Liver Metastases

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Liver Metastases

Karen L. Sherman and David M. Mahvi

Summary of Key Points

Etiology

• Metastatic liver disease is common in most gastrointestinal malignancies because of hepatic portal venous drainage from the gastrointestinal tract.

Diagnostic and Preoperative Evaluation

• Contrast-enhanced computed tomography is the most widely used imaging modality for detection of liver metastases, operative planning, and postoperative surveillance, with a sensitivity of 93% and a specificity of 100%.

• Percutaneous liver biopsy is rarely indicated.

• Underlying liver function and preoperative chemotherapy influence the minimum size of the future liver remnant after resection.

• Contraindications to resection of liver metastases have evolved such that tumor size and number are less important than obtaining an R0 resection. Resection may also be considered for patients with resectable extrahepatic metastases.

Management of Colorectal Liver Metastases

• Improvements in surgical technique and perioperative management have allowed for safer hepatic resections.

• Hepatic resection is the first-line treatment of liver metastases, with 5-year survival rates between 25% and 58%.

• Survival after resection of liver metastases is influenced by the following risk factors: node-positive primary cancer, disease-free interval, tumor number, tumor size, number of metastases, and preoperative carcinoembryonic antigen level.

• Preoperative systemic therapy, although helpful in identifying patients most likely to benefit from resection of liver metastases, is associated with hepatotoxicity and may affect postresection hepatic regeneration.

• Fluorouracil, oxaliplatin, and irinotecan-based perioperative chemotherapy regimens are most commonly used in the adjunctive treatment of liver metastases.

• In approximately 20% of patients with initially unresectable liver metastases, the metastases may become resectable after administration of neoadjuvant chemotherapy.

• Portal vein embolization and the two-staged hepatectomy are also strategies for improving the resectability of initially unresectable liver metastases.

• Unresectable liver metastases can be managed with systemic therapy and/or a variety of liver-directed techniques such as radiofrequency ablation, microwave ablation, cryotherapy, hepatic artery infusion, or yttrium-90 radioembolization.

Management of Noncolorectal Liver Metastases

• Surgical debulking of neuroendocrine liver metastases is widely accepted to improve symptoms and prolong survival but is associated with high recurrence rates.

• Noncolorectal nonneuroendocrine liver metastases are increasingly being resected, but outcomes are generally poorer than for colorectal liver metastases.

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

Computed Tomography

Computed tomography (CT) is the most widely used imaging modality for rapid survey of liver metastases and estimation of liver tumor burden. Contrast-enhanced CT has high sensitivity (93%) and specificity (100%) for detecting liver metastases. In most cases, portal-venous phase imaging is sufficient; however, for patients with highly vascular primary tumors such as renal cell carcinoma, neuroendocrine tumors, or melanoma, the addition of an arterial phase can improve detection of liver metastases.4 Newer developments in imaging technique allow for the creation of three-dimensional models that can more accurately estimate the areas at risk for devascularization or venous congestion after resection of liver metastases. These details allow for precise operative planning and allow for preservation of as little as 20% of liver volume provided there is normal hepatic function and adequate arterial and portal venous inflow, as well as venous and biliary outflow.3

Magnetic Resonance Imaging

Magnetic resonance imaging (MRI) provides information on the morphologic features of the tumor and the presence of satellite nodules or chronic liver disease and is frequently used for long-term follow-up.3,5 MRI is also the imaging study of choice for detection of hepatic metastases in patients with iodine allergy or renal insufficiency where radiographic contrast is contraindicated. Additionally, MRI provides better visualization of liver metastases in the presence of hepatic steatosis.4 A pooled metaanalysis comparing preoperative imaging modalities found that MRI had superior sensitivity (86%) when compared with CT (70%), fluorodeoxyglucose-positron emission tomography FDG-PET (55%), and PET-CT (51%).5

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.

Intraoperative Ultrasound

Intraoperative ultrasound is the final diagnostic evaluation of the liver before resection. All patients undergoing liver resection must undergo evaluation of the liver by ultrasound before resection. Intraoperative ultrasound identifies occult liver metastases indicating incurable disease in 25% to 48% of patients.10,11 In the past, intraoperative ultrasound was used in conjunction with bimanual palpation of liver parenchyma with a reported sensitivity for detection of liver metastases of 82%.12 As laparoscopic techniques emerged, use of laparoscopic intraoperative ultrasound increased. Studies investigating the benefit of contrast-enhanced intraoperative ultrasound have mixed results.10,13

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.1922 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.

Diagnostic Laparoscopy

Despite extensive preoperative imaging, almost 20% of patients have unresectable colorectal liver metastases at the time of surgery. Roughly half have extensive intrahepatic disease that is underestimated on preoperative imaging, and the other half have occult extrahepatic metastases.11 Diagnostic laparoscopy can be used to detect occult metastases and thereby prevent futile laparotomy, but it is reserved for patients at highest risk of having occult metastases. Mann et al.26 reported a series of 200 patients with colorectal liver metastases, in which 39 of 67 (58%) patients were identified as having incurable disease on diagnostic laparoscopy, leading to a change in management in 19.5% of patients. Fong and associates27 and Jarnagin and colleagues28 suggest using a clinical risk score to estimate the risk of occult metastatic disease based on five preoperative criteria (node positivity, relapse-free interval <12 months, more than one liver metastasis, carcinoembryonic antigen level >200 ng/mL [within 1 month of surgery], and tumor size <5 cm). When more than two of these factors were present, laparoscopy detected occult metastatic disease in 42% of patients. Diagnostic laparoscopy is also helpful in patients with suspicious findings on preoperative imaging. These criteria were established before neoadjuvant treatment, and it remains unclear how previous therapy factors into these treatment algorithms.

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.

Table 53-1

Natural History of Resectable Liver Metastases in Patients Who Did Not Undergo Resection

  n Overall Survival Rate Median Survival (Mo)
Study 1-Yr (%) 3-Yr (%) 5-Yr (%)
Wood, 1976          
 Solitary 15 60 13.3 8 16.7*
 Multiple Unilobar 11 27 9.9   10.6*
Wanebo, 1978 18 72 17   19
Wagner, 1984          
 Solitary 39 20     21
 Multiple Unilobar 31       15
Scheele, 1990 10       14.2
Norstein, 1997 10 80 0 0 18

image

*Mean survival rate reported.

Adapted from Norstein J, Silen W. Natural history of liver metastases from colorectal carcinoma. J Gastrointest Surg 1997;1(5):398–407.

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).19,27,3237

Table 53-2

Operative Mortality and Survival Rates After Resection of Colorectal Liver Metastases

    Operative Mortality (%) Overall Survival Rate Median Survival (Mo)
Study n 1-Yr (%) 3-Yr (%) 5-Yr (%) 10-Yr (%)
Adson, 1984 141 3 82 40 25   24
Hughes, 1986 607       33    
Scheele, 1991 219 5.5     39 28  
Scheele, 1995 434 4 85 45 33 20 40
Nordlinger, 1996 1568       28    
Jamison, 1997 280 4 84   27 20 33
Fong, 1999 1001 2.8 89 57 37 22 42
Iwatuski, 1999 305 1 88 48 32 24 34
Choti, 2002 226 1 93 57 40 26 46
Abdulla, 2004 190     73 58   21
Wei, 2006 423 1.6 93   47 28  
Morris, 2010 3116       44    
Swan, 2011 1202 1.2     42.3   48
Vigano, 2012 192 1     46    
Beppu, 2012 727 0.55   64 48 39

image

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.

Table 53-3

Fong’s Clinical Risk Score for Tumor Recurrence

    Overall Survival Rate (%)  
  Score 1-Yr 2-Yr 3-Yr 4-Yr 5-Yr Median (Mo)
Risk Factors* for tumor recurrence are node-positive primary, disease-free interval <12 mo, >1 tumor, preoperative carcinoembryonic antigen >200 ng/mL, and tumor size >5 cm 0 93 79 72 60 60 74
1 91 76 66 54 44 51
2 89 73 60 51 40 47
3 86 69 42 25 20 33
4 70 45 38 29 25 20
5 71 45 27 14 14 22

image

*Each risk factor is given one point to generate a Clinical Risk Score for tumor recurrence.

Adapted from Fong Y, Fortner J, Sun RL, et al. Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: analysis of 1001 consecutive cases. Ann Surg 1999;230(3):309–18; discussion 318–21.

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.3841 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 of Liver Metastases

Patient Selection

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.

Table 53-4

Evolving Indications for Surgical Resection of Liver Metastases

Characteristics Conventional Indications Current Approach
Tumor number <4 metastases Any
Lobar involvement Unilobar Unilobar or bilobar
Tumor size <5 cm Any
Extrahepatic disease None Untreatable extrahepatic disease
Future liver remnant Adequate remnant liver Increase FLR with PVE
Resection R0 RFA for R1
Synchronicity Metachronous only Either synchronous or metachronous
Lymph nodes No hepatic pedicle nodal metastases No celiac axis involvement
Venous involvement No vena cava/hepatic vein invasion Vein resection/reconstruction

FLR, Future liver remnant; PVE, portal vein embolism; RFA, radiofrequency ablation.

Adapted from Khatri VP, Petrelli NJ, Belghiti J. Extending the frontiers of surgical therapy for hepatic colorectal metastases: is there a limit? J Clin Oncol 2005;23(33):8490–9.

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

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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