Neoadjuvant chemotherapy for patients having resection or ablation of liver metastases from colorectal cancer.
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To assess the efficacy of adjuvant or neo‐adjuvant chemotherapy (whatever its type and mode of administration) in addition to curative surgery for initially resectable liver metastases from CRCs. The primary objective of the study is Progression Free Survival improvement with chemotherapy. The secondary objectives are the Overall survival improvement and the evaluation of liver toxicity after chemotherapy.
Background
About 50 % of patients with colorectal cancer (CRC) will develop liver metastases during their illness. Improvement of surgical techniques during the last 2 decades has allowed many more patients to benefit from surgical resection of liver metastases from CRCs (Fong 1999). Surgical treatment of liver metastases from CRCs is the only treatment providing a 5‐year overall survival to 25 ‐40 % of patients, with about 25 % of patients still alive at 10 years if it is a resection R0 (microscopic free resection) . Eighty per cent of patients cannot benefit from surgical resection of liver metastases due to extra‐hepatic disease, involvement of non resectable liver anatomical structures, or insufficient amount of residual liver tissue (Adam 2004). Very few patients with liver metastases from CRC have resectable liver metastases at diagnosis. At present, surgery could be considered for more patients because of reduced risks related to improved surgical technics. Although surgery alone can improve survival of this patients, the additional benefits of adjuvant or neo‐adjuvant chemotherapy must be evaluated. In some studies, chemotherapy was begun prior to surgery (neoadjuvant). The majority of studies used adjuvant chemotherapy after liver surgery.
Chemotherapy can be administered either by local intra‐arterial infusion or by systemic route. Combinations of 5 FU and oxaliplatin and/or irinotecan combined with antiangiogenic or anti‐EGFR treatment have improved survival and are now currently used in first line setting. Unhappily, published trials only studied 5FU‐based chemotherapy.
In this systematic review we will evaluate the efficacy of adjuvant or neo‐adjuvant chemotherapy plus surgery versus surgery alone for the 20 % of patients who had liver metastases resections of colo‐rectal cancer.
Objectives
To assess the efficacy of adjuvant or neo‐adjuvant chemotherapy (whatever its type and mode of administration) in addition to curative surgery for initially resectable liver metastases from CRCs. The primary objective of the study is Progression Free Survival improvement with chemotherapy. The secondary objectives are the Overall survival improvement and the evaluation of liver toxicity after chemotherapy.
Methods
Criteria for considering studies for this review
Types of studies
Randomized prospective clinical trials comparing survival after either surgery alone or peri‐operative chemotherapy + surgery. All strategies of chemotherapy will be pooled. This chemotherapy is either systemic peri‐operative chemotherapy or post‐operative chemotherapy. In case of post‐operative chemotherapy, this treatment is either systemic or intra‐arterial. We exculded studies with arms without surgery alone.
Types of participants
Patients with resectable liver metastases of CRC. The liver metastasis disease must be resectable at diagnosis. All patients are chemo naïve before inclusion and all patients are operated on. Patients with presumably resectable liver metastases who could not be operated on were exluded from the studies.
As stated, “Patients with resectable liver metastases of CRC” studies may include patients who do not undergo resection although their liver lesions are resectable.
Types of interventions
Assessment of usefulness of adjuvant chemotherapy in addition to liver surgery. A subgroup analysis assessing the effect of HAI on survival is planned. Conversely, a subgroup analysis comparing pre operative and post operative chemotherapies cannot be performed because only one study (Nordlinger) included pre operative chemotherapy in addition to post operative chemotherapy (3 months before and 3 months after liver surgery) .
Types of outcome measures
Primary outcomes: Overall Survival, Progression Free Survival after liver resection.
Secondary outcomes: mortality and morbidity shortly (1month) after liver surgery with and without chemotherapy.
Search methods for identification of studies
We will perform a PubMed query using the following strategy (table 1) and the following key words (colorectal neoplasms, secondary, liver, surgery, chemotherapy, randomised controlled trial). The references were obtained from cross‐checking articles dealing with this topic. Abstracts were also searched from ASCO meetings (1997‐2007). Whenever possible, we will take personal contact with the main author of each abstract to obtain the data allowing inclusion into our meta‐analysis.
A meta‐analysis of prospective clinical trials about hepatic arterial infusion of CRC metastases has been recently published (Clancy 2005).
In addition, the Cochrane Collaboration recently published a review entitled "Hepatic artery adjuvant chemotherapy for patients having resection or ablation of colorectal cancer metastatic to the liver (Nelson 2006).
(table 1)
9. Search #8 NOT #7 Field: Title/Abstract
8. Search colorectal AND liver AND metasta* AND surg* AND (chemotherapy OR fluorouracil*) AND randomized Field: Title/Abstract
7. Search #5 AND #6 Field: MeSH Terms, Limits: Randomized Controlled Trial
6. Search Antineoplastic Combined Chemotherapy Protocols OR Chemotherapy, Adjuvant OR Neoadjuvant Therapy Field: MeSH Terms
5. Search #3 AND #4 Field: MeSH Terms
4. Search liver neoplasms/su OR colorectal neoplasms/su Field: MeSH Terms
3. Search #1 AND #2 Field: MeSH Terms
2. Search colorectal neoplasms Field: MeSH Terms
1. Search Liver Neoplasms/sc Field: MeSH Terms
Data collection and analysis
Trials selection
The 3 reviewers (G Des Guetz, P Mariani and B Uzzan) examined all the citations and abstracts derived from the electronic searches. Reports of potentially relevant trials were retrieved in full. The reviewers independently applied the selection criteria to trials reports. Reviewers were not blind to the names of authors, institutions or journals. Any disagreements were resolved by discussion.
Quality assessment
The methodological quality of identified trials was assessed independently by the three reviewers taking into account the quality of random allocation concealment and the description of dropouts and withdrawals, as well as blinding of the patients and care givers to the intervention. Any disagreements were resolved by discussion. Studies were excluded if they were not randomised controlled trials in adults. The excluded studies and the reasons for their exclusion have been summarised in the Table of Excluded Studies.
Data extraction
Data extraction from the included trial was undertaken independently by the three reviewers. Data will be processed as described in the Cochrane Collaboration Handbook (Alderson 2004). Any difference of opinion will be resolved by discussion between the reviewers. An attempt was made to get all missing information from the trial's authors.
Analysis
Data will be analysed using the RevMan Analyses statistical programme in Review Manager.
Odds ratios and 95% confidence intervals will be calculated for dichotomous outcomes using the Mantel‐Haenszel method and a fixed effect model. Continuous variables will be analysed using fixed effect meta‐analyses of (weighted) mean differences (WMD).
Continuous variables were processed using mean and standard deviation values. If only means and ranges are available, an estimate of the standard deviation was made which will be discussed in more detail in the results section.
Subgroup analysis.
A subgroup analysis assessing the effect on survival of HAI compared to no chemotherapy is planned. No study compared different routes of chemotherapy.
A subgroup analysis comparing pre operative and post operative chemotherapies cannot be performed because only one study (Nordlinger) included pre operative chemotherapy in addition to post operative chemotherapy (3 months before and 3 months after liver surgery)
Sensitivity analysis
A sensitivity analysis was planned if we identify any instances of statistical heterogeneity. Currently, with the knowledge of eligible trials, this doesn't seem to be the case.
Publication bias
If sufficient number of trials this could be assessed using Funnel plots.
