter?

As with any oncologic resection, careful attention should be given to obtaining negative margins; however, conflicting results have been reported with regard to the width of surgical margins in the resection of liver metastases. Are et al.⁵⁸ reported on the impact of margins on outcomes after resection of colorectal liver metastases in 1019 patients. They demonstrated a stepwise improvement in median survival as margins increased from involved, or 0 mm margins (group I), to 1 to 10 mm (group II) to more than 1 cm (group III) (Fig. 53-7), suggesting that although 1-cm margins are associated with improved survival, subcentimeter margins are also associated with favorable outcomes and should not preclude resection in an otherwise appropriate surgical candidate.⁵⁸ Another study of 523 patients with nonpositive hepatic resection margins for colorectal liver metastases determined that subcentimeter resection margins are not associated with local recurrence.⁵⁹ Muratore et al.⁶⁰

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