Immediate lymphatic reconstruction (ILR) for prevention of secondary lymphedema after breast cancer surgery: a systematic review and meta‑analysis

Introduction

The most frequent chronic complication following breast cancer surgery is breast cancer-related lymphedema (BCRL). After 2 years of surgery, the incidence of upper limb lymphedema is reported to be 24% (1), and a higher incidence of lymphedema (up to 38%) has been observed in high-risk breast cancer patients (2). Such factor as radiotherapy, axillary surgery, and a higher body mass index (BMI) are all risk factors for the occurrence of BCRL (1). Since the past decade, as more comprehensive systemic therapy, such as surgery, chemotherapy, local radiotherapy, and especially endocrine therapy and targeted therapy for breast cancer, has been developed, survival rates following breast cancer treatment have shown longitudinal improvement. As a result, an increasing number of breast cancer survivors are now facing long-term adverse effects from their treatment.

Nowadays, BCRL is thought to be an incurable condition, and the primary treatment is nonoperative management with vigorous physiotherapeutic intervention (1). Lymphovenous anastomosis (LVA) is a recognized surgical treatment. When lymphedema occurs, LVA can relieve lymphedema; however, it cannot cure lymphedema (2). Once lymphedema occurs, it can cause great distress to patients and their families and seriously reduce their quality of life. Boccardo et al. first reported the name Lymphatic Microsurgical Preventing Healing Approach (LyMPHA) (3). Now, this is known as immediate lymphatic reconstruction (ILR). ILR is performed immediately after axillary lymph node dissection (ALND) to prevent the development of postoperative lymphedema. Over the past 5 years, an increasing number of cancer centres have used this approach (3-10). The goals of this study are to summarize the current body of evidence on the impact of ILR on the incidence of BCRL, as well as the current opportunities and challenges associated with ILR. We present this article in accordance with the PRISMA reporting checklist (available at https://gs.amegroups.com/article/view/10.21037/gs-2025-40/rc).

Methods

The study was prospectively registered in PROSPERO (CRD42023454441).

Literature search strategy

In October 2024, the meta-analysis was conducted following an extensive search performed in EMBASE, Web of Science and PubMed. We used the following phrases for conducting searches: “Breast Cancer Lymphedema”, “Breast Cancer Related Lymphedema”, “Breast Cancer Treatment Related Lymphedema”, “Breast Cancer Related Arm Lymphedema”, “Postmastectomy Lymphedema”, “Lymphedemas, Postmastectomy”, “Post mastectomy Lymphedema”, “LVA” and “ILR”. A comprehensive overview of the search strategy used can be found in Table S1. Additionally, all the systematic reviews were screened manually for additional references in their reference lists. Following the removal of duplicate entries and conference abstracts, the initial screening was carried out based on the titles and abstracts of the articles.

Identification of eligible studies

Every included study complied with the following requirements: (I) cohort studies or randomized controlled trials; (II) were conducted on breast cancer; (III) involved an ILR operation; (IV) patients had upper limb lymphedema recorded after the operation; (V) the outcome is whether lymphedema occurs; and (VI) reports were published in English. A review, a letter, an editorial comment, a case report, an abstract from a conference, an unpublished article, and an article without data were excluded from the study.

Data extraction and quality assessment

Two researchers independently examined the complete texts of the eligible studies to extract the data. The definition of lymphedema is characterized as persistent swelling in a limb due to impaired lymphatic function (6). We calculated the incidence of upper limb lymphedema based on the number of patients. These characteristics are presented in Table 1. Disagreements between authors were resolved through discussion. We gathered the first author’s name, publication year, location, cohort size, technique, case of upper limb lymphedema, case of ILR and no ILR, and length of follow-up from each eligible study. In addition, the Newcastle-Ottawa Scale (NOS) was used to assess the quality of cohort studies that met the inclusion criteria (23), and the Cochrane Risk of Bias Tool was used to evaluate randomized controlled trials that met the inclusion criteria (24).

Statistical analysis

A comparative meta-analysis was performed for five studies, and odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated to compare the incidence of upper limb lymphedema between the ILR and no ILR groups. In addition, to further explore the effect of ILR on BCRL, data from thirteen studies reporting upper limb lymphedema after ILR were utilized for the meta-analysis of a single proportion of patients. The heterogeneity between the studies was evaluated using the I² statistic. If a P value >0.05 or an I²<50% which suggested that there was no heterogeneity between the studies, a fixed effects model was employed to evaluate the findings (25). In order to obtain more conservative results, a random effects model was selected as an alternative approach (26).

Egger’s test in comparative meta-analysis and Peter’s test in meta-analysis of a single percentage were used to examine publication bias (27,28). The results of these tests were shown in Table 2 with heterogeneity. All data were analyzed in R software (R version 4.4.1) using the meta package (https://CRAN.R-project.org/package=meta), and P values <0.05 were considered to indicate statistical significance.

Results

Literature search

The literature search yielded 616 items, of which 218 were deemed duplicates. After a careful evaluation of the abstracts and titles, 324 entries were removed. Twelve papers that met the qualifying conditions were found after looking through the remaining 74 publications, and they were added to the analysis. The findings are displayed in Figure 1. Twelve full-text articles involving 1,139 patients (794 ILR versus 345 no LVA) were included in the pooled analysis (11-22), of which five studies with control group trials were included in the comparative meta-analysis (11-15). Finally, twelve papers that satisfied the criteria were added to the meta-analysis of the single proportion of patients with BCRL following ILR.

Figure 1 PRISMA flow diagram.

Study characteristics

Table 1 provides a detailed summary of the features of the 12 studies. The studies involved a varying number of participants, ranging from 26 to 281. From 8.3 to 24 months was the range of the mean follow-up period. A total of 6 studies used end-to-end technique to anastomose veins and lymphatic vessels, of which 1 study used multiple end-to-end and end-to-end methods. Two articles discuss the anastomosis of veins and lymphatic vessels through the combined anastomosis, and two studies used end-to-side and end-to-end techniques, and the remaining two articles did not record the anastomosis technique. Seven studies had only ILR experimental groups and no control groups. Four studies received six points on the NOS quality evaluation, six studies received seven points, and one study received eight points. Besides, the randomized clinical trial (13) is assessed by the Cochrane Risk of Bias Tool in Figure S1.

Comparative meta-analysis between IRL and no ILR

The comparative study evaluated the incidence of upper limb lymphedema using data from five trials totalling 803 individuals (458 with ILR and 345 without ILR). The heterogeneity assessment result, with I²=14.6%, P=0.32, indicated no heterogeneity among these studies, justifying the use of a fixed effects model for the analysis. According to the meta-analysis’s findings, there was a significant difference (P<0.001) between the two groups and a decreased risk of upper limb lymphedema in the ILR group compared to the no ILR group (OR =0.14; 95% CI: 0.08–0.24) (Figure 2). Bias analysis using Egger’s test, no bias analysis was found in the results (t=0.7, P=0.54). The results of heterogeneity and publication bias are shown in Table 2, and the results of the funnel plot are shown in Figure S2.

Figure 2 Forest plot of the comparative meta-analysis between ILR and no ILR group. CI, confidence interval; ILR, immediate lymphatic reconstruction; OR, odds ratio.

Meta-analysis of the single proportion of patients with BCRL following ILR

To further examine the precise occurrence of upper limb lymphedema following ILR, after conducting a meta-analysis of a single proportion (Figure 3), we used a random effect model as indicated by the analysis of heterogeneity (I²=57.3%, P=0.007). The detailed information on the heterogeneity and publication bias is presented in Table 2. Publication bias was not found (t=−0.11, P=0.91). The results of the funnel plot are shown in Figure S3.

Figure 3 Forest plot of meta-analysis of single proportion of patients with BCRL following ILR. BCRL, breast cancer-related lymphedema; CI, confidence interval; ILR, immediate lymphatic reconstruction.

As a result, of the 794 patients with ILR following ALND, 66 had upper limb lymphedema in 12 studies, for a total of 8.6% (95% CI: 6–12%).

Subgroup analysis of effect of follow-up time on BCRL after ILR

Based on the mean follow-up time included in the study, the patients were divided into a group with follow-up time of less than 1 year (5 articles) and a group with follow-up time of more than 1 year (6 articles). The result showed that the incidence of BCRL in the group with follow-up time less than one year after ILR was 8% (95% CI: 5–13%), while the incidence of BCRL in the group with follow-up time more than one year after ILR was 11% (95% CI: 7–18%) (Figure 4). However, there was no significant difference between the different follow-up time groups (P=0.4), so it is not possible to determine whether follow-up time is clearly associated with the occurrence of BCRL.

Figure 4 Forest plots of subgroup analyses: follow-up time. CI, confidence interval.

Discussion

Breast cancer, surpassing lung cancer, has become the most common malignancy worldwide (29,30). Certainly, the longitudinal improvement in survival after breast cancer treatment can be attributed to comprehensive systemic therapy, such as surgery, chemotherapy, local radiotherapy, and especially endocrine therapy and targeted therapy for breast cancer (31). Consequently, a growing number of breast cancer survivors are encountering long-term side effects from therapy. Once developed, lymphedema is not fully treatable and can have negative impacts on daily activities, health-related quality of life (HRQoL), and the ability to resume work. With the expansion of literature and experience on using LVA to treat lymphedema (32), it is widely recognized that LVA can reduce the severity of lymphedema. But the long-term impact of LVA on BCRL still needs further research. LVA cannot reverse the occurrence of BCRL, and patients continue to experience lymphedema, but ILR can help reduce the incidence of BCRL. In this study, the comparative analysis yielded significant results indicating that ILR has the potential to prevent BCRL (OR =0.14, 95% CI: 0.08–0.24; P<0.001). This result is consistent with Hill et al.’s study (33) and Cook et al.’s study (6), which show that ILR could reduce the incidence of BCRL. Moreover, we conducted a meta-analysis concentrating on the proportion of patients undergoing ILR, a data set not previously documented in other publications. Based on this single proportion meta-analysis, the occurrence of upper limb lymphedema with ILR was 8.6% (95% CI: 6–12%). This systematic review of the literature provides evidence supporting the immediate performance of the ILR after ALND for preventing BCRL in patients with breast cancer. ILR was found to reduce the incidence of lymphedema.

However, a meta-analysis of 23 studies shows that the incidence of upper limb lymphedema 2 years after breast cancer surgery is 24% (1). It is important to consider that not every postoperative breast cancer patient will develop lymphedema. The indications for ILR should be more selective. Based on previous research (2), we know that radiotherapy, chemotherapy, axillary surgery and high BMI are all high-risk factors for BCRL. And the extent of axillary surgery is closely related to the occurrence of postoperative lymphedema. N.A.C.B.’s article (1) shows that ALND patients experienced higher rates of lymphedema compared to those who underwent sentinel lymph node biopsy (SLNB), highlighting the necessity of de-escalating axillary surgery. The incidence of BCRL among breast cancer patients who underwent neoadjuvant chemotherapy (NAC) and axillary surgery within 3 years is 37.8% (2). With these highly selected breast cancer patients, we could consider ILR while performing ALND. In addition, in the study by Abdelfattah et al. (34), they believe that using indocyanine green (ICG) lymphography immediately after ALND can assist in determining if the patient needs rapid reconstruction. If sufficient lymphatic drainage through the axilla is seen during intraoperative proximal arm and axillary ICG lymphography, there is no need for immediate reconstruction; if there is a substantial disruption of lymphatic flow, lymphatic venous anastomosis is recommended. The use of ICG lymphography technology can better help us identify patients who need to undergo ILR. Although it’s an intriguing concept, the method used is not standardised, which prevents wider use and real-time usefulness.

There are several limitations in this systematic review. Firstly, regarding the diagnosis of lymphedema, BCRL is defined as the relative volume change (RVC) $10% or the weight-adjusted change (WAC) $10% more than 3 months after breast surgery (35), but the definition of lymphedema and lymphedema measurements vary in different literature. In the criteria research, six studies measured lymphedema by measuring the arm volume (13,14,16,18-20). The formula for RVC was recognized as a standardized method for lymphedema quantification in the literature (36). However, Médor et al.’s study (20) used Brørson’s truncated cone formula and the Pero-System (3D Scanner) to measure the arm volume. Five studies defined lymphedema as an increase in limb circumference measurements compared to the contralateral arm (positive if the diameter of the ipsilateral limb is more than 5% larger than the contralateral limb) (11,12,15-17). Moreover, five studies used bioimpedance spectroscopy (11,13,15,16,21), one study used patient-reported symptoms (15), and one study used the arm dermal backflow by ICG lymphography to measure lymphedema (22). This study also did not summarize the specific definition of BCRL, and more clinical research is needed to explore the most appropriate measurement standards. Secondly, the intussusception technique was often used to anastomose lymphatic channels end-to-end to the prepared vein using 9–0 or 10–0 nylon (13,14,16-18). End-to-side anastomosis was used if the vein was bigger than the lymphatic channel (12,21). Multiple end-to-end and other combination anastomotic techniques were also used to anastomose (15,19,20,22). Whether different anastomosis methods will affect lymphatic return still requires further research, and whether the long-term patency of different anastomosis methods varies. Thirdly, previous studies had a follow-up period that was too short, and we have not yet grasped the long-term effects of ILR. This is the reason why follow-up time of less than 1 year or more than 1 year after ILR is not significantly associated with the incidence of BCRL (P=0.33). Future long-term clinical trials may be needed to further demonstrate the preventive effect of ILR on BCRL. Finally, although we proposed performing ILR for patients at high risk of BCRL, the specific threshold for high risk has not been defined.

This systematic review has several limitations. First, the sample size was small, and only five research studies qualified for comparison analysis. The limited sample size restricts the ability to draw definitive conclusions from funnel plots. The final meta-analysis outcome required more qualifying research. Secondly, although we used a meta-analysis of a single proportion to further figure out the incidence of BCRL following ILR, the approach was not of high quality. The publication bias in the meta-analysis of single proportion was not found (P=0.91), however, eight of the twelve included articles were retrospective studies, which increases the meta-analysis’s vulnerability to confounding variables and selection bias, potentially leading to publication bias. The final meta-analysis outcome required more randomized clinical trials. And the heterogeneity is significant, which may be caused by factors such as uneven sample sizes and the experience of the surgeon. Additionally, the outcome variables and measurements were not standardized. A total of 5 studies used volumetry to measure lymphedema, 5 studies used limb circumference, only one used the ICG lymphography to determine the arm dermal backflow, and one identified by bioimpedance spectroscopy. Lymphedema typically manifests approximately one year after the surgery. Roughly 75% of patients experience the development of lymphedema within three years following a lymphatic injury (1,33). Five of the twelve included articles had a follow-up that was shorter than a year on average. Given the short follow-up period, a greater percentage of these people will probably eventually develop lymphedema.

Conclusions

There is a definite indication that ILR is beneficial in preventing BCRL. This might be a helpful intervention for improving the quality of life of breast cancer survivors.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://gs.amegroups.com/article/view/10.21037/gs-2025-40/rc

Peer Review File: Available at https://gs.amegroups.com/article/view/10.21037/gs-2025-40/prf

Funding: This study was supported by the National Natural Science Foundation of China (No. 82373380) and Guangdong Yiyang Healthcare Charity Foundation (No. JZ2023027).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://gs.amegroups.com/article/view/10.21037/gs-2025-40/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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