Disclosures: Alan P Venook, MD Grant/Research/Clinical Trial Support: BMS (cetuximab); Genentech (bevacizumab); Merck Serono (cetuximab). Steven A Curley, MD, FACS Nothing to disclose. Kenneth K Tanabe, MD Consultant/Advisory Boards: Astellas [hepatocellular carcinoma (enzalutamide)]. Patent Holder (no licenses/royalties to date): EGF SNP to determine risk for HCC (cirrhosis, hepatocellular carcinoma); Use of EGFR inhibitors to prevent HCC (cirrhosis, hepatocellular carcinoma). Diane MF Savarese, MD Employee of UpToDate, Inc.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence.
INTRODUCTION — Approximately 132,700 Americans are diagnosed with colon or rectal cancer annually, and 49,700 will die from this disease, most with metastatic tumors . Global, country-specific data on incidence and mortality are available from the World Health Organization (WHO) GLOBOCAN database.
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 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 resection and the role of systemic chemotherapy. Methods and results for local ablation, regional chemotherapy into the hepatic artery, radiation therapy, and management of the primary tumor in patients who present with stage IV disease are addressed elsewhere. (See "Nonsurgical local treatment strategies for colorectal cancer liver metastases" 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 [4-10]), although this complication was described in five 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", section on 'Histopathology'.)
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 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 [4-6,8-19]. 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 colorectal cancer 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. Unfortunately, no more than 20 percent of patients with isolated hepatic metastases are amenable to potentially curative resection. Most are not surgical candidates because of tumor size, location, multifocality, or inadequate hepatic reserve.
Some patients with initially unresectable disease may become resectable after induction chemotherapy, although the frequency with which this occurs depends on many factors, including the subjective assessment of resectability by the liver surgeon and is probably on the order of 5 to 15 percent  for a patient who has truly unresectable disease. Updated guidelines from the National Comprehensive Cancer Network (NCCN) suggest that patients who appear to have initially unresectable metastatic colorectal cancer 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 [8,25,26]) 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 [28-30]. 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.)
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 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 magnetic resonance imaging (MRI) of the liver identifies more hepatic lesions than are visualized by CT, especially in the presence of background fatty liver change  and is the preferred first-line imaging study for evaluating colorectal cancer 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 [37-44]. (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) five-and ten-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 importance of achieving wide margins was addressed in a multicenter report of 557 patients who underwent resection for CRC liver metastases . There was no difference in five-year overall survival rate or in the rate of tumor recurrence in the liver whether the tumor-free margin was 1 to 4, 5 to 9, or >10 mm . Only patients with a positive margin had worse survival and a higher intrahepatic recurrence rate. Similar results have been noted by others [43,46-48].
●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 [32,49-52].
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 to 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 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 colorectal cancer. An important caveat is that PET can be unreliable in this setting, especially after chemotherapy.
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 [4,56-58]. 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 [60-65], 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 [66-68]. 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 colorectal cancer. 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 [12,69].
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 5-FU/LV 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).
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), 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 steatosis (chemotherapy-associated steatohepatitis, CASH), vascular injury, and (now termed idiopathic noncirrhotic portal hypertension [including nodular regenerative hyperplasia]) in the livers of patients treated with preoperative irinotecan or oxaliplatin-containing chemotherapy regimens [71-82] (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 [75,78,79,81-86]. (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 (now termed idiopathic noncirrhotic portal hypertension [including nodular regenerative hyperplasia], precluding subsequent resection) has been reported in three patients treated with neoadjuvant oxaliplatin plus 5-FU for liver metastases . (See "Noncirrhotic portal hypertension", section on 'Idiopathic noncirrhotic portal hypertension (including nodular regenerative hyperplasia)'.)
●Irinotecan-containing regimens are more often been associated with steatosis and steatohepatitis [74,78,82,86]. One report compared outcomes from hepatic metastasectomy in 325 patients with steatosis and 160 patients without steatosis . Of the patients with markedly steatotic livers, 66 percent had received preoperative chemotherapy with a fluoropyrimidine, leucovorin, and/or irinotecan. Although mortality was not significantly worse in patients with steatotic as compared to nonsteatotic livers, marked steatosis was an independent predictor of perioperative infectious complications.
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 [72,74,75,79,81,83,84].
There are conflicting data as to whether sinusoidal damage or steatohepatitis increase the risk of perioperative morbidity/mortality [78,83,87,88]. In one study, patients with steatohepatitis had a significantly higher 90-day mortality rate as compared to those without steatohepatitis (15 versus 2 percent, respectively) .
Others suggest that risk depends on the duration and/or timing of preoperative therapy [79,89,90]:
●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 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 [93-100], 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 [99,102,103]. The rationale and technique for portal vein embolization in patients undergoing liver resection is discussed elsewhere. (See "Overview of hepatic resection", section on 'Preoperative portal vein embolization'.)
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 2 weeks, 2 to 4 weeks, 4 to 6 weeks, 6 to 8 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 [86,100,105-107]. 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 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 [108,109]. 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 an 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, eight 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 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 (if KRAS wild type) (table 4). (See "Treatment protocols for small and large bowel cancer".)
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 WT 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 EPOC trial, in which 272 patients with operable metastases from KRAS wild-type 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 PFS (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 'Agents targeting the EGFR'.)
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) [71,115-121]. 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 [71,122,123]. 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 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 [125,126]. Tumor response is usually quantified using the RECIST (Response Evaluation Criteria In Solid Tumors) criteria (table 3) [127,128]. (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. (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 (folinic acid, 5-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 in some trials [119,120,129] but not others. In the TRIBE trial, which compared bevacizumab plus either FOLFOXIRI or FOLFIRI in patients with unresectable mCRC, use of FOLFOXIRI did not result in a significantly higher secondary complete (R0) liver resection rate (15 versus 12 percent), and it was clearly more toxic ) (See "Systemic chemotherapy for metastatic colorectal cancer: Completed clinical trials", section on 'First-line IROX and FOLFOXIRI'.)
It is said, although not proven, that the addition of a biologic agent (ie, cetuximab or panitumumab [for individuals with RAS 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 [122,131-135]. (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 epidermal growth factor receptor (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, a preliminary report of 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 PFS (14.8 versus 24.2 months) . (See 'Regimen choice' above.)
As noted above, this is a controversial area. Although others disagree, we prefer that combinations of an anti-EGFR agent plus an oxaliplatin-containing chemotherapy backbone not be used as a first-line regimen for patients with potentially resectable liver metastases. (See "Systemic chemotherapy for nonoperable metastatic colorectal cancer: Treatment recommendations", section on 'Agents targeting the EGFR'.)
●The addition of dual antibody therapy to cytotoxic regimens failed to provide any benefit [138,139].
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 or
●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 KRAS only)
●Guidelines from the NCCN further recommend that patients be reevaluated for conversion to resectable disease every two months if resectability is a reasonable goal.
We consider the following regimens to be reasonable choices: FOLFOX alone (table 7), FOLFOXIRI (table 6) [119,120], or, for patients with wild-type RAS tumors, FOLFIRI plus either cetuximab (table 4) or panitumumab. (See "Systemic chemotherapy for nonoperable metastatic colorectal cancer: Treatment recommendations", section on 'Cetuximab' and "Systemic chemotherapy for nonoperable metastatic colorectal cancer: Treatment recommendations", section on '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.)
The benefit of regional rather than (or in addition to) systemic therapy to downstage hepatic metastases is unclear; most of the data supporting benefit from HIA alone or combined with systemic chemotherapy are from Memorial Sloan Kettering, and no randomized trials comparing either approach to systemic chemotherapy alone have been published:
●In a single institution study in which 49 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 5-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, this approach is not used by many clinicians outside of New York City. The only way to assess the contribution of HIA chemotherapy to neoadjuvant systemic chemotherapy is with a randomized controlled trial. Until such trials are completed, when neoadjuvant therapy is required, systemic rather than regional therapy is indicated. NCCN guidelines do not include hepatic artery infusional therapy as a neoadjuvant chemotherapy option for patients with initially unresectable disease.
LOCAL OPTIONS FOR INCOMPLETELY RESECTED METASTATIC DISEASE — Radiofrequency ablation (RFA) or cryosurgery is sometimes applied following macroscopically incomplete resection of 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, five- and ten-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 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 to 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 (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 5-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 FFCD 9002 and EORTC/NCIC trials), but both were closed prematurely because of slow accrual [143,144]. The FFCD trial randomly assigned 173 of a planned 200 patients to six months of postoperative systemic 5-FU and leucovorin (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 UFT/leucovorin versus no adjuvant therapy . In a preliminary report presented at the 2014 annual 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).
These data provide a proof of principle of the benefit of postresection adjuvant chemotherapy in this population. However, 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 colorectal cancer liver metastases [110,146]:
●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 colorectal cancer 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 5-FU and leucovorin 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 5-FU plus leucovorin 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 5-FU have failed to demonstrate a progression-free survival benefit over 5-FU plus leucovorin 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 from the EORTC evaluating perioperative oxaliplatin plus a fluoropyrimidine chemotherapy with or without cetuximab (12 weeks preoperatively, 12 weeks postoperatively) in patients with initially resectable liver metastases. In a preliminary report presented at the 2013 ASCO meeting, 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 "Adjuvant therapy for resected stage III (node-positive) colon cancer", section on 'Cetuximab'.)
Despite the paucity of data, updated guidelines from the 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 colorectal cancer. In view of the newly available data regarding the lack of benefit from adjuvant irinotecan plus 5-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 5-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 intrahepatic arterial (HIA) chemotherapy following metastasectomy.
Despite initially encouraging data from small randomized studies conducted in fewer than 40 patients [149,150], larger randomized controlled trials were disappointing. In one American Cooperative Group study that randomized patients to resection only versus resection plus HIA FUDR for a solitary or multiple resectable liver metastases, patient accrual was inadequate to address the utility of adjuvant therapy .
A later German trial was closed prematurely when interim analysis suggested a worse outcome from HIA therapy . In this randomized study comparing HIA 5-FU plus leucovorin versus no treatment following hepatic resection of colorectal metastases in 226 patients, the treated patients had a worse median survival (35 versus 41 months), and similar median time to tumor progression (14.2 versus 13.7 months) compared to those undergoing surgery alone.
The observation that many of these patients were failing outside of the liver led to efforts combining regional and systemic 5-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 5-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 significantly longer time to recurrence, a better four-year hepatic recurrence-free survival (67 versus 43 percent), and overall recurrence-free survival (46 versus 25 percent). However, there was no benefit in terms of median overall survival.
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 leucovorin-modulated 5-FU or six cycles of combination HIA with FUDR plus systemic chemotherapy with 5-FU and leucovorin 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 later report of this series with over 10 years of follow-up suggested that benefit might be limited to the subgroup of patients with the highest 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). This series demonstrates how well some patients can do with resection that is done in a center with substantial experience, and that regional therapy can improve the rate of hepatic tumor control.
More recent studies are exploring regimens that combine HIA chemotherapy and intravenous irinotecan or oxaliplatin [156,157]. Although treatment is tolerable and early results are promising, the ultimate proof of benefit will require a randomized controlled trial. Such a trial, NSABP C-09, is underway, comparing systemic capecitabine plus oxaliplatin alone or with alternating HIA FUDR after resection of colorectal cancer liver metastases.
Routine use of HIA chemotherapy after liver resection has not gained widespread acceptance. Placement of the HIA pump increases the complexity of the operation, and in one series, only 19 percent of the patients randomized to receive regional plus systemic chemotherapy completed the prescribed course of treatment . Concerns about hepatobiliary toxicity of FUDR delivered by HIA combined with high response rates with modern systemic chemotherapy regimens will limit 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 5-FU and leucovorin is a reasonable approach after liver resection at institutions with experience in both the surgical and medical aspects of this therapy. In our view, HIA chemotherapy should be considered only as part of a clinical trial at centers comfortable with this modality.
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 5-FU and leucovorin 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 5-FU plus leucovorin following resection of hepatic metastases [153,154]. Thus, the role for this approach appears to be limited.
Hepatic radiotherapy — The use of external beam radiotherapy and internal application of radiation therapy 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; 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 [10,160,161]. 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 [162,163], 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 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
●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 colorectal cancer 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 six to ten.
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 US 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) [16,50,165-178].
Patients with a relapse-free interval of longer than one year appear to have a more favorable outcome from reresection [161,167]. Other factors associated with a poor outcome include synchronous resection for the first liver metastases, and the presence of multiple lesions at second hepatectomy [168,169,173].
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 information: 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. 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 PET/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 NCCN, which recommend a staging PET scan for patients who appear to have potentially surgically curable metastatic colorectal cancer. 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 whose tumors lack RAS mutations). (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 wild-type RAS only) is a reasonable option. (See 'Choice of regimen' above and "Treatment protocols for small and large bowel cancer".)
●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.)
- Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin 2015; 65:5.
- Khatri VP, Petrelli NJ, Belghiti J. Extending the frontiers of surgical therapy for hepatic colorectal metastases: is there a limit? J Clin Oncol 2005; 23:8490.
- Kopetz S, Chang GJ, Overman MJ, et al. Improved survival in metastatic colorectal cancer is associated with adoption of hepatic resection and improved chemotherapy. J Clin Oncol 2009; 27:3677.
- Fernandez FG, Drebin JA, Linehan DC, et al. Five-year survival after resection of hepatic metastases from colorectal cancer in patients screened by positron emission tomography with F-18 fluorodeoxyglucose (FDG-PET). Ann Surg 2004; 240:438.
- Scheele J, Stang R, Altendorf-Hofmann A, Paul M. Resection of colorectal liver metastases. World J Surg 1995; 19:59.
- Steele G Jr, Bleday R, Mayer RJ, et al. A prospective evaluation of hepatic resection for colorectal carcinoma metastases to the liver: Gastrointestinal Tumor Study Group Protocol 6584. J Clin Oncol 1991; 9:1105.
- Wanebo HJ, Chu QD, Vezeridis MP, Soderberg C. Patient selection for hepatic resection of colorectal metastases. Arch Surg 1996; 131:322.
- Nordlinger B, Guiguet M, Vaillant JC, et al. Surgical resection of colorectal carcinoma metastases to the liver. A prognostic scoring system to improve case selection, based on 1568 patients. Association Française de Chirurgie. Cancer 1996; 77:1254.
- Yoon SS, Tanabe KK. Multidisciplinary management of metastatic colorectal cancer. Surg Oncol 1998; 7:197.
- Hughes KS, Simon R, Songhorabodi S, et al. Resection of the liver for colorectal carcinoma metastases: a multi-institutional study of patterns of recurrence. Surgery 1986; 100:278.
- Jamison RL, Donohue JH, Nagorney DM, et al. Hepatic resection for metastatic colorectal cancer results in cure for some patients. Arch Surg 1997; 132:505.
- Fong Y, Fortner J, Sun RL, et al. Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: analysis of 1001 consecutive cases. Ann Surg 1999; 230:309.
- Iwatsuki S, Dvorchik I, Madariaga JR, et al. Hepatic resection for metastatic colorectal adenocarcinoma: a proposal of a prognostic scoring system. J Am Coll Surg 1999; 189:291.
- Abdalla EK, Vauthey JN, Ellis LM, et al. Recurrence and outcomes following hepatic resection, radiofrequency ablation, and combined resection/ablation for colorectal liver metastases. Ann Surg 2004; 239:818.
- Wei AC, Greig PD, Grant D, et al. Survival after hepatic resection for colorectal metastases: a 10-year experience. Ann Surg Oncol 2006; 13:668.
- Simmonds PC, Primrose JN, Colquitt JL, et al. Surgical resection of hepatic metastases from colorectal cancer: a systematic review of published studies. Br J Cancer 2006; 94:982.
- Cummings LC, Payes JD, Cooper GS. Survival after hepatic resection in metastatic colorectal cancer: a population-based study. Cancer 2007; 109:718.
- Rees M, Tekkis PP, Welsh FK, et al. Evaluation of long-term survival after hepatic resection for metastatic colorectal cancer: a multifactorial model of 929 patients. Ann Surg 2008; 247:125.
- Morris EJ, Forman D, Thomas JD, et al. Surgical management and outcomes of colorectal cancer liver metastases. Br J Surg 2010; 97:1110.
- Robertson DJ, Stukel TA, Gottlieb DJ, et al. Survival after hepatic resection of colorectal cancer metastases: a national experience. Cancer 2009; 115:752.
- Ferrarotto R, Pathak P, Maru D, et al. Durable complete responses in metastatic colorectal cancer treated with chemotherapy alone. Clin Colorectal Cancer 2011; 10:178.
- Tomlinson JS, Jarnagin WR, DeMatteo RP, et al. Actual 10-year survival after resection of colorectal liver metastases defines cure. J Clin Oncol 2007; 25:4575.
- Adam R, Delvart V, Pascal G, et al. Rescue surgery for unresectable colorectal liver metastases downstaged by chemotherapy: a model to predict long-term survival. Ann Surg 2004; 240:644.
- Poston GJ, Adam R, Alberts S, et al. OncoSurge: a strategy for improving resectability with curative intent in metastatic colorectal cancer. J Clin Oncol 2005; 23:7125.
- Konopke R, Kersting S, Distler M, et al. Prognostic factors and evaluation of a clinical score for predicting survival after resection of colorectal liver metastases. Liver Int 2009; 29:89.
- Nagashima I, Takada T, Matsuda K, et al. A new scoring system to classify patients with colorectal liver metastases: proposal of criteria to select candidates for hepatic resection. J Hepatobiliary Pancreat Surg 2004; 11:79.
- Roberts KJ, White A, Cockbain A, et al. Performance of prognostic scores in predicting long-term outcome following resection of colorectal liver metastases. Br J Surg 2014; 101:856.
- Zakaria S, Donohue JH, Que FG, et al. Hepatic resection for colorectal metastases: value for risk scoring systems? Ann Surg 2007; 246:183.
- Small RM, Lubezky N, Shmueli E, et al. Response to chemotherapy predicts survival following resection of hepatic colo-rectal metastases in patients treated with neoadjuvant therapy. J Surg Oncol 2009; 99:93.
- Reissfelder C, Rahbari NN, Koch M, et al. Validation of prognostic scoring systems for patients undergoing resection of colorectal cancer liver metastases. Ann Surg Oncol 2009; 16:3279.
- Berri RN, Abdalla EK. Curable metastatic colorectal cancer: recommended paradigms. Curr Oncol Rep 2009; 11:200.
- Adam R, de Haas RJ, Wicherts DA, et al. Is hepatic resection justified after chemotherapy in patients with colorectal liver metastases and lymph node involvement? J Clin Oncol 2008; 26:3672.
- National Comprehensive Cancer Network (NCCN). NCCN Clinical practice guidelines in oncology. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp (Accessed on April 01, 2014).
- Carpizo DR, Are C, Jarnagin W, et al. Liver resection for metastatic colorectal cancer in patients with concurrent extrahepatic disease: results in 127 patients treated at a single center. Ann Surg Oncol 2009; 16:2138.
- Sahani DV, Bajwa MA, Andrabi Y, et al. Current status of imaging and emerging techniques to evaluate liver metastases from colorectal carcinoma. Ann Surg 2014; 259:861.
- Tanabe KK. Palliative liver resections. J Surg Oncol 2002; 80:69.
- Bolton JS, Fuhrman GM. Survival after resection of multiple bilobar hepatic metastases from colorectal carcinoma. Ann Surg 2000; 231:743.
- Weber SM, Jarnagin WR, DeMatteo RP, et al. Survival after resection of multiple hepatic colorectal metastases. Ann Surg Oncol 2000; 7:643.
- Malik HZ, Hamady ZZ, Adair R, et al. Prognostic influence of multiple hepatic metastases from colorectal cancer. Eur J Surg Oncol 2007; 33:468.
- Wicherts DA, Miller R, de Haas RJ, et al. Long-term results of two-stage hepatectomy for irresectable colorectal cancer liver metastases. Ann Surg 2008; 248:994.
- Pawlik TM, Abdalla EK, Ellis LM, et al. Debunking dogma: surgery for four or more colorectal liver metastases is justified. J Gastrointest Surg 2006; 10:240.
- Kornprat P, Jarnagin WR, Gonen M, et al. Outcome after hepatectomy for multiple (four or more) colorectal metastases in the era of effective chemotherapy. Ann Surg Oncol 2007; 14:1151.
- de Jong MC, Pulitano C, Ribero D, et al. Rates and patterns of recurrence following curative intent surgery for colorectal liver metastasis: an international multi-institutional analysis of 1669 patients. Ann Surg 2009; 250:440.
- Brouquet A, Abdalla EK, Kopetz S, et al. High survival rate after two-stage resection of advanced colorectal liver metastases: response-based selection and complete resection define outcome. J Clin Oncol 2011; 29:1083.
- Pawlik TM, Scoggins CR, Zorzi D, et al. Effect of surgical margin status on survival and site of recurrence after hepatic resection for colorectal metastases. Ann Surg 2005; 241:715.
- Are C, Gonen M, Zazzali K, et al. The impact of margins on outcome after hepatic resection for colorectal metastasis. Ann Surg 2007; 246:295.
- Andreou A, Aloia TA, Brouquet A, et al. Margin status remains an important determinant of survival after surgical resection of colorectal liver metastases in the era of modern chemotherapy. Ann Surg 2013; 257:1079.
- Viganò L, Capussotti L, Lapointe R, et al. Early recurrence after liver resection for colorectal metastases: risk factors, prognosis, and treatment. A LiverMetSurvey-based study of 6,025 patients. Ann Surg Oncol 2014; 21:1276.
- Jaeck D, Nakano H, Bachellier P, et al. Significance of hepatic pedicle lymph node involvement in patients with colorectal liver metastases: a prospective study. Ann Surg Oncol 2002; 9:430.
- Nordlinger B, Vaillant JC, Guiguet M, et al. Survival benefit of repeat liver resections for recurrent colorectal metastases: 143 cases. Association Francaise de Chirurgie. J Clin Oncol 1994; 12:1491.
- Pawlik TM, Schulick RD, Choti MA. Expanding criteria for resectability of colorectal liver metastases. Oncologist 2008; 13:51.
- Pulitanò C, Bodingbauer M, Aldrighetti L, et al. Colorectal liver metastasis in the setting of lymph node metastasis: defining the benefit of surgical resection. Ann Surg Oncol 2012; 19:435.
- Rau C, Blanc B, Ronot M, et al. Neither preoperative computed tomography nor intra-operative examination can predict metastatic lymph node in the hepatic pedicle in patients with colorectal liver metastasis. Ann Surg Oncol 2012; 19:163.
- Pulitanò C, Bodingbauer M, Aldrighetti L, et al. Liver resection for colorectal metastases in presence of extrahepatic disease: results from an international multi-institutional analysis. Ann Surg Oncol 2011; 18:1380.
- Moulton CA, Gu CS, Law CH, et al. Effect of PET before liver resection on surgical management for colorectal adenocarcinoma metastases: a randomized clinical trial. JAMA 2014; 311:1863.
- Wiering B, Krabbe PF, Jager GJ, et al. The impact of fluor-18-deoxyglucose-positron emission tomography in the management of colorectal liver metastases. Cancer 2005; 104:2658.
- Wiering B, Oyen W, Van der Sijp J, et al. Improved selection of patients for hepatic surgery of colorectal liver metastases with FDG-PET: a randomized study (abstract). J Clin Oncol 2008; 26:179s.
- Pawlik TM, Assumpcao L, Vossen JA, et al. Trends in nontherapeutic laparotomy rates in patients undergoing surgical therapy for hepatic colorectal metastases. Ann Surg Oncol 2009; 16:371.
- Ruers TJ, Wiering B, van der Sijp JR, et al. Improved selection of patients for hepatic surgery of colorectal liver metastases with (18)F-FDG PET: a randomized study. J Nucl Med 2009; 50:1036.
- Ruers TJ, Langenhoff BS, Neeleman N, et al. Value of positron emission tomography with [F-18]fluorodeoxyglucose in patients with colorectal liver metastases: a prospective study. J Clin Oncol 2002; 20:388.
- Fong Y, Saldinger PF, Akhurst T, et al. Utility of 18F-FDG positron emission tomography scanning on selection of patients for resection of hepatic colorectal metastases. Am J Surg 1999; 178:282.
- Lai DT, Fulham M, Stephen MS, et al. The role of whole-body positron emission tomography with [18F]fluorodeoxyglucose in identifying operable colorectal cancer metastases to the liver. Arch Surg 1996; 131:703.
- Valk PE, Abella-Columna E, Haseman MK, et al. Whole-body PET imaging with [18F]fluorodeoxyglucose in management of recurrent colorectal cancer. Arch Surg 1999; 134:503.
- Imdahl A, Reinhardt MJ, Nitzsche EU, et al. Impact of 18F-FDG-positron emission tomography for decision making in colorectal cancer recurrences. Langenbecks Arch Surg 2000; 385:129.
- Langenhoff BS, Oyen WJ, Jager GJ, et al. Efficacy of fluorine-18-deoxyglucose positron emission tomography in detecting tumor recurrence after local ablative therapy for liver metastases: a prospective study. J Clin Oncol 2002; 20:4453.
- Akhurst T, Kates TJ, Mazumdar M, et al. Recent chemotherapy reduces the sensitivity of [18F]fluorodeoxyglucose positron emission tomography in the detection of colorectal metastases. J Clin Oncol 2005; 23:8713.
- Glazer ES, Beaty K, Abdalla EK, et al. Effectiveness of positron emission tomography for predicting chemotherapy response in colorectal cancer liver metastases. Arch Surg 2010; 145:340.
- van Kessel CS, Buckens CF, van den Bosch MA, et al. Preoperative imaging of colorectal liver metastases after neoadjuvant chemotherapy: a meta-analysis. Ann Surg Oncol 2012; 19:2805.
- Jarnagin WR, Conlon K, Bodniewicz J, et al. A clinical scoring system predicts the yield of diagnostic laparoscopy in patients with potentially resectable hepatic colorectal metastases. Cancer 2001; 91:1121.
- Reddy SK, Zorzi D, Lum YW, et al. Timing of multimodality therapy for resectable synchronous colorectal liver metastases: a retrospective multi-institutional analysis. Ann Surg Oncol 2009; 16:1809.
- Adam R, Wicherts DA, de Haas RJ, et al. Patients with initially unresectable colorectal liver metastases: is there a possibility of cure? J Clin Oncol 2009; 27:1829.
- Fernandez FG, Ritter J, Goodwin JW, et al. Effect of steatohepatitis associated with irinotecan or oxaliplatin pretreatment on resectability of hepatic colorectal metastases. J Am Coll Surg 2005; 200:845.
- Parikh AA, Gentner B, Wu TT, et al. Perioperative complications in patients undergoing major liver resection with or without neoadjuvant chemotherapy. J Gastrointest Surg 2003; 7:1082.
- Kooby DA, Fong Y, Suriawinata A, et al. Impact of steatosis on perioperative outcome following hepatic resection. J Gastrointest Surg 2003; 7:1034.
- Rubbia-Brandt L, Audard V, Sartoretti P, et al. Severe hepatic sinusoidal obstruction associated with oxaliplatin-based chemotherapy in patients with metastatic colorectal cancer. Ann Oncol 2004; 15:460.
- Bilchik AJ, Poston G, Curley SA, et al. Neoadjuvant chemotherapy for metastatic colon cancer: a cautionary note. J Clin Oncol 2005; 23:9073.
- Tisman G, MacDonald D, Shindell N, et al. Oxaliplatin toxicity masquerading as recurrent colon cancer. J Clin Oncol 2004; 22:3202.
- Vauthey JN, Pawlik TM, Ribero D, et al. Chemotherapy regimen predicts steatohepatitis and an increase in 90-day mortality after surgery for hepatic colorectal metastases. J Clin Oncol 2006; 24:2065.
- Aloia T, Sebagh M, Plasse M, et al. Liver histology and surgical outcomes after preoperative chemotherapy with fluorouracil plus oxaliplatin in colorectal cancer liver metastases. J Clin Oncol 2006; 24:4983.
- Hubert C, Sempoux C, Horsmans Y, et al. Nodular regenerative hyperplasia: a deleterious consequence of chemotherapy for colorectal liver metastases? Liver Int 2007; 27:938.
- Ward J, Guthrie JA, Sheridan MB, et al. Sinusoidal obstructive syndrome diagnosed with superparamagnetic iron oxide-enhanced magnetic resonance imaging in patients with chemotherapy-treated colorectal liver metastases. J Clin Oncol 2008; 26:4304.
- Pawlik TM, Olino K, Gleisner AL, et al. Preoperative chemotherapy for colorectal liver metastases: impact on hepatic histology and postoperative outcome. J Gastrointest Surg 2007; 11:860.
- Hubert C, Fervaille C, Sempoux C, et al. Prevalence and clinical relevance of pathological hepatic changes occurring after neoadjuvant chemotherapy for colorectal liver metastases. Surgery 2010; 147:185.
- Karoui M, Penna C, Amin-Hashem M, et al. Influence of preoperative chemotherapy on the risk of major hepatectomy for colorectal liver metastases. Ann Surg 2006; 243:1.
- Soubrane O, Brouquet A, Zalinski S, et al. Predicting high grade lesions of sinusoidal obstruction syndrome related to oxaliplatin-based chemotherapy for colorectal liver metastases: correlation with post-hepatectomy outcome. Ann Surg 2010; 251:454.
- Robinson SM, Wilson CH, Burt AD, et al. Chemotherapy-associated liver injury in patients with colorectal liver metastases: a systematic review and meta-analysis. Ann Surg Oncol 2012; 19:4287.
- Nakano H, Oussoultzoglou E, Rosso E, et al. Sinusoidal injury increases morbidity after major hepatectomy in patients with colorectal liver metastases receiving preoperative chemotherapy. Ann Surg 2008; 247:118.
- Scoggins CR, Campbell ML, Landry CS, et al. Preoperative chemotherapy does not increase morbidity or mortality of hepatic resection for colorectal cancer metastases. Ann Surg Oncol 2009; 16:35.
- Welsh FK, Tilney HS, Tekkis PP, et al. Safe liver resection following chemotherapy for colorectal metastases is a matter of timing. Br J Cancer 2007; 96:1037.
- Kishi Y, Zorzi D, Contreras CM, et al. Extended preoperative chemotherapy does not improve pathologic response and increases postoperative liver insufficiency after hepatic resection for colorectal liver metastases. Ann Surg Oncol 2010; 17:2870.
- Overman MJ, Maru DM, Charnsangavej C, et al. Oxaliplatin-mediated increase in spleen size as a biomarker for the development of hepatic sinusoidal injury. J Clin Oncol 2010; 28:2549.
- Walter H, Thomas AL. Liver resection following FOLFOXIRI plus bevacizumab: a detailed pathological review. Br J Cancer 2013; 108:2417.
- Gruenberger B, Tamandl D, Schueller J, et al. Bevacizumab, capecitabine, and oxaliplatin as neoadjuvant therapy for patients with potentially curable metastatic colorectal cancer. J Clin Oncol 2008; 26:1830.
- Okines A, Puerto OD, Cunningham D, et al. Surgery with curative-intent in patients treated with first-line chemotherapy plus bevacizumab for metastatic colorectal cancer First BEAT and the randomised phase-III NO16966 trial. Br J Cancer 2009; 101:1033.
- D'Angelica M, Kornprat P, Gonen M, et al. Lack of evidence for increased operative morbidity after hepatectomy with perioperative use of bevacizumab: a matched case-control study. Ann Surg Oncol 2007; 14:759.
- Reddy SK, Morse MA, Hurwitz HI, et al. Addition of bevacizumab to irinotecan- and oxaliplatin-based preoperative chemotherapy regimens does not increase morbidity after resection of colorectal liver metastases. J Am Coll Surg 2008; 206:96.
- Kesmodel SB, Ellis LM, Lin E, et al. Preoperative bevacizumab does not significantly increase postoperative complication rates in patients undergoing hepatic surgery for colorectal cancer liver metastases. J Clin Oncol 2008; 26:5254.
- Tamandl D, Gruenberger B, Klinger M, et al. Liver resection remains a safe procedure after neoadjuvant chemotherapy including bevacizumab: a case-controlled study. Ann Surg 2010; 252:124.
- Wicherts DA, de Haas RJ, Sebagh M, et al. Impact of bevacizumab on functional recovery and histology of the liver after resection of colorectal metastases. Br J Surg 2011; 98:399.
- van der Pool AE, Marsman HA, Verheij J, et al. Effect of bevacizumab added preoperatively to oxaliplatin on liver injury and complications after resection of colorectal liver metastases. J Surg Oncol 2012; 106:892.
- Wicherts DA, de Haas RJ, Andreani P, et al. Impact of portal vein embolization on long-term survival of patients with primarily unresectable colorectal liver metastases. Br J Surg 2010; 97:240.
- Zorzi D, Chun YS, Madoff DC, et al. Chemotherapy with bevacizumab does not affect liver regeneration after portal vein embolization in the treatment of colorectal liver metastases. Ann Surg Oncol 2008; 15:2765.
- Aussilhou B, Dokmak S, Faivre S, et al. Preoperative liver hypertrophy induced by portal flow occlusion before major hepatic resection for colorectal metastases can be impaired by bevacizumab. Ann Surg Oncol 2009; 16:1553.
- Kozloff M, Yood MU, Berlin J, et al. Clinical outcomes associated with bevacizumab-containing treatment of metastatic colorectal cancer: the BRiTE observational cohort study. Oncologist 2009; 14:862.
- Ribero D, Wang H, Donadon M, et al. Bevacizumab improves pathologic response and protects against hepatic injury in patients treated with oxaliplatin-based chemotherapy for colorectal liver metastases. Cancer 2007; 110:2761.
- Klinger M, Eipeldauer S, Hacker S, et al. Bevacizumab protects against sinusoidal obstruction syndrome and does not increase response rate in neoadjuvant XELOX/FOLFOX therapy of colorectal cancer liver metastases. Eur J Surg Oncol 2009; 35:515.
- Imai K, Emi Y, Iyama KI, et al. Splenic volume may be a useful indicator of the protective effect of bevacizumab against oxaliplatin-induced hepatic sinusoidal obstruction syndrome. Eur J Surg Oncol 2014; 40:559.
- Chun YS, Vauthey JN, Boonsirikamchai P, et al. Association of computed tomography morphologic criteria with pathologic response and survival in patients treated with bevacizumab for colorectal liver metastases. JAMA 2009; 302:2338.
- Shindoh J, Loyer EM, Kopetz S, et al. Optimal morphologic response to preoperative chemotherapy: an alternate outcome end point before resection of hepatic colorectal metastases. J Clin Oncol 2012; 30:4566.
- Nordlinger B, Sorbye H, Glimelius B, et al. Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial. Lancet 2008; 371:1007.
- Nordlinger B, Sorbye H, Glimelius B, et al. Perioperative FOLFOX4 chemotherapy and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC 40983): long-term results of a randomised, controlled, phase 3 trial. Lancet Oncol 2013; 14:1208.
- Nasti G, Piccirillo MC, Izzo F, et al. Neoadjuvant FOLFIRI+bevacizumab in patients with resectable liver metastases from colorectal cancer: a phase 2 trial. Br J Cancer 2013; 108:1566.
- Primrose J, Falk S, Finch-Jones M, et al. Systemic chemotherapy with or without cetuximab in patients with resectable colorectal liver metastasis: the New EPOC randomised controlled trial. Lancet Oncol 2014; 15:601.
- Petrelli NJ. Plenary program discussion. 43rd annual meeting of the American Society of Clinical Oncology, Chicago, Illinois, June 4, 2007.
- Alberts SR, Horvath WL, Sternfeld WC, et al. Oxaliplatin, fluorouracil, and leucovorin for patients with unresectable liver-only metastases from colorectal cancer: a North Central Cancer Treatment Group phase II study. J Clin Oncol 2005; 23:9243.
- Delaunoit T, Alberts SR, Sargent DJ, et al. Chemotherapy permits resection of metastatic colorectal cancer: experience from Intergroup N9741. Ann Oncol 2005; 16:425.
- Barone C, Nuzzo G, Cassano A, et al. Final analysis of colorectal cancer patients treated with irinotecan and 5-fluorouracil plus folinic acid neoadjuvant chemotherapy for unresectable liver metastases. Br J Cancer 2007; 97:1035.
- Ychou M, Viret F, Kramar A, et al. Tritherapy with fluorouracil/leucovorin, irinotecan and oxaliplatin (FOLFIRINOX): a phase II study in colorectal cancer patients with non-resectable liver metastases. Cancer Chemother Pharmacol 2008; 62:195.
- Masi G, Loupakis F, Pollina L, et al. Long-term outcome of initially unresectable metastatic colorectal cancer patients treated with 5-fluorouracil/leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) followed by radical surgery of metastases. Ann Surg 2009; 249:420.
- Falcone A, Ricci S, Brunetti I, et al. Phase III trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) compared with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment for metastatic colorectal cancer: the Gruppo Oncologico Nord Ovest. J Clin Oncol 2007; 25:1670.
- Wein A, Riedel C, Köckerling F, et al. Impact of surgery on survival in palliative patients with metastatic colorectal cancer after first line treatment with weekly 24-hour infusion of high-dose 5-fluorouracil and folinic acid. Ann Oncol 2001; 12:1721.
- Blazer DG 3rd, Kishi Y, Maru DM, et al. Pathologic response to preoperative chemotherapy: a new outcome end point after resection of hepatic colorectal metastases. J Clin Oncol 2008; 26:5344.
- Adam R, Wicherts DA, de Haas RJ, et al. Complete pathologic response after preoperative chemotherapy for colorectal liver metastases: myth or reality? J Clin Oncol 2008; 26:1635.
- Benoist S, Brouquet A, Penna C, et al. Complete response of colorectal liver metastases after chemotherapy: does it mean cure? J Clin Oncol 2006; 24:3939.
- Folprecht G, Grothey A, Alberts S, et al. Neoadjuvant treatment of unresectable colorectal liver metastases: correlation between tumour response and resection rates. Ann Oncol 2005; 16:1311.
- Wagman LD. Importance of response to neoadjuvant therapy in patients with liver-limited mCRC when the intent is resection and/or ablation. Clin Colorectal Cancer 2013; 12:223.
- Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45:228.
- Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000; 92:205.
- Ychou M, Rivoire M, Thezenas S, et al. A randomized phase II trial of three intensified chemotherapy regimens in first-line treatment of colorectal cancer patients with initially unresectable or not optimally resectable liver metastases. The METHEP trial. Ann Surg Oncol 2013; 20:4289.
- Loupakis F, Cremolini C, Masi G, et al. Initial therapy with FOLFOXIRI and bevacizumab for metastatic colorectal cancer. N Engl J Med 2014; 371:1609.
- Adam R, Aloia T, Lévi F, et al. Hepatic resection after rescue cetuximab treatment for colorectal liver metastases previously refractory to conventional systemic therapy. J Clin Oncol 2007; 25:4593.
- Van Cutsem E, Köhne CH, Hitre E, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med 2009; 360:1408.
- Saltz LB, Clarke S, Díaz-Rubio E, et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol 2008; 26:2013.
- Folprecht G, Gruenberger T, Bechstein WO, et al. Tumour response and secondary resectability of colorectal liver metastases following neoadjuvant chemotherapy with cetuximab: the CELIM randomised phase 2 trial. Lancet Oncol 2010; 11:38.
- Bokemeyer C, Bondarenko I, Makhson A, et al. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol 2009; 27:663.
- Ye LC, Liu TS, Ren L, et al. Randomized controlled trial of cetuximab plus chemotherapy for patients with KRAS wild-type unresectable colorectal liver-limited metastases. J Clin Oncol 2013; 31:1931.
- Primrose JN, Falk S, Finch-Jones M, et al. A randomized clinical trial of chemotherapy compared to chemotherapy in combination with cetuximab in k-RAS wild-type patients with operable metastases from colorectal cancer: The new EPOC study (abstract). J Clin Oncol 31, 2013 (suppl; abstr 3504). http://meetinglibrary.asco.org/content/112298-132 (Accessed on August 13, 2013).
- Tol J, Koopman M, Cats A, et al. Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer. N Engl J Med 2009; 360:563.
- Hecht JR, Mitchell E, Chidiac T, et al. A randomized phase IIIB trial of chemotherapy, bevacizumab, and panitumumab compared with chemotherapy and bevacizumab alone for metastatic colorectal cancer. J Clin Oncol 2009; 27:672.
- DʼAngelica MI, Correa-Gallego C, Paty PB, et al. Phase II Trial of Hepatic Artery Infusional and Systemic Chemotherapy for Patients With Unresectable Hepatic Metastases From Colorectal Cancer: Conversion to Resection and Long-term Outcomes. Ann Surg 2015; 261:353.
- Goéré D, Deshaies I, de Baere T, et al. Prolonged survival of initially unresectable hepatic colorectal cancer patients treated with hepatic arterial infusion of oxaliplatin followed by radical surgery of metastases. Ann Surg 2010; 251:686.
- de Haas RJ, Wicherts DA, Flores E, et al. R1 resection by necessity for colorectal liver metastases: is it still a contraindication to surgery? Ann Surg 2008; 248:626.
- Mitry E, Fields AL, Bleiberg H, et al. Adjuvant chemotherapy after potentially curative resection of metastases from colorectal cancer: a pooled analysis of two randomized trials. J Clin Oncol 2008; 26:4906.
- Portier G, Elias D, Bouche O, et al. Multicenter randomized trial of adjuvant fluorouracil and folinic acid compared with surgery alone after resection of colorectal liver metastases: FFCD ACHBTH AURC 9002 trial. J Clin Oncol 2006; 24:4976.
- Kobayashi A, et al. A randomized controlled trial evaluating efficacy of adjuvant oral uracil-tegafur (UFT) with leucovorin after resection of folorectal cancer liver metastases: the UFT/LV study (abstract). J Clin Oncol 32: 5s, 2014 (suppl; abstr 3584). Abstract available online at http://meetinglibrary.asco.org/content/130970-144 (Accessed on July 07, 2014).
- Ychou M, Hohenberger W, Thezenas S, et al. A randomized phase III study comparing adjuvant 5-fluorouracil/folinic acid with FOLFIRI in patients following complete resection of liver metastases from colorectal cancer. Ann Oncol 2009; 20:1964.
- Nordlinger B,Sorbye H, Glimelius B, et al. EORTC liver metastases intergroup randomized phase III study 40983: Long-term survival results. J Clin Oncol 30, 2012 (suppl; abstr 3508). Abstract available online at http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=114&abstractID=99538 (Accessed on June 21, 2012).
- O'Neil BH, Goldberg RM. What is the standard chemotherapy for colorectal cancer patients with resectable liver metastases? Nat Clin Pract Oncol 2009; 6:14.
- Lygidakis NJ, Ziras N, Parissis J. Resection versus resection combined with adjuvant pre- and post-operative chemotherapy--immunotherapy for metastatic colorectal liver cancer. A new look at an old problem. Hepatogastroenterology 1995; 42:155.
- Asahara T, Kikkawa M, Okajima M, et al. Studies of postoperative transarterial infusion chemotherapy for liver metastasis of colorectal carcinoma after hepatectomy. Hepatogastroenterology 1998; 45:805.
- Kemeny MM, Goldberg DA, Browning S, et al. Experience with continuous regional chemotherapy and hepatic resection as treatment of hepatic metastases from colorectal primaries. A prospective randomized study. Cancer 1985; 55:1265.
- Lorenz M, Müller HH, Schramm H, et al. Randomized trial of surgery versus surgery followed by adjuvant hepatic arterial infusion with 5-fluorouracil and folinic acid for liver metastases of colorectal cancer. German Cooperative on Liver Metastases (Arbeitsgruppe Lebermetastasen). Ann Surg 1998; 228:756.
- Kemeny MM, Adak S, Gray B, et al. Combined-modality treatment for resectable metastatic colorectal carcinoma to the liver: surgical resection of hepatic metastases in combination with continuous infusion of chemotherapy--an intergroup study. J Clin Oncol 2002; 20:1499.
- Kemeny N, Huang Y, Cohen AM, et al. Hepatic arterial infusion of chemotherapy after resection of hepatic metastases from colorectal cancer. N Engl J Med 1999; 341:2039.
- Kemeny NE, Gonen M. Hepatic arterial infusion after liver resection. N Engl J Med 2005; 352:734.
- House MG, Kemeny NE, Gönen M, et al. Comparison of adjuvant systemic chemotherapy with or without hepatic arterial infusional chemotherapy after hepatic resection for metastatic colorectal cancer. Ann Surg 2011; 254:851.
- Bolton JS, O'Connell MJ, Mahoney MR, et al. Hepatic arterial infusion and systemic chemotherapy after multiple metastasectomy in patients with colorectal carcinoma metastatic to the liver: a North Central Cancer Treatment Group (NCCTG) phase II study, 92-46-52. Clin Colorectal Cancer 2012; 11:31.
- Weaver ML, Atkinson D, Zemel R. Hepatic cryosurgery in treating colorectal metastases. Cancer 1995; 76:210.
- Faynsod M, Wagman LD, Longmate J, et al. Improved hepatic toxicity profile of portal vein adjuvant hepatic infusional chemotherapy. J Clin Oncol 2005; 23:4876.
- Fong Y, Cohen AM, Fortner JG, et al. Liver resection for colorectal metastases. J Clin Oncol 1997; 15:938.
- Gomez D, Sangha VK, Morris-Stiff G, et al. Outcomes of intensive surveillance after resection of hepatic colorectal metastases. Br J Surg 2010; 97:1552.
- Jones RP, Jackson R, Dunne DF, et al. Systematic review and meta-analysis of follow-up after hepatectomy for colorectal liver metastases. Br J Surg 2012; 99:477.
- Verberne CJ, Wiggers T, Vermeulen KM, de Jong KP. Detection of recurrences during follow-up after liver surgery for colorectal metastases: both carcinoembryonic antigen (CEA) and imaging are important. Ann Surg Oncol 2013; 20:457.
- Meyerhardt JA, Mangu PB, Flynn PJ, et al. Follow-up care, surveillance protocol, and secondary prevention measures for survivors of colorectal cancer: American Society of Clinical Oncology clinical practice guideline endorsement. J Clin Oncol 2013; 31:4465.
- Fong Y, Blumgart LH, Cohen A, et al. Repeat hepatic resections for metastatic colorectal cancer. Ann Surg 1994; 220:657.
- Fernández-Trigo V, Shamsa F, Sugarbaker PH. Repeat liver resections from colorectal metastasis. Repeat Hepatic Metastases Registry. Surgery 1995; 117:296.
- Adam R, Bismuth H, Castaing D, et al. Repeat hepatectomy for colorectal liver metastases. Ann Surg 1997; 225:51.
- Yamamoto J, Kosuge T, Shimada K, et al. Repeat liver resection for recurrent colorectal liver metastases. Am J Surg 1999; 178:275.
- Petrowsky H, Gonen M, Jarnagin W, et al. Second liver resections are safe and effective treatment for recurrent hepatic metastases from colorectal cancer: a bi-institutional analysis. Ann Surg 2002; 235:863.
- Nagakura S, Shirai Y, Suda T, Hatakeyama K. Multiple repeat resections of intra- and extrahepatic recurrences in patients undergoing initial hepatectomy for colorectal carcinoma metastases. World J Surg 2002; 26:141.
- Tanaka K, Shimada H, Ohta M, et al. Procedures of choice for resection of primary and recurrent liver metastases from colorectal cancer. World J Surg 2004; 28:482.
- Pessaux P, Lermite E, Brehant O, et al. Repeat hepatectomy for recurrent colorectal liver metastases. J Surg Oncol 2006; 93:1.
- Ishiguro S, Akasu T, Fujimoto Y, et al. Second hepatectomy for recurrent colorectal liver metastasis: analysis of preoperative prognostic factors. Ann Surg Oncol 2006; 13:1579.
- Yan TD, Sim J, Black D, et al. Systematic review on safety and efficacy of repeat hepatectomy for recurrent liver metastases from colorectal carcinoma. Ann Surg Oncol 2007; 14:2069.
- Sa Cunha A, Laurent C, Rault A, et al. A second liver resection due to recurrent colorectal liver metastases. Arch Surg 2007; 142:1144.
- Jones NB, McNally ME, Malhotra L, et al. Repeat hepatectomy for metastatic colorectal cancer is safe but marginally effective. Ann Surg Oncol 2012; 19:2224.
- Adair RA, Young AL, Cockbain AJ, et al. Repeat hepatic resection for colorectal liver metastases. Br J Surg 2012; 99:1278.
- Wicherts DA, de Haas RJ, Salloum C, et al. Repeat hepatectomy for recurrent colorectal metastases. Br J Surg 2013; 100:808.
- Kopetz S, Vauthey JN. Perioperative chemotherapy for resectable hepatic metastases. Lancet 2008; 371:963.