Overview

The liver is the most common site of metastases from colorectal cancer (CRC). Approximately half of all patients with CRC will develop liver metastases at some point during their disease (Ekberg et al, 1987; Steele & Ravikumar, 1989), and half of these will be seen with synchronous liver metastases at the time of diagnosis (Bengmark & Hafstrom, 1969). Resection remains the best treatment for patients with resectable colorectal liver metastases (CLM; see Chapter 81A). Early studies reported 5-year survival rates of 25% to 48% following complete resection of the liver metastases (Adson et al, 1984; Fong et al, 1997; Sugihara et al, 1993) in an era when the only active chemotherapeutic agent used in the United States was the antimetabolite 5-fluorouracil (5-FU). With the single-agent regimen of 5-FU, or 5-FU plus leucovorin (LV), tumor response was seen in only 10% to 20% of those treated, which provided an overall survival of approximately a year in patients who were not candidates for an operation (Meta-Analysis Group in Cancer [MAGIC], 1998; Thirion et al, 2004). Substantial improvements in both response and survival have been reported with the use of the two “modern” cytotoxic agents, irinotecan and oxaliplatin.

Newer chemotherapeutic regimens that combine continuously infused 5-FU and LV with either oxaliplatin (FOLFOX) or irinotecan (FOLFIRI) yield overall response rates over 50% and provide a doubling of survival time in patients with unresectable disease (de Gramont et al, 2000; Tournigand et al, 2004). The integration of molecularly targeted agents, such as bevacizumab (monoclonal antibody to vascular endothelial growth factor) and cetuximab (antiepidermal growth factor receptor), into treatment strategies has further increased response rates to an impressive 70% (Folprecht et al, 2010). By combining surgery with these newer chemotherapeutic agents and regimens, 5-year survival rates approaching 60% have been reported following hepatic resection of CLM (Abdalla et al, 2004; Choti et al, 2002; Fernandez et al, 2004).

As the efficacy of systemic chemotherapy is increasing, the number of patients who potentially benefit from adjuvant and neoadjuvant chemotherapy is also growing. Traditional dogma of offering hepatic resection to only those patients with four or fewer lesions confined to one side of the liver no longer applies. Planning the right therapeutic approaches for individual patients is becoming more complex, and it requires a close multidisciplinary collaboration between surgical and medical oncologists. This chapter will discuss the current data on the role of systemic chemotherapy in a multidisciplinary approach in the treatment of metastatic CRC, and it will focus on the implications of surgical management.

Chemotherapeutic Agents

Molecular Targeted Agents

The monoclonal antibodies bevacizumab and cetuximab have emerged as useful adjuncts to systemic chemotherapy for metastatic CRC. Bevacizumab targets and effectively neutralizes circulating vascular endothelial growth factor (VEGF), and several mechanisms of action have been proposed. VEGF is one of the key growth factors required for development and stabilization of new blood vessels that supply tumor growth. Bevacizumab decreases microvascular density and integrity and reduces interstitial tumor pressure in vivo, potentially increasing local delivery of other concurrently administered cytotoxic drugs (Jain, 2001; Willett et al, 2004).

In 2004 Hurwitz and colleagues demonstrated a benefit of adding bevacizumab to systemic chemotherapy for metastatic CRC. In a randomized controlled double-blinded trial, they compared bolus 5-FU/LV plus irinotecan in conjunction with either bevacizumab (n = 402) or placebo (n = 411). Patients in the bevacizumab group had a near 5-month improvement in median survival compared with the placebo group (20.3 vs. 15.6 months; P < .001), and they had an increase in median progression-free survival (10.6 vs. 6.5 months; P = < .001). Although generally well tolerated, the toxicity seen in the bevacizumab group was that of increased gastrointestinal perforation (1.5% of patients) and major thrombotic events (2.5%). In addition, treatment with bevacizumab prior to surgery may be associated with increased wound infections and dehiscences, attributable to inhibition of neovascularization of the healing wound (Scappaticci et al, 2005); however, following hepatic resection for CLM, this phenomenon was not observed in a prospective Phase II trial, in which bevacizumab had been discontinued for 5 weeks (Gruenberger et al, 2008). The current recommendation is still to wait at least 28 days from cessation of bevacizumab to proceed with surgery, but many surgeons prefer to wait 6 weeks.

Cetuximab and the newer drug panitumumab are two recombinant chimeric monoclonal antibodies, which bind to the epidermal growth factor receptor (EGFR). Cetuximab is sometimes used as first-line therapy of unresectable metastatic colon cancer. By competitively blocking the transmembrane tyrosine kinase EGFR, these agents inhibit cell growth, induce apoptosis, and decrease matrix metalloproteinase and VEGF production; however, the effectiveness of both of these drugs seems to be significantly dependent on the wild-type phenotype of KRAS, as this protein is part of the downstream signal-transduction pathway of EGFR. Results from the CRYSTAL study showed that for patients with wild-type KRAS, the addition of cetuximab to FOLFIRI as first-line treatment for CLM increased the response rate to 59% compared with 43% using FOLFIRI alone (P = .003). A slight increase in progression-free survival was found (9.9 vs. 8.7 months; P = .017), a benefit not seen among patients with KRAS mutations (Van Cutsem et al, 2008). The OPUS study was constructed similarly and assessed the addition of cetuximab to FOLFOX, and it also showed benefits for the KRAS wild-type subgroup (61% vs. 37%; P = .011) but not for patients with KRAS mutations (Bokemeyer et al, 2009). Based on these results, the American Society of Clinical Oncology published a consensus statement that patients who have tumors with KRAS mutations in codon 12 or 13 were unaffected by EGFR inhibition, and they recommended that anti-EGFR drugs not be used as part of the treatment regimen for this patient population (Allegra et al, 2009).

The colorectal liver metastases (CELIM) study randomized patients with unresectable colorectal liver metastases to receive FOLFOX plus cetuximab or FOLFIRI plus cetuximab in a nonblinded fashion. Response rates for the 53 patients in each arm were similar (68% and 57%; P = not significant [NS]). When analyzed for KRAS mutation, an impressive overall response rate of 70% was found for the entire group (Folprecht et al, 2010). Following a median of eight cycles, complete resection was achieved in 41 patients (34%), suggesting that this regimen was useful for converting unresectable cases to resectable ones. In a secondary analysis, 68 patients were included in a retrospective reevaluation by seven experienced hepatobiliary surgeons. Twenty-two patients (32%) were considered to be resectable based on initial staging imaging studies, which increased to 41 patients (60%) based on restaging studies after chemotherapy (P = .001).

In summary, the array of chemotherapeutic and molecular targeted agents available to treat CRC and CLM is growing. As such, patients who were not typically considered candidates for liver-directed surgery for CLM are now sometimes considered for potentially curative resection. The following sections will illustrate how the availability of active medical therapy is changing the landscape of surgical therapy for CLM.

Conversion Therapy

One possible use of chemotherapy for patients with initially unresectable CLM is for downsizing tumors to the point where they become amenable to a complete resection. This treatment strategy is commonly referred to as conversion therapy, as opposed to neoadjuvant therapy, which is designated to those patients with resectable disease at initial presentation.

The first retrospective reports from France (Adam et al, 2001; Bismuth et al, 1996; Giacchetti et al, 1999) were updated in 2004 with a series of 1439 patients who underwent resection of colorectal liver metastases between 1988 and 1999. Among these, 1104 patients were described who were initially considered to have unresectable disease based on large tumor size, poor tumor location, multinodularity, or presence of extrahepatic disease. After receiving an average of 10 cycles of systemic chemotherapy (5-FU and chronomodulated oxaliplatin), 138 patients (12.5%) demonstrated enough response to become anatomically resectable, but within the median follow-up time of 49 months, 111 (80%) recurred. Recurrence was limited to the liver in 29%. Five-year overall and disease-free survival were 33% and 22%, both of which were lower than for those patients considered resectable prior to chemotherapy (48% and 30%, respectively; P = .01). The authors identified four preoperative factors independently associated with shorter survival: a rectal primary, three or more metastases, maximum tumor size greater than 10 cm, and a carbohydrate antigen (CA) 19-9 greater than 100 U/L. Mean adjusted 5-year survival rates—according to the presence of 0, 1, 2, 3, or 4 of these factors—were 59%, 30%, 7%, 0%, and 0%, respectively (Adam et al, 2004a).

Since those first retrospective reports, prospective trials have provided additional data concerning outcomes of conversion chemotherapy, but few studies report on long-term outcome after resection (Table 87.1). Resectability rates following preoperative chemotherapy for 20 patients presenting with unresectable CLM have been reported as high as 80% (Mentha et al, 2006). Subsequent reports with larger sample sizes provide more modest results with respect to conversion to resectability after chemotherapy (15% to 24%) (Masi et al, 2009; Tournigand et al, 2006). Variability in chemotherapy type, duration, and timing with respect to resection and a lack of standard definitions of resectability make comparison between studies impossible.

Two recent prospective studies compared long-term outcomes between primary resection and secondary resection following systemic therapy. Capussotti and colleagues (2006) found no statistical difference in overall survival after resection in 34 patients who were converted to resectable, compared with 116 patients who underwent immediate partial hepatectomy (median survival 41 vs. 50 months, respectively; P = NS). At a median follow-up of 35 months, a 94% recurrence rate was observed in the conversion group compared with 66% in the immediate-resection cohort (P = .001). Disease-free survival was 9 months in the converted group compared with 37 months in the immediate-surgery group (P = .001). These authors also noted that extrahepatic recurrence after resection was greater in patients who were converted from unresectable to resectable (Capussotti et al, 2006).

The second study by Nuzzo and colleagues (2007) compared the outcomes of 60 initially resectable patients to that of a cohort of 15 patients with initially unresectable CLM who underwent complete resection following conversion chemotherapy. This study also found no significant difference in overall survival between initially resectable and unresectable patients with a mean survival of 46 and 47 months, respectively (P = NS). At a median follow-up of 34 months, disease recurrence rates were higher in initially unresectable patients (53%) compared with those of the primarily resectable comparison group (28%), and 3-year disease-free survival rates were 31% and 58%, respectively (P = .04) (Nuzzo et al, 2007).

In summary, conversion chemotherapy is a reasonable strategy for managing CLM in motivated patients with good performance status; however, this group of patients must understand that the benefit of resection following conversion is lower than if they had presented with resectable disease at the outset. Furthermore, attempting to compare results among studies illustrates the need for standardized chemotherapy regimens and common definitions of resectability.

Combining Systemic Therapy with Surgery

In Vivo Response to Systemic Treatment

It seems clear that chemotherapy improves the results of resection, but it remains unclear whether such therapy is optimally given before or after surgery. One of the potential benefits of administering chemotherapy prior to hepatic resection for CLM is to assess in vivo response of disease. Adam and colleagues (2004b) investigated the response to chemotherapy as a predictor of long-term outcome in 131 patients after potentially curative resection of multiple liver metastases (≥4). After a median of nine courses of 5-FU/LV with either irinotecan or oxaliplatin, they observed objective tumor response in 58 patients (44%), stable disease in 39 (30%), and tumor progression in 34 (26%). Response to chemotherapy correlated with overall survival following hepatectomy at 37%, 30%, and 8%, respectively, at 5 years (P < .001). In another recent retrospective analysis of 88 patients treated with preoperative oxaliplatin or irinotecan-based chemotherapy regimens followed by partial hepatectomy for resectable CLM, Chiappa and colleagues (2009) also noted that response to chemotherapy on restaging was associated with a significantly improved 5-year survival compared with that of nonresponders (71% vs. 15 %; P = .026).

Two studies from Memorial Sloan-Kettering Cancer Center (MSKCC) addressed the question of chemoresponsiveness of CLM and survival in patients who had staged resections. Allen and colleagues (2003) found that the 46 patients who did not progress on chemotherapy administered prior to hepatic resection saw a 5-year survival benefit over that of the 54 patients who did not receive chemotherapy (85% vs. 35%; P = .03). The results of this analysis suggest that a clinical response to chemotherapy can identify a subset of patients with biologically favorable tumors, and treating clinicians can select them for more aggressive therapy. In a separate study by Gallagher and colleagues (2009) of 111 patients from MSKCC who underwent hepatic resection after preoperative chemotherapy, no differences were seen in median overall survival among patients who responded, had stable disease, or showed progression of disease (58 months vs. 65 months vs. 61 months; P = .98); however, it should be noted that the protocol for this evaluation was to proceed with hepatectomy at the first clinical sign of progression, as opposed to proceeding with resection at the first sign of response.

It remains unclear what the optimal duration of preoperative chemotherapy should be and when to proceed with hepatic resection; however, more surgeons are advocating proceeding with hepatic resection at the first signs of tumor response to avoid extended exposure of the liver to cytotoxic chemotherapy (see Chapter 65). To address this question, White and colleagues (2008) reviewed data for 35 patients with CLM who received FOLFOX with or without bevacizumab and evaluated radiologic tumor changes at 2-month intervals after the start of treatment; they found that the mean cumulative tumor reduction among responders (n = 30) was 39% at 2 months, and it increased to 56% at 4 months (P < .01) after commencing therapy. Importantly, no significant incremental tumor size reduction occurred between 4 and 6 months. Although this study was constructed to assess the time of maximal response in initially unresectable patients, these data suggest that 4 months of preoperative therapy may be sufficient to achieve the maximal tumor response in potentially resectable patients.

In summary, close multidisciplinary observation and communication are essential to avoid overtreating patients during preoperative chemotherapy for CLM. Borderline resectable and higher risk patients may benefit from in vivo response testing to systemic treatment.

Chemotherapy-Induced Liver Damage (See Chapter 65)

With increased use of preoperative chemotherapy, treating physicians are becoming more aware of the toxic effects of chemotherapy on liver parenchyma and how these changes affect postoperative outcome (Fong & Bentrem, 2006; Zorzi et al, 2007). Investigators have shown a wide spectrum of histopathologic changes to the underlying liver parenchyma in resection specimens (see Chapter 65 for a detailed description). Prolonged use of 5-FU and irinotecan-based chemotherapy has been associated with fatty liver changes ranging from mild forms of steatosis to more severe forms of steatohepatitis with additional necroinflammatory components (Peppercorn et al, 1998; Vauthey et al, 2006). Oxaliplatin-based regimens have been associated with venoocclusive injuries, termed sinusoidal obstruction syndrome (SOS) (Rubbia-Brandt et al, 2004). Although the association between chemotherapy and histopathologic changes has been well documented, the impact of chemotherapy-associated hepatotoxicity on surgical management of colorectal liver metastases remains somewhat ill defined.

From the transplant literature, we know that hepatic steatosis can impair liver function and postoperative regeneration. In a study of 485 patients undergoing liver resections for neoplasms (325 steatotic livers, 160 matched controls), steatosis was found to be an independent predictor of postoperative complications on multivariate analysis (P < .01) (Kooby et al, 2003). Overall and infective complication rates of 62% and 43% for the marked steatosis group (n = 102) were significantly higher than in the control group, at 35% and 14%, respectively (P < .01). The association between steatosis and previous exposure to chemotherapy was noted. Vauthey and colleagues (2006) systematically analyzed hepatic injury in 158 patients treated with varying preoperative chemotherapy regimens for metastatic CRC and correlated them to postoperative outcomes after hepatic resection. This study distinguished steatosis and steatohepatitis as separate pathologic findings and demonstrated that steatohepatitis induced by irinotecan-based chemotherapy was associated with an increase in 90-day mortality following major hepatectomy for CLM (14.7% vs. 1.4%, no steatohepatitis; P = .001). Furthermore, patients with steatohepatitis have a higher risk of death from postoperative liver failure compared with all other patients (6% vs. 1%; P = .01).

Karoui and colleagues (2006) reported that chemotherapy was significantly associated with sinusoidal dilation (P = .005), present in 49% of patients in the chemotherapy group (two thirds receiving oxaliplatin) compared with 14% in controls. Furthermore, significantly greater postoperative morbidity after major hepatectomy was found in the chemotherapy group compared with the control group (38% vs. 14%; P = .03), which was mostly attributed to the high incidence of transient liver failure in the chemotherapy group (11% vs. 0% in controls; P = NS). The addition of bevacizumab to oxaliplatin-based chemotherapy may have a protective effect on sinusoidal injury. Ribero and colleagues (2007) found that the addition of bevacizumab to oxaliplatin-based chemotherapy reduced the incidence of sinusoidal dilation of any grade by half (27% vs. 54%) and lowered severe, grade 2 to 3 sinusoidal dilation (8% vs. 28%) to about a third of reviewed pathologic specimens.

Although multiple studies support that patients with damaged livers have higher perioperative morbidity and mortality rates compared to those with healthy livers, others that directly compare perioperative outcome with and without preoperative chemotherapy for CLM have not been able to demonstrate this phenomenon (Pawlik et al, 2007; Scoggins et al, 2009). The reason for this discrepancy likely lies in factors of timing and dose of preoperative chemotherapy treatments and extent of hepatic resection. Both prolonged chemotherapy treatments and short intervals between the cessation of chemotherapy have been found to be associated with significantly increased morbidity (Aloia et al, 2006; Welsh et al, 2007). Although the optimal regimen and duration of systemic chemotherapy are still being assessed, dialogue between treating medical and surgical oncologists regarding the timing of surgery is critical. Theoretically, a longer interval may provide the liver time to recover from any reversible hepatotoxic effect of chemotherapy. On the other hand, a longer interval prior to hepatic resection may result in progression of disease. With this in mind, most surgeons will proceed with resection between 3 and 6 weeks after the last dose of chemotherapy.

Management of Synchronous Liver Metastases

Synchronously diagnosed CRC liver metastases pose additional challenges regarding the timing, sequence, and method of treatment. The traditional approach would be resection of the colorectal primary followed by a course of adjuvant chemotherapy and hepatic resection in the absence of interval disease progression; however, in the era of more active chemotherapy, this approach remains most applicable for patients with unresectable liver metastases, with the hope of conversion to secondarily resectable status. Alternative treatment pathways have also been proposed for patients with initially resectable synchronous liver disease (Fig. 87.1). The first issue specific to this patient subset is the question of whether the bowel or liver should be addressed first, or if they should both be removed at the same time.

FIGURE 87.1 Treatment pathways for colorectal cancer patients with synchronous liver metastases. *Primary goal in patients with obstructing or bleeding tumors. †Preferred for cases of minor hepatectomy or for selected cases of major hepatectomy. ‡Option for advanced local disease and initially resectable liver disease. §Option for selected patients with limited bilobar disease.

In recent years, two large studies have confirmed previous smaller reports that simultaneous colon and hepatic resections are safe and may demonstrate benefits of reduced morbidity and mortality compared with staged procedures (Martin et al, 2003; Reddy et al, 2007). In the earlier report, by Martin and colleagues (2003), simultaneous resections were more likely performed for right colon primaries and for smaller and fewer liver metastases, and they resulted in similar rates of major complications (27% vs. 25%; P = NS) and mortality (4% vs. 4%; P = NS) for patients undergoing major hepatic resections between the groups. Reddy and colleagues (2007) found similar morbidity between simultaneous and staged minor hepatectomy (overall 36% and 38%; P = NS), but a significantly higher rate of severe morbidity (36.1 vs. 17.6%; P = .05) and mortality (8.3 vs. 0%; P = .007) was reported after simultaneous major hepatic resection. Long-term outcomes are similar among simultaneous and staged hepatic resections for synchronous CLM, and more than one study has shown that timing of hepatic resection does not affect long-term outcome (Minagawa et al, 2006; Tanaka et al, 2004).

Another more recent report by de Haas and colleagues (2010) confirms the safety of simultaneous resection, but it suggests that this strategy is an independent predictor of earlier tumor recurrence compared with the delayed hepatectomy approach. The authors compared outcomes from 55 patients who had simultaneous hepatic and colorectal resections to 173 patients who had the staged approach. The morbidity rate was actually lower in the simultaneous group (11% vs. 25%; P = .015), but more recurrences were observed in the simultaneous group at 3 years (85% vs. 64%; P = .002).

The “liver first” approach has been introduced as alternative treatment strategy for patients with advanced CRC with synchronous liver metastases. Patients receive chemotherapy before the liver resection and then undergo resection of the colorectal primary at a later date. This approach resulted from the improved efficacy of chemotherapy and focuses on delivering chemotherapy to the liver without potential delays as a result of prolonged recoveries from colon surgery. This idea is based on the belief that the liver is the component that will ultimately limit survival. Secondly, authors have raised concerns of enhanced metastatic tumor growth after removal of the primary tumor (Demicheli et al, 2008). Published reports of this approach are limited to small case series. Mentha and colleagues (2008) have recently updated their initial series and reported 35 patients, of which 30 completed the pathway. With a clinical risk score of 3 or higher, the reported 5-year survival of 31%, with a median survival of 44 months, is encouraging. Limitations of this approach include risks of secondary obstruction, disease progression, and chemotherapy-induced liver damage.

The role of preoperative chemotherapy in patients with resectable synchronous liver metastases remains a subject of debate. Despite the theoretic benefits of preoperative chemotherapy, data on the actual survival benefits are equivocal. In a study of 151 patients initially evaluated at MSKCC, Fahy and colleagues (2009) reported an overall disease-specific survival of 26.7 months after diagnosis of synchronous colon cancer. Both liver resection and preoperative chemotherapy were treatment modalities significantly associated with survival, but most patients received some sort of postresection therapy. Reddy and colleagues (2009) specifically addressed timing of chemotherapy in their large multiinstitutional study of 499 patients undergoing resection for synchronous CLM. Postoperative chemotherapy alone was independently associated with recurrence-free survival, if given for 6 months or longer (HR, 0.75; P = .04), and with overall survival, if administered for 2 months or longer (HR, 0.59; P = .001). Preoperative chemotherapy alone was not associated with improved survival, but patients with perioperative chemotherapy had similar outcomes to patients who received postoperative chemotherapy alone, thus given the lack of level 1 evidence, the available data do not support use of prehepatectomy chemotherapy uniformly in all resectable synchronous CLM.

Among selected patients prehepatectomy therapy may be useful. Tanaka and colleagues (2003) found that prehepatectomy chemotherapy was associated with improved survival (5-year survival of 39% vs. 52%; P = .04) in a group of 71 patients with bilateral multiple, mostly synchronous CLM. Interestingly, the authors also noted a lower rate of major hepatectomy in their patients who received prehepatectomy chemotherapy (81% vs. 100%; P = .027). Given the fact that patients who received preoperative chemotherapy had unresectable extensive bilobar disease, this is one of the few studies that indicate the possibility for smaller resection after effective treatment; however, no studies directly compare extent of resection to the originally planned procedure before chemotherapy.

In rectal cancer patients, the potential need for locoregional radiotherapy further complicates the matter. Neoadjuvant chemosensitizing radiation has proven to lower local relapse rates to less than 10% (range, 6% to 8%) in locally advanced rectal cancer (T3 to T4) in several prospective randomized trials (Roh et al, 2009; Sauer et al, 2004). This outcome is extremely valuable, because surgical salvage options are slim and are generally associated with poor quality of life and poor survival (Salo et al, 1999); however, this treatment modality has not proven to be beneficial in terms of overall survival, and its role in patients with stage IV disease is unclear. Several potential approaches to integrating neoadjuvant chemoradiation exist in this stage of disease, and the question is in what sequence neoadjuvant chemotherapy, radiation, or chemoradiation should be given. This decision naturally is dictated by the toxicity of such extensive therapy and based on the needs of the individual patient. Although simultaneous resection can theoretically be achieved through one long midline incision, most surgeons recommend a staged procedure with initial resection of the rectal primary (Reddy et al, 2007). Early reports of the liver-first approach have also been published from a European Center (Verhoef et al, 2009). Of 22 patients with advanced local rectal primaries and synchronous liver metastases in this series, 16 patients (73%) completed the full treatment protocol, and all were alive after a median of 19 months. Morbidity of this approach was equivalent to that seen with the rectum-first approach and simultaneous resections in a second small case series (van der Pool et al, 2010).

Extrahepatic Disease

The presence of extrahepatic disease in the setting of CLM has traditionally been considered a contraindication for hepatic resection. With better systemic chemotherapy, survival has improved in all stages of disease, and surgeons have become more aggressive in considering resection in patients who were not candidates in the past. Several centers have published their experience with liver resection in patients with concomitant extrahepatic disease. Carpizo and colleagues (2009) reported the outcome of 127 patients with extrahepatic disease, which comprised 9% of all patients undergoing liver resection at MSKCC between 1997 and 2007. Overall survival of 47% and 26% at 3 and 5 years was significantly inferior to the 67% and 49% (P < .001) observed in patients without extrahepatic disease. Importantly, the survival observed in patients with extrahepatic disease in this study is similar to that observed for patients with only liver disease resected during the 1980s and 1990s.

It is noteworthy that recurrence was observed in 95% of patients in this group with median follow-up of 24 months. This included both local extrahepatic invasion and distant metastatic sites including lung, ovaries, peritoneum, and regional hepatic lymph nodes. Although this study found that patients with perihepatic lymph node metastases had worse survival than those with lung and ovarian metastases, with a median survival of 26, 45, and 82 months, respectively (P < .05). The incidence of occult microscopic lymph node involvement ranged from 2% to as high as 28% (Beckurts et al, 1997), likely because of the fact that hepatic lymph node dissection is not commonly performed. Adam and colleagues (2008a) found regional lymph node metastases in 6% of 763 patients undergoing hepatic resection for CLM and reported a predicted 5-year survival that was significantly inferior compared with that of patients without nodal involvement (18% vs. 53%; P = .001). The authors pointed out that all patients who survived 5 years had lymph node metastases in the hepatoduodenal ligament, and no long-term survivors were among those with celiac or retroperitoneal lymph node metastases.

Jaeck and colleagues (2002) prospectively performed systematic portal lymphadenectomy on 160 patients and examined differences in survival of different subsites; overall, metastatic lymph nodes were found in 17 patients (11%), with a 3-year survival of 19%. Similarly, this study distinguished between hepatoduodenal ligament nodes (zone 1) and celiac/common hepatic artery nodes (zone 2) and found a substantially worse survival for patients with zone 2 compared with zone 1 lymph node involvement (0% 1-year vs. 38% 3-year survival). The same group recently updated their results of 45 patients with regional lymph node involvement (Oussoultzoglou et al, 2009). After a change in multimodal treatment strategies, the vast majority received modern oxaliplatin- or irinotecan-based chemotherapy, with or without bevacizumab or cetuximab, and the surgical approach shifted toward a more aggressive lymphadenectomy. With a median follow up of 26 months, 3-year overall survival was increased to 29.7%, and 5-year survival of 17.3% was reported. Interestingly, no significant survival difference was found among patients with zone 1 and 2 nodal involvement, with a median survival of 19 and 20 months (P = .44), respectively. Elevated carcinoembryonic antigen (CEA) greater than 200 µg/L was found in 82% of patients and was found to be the only preoperative factor independently associated with overall survival (odds ratio [OR], 7.1; P < .001).

Given recent data, lymphadenectomy can provide a chance for long term-survival in selected patients with extrahepatic disease, and that may outweigh any additional associated morbidity. Data regarding resections of distant sites of extrahepatic disease are limited, and the surgical approach must be considered on a patient-by-patient basis.

Portal Vein Embolization and Chemotherapy

Preoperative portal vein embolization (PVE) is used to promote compensatory hypertrophy in patients whose future liver remnant (FLR) may be insufficient to support them during the recovery phase following major hepatic resection. Techniques, indications, and results of PVE are outlined in Chapter 93A, Chapter 93B ; they will only be discussed briefly here, as they may be affected by concurrent systemic chemotherapy or underlying chemotherapy-induced liver damage.

PVE increases the safety of hepatectomy for patients with marginal hepatic reserve. The average increase of the estimated FLR is between 8% and 16% at 2 to 4 weeks after PVE, depending on the measurement technique and underlying liver disease (Covey et al, 2005; Madoff et al, 2003; Vauthey et al, 2000). Long-term survival has been found to be comparable for patients with and without PVE before major hepatic resection for CLM, at 40% and 38% at 5 years (Azoulay et al, 2000).

Given the cytotoxic nature of chemotherapeutic agents and their ability to hinder cell proliferation, the question arises whether liver regeneration and hypertrophy are altered by concurrent chemotherapy. In particular, the inhibition of vascular endothelial growth factor (VEGF), as targeted by bevacizumab, has been shown to impair liver regeneration in animal models after partial hepatectomy (Bockhorn et al, 2007). One of the first reports to address this issue was from Goéré and colleagues (2006) in France. Data from 10 patients who had no chemotherapy between static portal embolization and surgery were compared with data from another 10 patients who had continuous chemotherapy. No significant difference was observed in FLR growth between the groups, but the sample size was small. Covey and colleagues (2008) further addressed this question in a study of 100 patients undergoing PVE before resection of CLM, 43 of whom received concurrent chemotherapy of various regimens. This study found no statistically significant difference in liver growth between the patients who had concurrent chemotherapy treatment and those who did not (22% vs. 26%; P = NS). Confirming results were presented by Zorzi and colleagues (2008), who showed no difference in FLR growth after PVE in patients treated without chemotherapy, those treated with systemic chemotherapy, and those treated with chemotherapy that included bevacizumab (10.1% vs. 8.8% vs. 6.8%; P = NS). More recently, one paper suggested that a bevacizumab-containing chemotherapy regimen impairs FLR hypertrophy after PVE (Aussilhou et al, 2009). The authors found a significantly smaller increase in FLR in the bevacizumab-treated group (n = 13) compared with the group that did not receive bevacizumab (n = 27) in their regimens (561 + 171 cm³ vs. 667 + 213 cm³; P = .031). Based on existing data, administration of systemic therapy appears to be acceptable around the time of PVE, but it may be prudent to avoid bevacizumab in these patients.

Data regarding the impact of chemotherapy-induced liver injuries on liver regeneration after PVE are scant. A recent study showed that steatosis was associated with significantly lower hypertrophy volume and hypertrophy ratios after right PVE in 35 patients after hemihepatectomy (Tanaka et al, 2010). Based on existing data, it appears safe to consider PVE in patients who receive chemotherapy prior to hepatic resection; however, the actual benefit of PVE for this set of patients still remains unclear. Our recommendation is to limit the use of PVE to patients who will undergo major hepatic resection with an FLR less than 25%. Further data on PVE in patients with CLM are needed.

Two-Stage Hepatectomy

Two-stage hepatectomy is a relatively new strategy to expand the criteria of resectability. Using this approach, complete resection is feasible in selected patients with bilateral CLM. PVE or portal vein ligation is often required after the first resection to promote hypertrophy of the FLR and to ensure sufficient liver remnant. In the first description by Adam and colleagues (2000), the authors proposed to remove as many tumor sites as possible during the first operation, followed by a course of chemotherapy, with or without PVE, and second-stage resection to clear the remaining liver. Among 13 patients who had both resections, reported 3-year survival was 35%. This strategy was then modified by Jaeck and colleagues (2004) because of concerns of accelerated tumor growth during the regeneration period after major hepatectomy and PVE. The new strategy is to initially remove tumor in the FLR, clear one side of the liver in a usually smaller operation prior to PVE, and resect the remaining tumor-bearing liver in a second operation.

Success rates and long-term outcome of patients who have both hepatic resections largely depend on patient selection and utilization of modern chemotherapy. The literature reports success rates from 69% to 92% (Adam et al, 2000; Jaeck et al, 2004; Tanaka et al, 2007; Wicherts et al, 2008), but perioperative morbidity and mortality rates are uniformly higher after the second hepatectomy. In the largest series of 41 patients who underwent two-stage hepatectomy, the cumulative morbidity was 79%, with an overall morbidity of 20% and 59% and mortality of 0% and 7% after the first- and second-stage hepatectomy, respectively (Wicherts et al, 2008).

The best long-term results were presented in a study by Chun and colleagues (2007) from the MDACC. In this study, all patients received a course of modern oxaliplatin- or irinotecan-based chemotherapy preoperatively, and 81% received additional chemotherapy postoperatively. With a median follow-up of 25 months, they reported an astonishing 3-year overall and disease-free survival of 86% and 51%, respectively, which was favorable when compared with patients who had a one-stage hepatectomy. Although this series presents a well-selected patient population, it demonstrates that in combination with modern chemotherapy, two-stage hepatectomy offers a chance of long-term survival for patients who would otherwise not be candidates for resection.