Elvira Buch-Villa^*1,2, Carlos Castañer-Puga³, Silvia Delgado-Garcia⁴, Carlos Fuster-Diana⁵, Beatriz Vidal-Herrador⁶, Francisco Ripoll-Orts⁷, Tania Galeote-Quecedo⁸, Antonio Prat⁹, Myrian Andrés-Matias¹⁰, Jaime Jimeno-Fraile¹¹, Marcos Adrianzen^1,2, Vicente López-Flor^1,2, Ernesto Muñoz- Sorsona^1,2, Verónica Gumbao-Pucho^l3, Joaquín Ortega^1,2

1. Department of Surgery. University Clinical Hospital of Valencia, Valencia, Spain

2. INCLIVA Biomedical Research Institute,Valencia, Spain

3. Department of Surgery. University General Hospital of Valencia, Valencia, Spain

4. Department of Surgery. University General Hospital of Alicante, Alicante, Spain

5. Department of Surgery. Instituto Valenciano Oncológico, IVO, Valencia, Spain

6. Department of Surgery. University Clinical Hospital of Santiago de Compostela, A Coruña, Spain

7. Department of Surgery. University and Politecnic Hospital of Valencia, la FE, Valencia, Spain

8. Department of Surgery. Hospital de Antequera, Málaga, Spain

9. Department of Surgery. General Hospital of Requena, Valencia, Spain

10. Department of Surgery. Hospital of San Pedro (la Rioja), Logroño, Spain

11. Department of Surgery. University Clinical Hospital Marques de Valdecillas, Santander, Spain

^*Corresponding author:Elvira Buch Villa, Department of Surgery, University Clinical Hospital of Valencia, Av. de Blasco Ibáñez, 17, 46010 Valencia, Spain

Abstract

Purpose: To compare HemopatchTM versus axillary drainage in patients undergoing axillary lymphadenectomy. Additionally, potential predictors of clinical outcomes were also evaluated. Methods: Multicentre, prospective and randomized study conducted on adult women diagnosed with breast cancer. Patients were randomly assigned (1:1) to underwent surgery with either patch or drainage. The primary end-points were the incidence rate of seroma and the needed-to-attend to the emergency-room for any event-related to the surgery. Results: One-hundred-and-eighty-two patients were included in the analysis, 94 (51.7%) in the patch- and 88 (48,3%) in the drainage-group. The incidence of seroma was significantly higher in the patch-group (53.2%; 95%confidence-interval [CI]: 38.9%-70.1%) than in the drainage-group (30.2%, 95%CI: 20.2%-44.4%); p=0.0196. Conversely, the incidence of emergency-department visits was significantly higher in the drainage group (28.4%; 95%CI: 18.4%-41.9%) than in the patch group (8.5%, 95%CI: 3.7%-16.8%), p=0.0016. The number of outpatients visits necessary to control the seroma was significantly greater in the drainage than in the patch group; Hodges-Lehmann median difference: 2.0 visits; 95%CI: 1.0-2.0 visits, p<0.0001. Factor predictor of seroma in the multivariate analysis was patch (OR: 2.90; 95%CI: 1.50-5.63). Patch was associated with a lower-risk of attending to the emergency-room (OR: 0.20; 95%CI: 0.08-0.50, p=0.0005); whereas previous axillary-surgery was associated with a greater-risk (OR: 5.78; 95%CI: 1.64-20.42, p=0.0065). Conclusions: HemopatchTM did not significantly reduce the incidence rate of seroma. Nevertheless, its use has been associated with a lower number of postoperative-visits and a lower number of visits to the emergency department, which, therefore, may be helpful for reducing costs.

Key words: Seroma; drainage; patch, breast cancer; axillary lymphadenectomy

Introduction

Over the last 30 years, significant changes have been introduced in the surgical management of breast cancer [1,2]. Currently, since most patients with breast cancer are diagnosed in the early stages of the disease [3], conservative surgery has become the treatment of choice [1,2].

Similarly, there have been significant changes in the management of the axilla in the last decade [1]. It is known that the presence of lymph node metastases is an important prognostic factor in breast cancer, influencing surgical, neoadjuvant and adjuvant treatment [4].

In those patients in whom it has not been possible to show the presence of breast cancer in the radiological examination or who have not manifested symptoms, their evaluation is fundamentally carried out by means of the selective sentinel lymph node biopsy (SLNB) [5]. In many patients with clinically negative nodes, SLNB has replaced routine axillary lymph node dissection (ALND), mainly because ALND is overly aggressive [6,7]. However, there are clinical situations in which ALND is indicated [7].

Traditionally all patients proceeded to ALND irrespective of nodal status [6], although the current trend is to perform increasingly conservative surgical approaches to the axilla [1,2,6,7]. However, the optimal management of the axilla has not been fully elucidated [8].

Despite all these facts, ALND is a surgical procedure usually performed as part of the surgical management of breast cancer, particularly in those cases in which there is axillary disease [9]. It provides accurate prognostic information essential for systemic treatment planning, better local control of the disease; and its use has been associated with greater survival [8,9].

ALND is associated with significant morbidity, including bleeding, postoperative infection, temporarily decreased range of motion of the shoulder, hematoma, lymphorrhagia requiring delayed drain removal, seroma, etc. Among them, seroma below skin flaps is the most common complication of breast cancer surgery, occurring in 15–81% of patients after node dissection [9-12]. Although it does not represent a complication that entails important morbidity, its onset can increase the incidence of postoperative complications, including delayed wound healing, infections, and a delay in the start of adjuvant treatment [9-12].

Different strategies have been tried to reduce the seroma, such as the use of suction drains [13]; physiotherapy [14,15]; meticulous closure of the axillary fossa with stitches [14,15]; early mobilization of the shoulder above 90º in the first week [16]; use of pharmacological aids such as haemostatic biological adhesives [17-19]; etc. However, to this day, drainage is considered the only valid method to reduce and treat seroma formation [14, 15]; although it is not free of complications. Drainage leads to discomfort, pain, and functional limitation of the arm, and its prolonged maintenance may be a cause of infection [15].

Due to this, alternatives are still being sought that reduce the complications associated with the use of drains. The polyethylene glycol (PEG)-coated patch HemopatchTM has been associated with positive outcomes in different surgical procedures [20,21].

The Spanish REDHEMOPACH was created with the purpose to examine, from a sample of Spanish breast cancer centres, a comprehensive dataset which includes patient characteristics, intraoperative variables, and postoperative management of breast cancer patients undergoing ALND with the PEG-coated patch HemopatchTM.

The aim of this paper was to perform an interim analysis of the REDHEMOPACH data base. This analysis was mainly focused on comparing the incidence rate of seroma between the PEG-coated patch versus (vs) axillary drainage in patients who underwent ALND. This study also evaluated the need to attendance to emergency room for any event-related to the surgery in both groups. In addition, our study also aimed to estimate and test factors for their association with the primary endpoints. Among them, we have paid special attention to the relationship between obesity and the incidence of seroma.

Methods

Study design and participants

Multicentre, prospective and randomized study conducted on adult women diagnosed with breast cancer, scheduled for conservative surgery, who underwent ALND.

The study protocol was approved by the Ethics Committee of the University Clinical Hospital of Valencia (Register number: REDHEMOPACH V.6; 29 de Julio 2020). Written informed consent was obtained in all the patients before the study. The ethical principles outlined in the Declaration of Helsinki and Good Clinical Practice were followed. The study was registered in ClinicalTrials.gov (ClinicalTrials.gov Identifier: NCT04487561).

Inclusion/exclusion criteria

Patients included in the study were women aged ≥18 years; diagnosed with breast cancer; who were scheduled for surgical treatment including conservative surgery and ALND; and willingness to comply with the investigators and protocol indications. Patients with selective sentinel node biopsy negative, subsidiary mastectomy patients and those who did not sign informed consent for axillary lymphadenectomy were excluded of the study.

Study groups

Patients were randomly assigned (1:1) to one of the study groups

Patch group

Before surgical closure of the axillary incision, the PEG-coated patch HemopatchTM (Sealing Hemostat, Baxter AG, Vienna, Austria) was placed. The Patch was placed in contact with the surgical bleb (white side). Sodium bicarbonate solution (concentration 1M) at room temperature was used in conjunction with patch application. A gentle and uniform pressure for 2 minutes using a dry gauze was performed and thereafter the incision was sutured by using the usual technique.

Drainage group

A 12G Redon drain was placed before surgical closure of the axillary incision. The 12G suction-drain tube was placed on the surgical bed. Subsequently, the skin was closed and the drainage was connected to a redon-type suction bottle. The drainage was maintained, beyond the first 24 hours, if the volume drained was > 30 mL.

In both groups, an external compressive bandage was applied, which was maintained for ≤24 hours.

Study visits

Follow-up visits were scheduled at day-1 and day 7 (±1). The patients continued with follow-up visits every 7 days (±1) until the seroma was resolved.

Outcomes

The primary end-points were the incidence rate of seroma and the need-to-attend to the emergency room for any event-related to the surgery.

The secondary endpoints included the total volume of the seroma and the incidence of adverse events.

Additionally, a combined secondary objective has been selected that takes into account the incidence of seroma and having attended to the emergency department. According to this criterion, the following assumptions have been defined: (1) Complete success, defined as those cases in which the presence of seroma was not evidenced and they did not attend to the emergency room; (2) Qualified success, defined as those cases that, presenting seroma, did not need to go to the emergency room; and (3) Failure, as those cases with seroma who went to the emergency room. Patients who attended to the emergency department for any reason related to surgery, even if they had not developed a seroma, were also considered failures.

Definitions

Seroma was defined as a palpable, uninfected, and clear fluid collection (≥20 mL) under the wound (in the dead space of the axilla). Seroma must require aspiration due to either high output or after removal of the drain, which can delay wound healing and increase the risk of wound infection.

According to the World Health Organization (WHO) classification, body mass index (BMI) was categorized into six groups: underweight (<18.5 Kg/m2), normal weight (18.5 Kg/m2–24.9 Kg/m2), pre-obesity (25.0 Kg/m2–29.9 Kg/m2), obesity class I (30.0 Kg/m2–34.9 Kg/m2), obesity class II (35.0 Kg/m2–39.9 Kg/m2) and obesity class III (≥40 Kg/m2) [22]. Considering the low number of underweight and obese patients in our study, the sample was stratified into normal weight (defined as BMI <25 Kg/m2), pre-obesity (defined as BMI ≥25 Kg/m2 to <30 Kg/m2), and obese (defined as BMI≥30 Kg/m2).

Statistical analysis

A standard statistical analysis was performed using MedCalc® Statistical Software version 20.033 (MedCalc Software Ltd, Ostend, Belgium; https://www.medcalc.org; 2022).

Sample size calculation was based on the assumption that a 18% difference in seroma incidence rate between the study groups was clinically relevant (two tailed test). Approxi mately 111 patients for each group were required, given an α of 0.05 and a 1-β of 0.80. A statistical power of 80% was chosen to decrease the risk of a false negative result.

According to our experience (unpublished data) the incidence rate of seroma in the patch group would be 29% and according to a Cochrane Database systematic review [see reference 13], the incidence rate of seroma in conservative surgery with drainage would be 47%.

Of the 222 patients planned to be included, this interim analysis evaluated the data from 182 patients, 94 patients in the patch group and 88 subjects in the drainage one.

Descriptive statistics number (percentage), mean and standard deviation (SD), mean and 95% confidence interval (95% CI), mean and standard error (SE), median and interquartile range (IqR) or median (95% CI) were used, as appropriate.

Data were tested for normal distribution using a D’Agostino-Pearson test.

The two-tailed unpaired Student’s t-test or the Mann-Whitney U test were used as appropriate to compare means between treatment groups for quantitative variables at baseline.

A logistic regression model was used to estimate and test factors for their association with seroma incidence and the need to attend to the emergency department. A backward strategy was adopted, with a statistically significant cut-off for variable screening of 0.05. Factors associated with progression in the univariate analysis at p≤0.1 were included in the multivariate analysis.

Regarding the role of obesity, two different analyses have been carried out. In the first one, the groups have been divided into normal weight (BMI<25Kg/m2); pre-obesity (BMI ≥25 Kg/m2 to <30 Kg/m2) and obese (BMI≥30 Kg/m2). In the second analysis, the groups were stratified into Non-obese (BMI<30 Kg/m2) and obese (BMI≥30 Kg/m2).

Categorical variables were compared using chi-square test and Fisher’s exact test, as required. P value of less than 0.05 was considered significant.

Results

This interim analysis included 185 patients. Three patients were removed from the analysis because it was necessary to perform a mastectomy. A total of 182 patients were included in the analysis 94 (51.7%) patients in the patch group and 88 (48,3%) in the drainage one.

Table 1 shows the main baseline demographic and clinical characteristics of the study sample. With the exception of the presence of positive sentinel node, which was significantly higher in the patch group (p=0.0327), no significant differences were observed in any of the preoperative variables between the two groups.

Table 1:Baseline demographic and clinical characteristics of the study populations

	Overall (n=182)	Patch (n=94)	Drainage (n=88)	p
Age, years Mean (SD) Median (IqR)	57.0 (12.7) 56.5 (47.0 to 67.0)	56.1 (12.8) 55.0 (46.0 to 64.0)	58.0 (12.5) 57.0 (49.5 to 67.5)	0.3218a
BMI, Kg/m2† Mean (SD) Median (IqR)	27.3 (6.3) 26.2 (23.1 to 30.0)	27.2 (6.9) 25.8 (23.0 to 29.0)	28.0 (5.7) 27.4 (23.7 to 30.4)	0.3842a
BMI, Kg/m2 , n (%) Normal weight Pre-obesity Obese	64 (36.0) 68 (38.2) 46 (25.8)	40 (42.6) 33 (35.1) 21 (22.3)	24 (28.6) 35 (41.7) 25 (29.8)	0.0675b
Comorbidities, n (%) Yes No	60 (33.0) 122 (67.0)	29 (30.9) 65 (69.1)	31 (35.2) 57 (64.8)	0.6362c
DM, n (%) Yes No	20 (11.0) 161 (89.0)	6 (6.4) 88 (93.6)	14 (16.1) 73 (83.9)	0.0559c
Previous axillary surgery,n (%) Yes No	14 (7.7) 168 (92.3)	7 (7.4) 87 (92.6)	7 (8.0) 81 (92.0)	1.0000c
Preoperative phenotype, n (%) Luminal A Luminal B Triple-negative HER2	55 (31.1) 78 (44.1) 32 (18.1) 12 (6.8)	28 (30.4) 38 (41.3) 21 (22.8) 5 (5.4)	27 (31.8) 40 (47.1) 11 (12.9) 7 (8.2)	0.6692b
PSN, n (%) Yes No	114 (62.6) 68 (37.4)	66 (70.2) 28 (29.8)	48 (54.5) 40 (45.5)	0.0327c
Neoadjuvant therapy, n (%) Yes No	102 (56.4) 79 (43.6)	55 (59.1) 38 (40.9)	47 (53.4) 41 (46.6)	0.4569c
ASA, N (%) ASA I ASA II ASA II	39 (21.5) 107 (59.1) 35 (19.3)	19 (20.2) 54 (57.4) 21 (22.3)	20 (23.0) 53 (60.9) 14 (16.1)	0.3425b

^a Two-tailed unpaired Student’s t-test
^b Chi-squared for trend test
^c Fisher exact test
^† Data were missed in 7 patients.
^* Ligasure® (Medtronic, Minneapolis, MN, USA).
^**Harmonic® (Ethicon Endo Surgery, Albuquerque, NM, USA)
SD: Standard deviation; IqR: Interquartile range; BMI: Body mass index; HER2: human epidermal growth factor receptor 2; PSN: Positive sentinel node; ASA: American Society of Anaesthesiologist Physical Status Classification System

Regarding the characteristics of the surgical procedure, no differences were observed between both groups (Table 2). The median number of patches used during the procedure was 1.0 (IqR: 1.0 to 1.0) patches, with 71 patients (76.3%) undergoing surgery with only one patch.

Table 2:Clinical characteristics of the surgical procedure

	Overall (n=182)	Patch (n=94)	Drainage (n=88)	p
TAI, n (%) TPM PPM U-shaped Others	84 (46.8) 89 (48.9) 4 (2.2) 5 (2.5)	41 (43.6) 46 (48.9) 3 (3.2) 4 (4.3)	43 (48.9) 43 (48.9) 1 (1.1) 1 (1.1)	0.1714a
Single breast and axillary incision, n (%) Yes No	24 (13.3) 157 (86.7)	12 (12.8) 82 (87.2)	12 (13.2) 75 (86.2)	1.0000b
Ligasure®, n (%)* Yes No	61 (33.5) 121 (66.5)	33 (35.1) 61 (64.9)	28 (31.8) 60 (68.2)	0.7535b
Harmonic®, n (%)** Yes No	98 (54.1) 83 (45.9)	49 (52.7) 44 (47.3)	49 (55.1) 39 (44.3)	0.7657b
Number of patches, n (%) 1 2 3	71 (76.3) 20 (21.5) 2 (2.2)	71 (76.3) 20 (21.5) 2 (2.2)	Not Applicable	N.A
Removed lymph nodes Mean (SD) Median (IqR)	16.2 (6.1) 15.0 (12.0 to 19.3)	16.3 (6.0) 15.0 (13.0 to 20.0)	16.2 (6.2) 15.0 (12.0 to 19.0)	0.8995c
Positive lymph nodes Mean (SD) Median (IqR)	3.0 (3.7) 2.0 (1.0 to 4.0)	3.3 (3.7) 2.0 (1.0 to 5.0)	2.8 (3.6) 2.0 (1.0 to 4.0)	0.3786c
Intraoperative complications, n (%) Yes No	2 (1.1) 180 (98.9)	1 (1.1) 93 (98.9)	1 (1.1) 87 (98.9)	1.0000b

^aChi-squared for trend test.
^bFisher exact test.
^cTwo-tailed unpaired Student’s t-test
Ligasure® (Medtronic, Minneapolis, MN, USA).
Harmonic® (Ethicon Endo Surgery, Albuquerque, NM, USA)
TAI: Type of axillary incision; TPM: Transverse to pectoralis major; PPM: Parallel to pectoralis major; NA: Not applicable; SD: Standard deviation; IqR: Interquartile range.

The incidence of seroma was significantly higher in the patch (incidence rate: 53.2%; 95% CI: 39.5% to 70.1%) than in the drain group (incidence rate: 30.2%, 95% CI: 20.2% to 44.4 %); incidence rate difference 22.5%; 95% CI: 3.6% to 41.4%, p=0.0196 (Table 3). In contrast, the incidence of emergency department visits was significantly higher in the drainage (incidence rate: 28.4%; 95% CI: 18.4% to 41.9%) than in the patch group (incidence rate: 8.5%, 95% CI: 3.7% to 16.8%), incidence rate difference: 19.9%; 95% CI: 7.5% to 32.3%, p=0.0016 (Table 3).

Table 3:Overview of the incidence of postoperative outcomes in the Intent-to-treat study population

	Overall (n=182)	Patch (n=94)	Drainage (n=88)	p
Seroma, n (%) Yes	77 (42.3)	50 (53.2)	27 (30.7)	0.0196a
Day of seroma onset Mean (SD) Median (IqR)	11.6 (5.4) 11.0 (8.00 to 15.0)	11.1 (5.8) 10.0 (7.00 to 14.5)	12.8 (4.0) 14.5 (10.0 to 15.0)	0.0589b
Patients requiring seroma puncture, n (%) Yes No	61 (33.3) 115 (65.3)	44 (48.4) 47 (51.6)	17 (20.0) 68 (80.0)	0.0001c
Number of punctures1 Mean (SD) Median (IqR)	3.1 (3.1) 2.0 (1.0 to 4.0)	2.9 (2.1) 2.0 (1.0 to 4.0)	3.4 (4.9) 2.0 (1.0 to 4.0)	0.6909b
Seroma volume, mL Mean (SD) Median (IqR)	459.4 (518.2) 267.5 (140.0 to 660.0)	405.1 (338.3) 275.0 (150.0 to 660.0)	603.1 (824.0) 260.0 (75.3 to 782.5)	0.7885b
Attendance to emergency room, n (%)* Yes	33 (18.1)	8 (8.5)	25 (28.4)	0.0016a
Reason, n (%)⁑ Seroma Redon Pain	11 (33.3) 21 (63.6) 1 (3.0)	7 (87.5) 0 (0.0) 1 (12.5)	4 (16.0) 21 (84.0) 0 (0.0)	0.0053d
Postoperative combined criterion, n (%) Success Qualified success⁂ Complete success⁂	149 (81.9) 59 (32.4) 90 (49.5)	86 (91.5) 42 (44.7) 44 (46.8)	63 (71.6) 17 (19.3) 46 (52.3)	0.0425a 0.0027a 0.6004a
Number of outpatient visits† Mean (SD) Median (IqR)	3.3 (2.5) 3.0 (1.0 to 4.0)	2.6 (2.1) 2.0 (1.0 to 3.0)	4.0 (2.7) 4.0 (3.0 to 5.0)	<0.0001b
Complication related to drainage, n (%) Yes No	24 (25.5) 70 (74.5)	0 (0.0) 13 (100.0)	24 (29.6) 57 (70.4)	0.0342c
Type of Complication** Bleeding Drain pipe extrusion Infection Pain Decubitus ulcer	0 (0.0) 15 (53.6) 6 (21.4) 3 (10.7) 4 (14.3)	Not Applicable		N.A.
Axillary wound dehiscence, n (%) Yes No	3 (1.6) 179 (98.4)	3 (3.2) 91 (96.8)	0 (0.0) 88 (100.0)	0.2467c
Axillary wound infection, n (%) Yes No	4 (2.2) 178 (97.8)	2 (2.1) 92 (97.9)	2 (2.3) 86 (97.7)	1.0000c
Number of Redon bottles Mean (SD) Median (IqR)	2.6 (1.5) 2.0 (1.0 to 4.0)	Not Applicable	2.6 (1.5) 2.0 (1.0 to 4.0)	N.A.

^aChi-squared test
^bMann-Whitney U test
^cFisher exact test.
^dChi-squared test for trend
1Among patients who needed seroma puncture.
*If the patient needed to go to the emergency department for any event related to the surgery.
*Reason for attending to the emergency room.
*Among success subjects.
†Number of outpatients visits necessary to control the seroma
**Type of complication related to the drainage. Patients may have had more than one complication. The percentages were calculated according to the patients who had complications NA: Not applicable; SD: Standard deviation; IqR: Interquartile range.

The time elapsed between surgery and the first seroma puncture was longer in the patch group (Hodges-Lehmann median difference: 3.0 days; 95% CI: 0.0 to 5.0 days), although it was not statistically significant (p=0.0589).

The number of outpatients visits necessary to control the seroma was significantly greater in the drainage (median: 4.0 visits, IqR: 3.0 to 5.0 visits) than in the patch group (median: 2.0 visits; IqR: 1.0 to 3.0 visits); Hodges-Lehmann median difference: 2.0 visits; 95% CI: 1.0 to 2.0 visits, p<0.0001.

The overall success rate was significantly greater in the patch group than in the drainage one, although this difference was mainly due to the qualified success (Table 3).

There were no significant differences in the incidence rate of postoperative complications between the patch (6.4%, 95% CI: 2.3% to 13.9%) and the drainage (1.1%; 95% CI: 0.02% to 6.3%) groups, p=0.1192.

Factors that were significant predictors of seroma incidence in the univariate analysis included group assignment [Odds ratio (OR): 2.57; 95CI: 1.40 to 4.72; p=0.0024] and presence of preoperative comorbidities (OR: 1.96; 95% C: 1.05 to 3.66, p=0.0359). While factors significantly associated with the need to attend to the emergency room in the univariate analysis were previous axillary surgery (OR: 5.78; 95% CI: 1.64 to 20.42, p=0.0065) and the group assignment (OR: 0.23; 95%CI: 0.10 to 0.55, p=0.0009) (Table 4).

Table 4 gives the results of the multivariate analysis. Patch group assignment increased the OR for seroma by 2.9 folds (OR: 2.90; 95% CI: 1.50 to 5.63) after adjustment for relevant factors. The patch reduced the probability of attending to the emergency room by 80% (OR: 0.20; 95% CI: 0.08 to 0.50, p=0.0005) after controlling for other predictors. Finally, having undergone a previous axillary intervention increased the probability of attending to the emergency room by 5.8 folds (OR: 5.78; 95% CI: 1.64 to 20.42, p=0.0065) after adjustment for relevant factors.

Table 4:Univariate and multivariate analysis of the 182 patients included in the study to evaluate the potential factors for seroma and whether the patient went to the emergency room. Factors associated with success in the univariate analysis at p < 0.1 were included in the multivariate analysis.

Variable	Seroma				Need to attend to emergency room
	Univariate		Multivariate		Univariate		Multivariate
	OR (95% CI)	p	OR (95% CI)	p	OR (95% CI)	p	OR (95% CI)	p
Age* >55 years	1.55 (0.86 to 2.80)	0.1496			1.52 (0.70 to 3.27)	0.2872
BMI Ref normal weight Pre-obesity Obese	1.36 (0.68 to 2.72) 2.00 (0.93 to 4.29)	0.3799 0.0750	1.90 (0.81 to 4.44)	0.1387	1.37 (0.56 to 3.38) 1.61 (0.61 to 4.25)	0.4936 0.3353
BMI Ref no obese Obese	1.71 (0.87 to 3.35)	0.1090			1.37 (0.59 to 3.14)	0.5637
Comorbidities Ref No Yes	1.96 (1.05 to 3.66)	0.0359	1.59 (0.76 to 3.31)	0.2161	1.65 (0.76 to 3.57)	0.2042
DM Ref No Yes	2.24 (0.87 to 5.78)	0.0958	1.96 (0.63 to 6.04)	0.2442	2.14 (0.76 to 6.07)	0.1516
Previous axillary surgery Ref No Yes	1.40 (0.47 to 4.18)	0.5458			5.46 (1.77 to 16.87)	0.0032	5.78 (1.64 to 20.42)	0.0065
Preoperative phenotype Ref Luminal A Luminal B Triple-negative HER2	1.51 (0.76 to 3.02) 1.86 (0.78 to 4.45) 1.33 (0.38 to 4.70)	0.2427 0.1644 0.6614			0.60 (0.26 to 1.38 0.43 (0.13 to 1.42) 0.27 (0.03 to 2.29)	0.2301 0.1662 0.2316
PSN Reference No Yes	2.16 (1.15 to 4.07)	0.0169	1.93 (0.99 to 3.75)	0.0533	0.77 (0.36 to 1.669	0.5072
Neoadjuvant therapy Ref No Yes	0.99 (0.55 to 1.78)	0.9629			0.59 (0.28 to 1.279	0.1783
ASA Ref ASA I ASA II ASA III	1.40 (0.66 to 2.98) 1.75 (0.69 to 4.44)	0.3813 9.2354			2.07 (0.66 to 6.48) 3.12 (0.87 to 11.22)	0.2120 0.0822	3.31 (0.83 to 13.28)	0.0911
Study group Ref Drainage Patch	2.57 (1.40 to 4.72)	0.0024	2.90 (1.50 to 5.63)	0.0016	0.23 (0.10 to 0.55)	0.0009	0.20 (0.08 to 0.50)	0.0005
Ligasure® Ref No Yes	1.13 (0.61 to 2.10)	0.7048			1.37 (0.63 to 2.98)	0.4303
Harmonic® Ref No Yes	0.80 (0.44 to 1.44)	0.4590			1.04 (0.49 to 2.21)	0.9290
Removed lymph nodes* > 15	1.19 (0.66 to 2.14)	0.5704			1.80 (0.84 to 3.87)	0.1301
Positive lymph nodes* > 2	0.89 (0.49 to 1.64)	0.7124			1.47 (0.68 to 3.14)	0.3253

*Reference group ≤ Median.
Ligasure® (Medtronic, Minneapolis, MN, USA).
Harmonic® (Ethicon Endo Surgery, Albuquerque, NM, USA)
BMI: Body mass index; DM: Diabetes mellitus; HER2: human epidermal growth factor receptor 2; PSN: Positive sentinel node; ASA: American Society of Anesthesiologist Physical Status Classification System.

Discussion

The incidence of seroma is probably one of the most frequent complications following breast cancer surgery [9-12]. Although its appearance does not represent a life-threatening condition, it accounts for prolonged patient discomfort which translates as pain, delayed wound healing, skin flap necrosis, repeated visits to outpatient clinics, and surgical-site infection [9-12].

The effectiveness of different strategies aimed at preventing or reducing the incidence of seroma has been previously analysed in different clinical studies [13-19].

According to the results of our study, the incidence of seroma in the overall study population was 42.3% (95% CI: 33.4% to 52.9%), with a significantly greater incidence in the patch than in the drainage group (incidence rate difference 22.5%; 95% CI: 3.6% to 41.4%, p=0.0196).

To the best of our knowledge, this is the first prospective, randomized and controlled study evaluating the effect of the PEG-coated patch on preventing the incidence of seroma.

The effectiveness of the use of sealant agents to prevent the incidence of seromas after axillary lymphadenectomy has not been clearly established. Differences in the methodology of the studies, as well as the clinical diversity of the patients analysed, makes it difficult to draw conclusions [19,20,23,24].

Many different factors, including patient demographic and clinical characteristics (age, BMI, diabetes mellitus, etc.); tumour-specific characteristics (tumour staging or grading, or presence of positive sentinel node; treatment-related (neoadjuvant chemotherapy, previous axillary surgery, etc.) have been evaluated regarding their association with seroma incidence [25-27]. However, only a few of these factors seem to have a significant effect on seroma production [25].

Body weight [19,28] and BMI [23,25-28] have been associated with increased seroma formation. However, in the current study obesity was not significantly associated with the incidence of seroma.

Although in our study, the presence of preoperative comorbidities was associated with a greater probability of seroma in the univariate analysis, this result was not confirmed in the multivariate analysis.

These results are in agreement with those reported by Ohlinger et al [29], although other authors have shown opposite results [27].

In our study, neither the use of Ligasure® nor the use of Harmonic® have been associated with a lower probability of seroma. These results are in agreement with those published previously by Gambardella et al [30], who suggested that these devices did not have any significant impact on seroma formation.

Regarding the cumulative total lymph volume collected, this study did not find significant differences between the patch and drainage groups. However, the incidence rate ratio of patients with a seroma volume ≥1000 mL was 3.97 (95% CI: 0.45 to 47.54) time-fold greater in the drainage group, although it was not statistically significant (p=0.1025).

In our study, patients assigned to the patch group had a significantly lower need to attend to the emergency room compared to the drainage group. In fact, the patch reduced the probability of attending to the emergency room, for any event related to the surgery, by 80%. Moreover, the use of HemopatchTM, in patients who underwent breast cancer surgery, reduced significantly the number of outpatients visits necessary to control the seroma. Fewer postoperative consultations may indicate that seroma is more easily controlled in the patch group. Additionally, the lower rate of large-volume seromas in the patch group speaks in favour of this hypothesis.

However, additional analyses will be necessary at the end of the study to confirm this hypothesis. Although it was not assessed in the current study, reducing the need to attend to the emergency room and fewer outpatient visits necessary to control the seroma would intuitively result in a smoother patient postoperative journey and increase overall satisfaction. Additionally, this may contribute to reducing significantly the costs, not only to the patient/family, but also to the Health Systems.

It is important to mention that the results of the current paper are a reflection of an interim analysis, which has not included the total sample planned at the beginning. Therefore, the final results and conclusions of our clinical trial may vary once the final analysis has been carried out.

Conclusions

In patients who underwent axillary lymphadenectomy, the PEG-coated patch HemopatchTM did not significantly reduce the incidence rate of seroma. Nevertheless, its use has been associated with a lower number of postoperative outpatient visits and a lower number of visits to the emergency department, which, therefore, may be helpful for reducing costs.

Because breast cancer is one of the most prevalent malignancies in women, a large number of axillary lymphadenectomies are performed every year. Therefore, it is crucial to have high-quality scientific evidence regarding the best practice management of these patients.

We have to wait for the final analysis of the results to establish the true value of using the PEG-coated patch in our clinical practice. In addition, the cost analysis may provide information on the cost-effectiveness of the procedure.

Abbreviations

ALND: Axillary lymph node dissection; BMI: Body mass index; CI: Confidence interval; G: Gauge; IqR: Interquartile range; OR: Odds ratio; PEG: Polyethylene glycol; SD: Standard deviation; SE: Standard error; SLNB: Selective sentinel lymph node biopsy; WHO: World Health Organization.

Acknowledgements

Medical writing and Editorial assistant services have been provided by Antonio Martinez (MD) of Ciencia y Deporte S.L. Support for this assistance was funded by Baxter. Baxter was not involved in the preparation of the recommendations nor did the company influence in any way the scientific consensus reached.

This work has been granted by the Spanish Association of Surgeons.

Funding

This study was funded by a grant from the Spanish Association of Surgeons (GRANT number: Not applicable).

Conflicts of Interest

None of the co-authors have any conflict of interest to declare.

References

1. Keelan S, Flanagan M, Hill ADK. Evolving Trends in Surgical Management of Breast Cancer: An Analysis of 30 Years of Practice Changing Papers. Front Oncol. 2021;11:622621. doi: 10.3389/fonc.2021.622621.

2. Veronesi U, Cascinelli N, Mariani L, et al. Twenty-year follow-up of a randomized study comparing breast-conserving surgery with radical mastectomy for early breast cancer. N Engl J Med. 2002;347(16):1227-1232.

3. Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and MortalityWorldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;71(3):209-249.

4. Nottegar A, Veronese N, Senthil M, et al. Extra-nodal extension of sentinel lymph node metastasis is a marker of poor prognosis in breast cancer patients: A systematic review and an exploratory meta-analysis. Eur J Surg Oncol. 2016;42(7):919-925.

5. Krag DN, Anderson SJ, Julian TB, et al. Sentinel-lymph-node resection compared with conventional axillary-lymph-node dissection in clinically node-negative patients with breast cancer: overall survival findings from the NSABP B-32 randomised phase 3 trial. Lancet Oncol. 2010;11(10):927-933.

6. Fisher B, Jeong JH, Anderson S, et al. Twenty-five-year follow-up of a randomized trial comparing radical mastectomy, total mastectomy, and total mastectomy followed by irradiation. N Engl J Med. 2002;347(8):567-575.

7. Ling DC, Iarrobino NA, Champ CE, et al. Regional Recurrence Rates With or Without Complete Axillary Dissection for Breast Cancer Patients with Node-Positive Disease on Sentinel Lymph Node Biopsy after Neoadjuvant Chemotherapy. Adv Radiat Oncol. 2019;5(2):163-170.

8. Mamounas ET. Optimal Management of the Axilla: A Look at the Evidence. Adv Surg. 2016;50(1):29-40.

9. Toomey A, Lewis CR. Axillary Lymphadenectomy. 2021 Dec 16. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan–. PMID: 32491796. Available in: https://www.ncbi.nlm.nih.gov/books/NBK557873/ Last accessed March 1, 2022.

10.Montalto E, Mangraviti S, Costa G, et al. Seroma fluid subsequent to axillary lymph node dissection for breast cancer derives from an accumulation of afferent lymph. Immunol Lett. 2010;131(1):67-72.

11. van Bemmel AJ, van de Velde CJ, Schmitz RF, et al. Prevention of seroma formation after axillary dissection in breast cancer: a systematic review. Eur J Surg Oncol. 2011;37(10):829-835.

12. Turner EJ, Benson JR, Winters ZE. Techniques in the prevention and management of seromas after breast surgery. Future Oncol. 2014;10(6):1049-1463.

13. Thomson DR, Sadideen H, Furniss D. Wound drainage after axillary dissection for carcinoma of the breast. Cochrane Database Syst Rev. 2013;2013(10):CD006823.

14. Petrek JA, Senie RT, Peters M, et al. Lymphedema in a cohort of breast carcinoma survivors 20 years after diagnosis. Cancer. 2001;92(6):1368-1377.

15. Puttawibul P, Sangthong B, Maipang T, et al. Mastectomy without drain at pectoral area: a randomized controlled trial. J Med Assoc Thai. 2003;86(4):325-331.

16. Lotze MT, Duncan MA, Gerber LH, et al. Early versus delayed shoulder motion following axillary dissection: a randomized prospective study. Ann Surg. 1981;193(3):288-295.

17. Piñero-Madrona A, Castellanos-Escrig G, Abrisqueta-Carrión J, et al. Prospective randomized controlled study to assess the value of a hemostatic and sealing agent for preventing seroma after axillary lymphadenectomy. J Surg Oncol. 2016;114(4):423-7.

18. Conversano A, Mazouni C, Thomin A, et al. Use of Low-Thrombin Fibrin Sealant Glue After Axillary Lymphadenectomy for Breast Cancer to Reduce Hospital Length and Seroma. Clin Breast Cancer. 2017;17(4):293-297.

19. Weber WP, Tausch C, Hayoz S, et al; Swiss Group for Clinical Cancer Research (SAKK). Impact of a Surgical Sealing Patch on Lymphatic Drainage After Axillary Dissection for Breast Cancer: The SAKK 23/13 Multicenter Randomized Phase III Trial. Ann Surg Oncol. 2018;25(9):2632-2640.

20. Lewis KM, Ikeme S, Olubunmi T, et al. Clinical effectiveness and versatility of a sealing hemostatic patch (HEMOPATCH) in multiple surgical specialties. Expert Rev Med Devices. 2018;15(5):367-376.

21. Nowak S, Schroeder HWS, Fleck S. Hemopatch^® as a new dural sealant: A clinical observation. Clin Neurol Neurosurg. 2019;176:133-137.

22. Srinivasa DR, Clemens MW, Qi J, et al. Obesity and Breast Reconstruction: Complications and Patient-Reported Outcomes in a Multicenter, Prospective Study. Plast Reconstr Surg. 2020;145(3):481e-490e.

23. Benevento R, Santoriello A, Pellino G, et al. The effects of low-thrombin fibrin sealant on wound serous drainage, seroma formation and length of postoperative stay in patients undergoing axillary node dissection for breast cancer. A randomized controlled trial. Int J Surg. 2014;12(11):1210-1215.

24. Chang YT, Shih SL, Loh EW, et al. Effects of Fibrin Sealant on Seroma Reduction for Patients with Breast Cancer Undergoing Axillary Dissection: Meta-Analysis of Randomized Controlled Trials. Ann Surg Oncol. 2020;27(13):5286-5295.

25. Woodworth PA, McBoyle MF, Helmer SD, Beamer RL. Seroma formation after breast cancer surgery: incidence and predicting factors. Am Surg. 2000;66(5):444-50; discussion 450-451.

26. Srivastava V, Basu S, Shukla VK. Seroma formation after breast cancer surgery: what we have learned in the last two decades. J Breast Cancer. 2012;15(4):373-380.

27. Zieliński J, Jaworski R, Irga N, et al. Analysis of selected factors influencing seroma formation in breast cancer patients undergoing mastectomy. Arch Med Sci. 2013;9(1):86-92.

28. Kuroi K, Shimozuma K, Taguchi T, et al. Evidence-based risk factors for seroma formation in breast surgery. Jpn J Clin Oncol. 2006;36(4):197-206.

29. Ohlinger R, Gieron L, Rutkowski R, et al. The Use of TissuGlu® Surgical Adhesive for Mastectomy With or Without Lymphonodectomy. In Vivo. 2018;32(3):625-631.

30. Gambardella C, Clarizia G, Patrone R, et al. Advanced hemostasis in axillary lymph node dissection for locally advanced breast cancer: new technology devices compared in the prevention of seroma formation. BMC Surg. 2019;18(Suppl 1):125.

Received: March 04, 2022;
Accepted: March 25, 2022;
Published: March 28, 2022.

To cite this article : Buch-Villa E, Castañer-Puga C, Delgado-Garcia S, et al. Polyethylene Glycol-Coated Collagen Patch (Hemopatchtm) Versus Axillary Drainage. In Patients Undergoing Axillary Lymphadenectomy: Interim Analysis of a Multicentre, Prospective, Randomized and Controlled Study. British Journal of Cancer Research. 2022; 5(2): 558- 567. doi: 10.31488/bjcr.176.

©2022 Buch-Villa E, et al.