射频消融术与肝切除术治疗乳腺癌肝转移:系统回顾和meta分析

Radiofrequency ablation versus hepatic resection for breast cancer liver metastasis: a systematic review and meta-analysis 射频消融术与肝切除术治疗乳腺癌肝转移:系统回顾和meta分析 first-author †E-mail:med_xyb@126.comyulianwu@zju.edu.cn †E-mail:med_xyb@126.comyulianwu@zju.edu.cn med_xyb@126.com corresp ‡Corresponding Author ‡Corresponding Author †E-mail:med_xyb@126.comyulianwu@zju.edu.cn †E-mail:med_xyb@126.comyulianwu@zju.edu.cn med_xyb@126.com Department of Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China Department of Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China Objective: 2 To evaluate the comparative therapeutic efficacy of radiofrequency ablation (RFA) and hepatic resection (HR) for breast cancer liver metastases (BCLMs). Methods: 2 Studies that had examined the outcomes for both RFA and HR for BCLM were identified by searching the electronic databases PubMed, EMBASE, and the Cochrane Library. Pooled analyzes of the overall survival (OS), disease-free survival (DFS), and short-term outcomes of BCLM were performed. Results: 2 Patients with BCLM gained many more survival benefits from HR than from RFA with regard to the 3-year OS rate (combined odds ratio (OR) 0.41, 95% confidence interval (CI) 0.29–0.59, P < 0.001), 5-year OS rate (combined OR 0.38, 95% CI 0.32–0.46, P < 0.001), 3-year DFS (combined OR 0.36, 95% CI 0.27–0.49, P < 0.001), and 5-year DFS (combined OR 0.51, 95% CI 0.40–0.66, P < 0.001). RFA had fewer postoperative complications (combined OR 0.30, 95% CI 0.20–0.44, P < 0.001) and shorter hospital stays (combined OR −9.01, 95% CI −13.49–4.54, P < 0.001) than HR. Conclusions: 2 HR takes precedence over RFA in the treatment of patients with BCLM, considering the better survival rate. RFA gives rise to fewer complications and can be carried out with a shorter hospital stay, compared to HR. RFA should be reserved for patients who are not optimum candidates for resection. 目的 2 评估射频消融术(RFA)和肝切除术(HR)治疗乳腺癌肝转移(BCLM)的效果. 创新点 2 首次采用meta分析的方法,精确评估RFA和HR治疗BCLM的效果,解决不同研究产生不同结论的矛盾. 方法 2 系统收集截止到2017年3月所有与RFA和HR治疗BCLM的效果相关文献,评价文献质量、提取数据并计算癌症预后相关指标的优势比(OR)及其95%置信区间(CI). 结论 2 HR比RFA对于提高BCLM患者生存率有更大 优势;RFA并发症少、可重复、患者术后住院时间短,具有明显微创优势.对于不适合行切除治疗的患者可考虑行RFA治疗. Breast cancer liver metastasis Radiofrequency ablation Hepatic resection Prognosis Meta-analysis 乳腺癌肝转移 肝切除术 射频消融 预后 Meta分析 Introduction 1 Metastatic breast cancer is a systemic disease, uncommonly involving a single organ. Liver metastasis from breast cancer (BCLM) occurs in approximately 50% of patients with breast cancer and is associated with a poor prognosis (Corona et al., 2017 2017 ). Metastatic breast cancer is usually considered a disseminated disease for which multimodality treatment remains the mainstay of therapy (Mansour et al., 2017 2017 ). However, many barriers exist when treating metastatic breast cancer such as a lack of effective chemotherapeutic agents, drug resistance, and toxicity (Kim and Scott, 2017 2017 ; Meattini et al., 2017 2017 ). To further complicate matters, metastatic breast tumors seldom maintain oestrogen and progesterone receptor positivity, restricting the effectiveness of hormonal treatments, which has raised the demand for other treatment strategies (Samaan et al., 1981 1981 ) such as hepatic resection (HR) and radiofrequency ablation (RFA). HR has long been considered the chance of a cure for patients with BCLM. Selzner et al. ( 2000 2000 ) reported that some groups of patients that have metastatic lesions confined to the liver (5%–12%) seem to have a better prognosis following HR than those undergoing chemotherapy alone (the 3-year overall survival (OS) rate was 65% vs. 31%). Adam et al. ( 2006 2006 ) reported that the median survival and 5-year OS rate for patients with BCLM were 46 months and 41%, respectively, after HR. HR improves survival by way of reducing tumor burden, allowing subsequent chemotherapy or biologic therapy to be more effective. Nonetheless, the associated liver cirrhosis limits the extent of resection and increases the risk of postoperative liver failure (Detry et al., 2003 2003 ). RFA is a medical procedure, the functioning process of which includes the following steps. To begin with, it generates high-frequency alternating current, which induces ionic agitation and conversion to heat. Then intracellular water evaporates, leading to irreversible cellular changes, involving melting of membrane lipid bilayers, protein denaturation of intracellular structures, and coagulative necrosis of individual tumor cells (Gillams, 2005 2005 ). RFA is an effective therapy for certain primary and metastatic liver neoplasms, especially for liver metastases from colorectal cancer (Frezza et al., 2007 2007 ). It has many advantages such as being easily repeated, less blood loss, well tolerated, and has a lower mortality rate compared to HR (Wong and Cooper, 2016 2016 ). Although RFA plays an important role in the treatment of metastatic liver cancer, it has a few limitations, including being unable to treat occult or microscopic metastases, having difficulty in treating tumors larger than a few centimetres and those adjacent to major vascular structures (Vogl et al., 2015 2015 ). So, the therapeutic efficacy of RFA for patients with resectable BCLM remains controversial. For example, Bruners et al. ( 2008 2008 ) reported equivalent median survival (41 vs. 37 months) and 3-year OS rates (55.4% vs. 52.6%) between BCLM patients receiving HR and RFA. By contrast, Travaini et al. ( 2008 2008 ) showed that patients in the “liver resection” group had significantly better OS (longer median survival (56 vs. 36 months) and higher 5-year OS rates (71% vs. 27%)). Therefore, the evidence of equipoise between HR and RFA is still disputable. As a useful and popular tool, meta-analysis overcomes the restrictions of a small sample size by combining results from certain individual studies to generate a best assessment (Nordmann et al., 2012 2012 ). Although no randomized controlled trials (RCTs) regarding this issue have been reported up to now, there is evidence that the pooling of high-quality non-randomized studies is as convincing as the pooling of RCTs when comparing clinical results (Abraham et al., 2010 2010 ). This study systematically analyzed high-quality clinical trials that have compared HR with RFA in the treatment of BCLM and performed a meta-analysis of combined clinical outcomes, aiming at determining the survival benefits of BCLM patients undergoing HR and RFA. Materials and methods 1 Search strategy and study selection 2 We searched the electronic databases of PubMed, EMBASE, and the Cochrane Library up to March 2017 for studies that compared HR and RFA for treatment of BCLM. The following search terms were used: “breast cancer liver metastases”, “hepatic resection”, “radiofrequency ablation”, “prognosis”, and “comparative study”. The language was confined to English and only studies on humans were considered for inclusion. References of all relevant articles were evaluated to identify other related studies. Titles and abstracts of all citations were independently screened by two reviewers (Yi-bin XIAO and Bo ZHANG). Reviews or unpublished reports were not considered. If more than one article was published by the same author containing the same case series, the most recent study or the study where the most cases were looked into was selected. Inclusion and exclusion criteria 2 We carried out and reported this systematic review and meta-analysis according to the PRISMA statement (Moher et al., 2009 2009 ). Eligibility criteria for inclusion in this meta-analysis were as follows: (1) all cases were diagnosed through pathology tests or more than two image logical examinations combined with clinical data comparing the initial therapeutic effects of HR and RFA for the treatment of BCLM, in spite of the aetiology of liver disease, differences in viral hepatitis, or cirrhotic status; (2) clearly documented indications for HR and RFA; (3) a report on at least one of the outcome measures mentioned below; (4) sufficient information for estimation of odds ratios (ORs) and their 95% confidence intervals (CIs); (5) if multiple studies were reported by the same authors and/or institution, either the study of higher quality or the most recent publication was included in the analysis; and (6) publication as a full research article in English language. Studies were excluded if: (1) only one treatment method was used and no controlled population was included in the study; (2) they were duplicates of an earlier publication; (3) they contained animal or cell experiments; and (4) they were articles published in a book, reviews, letters, case reports, or conference abstracts that had no original data. Data extraction and management 2 Data were extracted independently by two investigators (Yi-bin XIAO and Bo ZHANG) with the use of a predefined form. Topics in this form were first author’s name, year of publication, study location, number of patients, patients’ and tumor characteristics, study design, and therapeutic outcomes. All relevant texts, tables, and figures were reviewed for data extraction. Discrepancies between the two investigators were resolved through consensus discussion. Quality and methodological assessment 2 Quality assessment of the non-randomized studies was conducted according to the Newcastle-Ottawa scale (NOS) (Stang, 2010 2010 ) with some modifications to match the needs of this study (Selzner et al., 2000 2000 ; Sato et al., 2006 2006 ; Illing and Gillams, 2010 2010 ; Veltri et al., 2014 2014 ). The quality of the studies was assessed by examining three items: patient selection, comparability of HR and RFA groups, and outcome of interest. Studies were graded on an ordinal star scoring scale with higher scores representing studies of higher quality. Studies scoring equal to or higher than 7 points were considered “high-quality” studies, whereas those with scores less than 7 were regarded as “low-quality” studies. The quality assessment and scores are summarized in Tables 1 1 and 2 2 . Comparability variables: 1, age (≥50 years); 2, history of malignancies; 3, reoperation; 4, hepatic functional reserve before surgical treatment; 5, pre-hepatectomy therapy; 6, tumor number; 7, tumor size; 8, distribution of BCLM (unilobar); 9, extrahepatic metastases Check list Selection  1. Assignment for treatment: any criteria reported? (if yes, one star)  2. How representative was the hepatic resection (HR) group in comparison with the general population with BCLM? (if yes, one star; no star if the patients were selected or selection of group was not described)  3. How representative was the radiofrequency ablation (RFA) group in comparison with the general population with BCLM? (if drawn from the same community as the HR group, one star; no star if drawn from a different source or selection of group was not described) Comparability  4. Group comparable for 1, 2, 3, 4, 5 (if yes, two stars; one star was assigned if one of these five characteristics was not reported even if there were no other differences between the two groups and other characteristics had been controlled for; no star was assigned if the two groups differed)  5. Group comparable for 6, 7, 8, 9 (if yes, two stars; one star was assigned if one of these four characteristics was not reported even if there were no other differences between the two groups and other characteristics had been controlled for; no star was assigned if the two groups differed) Outcome assessment  6. Clearly defined outcome of interest (yes, one star for information ascertained by record linkage or interview: no star if this information was not reported)  7. Adequacy of follow-up (one star if follow-up >90%) 2 Study 3 Selection 2 Comparability 2 Outcome assessment 2 Newcastle-Ottawa scale 1 2 3 4 5 6 7 Barral et al., 2016 2016 * * * * * * * ******* Carrafiello et al., 2011 2011 * * * * * * * ******* Covey et al., 2008 * * * ** * * * ******** Gunabushanam et al., 2007 2007 * * ** ** * * ******** Kümler et al., 2015 2015 * * * ** * * ******* Lee et al., 2013 2013 * * ** ** * * ******** Livraghi et al., 2001 2001 * * * ** * * ******* Illing et al., 2010 * * ** ** * * ******** Meloni et al., 2009 2009 * * ** * * * ******* Sofocleou et al., 2007 * * * ** * * ******* Treska et al., 2014 2014 * * * * * * * ******* Veltri et al., 2014 2014 * * ** ** * * ******** Vogl et al., 2015 2015 * * * ** ** * * ********* Wong and Cooper, 2016 2016 * * * ** * * ******* Statistical analysis 2 OR and their 95% CI were used to analyze dichotomous variables. Time-to-event data including the 3-year OS, 3-year disease-free survival (DFS), 5-year OS, and 5-year DFS were extracted from individual studies. Pooled categorical comparisons were made by using the chi-square ( χ 2 ) test. Cochran’s χ 2 -based Q test and Higgins I -squared ( I 2 ) statistics were used to check heterogeneity among studies. We considered P > 0.10 or P ≤0.10/ I 2 ≤50% to indicate no significant heterogeneity between studies and a fixed effect model was used in such cases. Otherwise, we considered P ≤0.10/ I 2 > 50% to indicate significant heterogeneity, and a random effect model was used. P- value of < 0.05 and 95% CI that did not overlap 1 were considered statistically significant in the integration results. Subgroup analysis based on study region, sample size, publication year, tumor number, tumor size, distribution of BCLM, pre-hepatectomy therapy, and extrahepatic metastases were conducted in order to explore the reasons for inter-study heterogeneity. Sensitivity analysis was also carried out by omitting any single study sequentially to evaluate the stability of the results. In addition, publication bias was assessed using funnel plots (Nordmann et al., 2012 2012 ). All analyzes were performed using the RevMan systematic review and meta-analysis software package (Review Manager Version 5.3, Cochrane collaboration, Oxford, the United Kingdom). Results 1 Study selection and characteristics 2 The initial search retrieved a total of 268 potential studies according to the search criteria. After screening the title and abstract, 36 reports assessing the values of HA and RFA for survival in patients with BCLM were considered eligible for inclusion in the evaluation. After reading the abstract, six were excluded because they did not display a specific comparison of the effects of HR and RFA; five were excluded because they included patients with non-breast cancer. After reading the full text, eight reports were excluded because the estimation of ORs in these reports was not allowed due to insufficient original data provided by the authors; and three were excluded because they lacked information concerning 3-or 5-year OS. A total of 14 studies meeting the inclusion criteria were eligible for this systematic review and meta-analysis (Fig. 1 1 ). The characteristics of the 14 eligible studies are summarized in Table 3 3 . Twelve studies were retrospective cohort studies, the remaining two studies were prospective cohort studies. Four studies evaluated patients from Italy, three from America, and the others were from India, Korea, Czech, Denmark, England, Germany, and France separately. Five of these studies enrolled less than 150 patients and nine studies included more than 150 patients. The 14 studies together comprised 2533 patients, with sample sizes ranging from 92 to 298 patients. Of them, 1350 patients underwent HR and 1183 patients underwent RFA. Follow-up auxiliary examinations included physical examinations combining with radiographic tests, such as ultrasound, computed tomography, or magnetic resonance imaging. HR: hepatic resection; RFA: radiofrequency ablation; NRCT: nonrandomized controlled trial; Retro: retrospective cohort study; Prosp: prospective cohort study; NOS: Newcastle-Ottawa scale. Data are expressed as mean±SD for quantitative variables with normal distribution or medians (interquartile ranges) for quantitative variables with non-normal distribution Study Study location Trial type Study design HR/RFA Mean tumor size (cm) * * Mean tumor number * * Tumor stages (1–2/3–4) Median follow-up (HR/RFA) * * NOS Barral et al., 2016 2016 France NRCT Retro 60/42 3.5 (2.0–5.0) 1 32.3 (0.9–110.8)/32.3 (0.9–110.8) 7 Carrafiello et al., 2011 2011 Italy NRCT Retro 54/51 5.0 (1.0–12.0) 2.6 69/18 7 Covey et al., 2008 America NRCT Retro 90/71 2.6 (0.6–4.4) 1 19/142 47/25 8 Gunabushanam et al., 2007 2007 India NRCT Retro 58/34 3.0 (0.6–5.7) 2 (1–6) 23 (3–87)/16 (2–63) 8 Kümler et al., 2015 2015 Denmark NRCT Retro 93/55 2.3 3 (1–8) 40 (4–120)/36 (2–113) 7 Lee et al., 2013 2013 Korea NRCT Prosp 112/79 2.5 (0.8–4.8) 1 22 (2–77)/22 (2–77) 8 Livraghi et al., 2001 2001 Italy NRCT Retro 90/99 2.9 (1.9–6.3) 1.6 11/178 60/18 7 Illing et al., 2010 UK NRCT Retro 91/109 ≤3 cm: 63% (126) >3 cm: 37% (74) 2.3 46.3 (1.9–113.3)/46.3 (1.9–113.3) 8 Meloni et al., 2009 2009 Italy NRCT Retro 102/94 2.6±0.8 2 (1–5) 14/182 20/20 7 Sofocleou et al., 2007 America NRCT Retro 143/155 3.0 (0.8–4.6) 2.8 26/272 36 (3–129)/33 (2–87) 7 Treska et al., 2014 2014 Czech NRCT Retro 159/105 5.6±2.0 1 68/29 7 Veltri et al., 2014 2014 Italy NRCT Prosp 130/145 2.5 (0.7–3.3) 2 (1–11) 41.3 (5–138)/41.3 (5–138) 8 Vogl et al., 2015 2015 Germany NRCT Retro 72/55 3.3±0.8 1 6/121 22/22 9 Wong and Cooper, 2016 2016 America NRCT Retro 96/89 1.2 (0.5–3.9) Solitary: 93 Multiple: 92 26/26 7 We estimated the individual ORs of the 14 studies using the methods reported by Parmar et al. ( 1998 1998 ). Nine of these 14 studies provided their ORs directly. For the remaining five studies, three reported the overall number of events, with log-rank statistics or their P values according to which ORs can be calculated fairly accurately; two studies only offered the survival curves and OR had to be estimated by extrapolating information from the graphical representations of these survival curves. Study result report and meta-analysis 2 3.2.1 Impacts of HR and RFA on OS of patients with BCLM The different data acquired from previous studies on the impact of HR and RFA on OS enabled a quantitative aggregation of the survival results. All 14 studies including 2533 patients compared the 3-year OS rate after HR and RFA. The pooled OR of these studies was analyzed using the methods described above. Fig. 2a 2a shows a forest plot of the individual ORs and results from the meta-analysis. The results indicated that the 3-year OS rate after HR was significantly higher than that after RFA (combined OR 0.41, 95% CI 0.29–0.59, P < 0.001), despite the exhibition of significant heterogeneity among studies ( I 2 =73%, P < 0.001). Results are presented as individual and pooled OR and 95% CI The 5-year OS rates after HR and RFA were compared in ten studies consisting of 1951 patients in total. As indicated in Fig. 2b 2b , patients in the RFA group had inferior 5-year OS (combined OR 0.38, 95% CI 0.32–0.46, P < 0.001) when compared with patients in the HR group. The results did not show significant heterogeneity among studies ( I 2 =31%, P =0.16). 3.2.2 Impacts of HR and RFA on DFS of patients with BCLM The different data acquired from previous studies on the impacts of HR and RFA on DFS enabled a quantitative aggregation of the survival results. Twelve studies including 2177 patients were used to compare the difference in the 3-year DFS between HR and RFA. Fig. 3a 3a shows a forest plot of the individual ORs and results from the meta-analysis. These data revealed that the 3-year DFS after HR was significantly higher than that after RFA (combined OR 0.36, 95% CI 0.27–0.49, P < 0.001), in spite of the exhibition of heterogeneity among studies ( I 2 =64%, P =0.001). Results are presented as individual and pooled OR and 95% CI Six studies including 1154 patients were used to compare the difference in the 5-year DFS between HR and RFA. As indicated in Fig. 3b 3b , patients in the RFA group had shorter 5-year DFS (combined OR 0.51, 95% CI 0.40–0.66, P < 0.001) compared with patients in the HR group. The results did not show significant heterogeneity among studies ( I 2 =0%, P =0.75). 3.2.3 Impacts of HR and RFA on short-term outcomes of patients with BCLM 3.2.3.1 Postoperative complications The complications after treatment included jaundice, ascites, biliary duct injury, gastrointestinal bleeding, portal venous thrombosis, hepatic failure, and serious abdominal infection. Nine studies including 1872 patients reported postoperative complications. The results showed that the incidence of postoperative complications occurred more frequently in patients with HR (combined OR 0.30, 95% CI 0.20–0.44, P < 0.001; Fig. 4 4 ) and there existed heterogeneity among the studies ( I 2 =53%, P =0.03). Results are presented as individual and pooled OR and 95% CI 3.2.3.2 Hospital stay Four studies including 755 patients were used to compare the discrepancy in hospital stay between HR and RFA. As indicated in Fig. 5 5 , length of hospital stay was significantly longer in patients with HR (combined OR −9.01, 95% CI −13.49–4.54, P < 0.001), despite the exhibition of significant heterogeneity among the studies ( I 2 =99%, P < 0.001). Results are presented as individual and pooled weighed mean difference (WMD) and 95% CI 3.2.4 Subgroup analysis For the exploration of the source of heterogeneity, subgroup analysis was conducted with respect to study region, sample size, publication year, tumor number, tumor size, distribution of BCLM, pre-hepatectomy therapy, and extrahepatic metastases (Tables 4 4 and 5 5 ). The results showed that sample size ( P =0.016) and extrahepatic metastases ( P =0.033) were associated with heterogeneity in regard to 3-year OS rate; tumor number ( P =0.009), tumor size ( P =0.026), and extrahepatic metastases ( P =0.004) were associated with heterogeneity in regard to the 5-year OS rate; tumor number ( P =0.031), tumor size ( P =0.027), and distribution of BCLM ( P =0.015) were associated with heterogeneity in regard to 3-year DFS; extrahepatic metastases ( P =0.036) were associated with heterogeneity in regard to 5-year DFS. Other factors did not show any heterogeneity. OS: overall survival; OR: odds ratio; CI: confidential interval; Tumor No.: number of liver metastases; Tumor size: diameter of the largest tumor; Pre-hepatectomy therapy: chemotherapy and/or biological therapy and/or hormonal treatment; EM: extrahepatic metastases 2 Stratified analysis 2 No. of studies 2 No. of patients 2 OR (95% CI) 2 P 2 Heterogeneity Fixed Random I 2 (%) P value 3-year OS 14 2533 0.41 (0.29–0.59) <0.001 73 <0.001  Study region 7   Non-Europe 5 927 0.34 (0.14–0.80) 0.010 87 <0.001   Europe 9 1606 0.45 (0.32–0.63) <0.001 52 0.040 4  Sample size   ≤150 5 574 0.46 (0.28–0.77) 0.003 46 0.120   >150 9 1959 0.39 (0.24–0.63) <0.001 80 <0.001 5  Publication year   ≤2010 6 1136 0.77 (0.42–1.41) 0.542 54 0.012   >2010 8 1397 0.51 (0.28–1.01) 0.338 19 0.114 4  Tumor No.   Solitary 5 845 0.48 (0.19–1.22) 0.120 88 <0.001   >1 9 1688 0.37 (0.28–0.50) <0.001 38 0.110 4  Tumor size (cm)   ≤5 12 2164 0.47 (0.19–0.93) 0.303 40 0.178   >5 2 369 0.56 (0.27–1.02) 0.522 69 0.008 5  Distribution of BCLM   Unilobar 8 1548 0.69 (0.37–1.18) 0.212 68 0.022   Bilobar 6 985 0.66 (0.31–1.15) 0.452 33 0.285 8  Pre-hepatectomy therapy   Present 4 657 0.35 (0.19–0.54) 0.174 29 0.253   Absent 10 1876 0.29 (0.16–0.42) 0.069 25 0.108  EM   Yes 5 690 0.56 (0.33–0.98) 0.339 81 <0.001   No 9 1843 0.41 (0.23–0.59) 0.659 22 0.060 8 5-year OS 10 1951 0.38 (0.32–0.46) <0.001 31 0.160  Study region   Non-Europe 3 650 0.27 (0.14–0.70) 0.171 29 0.831   Europe 7 1301 0.33 (0.16–0.63) 0.116 76 <0.001  Sample size   ≤150 3 377 0.36 (0.24–0.74) 0.068 75 <0.001   >150 7 1574 0.33 (0.19–0.62) 0.073 63 <0.001  Publication year   ≤2010 4 844 0.23 (0.12–0.36) 0.093 25 0.253   >2010 6 1107 0.31 (0.19–0.36) 0.077 61 0.003  Tumor No.   Solitary 2 452 0.50 (0.26–0.99) 0.050 63 0.100   >1 8 1499 0.35 (0.28–0.43) <0.001 1 0.420  Tumor size (cm)   ≤5 9 1676 0.26 (0.13–0.74) 0.454 45 0.336   >5 1 275 0.45 (0.16–0.93) 0.214 90 <0.001 8  Distribution of BCLM   Unilobar 6 1114 0.79 (0.47–0.85) 0.303 11 0.552   Bilobar 4 837 0.41 (0.16–0.77) 0.872 27 0.257 8  Pre-hepatectomy therapy   Present 2 263 0.45 (0.29–0.73) 0.081 45 0.112   Absent 8 1688 0.51 (0.32–0.86) 0.163 26 0.069 8  EM   Yes 3 501 0.33 (0.22–0.47) <0.001 51 0.130   No 7 1450 0.41 (0.33–0.50) <0.001 26 0.230 DFS: disease-free survival; OR: odds ratio; CI: confidential interval; Tumor No.: number of liver metastases; Tumor size: diameter of the largest tumor; Pre-hepatectomy therapy: chemotherapy and/or biological therapy and/or hormonal treatment; EM: extrahepatic metastases 2 Stratified analysis 2 No. of studies 2 No. of patients 2 OR (95% CI) 2 P 2 Heterogeneity Fixed Random I 2 (%) P value 3-year DFS 12 2177 0.36 (0.27–0.49) <0.001 64 0.001  Study region 7   Non-Europe 4 835 0.23 (0.12–0.46) 0.228 33 0.063   Europe 8 1342 0.53 (0.39–0.76) 0.075 71 0.015 4  Sample size   ≤150 4 482 0.44 (0.26–0.72) 0.455 62 0.031   >150 8 1695 0.74 (0.45–1.08) 0.069 83 0.003 5  Publication year   ≤2010 5 1044 0.47 (0.24–0.68) 0.563 24 0.412   >2010 7 1133 0.52 (0.28–0.79) 0.363 11 0.136 4  Tumor No.    Solitary 4 551 0.34 (0.13–0.72) 0.077 22 0.590   >1 8 1626 0.44 (0.25–0.66) 0.059 81 <0.001 4  Tumor size (cm)   ≤5 10 1808 0.68 (0.33–0.94) 0.325 71 0.007   >5 2 369 0.77 (0.50–1.12) 0.036 90 0.022 5  Distribution of BCLM   Unilobar 6 1192 0.60 (0.37–0.89) 0.239 55 0.014   Bilobar 6 985 0.78 (0.39–0.96) 0.732 12 0.166 8  Pre-hepatectomy therapy   Present 3 448 0.56 (0.38–0.87) 0.066 44 0.357   Absent 9 1729 0.47 (0.33–0.82) 0.139 29 0.073  EM   Yes 5 919 0.44 (0.27–0.74) 0.002 73 0.005   No 7 1258 0.31 (0.21–0.45) <0.001 53 0.050 8 5-year DFS 6 1154 0.51 (0.40–0.66) <0.001 0 0.750  Study region   Non-Europe 3 650 0.45 (0.18–0.72) 0.263 28 0.239   Europe 3 504 0.53 (0.26–0.84) 0.532 63 <0.001  Sample size   ≤150 2 229 0.68 (0.27–1.03) 0.191 25 0.605   >150 4 925 0.41 (0.27–0.93) 0.164 73 <0.001  Publication year   ≤2010 2 459 0.39 (0.24–0.59) 0.174 22 0.257   >2010 4 695 0.23 (0.16–0.57) 0.115 81 <0.001  Tumor No.   Solitary 2 276 0.51 (0.32–0.80) 0.004 0 0.400   >1 4 878 0.51 (0.38–0.69) <0.001 0 0.580  Tumor size (cm)   ≤5 3 390 0.43 (0.16–0.83) 0.059 23 0.807   >5 3 764 0.61 (0.19–0.91) 0.228 61 <0.001 8  Distribution of BCLM   Unilobar 4 836 0.66 (0.28–1.15) 0.181 37 0.590   Bilobar 2 318 0.38 (0.19–0.72) 0.071 32 0.225 8  Pre-hepatectomy therapy   Present 2 400 0.46 (0.29–0.57) <0.001 44 0.075   Absent 4 754 0.53 (0.31–0.79) 0.277 36 0.141  EM   Yes 3 390 0.45 (0.20–0.77) 0.163 64 0.003   No 3 764 0.63 (0.34–0.95) 0.529 12 0.601 Moreover, the subgroup analysis indicated significant relationships existed between the two means of treatment and the 3-year OS rate with respect to tumor number > 1 (OR 0.37, 95% CI 0.28–0.50; Fig. 6a 6a ); between the two means of treatment and 5-year OS rate with respect to tumor number > 1 (OR 0.35, 95% CI 0.28–0.43; Fig. 6b 6b ). Other factors did not alter the impacts of HR and RFA on OS or DFS among patients with BCLM. Results are presented as individual and pooled OR and 95% CI 3.2.5 Publication bias Publication bias was evaluated using the inverted funnel plot approach recommended for meta-analyzes (Nordmann et al., 2012 2012 ). Funnel plots for all comparisons were conducted, and their asymmetry was inspected visually. The shapes of the funnel plots showed that there existed a low potential for publication bias (Figs. 7a–7f 7a–7f ). Moreover, we used an influence analysis to assess the influence of single study on the overall effect. The meta-analysis was not dominated by any individual study, and omitting any one study at a time made no difference. Each point represents a separate study for the indicated association. SE, standard error; OR, odds ratio; MD, mean difference; log[OR], natural logarithm of OR Discussion 1 Metastatic breast cancer is a kind of generalized disease with a poor long-term prognosis (Barral et al., 2016 2016 ). Treatment usually aims to minimize toxicity considering that patients with metastatic breast cancer are somewhat incurable (Zhang and Liu, 2008 2008 ; Treska et al., 2014 2014 ). Although modern systemic oncological therapies such as chemotherapy, hormonal therapy, and biological therapy have been used, median survival for patients with metastatic breast cancer is about 2 years (Yun et al., 2011 2011 ). Some scholars have confirmed that the prognosis of patients with metastatic breast cancer depends largely on the location of metastatic lesions, with bone metastases associated with a longer OS (Ruiterkamp and Ernst, 2011 2011 ). Furthermore, patients with multiple sites of metastases have a somewhat poor prognosis (Treska et al., 2012 2012 ). Liver is the third most frequent site of such metastases following lungs and bones (Golse and Adam, 2017 2017 ). Surgical treatment was considered to be traditional therapy for BCLM. The 3-year OS rate of 49%–53% and 5-year OS rate of 18%–34% for metastatic breast cancer after hepatectomy have been reported (Carrafiello et al., 2011 2011 ). Although there appears to be a survival benefit for BCLM patients undergoing HR, tumor relapse is commonly detected in these patients (Livraghi et al., 2001 2001 ). Moreover, under certain conditions, for instance, complex anatomic location, large tumor size, and poor physical status of patients, HR is not always possible (Gunabushanam et al., 2007 2007 ). RFA, which has the advantages of minimal invasiveness, fewer complications, and high repeatability, has mainly been used for primary hepatic carcinoma that cannot be easily resected, recurrent hepatic tumors after surgery, and for patients unwilling to undergo HR (Covey and Sofocleous, 2008 2008 ). Besides, with advances in the probe technology, imaging-guided location technology (such as computed tomography, ultrasound or magnetic resonance imaging) and artificial hydrothorax, the indications for RFA have been greatly expanded (Meloni et al., 2009 2009 ). Therefore, we perform this meta-analysis in order to evaluate the effectiveness and safety of the two kinds of therapies. Our analysis showed that BCLM patients in the HR group had significantly better 3-year OS (combined OR 0.41, 95% CI 0.29–0.59, P < 0.001) and 5-year OS (combined OR 0.38, 95% CI 0.32–0.46, P < 0.001) than the RFA group. Additionally, the 3-year DFS (combined OR 0.36, 95% CI 0.27–0.49, P < 0.001) and 5-year DFS (combined OR 0.51, 95% CI 0.40–0.66, P < 0.001) were significantly higher among patients after HR. The major contributing factors for this finding might be explained in several ways. Firstly, patients receiving RFA had a higher local recurrence rate than those after resection. Recurrent tumors were more likely to locate around original RFA sites because of the incomplete ablation, heat sink effect, or limitations of the technique (Illing and Gillams, 2010 2010 ). Secondly, small liver as well as peritoneal metastases can often only be recognized under direct visualization intra-operatively because they may not enhance on pre-operative imaging (Bortolotto et al., 2012 2012 ; Lee et al., 2013 2013 ). RFA is mostly directed at primary tumors, but some smaller lesions may be missed. By contrast, HR allows in-depth intraoperative exploration and pathological evaluations, thus making resection of the entire area of pre-existing tumors more possible (Lai et al., 2016 2016 ). A comprehensive understanding of the tumor status should be beneficial for treatment outcomes. Finally, patients who underwent RFA were often not eligible for HR due to their overall poor health condition, inadequate liver function reserve, or extensive tumor burden (Veltri et al., 2014 2014 ). With regard to the comparison of short-term outcomes, we found that RFA is associated with fewer complications (combined OR 0.30, 95% CI 0.20–0.44, P < 0.001) and a shorter hospital stay (combined OR −9.01, 95% CI −13.49–4.54, P < 0.001), indicating that RFA is a relatively safe treatment with minimal invasiveness. Subgroup analysis did not find any discrepancies in regarding to OS and DFS between patients with tumor size ≤5 cm and patients with tumor size > 5 cm; among patients with multiple hepatic metastases, the survival outcomes of HR are superior to those of RFA. We confirm that RFA is effective at controlling liver metastasis in all except those with either very large metastasis or numerous deposits. Sato et al. ( 2006 2006 ) found that the use of RFA to reduce tumor “bulk” was attractive and had been shown to be effective in treating BCLM patients, especially those with small and solitary liver metastasis. It is likely that for larger tumors, to achieve the safe margin, the RFA needle needs to be repositioned for multiple ablation zones, which will increase the chance of an incomplete ablation and the risk of a local recurrence (Keil et al., 2010 2010 ). Due to significant heterogeneity of the included studies, random-effects models were used during the process of pooling data. In the sensitivity analysis, omission of any single study did not help to interpret the source of heterogeneity. We surmised that the heterogeneity of the included studies might be caused by the heterogeneity in study design, patients’ baseline characteristics, follow-up duration, and so on. In addition, during the process of analysis, the method of extrapolating ORs from the studies was also a potential factor that might lead to heterogeneity. The estimated ORs might not be as reliable as those retrieved directly from reported statistics. Because of these, our estimated ORs and 95% CIs with their statistical significance in the reports were compared and any major deviations from the results available in the original studies were not identified. The results of this meta-analysis should be interpreted with caution for several reasons. Firstly, all data in the present study derived from non-randomized studies, and the overall level of clinical evidence was somewhat low. This issue could be interpreted by the reluctance of patients to be randomly assigned, difficulty in balancing the clinicopathological features (disease stage, tumor size, number of hepatic metastasis, extrahepatic disease, and so on), and the huge economic costs of performing the RCT. Secondly, the majority of the enrolled studies were retrospectively performed, which were susceptible to several biases. Thirdly, the clinicopathological features of patients in HR groups might not be comparable to those in RFA groups. Finally, the influence of chemotherapy and some other treatments on the prognosis is indeed important to be analyzed. However, only one study (Livraghi et al., 2001 2001 ) included survival outcomes with regard to whether patients received adjuvant therapies or not. Moreover, the detailed regiments and cycles were not comparable. Further randomized controlled studies might solve this problem and provide sounder clinical evidence. A quality assessment of the studies was performed to avoid several selection biases and ensure the comparability and quality of studies. Unpublished studies and conference abstracts were beyond the scope of our meta-analysis, because the required data were unavailable. Additionally, our analysis only included English studies, due to the fact that other languages were often not available for both the authors and readers. The included number of studies may be somehow insufficient. Conclusions 1 This study suggests that HR has more benefits than RFA in the treatment of patients with BCLM considering the higher OS rates. A significant relationship exists in the 3-year OS and 5-year OS in respect to tumor number >1. Since RFA is relatively simple to perform, gives rise to few complications, can be carried out with shorter hospital stay, and can be safely repeated for recurrent disease, it ought to be used for patients who are not optimum candidates for resection. 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