The effect of subcutaneous local spraying of Pseudomonas aeruginosa preparation to reduce postoperative drainage time in patients with breast cancer

Introduction

Breast cancer (BC) is the most frequent cancer in women of childbearing age and has the highest incidence and mortality rates among all female malignant tumors. Currently, about 2.89 million new cases of female BC arise globally each year, accounting for 24.2% of all female malignant tumors (1). According to a report published by the National Cancer Center of China in 2019, the incidence of BC in China was about 304,000 cases per year in 2015, with higher incidences in developed regions (2). Surgery remains the best treatment approach for BC, followed by chemotherapy, radiotherapy, endocrine therapy, targeted therapy, immunotherapy, and gene therapy (3). Yet, surgery is often affected by multiple factors, such as wide surgical scope, large surgical wounds, bleeding, and exudation which result in large amounts of postoperative drainage and are difficult resolve in a short time frame. These complications often delay the time of the next treatment (such as radiotherapy and chemotherapy) and increase social and medical costs. This study reviewed the treatments of 65 cases of BC by subcutaneous local spraying of Pseudomonas aeruginosa (PAP) on the operation area at West China Hospital of Sichuan University between June 2019 and October 2019. We determined that this specific treatment significantly reduced postoperative drainage volume and shortened drainage time.

We present the following article in accordance with the STROBE reporting checklist (available at http://dx.doi.org/10.21037/gs-20-797).

Methods

The study was approved by the ethics committee of the West China Hospital of Sichuan University. Written informed consent was obtained prior to the study. All procedures performed in this study involving human participants were in accordance with the Declaration of Helsinki (as revised in 2013).

Clinical information

BC patients whose surgeries were performed by the same surgeon from June 2019 to October 2019 at West China Hospital of Sichuan University were included in this study. Inclusion criteria were the following: (I) female patients; (II) exclusion of distant metastasis of BC with Chest CT, abdominal CT, gynecological color Doppler ultrasound, and bone scans; (III) pathologically confirmed with primary invasive BC; (IV) patients with no past BC surgery; (V) patients with BC unrelated to pregnancy. Exclusion criteria were as follows: (I) patients undergoing breast-conserving surgery and breast reconstruction (implant and autologous breast reconstruction); (II) patients undergoing sentinel lymph node biopsy (including internal mammary sentinel lymph node biopsy); (III) patients undergoing skin grafting in the operation area.

A total of 97 patients with modified radical mastectomy for BC were selected the inclusion and exclusion criteria. Sixty-five patients, aged 32–81 years, with an average age of 51.94±10.777 years, were intraoperatively assigned to the P. aeruginosa treatment group (PAP group); meanwhile, 32 patients, aged 33–74 years, with an average age of 53.97±11.488 years, were assigned to the non-P. aeruginosa group (non-PAP group). Postoperatively, there was one silicone drainage tube for parasternal and axillary draining for each patient. The screening process of the subjects is shown in Figure 1.

Figure 1 Screening process of study subjects.

Data collection

Basic data of patients and relevant information on surgery were preoperatively collected. The occurrence of postoperative complications, such as fever, infection, skin flap necrosis, and seroma within 1 month after extubation; and cumulative total drainage volume and drainage time (time after removal of both drainage tubes) were also collected. Wound infection and skin flap necrosis were analyzed when changing the wound dressing (every 3 days) by the same two wound therapists.

Extubation criteria included the following: drainage volume of the single tube for 2 consecutive days was ≤10 mL/day, and the drainage tube was smooth and without seroma. Seroma was defined according to the Marquez (4) and Srivastava (5) criteria, with seroma being considered any subcutaneous or axillary effusion that requires clinical or radiographic guidance for aspiration after mastectomy and axillary dissection.

Grouping

In the PAP group, PAP (2 mL) was sprayed on the wounds in operation area before placement of drainage tube (Figure 2), and was followed by placing two drainage tubes in the same area (a single drainage tube was placed in the sternum and in the axilla, respectively). Then, the tube was clamped, and an incision was made with an interrupted full-thickness suture. After closing the incision, the drainage tube clamp was opened, and finally, external low negative pressure sustained suction was initiated.

Figure 2 Subcutaneous local spraying of P. aeruginosa preparation.

In the non-PAP group, complete hemostasis was performed on the surgical wound, with direct placement of two drainage tubes (a single drainage tube was placed in the sternum and in the axilla, respectively). The incision was made with an interrupted full-thickness suture. After closing the incision, external low negative pressure sustained suction was initiated.

PAP

The PAP, manufactured by Beijing Wanter Bio-pharmaceutical Company (Figure 3), was prepared from an inactivated P. aeruginosa-mannose sensitive hemagglutinin (PA-MSHA) strain, a genetically engineered heat-inactivated PA strain with mannose-sensitive binding activity, which can induce tumor cell apoptosis.

Figure 3 Pseudomonas aeruginosa preparation injection and its outer packaging.

Statistical analysis

Statistical analysis was performed by SPSS (version 17.0) software using a two-sided probability test. A P value <0.05 was considered as statistically significant. Counting data are expressed as cases or percentages, and measurement data are expressed as mean and standard deviation (mean ± SD). Any differences between the two groups were analyzed by t-test, Mann-Whitney U test, or chi-square test.

Results

Comparison in baseline information

A total of 97 cases were included (65 in the PAP group and 32 in the non-PAP group). No significant differences in age, height, weight, age of initial menstruation, menopause, body mass index (BMI), tumor size, or lymph node metastasis were found between the two groups (P>0.05; Table 1).

Table 1 Basic information of patients
Full table

Comparison in efficacy

Total drainage volume and drainage time in the PAP group were both significantly lower compared to those in the non-PAP group (median volume 526.93±273.009 vs. 908.23±594.072 mL, median days 14.14±4.934 vs. 20.03±8.837; P<0.001) (Table 2). The incidence of seroma after extubation in the PAP group was significantly lower than that in the non-PAP group (χ²=6.908, P=0.009) (Table 3).

Table 2 Total drainage volume and drainage time in the PAP and non-PAP groups
Full table

Table 3 The incidence of seroma after extubation in the PAP and non-PAP groups
Full table

Comparison in complications

Fever wound infections and skin flap necrosis, occurred in both groups without a statistical difference (P>0.05) (Table 4). Six cases of fever (below 39 °C), which spontaneously disappeared within 24 hours, were observed in the PAP group.

Table 4 Complications after treatment in the PAP and non-PAP groups
Full table

Discussion

Surgery has an essential and irreplaceable role in the comprehensive treatment of BC. Although sentinel lymph node biopsy can help some patients avoid axillary lymph node dissection, modified radical mastectomy remains the primary surgical approach for BC in developing countries. Due to the wide scope of operation, large surgical wounds and extensive use of electrotome intraoperatively may cause considerably more damage to adipose tissue, blood and lymphatic vessels, which may, in turn, lead to increased postoperative exudates, higher drainage volume, longer drainage time, and even increased risk of infection and seroma.

Thus far, several chemical and physical methods, such as various types of negative pressure drainage, suture sewing, ultrasonic knife (6), affected side upper-limb immobilization, intracavitary injection of talc (7,8), local injection of protein glue (9), and streptococcal preparation OK-432 (10) have been tested with the aim of reducing postoperative drainage volume and drainage time, and preventing the occurrence of seroma. Yet, every method has some limitations. For example, talc causes pain and subcutaneous induration and other adverse reactions, while intraoperative sutures and OK-432 may increase operation time (11). It is also unclear whether long-term upper limb immobilization may increase the risk of exercise limitation.

In the present study, we evaluated the efficacy of subcutaneous local spraying of PAP to reduce the postoperative drainage time in patients with BC. The PAP was prepared from an inactivated PA-MSHA strain, a genetically engineered heat-inactivated PA strain with mannos-sensitive binding activity, which can induce tumor cell apoptosis (12,13). This genetically engineered strain can promote activation of human peripheral blood mononuclear cells, induce action of helper T cells and B cells, enhance the activity of natural killer cells, and increase levels of multiple cytokines (14). PAP has been used for the treatment of malignant pleural and pericardial effusions (15) and intractable chylous fistula in neck surgery (16). However, few studies have evaluated its effect on drainage time in BC patients undergoing modified radical mastectomy. Our data showed that the drainage volume was significantly reduced in the PAP group compared with the non-PAP group (526.93±273.009 vs. 908.23±594.072 mL, P<0.001), and the drainage time was significantly shortened (14.14±4.934 vs. 20.03±8.837 days, P<0.001). We propose that subcutaneous local spraying of PAP can help trigger tissue repair response, cause a strong local sterile inflammatory reaction between the tissue surfaces, and promote the skin and wounds in the operation area to be more prone to adhesion and fibrosis. Thus, PAP can reduce the total drainage volume after BC surgery and drainage time.

Srivastava et al. (5) have suggested that seroma is a side effect rather than a complication after BC surgery. In a report on wound healing and postoperative complications of BC surgery, Chiappa et al. (17) reported that the incidence of seroma was 37.5% in the conventional electrosurgical group. In this study, the incidence after extubation in the PAP group was not only lower than that in the non-PAP group (4.615 vs. 21.875, P=0.009), but was also lower than those reported in the above literature. This data suggests that subcutaneous local spraying of PAP on the operation area can reduce the incidence of seroma in BC patients undergoing surgery.

The standard for extubation in this study was a drainage that was less than or equal to 10 mL for 2 consecutive days before removal of the drainage tube. At present, there is no report on drainage time after BC surgery with the above standard extubation. In addition, studies reporting on the extubation index and drainage time are not consistent. In their study, Lohani et al. (18) removed the drainage tube when the drainage was less than or equal to 20 mL for 2 consecutive days; the drainage time was 11 days without intervention, and the incidence of seroma was 32.6%. Gogna et al. (19) reported that the drainage tube was removed when the drainage was less than 30 mL for 1 day; the drainage time was 13.7 days without intervention, and the incidence of seroma was 44%. Moreover, Chiappa et al. (17) reported that the drainage tube was removed when the daily drainage volume decreased to less than 50 ml. While the average drainage time in the control group was 10.93±5.173 days, there are some reported cases of the drainage tube being removed when the daily drainage volume was reduced to less than 100 mL (20). Nevertheless, the extubation criteria in this study was stricter, which is why the drainage time was shorter in our PAP group, but longer than that reported in the other above-mentioned studies. Lower incidence of seroma in this study may also be related to the strict extubation criteria.

Because PAP is an inactivated bacterial preparation, fever is the most common adverse reaction after injection. As expected, our results showed that the number of cases with fever was higher in the PAP group than in the non-PAP group (six cases vs. three cases, P=0.623). In the PAP group, fever (lower than 39 °C) lasted for 6–12 hours and was spontaneously alleviated within 24 hours postoperatively, with no increase in the incidence of other complications being observed.

The main limitation of this study is its retrospective nature. Future long-term, large-sample size randomized controlled trials are necessary to further verify our findings.

Conclusions

Subcutaneous local spraying of PAP on the operation area may be used to reduce postoperative drainage volume and shorten drainage time, and may reduce the formation of postoperative seroma. This treatment could alleviate local symptoms of patients, improve the patients’ quality of life, and save valuable time for further treatment.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at http://dx.doi.org/10.21037/gs-20-797

Data Sharing Statement: Available at http://dx.doi.org/10.21037/gs-20-797

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/gs-20-797). 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. The study was approved by the ethics committee of the West China Hospital of Sichuan University. Written informed consent was obtained prior to the study. All procedures performed in this study involving human participants were in accordance with the Declaration of Helsinki (as revised in 2013).

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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(English Language Editors: L. Gray and J. Gray)