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Management of potentially resectable colorectal cancer liver metastases Authors Alan P Venook, MD Steven A Curley, MD, FACS Section Editor

Kenneth K Tanabe, MD Deputy Editor Diane MF Savarese, MD Disclosures All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Feb 2013. | This topic last updated: мар 12, 2013. INTRODUCTION — Approximately 142,820 Americans are diagnosed with colon or rectal cancer annually, and 52,390 will die from this disease, most with metastatic tumors [1]. Global, country-specific data on incidence and mortality are available from the World Health Organization 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 [2]. 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 [3]. (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".) 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 [11]. Needle tract seeding more often complicates FNA biopsy of primary liver tumors. (See"Clinical features and diagnosis of primary hepatocellular carcinoma", section on 'Histopathology'.)

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 [20]. 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 [21]. (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 [22]. 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 [23] 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 nontreatable extrahepatic disease, unfitness for surgery, or involvement of more than 70 percent of the liver or six segments (figure 1) [24]. (See 'Conversion therapy for initially unresectable metastases'below.) Risk scoring systems (such as the clinical risk score [12] and others [8,25,26]) to predict which patients with metastatic CRC are most likely to benefit from resection are of limited clinical utility, particularly among patients undergoing neoadjuvant chemotherapy [27-29]. Whether changes in the clinical risk score after treatment translates into improved outcomes after resection is unknown. (See 'Conversion therapy for initially unresectable metastases' below.) Modern multidisciplinary consensus defines resectable CRC liver metastases simply as tumors that can be resected completely, leaving an adequate liver remnant [30]. 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, orceliac/paraaortic lymph nodes [31], 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

) As an example. This view has been challenged [31. A two-stage approach to hepatic resection may be needed in the presence of multiple bilobar metastases [38. in a report of 484 patients with multiple metastases (136 with ≥4.42.43]. the optimal selection of patients who are candidates for resection is evolving.46-49]. surgeons have been reluctant to offer resection to patients with more than three lesions. (See "Clinical manifestations.   . contraindications to liver resection were defined by retrospective series and recapitulated in a large multiinstitutional review of 856 patients [10]. although this maneuver is not known to be of any therapeutic value. the positive predictive value (PPV) of preoperative CT was only 56 percent. In the past. However.) As noted above. patients with portal lymph node or other extrahepatic metastases. these relative contraindications have been challenged [2]:  With safer surgery and better chemotherapy. section on 'Liver MRI'. 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. A major problem is the prediction of metastatic lymph nodes in the hepatic pedicle in patients with CRC liver metastases.) The modern approach to resection of CRC liver metastases is outlined in the table (table 2) [2]. and staging of colorectal cancer". 36 with ≥8) five-and ten-year survival was 47 and 29 percent [37]. thought to indicate systemic disease that could not be successfully treated surgically. Number and location of metastases — Contrast-enhanced magnetic resonance imaging (MRI) of the liver identifies more hepatic lesions than are visualized by CT. In one analysis. tumor involving any segments of the left and right hemi-liver). 5 to 9. those with bilobar distribution (ie. Only patients with a positive margin had worse survival and a higher intrahepatic recurrence rate.45]. and the primary tumor should have been resected for cure [32]. The importance of achieving wide margins was addressed in a multicenter report of 557 patients who underwent resection for CRC liver metastases [44]. One of the classic contraindications to hepatectomy is the presence of portal lymph node metastases. hepatic resection is playing an increasing role in patients with multiple. even bilobar tumors [35-42]. Similar results have been noted by others [41. Accurate oncologic assessment requires systematic pedicular lymph node clearance. diagnosis. or >10 mm [44]. Based upon these analyses. and those with liver metastases from cancers other than colorectal tumors [34]. particularly if the extrahepatic disease is surgically resectable lung or ovarian metastases [33]. and even intraoperative evaluation had a PPV of only 43 percent [50]. Even patients with ≥8 metastases had a five-year survival rate of 24 percent. and is the preferred first-line imaging study for evaluating colorectal cancer liver metastases in patients who have not previously undergone therapy. those in whom it was not possible to achieve 1 cm margins. (See 'Neoadjuvant chemotherapy' below and 'Therapy after resection of liver metastases' below. Concurrent resection of hepatic and extrahepatic disease in well-selected patients is associated with a possibility of long-term survival. There should be no unresectable extrahepatic sites of disease. (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". The presence of portal node metastases is not inevitably associated with distant metastases.resection must be feasible.

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. outcomes in this group are not as favorable. However. particularly when there are >6 liver metastases [51]. 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. for extrahepatic disease [52]. respectively. In one study. which compromises the detection of small metastases both within and outside of the liver. Chemotherapy may reduce the sensitivity of PET for the detection of liver metastases. section on 'Significance of synchronous or metachronous liver metastases'. the results of restaging PET scans (particularly if negative) must be interpreted in the context of recent therapy. For the six articles judged to be of the highest quality [55-60].52-54]. respectively. The percent change in clinical management from the performance of PET ranged from 20 to 32 percent (average 25 percent). the false-negative rate for hepatic metastases of a PET scan performed within four weeks of chemotherapy was 87 percent [62]. Nineteen percent of patients survived three years despite portal node metastases. 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. and 91 and 98 percent. this study used separate contrastenhanced CT and PET images and not the increasingly popular integrated PET/CT imaging. Secondly. First. The benefits of PET can be illustrated by the following studies:  The superiority of PET over CT for detection of extrahepatic disease was 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 [52]. mainly by reducing nontherapeutic laparotomy rates [4. thought due to decreased cellular metabolic activity following chemotherapy [61-63]. in which both PET and CT are performed sequentially during a single visit on a hybrid PET/CT scanner. respectively. respectively. 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 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 [53]. At some institutions. for hepatic disease. Jaeck et al reported outcomes of complete hepatic pedicle lymphadenectomy in patients with CRC liver metastases [46]. The CT component of integrated PET/CTimaging is performed in most institutions without the use of intravenous contrast material. the pooled sensitivity and specificity for PET were 80 and 92 percent. In a preliminary report. 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. for extrahepatic metastases. The corresponding values for CT were 83 and 84 percent. (See"Surgical resection of pulmonary metastases: Outcomes by histology". and 61 and 91 percent. . Surgical decisions should not be based on PET scan results.) PET scans — Whole body PET scans can identify radiographically occult extrahepatic disease and optimize the selection of appropriate candidates for hepatic resection. but this practice is not widespread.  Two caveats must be considered when interpreting these results. respectively). Similarly. PET/CT is carried out with intravenous contrast. for hepatic metastases.

Preoperative hepatic intraarterial chemotherapy is discussed below.) In one study. In modern treatment paradigms. particularly since many patients have undergone surgical exploration of the peritoneum at the time of resection of a synchronous primary tumor. or PET) and for selected other cases at high risk (eg. a metachronous presentation with several liver metastases that do not respond to chemotherapy).72. However.73.) Chemotherapy-related liver toxicity — Enthusiasm for systemic chemotherapy prior to hepatic resection has been tempered by reports of steatosis (chemotherapy-associated steatohepatitis.64]. MRI. CASH). it is not necessary in all patients. thereby preventing unnecessary laparotomy. While 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). Laparoscopy is usually reserved for those thought to be at the highest risk for occult metastatic disease. None of these changes were seen in the 66 patients undergoing liver resection who had not received preoperative chemotherapy. the clinical risk score is not used by the vast majority of hepatobiliary surgeons. CT. it may also be considered as a means of "downsizing" liver metastases prior to resection to lessen the complexity of hepatic metastasectomy or for initially unresectable metastatic disease. derived from five preoperative criteria (nodal positivity. Some data suggest that these patients can be identified using a clinical risk score. (See 'Role of hepatic intraarterial (HIA) chemotherapy' below. (See "Pathogenesis and clinical features of hepatic sinusoidal obstruction syndrome (veno-occlusive disease) following hematopoietic cell transplantation". and before resection of numerous liver lesions became commonplace. Selecting patients for diagnostic laparoscopy — Although diagnostic laparoscopy can identify occult intraperitoneal metastases. . vascular injury. such changes were present in 44 (51 percent) of 87 hepatic specimens from patients who had received preoperative chemotherapy.75-80]. more than one hepatic tumor. before chemotherapy was routinely administered prior to liver resection. predominantly in patients receiving oxaliplatin prior to hepatic metastasectomy [69. CEA level >200 ng/mL within one month of surgery. and nodular regenerative hyperplasia in the livers of patients treated with preoperative irinotecan or oxaliplatin-containing chemotherapy regimens [65-76] (see "Treatment protocols for colorectal cancer"):  Hepatic sinusoidal abnormalities (termed sinusoidal obstruction syndrome) have been described that are similar to those that characterize veno-occlusive disease. which were significant predictors of outcome from hepatic resection in multivariate analysis [12. mainly because it was derived from a database of patients treated in the 5-FU/LVera. relapse free interval <12 months. 77 percent oxaliplatin-containing [69]. and size of largest hepatic tumor >5 cm). laparoscopy is infrequently performed. We use diagnostic laparoscopy in patients with a suspicion of small volume carcinomatosis on radiographic imaging studies (ie. NEOADJUVANT CHEMOTHERAPY — The availability of increasingly effective systemic chemotherapy has prompted interest in preoperative or neoadjuvant systemic chemotherapy prior to liver resection.Guidelines from the NCCN recommend a staging PET scan for patients with potentially surgically curable metastatic colorectal cancer.

nodular regenerative hyperplasia (precluding subsequent resection) has been reported in three patients treated with neoadjuvantoxaliplatin plus 5-FU for liver metastases [74]. leucovorin.75. The sensitivity. specificity. 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. 24 of 60 patients treated with neoadjuvant chemotherapy (mostly 12 or more weeks of an oxaliplatinbased regimen) were suspected of having moderate to severe sinusoidal obstruction by MRI. . Steatohepatitis has been observed more frequently after chemotherapy in patients with a higher body mass index. patients with steatohepatitis had a significantly higher 90-day mortality rate as compared to those without steatohepatitis (15 versus 2 percent. and could serve as a simple method for identifying patients at risk for this complication [85]. and 23 cases were confirmed at surgery [75]. Others suggest that increases in spleen size during oxaliplatin therapy represent a biomarker for hepatic sinusoidal injury and resultant portal hypertension.77.) Irinotecan-containing regimens are more often been associated with steatosis and steatohepatitis [68. Furthermore. respectively.82].76. and negative predictive value of MRI were 87.  In addition to vascular changes.78]. One report compared outcomes from hepatic metastasectomy in 325 patients with steatosis and 160 patients without steatosis [68].68.or irinotecan-based regimen results in a modestly higher frequency of tumor regression compared to regimens that do not include bevacizumab. However. Although mortality was not significantly worse in patients with steatotic as compared to nonsteatotic livers.69. bowel perforation (2 percent).) Toxicity — Bevacizumab is associated with major complications that could interfere with metastasectomy. which may explain why this complication is reported more frequently in US studies [70]. Of the patients with markedly steatotic livers.83. 83. In one report. this is rarely clinically helpful. Furthermore. Others suggest that risk depends on the duration and/or timing of preoperative therapy [73. 89. administration of more than 12 weeks of chemotherapy.84]. concerns about impaired wound healing and possibly impaired hepatic regeneration may affect the safety of metastasectomy. marked steatosis was an independent predictor of perioperative infectious complications.72. higher rates of reoperation. these benefits have come at the cost of significant treatment-related toxicity. and bleeding (2 percent grade 3 to 4).77. (See "Systemic chemotherapy for metastatic colorectal cancer: Completed clinical trials". such as stroke and arterial thromboembolic events (approximately 2 percent). There are conflicting data as to whether sinusoidal damage or steatohepatitis increase the risk of perioperative morbidity/mortality [72. while vascular lesions are seen more commonly in Europeans [66.81. In one report. section on 'First-line use'. and longer hospital stay [83]. and 92 percent. Issues related to bevacizumab — The addition of bevacizumab to an oxaliplatin. (See "Nodular regenerative hyperplasia of the liver". positive predictive value. and/or irinotecan. respectively) [72]. or an interval of four or fewer weeks between stopping chemotherapy and resection predisposed patients to more postsurgical complications. In one study.73. Emerging data suggest utility for superparamagnetic iron oxide-enhanced MRI in the preoperative detection of sinusoidal damage in patients who have received neoadjuvant chemotherapy. 66 percent had received preoperative chemotherapy with a fluoropyrimidine.80]. This MRI technique is not widely available. In our experience.

(See "Hepatic resection". but preferably six to eight weeks should elapse between the last dose of bevacizumab and elective hepatic resection.100]. (See "Toxicity of molecularly targeted antiangiogenic agents: Non-cardiovascular effects" and "Toxicity of molecularly targeted antiangiogenic agents: Cardiovascular effects". Whether bevacizumab impairs hepatic regeneration after portal vein embolization (which increases resectability by increasing the volume of the future hepatic remnant [94]) is unclear. none of which suggest excess problems with bleeding. If there is widespread disease progression. the available data correlating the incidence of postoperative complications and the time since the last bevacizumab dose are conflicting:   At least some data suggest that the interval between bevacizumab and surgery can be shortened to 5 weeks without an increase in perioperative complications [86]. or functional recovery. the disease has responded or is stable. it is commonly recommended that at least 28 days. 4 to 6 weeks. 2 to 4 weeks. The rationale and technique for portal vein embolization in patients undergoing liver resection is discussed elsewhere. section on 'Preoperative portal vein embolization'. However. (See 'Timing of hepatectomy in patients presenting with metastases' below. Others have found no association between postoperative complications and days from last bevacizumab dose (≤60 versus >60 days) [90]. 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. In a report from the community-based BRiTE observational cohort of 521 patients who had surgery after bevacizumab. they may not be applicable to biologic agents such as bevacizumab. If. (table 3)) are used to evaluate tumor response to cytotoxic agents. resection of both the primary tumor and the metastatic disease could be attempted.particularly if performed too soon after bevacizumab administration. 3. and 2 percent. followed by reevaluation for surgery. which have a cytostatic mechanism of action. 6. Initially resectable disease — For patients with initially resectable liver metastases. section on 'Hepatic metastasectomy'. this finding has not been prospectively validated.102]. The question of whether perioperative chemotherapy improves survival in patients . or ≥8 week s before surgery was 10.) Upfront surgery is an appropriate option for patients with metachronous presentation of hepatic metastases.  The addition of bevacizumab to a neoadjuvant oxaliplatin-based regimen may reduce the incidence and severity of oxaliplatin-related liver injury [80.) Because of the long half-life of bevacizumab (20 days). both with and without bevacizumab [101.93. on the other hand. (See "Toxicity of molecularly targeted antiangiogenic agents: Non-cardiovascular effects". the incidence of serious wound complications in patients who had their last dose les than 2 weeks.) However. 3. Response evaluation — Standard criteria such as RECIST (Response Evaluation Criteria in Solid Tumors. respectively [98]. 6 to 8 weeks. Novel CT-based morphologic criteria have been proposed which may more closely predict pathologic response and prolonged survival in patients receiving preoperative chemotherapy. wound healing. the available data are conflicting [95-97]. these require external confirmation and validation.) The safety of metastasectomy in patients receiving bevacizumab prior to resection has been addressed in multiple retrospective series [86-93]. resection will likely provide no specific benefit. However.99.

and if so.undergoing hepatic metastasectomy was addressed in an EORTC trial in which 364 patients with up to four metastases without prior exposure tooxaliplatin were randomly assigned to liver resection with or without FOLFOX4 chemotherapy (table 4) [103]. how long ago?    Choice of regimen — The optimal regimen to be used in the neoadjuvant setting for patients with initially resectable hepatic metastases is not established. compared with only 8 of 159 (5 percent) in the initial chemotherapy group.058) [104]. there was also no difference when the analysis was restricted to colorectal cancer deaths. the difference was statistically significant. more easily avoid a critical hepatic vein. The postoperative complication rate was significantly higher in the chemotherapy group (25 versus 16 percent). the postoperative mortality rate was not higher than with surgery alone (1 versus 2 deaths). Among those undergoing upfront surgery. 83 percent of patients were successfully resected. initial chemotherapy improved patient selection for hepatic resection. obesity. p = 0. or other factors that compromise liver health.79.88. 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. 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. Furthermore. such that any degree of liver injury from preoperative chemotherapy might be significantly deleterious? Are the tumors resectable at present. HR for death 0. However.14). eight of whom were no longer considered resectable. similar to the number who were successfully resected in the surgery alone group (84 percent). When ineligible patients were excluded from the analysis. but just a minor response would make the operation significantly less difficult (eg. Patients receiving perioperative chemotherapy had higher rates of hepatic failure (7 versus 5 percent).5 years. hazard ratio [HR] 0. while 11 progressed. NCCNguidelines suggest FOLFOX or FOLFIRI or XELOX with or without bevacizumab or FOLFIRI with or without cetuximab (if K-ras wild type) or FOLFIRI .) Thus. Five-year overall survival was not significantly better in the chemotherapy group (52 versus 48 percent. Six cycles (12 weeks) of chemotherapy were administered prior to surgery and six cycles were administered postoperatively. In a preliminary report of the latest update. However. Overall. Thus. these decisions must often be made on a case-by case basis. and intraabdominal infection (7 versus 2 percent). We generally prefer immediate resection rather than upfront chemotherapy. progression on chemotherapy) would be sufficient to not offer resection? Does the patient have diabetes. at a median follow-up of 8. (See 'Therapy after resection of liver metastases' below. allow the surgeon to more easily achieve a margin-free resection. or convert from an open to a laparoscopic resection)? Did the patient complete adjuvant FOLFOX previously. 95% CI 0. The key findings were as follows:  Sixty-seven of the 182 patients assigned to chemotherapy had an objective response (four complete). biliary fistulas (8 versus 4 percent). the fear that initial chemotherapy would cause resectable liver metastases to become unresectable was not realized in this study.68-1. The implications of these findings on the decision to pursue chemotherapy after resection are discussed below. there was a nonstatistically significant trend in five-year progression-free survival favoring the chemotherapy group (35 versus 28 percent. 18 of 170 (11 percent) had a nontherapeutic laparotomy.

section on 'Assessment during therapy'. showed modestly improved resection rates from 3. Even with the most effective regimens. given the strong correlation between response rate and subsequent resection rate in patients with initially unresectable metastatic disease [116] . 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) [65. given the marginal benefits and risk for major complications. even with the most active regimens). but a regimen with a high objective response rate is typically chosen. Five-year survival rates average 30 to 35 percent. resectability was increased from 4 to 10 percent. section on 'K-ras' and "Treatment protocols for colorectal cancer". cetuximab or panitumumab [for individuals with K-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 [113. when the analysis was limited to patients with wild-type K-ras mutation status. (See 'PET scans' above. but the absence of a control group not receiving cetuximab precludes assessment of the contribution of cetuximab [122]. (See"Systemic chemotherapy for nonoperable metastatic colorectal cancer: Treatment recommendations". respectively with the addition of cetuximab to an irinotecan or oxaliplatin-based regimen [120. the definition of “initially unresectable” in these reports is subjective and based in part on the aggressiveness of the liver surgeon.119-123]. 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. the CRYSTAL and OPUS trials. Any of these regimens is an acceptable option. (See "Systemic chemotherapy for nonoperable metastatic colorectal cancer: Treatment recommendations" and "Systemic chemotherapy for metastatic colorectal cancer: General principles".106-112]. Two randomized trials. that the addition of a biologic agent (ie.) Choice of regimen — The optimal regimen to be used in the neoadjuvant setting is not established. although not proven. although we do not use bevacizumab in this setting. or FOLFOXIRI (table 4). but these data are based on very small numbers (3 of 73 with .7 percent. Thus.7 to 7 percent.123]. resection is still needed.) However. 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.) It is said. results that are substantially better than expected using chemotherapy alone (10 to 11 percent five-year survival. (See "Systemic chemotherapy for metastatic colorectal cancer: General principles".or FOLFOX with or without panitumumab (if K-ras wild type).4 to 4. even in the hands of aggressive surgeons). at best.) 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 [105].114]. section on 'Chemotherapy versus supportive care'. (See "Treatment protocols for colorectal cancer".113. and from 2. In the OPUS trial. Issues surrounding the accuracy of PET scans in patients who undergo chemotherapy are discussed above. Tumor response is usually quantified using the RECIST (Response Evaluation Criteria In Solid Tumors) criteria (table 3) [117. the complete pathologic response rate after neoadjuvant chemotherapy is only 4 to 9 percent [65. In our own experience.) The following represents the available data [124]:  The benefit of agents targeting the epidermal growth factor receptor (EGFR) is modest. even in the setting of a complete clinical response.118]. The majority of radiographic completely responding lesions (83 percent in one series [115]) contain viable tumor.

the benefit of cetuximab in combination with first-line oxaliplatin-based chemotherapy has been called into question in two other trials. (See "Systemic chemotherapy for nonoperable metastatic colorectal cancer: Treatment recommendations".4 versus 6. section on 'Plus oxaliplatin'.1 percent with chemotherapy alone) [121]. section on 'Cetuximab or panitumumab as a component of initial therapy'.) The benefit of regional rather than (or in addition to) systemic therapy to downstage hepatic metastases is unclear:  A combined approach of HIA floxuridine plus systemic chemotherapy (oxaliplatin plus irinotecan) was explored in a single institution study of 49 patients with initially unresectable CRC liver metastases [128].) Role of hepatic intraarterial (HIA) chemotherapy — The rationale for administering chemotherapy into the hepatic artery is discussed in detail below. Overall. (See "Systemic chemotherapy for metastatic colorectal cancer: Completed clinical trials". (See 'Issues related to bevacizumab' above.FOLFOX versus 6 of 61 for FOLFOX plus cetuximab). EGFR-expressing mCRC. The addition of dual antibody therapy to cytotoxic regimens failed to provide any benefit [126.111]. in combination with FOLFIRI. (See 'Regional therapy' below. particularly withbevacizumab. largely based upon these data.) Guidelines from the NCCN suggest any of the following regimens are appropriate (table 4) (see "Treatment protocols for colorectal cancer"):     FOLFOX or CAPOX or FOLFIRI with or without bevacizumab or FOLFOX or CAPOX or FOLFIRI plus cetuximab or panitumumab (wild-type K-ras only) FOLFOXIRI For patients with metachronous metastases who have received adjuvant FOLFOX in the preceding 12 months. (See 'Chemotherapy-related liver toxicity' above. FOLFIRI with or without bevacizumab.) On the other hand. FOLFOXIRI (table 7) [110. for first-line therapy of K-ras wild-type. or FOLFIRI plus cetuximab (table 4) or panitumumab(for patients whose tumors lack K-ras mutations). (See "Treatment protocols for colorectal cancer". the FDA has approved cetuximab.) Similarly. the number of preoperative cycles should be limited because of the potential for liver toxicity. the addition of panitumumab to oxaliplatin did not improve resectability [125]. Nevertheless.   The modest benefits of adding a biologic agent to the chemotherapy backbone must be counterbalanced by the high cost and potential for added toxicity.) Regardless of the regimen that is used. or FOLFIRI withcetuximab or panitumumab (for wild-type K-ras 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. bevacizumab only moderately improved resectability rates when added to XELOX or FOLFOX in a large randomized trial (8.127]. In another trial. 92 percent had either a complete or partial response rate to .  We consider the following regimens to be reasonable choices: FOLFOX alone (table 6).

followed by postoperative chemotherapy. although the true frequency with which this occurs is probably low. Summary — Neoadjuvant systemic chemotherapy has the potential to convert some patients with initially unresectable large or critically located liver metastases to resectable disease. NCCN guidelines do not include hepatic artery infusional therapy as a neoadjuvant chemotherapy option for patients with initially unresectable disease. potentially resectable patients. when neoadjuvant therapy is required. (See "Treatment protocols for colorectal cancer". most of whom had initially unresectable but isolated hepatic CRC metastases with failure of prior systemic chemotherapy to render them potentially resectable [129]. the duration of neoadjuvant chemotherapy should be limited. but only one patient remained recurrence-free. 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. chemotherapy. and surgery undertaken as soon as the metastases become clearly resectable. radiographic response assessment performed at approximately six-week intervals. systemic rather than regional therapy is indicated. For patients who have higher risk. We recommend the following approach:  For low-risk (medically fit. Guidelines from the National Comprehensive Cancer Network (NCCN) suggest any of the following:    FOLFOX or CAPOX or FOLFIRI with or without bevacizumab or FOLFOX or CAPOX or FOLFIRI plus cetuximab (wild-type K-ras only) or FOLFOXIRI We consider the following combinations to represent reasonable choices: FOLFOX (table 6). A total of 23 patients underwent surgery. particularly in patients with a small number of initially resectable liver metastases. neoadjuvant chemotherapy is the preferred approach. borderline resectable or unresectable disease. and 23 (43 percent) were able to undergo a later resection. While these results seem promising. The median number of HIA courses was eight. 19 with negative margins. The optimal selection criteria.  The optimal regimen has not been established. Liver resection should be delayed at . and resection was performed in 14. specific regimen and duration of neoadjuvant chemotherapy. four or fewer lesions).) Regardless of the specific regimen chosen. 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. HIA oxaliplatin was combined with systemic 5-FU and leucovorin in a series of 87 patients. or FOLFIRI plus cetuximab (table 4) or panitumumab (for patients whose tumors lack K-ras mutations). initial surgery rather than neoadjuvant chemotherapy should be chosen. FOLFOXIRI (table 7). Among all patients undergoing surgery. The median overall survival from pump placement for the entire cohort was 40 months. the five-year survival was 56 percent (versus zero in those who did not get surgery). and the best way in which chemotherapy should be interdigitated with surgery in patients who present with synchronous metastatic disease [130] have not been defined. this approach is not used by many clinicians outside of New York City.

and several surgical case series have failed to confirm inferior survival or greater morbidity . delaying hepatic surgery by three to six months would permit the biological behavior of the metastatic disease to become evident. it can increase the volume of resected liver. This was shown in a collective series of 436 patients undergoing macroscopically complete. (See 'Neoadjuvant chemotherapy' above and "Nonsurgical local treatment strategies for colorectal cancer liver metastases". although if patients are untreated during this interval. 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). versus 57 and 37 percent in the R1 group). a complete (R0) resection must always be the goal of any resection. five. 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). Some reports indicate a poor prognosis in such patients. 234 were microscopically complete (R0). (See "Nonsurgical local treatment strategies for colorectal cancer liver metastases". Furthermore. At a median follow-up of 40 months.132]. potentially curative resection for CRC liver metastases at three institutions. However. In multivariate analysis. One potential solution is to perform percutaneous RFA during the interval between diagnosis and hepatic metastasectomy [134]. Delayed resection does not seem to increase the risk of patients becoming unresectable due to growth of the initial metastases [133]. Another is to administer chemotherapy during this period.) Simultaneous resection of the primary and metastatic disease is clearly preferable from the patient's perspective. In theory. thus improving the selection of patients for whom hepatic metastasectomy might be curative. section on 'Tumor ablation'. particularly if an ultrasonic dissector is used for the hepatic resection [44]. further locoregional therapy may not be necessary. Current data do not support planning for surgical resection with foreknowledge that residual disease will be left behind. while 202 had microscopically positive margins (R1 resection) [131].) For patients with a macroscopically complete resection in whom a tumor-free resection margin cannot be obtained because of vascular proximity or multinodularity. an approach that might also allow some patients with initially unresectable or borderline resectable liver metastases to undergo successful later hepatic resection. six to eight weeks if bevacizumab was a component of therapy.and ten-year overall survival rates were not dissimilar between the two groups (61 and 43 percent in the R0 group. (See 'Chemotherapy-related liver toxicity' above.) 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. but the majority (88 percent) had postoperative chemotherapy (as did 78 percent of the patients who underwent R0 resection). 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. preoperative CEA level and major hepatectomy (≥3 segments) but not R1 resection were independent predictors of poor outcome. a significant predictor of postoperative complications.least four weeks after completion of chemotherapy. at least in part attributable to the failure to resect clinically occult micrometastatic liver disease [5. 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. This subject is discussed in detail elsewhere.

One-stage surgery is probably a reasonable option for patients who present with low-volume (four or fewer.for patients who undergo a one-stage procedure as compared to delayed (staged) hepatic resection. the chemotherapy used in these trials is considered inferior by modern standards. p = 0. while potentially clinical meaningful. the differences in median progression-free survival (28 versus 19 months. were not statistically significant [142]. or all in the same lobe) resectable hepatic metastases. the introduction of newer drugs such as oxaliplatin. (See 'Neoadjuvant chemotherapy'above. (See 'Therapy after resection of liver metastases' above.) THERAPY AFTER RESECTION OF LIVER METASTASES — As noted previously.143]. clear evidence of a survival benefit compared to observation alone has not yet emerged.144]:  A randomized trial from the EORTC evaluating perioperative FOLFOX chemotherapy (six cycles preoperatively. initial chemotherapy followed by reassessment and delayed resection is probably a better strategy. if there are five or more simultaneous potentially resectable hepatic metastases (unless all are located in one lobe). In a combined analysis of both trials (totaling 278 patients). but only a trend toward better survival (51 versus 41 percent). patients receiving chemotherapy had a significantly better disease-free survival. (See "Surveillance after colorectal cancer resection". Systemic chemotherapy — A limited number of studies have explored the benefit of systemic 5-FUbased chemotherapy following resection of hepatic metastases. Because of the incidence of synchronous second primary colorectal cancers (approximately 3 to 5 percent). there is a clear survival benefit from resection in patients with limited hepatic metastases from colorectal cancer (CRC). (See "Systemic chemotherapy for metastatic colorectal cancer: Completed clinical trials". Two randomized trials of similar design were initiated in the early 1990s (the French FFCD 9002 and EORTC/NCIC trials). The role of systemic or regional therapy following metastasectomy is far less certain. These data provide a proof of principle of the benefit of postresection adjuvant chemotherapy in this population.) There are limited data available from randomized trials on the benefits of these modern chemotherapy regimens following resection of colorectal cancer liver metastases [103.135-141]. but the results have not been published separately. five-year overall survival was not significantly better in . if feasible. For patients with unresectable metastatic CRC.058) and overall survival (62 versus 47 months). in the latest update of this trial. but both were closed prematurely because of slow accrual [142. At five years. The EORTC trial used the same chemotherapy regimen. six postoperatively) versus observation alone in patients with initially resectable liver metastases showed that chemotherapy was associated with a trend toward improved threeyear progression-free survival relative to surgical resection alone [103]. which was the primary endpoint (34 versus 27 percent at five years).) On the other hand. The FFCD trial randomly assigned 173 of a planned 200 patients to six months of postoperative systemic 5FU and leucovorin (with both drugs administered for five consecutive days once per month for six months) versus observation alone following hepatic resection [143].) However. complete colonoscopy prior to surgical resection should be undertaken. or if disease is borderline resectable due to location. bevacizumab. bilobar involvement. unless major hepatic resection (three or more segments) is needed [133. However. irinotecan. section on 'Diagnosing second cancers and polyps'. and cetuximabhas been accompanied by a marked improvement in median survival from six to seven months to 20 to 24 months.

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. HR for death 0. coupled with the proven efficacy of adjuvant systemic 5FU-based chemotherapy in patients with node-positive colon cancer. there was also no difference when the analysis was restricted to colorectal cancer deaths [104]. based on indirect evidence. we and others consider FOLFOX alone (table 6) to be the reference regimen for this group of patients [145]. This study randomly assigned 226 patients to receive HIA 5-FU plus leucovorin or no treatment following hepatic resection of colorectal metastases.) NCCN recommendations — Despite the paucity of data. Thus. Despite initially encouraging data from small randomized studies conducted in fewer than 40 patients [146. Of note. Acceptable options include:   FOLFOX or CAPOX or FOLFIRI with or without bevacizumab or FOLFOX or CAPOX or FOLFIRI plus cetuximab (wild-type K-ras only) In view of the newly available data regarding the lack of benefit from adjuvant irinotecan plus 5-FU [144]. led to the study of regional treatment. However. However. This observation. (See 'Initially resectable disease' above.14). 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. A later German trial was closed prematurely when interim analysis suggested a worse outcome from HIA [149]. administration of postoperative irinotecan-containing chemotherapy should not be considered a standard approach following resection of liver-isolated metastatic disease. Regional therapy — The liver is the dominant site of recurrence in over one-half of patients undergoing potentially curative resection. 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. 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. 95% CI 0. there was no significant disease-free survival advantage for adding irinotecan (median 25 versus 22 months). The trial was not powered for overall survival as an endpoint.88.68-1. We generally do not use bevacizumab in this setting. and treated patients had a worse median survival . section on 'Irinotecan'. At a median follow-up of 42 months. larger randomized controlled trials were disappointing. (See "Adjuvant therapy for resected stage III (node-positive) colon cancer". given the marginal benefits and risk for major complications. we would consider most of these regimens to represent acceptable options except FOLFIRI. these results cannot be used to conclude that there is a lack of benefit for adjuvant chemotherapy after resection of CRC liver metastases.) 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 2 without or with irinotecan (180 mg/m every other week) [144].147]. the chemotherapy group (52 versus 48 percent. patient accrual was inadequate to address the utility of adjuvant therapy [148].

and similar median time to progression (14. The observation that many of these patients were failing outside of the liver led to efforts combining regional and systemic 5-FU-based chemotherapy.154].7 months) compared to those undergoing surgery alone. 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). However. comparing systemic capecitabine plus oxaliplatin alone or with alternating HAI FUDR after resection of colorectal cancer liver metastases. only 19 percent of the patients randomized to receive regional plus systemic chemotherapy completed the prescribed course of treatment [151]. Unfortunately. This series demonstrates how well some patients can do with resection that is done in a center with substantial experience. disease-free interval from primary to metastases <12 months. the ultimate proof of benefit will require a randomized controlled trial.(35 versus 41 months). is underway. (See "Chemotherapy hepatotoxicity and dose modification in patients with liver disease". 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 [151]. Although treatment is tolerable and early results are promising. largest hepatic tumor >5 cm. only 109 patients were accrued during nine years [150]. 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 the final analysis. and overall recurrence-free survival (46 versus 25 percent). and CEA level >200 ng/ml [12]). more than one hepatic metastasis. Placement of the HIA pump increases the complexity of the operation. However. Such a trial. there was no benefit in terms of median overall survival. and in one series. 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. More recent studies are exploring regimens that combine HIA chemotherapy and intravenous irinotecan or oxaliplatin [153. 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 [152].2 versus 13.) Nevertheless. a better four-year hepatic recurrence-free survival (67 versus 43 percent). which was limited to 75 eligible patients (45 controls and 30 chemotherapy-treated patients). 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. 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). NSABP C09. section on 'Floxuridine'. Routine use of HIA chemotherapy after liver resection has not gained widespread acceptance. . outcomes were significantly better with combined therapy in those with a clinical risk score of 3 to 5 (median survival 60 versus 38 months. Using a clinical risk score as defined by Fong et al (assigning one point for each of the following: node-positive primary. combined systemic and regional therapy was associated with significantly longer time to recurrence. 10-year survival 39 versus 16 percent). and that regional therapy can improve the rate of hepatic tumor control.

which derive 90 percent of their blood supply from the hepatic artery. overall and disease-free survival (at three years 42 and 19 percent.) The liver is the only site of recurrence in approximately 35 to 40 percent [10. either via surgical resection or with cryosurgery [155]. portal vein infusion (PVI) carries with it a significant regional exposure advantage. administration into the portal vein has been explored as an alternative. including advanced disease.159. Like HIA infusion. are available from the National Comprehensive Cancer Network (NCCN) (table 8).160]. hepatic micrometastases (as well as the biliary tree) are primarily dependent on the portal vein for their blood supply.) SURVEILLANCE AFTER METASTASECTOMY — Posttreatment surveillance is recommended following resection of a primary colorectal cancer.158]. (See "Surveillance after colorectal cancer resection". Although evidence regarding the optimal follow-up strategy after liver resection for metastatic CRC is limited [157. (See 'Repeat resection for recurrent metastases' below. Portal vein infusion — Because HIA FUDR carries a risk for biliary sclerosis. Systemic administration of 5-FU and leucovorin was given in conjunction with PVI FUDR. Although there was a low incidence of hepatic drug-induced toxicity. (See "Nonsurgical local treatment strategies for colorectal cancer liver metastases". All were followed with a similar . Until the results are known from such pilot studies. 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. which was administered for 14 days on and 14 days off at a dose approximately twofold higher than that used with HIA FUDR. for resected stage IV disease.HIA plus other local approaches — Other investigators are exploring the role of HIA FUDR-based chemotherapy in conjunction with partial debulking of liver metastases. the goal is identification of those patients who might potentially be cured by further surgical intervention. consensus-based guidelines addressing the surveillance strategy and frequency of follow-up for CRC. (See "Nonsurgical local treatment strategies for colorectal cancer liver metastases". section on 'Optimizing chemotherapy'.151]. the use of HIA chemotherapy in that setting should be considered investigational.) The majority of patients with resected isolated liver metastases from CRC will develop recurrences in liver and lung. with acceptable morbidity and perioperative mortality. CT is recommended every three to six months for two years then every 6 to 12 months for a total of five years. which could be potentially treated with further resection.) The rationale is based upon the observation that in contrast to clinically detectable metastases. and to screen for second primary cancers and polyps. (See "Surgical resection of pulmonary metastases: Outcomes by histology" and "Surgical resection of pulmonary metastases: Outcomes by histology". 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 [156]. section on 'Colorectal cancer'. the role for this approach appears to be limited. Thus. respectively) were somewhat lower than has been reported with HIA FUDR and systemic 5-FU plus leucovorin following resection of hepatic metastases [150. Five-year survival rates up to 43 percent are reported following repeat liver resection for a second recurrence. In addition.) 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 [160].

if advanced adenoma is found. which included outpatient clinical examinations at 3. and they answer the four or five key questions a patient might have about a given condition. then annually from year six to ten. The mean number of scans performed per resectable recurrence was 35. in 46 percent through a CEA rise concurrent with positive imaging. INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials. “The Basics” and “Beyond the Basics. then every five years. 6. Other factors associated with a poor outcome include synchronous resection for the first liver metastases.3. and the presence of multiple lesions at second hepatectomy [164. then every 6 to 12 months up to a total of five years Colonoscopy in one year. . at six monthly intervals for three more years. 12. At every time point (within one year of original surgery. beyond two years). perioperative mortality rates were less than 5 percent. In addition. The site of recurrent disease was liver only in 36 percent.) 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.  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 months for two years.47. a value that compares favorably to other cost-effectiveness ratios that are considered acceptable in the US and elsewhere. In several reported series. with measurement of CEA and CA 19-9 levels at each visit. then every six months for three to five years CT of the chest/abdomen and pelvis every three to six months for two years. repeat hepatic resection may be considered in selected patients who recur in the liver with no evidence of extrahepatic disease. at th th the 5 to 6 grade reading level. if no advanced adenoma repeat in three years.” The Basics patient education pieces are written in plain language. These articles are best for patients who want a general overview and who prefer short. repeat in one year REPEAT RESECTION FOR RECURRENT METASTASES — Although randomized trials have not been conducted to prove benefit. 404 were detected within two years. Patients with a relapse-free interval of longer than one year appear to have a more favorable outcome from reresection [160. Beyond the Basics patient education pieces are longer. extrahepatic only in 38 percent. section on 'Interpretation'.169]. and relapse-free survival rates ranged from 20 to 43 percent at two to five years (table 9) [16.165. easy-to-read materials. and in 31 percent through positive imaging alone [158].surveillance protocol. one to two years. abdomen and pelvis every three months for the first two years. and a good performance status. th th and more detailed. and 24 months. and annually thereafter. Of the 444 patients with a recurrence diagnosed on a surveillance CT. (See "A short primer on cost-effectiveness analysis". those patients treated by liver and/or lung resection had significantly better median survival than did those who received palliative chemotherapy alone. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. In total.163]. recurrent disease was treated surgically in 124 patients. The authors did not report how many recurrences were detected by serum tumor markers versus CT scans. more sophisticated.161-173]. 18. and both hepatic and extrahepatic sites in 26 percent. and the cost per life-year gained was £2883. all patients had CT of the thorax.

or main portal vein Extensive liver involvement (>70 percent. a patient with a metachronous presentation of the primary and metastases who has several liver metastases that are not responding to chemotherapy).) If the hepatic metastases are potentially resectable. instead recommending two to three courses of preoperative chemotherapy in all patients with potentially resectable liver metastases. tumor involving any segments of the left and right hemi-liver).Here are the patient education articles that are relevant to this topic. However. or involvement of all three hepatic veins) Inadequate predicted postresection functional hepatic reserve  We suggest not using a clinical risk score to select patients for diagnostic laparoscopy ( Grade 2C). metastatic cancer (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS  Surgical resection is the only potentially curative option for patients with liver-isolated metastatic colorectal cancer. common hepatic or common bile duct. we suggest immediate surgical resection rather than initial chemotherapy for medically fit patients with four or fewer metastases. For patients with a good performance status who have more than four metastases (unless all are localized to a single lobe). in part to select those patients who are most likely to benefit from resection [174].) The optimal selection of patients for resection is evolving. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest. the number of courses should be minimized. 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. in at least four contemporary series. five-year overall survival rates are approximately 58 percent.) Others disagree. radiographic suspicion for portal node involvement. more than six segments (figure 1). we suggest initial systemic chemotherapy followed by surgical reevaluation ( Grade 2C). For appropriately selected patients with four or fewer metastases. (See 'Surgical resection' above. Since the criteria for potential liver directed therapies have been expanded. and surgery undertaken as soon as the metastases are clearly . if preoperative chemotherapy is selected. 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. Radiographic response assessment should be performed at six week intervals. unless a response to chemotherapy is anticipated to allow for a significantly less complex resection (Grade 2B). (See 'Selecting patients for diagnostic laparoscopy' above. or bilobar disease (ie. We encourage you to print or e-mail these topics to your patients. five-year relapse-free survival rates average 30 percent. (See 'Initially resectable disease' above.)   Basics topics (see "Patient information: Colon and rectal cancer (The Basics)") Beyond the Basics topics (see "Patient information: Colon and rectal cancer (Beyond the Basics)" and "Patient information: Colorectal cancer treatment.

resectable. For patients with metachronous metastases who have received adjuvant FOLFOX in the preceding 12 months. We consider the following combinations to represent reasonable choices: FOLFOX (table 6). the optimal regimen for conversion therapy in this setting is not established.) The relative benefit and indications for hepatic intraarterial chemotherapy in patients with hepatic metastases from CRC remains uncertain. (See 'Chemotherapy-related liver toxicity' above. (See 'Timing of hepatectomy in patients presenting with metastases' above. (See 'HIA plus systemic therapy' above. If not feasible. 23:8490. et al. Chang GJ. (See 'Surveillance after metastasectomy'above. Cancer statistics. (See 'Choice of regimen' above and"Treatment protocols for colorectal cancer". Petrelli NJ. (See 'Choice of regimen' above and "Treatment protocols for colorectal cancer". Jemal A. Overman MJ. posttreatment surveillance is warranted if they would be considered candidates for a second potentially curative surgical procedure. In the absence of published randomized trials to guide clinical practice following metastasectomy. 3. if feasible (Grade 2C). We suggest one-stage surgery. If it is attempted. Extending the frontiers of surgical therapy for hepatic colorectal metastases: is there a limit? J Clin Oncol 2005. Naishadham D. FOLFOXIRI (table 7).) The optimal chemotherapy regimen is not established. the optimal timing of liver resection is uncertain.) For patients who have hepatic metastases at initial presentation.     .) Following complete resection of liver metastases.) Upfront chemotherapy is an appropriate option for patients with initially unresectable liver metastases. Improved survival in metastatic colorectal cancer is associated with adoption of hepatic resection and improved chemotherapy. We suggest that this approach be restricted to institutions with expertise in both the medical and surgical oncologic aspects of this procedure. or FOLFOXIRI (for young healthy patients who are able to tolerate it). Belghiti J. Furthermore. J Clin Oncol 2009. Khatri VP. 63:11. resection of liver metastases can follow six to eight weeks after resection of the primary tumor. Consensusbased guidelines for the posttreatment surveillance strategy are available from the NCCN. 2. we suggest completion of a full six month course of systemic chemotherapy containing oxaliplatin (Grade 2C). (See 'Therapy after resection of liver metastases' above. we prefer an oxaliplatin-based systemic combination regimen without bevacizumab. 27:3677. FOLFIRI with or without cetuximab or panitumumab (for wild-type K-ras only) is a reasonable option. We recommend against the use of an irinotecan-based regimen in this setting (Grade 1B). or FOLFIRI plus cetuximab (table 4) or panitumumab (for patients whose tumors lack K-ras mutations). Given the potential for treatment-related toxicity with bevacizumab and the modest improvement in overall response rate when this agent is added to oxaliplatin. REFERENCES 1.) For patients who are rendered free of disease. CA Cancer J Clin 2013. Kopetz S.) Use of UpToDate is subject to the Subscription and License Agreement. the likelihood of downstaging a patient with truly unresectable disease to the point of resectability is only 10 to 15 percent. 2013. longer durations of preoperative chemotherapy increase the potential for liver toxicity and postoperative complications. the best postoperative strategy is uncertain. however. Siegel R.

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