Liver resection versus non‐surgical treatment for hepatic node positive patients with colorectal metastases
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To determine the benefits and harms of potentially curative liver resection with lymphadenectomy versus palliative treatment of colorectal liver metastases with hepatic node involvement.
Background
Colorectal cancer is the third commonest malignancy in the United Kingdom with an estimated 34000 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 16000 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). 20% to 32% of these metastatic deposits 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). Involvement of hepatic lymph nodes during liver resection is considered as a poor prognostic factor (Rodgers 2000; Abdalla 2006), with five‐year survival rate 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 nodes (draining the liver) considered uninvolved macroscopically are infiltrated by tumour cells microscopically (Jaeck 2002; Laurent 2004). Patients who have involvement of common hepatic artery nodes 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 rates 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 leukovorin, 5‐fluorouracil, oxaliplatin, and irinotecan has been recently reported to be around 20 months (Kemeny 2006; Falcone 2007) with an estimated 3‐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 (5 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 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.
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 2007) and the optimal management of these patients remains unclear. There has been no review of randomised clinical trials comparing potentially curative liver resection with lymphadenectomy and other 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 palliative treatment of colorectal liver metastases with hepatic node involvement.
Methods
Criteria for considering studies for this review
Types of studies
We will consider all randomised clinical trials (irrespective of language, blinding, publication status, or sample size) for inclusion.
Quasi‐randomised trials (where the method of allocating participants to a treatment are not strictly random, for example, date of birth, hospital record number, alternation) will not be included regarding assessment of benefit, but will be included 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).
Types of interventions
We will include the following interventions.
(1) Potentially curative surgical liver resection (liver resection where all macroscopic disease is removed) with lymphadenectomy versus palliative treatment (where potentially curative surgical resection is not possible; includes chemotherapy mainly).
(2) Potentially curative surgical resection with lymphadenectomy as part of neo‐adjuvant chemotherapy versus palliative treatment.
Co‐interventions will be allowed if carried out equally in the trial arms.
Types of outcome measures
(1) Proportion dead after one, three, and five years.
(2) Estimated median mortality.
(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 will search 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 (Royle 2003) and LILACS (Clark 2002). We have given the preliminary search strategies in Appendix 1 with the time span for the searches. As the review progresses, we will improve the search strategies if necessary.
We will also search the references of the identified trials to identify further relevant trials.
Data collection and analysis
Trial selection and extraction of data
Two authors (KSG and CI), independently of each other, will identify the trials for inclusion. We will also list the excluded studies with the reasons for the exclusion.
We will 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 embolisation).
(16) Outcomes (mentioned above).
(17) Methodological quality (described below).
(18) Sample size calculation.
(19) Intention‐to‐treat analysis.
Any unclear or missing information will be sought by contacting the authors of the individual trials. If there is any doubt whether the trials share the same patients ‐ completely or partially (by identifying common authors and centres) ‐ the authors of the trials will be contacted to clarify whether the trial has been duplicated.
We will resolve any differences in opinion through discussion or arbitration of the third author (BRD).
Assessment of methodological quality
The authors will assess the methodological quality of the trials independently, without masking of the trial names. The authors will follow the instructions given in Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2006) and the Cochrane Hepato‐Biliary Group Module (Gluud 2006). Due to the risk of biased overestimation of intervention effects in randomised trials with inadequate methodological quality (Schulz 1995; Moher 1998; Kjaergard 2001), we will 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 is not available in the published trial, we will contact the authors in order to assess the trials correctly. We will assess generation of allocation sequence, allocation concealment, blinding, and follow‐up.
Generation of the allocation sequence
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Adequate, if the allocation sequence was generated by a computer or random number table. Drawing of lots, tossing of a coin, shuffling of cards, or throwing dice will be considered as adequate if a person who was not otherwise involved in the recruitment of participants performed the procedure.
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Unclear, if the trial was described as randomised, but the method used for the allocation sequence generation was not described.
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Inadequate, if a system involving dates, names, or admittance numbers were used for the allocation of patients. These studies are known as quasi‐randomised and will be excluded from the review.
Allocation concealment
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Adequate, if the allocation of patients involved a central independent unit, on‐site locked computer, or sealed envelopes.
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Unclear, if the trial was described as randomised, but the method used to conceal the allocation was not described.
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Inadequate, if the allocation sequence was known to the investigators who assigned participants. Such studies will be excluded.
Blinding
It is not possible to blind the surgeons to the groups. However, it is possible to blind the patients and the outcome assessors. For the purpose of this review, double blinding indicates blinding of patients and outcome assessors.
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Adequate, if the trial was described as double blind and the method of blinding was described.
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Unclear, if the trial was described as double blind, but the method of blinding was not described.
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Not performed, if there was no blinding at all.
Follow‐up
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Adequate, if the numbers and reasons for dropouts and withdrawals in all intervention groups were described or if it was specified that there were no dropouts or withdrawals.
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Unclear, if the report gave the impression that there had been no dropouts or withdrawals, but this was not specifically stated.
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Inadequate, if the number or reasons for dropouts and withdrawals were not described.
Statistical methods
We will perform the meta‐analyses according to the recommendations of The Cochrane Collaboration (Higgins 2006) and the Cochrane Hepato‐Biliary Group Module (Gluud 2006). We will use the software package RevMan 4.2 (RevMan 2003). For dichotomous variables, we will calculate the relative risk (RR) with 95% confidence interval. For continuous variables, we will calculate the weighted mean difference (WMD) with 95% confidence interval. We will use a random‐effects model (DerSimonian 1986) and a fixed‐effect model (DeMets 1987). In case of discrepancy between the two models we will report both results; otherwise we will report the results of fixed‐effect model. Heterogeneity will be explored by chi‐squared test with significance set at P value 0.10, and the quantity of heterogeneity will be measured by I2 (Higgins 2002).
We will adopt the 'available‐case analysis' (Higgins 2006). The analysis will be performed on an intention‐to‐treat basis (Newell 1992). In case we find 'zero‐event' trials in statistically significant outcomes, we will perform a sensitivity analysis with and without empirical continuity correction factors as suggested by Sweeting et al (Sweeting 2004).
Subgroup analysis
We will perform the following subgroup analyses:
‐ trials with low bias risk (adequate generation of allocation sequence, allocation concealment, blinding, and follow‐up) compared to trials with high bias risk (more than one of the four components inadequate or unclear).
‐ surgical resection compared to surgical resection with post‐operative chemotherapy or neoadjuvant chemotherapy.
‐ groups of nodes involved (group 1 compared to group 2).
‐ groups of nodes resected (group 1 compared to group 1 and group 2).
‐ different methods of diagnosing nodal involvement (radiological compared to surgical).
‐ different methods of confirmation of diagnosis (microscopic compared to immunocytochemistry).
Bias exploration
We will use a funnel plot to explore bias (Egger 1997; Macaskill 2001). Asymmetry in funnel plot of trial size against treatment effect will be used to assess this bias. We will perform linear regression approach described by Egger 1997 to determine the funnel plot asymmetry.
