Transarterial (chemo)embolisation versus other nonsurgical ablation methods for liver metastases
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To study the beneficial and harmful effects of transarterial (chemo)embolisation compared with other nonsurgical ablation methods in patients with liver metastases.
Background
Description of the condition
Primary liver tumours and liver metastases from colorectal carcinoma are the two most common malignant tumours to affect the liver (Lau 2000; Michel 2002). Primary liver tumours arise from malignant cells within the liver, and hepatocellular carcinoma represents the most common form of primary liver cancer (Lau 2000; Michel 2002). Metastatic liver disease is more common than primary liver cancer and develops when malignant cells migrate from other organs to the liver (Bilchik 2000; McCarter 2000).
The liver is second only to the lymph nodes as the most common site for metastatic disease (Weiss 1986). More than half of the patients with metastatic liver disease will die from metastatic complications (Wood 1976; Markovic 1998). The most common primary sites for liver metastases are lung, breast, colon and rectum, and uterus. On pre‐operative imaging, liver metastases are found in 35% of patients with colorectal cancer, and 8% to 30% of other patients will subsequently be found to have liver involvement. Almost half of patients dying from stomach, pancreatic, or breast cancer are found to have liver metastases at autopsy, while in patients with endometrial cancer they occur in about 40% of patients (Hugh 1997). Colorectal carcinoma is the third leading cancer in the United States and the third in cancer‐related deaths. Approximately 142,570 new patients with large bowel cancer are diagnosed each year in the United States, of which 102,900 have colon and the remainder rectal cancers. Annually, approximately 51,370 Americans die of colorectal cancer, accounting for approximately 9% of all cancer deaths (Jemal 2010). Globally, the age‐adjusted annual incidence rate for colorectal cancer is 17.2 per 100,000 (IARC 2008). The highest annual incidence is observed in North America (age adjusted, 30.1 per 100,000), Australia and New Zealand (age adjusted, 39.0), northern Europe (age adjusted, 30.5), and western Europe (age adjusted, 33.1). Lower annual incidences are observed in Africa (age adjusted, 5.9) and Asia (age adjusted, 12.9). Globally, the annual age‐adjusted mortality for colorectal cancer is 8.2 per 100,000, and it is higher in the countries with a higher incidence and lower in the countries with a lower incidence. In the United States, five‐year survival after the diagnosis of colorectal cancer is 66.6% (NCI 2009). In all developed countries analysed together, the estimated five‐year survival is 55% (Parkin 2002) with the lowest survival reported for Eastern Europe (35% male and 36% female). In developing countries analysed together, it is 39% (Parkin 2002) with the lowest rate reported for Sub‐Saharan Africa (13% for males and 14% for females). Approximately 50% of colorectal cancer patients will develop a recurrence within five years of initial diagnosis, with the liver being the most common site for metastatic disease (Geoghegan 1999). For the other common primary sites for liver metastases, the age‐standardised incidence and mortality rates are as follows: lung cancer 23.0 and 19.4 per 100,000 people of both sexes respectively, stomach 14.1 and 10.3 per 100,000 people of both sexes, pancreas 3.9 and 3.7 per 100,000 people of both sexes, breast 39.0 and 12.5 per 100,000 women, and corpus uteri 8.2 and 2.0 per 100,000 women (IARC 2008). In the United States, five‐year survival after the diagnosis of lung cancer is 16.4%, stomach 26.7%, pancreas 5.7%, breast cancer 89.9%, and corpus uteri cancer 84.1% (NCI 2009). In all developed countries analysed together, the estimated annual survival after the diagnosis of lung cancer is 13% in men and 20% in women; the estimated annual survival for stomach cancer is 35% in men and 31% in women; for breast cancer it is 75%; and for cancer of the corpus uteri it is 82% (Parkin 2002). In all developing countries analysed together, the estimated survival after the diagnosis of lung cancer is 12% in men and women, for stomach cancer it is 21% in men and 20% in women, for breast cancer it is 57%, and for cancer of the corpus uteri it is 67% (Parkin 2002).
For many patients, the progressive involvement of the liver is the primary determinant of long‐term survival. Surgical resection is the only curative option for patients with malignant liver neoplasm, with median survival times of 21 to 46 months or five‐year survival rates of 20% to 58% (McLoughlin 2006). However, only 20% of patients with hepatic tumours are candidates for resection (Bilchik 2000; Bipat 2007). Other options for patients with unresectable liver metastases include chemotherapy delivered intra‐arterially (5‐fluorouracil), called 'regional chemotherapy'; systemic chemotherapy (5‐fluorouracil, irinotecan, oxaliplatin, leucovorin, capecitabine); or monoclonal antibodies (such as bevacizumab or cetuximab). Additional methods include local tumour ablative techniques, transarterial (chemo)embolisation, percutaneous ethanol injection, microwave coagulation, laser‐induced thermotherapy, radiofrequency ablation, or cryosurgical ablation (Riemsma 2009).
Description of the intervention
Chemoembolisation is defined as a selective administration of chemotherapy usually combined with embolisation of the vascular supply to the tumour (Vogl 2009). This treatment results in selective ischaemic and cytotoxic effects on liver metastases (Vogl 2007). Vascular occlusive agents can be used either temporary, like microspheres, degradable starch microspheres, collagen and gelatine sponge, or permanent, like polyvinyl alcohol (Vogl 2007). Embolisation can also be performed without cytotoxic agent (bland embolisation).
How the intervention might work
(Chemo)embolisation is based on the concept that the blood supply to hepatic tumours originates predominantly from the hepatic artery, while 75% of the normal liver parenchyma is supplied by the portal vein (Breedis 1954; Vogl 2003). It is well established that both primary and secondary liver tumours derive their blood supply from the hepatic artery (Breedis 1954). Therefore, embolisation of the hepatic artery can lead to selective necrosis of the liver tumour while it leaves normal parenchyma virtually unaffected (Vogl 2003). This ischaemic damage increases vascular permeability and promotes penetration of the cytotoxic drug into the tumour (Wallace 1990). However, ligation of the hepatic artery increases the portal vein blood supply to liver metastases and this may cause poor results for hepatic artery ligation and perfusion alone (Taylor 1978). The selective administration of the drugs into the affected part of the liver may prevent extensive liver parenchymal damage. Portal vein thrombosis, high grade liver dysfunction, and hepatorenal syndrome are common contraindications for transarterial embolisation or transarterial chemoembolisation. In hepatocellular carcinoma, transarterial embolisation or transarterial chemoembolisation may reduce tumour growth, but randomised trials and meta‐analyses assessing survival have found no significant effect on mortality (Oliveri 2011).
Why it is important to do this review
In patients with liver metastases, local or regional treatment methods can provide local control but it is uncertain what the long‐term outcomes are of some of these therapies. Systematic reviews may help to establish the effectiveness and the trade off between the benefits and harms associated with different nonsurgical ablation methods for the treatment of all forms of malignant liver tumours (primary and metastatic). Reviews and meta‐analyses published so far focus mostly on primary liver tumours or colorectal cancer liver metastases and include studies only up to April 2006 (Llovet 2003; Decadt 2004; Lopez 2006; Marlow 2006; Sutherland 2006). The methods used in these publications lack clarity on how the risk of systematic errors (bias) and the risks of random errors (play of chance) have been addressed (Oliveri 2011). We assessed transarterial chemoembolisation versus no intervention or placebo in another review (Riemsma 2012). There is no Cochrane review comparing transarterial (chemo)embolisation with other nonsurgical ablation methods in people with liver metastases from any sources. Therefore, a new review with updated searches and dealing with all types of malignant liver metastases is warranted.
Objectives
To study the beneficial and harmful effects of transarterial (chemo)embolisation compared with other nonsurgical ablation methods in patients with liver metastases.
Methods
Criteria for considering studies for this review
Types of studies
We will include all randomised clinical trials assessing the beneficial and harmful effects of transarterial (chemo)embolisation and its comparators, irrespective of publication status, language, or blinding. Quasi‐randomised and other controlled studies that come up in the search will be considered only for the reporting of data on harm.
Types of participants
Patients with liver metastases regardless of the location of the primary tumour. The trials will be grouped by the location of the primary cancer.
Types of interventions
Transarterial (chemo)embolisation compared with other nonsurgical ablation methods. Co‐interventions will be allowed if they are provided equally to the experimental and control groups of the individual randomised trials. The trials will be grouped according to the comparator intervention.
Types of outcome measures
Primary outcomes
1. All‐cause mortality at last follow‐up and time to mortality.
2. Cancer mortality.
3. All adverse events and complications, separately and in total. The International Conference on Harmonisation (ICH) Guidelines (ICH‐GCP 1997) define adverse events as serious and non‐serious. A serious fatal or nonfatal adverse event is any event that leads to death, is life‐threatening, requires in‐patient hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability, and any important medical event which may have jeopardised the patient or requires intervention to prevent it. All other adverse events will be considered non‐serious.
4. Quality of life.
Secondary outcomes
1. Proportion of patients with failure to clear liver metastases or recurrence of liver metastases.
2. Time to progression of liver metastases.
3. Tumour response measures (complete response, partial response, stable disease, disease progression).
We will extract data on outcome measures at the end of treatment and at the longest follow‐up.
Search methods for identification of studies
Electronic searches
We will search the Cochrane Hepato‐Biliary Group Controlled Trials Register (Gluud 2012), Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded, LILACS, and CINAHL (Royle 2003) as well as the World Health Organization (WHO) International Trials Registry Platform (WHO 2013).
One global search will be used for all nonsurgical ablation methods for primary malignant liver tumours and liver metastases. Preliminary search strategies with the expected time spans of the searches are given in Appendix 1. The searches will be improved at the review stage, if necessary.
In addition, we will assess for inclusion all United States Food and Drug Administration (FDA) approvals and investigational device exemptions as found on the FDA web site (FDA 2011).
Searching other resources
We will search the reference lists of reviews (such as Schwartz 2004 and Lopez 2006), health technology assessment reports (such as Marlow 2006 (ASERNIP‐S)), Cochrane reviews, and all included trials for relevant studies.
Data collection and analysis
Selection of studies
Two authors will independently evaluate the titles and abstracts for ordering the full papers (RR and MB). Any differences in opinion will be resolved by discussion or, if necessary, by consulting a third author (JK). For titles and abstracts that potentially fit our inclusion criteria, full papers will be ordered. These papers will be assessed by two independent authors (RR, MB, and RW) and differences in opinion will be resolved using the above mentioned procedure.
Data extraction and management
We will extract the relevant information on participant characteristics, interventions, study outcome measures, and data on the outcome measures for our review, as well as information on the design and methodology of the studies. Quality assessment of the trials fulfilling the inclusion criteria and data extraction will be done by one author (RR, MB, or RW) and checked by a second author (RR, MB, or RW).
Assessment of risk of bias in included studies
We will assess the methodological quality of the trials, and hence risk of bias. We will use the domains described below (Schulz 1995; Moher 1998; Kjaergaard 2001; Gluud 2008; Wood 2008; Higgins 2011; Sarovic 2012; Sarovic 2012a). We will present our assessment by trial, and we describe the results of each trial in relation to their reliability. Weak points will be stressed and recommendations for further research will be presented with reference to the shortcomings of existing trials. Due to the limited number of existing trials, we expect that meta‐regression analyses using individual quality criteria will not be feasible.
Allocation sequence generation
‐ Low risk of bias: sequence generation was achieved using computer random number generation or a random number table. Drawing lots, tossing a coin, shuffling cards, and throwing dice are adequate if performed by an independent person not otherwise involved in the trial.
‐ Uncertain risk of bias: the method of sequence generation was not specified.
‐ High risk of bias: the sequence generation method was not random.
Allocation concealment
‐ Low risk of bias: the participant allocations could not have been foreseen in advance of, or during, enrolment. Allocation was controlled by a central and independent randomisation unit. The allocation sequence was unknown to the investigators (e.g., if the allocation sequence was hidden in sequentially numbered, opaque, and sealed envelopes).
‐ Uncertain risk of bias: the method used to conceal the allocation was not described so that intervention allocations may have been foreseen in advance of, or during, enrolment.
‐ High risk of bias: the allocation sequence was likely to be known to the investigators who assigned the participants.
Blinding of participants, personnel, and outcome assessors
‐ Low risk of bias: blinding was performed adequately, or the assessment of outcomes was not likely to be influenced by lack of blinding.
‐ Uncertain risk of bias: there was insufficient information to assess whether blinding was likely to induce bias on the results.
‐ High risk of bias: no blinding or incomplete blinding, and the assessment of outcomes was likely to be influenced by lack of blinding.
Incomplete outcome data
‐ Low risk of bias: missing data were unlikely to make treatment effects depart from plausible values. Sufficient methods, such as multiple imputation, have been employed to handle missing data.
‐ Uncertain risk of bias: there was insufficient information to assess whether missing data in combination with the method used to handle missing data were likely to induce bias on the results.
‐ High risk of bias: the results were likely to be biased due to missing data.
Selective outcome reporting*
‐ Low risk of bias: all outcomes were pre‐defined and reported, or all clinically relevant and reasonably expected outcomes were reported.
‐ Uncertain risk of bias: it is unclear whether all pre‐defined and clinically relevant and reasonably expected outcomes were reported.
‐ High risk of bias: one or more clinically relevant and reasonably expected outcomes were not reported, and data on these outcomes were likely to have been recorded.
*For a trial to be assessed as having low risk of bias in the selective outcome reporting domain, the trial should have been registered either on the www.clinicaltrials.gov web site or a similar register, or there should be a protocol, e.g., published in a paper journal. In the case of trials run and published in the years when trial registration was not required, we will carefully scrutinise all publications reporting on the trial to identify the trial objectives and outcomes. If usable data on all outcomes specified in the trial objectives are provided in the publication's results section, then the trial can be considered to have low risk of bias for the selective outcome reporting domain.
For‐profit bias
‐ Low risk of bias: the trial appears to be free of industry sponsorship or other kind of for‐profit support that may manipulate the trial design, conductance or results of the trial.
‐ Uncertain risk of bias: the trial may or may not be free of for‐profit bias as no information on clinical trial support or sponsorship is provided.
‐ High risk of bias: the trial is sponsored by industry or has received other kind of for‐profit support.
The trials will be described as having low risk of bias if they are judged with low risk of bias in all individual components of the above mentioned domains. In all other cases, the trials will be judged as having high risk of bias.
Measures of treatment effect
For dichotomous variables, we plan to calculate the relative risk (RR) with 95% confidence interval (CI). For continuous variables, we plan to calculate the standardised mean difference (SMD) (for outcomes such as quality of life, where different scales could be used) with 95% CI. For outcomes such as hazard ratio for death, we plan to use the generic inverse variance method for the meta‐analysis.
Dealing with missing data
Data will be analysed using the intention‐to‐treat principle, that is, patients with missing data (in all treatment groups of a trial) will be considered as treatment failures, and all randomised patients will be included in the denominator.
Sensitivity analyses will be performed to assess how sensitive results are to reasonable changes in the assumptions that are made, that is, to perform a worst‐best case scenario, best‐worst case scenario, best‐best case scenario, and a worst‐worst case scenario. The potential impact of missing data on findings of the review will be discussed.
Assessment of heterogeneity
Heterogeneity will be assessed using the Chi2 test and I2 statistic. Any plausible possible causes of heterogeneity will be discussed.
Data synthesis
The authors will follow the instructions given in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) and the Cochrane Hepato‐Biliary Group Module (Gluud 2012).
The evidence synthesis will most likely be done in a narrative way but, where possible and meaningful, we will use meta‐analyses. We will calculate pooled estimates using the random‐effects model (DerSimonian 1986) and the fixed‐effect model (Mantel 1959; Greenland 1985). We will present both results if there are discrepancies in the results. If not, we plan to report the random‐effects model (DerSimonian 1986), and we plan to measure the quantity of heterogeneity using I2 (Higgins 2011).
In principle, all data are suitable for meta‐analysis. Measures of effect will be calculated as relevant (hazard ratios, odds ratios, relative risks, risk differences, mean differences, and standardised mean differences). Where possible, hazard ratios will be calculated using methods described by Parmar and Tierney (Parmar 1998). Information (for example, hazard rates, P values, events, ratios, curve data, and information on follow‐up) will be extracted from the publications and, if necessary, will be entered into a Microsoft Office Excel 2003 spreadsheet to calculate hazard ratios (Thierney 2007). Where data are available for the same outcomes using similar methods, these will be pooled statistically. If data cannot be pooled statistically, for example in the case of extreme heterogeneity, results will be presented in a forest plot without the pooled estimate in order to show the variance of the effects. Cross‐over trials will be included using results of the first period only (before cross‐over), as if they were parallel group trials.
If a meta‐analysis is not possible, the results will be presented in a narrative way. This means that we will present text, tables, and figures to summarise the data and to allow the reader to judge the results based on the differences and similarities of the included trials and their quality assessment. The trials will be grouped by intervention, patient characteristics, and outcomes, and the most important characteristics of the included trials will be described, including a detailed review of the methodological shortcomings of the trial.
If available data allow, we will use funnel plots to identify any possible small study biases, such as publication bias. We will test for funnel plot asymmetry if there are at least 10 studies included in the meta‐analysis (Higgins 2011). If present, we will discuss possible implications for our findings.
Where possible, we will examine apparently significant beneficial and harmful intervention effects with trial sequential analyses (CTU 2011; Thorlund 2011) in order to evaluate if these apparent effects could be caused by random error (play of chance) (Brok 2008; Wetterslev 2008; Brok 2009; Thorlund 2009; Wetterslev 2009; Thorlund 2010). We plan to estimate the diversity‐adjusted required information size based upon the occurrence of the outcome in the control intervention group, a relative risk reduction of 20%, and as observed in trials with low risk of bias, an alpha of 5%, a beta of 20%, and the diversity observed in the meta‐analysis (Wetterslev 2008; Wetterslev 2009; Thorlund 2011).
Subgroup analysis and investigation of heterogeneity
We will subgroup the trials according to the location of the primary cancer. We will also subgroup the trials according to the control intervention. Subgroup analyses will be performed, where possible, based on the following prognostic indicators: age, sex, tumour size, location of primary tumour, and use of any co‐interventions as well as risk of bias in the included trials.
Sensitivity analysis
Outcomes following the intervention after up to and including six months, six to 12 months, one year or more will be summarised separately.
Summary of findings
We will summarise the evidence in a summary of findings table using GRADEpro (http://ims.cochrane.org/revman/other‐resources/gradepro).
