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INTRODUCTION — Hepatic metastatic disease from colorectal cancer (CRC) is a significant clinical problem. The liver is the dominant metastatic site for patients with CRC, and although two-thirds of affected patients have extrahepatic spread, some have disease that is isolated to the liver. For patients with isolated liver metastases, regional treatment approaches may be considered as an alternative to or in combination with systemic chemotherapy.
The available regional treatments for hepatic metastases from CRC include surgical resection, local tumor ablation (ie, instillation of alcohol or acetic acid directly into the metastatic lesions, radiofrequency ablation [RFA]), regional hepatic intraarterial chemotherapy or chemoembolization, and radiation therapy (RT). Among these treatments, only surgery is associated with a survival plateau.
Although hepatic resection used to be reserved for patients with a maximum of three lesions in the same lobe if it was possible to achieve 1 cm margins and those without portal lymph node metastases, all of these "rules" have been challenged in the modern era, particularly with advancements in both surgical technique and systemic therapy . Profound improvements in the outcomes of patients with metastatic CRC over the past 15 years have been attributed to increased use of hepatic resection in selected patients and more effective chemotherapy . (See "Systemic chemotherapy for metastatic colorectal cancer: Completed clinical trials".)
As a result, the criteria for defining which patients are suited for surgical therapy have evolved, and many surgeons take an aggressive stance in the management of hepatic metastases.
This topic review will focus on the selection of patients for and benefits of resection, and integration of systemic chemotherapy. Surgical techniques for hepatic resection and results for local ablation, regional chemotherapy into the hepatic artery, RT, and management of the primary tumor in patients who present with stage IV disease are addressed elsewhere. (See "Overview of hepatic resection" and "Nonsurgical local treatment strategies for colorectal cancer liver metastases" and "Hepatic resection techniques" and "Preoperative portal vein embolization" and "Locoregional methods for management and palliation in patients who present with stage IV colorectal cancer" and "Neoadjuvant chemoradiotherapy and radiotherapy for rectal adenocarcinoma", section on 'Local treatment for patients with synchronous liver metastases'.)
BIOPSY CONFIRMATION — A biopsy may be indicated to confirm the diagnosis, depending upon the clinical picture. The risk of tract seeding from percutaneous fine needle aspiration (FNA) biopsy appears small (only a handful of case reports are described in journals listed in Medline [3-9]), although this complication was described in 5 of 51 cases of biopsy-proven hepatic colorectal metastases in one series . Needle tract seeding more often complicates FNA biopsy of primary liver tumors. (See "Clinical features and diagnosis of primary hepatocellular carcinoma".)
During laparotomy or laparoscopy for colectomy, if confirmation of liver metastases is clinically indicated, needle biopsy should be performed rather than incising into a tumor with a scalpel or with biopsy forceps to minimize the risk of peritoneal seeding. In patients with multiple suspicious liver lesions, biopsy of a single lesion to confirm the presence of metastases is generally sufficient.
SURGICAL RESECTION — Resection offers the greatest likelihood of cure for patients with liver-isolated colorectal cancer (CRC). In surgical case series, five-year survival rates after resection range from 24 to 58 percent, averaging 40 percent (table 1), and surgical mortality rates are generally <5 percent [3-5,7-18]. Subgroups with advanced age, comorbid disease, and synchronous hepatic and colon resection may have higher procedure-related mortality and worse long-term outcomes. As an example, five-year survival rate was only 25 percent in a population-based retrospective report of 3957 US Medicare enrollees undergoing hepatic resection for CRC liver metastases . Even so, five-year survival rates with the most active systemic chemotherapy regimens are only 10 to 11 percent, only about one-fifth of whom have a sustained disease remission . (See "Systemic chemotherapy for metastatic colorectal cancer: General principles", section on 'Chemotherapy versus supportive care'.)
Approximately one-third of five-year survivors suffer a cancer-related death, while those who survive 10 years appear to be cured . In an analysis of 612 consecutive patients who underwent resection of CRC liver metastases and were followed for at least 10 years, there were 102 actual 10-year survivors (17 percent), and only one patient experienced a disease-specific death after 10 years of survival.
Because of its clear survival impact, surgical resection is the treatment of choice when feasible. The percentage of patients with isolated hepatic metastases who are amenable to potentially curative resection is a bit of a moving target since surgeons may have different interpretations of "resectable." It is safe to say that a majority of patients, with metastatic disease are not curative surgical candidates because of tumor size, location, multifocality, or inadequate hepatic reserve.
Some patients with initially unresectable disease may become resectable after induction chemotherapy. While this is commonly stated, probably no more than 5 to 15 percent of patients fall into this category when an assessment of resectability is done initially by a liver surgeon. . Updated guidelines from the National Comprehensive Cancer Network (NCCN) suggest that patients who appear to have initially unresectable metastatic CRC be categorized as potentially convertible or unconvertible. Patients whose disease is felt to be unconvertible should be referred for alternative treatment (most often palliative chemotherapy), while induction chemotherapy is appropriate for those whose disease is potentially convertible. (See 'Neoadjuvant chemotherapy' below.)
Patient selection — The optimal selection of patients for hepatic resection is evolving, and the criteria for resectability differ among individual liver surgeons regarding borderline cases, from center to center and from country to country. One consensus statement defined absolute unresectability as non-treatable extrahepatic disease, unfitness for surgery, or involvement of more than 70 percent of the liver or six segments (figure 1) . (See 'Conversion therapy for initially unresectable metastases' below.)
Risk scoring systems (such as the clinical risk score  and others [7,24,25]) to predict which patients with metastatic CRC are most likely to benefit from resection are of limited clinical utility; none has sufficient discriminatory ability to accurately predict disease-specific survival at all time points following resection . Utility is particularly uncertain among patients undergoing neoadjuvant chemotherapy [27-29]. Whether changes in the clinical risk score after treatment translates into improved outcomes after resection is unknown (see 'Conversion therapy for initially unresectable metastases' below). Not enough is yet known about the prognostic value of molecular markers in patients being considered for resection of metastatic disease in the liver, but it is possible, if not likely, that certain biomarkers will be identified that may reflect either more or fewer reasons to consider metastasectomy.
Modern multidisciplinary consensus defines resectable CRC liver metastases simply as tumors that can be resected completely, leaving an adequate liver remnant . For resection to be considered, most surgeons would require that there be no radiographic evidence of involvement of the hepatic artery, major bile ducts, main portal vein, or celiac/paraaortic lymph nodes , and adequate predicted functional hepatic reserve postresection. Preoperative liver magnetic resonance imaging (MRI) and intraoperative ultrasound offer the optimal assessment of the number, size, and proximity of tumors to key vascular and biliary structures. Complete resection must be feasible. There should be no unresectable extrahepatic sites of disease, and the primary tumor should have been resected for cure .
Concurrent resection of hepatic and extrahepatic disease in well-selected patients is associated with a possibility of long-term survival, particularly if the extrahepatic disease is surgically resectable lung or ovarian metastases . (See "Surgical resection of pulmonary metastases: Outcomes by histology" and "Locoregional methods for management and palliation in patients who present with stage IV colorectal cancer".)
Number and location of metastases — Contrast-enhanced MRI of the liver identifies more hepatic lesions than are visualized by computed tomography (CT), especially in the presence of background fatty liver change , and is the preferred first-line imaging study for evaluating CRC liver metastases in patients who have not previously undergone therapy. (See "Clinical presentation, diagnosis, and staging of colorectal cancer", section on 'Liver MRI'.)
As noted above, the optimal selection of patients who are candidates for resection is evolving. In the past, contraindications to liver resection were defined by retrospective series and recapitulated in a large multi-institutional review of 856 patients . Based upon these analyses, surgeons have been reluctant to offer resection to patients with more than three lesions, those with bilobar distribution (ie, tumor involving any segments of the left and right hemi-liver), those in whom it was not possible to achieve 1 cm margins, patients with portal lymph node or other extrahepatic metastases, and those with liver metastases from cancers other than colorectal tumors .
However, these relative contraindications have been challenged :
●With safer surgery and better chemotherapy, hepatic resection is playing an increasing role in patients with multiple, even bilobar tumors [36-43] (see 'Neoadjuvant chemotherapy' below and 'Therapy after resection of liver metastases' below). As an example, in a report of 484 patients with multiple metastases (136 with ≥4, 36 with ≥8) 5-and 10-year survival was 47 and 29 percent . Even patients with ≥8 metastases had a five-year survival rate of 24 percent.
A two-stage approach to hepatic resection may be needed in the presence of multiple bilobar metastases. (See "Overview of hepatic resection", section on 'Type and extent of resection'.)
●The surgical community has generally advocated for resection margins of 10 mm or greater in order to minimize local recurrence and optimize overall survival. However, advances in surgical equipment and adjunctive intraoperative ablative techniques have led multiple groups to revisit this 10 mm requirement [44,45], and their findings have altered the algorithm for management of CRC liver metastases. This subject is discussed in detail elsewhere. (See "Overview of hepatic resection", section on 'Resection margins'.)
●One of the classic contraindications to hepatectomy is the presence of portal lymph node metastases, thought to indicate systemic disease that could not be successfully treated surgically. This view has been challenged [31,46-49].
A major problem is the prediction of metastatic lymph nodes in the hepatic pedicle in patients with CRC liver metastases. In one analysis, the positive predictive value (PPV) of preoperative CT was only 56 percent, and even intraoperative evaluation had a PPV of only 43 percent . Accurate oncologic assessment requires systematic pedicular lymph node clearance, although this maneuver is not known to be of any therapeutic value.
The presence of portal node metastases is not inevitably associated with distant metastases. Jaeck et al reported outcomes of complete hepatic pedicle lymphadenectomy in patients with CRC liver metastases . Nineteen percent of patients survived three years despite portal node metastases. Outcome was more favorable if nodal involvement was limited to the porta as compared with along the common hepatic artery (three-year survival 38 versus 0 percent, respectively). An important caveat is that this was a retrospective review of highly selected patients who did not have enlarged portal nodes detected preoperatively. Whether this principle can be extrapolated to patients with grossly enlarged nodes is unclear.
●Similarly, the presence of other sites of limited extrahepatic metastases (particularly lung) should not be considered a contraindication to resection as long as the disease is amenable to complete extirpation. However, outcomes in this group are not as favorable, particularly when there are >6 liver metastases . (See "Surgical resection of pulmonary metastases: Outcomes by histology", section on 'Significance of synchronous or metachronous liver metastases'.)
PET scans — The role of integrated positron emission tomography (PET)/CT in selecting optimal surgical candidates is uncertain. However, until additional data are available, including long-term follow-up of the Canadian trial , we agree with guidelines from the NCCN, which recommend a staging PET scan for patients who appear to have potentially surgically curable metastatic CRC. An important caveat is that PET can be unreliable in this setting, especially after chemotherapy, since changes in tumor metabolism may be induced by chemotherapy but the cancer may remain viable.
At least in theory, whole body PET scans have the potential to identify radiographically occult extrahepatic disease and optimize the selection of appropriate candidates for hepatic resection, mainly by reducing nontherapeutic laparotomy rates [3,53-55]. However, the data supporting a benefit for PET in this setting are mixed:
●The benefit of adding PET to the staging strategy was subsequently shown in a randomized trial in which 150 patients with CRC liver metastases selected for hepatic resection by CT were randomly assigned to triple-phase contrast-enhanced CT imaging only or CT plus a separate PET scan . The primary outcome measure was the number of futile laparotomies (any laparotomy that did not result in complete tumor treatment or that did not result in a disease-free survival period of at least six months). The addition of PET significantly reduced the number of futile surgeries (28 versus 45 percent) and prevented unnecessary surgery in one of every six patients.
Two caveats must be considered when interpreting these results. First, this study used separate contrast-enhanced CT and PET images and not the increasingly popular integrated PET/CT imaging, in which both PET and CT are performed sequentially during a single visit on a hybrid PET/CT scanner. The CT component of integrated PET/CT imaging is performed in most institutions without the use of intravenous contrast material, which compromises the detection of small metastases both within and outside of the liver. At some institutions, PET/CT is carried out with intravenous contrast, but this practice is not widespread.
●A benefit for integrated PET/CT could not be confirmed in a later randomized trial in which 404 patients with potentially resectable isolated CRC liver metastases (as established by contrast-enhanced CT of the chest, abdomen, and pelvis within 30 days of randomization) were randomly assigned to preoperative integrated PET/CT or no PET/CT . Of the 263 patients who underwent preoperative PET/CT, only 21 (8 percent) had a change in surgical management; these included seven (2.7 percent) who did not undergo laparotomy, four who had more extensive hepatic surgery, and nine (3.4 percent) who had additional organ surgery. Liver resection was performed in a similar proportion of both groups (91 versus 92 percent of the control group), and at a median follow-up of 36 months, survival did not differ among the groups (two-year survival 80 percent in both groups).
●The superiority of PET over CT alone for detection of extrahepatic disease was also suggested in a systematic overview of retrospective data, which utilized a scoring system to weigh the individual studies according to the quality of the data and the clinical impact of the radiographic findings . For the six articles judged to be of the highest quality [57-62], the pooled sensitivity and specificity for PET were 80 and 92 percent, respectively, for hepatic disease, and 91 and 98 percent, respectively, for extrahepatic disease . The corresponding values for CT were 83 and 84 percent, respectively, for hepatic metastases, and 61 and 91 percent, respectively, for extrahepatic metastases. The percent change in clinical management from the performance of PET ranged from 20 to 32 percent (average 25 percent).
The results of restaging PET scans (particularly if negative) must be interpreted in the context of recent therapy. Chemotherapy may reduce the sensitivity of PET for the detection of liver metastases, thought due to decreased cellular metabolic activity following chemotherapy [63-65]. In one study, the false-negative rate for hepatic metastases of a PET scan performed within four weeks of chemotherapy was 87 percent . Surgical decisions should not be based on PET scan results.
The role of integrated PET/CT in selecting optimal surgical candidates is uncertain. However, until additional data are available, including long-term follow-up of the Canadian trial, we agree with guidelines from the NCCN, which recommend a staging PET scan for patients who appear to have potentially surgically curable metastatic CRC. An important caveat is that PET can be unreliable in this setting, especially after chemotherapy.
Selecting patients for diagnostic laparoscopy — Although diagnostic laparoscopy can identify occult intraperitoneal metastases, thereby preventing unnecessary laparotomy, it is not necessary in all patients. Laparoscopy is usually reserved for those thought to be at the highest risk for occult metastatic disease.
Some data suggest that these patients can be identified using a clinical risk score, derived from five preoperative criteria (nodal positivity, relapse free interval <12 months, more than one hepatic tumor, CEA level >200 ng/mL within one month of surgery, and size of largest hepatic tumor >5 cm), which were significant predictors of outcome from hepatic resection in multivariate analysis [11,66].
However, the clinical risk score is not used by the vast majority of hepatobiliary surgeons, mainly because it was derived from a database of patients treated in the fluorouracil/leucovorin era, before chemotherapy was routinely administered prior to liver resection, and before resection of numerous liver lesions became commonplace. In modern treatment paradigms, laparoscopy is infrequently performed, particularly since many patients have undergone surgical exploration of the peritoneum at the time of resection of a synchronous primary tumor.
We use diagnostic laparoscopy in patients with a suspicion of small volume carcinomatosis on radiographic imaging studies (ie, CT, MRI, or PET) and for selected other cases at high risk (eg, a metachronous presentation with several liver metastases that do not respond to chemotherapy). Given current imaging, diagnostic laparoscopy is becoming less and less common.
NEOADJUVANT CHEMOTHERAPY — The availability of increasingly effective systemic chemotherapy has prompted interest in preoperative or neoadjuvant systemic chemotherapy prior to liver resection. Initial systemic chemotherapy is often undertaken as a means of assessing the natural history of metastatic disease prior to embarking on metastasectomy (particularly in patients with a synchronous presentation of metastatic disease). However, neoadjuvant systemic chemotherapy also has the potential to convert some patients with initially unresectable large or critically located liver metastases to resectable disease, although the true frequency with which this occurs is probably low. The optimal selection criteria, specific regimen and duration of neoadjuvant chemotherapy, and the best way in which chemotherapy should be interdigitated with surgery in patients who present with synchronous metastatic disease  have not been defined.
The growing number of reports describing liver toxicity and higher rates of perioperative morbidity in patients undergoing resection after receiving oxaliplatin or irinotecan-based neoadjuvant chemotherapy has somewhat tempered enthusiasm for this approach, particularly in patients with a small number of initially resectable liver metastases.
We recommend the following approach:
●For low-risk (medically fit, four or fewer lesions, metachronous, liver only site), potentially resectable patients, initial surgery rather than neoadjuvant chemotherapy should be chosen, followed by postoperative chemotherapy.
●For patients who have higher risk, borderline resectable or unresectable disease, neoadjuvant chemotherapy is the preferred approach.
Regardless of the specific regimen chosen, the duration of neoadjuvant chemotherapy should be limited, radiographic response assessment performed at approximately six-week intervals, and surgery undertaken as soon as the metastases become clearly resectable. Liver resection should be delayed at least four weeks after completion of chemotherapy, six to eight weeks if bevacizumab was a component of therapy. (See 'Chemotherapy-related liver toxicity' below.)
Chemotherapy-related liver toxicity — Enthusiasm for systemic chemotherapy prior to hepatic resection has been tempered by reports of long-lasting steatohepatitis (chemotherapy-associated steatohepatitis [CASH]), vascular injury, and noncirrhotic portal hypertension (also termed nodular regenerative hyperplasia) in the livers of patients treated with preoperative irinotecan- or oxaliplatin-containing chemotherapy regimens [68-79] (see "Noncirrhotic portal hypertension", section on 'Idiopathic noncirrhotic portal hypertension (including nodular regenerative hyperplasia)' and "Systemic chemotherapy for nonoperable metastatic colorectal cancer: Treatment recommendations"):
●Hepatic sinusoidal abnormalities (termed sinusoidal obstruction syndrome) have been described that are similar to those that characterize veno-occlusive disease, predominantly in patients receiving oxaliplatin prior to hepatic metastasectomy [72,75,76,78-83]. (See "Diagnosis of hepatic sinusoidal obstruction syndrome (veno-occlusive disease) following hematopoietic cell transplantation".)
In one study, such changes were present in 44 (51 percent) of 87 hepatic specimens from patients who had received preoperative chemotherapy, 77 percent oxaliplatin-containing . None of these changes were seen in the 66 patients undergoing liver resection who had not received preoperative chemotherapy.
●In addition to vascular changes, nodular regenerative hyperplasia (noncirrhotic portal hypertension, sometimes precluding subsequent resection) has been reported in patients treated with neoadjuvant oxaliplatin plus fluorouracil (FU) for liver metastases . (See "Noncirrhotic portal hypertension", section on 'Idiopathic noncirrhotic portal hypertension (including nodular regenerative hyperplasia)'.)
●Irinotecan-containing regimens are more often associated with steatosis and steatohepatitis [71,75,79,83]. One report compared outcomes from hepatic metastasectomy in 325 patients with steatosis and 160 patients without steatosis . Patients with steatosis were more likely to have been treated with preoperative chemotherapy (including 66 percent of those with marked steatosis and 55 percent of those with mild steatosis, compared to 38 percent of the control group). The presence of marked steatosis was associated with a trend toward higher 60-day mortality, and marked steatosis was also an independent predictor of complications following hepatic resection.
Steatohepatitis has been observed more frequently after chemotherapy in patients with a higher body mass index, which may explain why this complication is reported more frequently in United States studies , while vascular lesions are seen more commonly in Europeans [69,71,72,76,78,80,81].
There are conflicting data as to whether sinusoidal damage or steatosis/steatohepatitis increases the risk of perioperative morbidity/mortality [75,76,80,84-88]:
●In an early study, patients with steatohepatitis had a significantly higher 90-day mortality rate as compared with those without steatohepatitis (15 versus 2 percent, respectively) .
●In a systematic review of a consolidated database of 788 patients undergoing hepatectomy, an increase in postoperative major morbidity and liver surgery-specific complications was observed among those patients with severe sinusoidal dilatation and steatohepatitis (but not steatosis); postoperative liver failure occurred more often in patients with severe sinusoidal dilation .
Others suggest that risk depends on the duration and/or timing of preoperative therapy [76,86,87]:
●In one report, administration of more than 12 weeks of chemotherapy, or an interval of four or fewer weeks between stopping chemotherapy and resection predisposed patients to more postsurgical complications, higher rates of reoperation, and longer hospital stay .
●Others advocate limiting chemotherapy to four cycles (16 weeks) if surgery is planned as treatment for >16 weeks increases risk of chemotherapy-associated liver injury and postoperative complications without improving pathologic response .
Emerging data suggest utility for superparamagnetic iron oxide-enhanced magnetic resonance imaging (MRI) in the preoperative detection of sinusoidal damage in patients who have received neoadjuvant chemotherapy. In one report, 24 of 60 patients treated with neoadjuvant chemotherapy (mostly 12 or more weeks of an oxaliplatin-based regimen) were suspected of having moderate to severe sinusoidal obstruction by MRI, and 23 cases were confirmed at surgery . The sensitivity, specificity, positive predictive value, and negative predictive value of MRI were 87, 89, 83, and 92 percent, respectively. This MRI technique is not widely available.
Furthermore, whether patients who are identified noninvasively as having this pattern of liver damage after neoadjuvant chemotherapy can be more safely resected after a delay and how much of a delay is needed is uncertain.
Others suggest that increases in spleen size during oxaliplatin therapy represent a biomarker for hepatic sinusoidal injury and resultant portal hypertension, and could serve as a simple method for identifying patients at risk for this complication . In our experience, this is rarely clinically helpful.
Issues related to bevacizumab — The addition of bevacizumab to an oxaliplatin- or irinotecan-based regimen results in a modestly higher frequency of tumor regression compared to regimens that do not include bevacizumab . However, these benefits have come at the cost of significant treatment-related toxicity. (See "Systemic chemotherapy for metastatic colorectal cancer: Completed clinical trials", section on 'First-line use'.)
Toxicity — Bevacizumab is associated with major complications that could interfere with metastasectomy, such as stroke and arterial thromboembolic events (approximately 2 percent), bowel perforation (2 percent), and bleeding (2 percent grade 3 to 4). Furthermore, concerns about impaired wound healing and possibly impaired hepatic regeneration may affect the safety of metastasectomy, particularly if performed too soon after bevacizumab administration. (See "Toxicity of molecularly targeted antiangiogenic agents: Non-cardiovascular effects" and "Toxicity of molecularly targeted antiangiogenic agents: Cardiovascular effects".)
The safety of metastasectomy in patients receiving bevacizumab prior to resection has been addressed in multiple retrospective series [91-98], none of which suggest excess problems with bleeding, wound healing, or functional recovery. Whether bevacizumab impairs hepatic regeneration after portal vein embolization (which increases resectability by increasing the volume of the future hepatic remnant ) is unclear; the available data are conflicting [97,100,101]. The rationale and technique for portal vein embolization in patients undergoing liver resection is discussed elsewhere. (See "Overview of hepatic resection", section on 'Preoperative PVE and other alternatives' and "Preoperative portal vein embolization", section on 'Introduction'.)
Because of the long half-life of bevacizumab (20 days), it is commonly recommended that at least 28 days, but preferably six to eight weeks should elapse between the last dose of bevacizumab and elective hepatic resection. (See "Toxicity of molecularly targeted antiangiogenic agents: Non-cardiovascular effects", section on 'Hepatic metastasectomy'.)
However, the available data correlating the incidence of postoperative complications and the time since the last bevacizumab dose are conflicting:
●In a report from the community-based BRiTE observational cohort of 521 patients who had surgery after bevacizumab, the incidence of serious wound complications in patients who had their last dose less than two weeks, two to four weeks, four to six weeks, six to eight weeks, or ≥8 weeks before surgery was 10, 3, 3, 6, and 2 percent, respectively .
The addition of bevacizumab to a neoadjuvant oxaliplatin-based regimen may reduce the incidence and severity of oxaliplatin-related liver injury [83,98,103-105]. However, this finding has not been prospectively validated.
Response evaluation — Standard criteria such as RECIST (Response Evaluation Criteria in Solid Tumors (table 3)) are used to evaluate tumor response to cytotoxic agents; they may not be applicable to biologic agents such as bevacizumab, which have a cytostatic mechanism of action. Novel computed tomography (CT)-based morphologic criteria have been proposed which may more closely predict pathologic response and prolonged survival in patients receiving preoperative chemotherapy, both with and without bevacizumab [106,107]. However, these require external confirmation and validation.
Initially resectable disease — For patients with initially resectable liver metastases, a common sequence (particularly for patients with a synchronous presentation of metastatic disease) is initial systemic chemotherapy to allow early aggressive disease progression to become manifest, followed by reevaluation for surgery. If there is widespread disease progression, resection will likely provide no specific benefit. If, on the other hand, the disease has responded or is stable, resection of both the primary tumor and the metastatic disease could be attempted. (See 'Timing of hepatectomy in patients presenting with metastases' below.)
Upfront surgery is an appropriate option for patients with metachronous presentation of hepatic metastases. The question of whether perioperative chemotherapy improves survival in patients undergoing hepatic metastasectomy was addressed in a European Organisation for Research and Treatment of Cancer (EORTC) trial in which 364 patients with up to four metastases without prior exposure to oxaliplatin were randomly assigned to liver resection with or without FOLFOX4 chemotherapy (table 4) . Six cycles (12 weeks) of chemotherapy were administered prior to surgery and six cycles were administered postoperatively. The key findings were as follows:
●Sixty-seven of the 182 patients assigned to chemotherapy had an objective response (four complete), while 11 progressed, 8 of whom were no longer considered resectable. Overall, 83 percent of patients were successfully resected, similar to the number who were successfully resected in the surgery alone group (84 percent). Thus, the fear that initial chemotherapy would cause resectable liver metastases to become unresectable was not realized in this study. Furthermore, initial chemotherapy improved patient selection for hepatic resection. Among those undergoing upfront surgery, 18 of 170 (11 percent) had a nontherapeutic laparotomy, compared with only 8 of 159 (5 percent) in the initial chemotherapy group.
●The postoperative complication rate was significantly higher in the chemotherapy group (25 versus 16 percent). Patients receiving perioperative chemotherapy had higher rates of hepatic failure (7 versus 5 percent), biliary fistulas (8 versus 4 percent), and intraabdominal infection (7 versus 2 percent). However, the postoperative mortality rate was not higher than with surgery alone (1 versus 2 deaths).
●In the latest update, at a median follow-up of 8.5 years, there was a nonstatistically significant trend in five-year progression-free survival favoring the chemotherapy group (38 versus 30 percent, hazard ratio [HR] 0.81, p = 0.068) . When ineligible patients were excluded from the analysis, the difference was statistically significant.
Five-year overall survival was not significantly better in the chemotherapy group (51 versus 48 percent, HR for death 0.88, 95% CI 0.68-1.14). The implications of these findings on the decision to pursue chemotherapy after resection are discussed below. (See 'Therapy after resection of liver metastases' below.)
Thus, whether there is a net benefit for upfront chemotherapy as compared to initial resection for patients with a metachronous presentation of potentially resectable colorectal cancer (CRC) liver metastases remains uncertain. We generally prefer immediate resection rather than upfront chemotherapy. However, these decisions must often be made on a case-by case basis, with consideration of the following issues:
●Are there sufficient risks or suggestions of possible poor tumor biology such that the addition of one additional factor (ie, progression on chemotherapy) would be sufficient to not offer resection?
●Does the patient have diabetes, obesity, or other factors that compromise liver health, such that any degree of liver injury from preoperative chemotherapy might be significantly deleterious?
●Are the tumors resectable at present, but just a minor response would make the operation significantly less difficult (eg, allow the surgeon to more easily achieve a margin-free resection, more easily avoid a critical hepatic vein, or convert from an open to a laparoscopic resection)?
●Did the patient complete adjuvant FOLFOX previously, and if so, how long ago?
Regimen choice — The optimal regimen to be used in the neoadjuvant setting for patients with initially resectable hepatic metastases is not established. NCCN guidelines suggest FOLFOX or FOLFIRI or XELOX with or without bevacizumab, or FOLFIRI with or without cetuximab or panitumumab, or FOLFOX with or without panitumumab or cetuximab (if RAS wild type) (table 4). Updated consensus-based 2016 guidelines from the European Society for Medical Oncology (ESMO) suggest FOLFOX or XELOX in this setting  (See "Treatment protocols for small and large bowel cancer".)
We consider that the following regimens are appropriate in this setting:
●For patients who received adjuvant FOLFOX, we use FOLFIRI alone or FOLFIRI plus cetuximab (or panitumumab) for left-sided tumors lacking RAS/BRAF mutations. Based upon accumulating data suggesting that the site of the primary tumor influences the effectiveness of anti-epidermal growth factor receptor (EGFR) agents, we avoid use of an anti-EGFR agent in right-sided primary tumors, even if RAS/BRAF wild type. (See "Systemic chemotherapy for nonoperable metastatic colorectal cancer: Treatment recommendations", section on 'Anti-EGFR agent versus bevacizumab with first-line chemotherapy'.)
We do not use bevacizumab in this setting, given the marginal benefits and risk for major complications . (See "Toxicity of molecularly targeted antiangiogenic agents: Non-cardiovascular effects" and "Toxicity of molecularly targeted antiangiogenic agents: Cardiovascular effects".)
We would also not choose upfront FOLFOX with either cetuximab or panitumumab even in patients with RAS wild-type tumors given concerns about incremental benefit and potentially worse outcomes from the addition of cetuximab in at least some trials. As an example, in the new EPOC trial, in which 272 patients with operable metastases from KRAS wild-type metastatic CRC (mCRC) were randomly assigned to FOLFOX with or without cetuximab for 12 weeks before and 12 weeks after surgery, the addition of cetuximab was associated with a significantly worse progression-free survival (14.1 versus 20.5 months) .
However, the data from randomized trials evaluating the benefit of adding an anti-EGFR agent to a front-line oxaliplatin-containing regimen are mixed, and others disagree with this position. This controversial subject is discussed in detail elsewhere. (See "Systemic chemotherapy for metastatic colorectal cancer: Completed clinical trials", section on 'Plus oxaliplatin' and "Systemic chemotherapy for metastatic colorectal cancer: Completed clinical trials", section on 'Panitumumab combinations' and "Systemic chemotherapy for nonoperable metastatic colorectal cancer: Treatment recommendations", section on 'RAS/BRAF wild-type tumors'.)
An algorithmic approach to selecting initial chemotherapy for patients with mCRC, which includes recommendations for those with potentially resectable liver metastases, is presented in the algorithm (algorithm 1).
Conversion therapy for initially unresectable metastases — The term "conversion therapy" has been proposed to designate the use of induction chemotherapy in patients with isolated but initially unresectable CRC liver metastases . It is reported that between 12 and 33 percent of patients with "initially unresectable" hepatic metastases have a sufficient objective response to permit a subsequent complete (R0) resection (table 5) [68,114-120]. Five-year survival rates average 30 to 35 percent, results that are substantially better than expected using chemotherapy alone (10 to 11 percent five-year survival, even with the most active regimens). (See "Systemic chemotherapy for metastatic colorectal cancer: General principles", section on 'Chemotherapy versus supportive care'.)
However, the definition of "initially unresectable" in these reports is subjective and based in part on the aggressiveness of the liver surgeon. In our own experience, the frequency of converting a patient with truly unresectable disease to the point of resectability through the use of neoadjuvant chemotherapy is fairly low (on the order of 5 to 15 percent, even in the hands of aggressive surgeons).
Even with the most effective regimens, the complete pathologic response rate after neoadjuvant chemotherapy is only 4 to 9 percent [68,121,122]. The majority of radiographic completely responding lesions (83 percent in one series ) contain viable tumor. Thus, even in the setting of a complete clinical response, resection is still needed. Issues surrounding the accuracy of PET scans in patients who undergo chemotherapy are discussed above. (See 'PET scans' above.)
Choice of regimen — The optimal regimen for conversion therapy is not established. Given the potential for treatment-related toxicity with bevacizumab and the modest improvement in overall response rate when this agent is added to oxaliplatin, we prefer an oxaliplatin-based systemic combination regimen without bevacizumab, or FOLFOXIRI (for young healthy patients who are able to tolerate it). Others prefer FOLFOX or FOLFOXIRI with bevacizumab. For patients with metachronous metastases who have received adjuvant FOLFOX in the preceding 12 months, FOLFIRI with or without cetuximab or panitumumab (for left sided tumors lacking RAS/BRAF mutations) is a reasonable option. An algorithmic approach to selection of first-line chemotherapy for mCRC, which includes recommendations for patients with potentially resectable CRC liver metastases, is presented in the algorithm (algorithm 1).
The optimal regimen to be used in the neoadjuvant setting is not established, but a regimen with a high objective response rate is typically chosen, given the strong correlation between response rate and subsequent resection rate in patients with initially unresectable metastatic disease [124,125]. Tumor response is usually quantified using the RECIST criteria (table 3) [126,127]. (See "Systemic chemotherapy for nonoperable metastatic colorectal cancer: Treatment recommendations" and "Systemic chemotherapy for metastatic colorectal cancer: General principles", section on 'Assessment during therapy'.)
Doublets containing either irinotecan or oxaliplatin plus a fluoropyrimidine are essentially equivalent in patients with mCRC; the choice is typically governed by toxicity profile. We generally prefer an oxaliplatin-based combination for most patients but choose FOLFIRI for patients who have received adjuvant FOLFOX. (See "Systemic chemotherapy for metastatic colorectal cancer: Completed clinical trials", section on 'Oxaliplatin/FU/LV versus irinotecan/FU/LV'.)
Whether higher resectability rates can be achieved using regimens that contain both oxaliplatin and irinotecan such as FOLFOXIRI (leucovorin, FU, oxaliplatin, and irinotecan (table 6)) is unclear. High rates of successful resection for patients with initially unresectable liver metastases have been reported for the FOLFOXIRI regimen, with or without bevacizumab, in some trials and pooled analyses [118,119,128-130] but not others. This subject is discussed in detail elsewhere. (See "Systemic chemotherapy for metastatic colorectal cancer: Completed clinical trials", section on 'First-line IROX and FOLFOXIRI'.)
A separate issue is the benefit from the addition of a biologic agent. It is said, although not proven, that the addition of a biologic agent (ie, cetuximab or panitumumab [for individuals with RAS and BRAF wild-type tumors] or bevacizumab) to a chemotherapy backbone containing oxaliplatin or irinotecan may increase the number of patients potentially eligible for resection and improve outcomes [121,131-135]. (See "Systemic chemotherapy for nonoperable metastatic colorectal cancer: Treatment recommendations", section on 'RAS mutations' and "Treatment protocols for small and large bowel cancer".)
The following represents the available data from randomized trials of chemotherapy with and without a biologic agent:
●The benefit of agents targeting the EGFR is modest, at best. The randomized phase II CELIM trial of cetuximab in combination with either an irinotecan or oxaliplatin-based regimen showed a high resectability rate of 34 percent, but the absence of a control group not receiving cetuximab precludes assessment of the contribution of cetuximab .
Two randomized trials, the CRYSTAL and OPUS trials, showed modestly improved resection rates from 3.7 to 7 percent, and from 2.4 to 4.7 percent, respectively, with the addition of cetuximab to an irinotecan or oxaliplatin-based regimen [132,135]. In the OPUS trial, when the analysis was limited to patients with wild-type KRAS mutation status, resectability was increased from 4 to 10 percent, but these data are based on very small numbers (3 of 73 with FOLFOX versus 6 of 61 for FOLFOX plus cetuximab).
A benefit for adding cetuximab was also suggested in a small Chinese trial in which 138 patients with initially unresectable liver metastases from KRAS wild-type mCRC were randomly assigned chemotherapy (FOLFIRI or mFOLFOX6) with or without cetuximab . The complete (R0) resection rates were 26 percent (18 of 70) in the cetuximab group and 7 percent (5 of 68) with chemotherapy alone. Benefit was seen regardless of the chemotherapy regimen used.
On the other hand, in the setting of potentially operable liver metastases, the new EPOC trial (FOLFOX with or without cetuximab for 12 weeks before and 12 weeks after surgery) showed that the addition of cetuximab was associated with a significantly worse progression-free survival (14.8 versus 24.2 months) . (See 'Regimen choice' above.)
This is a controversial area. Accumulating data on the influence of primary tumor site on the effectiveness of anti-EGFR agents suggest that patients with mCRC whose cancers arise in the right colon derive no benefit from anti-EGFR antibodies for initial therapy, even if they are RAS/BRAF wild type. Thus, we would only choose an anti-EGFR agent for a patients with a left-sided primary tumor. (See "Systemic chemotherapy for nonoperable metastatic colorectal cancer: Treatment recommendations", section on 'Anti-EGFR agent versus bevacizumab with first-line chemotherapy'.)
●The addition of dual antibody therapy to cytotoxic regimens failed to provide any benefit, and it is not recommended.
The modest benefits of adding a biologic agent to the chemotherapy backbone must be counterbalanced by the high cost and potential for added toxicity, particularly with bevacizumab. (See 'Issues related to bevacizumab' above.)
Regardless of the regimen that is used, the number of preoperative cycles in patients with resectable liver metastases should be limited to four because of the potential for liver toxicity. Two to four additional preoperative cycles may be beneficial if further tumor shrinkage would significantly reduce the complexity of liver resection. (See 'Chemotherapy-related liver toxicity' above.)
Guidelines from the NCCN suggest any of the following regimens are appropriate (table 4) (see "Treatment protocols for small and large bowel cancer"):
●FOLFOX or XELOX or FOLFIRI with or without bevacizumab
●FOLFOXIRI with or without bevacizumab
●For patients with metachronous metastases who have received adjuvant FOLFOX in the preceding 12 months, FOLFIRI or irinotecan with or without bevacizumab, or FOLFIRI or irinotecan with cetuximab or panitumumab (for wild-type RAS only)
●Guidelines from NCCN further recommend that patients be reevaluated for conversion to resectable disease every two months if resectability is a reasonable goal.
On the other hand, update guidelines from ESMO suggest the following :
●For patients with RAS/BRAF wild-type disease, a cytotoxic doublet plus an anti-EGFR antibody or a combination of FOLFOXIRI plus bevacizumab; a cytotoxic doublet plus bevacizumab was felt to be less favorable.
●For patients with RAS-mutant disease, a cytotoxic doublet plus bevacizumab or FOLFOXIRI plus bevacizumab.
We prefer one of the following regimens for initially unresectable but potentially resectable or borderline resectable mCRC: FOLFOX alone (table 7), FOLFOXIRI alone (table 6) [118,119], or for patients with wild-type RAS and BRAF tumors that are not right sided, FOLFIRI plus either cetuximab (table 4) or panitumumab. An algorithmic approach to selection of first-line chemotherapy for mCRC, which includes recommendations for patients with potentially resectable CRC liver metastases, is presented in the algorithm (algorithm 1). (See "Systemic chemotherapy for nonoperable metastatic colorectal cancer: Treatment recommendations", section on 'Benefit of cetuximab and panitumumab' and "Treatment protocols for small and large bowel cancer".)
Role of hepatic intraarterial (HIA) chemotherapy — The rationale for administering chemotherapy into the hepatic artery is discussed in detail below. (See 'Regional therapy' below.)
Two single-institution studies suggest there may be a benefit for regional, in addition to systemic, therapy to downstage hepatic metastases:
●Forty-nine patients with initially unresectable CRC liver metastases received combined treatment with HIA floxuridine plus systemic chemotherapy (bevacizumab plus either oxaliplatin plus irinotecan or irinotecan plus short-term infusional FU plus leucovorin), 76 percent had either a complete or partial response rate to chemotherapy . Twenty-three (47 percent) were able to undergo a later resection; 16 had concurrent ablation. At histologic analysis, 15 of the 23 resected specimens had negative margins. It is unclear how much of the increase in observed rate of conversion from unresectable to resectable was a result of tumor regression, and how much was a result of the use of thermal ablation as an adjunct to resection. At a median follow-up of 38 months, median survival was 38 months.
●HIA oxaliplatin was combined with systemic FU and leucovorin in a series of 87 patients, most of whom had initially unresectable but isolated hepatic CRC metastases. Twenty-two percent of patients were chemotherapy-naive . The median number of HIA courses was eight. A total of 23 patients underwent surgery, and resection was successfully performed in 14 (16 percent of the total). Among all patients undergoing surgery, the five-year survival was 56 percent (versus zero in those who did not get surgery), but only one patient remained recurrence-free.
While these results seem promising, others note that the likelihood of achieving a response sufficient to allow a later resection with initial HIA plus systemic chemotherapy for unresectable hepatic metastases is fairly small (3 out of 40) . The only way to assess the contribution of HIA chemotherapy to neoadjuvant systemic chemotherapy is with a randomized controlled trial. NCCN guidelines do not include hepatic artery infusional therapy as a neoadjuvant chemotherapy option for patients with initially unresectable disease. This subject is discussed in more detail elsewhere. (See "Nonsurgical local treatment strategies for colorectal cancer liver metastases", section on 'HIA chemotherapy'.)
Patients undergoing preoperative portal vein embolization — Preoperative portal vein embolization (PVE) is the elective obliteration of portal blood flow to a selected portion of the liver a few weeks prior to planned major liver resection. PVE elicits a hypertrophic physiologic response in the nonembolized portion, augmenting the volume and, potentially, the function of the future liver remnant to a safe threshold to permit potentially curative liver resection. For patients undergoing preoperative PVE, neoadjuvant chemotherapy should be continued while awaiting hypertrophy as this practice significantly reduces rates of hepatic tumor progression and does not inhibit liver hypertrophy. This subject is discussed in detail elsewhere. (See "Preoperative portal vein embolization", section on 'Ongoing neoadjuvant chemotherapy post-PVE'.)
LOCAL OPTIONS FOR INCOMPLETELY RESECTED METASTATIC DISEASE — Radiofrequency ablation (RFA) or cryosurgery is sometimes applied following macroscopically incomplete resection of colorectal cancer (CRC) liver metastases or if there are incidentally found small lesions that are surgically inaccessible. This subject is discussed in detail elsewhere. (See "Nonsurgical local treatment strategies for colorectal cancer liver metastases", section on 'Tumor ablation'.)
For patients with a macroscopically complete resection in whom a tumor-free resection margin cannot be obtained because of vascular proximity or multinodularity, further locoregional therapy may not be necessary, particularly if an ultrasonic dissector is used for the hepatic resection . This was shown in a collective series of 436 patients undergoing macroscopically complete, potentially curative resection for CRC liver metastases at three institutions; 234 were microscopically complete (R0), while 202 had microscopically positive margins (R1 resection) . Further locoregional therapy was not given to those with an R1 resection (with the exception of argon beam or bipolar coagulation of the cut resection margin), but the majority (88 percent) had postoperative chemotherapy (as did 78 percent of the patients who underwent R0 resection).
At a median follow-up of 40 months, there were more intrahepatic recurrences among the patients who had an R1 resection, but the rate of recurrence at the surgical margin was not higher in this group. Furthermore, 5- and 10-year overall survival rates were not dissimilar between the two groups (61 and 43 percent in the R0 group, versus 57 and 37 percent in the R1 group). In multivariate analysis, preoperative CEA level and major hepatectomy (≥3 segments) but not R1 resection were independent predictors of poor outcome.
These data support the view that the inability to obtain clear resection margins is not necessarily a strict contraindication to resection of liver metastases (see 'Patient selection' above). However, a complete (R0) resection must always be the goal of any resection. Current data do not support planning for surgical resection with foreknowledge that residual disease will be left behind.
TIMING OF HEPATECTOMY IN PATIENTS PRESENTING WITH METASTASES — A controversial issue is the timing of hepatic resection in patients who have liver metastases at initial presentation. Some reports indicate a poor prognosis in such patients, at least in part attributable to the failure to resect clinically occult micrometastatic liver disease. In theory, delaying hepatic surgery by three to six months would permit the biological behavior of the metastatic disease to become evident, thus improving the selection of patients for whom hepatic metastasectomy might be curative. Delayed resection does not seem to increase the risk of patients becoming unresectable due to growth of the initial metastases, although if patients are untreated during this interval, it can increase the volume of resected liver, a significant predictor of postoperative complications.
One potential solution is to perform percutaneous radiofrequency ablation (RFA) during the interval between diagnosis and hepatic metastasectomy. A more commonly used approach is to administer chemotherapy during this period, which might also allow some patients with initially unresectable or borderline resectable liver metastases to undergo successful later hepatic resection. (See 'Neoadjuvant chemotherapy' above and "Nonsurgical local treatment strategies for colorectal cancer liver metastases".)
Simultaneous resection of the primary and metastatic disease is clearly preferable from the patient's perspective, and several surgical case series and meta-analyses have failed to confirm inferior survival or greater morbidity for patients who undergo a one-stage procedure as compared with delayed (staged) hepatic resection, unless major hepatic resection (three or more segments) is needed. One-stage surgery is probably a reasonable option for patients who present with low-volume (four or fewer, less than three segments involved, or all in the same lobe) potentially resectable hepatic metastases. Because of the incidence of synchronous second primary colorectal cancers (CRCs) (approximately 3 to 5 percent), complete colonoscopy prior to surgical resection should be undertaken, if feasible. (See "Surveillance after colorectal cancer resection", section on 'Diagnosing second cancers and polyps'.)
On the other hand, if there are five or more simultaneous potentially resectable hepatic metastases (unless all are located in one lobe), bilobar involvement, or if disease is borderline resectable due to location, initial chemotherapy followed by reassessment and delayed resection is probably a better strategy. (See 'Neoadjuvant chemotherapy' above.)
This subject is discussed in more detail elsewhere. (See "Locoregional methods for management and palliation in patients who present with stage IV colorectal cancer", section on 'Potentially curable metastatic disease'.)
THERAPY AFTER RESECTION OF LIVER METASTASES — As noted previously, there is a clear survival benefit from resection in patients with limited hepatic metastases from colorectal cancer (CRC). The role of systemic or regional therapy following metastasectomy is far less certain.
Systemic chemotherapy — A limited number of studies have explored the benefit of systemic fluorouracil (FU)-based chemotherapy following resection of hepatic metastases; clear evidence of a survival benefit compared to observation alone has not yet emerged.
Two randomized trials of similar design were initiated in the early 1990s (the French Fédération Francophone de Cancérologie Digestive [FFCD] 9002 and European Organisation for Research and Treatment of Cancer/National Cancer Institute of Canada [EORTC/NCIC] trials), but both were closed prematurely because of slow accrual [141,142]. The FFCD trial randomly assigned 173 of a planned 200 patients to six months of postoperative systemic FU and leucovorin (LV; with both drugs administered for five consecutive days once per month for six months) versus observation alone following hepatic resection . At five years, patients receiving chemotherapy had a significantly better disease-free survival, which was the primary endpoint (34 versus 27 percent at five years), but only a trend toward better survival (51 versus 41 percent).
The EORTC trial used the same chemotherapy regimen, but the results have not been published separately. In a combined analysis of both trials (totaling 278 patients), the differences in median progression-free survival (28 versus 19 months, p = 0.058) and overall survival (62 versus 47 months), while potentially clinical meaningful, were not statistically significant .
A Japanese trial randomly assigned 180 patients undergoing curative resection of CRC liver metastases to five 35-day cycles of adjuvant uracil-tegafur (UFT)/LV versus no adjuvant therapy . In a preliminary report presented at the 2014 annual American Society of Clinical Oncology (ASCO) meeting, at a median follow-up of 4.76 years, adjuvant UFT/LV was associated with a significant improvement in three-year, relapse-free survival, the primary endpoint (39 versus 32 percent; hazard ratio for relapse 0.56, 95% CI 0.38-0.83), but there was no differences in overall survival (83 versus 82 percent).
The chemotherapy used in these trials is considered inferior by modern standards. For patients with unresectable metastatic CRC, the introduction of newer drugs such as oxaliplatin, irinotecan, bevacizumab, and cetuximab has been accompanied by a marked improvement in median survival from six to seven months to 20 to 24 months. (See "Systemic chemotherapy for metastatic colorectal cancer: Completed clinical trials".)
There are limited data available from randomized trials on the benefits of these modern chemotherapy regimens following resection of CRC liver metastases [108,109,144]:
●A randomized trial from the EORTC evaluating perioperative FOLFOX chemotherapy (six cycles preoperatively, six postoperatively) versus observation alone in patients with initially resectable liver metastases showed that chemotherapy was associated with a trend toward improved three-year progression-free survival relative to surgical resection alone . (See 'Initially resectable disease' above.)
However, in the latest update of this trial, five-year overall survival was not significantly better in the chemotherapy group (52 versus 48 percent, HR for death 0.88, 95% CI 0.68-1.14); there was also no difference when the analysis was restricted to CRC deaths . However, these results cannot be used to conclude that there is a lack of benefit for adjuvant chemotherapy after resection of CRC liver metastases. The trial was not powered for overall survival as an endpoint. (See 'Initially resectable disease' above.)
●The benefit of adding irinotecan to FU and LV was tested in a multicenter trial in which 321 patients undergoing complete surgical resection for liver-isolated metastatic disease were randomly assigned to short-term infusional FU plus LV every other week for 24 weeks without or with irinotecan (180 mg/m2 every other week) . At a median follow-up of 42 months, there was no significant disease-free survival advantage for adding irinotecan (median 25 versus 22 months).
Of note, at least two trials of adjuvant irinotecan plus short-term infusional FU have failed to demonstrate a progression-free survival benefit over FU plus LV alone in patients with resected stage II or III disease. Thus, administration of postoperative irinotecan-containing chemotherapy should not be considered a standard approach following resection of liver-isolated metastatic disease. (See "Adjuvant therapy for resected stage III (node-positive) colon cancer", section on 'Irinotecan'.)
●The benefit of cetuximab was addressed in a randomized trial (the new EPOC study) evaluating perioperative oxaliplatin plus a fluoropyrimidine chemotherapy with or without cetuximab (12 weeks preoperatively, 12 weeks postoperatively) in patients with initially resectable liver metastases . As noted above, the addition of cetuximab was associated with significantly worse progression-free survival. Given these data and the lack of benefit from cetuximab for adjuvant treatment of patients with stage II or III colon cancer, the use of cetuximab in this setting cannot be recommended. (See 'Regimen choice' above and "Adjuvant therapy for resected stage III (node-positive) colon cancer", section on 'Cetuximab'.)
Despite the paucity of data regarding a survival benefit, updated guidelines from the National Comprehensive Cancer Network (NCCN) recommend a total of six months of perioperative therapy with an active systemic chemotherapy regimen for patients who have undergone resection of hepatic metastases from CRC. In view of the newly available data regarding the lack of benefit from adjuvant irinotecan plus FU, cetuximab, and bevacizumab, we would consider that FOLFIRI and any regimen containing cetuximab or bevacizumab are not acceptable options. We and others (including the NCCN) consider FOLFOX alone (table 7) or XELOX (table 8) to represent the preferred regimen for this group of patients .
Regional therapy — The liver is the dominant site of recurrence in over one-half of patients undergoing potentially curative resection. This observation, coupled with the proven efficacy of adjuvant systemic FU-based chemotherapy in patients with node-positive colon cancer, led to the study of regional treatment.
Hepatic intraarterial chemotherapy alone — The fact that liver metastases derive their blood supply predominantly from the hepatic artery provides the rationale to apply regional hepatic intraarterial (HIA) chemotherapy following metastasectomy.
Despite initially encouraging data from small randomized studies conducted in fewer than 40 patients [146,147], larger randomized controlled trials failed to confirm a survival benefit of HIA treatment alone. A study that randomized patients to resection only versus resection plus HIA FUDR for a solitary or multiple resectable liver metastases was undertaken, but the extreme heterogeneity of the patient population precluded any conclusions regarding the utility of adjuvant therapy .
A later German trial was closed prematurely when an interim analysis suggested that the experimental HIA arm could not meet the preplanned overall survival benefit . In the 226 patients who were randomized to HIA FU plus LV versus no treatment following hepatic resection of colorectal metastases, the intent to treat analysis showed that the intervention-arm patients had a worse median survival (35 versus 41 months) and similar median time to tumor progression (14.2 versus 13.7 months) compared with those undergoing surgery alone. However, due to technical and other issues, more than 20 percent of patients did not receive the intended treatment; among those who did, survival was nearly doubled (44.8 versus 23.3 months).
The observation that many of these patients were failing outside of the liver led to efforts combining regional and systemic FU-based chemotherapy.
HIA plus systemic therapy — The benefit of combined systemic and intrahepatic arterial chemotherapy was evaluated in an Intergroup study that randomly assigned completely resected patients to observation versus a combination of HIA FUDR and infusional FU following resection. Unfortunately, only 109 patients were accrued during nine years . In the final analysis, which was limited to 75 eligible patients (45 controls and 30 chemotherapy-treated patients), combined systemic and regional therapy was associated with a significantly longer time to recurrence, and a better four-year hepatic recurrence-free survival (RFS; 67 versus 43 percent) and overall RFS (46 versus 25 percent, p = 0.004). There was no benefit in terms of median overall survival, but the study was not powered to answer that question.
A slightly different approach was employed in a study of 156 patients with metastatic CRC who were randomly assigned to receive either six months of systemic therapy with LV-modulated FU or six cycles of combination HIA with FUDR plus systemic chemotherapy with FU and LV following surgical resection of liver metastases . Combination therapy was associated with a significantly better two-year survival rate (86 versus 72 percent) and two-year freedom from tumor recurrence in the liver (90 versus 60 percent).
A subsequent report of this series after more than 10 years of follow-up showed that the RFS difference was maintained with further follow-up, and also provided the outcomes to inform a method to approximate the risk for recurrence following resection alone . Using a clinical risk score as defined by Fong et al (assigning one point for each of the following: node-positive primary, disease-free interval from primary to metastases <12 months, more than one hepatic metastasis, largest hepatic tumor >5 cm, and CEA level >200 ng/ml ), outcomes were not significantly different with combined therapy versus surgery alone for those with a clinical risk score of 0 to 2 (median survival 83 months in both groups). However, outcomes were significantly better with combined therapy in those with a clinical risk score of 3 to 5 (median survival 60 versus 38 months, 10-year survival 39 versus 16 percent).
Critics have argued that the survival benefit attributed to HIA therapy might disappear in the era of modern systemic chemotherapy using oxaliplatin or irinotecan. More recent studies exploring regimens that combine HIA chemotherapy and modern intravenous irinotecan or oxaliplatin have shown that treatment is tolerable [153,154], and that the survival improvement reported with HIA chemotherapy appears to persist in the era of modern systemic chemotherapy . However, a randomized controlled trial, NSABP C-09 (comparing systemic capecitabine plus oxaliplatin alone or with alternating HIA FUDR after resection of CRC liver metastases) was closed for lack of accrual. The experience with that study reflects the reasons that HIA chemotherapy after liver resection has not gained widespread acceptance. The concern that pump placement increases the complexity of the operation, and that surgical complications and the hepatobiliary toxicity of FUDR delivered by HIA may compromise the high response rates with modern systemic chemotherapy regimens limits the use of HIA chemotherapy after hepatic resection. (See "Chemotherapy hepatotoxicity and dose modification in patients with liver disease", section on 'Floxuridine'.)
Nevertheless, updated guidelines from the NCCN indicate that hepatic arterial infusion with or without systemic FU and LV is at least an option after liver resection at institutions with experience in both the surgical and medical aspects of this therapy. On the other hand, updated guidelines from the European Society for Medical Oncology (ESMO) recommend adjuvant therapy with systemic oxaliplatin-based chemotherapy alone following hepatic metastasectomy in patients who have not received preoperative chemotherapy, unless they were previously exposed to oxaliplatin .
HIA plus other local approaches — Other investigators are exploring the role of HIA FUDR-based chemotherapy in conjunction with partial debulking of liver metastases, either via surgical resection or with cryosurgery . Until the results are known from such pilot studies, the use of HIA chemotherapy in that setting should be considered investigational.
Portal vein infusion — Because HIA FUDR carries a risk for biliary sclerosis, administration into the portal vein has been explored as an alternative (see "Nonsurgical local treatment strategies for colorectal cancer liver metastases", section on 'Optimizing chemotherapy'). The rationale is based upon the observation that in contrast to clinically detectable metastases, which derive 90 percent of their blood supply from the hepatic artery, hepatic micrometastases (as well as the biliary tree) are primarily dependent on the portal vein for their blood supply. Like HIA infusion, portal vein infusion (PVI) carries with it a significant regional exposure advantage.
The potential benefit of adjuvant PVI with FUDR after resection or ablation of isolated hepatic metastases was evaluated in two trials conducted at the City of Hope Medical Center . Systemic administration of FU and LV was given in conjunction with PVI FUDR, which was administered for 14 days on and 14 days off at a dose approximately twofold higher than that used with HIA FUDR. Although there was a low incidence of hepatic drug-induced toxicity, overall and disease-free survival (at three years 42 and 19 percent, respectively) were somewhat lower than has been reported with HIA FUDR and systemic FU plus LV following resection of hepatic metastases [150,151]. Thus, the role for this approach appears to be limited.
Hepatic radiotherapy — The use of external beam radiotherapy and internal application of radiation therapy (RT) through the use of yttrium-labeled microspheres is discussed in detail elsewhere. (See "Nonsurgical local treatment strategies for colorectal cancer liver metastases".)
SURVEILLANCE AFTER METASTASECTOMY — Posttreatment surveillance is recommended following resection of a primary colorectal cancer (CRC); the goal is identification of those patients who might potentially be cured by further surgical intervention, and to screen for second primary cancers and polyps. (See "Surveillance after colorectal cancer resection".)
The majority of patients with resected isolated liver metastases from CRC will develop recurrences in liver and lung, which could be potentially treated with further resection. (See "Surgical resection of pulmonary metastases: Outcomes by histology" and "Surgical resection of pulmonary metastases: Outcomes by histology", section on 'Colorectal cancer'.)
The liver is the only site of recurrence in approximately 35 to 40 percent [9,158,159]. Five-year survival rates up to 43 percent are reported following repeat liver resection for a second recurrence, with acceptable morbidity and perioperative mortality. (See 'Repeat resection for recurrent metastases' below.)
Evidence regarding the optimal follow-up strategy after liver resection for metastatic CRC is limited [160,161], and a 2013 updated guideline on posttreatment surveillance in CRC from the American Society of Clinical Oncology (ASCO) concluded that specific recommendations for this group could not be made . However, consensus-based guidelines from the National Comprehensive Cancer Network (NCCN) recommend the following surveillance strategy for patients with stage IV disease who are rendered surgically NED (no evidence of disease):
●CEA every three to six months for two years, then every six months for three years
●Computed tomography (CT) of the chest/abdomen and pelvis every three to six months for two years, then every 6 to 12 months up to a total of five years
●Colonoscopy in one year; if no advanced adenoma repeat in three years, then every five years; if advanced adenoma is found, repeat in one year
We agree with these recommendations. However, posttreatment surveillance is warranted only if the patient would be considered a candidate for a second potentially curative surgical procedure.
The impact of CT-based follow-up for the detection of resectable disease recurrence has been addressed in the following reports:
●One review included 705 patients who underwent resection of isolated CRC liver metastases at a single institution over a 14-year period . All were followed with a similar surveillance protocol, which included outpatient clinical examinations at 3, 6, 12, 18, and 24 months, and annually thereafter, with measurement of CEA and CA 19-9 levels at each visit. In addition, all patients had CT of the thorax, abdomen, and pelvis every three months for the first two years, at six monthly intervals for three more years, then annually from year 6 to 10.
Of the 444 patients with a recurrence diagnosed on a surveillance CT, 404 were detected within two years. The site of recurrent disease was liver only in 36 percent, extrahepatic only in 38 percent, and both hepatic and extrahepatic sites in 26 percent. The authors did not report how many recurrences were detected by serum tumor markers versus CT scans.
In total, recurrent disease was treated surgically in 124 patients. At every time point (within one year of original surgery, one to two years, beyond two years), those patients treated by liver and/or lung resection had significantly better median survival than did those who received palliative chemotherapy alone. The mean number of scans performed per resectable recurrence was 35.3, and the cost per life-year gained was £2883, a value that compares favorably to other cost-effectiveness ratios that are considered acceptable in the United States and elsewhere. (See "A short primer on cost-effectiveness analysis", section on 'Interpretation'.)
●Another series addressing the detection of recurrences after liver surgery for CRC metastases reported that recurrences were detected in 23 percent through a CEA increase without positive findings on routine imaging, in 46 percent through a CEA rise concurrent with positive imaging, and in 31 percent through positive imaging alone .
REPEAT RESECTION FOR RECURRENT METASTASES — Although randomized trials have not been conducted to prove benefit, repeat hepatic resection may be considered in selected patients who recur in the liver with no evidence of extrahepatic disease, and a good performance status. In several reported series, perioperative mortality rates were less than 5 percent, and overall survival rates ranged from 20 to 43 percent at two to five years (table 9) [15,47,163-176].
Patients with a relapse-free interval of longer than one year appear to have a more favorable outcome from reresection [159,164]. Other factors associated with a poor outcome include synchronous resection for the first liver metastases, and the presence of multiple lesions at second hepatectomy [165,166,170].
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Colon and rectal cancer (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Surgical resection is the only potentially curative option for patients with liver-isolated metastatic colorectal cancer (CRC). For appropriately selected patients with four or fewer metastases, five-year relapse-free survival rates average 30 percent; in at least four contemporary series, five-year overall survival rates are approximately 58 percent. (See 'Surgical resection' above.)
The optimal selection of patients for resection, particularly the utility of preoperative integrated positron emission tomography (PET)/computed tomography (CT), is evolving. Since the criteria for potential liver-directed therapies have been expanded, hepatic surgical consultation should be obtained for surgically-fit patients with apparently isolated liver metastases unless they fall into one of the following categories (see 'Patient selection' above):
•Radiographic evidence of involvement of the common hepatic artery, common hepatic or common bile duct, or main portal vein
•Extensive liver involvement (>70 percent, more than six segments (figure 1), or involvement of all three hepatic veins)
•Inadequate predicted postresection functional hepatic reserve
●The role of integrated PET/CT in selecting optimal surgical candidates is uncertain. However, until additional data are available, including long-term follow-up of the Canadian trial , we agree with guidelines from the National Comprehensive Cancer Network (NCCN), which recommend a staging PET scan for patients who appear to have potentially surgically curable metastatic CRC. An important caveat is that PET can be unreliable in this setting, especially after chemotherapy. (See 'PET scans' above.)
●We suggest not using a clinical risk score to select patients for diagnostic laparoscopy (Grade 2C). We perform an initial diagnostic laparoscopy only in patients with a suspicion of low-volume carcinomatosis based on preoperative radiographic imaging and for selected other cases at high risk for intraperitoneal metastatic disease (eg, a patient with a metachronous presentation of the primary and metastases who has several liver metastases that are not responding to chemotherapy). (See 'Selecting patients for diagnostic laparoscopy' above.)
●If the hepatic metastases are potentially resectable, we suggest immediate surgical resection rather than initial chemotherapy for medically fit patients with four or fewer metastases, unless a response to chemotherapy is anticipated to allow for a significantly less complex resection (Grade 2B). For patients with a good performance status who have more than four metastases (unless all are localized to a single lobe), radiographic suspicion for portal node involvement, or bilobar disease (ie, tumor involving any segments of the left and right hemi-liver), we suggest initial systemic chemotherapy followed by surgical reevaluation (Grade 2C). (See 'Initially resectable disease' above.)
Others disagree, instead recommending two to three courses of preoperative chemotherapy in all patients with potentially resectable liver metastases, in part to select those patients who are most likely to benefit from resection . However, if preoperative chemotherapy is selected, the number of courses should be minimized. Radiographic response assessment should be performed at six week intervals, and surgery undertaken as soon as the metastases are clearly resectable. (See 'Chemotherapy-related liver toxicity' above.)
The optimal chemotherapy regimen is not established. We consider the following combinations to represent reasonable choices: FOLFOX (table 7), FOLFOXIRI (table 6), or FOLFIRI plus either cetuximab (table 4) or panitumumab (for patients with left-sided tumors lacking RAS and BRAF mutations). An algorithmic approach to selection of first-line chemotherapy for metastatic CRC, which includes recommendations for patients with potentially resectable CRC liver metastases, is presented in the algorithm (algorithm 1). (See 'Regimen choice' above and "Treatment protocols for small and large bowel cancer".)
●Upfront chemotherapy is an appropriate option for patients with initially unresectable liver metastases; however, the likelihood of downstaging a patient with truly unresectable disease to the point of resectability is only 10 to 15 percent. Furthermore, longer durations of preoperative chemotherapy increase the potential for liver toxicity and postoperative complications.
If it is attempted, the optimal regimen for conversion therapy in this setting is not established. Given the potential for treatment-related toxicity with bevacizumab and the modest improvement in overall response rate when this agent is added to oxaliplatin, we prefer an oxaliplatin-based systemic combination regimen without bevacizumab, or FOLFOXIRI (for young healthy patients who are able to tolerate it). For patients with metachronous metastases who have received adjuvant FOLFOX in the preceding 12 months, FOLFIRI with or without cetuximab or panitumumab (for left sided tumors lacking RAS/BRAF mutations) is a reasonable option. (See 'Choice of regimen' above and "Treatment protocols for small and large bowel cancer".)
Other clinicians would support use of a bevacizumab-containing regimen in this setting, particularly for a right-sided or RAS/BRAF mutant tumor. Updated, consensus-based guidelines from the European Society for Medical Oncology (ESMO) suggest a cytotoxic chemotherapy doublet (either FOLFOX or FOLFIRI) or FOLFOXIRI for those with RAS mutant disease, and a cytotoxic doublet (FOLFIRI or FOLFOX) plus an anti-epidermal growth factor receptor (EGFR) antibody for those with RAS wild type disease, although the combination of FOLFOXIRI plus bevacizumab could also be considered in this situation . Consensus-based NCCN guidelines suggest FOLFOX, XELOX, FOLFIRI or FOLFOXIRI with or without bevacizumab, or for patients lacking RAS and BRAF mutations, FOLFOX or FOLFIRI plus either cetuximab or panitumumab. An algorithmic approach to selection of first-line chemotherapy for metastatic CRC, which includes recommendations for patients with potentially resectable CRC liver metastases, is presented in the algorithm (algorithm 1).
●For patients who have hepatic metastases at initial presentation, the optimal timing of liver resection is uncertain. We suggest one-stage surgery, if feasible (Grade 2C). If not feasible, resection of liver metastases can follow six to eight weeks after resection of the primary tumor. (See 'Timing of hepatectomy in patients presenting with metastases' above.)
●Following complete resection of liver metastases, the best postoperative strategy is uncertain. In the absence of published randomized trials to guide clinical practice following metastasectomy, we suggest completion of a full six-month course of systemic chemotherapy containing oxaliplatin plus a fluoropyrimidine (Grade 2C). We recommend against the use of an irinotecan-based regimen in this setting (Grade 1B). (See 'Therapy after resection of liver metastases' above.)
The relative benefit and indications for hepatic intraarterial chemotherapy in patients with hepatic metastases from CRC remains uncertain. We suggest that this approach be restricted to institutions with expertise in both the medical and surgical oncologic aspects of this procedure. (See 'HIA plus systemic therapy' above.)
●For patients who are rendered free of disease, posttreatment surveillance is warranted if they would be considered candidates for a second potentially curative surgical procedure. Consensus-based guidelines for the posttreatment surveillance strategy are available from the NCCN. (See 'Surveillance after metastasectomy' above.)
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