Axillary Lymph Node Dissection With and Without Immediate Lymphatic Reconstruction: Association With Drain Days and Seromas

Abstract

Background: Immediate lymphatic reconstruction (ILR) via lymphovenous anastomosis is performed in patients undergoing axillary lymph node dissection (ALND) to minimize the risk of lymphedema. Following ALND, drains are placed to prevent seromas, while prolonged drain days are associated with increased risk of infection. The study aim was to determine the impact of ILR on the number of drain days following ALND in patients with breast cancer.

Methods: We report a post-hoc analysis of a prospective trial (April 2018-January 2023) comparing patients with breast cancer who underwent ALND with ILR (intervention arm) vs ALND without ILR (control arm). Wilcoxon rank sum test and chi-squared or Fisher’s exact tests compared continuous and categorical variables, respectively. Multivariable quantile regression models evaluated the difference in drain days and days until drain removal criteria were met with covariates adjusted.

Results: Data from 214 patients were analyzed (n = 115 interventional arm, n = 99 control arm). The intervention arm had a median of 15 axillary drain days compared to 11 days in the control arm (P = .001). There was no significant difference between groups when measuring drain days based on the date the drain met removal criteria, rather than actual drain removal date. Seroma incidence was lower in the intervention arm (3.5%) vs the control arm (12.1%) (P = .017) without a statistical difference in incidence of infection.

Conclusion: ALND with ILR does not decrease the number of drain days compared to ALND without ILR in patients with breast cancer, although we found the incidence of seromas to be lower without increase in incidence of infection.

Keywords

LYMPHA lymphovenous bypass lymphaticovenous anastomosis breast cancer breast cancer-related lymphedema (BCRL)surgical site infection

Key Takeaways

• Immediate lymphatic reconstruction (ILR) is performed at the time of axillary lymph node dissection (ALND) to decrease the risk of lymphedema, but the relationship between ILR and other postoperative events is unclear.

• In our cohort of patients with breast cancer, ALND with ILR did not decrease the number of drain days compared to ALND without ILR, although the incidence of seromas was lower with no difference in incidence of infection.

• As ongoing trials examine the relationship between ILR and lymphedema outcomes, our findings suggest that ILR is safe in the context of other frequently reported postoperative complications.

Introduction

Axillary lymph node dissection (ALND) is a well-known cause of secondary lymphedema in patients with breast cancer.^1,2 Breast cancer-related lymphedema (BCRL) leads to progressive functional impairment with a significant burden on affected patients and the health care system.^3,4 In an effort to decrease the incidence and severity of BCRL, immediate lymphatic reconstruction (ILR) via lymphovenous anastomosis has been proposed as a method to decrease lymphedema associated with lymphadenectomy.^5,6 Despite more patients undergoing ALND with ILR, there remains a gap in the literature regarding the impact of ILR on clinically relevant postoperative events beyond lymphedema. This is particularly true for postoperative drain outcomes.

Following ALND, it is standard practice to place closed-suction axillary drains to prevent seroma formation.⁷ Several studies have analyzed the optimal timing for drain removal following ALND, balancing seroma formation vs prolonged drain days and higher risk of surgical site infection (SSI), although there are no consensus recommendations.^8,9 From the patient perspective, a shorter drain period is correlated with improved comfort and recovery.¹⁰ Adopting new procedures can have unanticipated secondary outcomes. Given that length of drain days may influence patient satisfaction, infections, seromas, and other outcomes, drain timelines should be studied in the setting of new axillary or breast interventions.

It has been hypothesized that restoration of lymphatic channels would decrease the accumulation of fluid in the surgical space.^11-14 We therefore suspected that length of drain days would be decreased in the setting of ILR. To the best of our knowledge, the only publication that directly assesses the role of ILR in postoperative drainage is a small retrospective study reported by Lin et al with a specific focus on drain output within 3 postoperative days after ALND.¹² We are not aware of any studies that report or discuss the relationship between ALND with ILR and total postoperative drain days, incidence of seroma formation, and incidence of SSI.

The primary aim of this study was to determine the impact of ILR on the number of postoperative drain days following ALND in patients with breast cancer. Secondary aims were to determine the impact of ILR on the incidence of postoperative seroma formation and infection. We hypothesized that patients who underwent ALND with ILR would have fewer postoperative drain days and decreased incidence of seroma, without a measurable difference in infections compared to patients who underwent ALND without ILR.

Materials and Methods

Study Design

This study was a post-hoc analysis of a two-site prospective pragmatic study of ALND with or without ILR, employing cohort assignment at the individual surgeon level, based on breast surgeon’s preferred standard practice of ALND with or without ILR and thus functionally similar to a 2-arm cluster-randomized design (NCT03428581).¹³ The primary study’s aim was to compare lymphedema rates between the intervention and control arm. Our current post-hoc analysis explores the impact of ILR on postoperative drain days. Exclusion criteria for the prospective study included prior ipsilateral ALND, prior ipsilateral axillary radiation, history of lymphedema and pregnancy. Patients were enrolled between April 2018 and January 2023. The study was approved by the institutional review board (IRB) at both sites, and consent was obtained from all the participants. Axillary lymph node dissection and ILR techniques are described in the methods section of the primary manuscript.¹³

Herein, we report on patients with breast cancer who underwent ALND between April 5, 2018, and January 3, 2023. Study groups presented in this trial are based on actual treatment received. Patients were excluded from this post-hoc analysis if they did not receive the intended treatment or the date of drain removal was not clearly defined. Number and location of surgical drains (breast or axilla), date drain met criteria for removal, date of drain removal, seroma formation, and surgical site infection were retrospectively extracted from the electronic medical records (EMRs). All other variables (Table 1) were obtained prospectively at the time of the study. Total drain days were quantified as the number of days between the date of ALND and the removal of the drain. If a drain had to be replaced, days with the new drain were included in the total drain days. To account for delays in drain removal, we also analyzed the number of days between the date of ALND and the date the drain met criteria for removal. This information was gathered from records of patient phone calls, portal messages, and follow-up notes in EMR. Patients met criteria for drain removal when output was <30 cc for 2 consecutive days, which is standard for our institution. Separate analyses were run using the axillary drain and the last drain removed (axillary or breast wound). Seromas and surgical site infections were documented when they occurred within 90 days of the date of surgery.

Table 1.

Demographic, Staging, and Pathologic Data.

	A. ALND w/ILR (N = 115)	B. ALND (N = 99)	Total (N = 214)	P-Value
Age				.51
n	115	99	214
Median: years (range)	57.8 (28.5, 78.7)	55.8 (28.9, 78.2)	56.9 (28.5, 78.7)
Sex				.92
Female	114 (99.1%)	98 (99.0%)	212 (99.1%)
Male	1 (0.9%)	1 (1.0%)	2 (0.9%)
Race				.89
White	96 (88.1%)	85 (89.5%)	181 (88.7%)
African American	3 (2.8%)	3 (3.2%)	6 (2.9%)
Other	10 (9.2%)	7 (7.4%)	17 (8.3%)
Missing	6	4	10
BMI				.64
n	115	99	214
Median: kg/m² (range)	28.4 (16.6, 68.4)	29.3 (16.5, 54.8)	28.8 (16.5, 68.4)
Smoking history				.39
Never	73 (63.5%)	73 (73.7%)	146 (68.2%)
Former smoker (quit <6 weeks ago)	1 (0.9%)	1 (1.0%)	2 (0.9%)
Former smoker (quit >6 weeks ago)	32 (27.8%)	21 (21.2%)	53 (24.8%)
Current/active smoker	9 (7.8%)	4 (4.0%)	13 (6.1%)
Clinical T category (AJCC 8th ed)				.008
T0	13 (11.3%)	3 (3.0%)	16 (7.5%)
T1	21 (18.3%)	14 (14.1%)	35 (16.4%)
T2	38 (33.0%)	29 (29.3%)	67 (31.3%)
T3	23 (20.0%)	29 (29.3%)	52 (24.3%)
T4	20 (17.4%)	17 (17.2%)	37 (17.3%)
Recurrent	0 (0.0%)	7 (7.1%)	7 (3.3%)
Clinical N category (AJCC 8th ed)				.002
N0	1 (0.9%)	5 (5.1%)	6 (2.8%)
NI	92 (80.0%)	58 (58.6%)	150 (70.1%)
N2	6 (5.2%)	10 (10.1%)	16 (7.5%)
N3	16 (13.9%)	19 (19.2%)	35 (16.4%)
Recurrent	0 (0.0%)	7 (7.1%)	7 (3.3%)
Pathologic N category				.65
N0	19 (16.5%)	15 (15.2%)	34 (15.9%)
N1	51 (44.3%)	39 (39.4%)	90 (42.1%)
N2	27 (23.5%)	31 (31.3%)	58 (27.1%)
N3	18 (15.7%)	14 (14.1%)	32 (15.0%)
Indication for ALND				.45
Missing	1	0	1
Primary	100 (87.7%)	90 (90.9%)	190 (89.2%)
Recurrence	14 (12.3%)	9 (9.1%)	23 (10.8%)
Neoadjuvant chemotherapy				.16
No	43 (37.4%)	28 (28.3%)	71 (33.2%)
Yes	72 (62.6%)	71 (71.7%)	143 (66.8%)
Neoadjuvant endocrine therapy				.88
No	95 (82.6%)	81 (81.8%)	176 (82.2%)
Yes	20 (17.4%)	18 (18.2%)	38 (17.8%)
Adjuvant chemotherapy				.84
No	85 (73.9%)	72 (72.7%)	157 (73.4%)
Yes	30 (26.1%)	27 (27.3%)	57 (26.6%)
Level of axillary dissection				.45
I	2 (1.5%)	0 (0.0%)	2 (0.9%)
I-II	121 (92.4%)	91 (92.9%)	212 (92.6%)
I-III	8 (6.1%)	7 (7.1%)	15 (6.6%)
Positive LN at ALND				.92
No	25 (21.7%)	21 (21.2%)	46 (21.5%)
Yes	90 (78.3%)	78 (78.8%)	168 (78.5%)
Total no. of positive LNs at ALND				.30
n	115	99	214
Median (range)	2 (0, 30)	3 (0, 30)	2 (0, 30)
Total no. of LNs pathologically identified at ALND				.001
n	115	99	214
Median (range)	22 (7, 63)	18 (4, 48)	20 (4, 63)
Breast surgery performed with ALND				.014
None	22 (19.1%)	19 (19.2%)	41 (19.2%)
Lumpectomy	28 (24.3%)	9 (9.1%)	37 (17.3%)
Mastectomy with reconstruction	19 (16.5%)	28 (28.3%)	47 (22.0%)
Mastectomy without reconstruction	46 (40.0%)	43 (43.4%)	89 (41.6%)

Bolded numbers are p < 0.05 and noted to be statistically significant.

Statistical Analysis

Categorical variables were summarized as frequency (percentage) and continuous variables were reported as median (range) and interquartile range. Continuous variables were compared between groups using the Wilcoxon rank sum test while categorical variables were compared using the chi-squared test or Fisher’s exact test. Multivariable quantile regression models predicting the 25th, 50th, and 75th percentiles of drain days were used to evaluate the difference in drain days and days until drain removal criteria were met between the 2 arms with baseline covariates adjusted. Linear models were not used due to skewed distribution of drain data. Based on the low number of events, descriptive analysis was used to report the incidence of seromas and infections. All tests were two-sided with P value <.05 considered statistically significant. The analysis was done using R4 version 1.3 (R Foundation for Statistical Computing, Vienna, Austria, https://www.R-project.org/).

Results

The trial enrolled 250 patients, 230 of which had breast cancer. Of the 131 who proceeded to surgery with intent to perform ILR, 115 (87.8%) were able to be performed. Thus, inclusion criteria were met by 214 patients with breast cancer, including 115 patients who underwent ALND with ILR in the study cohort and 99 patients who underwent ALND without ILR in the control cohort (Figure 1). Patient baseline characteristics are shown in Table 1. The median age was 56.9 years (range, 28.5-78.7 years). Of these patients, 212 (99.1%) were female and 181 (88.7%) were White. Median BMI was 28.8 and not significantly different between the 2 cohorts.

Patients undergoing ALND for breast cancer in the current era typically have fairly advanced and/or systemic therapy resistant disease, as is reflected in our population (Table 1). The vast majority of patients underwent ALND for gross clinical disease (171/214, 79.9%) and only 39 (18.2%) for a positive SLN, frequently a persistently positive SLN despite neoadjuvant chemotherapy. Despite 77% receiving neoadjuvant systemic therapy, 43% had ypN2-3 nodal disease including 16% with 10 or more positive LNs. The primary clinical tumor size was >2 cm in 163 (76.2%) patients and 23 (10.8%) presented with recurrent disease as an indication for ALND. The study cohort had a higher number of axillary LNs pathologically identified at ALND (22 vs 18, respectively, P < .001). There was a significant difference in distribution of breast operations performed at the time of ALND between groups (P = .014). In the entire cohort, 89 (41.6%) patients underwent mastectomy with reconstruction, 47 (22.0%) underwent mastectomy without reconstruction, and 37 (17.3%) underwent lumpectomy at the time of ALND, while 41 (19.2%) patients underwent ALND alone.

Drain characteristics and outcomes are shown in Table 2. Consistent with our institutional guidelines, the median drain output was 30 cc or less in the 24 h prior to drain removal for both groups. On the ipsilateral side of the ALND, the study cohort had a median of 1.0 drain while the control cohort had a median of 2.0 (P < .001). For the time between surgery and last drain removed, the study arm had significantly higher median drain days compared to the control arm (15 vs 13, respectively, P = .003). Similarly, for the axillary drain, there was a significant difference between cohorts with a median of 15 drain days (range 3-69) in the study arm vs 11 drain days (range 3-45) in the control arm (P = .001) (Figure 2(A)). Since many factors can influence the date of drain removal after criteria have been met, we next evaluated the median number of days from the date of surgery to the date the drain met removal criteria. There was no statistical difference between the groups when measuring drain days based on the date the axillary drain (Figure 2(B)) or last drain removed met removal criteria, rather than actual drain removal date.

Table 2.

Drain Characteristics and Outcomes.

	A. ALND w/ ILR (N = 115)	B. ALND (N = 99)	Total (N = 214)	P-Value
No. of drains on ipsilateral side of ALND				<.001
n	115	98	213
Median (range)	1 (1, 2)	2 (1, 2)	1 (1, 2)
Days from surgery to date of removal of the last drain removed (breast wound or axillary)				.003
n	108	95	203
Median (range)	15 (3, 69)	13 (3, 45)	14 (3, 69)
Q1, Q3	11, 24	10, 16	10, 21
Days from surgery to date of axillary drain removal				.001
n	95	90	185
Median (range)	15 (3, 69)	11 (3, 45)	14 (3, 69)
Q1, Q3	10, 24	9, 16	9, 20
Days from surgery to date that removal criteria were met for the last drain removed (breast wound or axillary)				.34
n	89	91	180
Median (range)	12 (2, 38)	11 (3, 45)	11 (2, 45)
Q1, Q3	8, 20	8, 15	8, 17
Days from surgery to date that removal criteria were met for the axillary drain				.19
n	74	86	160
Median (range)	10 (2, 38)	10 (3, 45)	10 (2, 45)
Q1, Q3	8, 20	7, 14	7, 16
Incidence of seroma formation	4 (3.5%)	12 (12.1%)	16 (7.5%)	.017
Incidence of SSI	2 (1.7%)	3 (3.0%)	5 (2.3%)	.53

Bolded numbers are p < 0.05 and noted to be statistically significant.

Next, we assessed axillary drain removal outliers between groups by quantile. Univariate quantile regression for the axillary drain predicted the intervention cohort to have a higher number of drain days at the 50th percentile (+4 days, range −1.62-5.12) and 75th percentile (+7 days, range 2.38-14.23, P = .002) (Table 3). Comparatively, univariate analysis predicted the intervention cohort to have a higher number of axillary drain days at the 75th percentile only (+7 days, range −3.02-12.02, P = .022) when using the date that axillary drain met criteria for removal as the endpoint (Table 3).

Table 3.

Predicting the Difference in Axillary Drain Days and Days to Meeting Removal Criteria by Quantile Regression Analysis.

	25th Percentile		50th Percentile		75th Percentile
	Est. 95% CI	P-Value	Est. 95% CI	P-Value	Est. 95% CI	P-Value
Days from surgery to date of axillary drain removal
Univariate analysis	1 (−1.12, 5.49)	.4	4 (−1.62, 5.12)	.003	7 (2.38, 14.23)	.002
Multivariate analysis*			4 (−2.46, 5.46)	.003	6 (−0.23, 14.23)	.006
Days from surgery to date that axillary drain removal criteria were met
Univariate analysis	1 (−4.02, 1.00)	.2	0 (−5.22, 5.22)	>.99	7 (−3.02, 12.02)	.022
Multivariate analysis*					6 (0.0, 10.0)	.038

Bolded numbers are p < 0.05 and noted to be statistically significant.

On univariate quantile regression analysis, significant covariates included ALND indication being recurrent disease, which was significant at the 75th percentile of days from surgery to date axillary drain removal criteria was met (+9 days, range 4.61-29.4, P = .037) and mastectomy with reconstruction at the time of ALND, which was significant at the 50th and 75th percentiles of days from surgery to date of axillary drain removal (−5 days, range −8.77 to −1.23, P = .027 and −10 days, range −12.37 to −3.51, P < .001, respectively). When adjusting for respective significant covariates on multivariable quantile regression analysis, all univariately significant increases in predicted drain days for the intervention cohort persisted (Table 3).

The incidence of postoperative seroma was different between groups: 3.5% (4/115) in the intervention cohort and 12.1% (12/99) in the control cohort (P = .017). There was no difference in incidence of infection between the groups (1.7% intervention vs 3.0% control, P = .53).

Discussion

In our cohort of patients with breast cancer, ALND with ILR did not decrease the number of postoperative drain days or the number of days until the drains met criteria for removal. Although the study cohort demonstrated a higher median number of drain days, this result was no longer statistically significant when accounting for the date that the drain met criteria for removal. This suggests a theme of delays in drain removal despite meeting criteria, which may be due to patient schedule, access to care, delays in communication of drain status, and/or care team schedule.

Importantly, the incidence of seroma was lower in participants who underwent ALND with ILR without a meaningful difference in incidence of infection. Documentation of seroma incidence after breast surgery varies considerably based on the extent of breast and axillary surgery (3-50%).^7,14-17 Seromas develop from accumulation of serous fluid in surgical dead space; thus, it makes sense that restoring lymphatic flow from the surgical field to the systemic venous circulation with ILR would decrease seroma occurrence as seen in our study.^15,18 However, the contradictory predictive models of more patients in the high outlier status of prolonged drain output at the 50th and 75th percentiles make these results less intuitive and counter our hypothesis. While an explanation for this finding is not entirely clear, the addition of ILR to the operation often indicates involvement of microvascular-trained surgeons, who will typically take ownership of the drain in this scenario. The workflow for having drain removal among the different specialties when criteria are met could be slightly different. It is also possible that the suction from the drain on the closed axillary space could cause a prolonged leak from the lymphovenous anastomosis in a few patients and preferential flow to the negative pressure of the drain over the venous output. Lastly, participants who underwent ALND with ILR were more likely to have 2 drains, which could contribute to fewer postoperative seromas.

There is currently no conclusive evidence that ILR decreases the incidence of seroma or that there is any relationship between ILR and drain days. A study by Lin et al on 76 patients with breast cancer proposed that ALND with ILR decreased drain volume in the first three postoperative days and found no difference in seroma occurrence when compared to the non-ILR group.¹² Similar to our findings, the incidence of seroma did not seem to be associated with changes in drain output or drain days in their study.¹² It is difficult to evaluate our findings in the context of existing ALND literature given that drain removal criteria (mL/24-hour periods or time-controlled recommendations) and management vary by institution.^8,19,20 Variability in drain management is a barrier to multicenter studies or meta-analyses and indicates the need for standard protocols following breast and axillary operations.^8,19,20

In conclusion, while reducing lymphedema rates is the primary goal of adding ILR to ALND, our study suggests that ILR is safe in the context of other serious, although less feared, postoperative complications. Further, despite no statistically significant decrease in number of drain days, ALND with ILR may be beneficial in preventing seromas without increasing SSI. Future prospective studies are needed to make definitive recommendations for postoperative drain management in patients undergoing ALND with or without ILR.

The strength of our study is the large number of patients accrued in a 2-site, 2-cohort prospective with similar drain education, postoperative instructions, and criteria for drain removal. Limitations include drain days, seroma, and SSI data collected as a post-hoc analysis. Capture of daily drain output would allow for a more ideal analysis. While all patients maintained daily drain output logs, which were used to guide drain removal, these logs were not uploaded to their records. Thus, our analysis was limited to the number of days when the drain output was <30 cc/day, which was recorded in each EHR. We also demonstrated date of drain removal does not necessarily reflect the day criteria for removal was met. We attempted to address this discrepancy by recording the first indication (portal message, documented phone call, and visit notes) that the patient met criteria for drain removal, as well as date of actual drain removal. Further, the absence of standardized guidelines for optimal timing and criteria for drain removal poses a challenge in comparing our results to existing literature and generalizing results in broader clinical practice. Finally, as addressed in the primary manuscript, techniques to verify the patency of the lymphatic-venous anastomoses following ILR were rarely used, which should be considered when interpreting this data.¹³

Conclusions

In our cohort of patients with breast cancer, ALND with ILR did not decrease drain days or the days until patients met criteria for drain removal. Predicted drain days at the 75th percentile was higher in patients who underwent ALND with ILR vs ALND alone. However, incidence of seroma was lower in patients who underwent ALND with ILR without a difference in infection. Given the primary goal of ILR, if ILR is established to reduce lymphedema rates in future prospective randomized trials, the secondary potential consequences of drain days, seroma, and SSI rates should not be a barrier to adoption.

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

Dr Judy C. Boughey receives research support paid to her institution from Eli Lilly and SymBioSis and is on a DSMB for CairnSurgical. She has received honoraria for speaking for PER, PeerView, and Endomag and contributed a chapter to UpToDate. Dr Tina J. Hieken receives unrelated research funding from Genentech and Skyline DX BV. All other authors have no disclosures to report.

Ethical Statement

Trial Registration

Clinical trial number: , NCT03428581.

ORCID iDs

Samantha J. Brown

Antonio J. Forte

James W. Jakub

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