Summary of findings
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 the remaining colorectal cancer patients will subsequently be found to have liver involvement. Almost half of patients dying from stomach, pancreas, or breast cancer are found to have liver metastases at autopsy while in patients with endometrial cancer it occurs 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 colorectal cancer are diagnosed each year in the United States, of which 102,900 are patients with colon cancer and the remainder with 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 for colorectal cancer is 17.2 per 100,000 people (IARC 2008). The highest 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 incidences are observed in Africa (age-adjusted 5.9) and Asia (age-adjusted 12.9). Globally, age-adjusted mortality for colorectal cancer is 8.2 per 100,000 people; 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), while in developing countries analysed together it is 39% (Parkin 2002) with the lowest survival reported for Sub-Saharan Africa (13% for male and 14% for female). Approximately 50% of colorectal cancer patients will develop recurrence within five years of the initial diagnosis with the liver being the most common site for metastatic disease (Geoghegan 1999).
Globally, the age-standardised incidence and mortality for lung cancer are 23.0 and 19.4 per 100,000 people of both sexes respectively, stomach 14.1 and 10.3, pancreas 3.9 and 3.7, 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 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, the estimated survival for stomach cancer 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 cancer 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 months to 46 months or five-year survival of 20% to 58% (McLoughlin 2006). However, only 20% of patients with hepatic tumours are candidates for resection as for many the metastases have spread too extensively in the liver (Bilchik 2000; Bipat 2007). 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) (Riemsma 2009). Other methods include local tumour ablative techniques, such as 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 selective administration of chemotherapy usually combined with embolisation of the vascular supply to the tumour (Vogl 2009). This treatment results in selective ischaemic and chemotherapeutic effects on liver metastases (Vogl 2007).
How the intervention might work
Chemoembolisation is based on the concept that the blood supply to hepatic tumours originates predominantly from the hepatic artery (Breedis 1954; Vogl 2003). Therefore, embolisation of the hepatic artery can lead to selective necrosis of the liver tumour while it may leave normal parenchyma virtually unaffected (Jaeger 1996; Vogl 2003). However, ligation of the hepatic artery increases 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 (chemo)embolisation. In hepatocellular carcinoma, transarterial (chemo)embolisation 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 of some of these therapies are. Systematic reviews may help to establish the effectiveness and the trade off between the benefit and harm associated with different non-surgical ablation methods for the treatment of all forms of malignant liver tumours (primary and metastases). Reviews and meta-analyses published so far focus mostly on primary liver tumours or colorectal cancer liver metastases and include studies up to April 2006 (Llovet 2003; Decadt 2004; ASERNIP-S 2006; Lopez 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). Therefore, a systematic review dealing with all types of malignant liver metastases is warranted.
To study the beneficial and harmful effects of transarterial (chemo)embolisation compared with no intervention or placebo intervention in patients with liver metastases.
Criteria for considering studies for this review
Types of studies
We included all randomised clinical trials assessing beneficial and harmful effects of transarterial (chemo)embolisation irrespective of publication status, language, or blinding. Quasi-randomised and other controlled studies that came up with the search results were considered only for the report of data on harm.
Types of participants
Patients with liver metastases no matter the location of the primary tumour.
Types of interventions
Transarterial (chemo)embolisation compared with no intervention or placebo intervention. Co-interventions were allowed if provided equally to the experimental and control groups of the individual randomised trial.
Types of outcome measures
1. Mortality at last follow-up.
2. Time to mortality.
3. All adverse events and complications, separately and in total. The International Conference on Harmonisation (ICH) Guidelines (ICH-GCP 1997) defines adverse events as serious and non-serious. A serious fatal or non-fatal 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 are considered non-serious.
4. Quality of life.
1. Failure or proportion of patients with recurrence.
2. Time to progression of liver metastasis.
3. Tumour response measures (complete response, partial response, stable disease, disease progression).
Search methods for identification of studies
We searched the Cochrane Hepato-Biliary Group Controlled Trials Register (Gluud 2013), the 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 Trial Registry platform (WHO 2011).
One global search was used for all non-surgical ablation methods for primary malignant liver tumours and liver metastases. Search strategies with the time spans of the searches are given in Appendix 1 (up to December 2012). There was no need to improve the search strategies.
In addition, we assessed for inclusion all United States Food and Drug Administration (FDA) approvals and investigational device exemptions as found on the FDA website (FDA 2011).
Searching other resources
We searched reference lists of reviews (such as Schwartz 2004 and Lopez 2006), Health Technology Assessment (HTA) reports (such as ASERNIP-S 2006), all Cochrane reviews, and all trials that were included for relevant studies.
Data collection and analysis
We performed the systematic review following the recommendations of The Cochrane Collaboration (Higgins 2011) and the Cochrane Hepato-Biliary Group module (Gluud 2013) using Review Manager 5 (RevMan 2012).
Selection of studies
Two authors independently evaluated titles and abstracts for ordering papers (RR and MB). Any differences in opinion were resolved by discussion or, if necessary, by consulting a third author (JK). For titles and abstracts that potentially fitted our inclusion criteria, full papers were ordered. These papers were assessed by two independent authors (RR and MB) and differences in opinion, if any, were resolved using the above-mentioned procedure.
Data extraction and management
We extracted 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 trials. Quality assessment of the trials, assessment for fulfilling the inclusion criteria, and data extraction from the retrieved final evaluation trials were 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 assessed the risk of bias of the trials based on the domains described below (Schulz 1995; Moher 1998; Kjaergard 2001; Gluud 2008; Wood 2008; Lundh 2012; Savović 2012a; Savović 2012b). This assessment was presented by trial and was used to describe the results of each trial in relation to reliability.
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 adjudicator.
- Uncertain risk of bias: the trial is described as randomised, but the method of sequence generation was not specified.
- High risk of bias: the sequence generation method is not, or may not be, random. Quasi-randomised studies, those using dates, names, or admittance numbers in order to allocate patients, are inadequate and will be excluded for the assessment of benefits but not for harms.
- Low risk of bias: allocation was controlled by a central independent randomisation unit, using sequentially numbered, opaque and sealed envelopes, or similar, so that intervention allocations could not have been foreseen either in advance of or during enrolment.
- Uncertain risk of bias: the trial was described as randomised but the method used to conceal the allocation was not described so that intervention allocations may have been foreseen either in advance of or during enrolment.
- High risk of bias: if the allocation sequence was known to the investigators who assigned participants or if the study was quasi-randomised. Quasi-randomised studies will be excluded for the assessment of benefits but not for harms.
Blinding of participants, personnel, and outcome assessors
- Low risk of bias (blinding was performed adequately, or the outcome measurement is not likely to be influenced by lack of blinding).
- Uncertain risk of bias (there is insufficient information to assess whether the type of blinding used is likely to induce bias on the estimate of effect).
- High risk of bias (no blinding or incomplete blinding, and the outcome or the outcome measurement is likely to be influenced by lack of blinding).
Incomplete outcome data
- Low risk of bias (the underlying reasons for missingness are unlikely to cause 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: pre-defined or clinically relevant and reasonably expected outcomes are reported on.
- Uncertain risk of bias: not all pre-defined or clinically relevant and reasonably expected outcomes are reported on or are not reported fully, or it is unclear whether data on these outcomes were recorded or not.
- High risk of bias: one or more clinically relevant and reasonably expected outcome was not reported on; data on these outcomes were likely to have been recorded.
Other sources of bias
- Low risk of other bias: the trial appears to be free of other components that could put it at risk of bias.
- Uncertain risk of other bias: the trial may or may not be free of other components that could put it at risk of bias.
- High risk of other bias: there are other factors in the trial that could put it at risk of bias, eg, for-profit involvement, authors have conducted trials on the same topic etc.
Trials judged as having 'low risk of bias' in all of the above specified individual domains were considered to be 'trials with low risk of bias'. All other instances led to classifying the trials in the group of trials with high risk of bias.
Measures of treatment effect
For dichotomous variables, we planned to calculate the relative risk (RR) with 95% confidence interval (CI). For continuous variables, we planned to calculate the standardised mean difference (SMD) (for outcomes such as quality of life when different scales could be used) with 95% CI. For outcomes such as hazard ratio for death, we planned to use the generic inverse variance method for the meta-analysis.
Unit of analysis issues
The number of the randomised participants was to be used to calculate estimates of intervention effects and CIs. In cluster randomised trials, the unit of analysis would have been the cluster. For cross-over trials, we planned to include only data from the first intervention period (Higgins 2011). We calculated pooled estimates using the random-effects model (DerSimonian 1986) and the fixed-effect model (Mantel 1959; Greenland 1985). We planned to present both results if there were discrepancies in the results. If not, we planned to report the random-effects model. We planned to measure the quantity of heterogeneity using the I
Dealing with missing data
Data were planned to be analysed using the intention-to-treat principle, that is, patients with missing data (in all treatment groups of a trial) were to be considered as treatment failures and all randomised patients were to be included in the denominator.
Assessment of heterogeneity
Heterogeneity was to be assessed using the Chi
The evidence synthesis was done in a narrative way, and it was not possible to do meta-analyses.
In principle, all data are suitable for meta-analysis. We planned to calculate measures of effect, as relevant (hazard ratios, odds ratios, relative risks, risk differences, mean differences, and standardised mean differences). Where possible, we planned to calculate hazard ratios using methods described by Parmar and Tierney (Parmar 1998). We planned to extract information (for example, hazard rates, P values, events, ratios, curve data, and information on follow-up) from the publication and, if necessary, to enter data into a Microsoft Office Excel 2003 spreadsheet to calculate hazard ratios (Tierney 2007). Where data were available for the same outcomes using similar methods, meta-analyses were to be performed. If data could not be meta-analysed statistically, for example in the case of extreme heterogeneity, we planned to present results in a forest plot, without the estimate, in order to show the variance of the effects (Egger 1997). We planned to include cross-over trials using the results of the first period only (before cross-over), as if they were parallel trials.
In cases without heterogeneity and yet with meta-analysis not being possible, we planned to present the results in a narrative way, including 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 risk of bias assessment. We planned to group the trials by intervention, patient characteristics, and outcomes and to describe the most important characteristics of the included trials, including a detailed review of the methodological shortcomings of a trial.
We planned to use funnel plots to identify any possible small trial biases, such as publication bias, if data were available (Egger 1997). We planned to discuss the possible implications of our findings if bias was present.
Where possible, we planned to examine apparent significant beneficial and harmful intervention effects with trial sequential analysis (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 planned to create a 'Summary of findings' table including, where possible, survival, response, recurrence, and adverse events, using GRADEpro (http://ims.cochrane.org/revman/other-resources/gradepro).
Subgroup analysis and investigation of heterogeneity
We planned to perform subgroup analyses, where possible, based on prognostic indicators such as age, sex, tumour size, location of primary tumour, and use of any co-interventions.
For an extra subgroup analysis, a trial with a lower risk of bias was to be defined where three or more domain items were met, including sequence generation and allocation concealment.
We planned to summarise the separate outcomes after intervention, at six months or less, six to 12 months, and one year or more.
Description of studies
Results of the search
Our original searches for "non-surgical ablation methods (and possible combinations) compared with no intervention, each other, combinations of ablation methods, or systemic treatments in patients with primary malignant liver tumours and liver metastases" were performed in December 2012.
The searches produced 5497 references. Based on titles and abstracts, 4869 references were excluded, resulting in 628 full papers to be retrieved. In addition, we found 27 references through handsearching. Therefore, 655 full papers were retrieved. Based on the full papers we excluded 534 publications, mainly because they were not randomised trials.
One hundred and twenty-one papers, describing 84 trials and 144 comparisons, were included in the full review of non-surgical ablation methods in patients with liver metastases or primary malignant liver tumours (Riemsma 2009). One trial was found to be relevant for this review (Hunt 1990) (Figure 1).
|Figure 1. Flow diagram of identification of randomised trials for inclusion.|
We included one randomised trial comparing three groups: hepatic artery embolisation, hepatic artery infusion chemotherapy, and control, the latter described as "no active therapeutic intervention, although symptomatic treatment was provided whenever necessary" (Hunt 1990). In the embolisation group the procedure was performed with homologous lyophilised dura mater and gel foam. The number of sessions was not reported. Sixty-one patients with unresectable colorectal liver metastases were included; 22 received hepatic artery embolisation, 19 received hepatic artery infusion chemotherapy, and 20 received the control.
The trial included 43 male and 18 female participants. The mean age was not reported but patients aged between 18 and 75 years were eligible. The diagnosis was confirmed by histological assessment or by a combination of imaging procedures. The mean size of the tumour was not reported; most were synchronous metastases involving up to 75% of the liver. All of the tumours were non-resectable, and the reasons for non-resectability were not reported. The authors did not report baseline characteristics of the groups but stated that they were comparable for age, sex, primary carcinoma site, Duke’s staging, histology of the primary tumour, proportion of synchronous or metachronous metastases, or the percentage of liver involvement. Participants were followed for a minimum of seven months.
Risk of bias in included studies
The trial was described as a randomised clinical trial.
Overall, we assessed the risk of bias of this trial as high. For an overview of the methodological quality of the included trial see Figure 2 and Figure 3.
|Figure 2. Risk of bias summary: review authors' judgements about each risk of bias item for each included study.|
|Figure 3. Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.|
The trial was described as a randomised clinical trial. However, there was no information to assess sequence generation or allocation concealment.
There was also insufficient information to assess whether participants, physicians, or outcome assessors were properly blinded.
Incomplete outcome data
The method of analysis was deemed appropriate and there were no missing outcome data reported.
Local recurrence was reported for 10 patients in the trial without details about which intervention groups they belonged to. Adverse events in the control group were not reported.
Other potential sources of bias
It was not possible to assess whether the trial was free of other problems that could put it at a higher risk of bias.
Effects of interventions
Mortality at last follow-up
The trial reported that the mortality was 86% (19/22) in the hepatic artery embolisation group versus 95% (19/20) in the control group (RR 0.91; 95% CI 0.75 to 1.1) (our calculation using the Mantel-Haenszel test in RevMan). As this was based on only one trial and given that the number of events were high, we checked the result using Fischer's exact test, which produced a two-sided P value of 0.6079, confirming that the difference was not statistically significant.
Time to mortality
Median survival after trial entry was 7.0 months (range 2 to 44) in the hepatic artery embolisation group and 7.9 months (range 1 to 26) in the control group. This difference was not statistically significant.
Most patients in the embolisation group experienced post-embolic syndrome (82%); one patient had a local haematoma. No other adverse events were reported. The authors did not report if there were any adverse events in the control group.
Quality of life
The trial did not report on quality of life.
Failure or proportion of patients with recurrence
This outcome was reported in terms of extrahepatic disease. Nine out of 22 (41%) in the hepatic artery embolisation group and five out of 20 (25%) in the control group developed evidence of extrahepatic disease (RR 1.64; 95% CI 0.60 to 4.07). Local recurrence was reported for 10 patients in the trial without details about the trial groups they were in.
Time to progression of liver metastasis
Time to progression of liver metastasis was not reported.
Tumour response measures (complete response, partial response, stable disease, disease progression) were not reported.
There were no significant differences in the effects in subgroups of synchronous or metachronous metastases, and less than 50% or more than 50% hepatic replacement with tumour.
Summary of main results
On the basis of one small randomised trial which did not describe sequence generation, allocation concealment or blinding, and probably was not free from selective outcome reporting bias, it can be concluded that no significant survival benefit or benefit in extrahepatic recurrence was found in the embolisation group in comparison with the palliation group in patients with liver metastases.
Due to the presence of one trial only, meta-regression analyses using individual quality criteria were not feasible.
Overall completeness and applicability of evidence
The search strategy was very wide as it was designed for all non-surgical ablation interventions. Additionally, by searching the reference lists of the included trials and by checking recent review articles we made sure that none of the relevant studies were overlooked.
Quality of the evidence
The trial did not provide sufficient details in order to judge the quality of the randomisation process, allocation concealment or presence of blinding, and selective outcome reporting bias. Therefore, the main limitation of this review is the quality of the available evidence.
Analyses with trial sequential analysis (TSA) (CTU 2011; Thorlund 2011) have shown that apparent significant beneficial and harmful intervention effects may in fact have been caused by random error (‘play of chance’) (Brok 2008; Wetterslev 2008; Brok 2009; Thorlund 2009, Wetterslev 2009; Thorlund 2010). This was not formally assessed in this review. Accordingly, any significant results, had they been found, need to be interpreted with caution as some of the results may have been caused by random error.
Potential biases in the review process
Publication bias might be an issue here; however, due to the small number of trials (one trial for this comparison) it is not possible to assess this formally. Another issue is reporting bias; there was no protocol available for the included trial. therefore, we could not assess the extent of this but it might be an issue (Chan 2004).
Agreements and disagreements with other studies or reviews
No other reviews of transarterial chemoembolisation versus no intervention were found for people with liver metastases.
Implications for practice
There is insufficient evidence to assess the effect of transarterial (chemo)embolisation versus no intervention in liver metastases. Transarterial (chemo)embolisation cannot be recommended outside randomised clinical trials.
Implications for research
There is a need for good quality, large randomised clinical trials of transarterial (chemo)embolisation versus no intervention for people with liver metastases. As the quality of the included trial was less than optimal, it is important that the randomisation process is clearly described as well as the interventions used. The patient flow should be well specified as well as data handling. The trial must be designed and described following the CONSORT Statement (www.consort-statement.org).
We would like to thank Christian Gluud for his advice in the preparation of this systematic review.
Peer Reviewers: Kang Mo Kim, South Korea; Timothy Price, Australia; Luit Peninga, Denmark.
Contact Editor: Christian Gluud, Denmark.
Data and analyses
This review has no analyses.
Appendix 1. Search strategy
Last assessed as up-to-date: 11 March 2013.
Contributions of authors
JK developed the concept for the project. RR and JK formulated the search strategy and carried out the searches. Study inclusion and data extraction were done by MB, RR, and RW. Analyses were performed by MB, RR, and RW. The text of the review was prepared by MB, RR, RW, and JK.
Declarations of interest
No conflicts of interest
Sources of support
- Kleijnen Systematic Reviews Ltd. (KSR), UK.
- KSR funded the updating of the review and producing Cochrane Reviews.
- The Dutch Health Care Insurance Board (CVZ), Netherlands.
- This systematic review was funded by the Dutch Health Care Insurance Board (CVZ). CVZ commissioned a systematic review of the effectiveness of non-surgical ablation methods for liver metastases.
Differences between protocol and review
Amended inclusion criteria for data on harm from: "Quasi-randomised and observational studies that will come up with the search, will be considered only for the report of data on harm." to: "Quasi-randomised and other controlled studies that will come up with the search, will be considered only for the report of data on harm."
We removed the domains 'baseline imbalance' and 'early stopping of trials'. The argumentation for not considering baseline imbalance is that it may occur due to random error ('play of chance'), and that such random error is likely to be levelled out by conducting a meta-analysis of several trials. The argumentation for not considering early stopping is that such trials, although they may overestimate intervention effects, are likely to be counterbalanced by trials finding no significant difference. By solely excluding trials that are stopped early one would bias the meta-analysis towards a neutral effect (Gluud 2013).
Medical Subject Headings (MeSH)
*Colorectal Neoplasms; *Hepatic Artery; Chemoembolization, Therapeutic [methods]; Embolization, Therapeutic [*methods]; Infusions, Intra-Arterial [methods]; Liver Neoplasms [blood supply; secondary; *therapy]; Randomized Controlled Trials as Topic
MeSH check words
Female; Humans; Male