Does Hepatic Metastasectomy for Breast Cancer Oligo-Metastasis to the Liver Offer Survival Advantage? Systematic Review and Meta-Analysis

Abstract

Background:

The impact of liver resection on survival in patients with hepatic metastasis from breast cancer has remained a controversial topic, with multiple studies reporting conflicting results.

Objective:

We perform this meta-analysis comparing metastasectomy to systemic therapy in terms of survival outcomes in cases of hepatic oligo-metastasis from breast cancer.

Materials and Methods:

A systematic search of PubMed, Embase, and Cochrane Library was conducted for relevant studies. The search terms used included “Breast Neoplasms,” “Liver,” hepatic” “Metastasis” “Hepatectomy,” “Metastasectomy” “resection,” and “surgery.” The primary outcome was overall survival (OS). Only studies published in English and studies that compared OS between patients that had metastasectomy and those that received systemic therapy were included.

Results:

Thirteen studies were included in the meta-analysis. The one year overall survival of patients who had surgery is superior to those who received systemic therapy only, with a risk ratio (RR) of 7.59 and P value of <0.00001. There is also a superior overall survival at 3 years after metastasectomy when compared with patients that received systematic therapy (RR = 2.83, P = 0.005). Five years is also superior, with RR of 2.78 and P value of 0.005.

Conclusion:

Hepatic metastasectomy in combination with systemic therapy is superior to systemic therapy alone in patients with breast cancer and oligo-metastasis of the liver.

Introduction

Breast cancer is the most common cancer among female patients, and in 2020, it was reported as the cancer with the highest incidence by the latest World Health Organisation (WHO) report.[1,2] Reports have shown that up to 30% patients diagnosed with breast cancer will have regional lymph node involvement, while about 5% will have metastatic disease at presentation.[3,4] However, most reports from Sub-Saharan Africa revealed that about 25%–47% of patients have metastatic disease at the time of presentation.[5,6] The most common sites of metastasis in breast cancer are the skeletal system, followed by lungs, then the liver.[7,8] However, in West African patients, Adisa et al.[9] reported that the most common site of metastasis is the liver, then lungs and pleural tissues.

The prognosis of patients with metastatic breast cancer is poor, with a 5-year survival rate of 25%–29% from the time of diagnosis of the metastasis.[3,10] These findings were not replicated in our settings, as most studies in Sub-Saharan Africa report a 5-year survival rate of around 10%–15% from the time of appearance of metastasis.[5,6,9] Oligo-metastatic breast cancer is defined as a form of metastatic breast cancer with less than five metastatic lesions that are in close proximity such that the lesions can be treated by local ablative therapies such as surgical resection or radio frequency ablation.[11,12,13]

The current gold standard treatment for metastatic breast cancer is systemic chemotherapy, targeted therapy, immunotherapy, and/or hormonal therapy.[14,15] However, in patients with isolated hepatic oligo-metastasis, some have advocated local treatment (in addition to the systemic therapy) targeting the lesions if the primary disease has been controlled.[7,8] The available therapeutic options vary from surgical resection to nonsurgical treatment such as ablation, stereotactic radiotherapy, intrahepatic chemotherapy, and embolisation.[8] Initial studies comparing these interventions with systemic therapy have been published, but the findings were inconsistent and limited by retrospective nature of the studies, single-centre design, and small cohorts of patients.[16,17,18] A couple of meta-analyses[19,20] were also done, but some of the studies included in these meta-analyses compared resection and radiofrequency ablation (RFA) to systemic therapy. Due to the lack of RFA in our setting, we felt the need for a meta-analysis that compares surgical resection to systemic therapy in the treatment of patients with isolated liver oligo-metastases from breast cancer.

We perform this meta-analysis comparing hepatic metastasectomy to systemic therapy only in terms of survival outcomes in cases of isolated hepatic oligo-metastasis from breast cancer.

Materials and Methods

We performed this systematic review in compliance with the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guideline. The protocol for the review was prospectively registered in the International Prospective Register of Systematic Reviews, PROSPERO (CRD42024497558).

Search strategy

Two independent reviewers searched the following electronic databases: PubMed, Embase, Web of Science, Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov. The search terms used include “Breast Neoplasms,” “breast cancer,” “breast,” “Liver,” hepatic” “Metastasis”, Öligo-metastasis,” “Hepatectomy,” “Metastasectomy” “resection,” and “surgery.”

The search terms were combined with the use of Boolean logic. Related articles and reference lists were searched for the completeness of the search. The conflict was resolved by involving a third researcher.

Study selection criteria

The inclusion criteria for a study to be included in the review are as follows: 1. All published studies that compared the outcome of hepatic resection/metastasectomy to systemic therapy in patients with isolated hepatic oligometastasis from breast cancer. 2. Studies with full texts.

The exclusion criteria are as follows: 1. Conference presentations, editorials, and commentaries. 2. Absence of relevant data for comparison

Quality assessment and risk of bias assessment

Quality assessment was done using the Newcastle–Ottawa scale (NOS) for the assessment of case control studies. The NOS included three categorical criteria with a maximum score of 9 points. The quality of each study was rated using the following scoring algorithms: ≥7 points were considered as “good,” 2–6 points were considered as “fair,” and ≤1 point was considered as “poor” quality.

Publication bias

If 10 or more studies were included in the meta-analysis of a particular outcome, then publication bias was evaluated using the funnel plot recommended by the Cochrane handbook.

Data extraction

Data extraction was performed by two independent researchers. The following information was extracted from each study: First author, year of manuscript publication, study design, number of patients in each group, gender of patients per group, mean age, time from treatment of primary disease to appearance of metastasis, size of metastatic lesion, number of lesions, lobe of the liver affected, type of resection, and outcome data. In cases of conflicts between the two researchers, a third researcher is involved to resolve the conflict.

Outcome

The primary outcome of interest is the overall survival from the time of diagnosis of hepatic metastasis.

Statistical analysis

Statistical analyses were done using RevMan software (version 5.4.1). If the variable is dichotomous, the pooled risk ratio (RR) was calculated with 95% confidence interval. However, if the variable is continuous, the weighted mean difference (WMD) or standardised mean difference (SMD) with 95% CI was calculated from the mean and standard deviation reported from individual studies. If a study did not report the mean and standard deviation, the Wan et al. method of extracting mean and standard deviation from the median and interquartile range was utilised. Fixed-effects model was used to calculate the pooled effect sizes if the data were not significantly heterogeneous. Otherwise, a random-effects model was used. Heterogeneity was assessed using the I² statistics. I² > 50% was considered as a statistically significant heterogeneity. Sensitivity analysis was done by sequential elimination of each of the included studies in the meta-analysis to identify the main source of heterogeneity. Funnel plot and Egger’s test will be used to assess publication bias if 10 or more studies were included in the meta-analysis of a particular outcome.

Results

Results were reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist.

Study selection process and description of selected studies

We identified 1239 references during the initial search. Out of these, 1062 articles were excluded because of duplicate publications [Figure 1]. The 177 remaining references were further assessed in terms of title and abstracts. A total of 146 were excluded for lack of relevant data. Thirty-one full-text articles were retrieved, but 18 articles were excluded for lack of complete data. Thirteen studies[16,17,18,21,22,23,24,25,26,27,28,29,30] were included for the data synthesis and meta-analysis. Details of selected studies are displayed in Table 1.

Figure 1.

Study selection criteria

Table 1.

Characteristics of included studies

S/N	Author	Year of publication	Sample size per group		NOS Score	Quality of the study
			Surgery	Systemic therapy
1	Abbas et al.	2017	23	27	7	Good quality
2	Chen et al.	2022	89	1027	7	Good quality
3	Chun et al.	2020	72	72	8	Good quality
4	Dittmar et al.	2013	34	6	7	Good quality
5	Ellis et al.	2021	90	2805	6	Fair quality
6	Feng et al.	2020	33	119	7	Good quality
7	Mariani et al.	2013	51	51	8	Good quality
8	Polistina et al.	2013	12	14	8	Good quality
9	Ruiz et al.	2019	49	49	8	Good quality
10	Sadot et al.	2016	69	98	7	Good quality
11	Sunden et al.	2020	29	29	8	Good quality
12	Treska et al.	2014	13	11	7	Good quality
13	Weinrich et al.	2014	21	8	6	Fair quality

NOS: Newcastle–Ottawa scale

Sociodemographic variables

Pooled analysis of the two groups did not show any statistical significance in age distribution. (SMD = 0.43, P = 0.74) The mean age of patients in the metastasectomy group was 47.58 ± 8.92 years. The patients that had systemic therapy had a mean age of 49.23 ± 5.04 years.

Baseline characteristics of hepatic metastasis

Pooled analysis of the baseline characteristics of the liver metastasis of the two groups showed that there is no statistically significant difference between the groups when the interval from diagnosis of breast cancer to the time of appearance of liver metastasis was compared. For the patients in the metastasectomy group, the median interval from diagnosis of breast cancer to appearance of liver metastasis was 38.1 months, while for the patients that received systemic therapy only, the median time of diagnosis was 42.34 months from the time of diagnosis of breast cancer. This difference was not statistically significant, with a P value of 0.25 and a standardised mean difference (SMD) of 1.16.

The pooled analysis also revealed that the two groups did not display any significant difference in the size of the metastasis (SMD = 0.26, P = 0.80). The mean size of the liver lesion in the metastasectomy group was 3.8 cm, which is similar to the size of 3.13 cm observed among patients that had systemic therapy only.

The number of patients with solitary hepatic metastasis was also assessed, and we found that for patients that had metastasectomy, up to 49.5% of them had solitary hepatic metastasis at the time of diagnosis, while about 42.6% of patients that had systemic therapy only had solitary liver metastasis at the time of diagnosis. The difference was, however, not significant, with RR of 1.09 and P value of 0.28.

Overall survival after the appearance of liver metastasis

Nine studies[16,17,18,21,22,23,24,28,30] compared the one-year overall survival of patients in the surgery (plus systemic therapy) group to those that received systemic therapy only. The pooled analysis of these studies showed that a total of 382 patients underwent surgery in addition to systemic therapy, compared to 4116 patients who received systemic therapy alone. The one-year overall survival of patients who had surgery was 94.2%, which was superior to the OS of those who received systemic therapy alone, which was 62.4%. The difference was statistically significant, with a RR of 7.59 and P value of <0.00001. The heterogeneity among the included studies was not significant with an I² of 31%, so the fixed effect was used to estimate the pooled effect size. Detailed meta-analysis of 1-year OS is displayed in Figure 2.

Figure 2.

Forest plot comparing overall survival at 1 year

Three-year survival was compared in 10 of the included studies.[16,17,21,22,23,26,27,28,29,30] Our meta-analysis revealed that patients with hepatic oligo-metastasis from breast cancer have superior overall survival at 3 years after metastasectomy (64.3%) when compared with patients that received systematic therapy (29.5%). The difference is statistically significant with a RR of 2.83 and P value of 0.0005. Eleven studies[16,17,18,21,22,23,25,27,28,29,30] reported and compared overall survival at 5 years, and the meta-analysis of these studies revealed that patients with hepatic oligo-metastasis from breast cancer have superior overall survival at 5 years after metastasectomy (40.4%) when compared with patients that received systematic therapy (11.7%). The difference is statistically significant with a RR of 2.78 and P value of 0.0005.

There was significant heterogeneity among studies included in the meta-analysis of 3 and 5-year survival with I² > 50% so the random effect was used in estimating the pooled effect size. Detailed meta-analysis of overall survival at 3 years and at 5 years is displayed in Figures 3 and 4, respectively.

Figure 3.

Forest plot comparing overall survival at 3 years

Figure 4.

Forest plot comparing overall survival at 5 years

Publication bias was assessed for the meta-analysis of overall survivals at 3 years and at 5 years since at least 10 studies were included in the meta-analysis. The publication bias assessment was done by visual inspection of the funnel plot, and it revealed minimal publication bias, which increased the validity of the meta-analysis [Figure 5A and B].

Figure 5.

Funnel plot assessing publication bias. (A) publication bias at 3 years. (B) publication bias at 5 years

Discussion

Metastatic breast cancer is associated with poor prognosis due to reduced quality of life and reduced survival after the appearance of metastasis.[8,10] The commonest site of metastasis is bone, followed by pulmonary metastasis. The liver is the third-most common site of metastasis in patients with breast cancer.[7,8] Studies among sub Saharan African patients, however, do not follow this global trend.[5,6,9,31] Adisa et al.[9] reported that the liver is the most common site of metastatic among Nigerian patients with breast cancer.

The median survival of patients with metastatic breast cancer is between 15 and 29 months from the time of appearance of metastasis with a 5-year survival of 19% in males and about 30% in females.[32] The median and overall survival are affected by the site of metastasis and the number of organs with metastasis. Patients with isolated skeletal metastasis have the best survival among patients with MBC. Lobbezoo et al.[10] reported a median survival of 39.3 months among patients with isolated skeletal metastasis. In the same study, it was reported that patients with isolated hepatic metastasis have the second-worst prognosis with a median survival of 15.7 months. The worst-survival was seen in patients with brain metastasis and patients with multi-systemic metastasis.[10]

The current therapy for metastatic breast cancer is systemic therapy in the forms of chemotherapy, targeted therapy, and hormonal therapy, depending on the pathological characteristics of the tumour.[8] The role of surgery was initially limited to palliative care such as tube thoracostomy for pleural effusion and open fixations of pathological fractures. However, there are recent reports of local ablative therapies targeting patients with isolated mono-systemic metastasis aiming at cure.[21,27,33] The therapeutic options can be surgical or nonsurgical options, such as ablation, stereotactic radiotherapy, intrahepatic chemotherapy, and embolisation.[8]

In patients with isolated hepatic oligo-metastasis, the surgical options include metastasectomy for patients with solitary metastasis or hepatic resection for patients with multiple lesions amenable to resection.[11,23,24] Due to the associated morbidity and mortality associated with hepatic surgery, there is some reluctance in accepting it as an option for treatment, but recent studies have shown significant increase in survival after the surgery, so some surgeons believe it is worth the risks in carefully selected patients.[19,23,34,35] In our meta-analysis, we found that a combination of systemic therapy with hepatic metastasectomy or resection is associated with superior survival at 1, 3, and 5 years after the appearance of liver metastasis.

Most of the studies included reports on patients with hepatic metastasis presented in a metachronous manner after an initial mastectomy for breast cancer. However, Reynolds et al.[33] reported four cases that had isolated hepatic oligo-metastasis at the time of diagnosis of breast cancer. Among the reported patients, one had synchronous mastectomy and hepatectomy in the same setting while the remaining three had mastectomy followed by metastasectomy within 6 months. The outcome of these patients was still favourable with further analysis revealing no difference in long- and short-term outcomes with patients with metachronous hepatic oligo-metastasis.

One of the limitations of this meta-analysis is that there was no comparison of the patients’ performance status and baseline liver functions between the two groups because none of the included studies compared these parameters among the patients. These factors may play a role in the survival of patients after the diagnosis of liver metastasis. There is a need for multicenter randomised controlled trials with consideration of all factors that can affect survival in patients with metastatic breast cancer.

Conclusion

Hepatic metastasectomy for hepatic oligo-metastasis from breast cancer is associated with improved survival when combined with systemic therapy when compared with systemic therapy alone.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.