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Negative pressure wound therapy versus conventional wound care in cancer surgical wounds: A meta‐analysis of observational studies and randomised controlled trials

Abstract The application of negative pressure wound therapy (NPWT) in cancer surgical wounds is still controversial, despite its promising usage, because of the risks of increased tumorigenesis and metastasis. This study aimed to review the risks and benefits of NPWT in surgical wounds with the underlying malignant disease compared with conventional wound care (CWC). The first outcome was wound complications, divided into surgical site infection (SSI), seroma, hematoma, and wound dehiscence. The secondary outcome was hospital readmission. We performed a separate meta‐analysis of observational studies and randomised controlled trials (RCTs) with CI 95%. Thirteen observational studies with 1923 patients and seven RCTs with 1091 patients were included. NPWT group showed significant decrease in the risk of SSI (RR = 0.45) and seroma (RR = 0.61) in observational studies with P value <0.05, as well as RCTs but were not significant (RR = 0.88 and RR = 0.68). Wound dehiscence (RR = 0.74 and RR = 1.15) and hospital readmission (RR = 0.90 and RR = 0.62) showed lower risks in NPWT group but were not significant. Hematoma (RR = 1.08 and RR = 0.87) showed no significant difference. NPWT is not contraindicated in cancer surgical wounds and can be considered a beneficial palliative treatment to promote wound healing.

• NPWT is not contraindicated in cancer surgical wounds and can be considered a beneficial palliative treatment to promote wound healing

| INTRODUCTION
One of the leading causes of death globally is malignancy, which is a wound associated with cancer. 1 According to a 2019 research by the World Health Organization (WHO) cancer ranks first and second as the foremost cause of death in 112 of 183 countries and fourth in 23 others. 2 Most patients with cancer have a combination of treatment, such as surgery with chemotherapy and/or radiation therapy. 3 However, despite the disease itself, chemotherapy and radiation therapy can delay postoperative wound healing. 4 Wounds that are slow to heal can turn into chronic wounds, which can easily increase complications including seroma, wound dehiscence, infection, hematoma, or other problems that can reduce the quality of life. 5 Negative pressure wound therapy (NPWT), also recognised as vacuum-assisted closure (VAC), is a system used to close large and complicated wounds by applying sub-atmospheric pressure. 6 The mechanism of NPWT involves wound contraction, extracellular fluid removal, and wound environment stabilisation, which results in a decrease of tissue edema and bacterial colonisation, increase in blood flow, angiogenesis, granulation formation, and faster wound healing. 7 NPWT decreases the biological destruction caused by local harmful substances to the body. Meanwhile, the continuous negative pressure significantly increases the flow rate of local microcirculation and the diameter of microvessels. 8 This technique is applied to promote the formation of granulation tissue in open wounds, clean surgical incisions, and cover skin grafts. 9 NPWT gave advantages by reducing the wound healing time and the risk of surgical complications, including surgical site infection (SSI), 10 seroma, haematoma, and wound dehiscence. 11 Despite its promising clinical usage, previously, NPWT was an absolute contraindication for wounds with underlying malignant diseases because of risks of increased tumorigenesis and metastasis. 12 This belief is derived from the study of normal tissues, and to the authors' knowledge, there has been no literature that directly supports the hypothesis that NPWT regulates tumour progression. However, with the development of new research, regarding its benefits for the palliative treatment of malignant wounds, the NPWT use in cancer wounds has changed from absolute contraindications to relative contraindications. 13 In patients with malignancy, the normal wound healing process is often interrupted, influenced by both the malignancy itself and the treatment's course, 14 which resulted in consideration of NPWT use.
Presently, there is no substantial evidence that prevents the use of NPWT on wounds with underlying malignant diseases. Therefore, we aim to conduct a metaanalysis assessing the risks and benefits of NPWT in surgical wounds with the underlying malignant disease compared with conventional wound care (CWC); thus, NPWT can be considered as a beneficial palliative treatment to promote wound healing.

| Study selection
Three reviewers (LB. Adzalika, R. Pramanasari, IL. Putri) searched for observational studies and randomised controlled trials (RCTs) that compared NPWT with CWC for wounds with the underlying malignant diseases and compared postoperative wound complications after interventions between the two groups. Only human studies reported in English with full-text availability were included. Any disagreement was solved by negotiation or a consensus meeting with the fourth investigator (CDK. Wungu).
The main outcome was wound complications divided into SSI, seroma, haematoma, and wound dehiscence. The secondary outcome was hospital readmission. We eliminated studies with unspecific wound complications and studies without comparators.

| Literature search
This systematic study was carried out with the metaanalysis appropriate with the guidelines of Preferred Reporting Items for Systematic Reviews and Metaanalysis (PRISMA), as shown in Figure 1.
Some of the keywords used to carry out this study are negative pressure wound therapy, NPWT, VAC, vacuumassisted closure, cancer, malignant/malignancy, wound, included their synonyms and controlled vocabulary (MeSH or Emtree terms) when ready. The search term was such as ("negative pressure wound therapy" OR "vacuum-assisted closure" OR "NPWT" OR "VAC") AND (malignan* OR cancer) wound. Figure 1 illustrates the search strategy in detail. Three researchers identified relevant studies from PubMed, ScienceDirect, Web of Science, ProQuest, and the registry trial (www.clinicaltrials.gov) from July 15, 2021, to July 28, 2021. All studies were then exported to Mendeley to be sorted out.

| Data extraction
We independently selected data on authors, publication year, country, study design, population, mean age, follow-up periods, type of cancer, type of surgery, NPWT pressure, mode, length of use, the occurrence of SSI, seroma, haematoma, dehiscence, and readmission (Tables 1, 2). Data were extracted from preliminary studies and cross-checked to eliminate discrepancies.

| Risk of bias and quality assessment
The observational studies' quality, such as case-control and cohort studies, was evaluated applying the Jadad scale for RCT studies (Table 3), and the Newcastle-Ottawa scale (NOS) (Tables 4, 5). The score is considered high quality if the score is 7 or higher for the NOS score 34 and 3 or higher for the Jadad scale. 35

| Statistical analysis
RevMan 5.4 statistical software (Cochrane Collaboration) was used to determine statistical analysis with a relative risk ratio (RR) of 95% confidence intervals (CIs) applied to analyse the random-or fixed-effect models. Furthermore, the significant outcome of the two-sided statistical tests was determined with a P value <0.05. This study uses the inconsistency index statistic (I 2 ) to assess heterogeneity, and the value of the I 2 statistic also reflects the level of heterogeneity. If I 2 was >50% and P value <0.05, the trials were used to determine the heterogeneous, and random-effects models. Otherwise, the fixed-effects model was chosen. A funnel plot was performed to estimate publication bias. animal studies (n = 212); studies other than observational studies or RCT (n = 798). Based on the screening criteria for the relevance in titles and abstracts, 318 studies were removed. After full-text reviews, we eliminated 13 studies. Finally, 20 eligible studies were selected for a qualitative review, including 13 observational studies and 7 RCTs. The flow chart of the study selection process can be seen in Figure 1.

| Studies' quality assessment and bias risk
The mean NOS score was 7.3/9, indicating high quality of the included observational studies, and the mean Jadad scale was 2.3/5 for RCT studies, indicating low quality. Table 3 presents the quality of RCT studies evaluated by the Jadad scale. Meanwhile, Tables 4 and 5 presents the quality of 11 included case-control and two cohort studies evaluated by NOS. Funnel plot analysis of included observational studies showed no significant publication bias ( Figure 2). We identified an outlier by De Rooij 2021. After temporarily excluding the study, there was no significant effect. Funnel plot analysis of included RCT studies was not performed because of the limited studies.
Most of the studies were considered representative and were in line with the studies we included, as most malignant tumours are treated in medical centres. All included studies reported SSI, and some studies reported other complications, ie, seroma, haematoma, dehiscence. Most of the studies reported hospital readmission, therefore we added it as the secondary outcome.

| Surgical site infection
Observational studies Thirteen observational studies reported the data on the SSI risk after NPWT use or CWC. The SSI rate in the NPWT group was 10.27% and in the CWC was 25%. The use of NPWT was associated with a significant decrease in the risk of SSI in patients with cancer compared with CWC (RR = 0.45; 95% CI 0.35-0.57; P < 0.00001). There was no statistical heterogeneity among the evaluated studies (I 2 = 46%; P = 0.03) (Figure 3).

RCTs
Seven RCTs reported the data on the risk of SSI after NPWT use or CWC. The SSI rate in the NPWT group was 12.89% and in the CWC was 15.32%. The NPWT occurred because of the decrease in risk of SSI in cancer patients, which is insignificant (RR = 0.88; 95% CI 0.67-1.16; P = 0.38). There was no statistical heterogeneity among the evaluated studies (I 2 = 0%; P = 0.66) (Figure 3).

| Seroma
Observational studies Six observational studies reported the data on the seroma risk after NPWT use or CWC. The seroma rate in the NPWT group was 5.12% and in the CWC group was 10%. The significant decrease in the occurrence of seroma in patients suffering from cancer was associated with CWC (RR = 0.61; 95% CI 0.38-0.98; P = 0.04). Furthermore, the evaluated studies have no statistical heterogeneity (I 2 = 53%; P = 0.06) (Figure 4).

RCTs
Five RCTs reported the data on the risk of seroma after NPWT use or CWC. The seroma rate in the NPWT group was 4.7% and in the CWC group was 7.04%. The use of NPWT was correlated with a decrease in the SSI risk in patients with cancer compared with CWC, but was not significant (RR = 0.68; 95% CI 0.41-1.13; P = 0.14). There was no statistical heterogeneity among the evaluated studies (I 2 = 0%; P = 0.68) (Figure 4).

| Hematoma
Observational studies Approximately four observational studies were used to analyse the data associated with the hematoma risk after NPWT or CWC. The haematoma rate in the NPWT group was 1.6% and in the CWC was 1.74%. The use of NPWT showed no significant difference in decreasing the haematoma risk (RR = 1.08; 95% CI 0.42-2.75; P = 0.88). There was no statistical heterogeneity among the evaluated studies (I 2 = 36%; P = 0.20) (Figure 5).

RCTs
Four RCTs reported the data on the risk of haematoma after NPWT use or CWC. The NPWT and CWC groups had haematoma rates of 0.88% and 1.08%. The use of NPWT also showed no significant difference in decreasing the risk of hematoma (RR = 0.87; 95% CI 0.27-2.84; P < 0.82). Furthermore, there was no statistical

| Wound dehiscence
Observational studies A total of seven observational studies were used to determine the data associated with the risk of wound dehiscence after the occurrence of NPWT and CWC. The dehiscence rate in the NPWT group was 5.33% and in the CWC was 10%. The use of NPWT was correlated with a decrease in the wound dehiscence risk in patients with cancer compared with CWC, but was not significant (RR = 0.74; 95% CI 0.45-1.19; P = 0.21). There was no statistical heterogeneity among the evaluated studies (I 2 = 21%; P = 0.27) ( Figure 6).

RCTs
Five RCTs reported the data on the risk of wound dehiscence after NPWT use or CWC. The wound dehiscence rate in the NPWT group was 7.56% and in the CWC was 6.56%. CWC is correlated with a reduction in the risk of wound dehiscence in patients suffering from cancer compared with NPWT, but was not significant (RR = 1.15; 95% CI 0.73-1.81; P = 0.54). Furthermore, there was no statistical heterogeneity inherent in the evaluated studies, as shown in Figure 6 (I 2 = 0%; P = 0.94).

| Hospital readmission
Observational studies Four observational studies reported the data on the hospital readmission risk after NPWT use or CWC. The hospital readmission rate in the NPWT group was 10% and in the CWC group was 11.2%. The possibility of readmitting patients with cancer decreases with NPWT use compared with CWC (RR = 0.90; 95% CI 0.61-1.32; F I G U R E 3 Surgical site infection P = 0.58). Figure 7 shows there was no statistical heterogeneity associated with the evaluated studies (I 2 = 0%; P = 0.97).

RCTs
Three RCTs reported the data on the risk of hospital readmission after NPWT use or CWC. The hospital

F I G U R E 4 Seroma
F I G U R E 5 Haematoma readmission rate in the NPWT group was 4.06% and in the CWC group was 6.18%. NPWT is associated with a decrease in the rate at which patients with cancer are readmitted into the hospital (RR = 0.62; 95% CI 0.25-1.52; P = 0.30). There was no statistical heterogeneity among the evaluated studies (I 2 = 0%; P = 0.40) (Figure 7).

| DISCUSSION
According to Mendez-Eastman 37 the use of NPWT is inappropriate with malignancy because when the mechanical stretch is performed to normal cells, it leads to increased proliferation. Furthermore, in malignancy, cancerous cells often are not anchored because of their inability to respond to the stimuli, thereby making NPWT ineffective. However, several studies have been done using NPWT in cancer surgical wounds and gave interesting results. This research summarised the available evidence associated with the effects of NPWT for cancer surgical wounds. Almost all of the studies included were from developed countries. 38 Only one study, an RCT, was from a developing country, China. Nevertheless, that did not correlate with the completeness of the data. The ratio of subjects treated with NPWT and CWC in observational studies was 1:2, demonstrating that the use of NPWT in malignancies was lower may be because of its high cost, less availability, fear of harming patients, and risk of accelerated metastasis, although none have provided solid evidence to support this hypothesis. A recent metaanalysis 39 consisted of six observational studies that evaluated local oncological recurrence of NPWT use in cancer surgical wounds without residual malignancy and its complications showed that there was no significant difference between NPWT and CWC. The differences with our study were that we performed a meta-analysis of observational studies consisted of 13 studies and RCTs consisted of 7 studies, and evaluated more detailed postoperative wound complications divided into SSI, seroma, haematoma, wound dehiscence, and hospital readmission. Overall, our analysis showed a better result in SSI and seroma rates in observational studies and no significant difference in other parameters.
As a risk factor for cancer in 2021, the National Cancer Institute stated that the median age of patients diagnosed with cancer was 66 years, which means half of all cancers occur in people older than this age and half in people younger than this age for several common cancers, such as breast cancer, colorectal cancer, prostate cancer, and lung cancer. 40 Meanwhile, a study that analysed the incidence and mean age at diagnosis for global cancer stated that the average age of cancer incidence in the world was 65.73 years. 41 In this study, the patients' mean age was 60.96 years, ranging between 53.2 and 73.18 years.
The follow-up period of all included studies lasted for a minimum of 30 days, as the postoperative wound complication can take place up to 30 days after the surgery, particularly for SSI, and influencing the incision or deep tissue at the operation site. 42 Another study 43 showed a similar postoperative follow-up ranged from 28 to 42 days but was most commonly limited to a 30-day-follow-up as advised by the CDC guidelines. 44 Most of the included studies were using NPWT with the pressure of À125 mmHg with a continuous mode that lasted for 2 to 10 days. Two observational studies were using À80 mmHg and one study was using À100 mmHg pressure. This corresponds to the meta-analysis done by Borgquist in 2010, which stated the clinical standard pressure for treating wounds with NPWT is À125 mmHg. 45 Kairinos (2008) carried out a research to determine the standard pressure on wounds and the clinical inconsistencies associated with the use of NPWT. 46 According to Kairinos, higher magnitudes inflict pain on the patient as opposed to negative pressure, which lowers it from À125 to À50 mmHg. Secondly, care need to be taken when determining the vascularity of compromised tissue because the high levels of negative pressure cause ischaemia. According to preliminary studies, NPWT contradicts because of inconsistency in vascularity. Miller and Lowery stated that the specific suction pressures universally accepted is À125 mmHg. 47 Contrary to complete data of NPWT in observational studies, four out of seven RCTs did not state the pressure, mode, and duration of NPWT. This could lead to immeasurable results of the study.
Observational studies indicated a significant SSI risk reduction in the NPWT group, which is consistent with the results of several previous reviews in other surgical wounds. 48,49 NPWT is suggested to reduce the infection rate for the following reasons: For wound care, NPWT systems reduce the frequency of dressings, the wound site would be less exposed. 48 NPWT tends to create a positive wound healing environment by removing inhibitors such as metalloproteinases, microorganisms, 50 promoting better microvascular circulation to reduce bacterial colonisation. 51 The seroma rate was also significantly lower in the NPWT group in observational studies, which is in accordance with several past study. 52,53 It is not fully understood how NPWT leads to a reduced seroma formation in the wound. Horch et al 15 suggested that NPWT leads to a significant increase in tissue perfusion and oxygenation.
Both hematoma rates in observational studies and RCTs did not show significant differences, while a study done by Ge in 2018 11 showed a significant result in reducing haematoma risk on various surgical wounds. Nevertheless, the incidence rate was low in both analyses (1.6% and 0.88%) because NPWT application was done in the operating room so that excellent wound haemostasis could be ensured.
We found that the wound dehiscence rate in observational studies favoured the NPWT group. Contrary to that, RCTs showed a trend towards a lower wound dehiscence rate in patients treated with CWC. Nonetheless, there was not much difference in the incidence of wound dehiscence in the two groups (7.56% and 6.56%). This could be because of the low quality of the included RCT studies, which also did not show significant results in all analyses. Some of the studies did not include the pressure, mode, and duration of the installed NPWT, so a thorough look could not be done.
The hospital readmission rate in both analyses favoured towards NPWT group, which indicated fewer complications in the NPWT group compared with CWC only, therefore no need for re-hospitalisation. A study 16 also stated that patients who smoked or patients with alcohol/drug abuse had a higher hospital readmission rate.
Overall, the NPWT groups showed a better improvement in decreasing the complications rate in both observational studies and RCTs. However, all of these RCT analysis results may require more exploration with a higher number and better quality of RCTs.

| LIMITATION
Our study has some limitations. Because the number of RCTs performed was limited compared with observational studies, and the included RCT studies were low in quality because of the nature of inability to double-blind the intervention, coupled with the large number of patients who dropped out, led to the ratio of poor quality to good quality RCTs into 4:3. Another limitation was this study did not analyse the tumour recurrence, but only the postoperative wound complications and hospital readmission.

| CONCLUSION
Our meta-analysis showed the best results in the risk of SSI and seroma between NPWT and CWC in cancer surgical wounds. The NPWT use was correlated with fewer complications such as SSI, seroma, haematoma, wound dehiscence, and hospital readmission. Therefore, NPWT is not contraindicated in cancer surgical wounds and can be considered a beneficial palliative treatment to promote wound healing.