Prospective comparison of Sapylin and Avitene for reducing hydrops after axillary lymphadenectomy in breast cancer patients

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Prospective comparison of Sapylin and Avitene for reducing hydrops after axillary lymphadenectomy in breast cancer patients Jinghua Zhao, PhD, Fengxi Su, MD, Yue Hu, MD, Jiannan Wu, MD, Yaping Yang, PhD, Fengtao Liu, MD, Ran Gu, PhD, and Weijuan Jia, PhD* Breast Tumor Department, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong Province, People’s Republic of China

article info

abstract

Article history:

Background: This study compared the efficacy of Sapylin and Avitene in reducing postoperative

Received 11 August 2016

axillary seroma formation and effusion when applied topically after axillary lymphadenectomy.

Received in revised form

Methods: A total of 224 patients were randomly divided into a Sapylin treatment group

14 October 2016

(STG), an Avitene treatment group, and a control group (CG). All patients underwent

Accepted 28 October 2016

axillary lymphadenectomy and were treated during surgery with Sapylin, Avitene, or

Available online 5 November 2016

neither according to their group assignment. The duration and amount of postoperative drainage, as well as the occurrence of seromas were recorded. Outcomes were compared

Keywords:

by one-way analysis of variance and chi-square tests.

Sapylin

Results: Baseline patient data, including age, body mass index, history of neoadjuvant chemo-

Avitene

therapy, type of surgery, number of resected lymph nodes, and number of positive metastases

Seroma

did not differ among the three groups. Patients in both the STG and the Avitene treatment group

Axillary lymphadenectomy

experienced significantly fewer days of drainage than those in the CG; there was no significant difference in drainage tube retention time between the two treated groups. The STG experienced significantly less drainage volume than the CG. Fewer patients in both treatment groups required seroma treatment or experienced complications compared with CG patients. Conclusions: Both Sapylin and Avitene effectively reduced postoperative subcutaneous fluid accumulation after axillary lymphadenectomy. These treatments may be particularly useful for breast cancer patients at high risk of seroma formation, especially those with hypertension, diabetes mellitus, or a high body mass index who undergo axillary lymphadenectomy. ª 2016 Published by Elsevier Inc.

Introduction Breast cancer is a leading cause of cancer-related mortality that affects millions of women worldwide.1 Although extensive mammary gland resection was the most common

treatment for breast cancer for many years, there have been recent improvements in diagnosis and treatment, including sentinel lymph node biopsy, radiotherapy, chemotherapy, and targeted breast cancer therapies. Besides, American College of Surgeons Oncology Group (ACOSOG) Z0011 was also a

J.Z. and F.S. contributed equally as first authors. * Corresponding author. Breast Tumor Department, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, No.33 Yingfeng Road, Haizhu District, Guangzhou, Guangdong Province, People’s Republic of China. Tel./fax: 0086-020-34071051. E-mail address: [email protected] (W. Jia). 0022-4804/$ e see front matter ª 2016 Published by Elsevier Inc. http://dx.doi.org/10.1016/j.jss.2016.10.032

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drug clinical trial for reducing seroma formation

pivotal clinical trial which showed that axillary lymph node dissection was not necessary for selected patients with earlystage breast cancer treated with breast-conserving therapy and adjuvant systemic therapy. These results changed the clinical practice guidelines, making less invasive treatment possible in many cases.2 However, for patients with positive sentinel lymph nodes but beyond the scope of what was considered safe in the Z0011 trial, complete axillary lymphadenectomy is still necessary. Complications from this procedure include lymphatic fistulae, axillary and upper extremity lymphedema, and seroma formation.3-7 Seromas have been reported to occur in 6%-52% of patients who undergo axillary lymph node resection.8,9 Although axillary seroma formation does not usually result in severe adverse effects, it can lead to wound infection, delayed wound healing, prolonged hospital stays, higher medical expenses, and postponed adjuvant therapy.10-12 These complications have a negative effect on the quality of life and mental status of patients, and prevention and control of seromas is considered clinically important. Methods for reducing seroma formation include compression bandaging of wounds, intraoperative use of an ultrasound knife, talcum powder, fibrin glueecoated collagen patches, and vacuum suction10,13-17; however, none of these are universally effective in reducing seroma-associated complications. Sapylin (OK-432) is an inactivated bacterial preparation made from hemolytic streptococcus A3 or SIPI722 low-toxicity variant strains that contain penicillin sodium and other active ingredients. Sapylin is currently used for immunotherapy of various malignant neoplasms and has been reported in clinical experiments to penetrate cancer cells and directly destroy their RNA processes, resulting in dilation, vacuolization, and necrosis of those cells. It can also incite local, bacteria-free inflammation, cause local tissue adhesion, and lessen the volume of local exudate.18-21 Its efficacy at reducing pleural and abdominal effusion is widely recognized.22,23 Avitene (Microfibrillar Collagen Hemostat) is an absorbable hemostatic material that is composed mainly of fibrillary collagen from cow dermis. When it contacts blood, fibrillar collagen triggers platelet aggregation resulting in rapid clot formation. In most cases, bleeding will stop within 2-5 min of its application. Avitene is particularly suitable for localized bleeding where ligation is difficult or cauterization is ineffective, for bleeding from fragile tissues or those with extensively distributed blood vessels, and for severe soft tissue hemorrhage.24-28 It has been shown to be more effective than previous fibrous collagen hemostatic agents and can be used to successfully control extensive exudation from the parenchyma.28 The aim of this prospective, randomized, controlled clinical trial was to evaluate the safety and efficacy of locally applied Sapylin and Avitene for the reduction of seroma formation after axillary adenectomy in breast cancer patients.

Methods Patients All eligible breast cancer patients admitted to the Department of Breast Surgery at Sun Yat-Sen Memorial Hospital in China

9

between September 2013 and December 2015 were asked to participate in this study, and all 224 patients signed the informed consent form before the trial began to show their willingness to do so. It is approved by the Ethics Committee of Guangzhou Women and Children Medical Center. This study has been filed as a clinical trial (ID: NCT02158299). The patients enrolled as the inclusion criteria (1) patient willingness to participate and sign the informed consent; (2) confirmed lymph node metastasis (diagnosed by preoperative biopsy or intraoperative sentinel lymph node biopsy) requiring axillary adenectomy; (3) no history of penicillin allergy or confirmed negative for penicillin allergy by a preoperative skin test; (4) no history of rheumatic heart disease; (5) no history of hematopathy; (6) no significant incidence of asthma or rashes in the patient or their immediate family; and (7) no previous history of axillary surgery. Exclusion criteria included: (1) severe hypertension; (2) history of diabetes or fasting plasma glucose of >6.9 mmol/L or postprandial blood glucose >11.1 mmol/L 2 h after a meal; (3) anticoagulant therapy within the past year; (4) body mass index (BMI) > 30; and (5) inability or unwillingness to participate in follow-up hospital visits and telephone calls. Eligible patients were randomly assigned following a random number table to a control group (CG), a Sapylin treatment group (STG), and an Avitene treatment group (ATG). After a preliminary experiment including 60 patients, we used PASS.11 to calculate the required sample size. And more than 160 volunteers were planned to be enrolled. Patients had no knowledge of the treatment groupings or their potential therapeutic outcomes (Figure).

Treatment All patients underwent conventional intraoperative dissection of the entire axilla, followed by wound surface flushing with normal saline. In the CG, conventional methods were used to place a vacuum-assisted drainage tube and the surgical incision was closed with continuous intradermal sutures. In the STG, after the wound surface was flushed with normal saline, 100 mL (10 KE) of Sapylin was locally applied for 30 min. In the ATG, 50 mg of Avitene powder was applied to the axillary wound surface after flushing. Drainage tubes were placed in the surgical wounds of patients in both the STG and ATG as in the CG, and the wounds were closed using standard techniques. All patients were treated with compression bandaging and vacuum aspiration after wound closure. Close attention was paid to vital signs and the amount of effusion. The drainage tube was removed when the volume of fluid obtained from the drainage tube was less than 30 mL for two consecutive days. All surgeries were performed by the same team to minimize bias. After drainage tube removal, patients regularly revisited the hospital for follow-up examinations. After removal, the patients’ primary care doctors conducted telephone follow-up interviews once a week for 1 month to ask whether they felt any pain or touched seroma. If so, these patients were called back to the hospital for examination. All patients were encouraged to make outpatient visits anytime they felt uncomfortable during 1 month after removal. Information about any palpable subcutaneous seromas was recorded. B

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Recruitment

Assessed for eligibility (n=250 ) Excluded (n=26 ) Not meeting inclusion criteria (n= 25 ) Declined to participate (n= 0 ) Other reasons (n=1 )

Randomized (n=224 )

Allocation Allocated to Sapylin Treatment (n=78 ) Received (n= 78 ) Did not received(give reasons) (n=0 )

Allocated to Avitene Treatment (n=68 ) Received (n= 68 ) Did not received(give reasons) (n=0 )

Allocated to negtive control (n=78 ) Received (n= 78 ) Did not received(give reasons) (n=0 )

Follow UP Lost to follow up （give reasons） (n=0 ）Discontinued intervention （give reasons） (n=0 )

Lost to follow up （give reasons） (n=0 ）Discontinued intervention （give reasons） (n=0 )

Lost to follow up （give reasons） (n=0 ）Discontinued intervention（give reasons） (n=0 )

Analysis Analyzed (n= 78) Excluded from analysis (give reasons) (n=0 )

Analyzed (n= 68) Excluded from analysis (give reasons) (n=0 )

Analyzed (n= 78) Excluded from analysis (give reasons) (n=0 )

Figure e Consolidated Standards of Reporting Trials (CONSORT) diagram for the trial. (Color version of figure is available online.)

ultrasonography of any axillary effusion was also carried out to determine if B-ultrasoundeguided paracentesis was necessary. Patient group assignment was not disclosed to their physicians.

Statistical analysis The mean postoperative drainage tube retention times and the mean volumes of effusion were recorded for each group. We also recorded the number of patients in each group who developed palpable seromas within 1 month after drainage tube removal, who had a large volume of local effusion accompanied by complications including wound infection, disunion, or delayed union. For this prospective, randomized, controlled clinical trial, we used one-way analysis of variance to assess the significance of between-group differences in normally distributed continuous data and chi-square or Fisher’s exact tests for nonparametric data. All analyses were performed using SPSS 19.0 statistical software, and differences with a P value < 0.05 were considered statistically significant.

Results Basic characteristics We initially recruited a total of 250 patients, but 26 were excluded because of severe hypertension, poorly controlled

diabetes, or high BMI. The remaining 224 patients all gave their informed consent to participate. Patient information for each of the three groups is shown in Table 1. There were no significant differences between the three groups in any characteristics, including age, BMI, application of neoadjuvant chemotherapy, total number of lymph nodes removed, and number of positive lymph nodes and operation times.

Postoperative test Major postoperative test indices for the three groups are shown in Table 2, and the comparisons between two-group pairings are shown in Table 3. The mean postoperative drainage tubes’ retention times were 7.97  0.41 days in the STG, 8.68  0.39 days in the ATG, and 11.64  0.65 days in the CG. Compared with the CG, drainage tube retention time was significantly shorter in both of the two treated groups (P < 0.001 for both). Although the mean drainage tube retention time was numerically less in the STG than the ATG, this difference was not statistically significant (P ¼ 0.336). The mean total volume of drainage was 430.49  34.42 mL in the STG, 493.46  37.59 mL in the ATG, and 602.74  48.54 mL in the CG. When these values were compared, patients in the STG produced significantly less effusion than the control patients (P ¼ 0.003), patients in the ATG showed a strong trend toward less drainage volume than the CG patients (P ¼ 0.064), and there was no significant difference between the mean volume of drainage produced by patients in the two treated

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drug clinical trial for reducing seroma formation

Table 1 e The details of general data of the 224 patients. Variable

Sapylin (n ¼ 78)

Avitene (n ¼ 68)

Control (n ¼ 78)

P value

Age w35

11

9

10

35w50

26

29

41

50w

41

30

27

1

39

32

34

2

27

28

30

3

12

8

14

4

0

0

0

0.794

The number of lymph nodes section

17.20  1.16

17.23  1.12

14.85  0.93

0.194

The number of positive lymph nodes

4.59  1.05

5.62  1.04

4.31  0.68

0.599

Body mass index

22.03  0.33

23.15  0.36

22.81  0.31

0.724

Yes

30

26

28

No

48

43

50

Breast-conserving surgery

33

29

22

Mastectomy

45

39

56

77

67

78

1

1

0

0.178

T stage (pathology)

Whether neoadjuvant chemotherapy

0.945

Operation method

0.110

Operative times Only 1 time 2 times

0.756

complication is more common in elderly and obese patients with severe hypertension or diabetes, and in those who are receiving neoadjuvant chemotherapy.29-31 Although seromas generally last less than 1 month after surgery and are usually not life-threatening,32 they may cause local infection, wound healing delay, and the extension of subsequent treatments. Furthermore, seromas may affect the postoperative recovery, exercise, length of hospitalization, medical expenses, and the mental status of the patients and their relatives.10 Many researchers have do the studies of the methods for reducing seroma formation, including compression bandaging of wounds, intraoperative use of an ultrasound knife, talcum powder, fibrin glueecoated collagen patches, and sealing device for vacuum suction after surgery routinely.10,13-17 These methods have been accepted by most surgeons around the world, but still there is part of the patients suffer the seroma formation. None of these ways could totally prevent this complication.

groups. Five of 78 patients in the STG and five of 68 patients in the ATG required seroma treatment (P ¼ 0.822). These were significantly lower proportions of patients than in the CG, 14 of 78 CG patients required seroma removal (P ¼ 0.048 and P ¼ 0.058 for STG versus CG and ATG versus CG, respectively). The STG also experienced significantly fewer complications than the CG (1/78 versus 5/78, P ¼ 0.043); in the STG, one suffered a wound infection, and in the CG, three patients had an infection, and two others had delayed wound union.

Discussion Surgical treatment is still indispensable for most breast cancer patients, although these procedures are usually accompanied by potential postoperative complications. Among these, seroma formation is the most common complication following mastectomy and axillary surgery.3-7 This

Table 2 e Major postoperative test indexes of the three treatment groups. Observation index Mean total drainage volume (mL) Mean duration of drainage (d)

Sapylin (n ¼ 78)

Avitene (n ¼ 68)

Control (n ¼ 78)

P value

430.49  34.42

493.46  37.59

602.74  48.54

0.01

7.97  0.41

8.68  0.39

11.64  0.65

<0.001

The number of patients who developed a palpable seroma

5

5

14

0.037

The number of patients who suffered complications

1

2

5

0.047

Overall complication rate (including palpable seroma)

6.41%

7.35%

17.9%

0.008

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Table 3 e Observation indexes between any of two treatment groups. Observation index

Sapylin versus control

Mean total drainage volume (mL) Mean duration of drainage (d)

Avitene versus control

Sapylin versus Avitene

0.003

0.064

0.285

<0.001

<0.001

0.336

The number of patients who developed a palpable seroma

0.048

0.058

0.822

The number of patients who suffered complications

0.043

0.275

0.215

Overall complication rate

0.009

0.019

0.774

In 1987, Tadych et al.33 discovered that the contents of a seroma were similar to lymph, which suggested that the seroma may caused by damage of lymphoid tissues during surgery. However, Watt-Boolsen et al.34 considered that the fluid was inflammatory exudate produced in process of the wound healing and its volume was related to the intensity and duration of the surgery. Bonnema et al.35 analyzed the composition of the fluid draining from the axilla after lymph node resection. Their findings suggested that the fibrinogen was insufficient in the postsurgical tissue cavity. Recently, great effort has been made to prevent the occurrence of seroma, like quilting sutures, delaying shoulder exercises, fibrin glue, octreotide, and the use of Sapylin.36,37 Sapylin was originally developed as an immunotherapeutic agent for cancer patients, and it was shown to decrease malignant effusions and significantly prolonged the survival of patients who responded well to treatment. Sapylin has been widely and effectively used for the treatment of ascites and pleural effusion caused by tumors or benign lesions.22,23,36,37 Recently, OK-432 was shown to reduce the incidence of seroma after axillary lymphadenectomy for breast cancer and breast reconstruction.38,39 Furthermore, OK-432 is more effective and safer than other sclerosing agents. The complication rate after intracystic injection of OK-432 is minimal, with no major side effects except for temporary pain and fever.40 Avitene has been used clinically since the 1970s.24 As a new-type styptic, Avitene is made from pure cow dermal collagen, which has excellent biocompatibility, biodegradability, hemostatic activity, antimicrobial activity, and wound-healing properties.41,42 Aside from reducing obvious and concealed bleeding in the surgical field, Avitene also works effectively to decrease parenchymal exudation. The mechanism would be supported by the absence of fibrinogen in the serum from the drainage of the patients, therefore suggesting that the addition of fibrin would reduce the formation of seroma. Several studies compared the effects of fibrin glue after axillary lymphadenectomy.43,44 Ruggiero et al.43 assigned 90 patients receiving quadrantectomy or mastectomy and axillary node dissection to treatment with fibrin glue plus drainage (45 patients) or with drainage alone (45 patients) and found that fibrin glue did not always prevent seroma formation, even if it may reduce seroma magnitude and duration. A previous meta-analysis44 of 11 randomized trials showed that fibrin sealant after breast surgery did not reduce the rate of postoperative seroma (relative risk: 1.14), the volume of drainage (weighted mean difference e: 117.7), or the length of stay (weighted mean difference e: 0.38). The authors concluded that the available evidences did not

support the use of fibrin sealant in breast cancer surgery to reduce postoperative drainage or seroma formation.44 However, they also found that most trials were small and of poor methodological quality. Our results showed that both Sapylin and Avitene significantly could reduce the duration of local drainage after axillary lymphadenectomy in breast cancer patients. Sapylin’s effect seemed better than Avitene in reducing total drainage volume, however, Sapylin required approximately additional 30 min for soaking and contained penicillin, which is contraindicated for some patients. Therefore, Sapylin it is not used as widely as Avitene in the clinical application. In conclusion, both Sapylin and Avitene could effectively reduce seroma formation after axillary lymphadenectomy. These treatments may be particularly useful for patients with high BMI, diabetes, or hypertension, or for those concurrently undergoing neoadjuvant chemotherapy.

Acknowledgment The authors would like to thank the patients who volunteered to participate in this prospective, randomized, controlled clinical trial. This study was supported by the National Natural Science Foundation of China (Grant No. 81372817). Author Contributions: Weijuan Jia and Jinghua Zhao did conception and design; Jinghua Zhao, Fengxi Su, Yue Hu, Jiangnan Wu, Fengtao Liu, and Ran Gu were responsible for data aquisition and analysis; and Jinghua Zhao contributed to article writing and editing for final submitting.

Disclosure The authors reported no proprietary or commercial interest in any product mentioned or concept discussed in the article.

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