Skip to main content
PMC home page
The Cochrane Database of Systematic Reviews logoLink to The Cochrane Database of Systematic Reviews
. 2010 Jan 20;2010(1):CD006797. doi: 10.1002/14651858.CD006797.pub2

Surgical resection versus non‐surgical treatment for hepatic node positive patients with colorectal liver metastases

Kurinchi Selvan Gurusamy 1,✉, Rajarajan Ramamoorthy 1, Charles Imber 2, Brian R Davidson 1
Editor: Cochrane Hepato‐Biliary Group
PMCID: PMC7389879  PMID: 20091607

Abstract

Background

Involvement of hepatic lymph node in patients with colorectal liver metastases is associated with poor prognosis.

Objectives

To determine the benefits and harms of curative liver resection with lymphadenectomy versus other treatments for colorectal liver metastases with hepatic node involvement.

Search methods

We searched The Cochrane Hepato‐Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded, and LILACS until September 2009 for identifying the randomised trials.

Selection criteria

We considered only randomised clinical trials (irrespective of language, blinding, or publication status) comparing liver resection (alone or in combination with radiofrequency ablation or cryoablation) versus other treatments (neo‐adjuvant chemotherapy, chemotherapy, or radiofrequency ablation) in patients with colorectal liver metastases with hepatic node involvement.

Data collection and analysis

Two authors independently identified trials for inclusion.

Main results

We were unable to identify any randomised clinical trial fulfilling the inclusion criteria of this review. We were also unable to identify any quasi‐randomised or cohort studies, which could meaningfully answer this important issue.

Authors' conclusions

There is no evidence in the literature to assess the role of surgery versus other treatments for patients with colorectal liver metastases with hepatic node involvement. High quality randomised clinical trials are feasible and are necessary to determine the optimal management of patients with colorectal liver metastases with hepatic node involvement.

Plain language summary

No evidence from randomised clinical trials for optimal management of patients with large bowel cancer spread to lymph glands draining the liver

Nearly a third of patients with large bowel cancers (colorectal cancer) spread to the liver (liver metastases) within five years of diagnosis of bowel cancer. The affected part of the liver can be removed surgically in a quarter of such patients who develop liver spread from bowel cancer. About a seventh of these patients, in whom the affected part of the liver is suitable for removal, develop cancer involvement of lymph glands draining the liver (hepatic lymph node). Such patients are associated with poor survival even after removal of the affected part of the liver and the involved nodes. This Cochrane review attempted to answer the question of whether removing the part of the liver is better than other forms of treatment (such as no treatment, chemotherapy, heat destructive therapy using radiofrequency waves, ie, radiofrequency ablation) in such patients but did not find any randomised clinical trial addressing the issue. Currently, there is no evidence from randomised clinical trials for optimal management of these patients. High quality randomised clinical trials are feasible and are necessary to determine the optimal management of patients with colorectal liver metastases with hepatic node involvement.

Background

Colorectal cancer is the third commonest malignancy in the United Kingdom with an estimated 34,000 patients diagnosed every year (Wood 2005). It is the second most common cause of cancer mortality (next only to lung cancer) accounting for nearly a tenth of cancer deaths in UK (Wood 2005) and for 1 in 40 deaths from all causes (Wood 2005). Nearly 16,000 people die annually due to colorectal cancer (Wood 2005).

Nearly a third of patients with colorectal cancers develop spread to the liver (liver metastases) within five years (Manfredi 2006). Of these metastatic deposits, 20% to 32% are resectable (Adam 2001; Tepper 2003; Adam 2004). The five‐year survival after liver resection varies between 16% and 30% (Beckurts 1997; Ambiru 1999; Adam 2004; Mutsaerts 2005; Vassiliou 2007). Cancer seed to hepatic lymph nodes identified during liver resection is considered as a poor prognostic factor (Rodgers 2000; Abdalla 2006), with five‐year survival after liver resection varying between 0% and 4.3% (Beckurts 1997; Jaeck 2002; Laurent 2004). In studies of patients with liver metastases who underwent routine lymphadenectomy, about 14% to 15% of patients with nodes (draining the liver) considered uninvolved macroscopically are infiltrated by tumour cells microscopically (Jaeck 2002; Laurent 2004). Patients who have involvement of common hepatic and coeliac artery nodes (considered as group 2 nodes) (Jaeck 2003) have been reported to have a poorer prognosis than the patients with involvement of hepato‐duodenal or retro‐pancreatic group of nodes (considered as group 1 nodes) (Jaeck 2003). Approximately half of the microscopic disease is in the hepato‐duodenal and the retro‐pancreatic group (Jaeck 2003) and therefore amenable to radical lymphadenectomy.

The mechanism for development of hepatic node involvement is not known, nor whether they represent spread from the liver metastases (Beckurts 1997) or the primary bowel cancer. In people with positive nodes, after adjusting for different factors, such as tumour number (Beckurts 1997; Kokudo 1998; Jaeck 2002; Tocchi 2004), size (Kokudo 1998; Jaeck 2002; Tocchi 2004), distribution (Jaeck 2002; Tocchi 2004), and surgical resection margin (Kokudo 1998), survival after liver resection are similar to those in patients with unresectable colorectal metastasis who underwent hepatic infusion chemotherapy (Bennett 2005; Kemeny 2005). Median survival after systemic chemotherapy with leucovorin, 5‐fluorouracil, oxaliplatin, and irinotecan has been recently reported to be around 20 months (Kemeny 2006; Falcone 2007) with an estimated three‐year survival of about 10% (Kemeny 2006). In light of this, hepatic node involvement detected pre‐operatively or during surgery is generally considered a contra‐indication for liver resection for liver secondaries from colorectal primary (Irie 1999; Imamura 2001). With the improving results of resection of extra‐hepatic disease (five‐year survival of 18%) following neo‐adjuvant chemotherapy, ie, chemotherapy followed by surgery followed by chemotherapy (Adam 2001), hepatic node involvement as a contra‐indication for liver resection for colorectal liver metastases requires to be reconsidered. Regional nodal involvement in other cancers, such as oesophageal cancers (Tsuchiya 2002; Yano 2006) and rectal cancers (Onaitis 2001; Stipa 2004), have been treated with pre‐operative chemotherapy in order to down‐stage the disease, which may improve the median survival (Tsuchiya 2002). Down‐staging the disease in patients with colorectal liver metastases associated with hepatic nodal involvement may improve the survival.

Besides the heterogeneity arising due to the involvement of different groups of nodes, other factors such as the method used for determining nodal involvement, the number of nodes examined, whether routine or selective lymphadenectomy was performed may contribute to the heterogeneity in the patients included in the studies. In spite of this clinical heterogeneity, the prognosis for patients with hepatic node involvement who underwent liver resection is poor (Gurusamy 2008) and the optimal management of these patients remains unclear. Recently, there have been reports that radiofrequency ablation for colorectal metastases is associated with reasonable survival even in patients with colorectal liver metastases deemed unresectable (Oshowo 2003; Leblanc 2008). Radiofrequency ablation has been suggested as an alternative to surgical resection even in patients with resectable disease (Mulier 2008).

There has been no meta‐analysis or systematic review of randomised clinical trials comparing potentially curative liver resection with lymphadenectomy and other potentially curative or palliative modalities of treatment of colorectal liver metastases with hepatic node involvement.

Objectives

To determine the benefits and harms of potentially curative liver resection with lymphadenectomy versus other potentially curative or palliative treatments of patients with colorectal liver metastases with hepatic node involvement.

Methods

Criteria for considering studies for this review

Types of studies

We considered all randomised clinical trials (irrespective of language, blinding, publication status, or sample size) for inclusion.

Quasi‐randomised studies (where the method of allocating participants to a treatment are not strictly random, for example, date of birth, hospital record number, alternation) were not included regarding assessment of benefit but were considered for inclusion regarding assessment of harm.

Types of participants

Patients with colorectal liver metastases, who are found to have hepatic node involvement (irrespective whether group 1 or group 2 nodes) and otherwise resectable (however defined by authors).

Types of interventions

We planned to study the following interventions.

  1. Potentially curative surgical liver resection (liver resection where all macroscopic disease is removed) with lymphadenectomy versus other potentially curative (radiofrequency ablation) or palliative treatment (where potentially curative surgical resection or radiofrequency ablation is not possible; including chemotherapy and radiofrequency ablation).

  2. Potentially curative surgical resection or ablation with lymphadenectomy or lymph node ablation as part of neo‐adjuvant chemotherapy versus palliative treatment.

We planned to allow co‐interventions if carried out equally in the trial groups.

Types of outcome measures

Primary outcomes

  1. Mortality

    1. Proportion dead after one, three, five, and ten years.

    2. Estimated median survival.

    3. Hazard ratio for death.

Secondary outcomes

  1. Proportion with recurrence of liver metastases (for comparison of surgery, radiofrequency ablation, and cryoablation).

  2. Disease‐free survival.

  3. Treatment‐related morbidity (surgery ‐ 30‐day mortality, bile leak, lymphorrhoea, abdominal collections requiring treatment, wound related complications, such as wound infection, wound dehiscence; chemotherapy ‐ systemic effects, such as bone marrow suppression, nausea, vomiting, diarrhoea; hepatic infusion chemotherapy ‐ systemic adverse effects of chemotherapy and other toxicities, such as peptic ulceration, chemical hepatitis, and biliary sclerosis (Cohen 2003)).

  4. Blood transfusion requirements.

  5. Total hospital stay.

  6. Quality of life (however defined by authors).

Search methods for identification of studies

We searched The Cochrane Hepato‐Biliary Group Controlled Trials Register (Gluud 2009), the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded (Royle 2003) and LILACS (Clark 2002). We have given the search strategies in Appendix 1 with the time span for the searches. The last search was performed on the 6th of September 2009. We also searched the reviews of treatment of colorectal liver metastases for references to identify relevant trials.

Data collection and analysis

Trial selection and extraction of data

Two authors (KSG and RR), independently of each other, searched for trials and planned to group the identified trials into included or excluded, and to list the latter with reasons for the exclusion.

KSG and RR planned to independently extract the following data.

  1. Year and language of publication.

  2. Country.

  3. Year of study.

  4. Inclusion and exclusion criteria.

  5. Method of diagnosing nodal involvement (radiological, laparoscopic or open surgical).

  6. Method of confirmation of nodal involvement (histopathology, immunocytochemistry).

  7. Synchronous or metachronous metastases.

  8. Mean number of tumours.

  9. Mean size of tumours.

  10. Unilobar or bilobar metastases.

  11. First resection or repeat liver resection.

  12. Pre‐operative chemotherapy.

  13. Post‐operative chemotherapy.

  14. Operating time.

  15. Other co‐interventions (such as portal vein embolization).

  16. Outcomes (mentioned above).

  17. Risk of bias in trials (described below).

We planned to seek any unclear or missing information by contacting the authors of the individual trials. If there was any doubt whether the trials share the same patients ‐ completely or partially (by identifying common authors and centres), we planned to contact the authors of the trials to clarify whether the trial report had been duplicated.

We resolved any differences in opinion through discussion or arbitration of the third author (BRD).

Assessment of risk of bias

We planned to assess the risk of bias in the trials independently, without masking of the trial names. We planned to follow the instructions given in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008) and the Cochrane Hepato‐Biliary Group Module (Gluud 2009). Due to the risk of biased overestimation of intervention effects in randomised trials with inadequate methodological quality (Schulz 1995; Moher 1998; Kjaergard 2001; Wood 2008), we planned to look at the influence of methodological quality of the trials on the results by evaluating the reported randomisation and follow‐up procedures in each trial. If information was not available in the published trial, we planned to contact the trial authors in order to assess the trials correctly.

Sequence generation

  • Low risk of bias (the methods used is either adequate (eg, computer generated random numbers, table of random numbers) or unlikely to introduce confounding).

  • Uncertain risk of bias ( there is insufficient information to assess whether the method used is likely to introduce confounding).

  • High risk of bias (the method used (eg, quasi‐randomised trials) is improper and likely to introduce confounding).

Allocation concealment

  • Low risk of bias (the method used (eg, central allocation) is unlikely to induce bias on the final observed effect).

  • Uncertain risk of bias (there is insufficient information to assess whether the method used is likely to induce bias on the estimate of effect).

  • High risk of bias (the method used (eg, open random allocation schedule) is likely to induce bias on the final observed effect).

Blinding

It is not possible to blind the health‐care provider (surgeons or radiologists or oncologists) to the groups. However, it is possible to blind the patients (for comparisons such as liver resection versus open radiofrequency ablation) and the outcome assessors.

  • Low risk of bias, if the patients (whenever possible) and outcome assessors were blinded and the method of blinding was described.

  • Uncertain risk of bias, if the patients (whenever possible) and outcome assessors were blinded and the method of blinding was not described.

  • High risk of bias, if the patients (whenever possible) or outcome assessors were not blinded.

Incomplete outcome data

  • Low risk of bias (the underlying reasons for missingness are unlikely to make treatment effects departure from plausible values, or proper methods have been employed to handle missing data).

  • Uncertain risk of bias (there is insufficient information to assess whether the missing data mechanism in combination with the method used to handle missing data is likely to induce bias on the estimate of effect).

  • High risk of bias (the crude estimate of effects (eg, complete case estimate) will clearly be biased due to the underlying reasons for missingness, and the methods used to handle missing data are unsatisfactory).

Selective outcome reporting

  • Low risk of bias (the trial protocol is available and all of the trial's pre‐specified outcomes that are of interest in the review have been reported or similar or all of the primary outcomes in this review have been reported).

  • Uncertain risk of bias (there is insufficient information to assess whether the magnitude and direction of the observed effect is related to selective outcome reporting).

  • High risk of bias (not all of the primary outcomes in this review have been reported and not all of the trial's pre‐specified outcomes that are of interest in the review have been reported).

Baseline imbalance

  • Low risk of bias (there was no baseline imbalance in important characteristics).

  • Uncertain risk of bias (the baseline characteristics were not reported).

  • High risk of bias (there was a baseline imbalance due to chance or due to imbalanced exclusion after randomisation).

Early stopping

  • Low risk of bias (sample size calculation was reported and the trial was not stopped or the trial was stopped early by a formal stopping rule at a point where the likelihood of observing an extreme intervention effect due to chance was low).

  • Uncertain risk of bias (sample size calculations were not reported and it is not clear whether the trial was stopped early or not).

  • High risk of bias (the trial was stopped early due to an informal stopping rule or the trial was stopped early by a formal stopping rule at a point where the likelihood of observing an extreme intervention effect due to chance was high).

Academic bias

  • Low risk of bias (the author of the trial has not conducted previous trials addressing the same interventions).

  • Uncertain risk of bias (It is not clear if the author has conducted previous trials addressing the same interventions).

  • High risk of bias (the author of the trial has conducted previous trials addressing the same interventions).

Source of funding bias

  • Low risk of bias (the trial's source(s) of funding did not come from any parties that might have conflicting interest (eg, instrument or drug manufacturer).

  • Uncertain risk of bias (the source of funding was not clear).

  • High risk of bias (the trial was funded by an instrument or drug manufacturer).

We considered trials to be of low risk of bias if we assessed them to have low risk of bias in all the above domains.

Statistical methods

We planned to perform the meta‐analyses according to the recommendations of The Cochrane Collaboration (Higgins 2008) and the Cochrane Hepato‐Biliary Group Module (Gluud 2009) using the software package RevMan 5 (RevMan 2008). For dichotomous variables, we planned to calculate the risk ratio with 95% confidence interval. For continuous variables, we planned to calculate the mean difference (for outcomes like hospital stay) and standardised mean difference (for outcomes like patient quality of life where different scales can be used). For calculation of time to event outcomes such as survival or recurrence, we planned to extract the logarithm of hazard ratios (ln(HR)) and the standard error (SE) of ln(HR) using the methods described by Parmar et al (Parmar 1998) using the excel sheet provided by Tierney et al (Tierney 2007). We planned to use a random‐effects model (DerSimonian 1986) and a fixed‐effect model (DeMets 1987). In case of discrepancy between the two models we planned to report both results; otherwise we planned to report only the results from the fixed‐effect model. We planned to explore heterogeneity using a chi‐squared test with significance set at P value 0.10, and measure the quantity of heterogeneity by I2 (Higgins 2002) set at 30%.

We planned to perform the analysis on an intention‐to‐treat analysis (Newell 1992) whenever possible. Otherwise, we planned to adopt the 'available case analysis'. In case we found 'zero‐event' trials for outcomes that are statistically significant without including the 'zero‐event' trials, we planned to perform a sensitivity analysis with and without empirical continuity correction factors as suggested by Sweeting et al (Sweeting 2004). We also planned to report the risk difference if the results were different from risk ratio.

Subgroup analysis

We planned to perform subgroup analyses for trials with low risk of bias compared to those with high risk of bias.

Bias exploration

We planned to use a funnel plot to explore bias (Egger 1997; Macaskill 2001). We planed to perform linear regression approach described by Egger et al to determine the funnel plot asymmetry (Egger 1997).

Results

Description of studies

We identified a total of 3986 references through electronic searches of The Cochrane Hepato‐Biliary Group Controlled Trials Register and the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (n = 170), MEDLINE (n = 1358), EMBASE (n = 1772), Science Citation Index Expanded (n = 686) and LILACS (n = 0). We excluded 906 duplicates. It was clear from reading titles and abstracts that none of the remaining 3080 references were randomised clinical trials. Although we would have excluded quasi‐randomised trials for survival, we searched for any quasi‐randomised trial in order to calculate the sample size and outcomes that can be used for any new randomised clinical trial. We were not able to identify any quasi‐randomised study also from the retrieved references.

Risk of bias in included studies

None of the studies identified through the search strategy qualified for inclusion in this review. We were also unable to identify any cohort studies or any case‐control studies that could meaningfully try to answer the questions posed in this systematic review.

Effects of interventions

None of the studies identified through the search strategy qualified for this review.

Discussion

The involvement of hepatic lymph node in patients with colorectal liver metastases is associated with poor prognosis irrespective of whether these are evident macroscopically or microscopically (Gurusamy 2008). Some surgeons consider involvement of hepatic lymph node to be a contra‐indication for liver resection (Irie 1999; Imamura 2001). This review was undertaken to address the issue of optimal management of such patients.

None of the studies identified through the search strategy qualified for this review. We were also unable to identify non‐randomised controlled studies (where the controls were similar in characteristics to the liver resection group), which could give information to facilitate the design of a randomised clinical trial.

Traditionally liver resection has offered better survival than other treatments for colorectal liver metastases. However, this was before the advent of the new modalities of treatment. Now the new modalities of treatment are reserved for patients who are not eligible for surgery. Thus, a fair comparison between surgical resection and other new modalities is not possible as surgical resection is performed in patients with favourable features, and the other treatments are performed in patients with unfavourable features. There is ethical dilemma in such situations. However, a previous review by our group showed that involvement of hepatic lymph node in patients with colorectal liver metastases is associated with poor prognosis even after liver resection combined with lymphadenectomy (Gurusamy 2008). Thus, there seems to be no ethical dilemma for the surgeon in randomising such patients to resection versus other treatments.

We considered various comparisons for a randomised clinical trial on surgical resection. One possible comparison is the comparison of neo‐adjuvant chemotherapy plus surgical resection (chemotherapy followed by surgery followed by chemotherapy) versus chemotherapy alone in patients with colorectal liver metastases with hepatic node involvement. Regional nodal involvement in other cancers, such as oesophageal cancers (Tsuchiya 2002; Yano 2006) and rectal cancers (Onaitis 2001; Stipa 2004), have been treated with pre‐operative chemotherapy for down‐staging the disease, which may improve the median survival (Tsuchiya 2002). Down‐staging the disease in patients with colorectal liver metastases associated with hepatic nodal involvement may improve the survival. However, this would necessitate a pre‐operative diagnosis of nodal involvement and, therefore, only patients with macroscopic positive hepatic lymph nodes (available to biopsy) could be included in this trial. The incidence of macroscopically positive hepatic lymph nodes is 4.8% in patients with otherwise resectable colorectal hepatic metastases (Beckurts 1997). Approximately 50% of the patients with hepatic node disease are alive at one year (Gurusamy 2008). In order to demonstrate an improvement of median survival from 12 months to 18 months with a recruitment period of 24 months and an additional follow‐up period of 24 months with an alpha error of 0.05 and a power of 80%, an overall sample size of 240 patients are required (120 patients in each group). However, in such a trial, there will be a high percentage of cross‐over between the groups as patients, who progress in spite of chemotherapy in the surgery group and may no longer be resectable. It may also be unethical to refuse surgery for patients belonging to the chemotherapy group, whose disease has been down staged by chemotherapy. However, these patients could be considered for a longitudinal study involving surgical resection for patients responding to systemic chemotherapy. It is important that hepatic node involvement of the patients included in such a study is identified by histological examination rather than imaging since a significant proportion of patients considered to have hepatic node positive disease by computerised tomogram (CT scan) turned out to have no nodal involvement on histological examination (Beckurts 1997).

Another trial that can be performed is neo‐adjuvant chemotherapy versus liver resection with hepatic lymphadenectomy (with or without post‐operative chemotherapy) in hepatic node positive patients. Again, the patients included in the trial must have a histological confirmation of hepatic node involvement before randomisation. Some patients in the neo‐adjuvant chemotherapy group may have cancer progression in spite of chemotherapy. Such patients may no longer have resectable cancer. Patients in the direct surgery group may be found to have unresectable cancer on laparotomy. It is likely that a proportion of patients in both groups would not undergo surgical resection. However, these patients should be included for all the outcomes on an intention‐to‐treat analysis, which will provide necessary information to perform a cost‐utility analysis between neo‐adjuvant chemotherapy and direct surgery. Blinding of health‐care providers and patients is not possible in such a trial, and the trial is likely to suffer from high bias‐risk for outcomes such as quality of life. However, the primary outcome of survival is likely to be free from bias due to lack of blinding (Wood 2008).

Another trial that can be performed is comparison of surgical resection versus radiofrequency ablation in this group of patients. Both groups can be combined with chemotherapy. Routine or selective lymph node dissection is likely to result in a higher morbidity than just liver resection. Radiofrequency ablation has been reported to provide a two‐year survival of 75% and three‐year survival of 50% of patients with unresectable colorectal liver metastases (Oshowo 2003; Leblanc 2008). Radiofrequency ablation is generally considered to be associated with lower morbidity than major liver resection. However, there are concerns about a higher recurrence rate after radiofrequency ablation than surgical resection (Sutherland 2006; Curley 2008). Considering the low survival after resection in patients with hepatic node positive colorectal liver metastases, radiofrequency ablation may provide an equivalent survival in these patients with lower morbidity. However, if percutaneous radiofrequency ablation is contemplated, it is important that hepatic node involvement is identified by histological examination as mentioned previously. Blinding of health‐care providers (surgeon or radiologist) is not possible. Blinding of patients is possible only in a comparison of surgical resection versus open radiofrequency ablation and not in a trial comparing surgical resection and percutaneous radioablation (after confirmation of hepatic node involvement by CT guided biopsy). Although it is possible to blind the outcome assessors for all the outcomes, lack of patient blinding is likely to introduce bias in quality of life. However, a properly conducted trial is likely to provide a low‐bias risk estimate of survival.

Another trial that we considered was that of surgical resection versus no treatment (no chemotherapy but palliation of symptoms such as pain, nausea, vomiting etc will be allowed) for this group of patients. Studies on the natural history of patients with colorectal liver metastases who did not undergo resection or chemotherapy show widely varying results from 10% one‐year survival to 40% one‐year survival in patients with disseminated metastases (Bengtsson 1981; Wagner 1984). This is in comparison with approximately 50% one year survival in the patients eligible for surgical resection (ie, good general medical condition and metastases confined to the liver or resectable extra‐hepatic spread). Besides, there was no difference in the survival between patients who underwent chemotherapy and those who did not undergo chemotherapy after adjusting for the extent of the metastases in one of the studies (Wagner 1984). However, these studies were conducted more than 25 years ago and we decided that a comparison of surgical resection versus no treatment might be unethical, given the recent advances in chemotherapy including oxaliplatin. Besides, it is unlikely that patients agree to participate in such a trial. Trials assessing neo‐adjuvant chemotherapy plus surgical resection versus chemotherapy alone; neo‐adjuvant chemotherapy versus surgical resection with or without post‐operative chemotherapy; and/or surgical resection versus radiofrequency ablation (both groups may or may not have adjuvant chemotherapy) are likely to be ethical and patients may be more willing to participate in such trials.

Authors' conclusions

Implications for practice.

There is no evidence in the literature to assess the role of resection versus other treatments for patients with colorectal liver metastases with hepatic node involvement.

Implications for research.

High quality randomised clinical trials are feasible and are necessary to determine the optimal management of patients with colorectal liver metastases with hepatic node involvement. Such trials ought to be reported according to the Consort Statement (http://www.consort‐statement.org).

Acknowledgements

To TC Mahendran, Chennai, India, who was the first surgical teacher of the first author. 
 To The Cochrane Hepato‐Biliary Group for the support that they have provided.

Peer Reviewers: J Kleijnen, UK; P Wille‐Jørgensen, Denmark. 
 Contact Editor: C Gluud, Denmark.

Appendices

Appendix 1. Search strategy

Database Period Search strategy used
The Cochrane Hepato‐Biliary Group Controlled Trials Register September 2009 (metasta* OR secondar* OR spread OR cancer OR carcinoma OR tumour Or tumor OR neoplasm) AND (colon Or colonic OR colorect* OR rectal OR rectum OR gut OR intestine OR bowel) AND (liver OR hepatic) AND (segmentectomy OR resection)
Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (Wiley) Issue 3, 2009 #1 MeSH descriptor Neoplasm Metastasis explode all trees in MeSH products 
 #2 metasta* OR secondar* OR spread OR cancer OR carcinoma OR tumour Or tumor OR neoplasm in All Fields in all products 
 #3 (#1 OR #2) 
 #4 MeSH descriptor Intestine, Large explode all trees 
 #5 MeSH descriptor Colorectal Surgery explode all trees 
 #6 MeSH descriptor Intestinal Neoplasms explode all trees 
 #7 colon Or colonic OR colorect* OR rectal OR rectum OR gut OR intestine OR bowel 
 #8(#4 OR #5 OR #6 OR #7) 
 #9 MeSH descriptor Liver explode all trees 
 #10 MeSH descriptor Liver Neoplasms explode all trees 
 #11 MeSH descriptor Liver Diseases explode all trees 
 #12 liver OR hepatic 
 #13 (#9 OR #10 OR #11 OR #12) 
 #14 segmentectomy OR resection 
 #15 (#13 AND #14) 
 #16 MeSH descriptor Hepatectomy explode all trees 
 #17 (#15 OR #16) 
 #18 (#3 AND #8 AND #17)
MEDLINE (Pubmed) January 1951 to September 2009 ("Neoplasm Metastasis"[MeSH] OR metasta* OR secondar* OR spread OR cancer OR carcinoma OR tumour Or tumor OR neoplasm) AND (colon Or colonic OR colorect* OR rectal OR rectum OR gut OR intestine OR bowel OR "Intestine, Large"[MeSH] OR "Colorectal Surgery"[MeSH] OR "Intestinal Neoplasms"[MeSH]) AND ((("Liver"[MeSH] OR "Liver Neoplasms"[MeSH] OR "Liver Diseases"[MeSH] OR liver OR hepatic) AND (segmentectomy OR resection)) OR "Hepatectomy"[MeSH]) AND ((randomised controlled trial [pt] OR controlled clinical trial [pt] OR randomised [tiab] OR placebo [tiab] OR drug therapy [sh] OR randomly [tiab] OR trial [tiab] OR groups [tiab]) AND humans [mh])
EMBASE (OvidSP) January 1974 to September 2009 1 LIVER‐METASTASIS#.DE. OR METASTASIS#.W..DE. OR metasta$ OR secondary$ OR spread OR cancer OR carcinoma OR tumour OR tumor OR neoplasm 
 2 COLORECTAL‐CANCER#.DE. OR colon OR colonic OR colorect$ OR rectal OR rectum OR gut OR intestine OR bowel 
 3 liver OR hepatic 
 4 segmentectomy OR resection 
 5 3 AND 4 
 6 hepatectomy OR LIVER‐RESECTION.DE. 
 7 5 OR 6 
 8 1 AND 2 AND 7 
 9 RANDOM$ OR FACTORIAL$ OR CROSSOVER$ OR CROSS ADJ OVER$ OR PLACEBO$ OR DOUBL$ ADJ BLIND$ OR SINGL$ ADJ BLIND$ OR ASSIGN$ OR ALLOCAT$ OR VOLUNTEER$ OR CROSSOVER‐PROCEDURE#.MJ. OR DOUBLE‐BLIND‐PROCEDURE#.DE. OR SINGLE‐BLIND‐PROCEDURE#.DE. OR RANDOMIZED‐CONTROLLED‐TRIAL#.DE. 
 10 8 AND 9
Science Citation Index Expanded (http://apps.isiknowledge.com) January 1970 to September 2009 #1TS=(metasta* OR secondar* OR spread OR cancer OR carcinoma OR tumour Or tumor OR neoplasm) 
 #2 TS=(colon Or colonic OR colorect* OR rectal OR rectum OR gut OR intestine OR bowel) 
 #3 TS=(liver OR hepatic) 
 #4 TS=(segmentectomy OR resection) 
 #5 TS=(random* OR blind*OR placebo* OR meta‐analysis) 
 #6 #5 AND #4 AND #3 AND #2 AND #1
LILACS (http://bases.bireme.br/cgi‐bin/wxislind.exe/iah/online/ 
 ?IsisScript=iah/iah.xis&base=LILACS&lang=i&form=F) September 2009 (((Pt randomised controlled trial OR Pt controlled clinical trial OR Mh randomised controlled trials OR random Mh allocation OR Mh double‐blind method OR Mh single‐blind method) AND NOT (animal Ct AND NOT (Ct human and animal Ct)) OR (Former clinical Pt trial OR E05.318.760.535$ OR (Tw clin$ AND (Tw trial$ OR Tw ensa$ OR Tw estud$ OR Tw experim$ OR Tw investiga$)) OR ((Tw singl$ OR Tw simple$ OR Tw doubl$ OR Tw doble$ OR Tw duplo$ OR Tw trebl$ OR Tw trip$) AND (Tw blind$ OR Tw cego$ OR Tw ciego$ OR Tw mask$ OR Tw mascar$)) OR Placebos OR Mh OR Tw placebo$ OR (Tw random$ OR Tw randon$ OR Tw casual$ OR Tw acaso$ OR Tw bad luck OR Tw aleator$) OR Mh research design) AND NOT (animal Ct AND NOT (Ct human and animal Ct)) OR (Ct comparative Former study OR E05.337$ OR Mh follow‐up studies OR Mh prospective studies OR Tw control$ OR Tw prospectiv$ OR Tw volunt$ OR Tw volunteer$) AND NOT (animal Ct AND NOT (Ct human and animal Ct)))) AND (liver OR hepato$ OR hepatic)
Open in a new tab

Differences between protocol and review

The interventions that will be included for this review have been clarified. The outcomes have now been classified into primary and secondary outcomes. The method of assessment of bias‐risk has been updated in line with the methodology stated in the Cochrane Handbook (Higgins 2008).

Contributions of authors

KS Gurusamy wrote the review and assessed the trials for inclusion. R Ramamoorthy independently assessed the trials for inclusion. C Imber and BR Davidson critically commented on the review, provided advice for improving the review and the design of the randomised clinical trials. All authors approved of the final version of the review.

Sources of support

Internal sources

  • None, Not specified.

External sources

  • None, Not specified.

Declarations of interest

None.

New

References

Additional references

Abdalla 2006

  1. Abdalla EK, Adam R, Bilchik AJ, Jaeck D, Vauthey JN, Mahvi D. Improving resectability of hepatic colorectal metastases: expert consensus statement. Annals of Surgical Oncology 2006;13(10):1271‐80. [DOI] [PubMed] [Google Scholar]

Adam 2001

  1. Adam R, Avisar E, Ariche A, Giachetti S, Azoulay D, Castaing D, et al. Five‐year survival following hepatic resection after neoadjuvant therapy for nonresectable colorectal [liver] metastases. Annals of Surgical Oncology 2001;8(4):347‐53. [DOI] [PubMed] [Google Scholar]

Adam 2004

  1. Adam R, Delvart V, Pascal G, Valeanu A, Castaing D, Azoulay D, et al. Rescue surgery for unresectable colorectal liver metastases downstaged by chemotherapy: a model to predict long‐term survival. Annals of Surgery 2004;240(4):644‐58. [DOI] [PMC free article] [PubMed] [Google Scholar]

Ambiru 1999

  1. Ambiru S, Miyazaki M, Isono T, Ito H, Nakagawa K, Shimizu H, et al. Hepatic resection for colorectal metastases: analysis of prognostic factors. Diseases of the Colon and Rectum 1999;42(5):632‐9. [DOI] [PubMed] [Google Scholar]

Beckurts 1997

  1. Beckurts KT, Holscher AH, Thorban S, Bollschweiler E, Siewert JR. Significance of lymph node involvement at the hepatic hilum in the resection of colorectal liver metastases. British Journal of Surgery 1997;84(8):1081‐4. [PubMed] [Google Scholar]

Bengtsson 1981

  1. Bengtsson G, Carlsson G, Hafstrom L, Jonsson PE. Natural history of patients with untreated liver metastases from colorectal cancer. American Journal of Surgery 1981;141(5):586‐9. [PUBMED: 7223955] [DOI] [PubMed] [Google Scholar]

Bennett 2005

  1. Bennett JJ, Cao D, Posner MC. Determinants of unresectability and outcome of patients with occult colorectal hepatic metastases. Journal of Surgical Oncology 2005;92(1):64‐9. [DOI] [PubMed] [Google Scholar]

Clark 2002

  1. Clark OA, Castro AA. Searching the Literatura Latino Americana e do Caribe em Ciencias da Saude (LILACS) database improves systematic reviews. International Journal of Epidemiology 2002;31(1):112‐4. [DOI] [PubMed] [Google Scholar]

Cohen 2003

  1. Cohen AD, Kemeny NE. An update on hepatic arterial infusion chemotherapy for colorectal cancer. The Oncologist 2003;8(6):553‐66. [DOI] [PubMed] [Google Scholar]

Curley 2008

  1. Curley SA. Radiofrequency ablation versus resection for resectable colorectal liver metastases: time for a randomized trial?. Annals of Surgical Oncology 2008;15(1):11‐3. [DOI] [PMC free article] [PubMed] [Google Scholar]

DeMets 1987

  1. DeMets DL. Methods for combining randomized clinical trials: strengths and limitations. Statistics in Medicine 1987;6(3):341‐50. [DOI] [PubMed] [Google Scholar]

DerSimonian 1986

  1. DerSimonian R, Laird N. Meta‐analysis in clinical trials. Controlled Clinical Trials 1986;7(3):177‐88. [DOI] [PubMed] [Google Scholar]

Egger 1997

  1. Egger M, Davey SG, Schneider M, Minder C. Bias in meta‐analysis detected by a simple, graphical test. BMJ (Clinical Research Ed.) 1997;315(7109):629‐34. [DOI] [PMC free article] [PubMed] [Google Scholar]

Falcone 2007

  1. Falcone A, Ricci S, Brunetti I, Pfanner E, Allegrini G, Barbara C, 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. Journal of Clinical Oncology 2007;25(13):1670‐6. [DOI] [PubMed] [Google Scholar]

Gluud 2009

  1. Gluud C, Nikolova D, Klingenberg SL, Whitfield K, Alexakis N, Als‐Nielsen B, et al. Cochrane Hepato‐Biliary Group. About The Cochrane Collaboration (Cochrane Review Groups (CRGs)). 2009, Issue 4. Art. No.: LIVER.

Gurusamy 2008

  1. Gurusamy K, Imber C, Davidson BR. Management of the hepatic lymph nodes during resection of liver metastases from colorectal cancer ‐ a systematic review. HPB Surgery 2008;2008:684150 (Electronic). [DOI: 10.1155/2008/684150] [DOI] [PMC free article] [PubMed] [Google Scholar]

Higgins 2002

  1. Higgins JPT, Thompson SG. Quantifying heterogeneity in a meta‐analysis. Statistics in Medicine 2002;21(11):1539‐58. [DOI] [PubMed] [Google Scholar]

Higgins 2008

  1. Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Intervention 5.0.0 [updated February 2008]. The Cochrane Colloboration, 2008. Available from www.cochrane‐handbook.org. [Google Scholar]

Imamura 2001

  1. Imamura H, Matsuyama Y, Shimada R, Kubota M, Nakayama A, Kobayashi A, et al. A study of factors influencing prognosis after resection of hepatic metastases from colorectal and gastric carcinoma. American Journal of Gastroenterology 2001;96(11):3178‐84. [DOI] [PubMed] [Google Scholar]

Irie 1999

  1. Irie T, Itai Y, Hatsuse K, Mochizuki H. Does resection of small liver metastases from colorectal cancer improve survival of patients?. British Journal of Radiology 1999;72(855):246‐9. [DOI] [PubMed] [Google Scholar]

Jaeck 2002

  1. Jaeck D, Nakano H, Bachellier P, Inoue K, Weber JC, Oussoultzoglou E, et al. Significance of hepatic pedicle lymph node involvement in patients with colorectal liver metastases: a prospective study. Annals of Surgical Oncology 2002;9(5):430‐8. [DOI] [PubMed] [Google Scholar]

Jaeck 2003

  1. Jaeck D. The significance of hepatic pedicle lymph nodes metastases in surgical management of colorectal liver metastases and of other liver malignancies. Annals of Surgical Oncology 2003;10(9):1007‐11. [DOI] [PubMed] [Google Scholar]

Kemeny 2005

  1. Kemeny N, Jarnagin W, Paty P, Gonen M, Schwartz L, Morse M, et al. Phase I trial of systemic oxaliplatin combination chemotherapy with hepatic arterial infusion in patients with unresectable liver metastases from colorectal cancer. Journal of Clinical Oncology 2005;23(22):4888‐96. [DOI] [PubMed] [Google Scholar]

Kemeny 2006

  1. Kemeny NE, Niedzwiecki D, Hollis DR, Lenz HJ, Warren RS, Naughton MJ, et al. Hepatic arterial infusion versus systemic therapy for hepatic metastases from colorectal cancer: a randomized trial of efficacy, quality of life, and molecular markers (CALGB 9481). Journal of Clinical Oncology 2006;24(9):1395‐403. [DOI] [PubMed] [Google Scholar]

Kjaergard 2001

  1. Kjaergard LL, Villumsen J, Gluud C. Reported methodologic quality and discrepancies between large and small randomized trials in meta‐analyses. Annals of Internal Medicine 2001;135(11):982‐9. [DOI] [PubMed] [Google Scholar]

Kokudo 1998

  1. Kokudo N, Seki M, Ohta H, Azekura K, Ueno M, Sato T, et al. Effects of systemic and regional chemotherapy after hepatic resection for colorectal metastases. Annals of Surgical Oncology 1998;5(8):706‐12. [DOI] [PubMed] [Google Scholar]

Laurent 2004

  1. Laurent C, Sa CA, Rullier E, Smith D, Rullier A, Saric J. Impact of microscopic hepatic lymph node involvement on survival after resection of colorectal liver metastasis. Journal of the American College of Surgeons 2004;198(6):884‐91. [DOI] [PubMed] [Google Scholar]

Leblanc 2008

  1. Leblanc F, Fonck M, Brunet R, Becouarn Y, Mathoulin‐Pelissier S, Evrard S. Comparison of hepatic recurrences after resection or intraoperative radiofrequency ablation indicated by size and topographical characteristics of the metastases. European Journal of Surgical Oncology 2008;34(2):185‐90. [DOI] [PubMed] [Google Scholar]

Macaskill 2001

  1. Macaskill P, Walter SD, Irwig L. A comparison of methods to detect publication bias in meta‐analysis. Statistics in Medicine 2001;20(4):641‐54. [DOI] [PubMed] [Google Scholar]

Manfredi 2006

  1. Manfredi S, Lepage C, Hatem C, Coatmeur O, Faivre J, Bouvier AM. Epidemiology and management of liver metastases from colorectal cancer. Annals of Surgery 2006;244(2):254‐9. [DOI] [PMC free article] [PubMed] [Google Scholar]

Moher 1998

  1. Moher D, Pham B, Jones A, Cook DJ, Jadad AR, Moher M, et al. Does quality of reports of randomised trials affect estimates of intervention efficacy reported in meta‐analyses?. Lancet 1998;352(9128):609‐13. [DOI] [PubMed] [Google Scholar]

Mulier 2008

  1. Mulier S, Ni Y, Jamart J, Michel L, Marchal G, Ruers T. Radiofrequency ablation versus resection for resectable colorectal liver metastases: Time for a randomized trial?. Annals of Surgical Oncology 2008;15(1):144‐57. [DOI] [PubMed] [Google Scholar]

Mutsaerts 2005

  1. Mutsaerts EL, Ruth S, Zoetmulder FA, Rutgers EJ, Hart AA, Coevorden F. Prognostic factors and evaluation of surgical management of hepatic metastases from colorectal origin: a 10‐year single‐institute experience. Journal of Gastrointestinal Surgery 2005;9(2):178‐86. [DOI] [PubMed] [Google Scholar]

Newell 1992

  1. Newell DJ. Intention‐to‐treat analysis: implications for quantitative and qualitative research. International Journal of Epidemiology 1992;21(5):837‐41. [DOI] [PubMed] [Google Scholar]

Onaitis 2001

  1. Onaitis MW, Noone RB, Hartwig M, Hurwitz H, Morse M, Jowell P, et al. Neoadjuvant chemoradiation for rectal cancer: analysis of clinical outcomes from a 13‐year institutional experience. Annals of Surgery 2001;233(6):778‐85. [DOI] [PMC free article] [PubMed] [Google Scholar]

Oshowo 2003

  1. Oshowo A, Gillams A, Harrison E, Lees WR, Taylor I. Comparison of resection and radiofrequency ablation for treatment of solitary colorectal liver metastases. The British Journal of Surgery 2003;90(10):1240‐3. [DOI] [PubMed] [Google Scholar]

Parmar 1998

  1. Parmar MK, Torri V, Stewart L. Extracting summary statistics to perform meta‐analyses of the published literature for survival endpoints. Statistics in Medicine 1998;17(24):2815‐34. [PUBMED: 9921604] [DOI] [PubMed] [Google Scholar]

RevMan 2008 [Computer program]

  1. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager (RevMan). Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2008.

Rodgers 2000

  1. Rodgers MS, McCall JL. Surgery for colorectal liver metastases with hepatic lymph node involvement: a systematic review. The British Journal of Surgery 2000;87(9):1142‐55. [DOI] [PubMed] [Google Scholar]

Royle 2003

  1. Royle P, Milne R. Literature searching for randomized controlled trials used in Cochrane reviews: rapid versus exhaustive searches. International Journal of Technology Assessment in Health Care 2003;19(4):591‐603. [DOI] [PubMed] [Google Scholar]

Schulz 1995

  1. Schulz KF, Chalmers I, Hayes RJ, Altman DG. Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment effects in controlled trials. JAMA 1995;273(5):408‐12. [DOI] [PubMed] [Google Scholar]

Stipa 2004

  1. Stipa F, Zernecke A, Moore HG, Minsky BD, Wong WD, Weiser M, et al. Residual mesorectal lymph node involvement following neoadjuvant combined‐modality therapy: rationale for radical resection?. Annals of Surgical Oncology 2004;11(2):187‐91. [DOI] [PubMed] [Google Scholar]

Sutherland 2006

  1. Sutherland LM, Williams JA, Padbury RT, Gotley DC, Stokes B, Maddern GJ. Radiofrequency ablation of liver tumors: a systematic review. Archives of Surgery 2006;141(2):181‐90. [DOI] [PubMed] [Google Scholar]

Sweeting 2004

  1. Sweeting MJ, Sutton AJ, Lambert PC. What to add to nothing? Use and avoidance of continuity corrections in meta‐analysis of sparse data. Statistics in Medicine 2004;23(9):1351‐75. [DOI] [PubMed] [Google Scholar]

Tepper 2003

  1. Tepper JE, O'Connell M, Hollis D, Niedzwiecki D, Cooke E, Mayer RJ. Analysis of surgical salvage after failure of primary therapy in rectal cancer: results from Intergroup Study 0114. Journal of Clinical Oncology 2003;21(19):3623‐8. [DOI] [PubMed] [Google Scholar]

Tierney 2007

  1. Tierney JF, Stewart LA, Ghersi D, Burdett S, Sydes MR. Practical methods for incorporating summary time‐to‐event data into meta‐analysis. Trials 2007;8:16. [PUBMED: 17555582] [DOI] [PMC free article] [PubMed] [Google Scholar]

Tocchi 2004

  1. Tocchi A, Mazzoni G, Brozzetti S, Miccini M, Cassini D, Bettelli E. Hepatic resection in stage IV colorectal cancer: prognostic predictors of outcome. International Journal of Colorectal Disease 2004;19(6):580‐5. [DOI] [PubMed] [Google Scholar]

Tsuchiya 2002

  1. Tsuchiya Y, Onda M, Sasajima K, Yamashita K, Nomura T, Makino H, et al. Effects of preoperative chemotherapy on metastatic lymph nodes in esophageal squamous cell carcinoma. Diseases of the Esophagus 2002;15(3):226‐31. [DOI] [PubMed] [Google Scholar]

Vassiliou 2007

  1. Vassiliou I, Arkadopoulos N, Theodosopoulos T, Fragulidis G, Marinis A, Kondi‐Paphiti A, et al. Surgical approaches of resectable synchronous colorectal liver metastases: timing considerations. World Journal of Gastroenterology 2007;13(9):1431‐4. [DOI] [PMC free article] [PubMed] [Google Scholar]

Wagner 1984

  1. Wagner JS, Adson MA, Heerden JA, Adson MH, Ilstrup DM. The natural history of hepatic metastases from colorectal cancer. A comparison with resective treatment. Annals of Surgery 1984;199(5):502‐8. [PUBMED: 6721600] [DOI] [PMC free article] [PubMed] [Google Scholar]

Wood 2005

  1. Wood H, Rowan S, Quinn M, Cooper N. National Cancer Intelligence Centre, Office for National Statistics. Cancer incidence and mortality in the United Kingdom 2001‐03. http://www.statistics.gov.uk/downloads/theme_health/UK_inc&mort_final.xls 2005 (accessed on 9 September 2009).

Wood 2008

  1. Wood L, Egger M, Gluud LL, Schulz KF, Jüni P, Altman GD, et al. Empirical evidence of bias in treatment effect estimates in controlled trials with different interventions and outcomes: meta‐epidemiological study. BMJ (Clinical Research Ed.) 2008;336:601‐5. [DOI] [PMC free article] [PubMed] [Google Scholar]

Yano 2006

  1. Yano M, Takachi K, Doki Y, Miyashiro I, Kishi K, Noura S, et al. Preoperative chemotherapy for clinically node‐positive patients with squamous cell carcinoma of the esophagus. Diseases of Esophagus 2006;19(3):158‐63. [DOI] [PubMed] [Google Scholar]

Articles from The Cochrane Database of Systematic Reviews are provided here courtesy of Wiley

RESOURCES