Prevention of seroma following inguinal lymph node dissection with prophylactic, incisional, negative-pressure wound therapy (SEROMA trial): study protocol for a randomized controlled trial

The incidence of malignant melanoma is rising. If malignant melanoma spreads, it is most commonly to the regional lymph nodes [1]. Inguinal or ilioinguinal lymph node dissection (ILND) is an operative intervention, where the lymphatic tissue and surrounding fat is removed from the groin en bloc to try to prevent further dissemination of the melanoma [2]. In case of verified or suspected metastasis to the pelvis, lymph nodes inferior to the internal iliac artery are also removed. However, the procedure is associated with a significant morbidity rate [3]. Studies have shown that up to 80% of patients undergoing ILND experience major postoperative complications such as seroma, surgical site infection (SSI), wound breakdown, hematoma and lymphedema [4]. Seroma is a collection of serous fluid in the wound cavity, formed by inflammatory exudates in response to the acute phase of wound healing following surgical trauma and/or by leaking lymph vessels [5]. Postoperative seroma is seen in about 50% of patient undergoing ILND [4], and is, therefore, one of the most frequently encountered complications. The serous fluid accumulation distends the wound cavity leading to increased risk of SSI, prolonged wound healing and possibly leading to higher risk of lymphedema [3]. Patients suffering from seroma and related wound complications often require prolonged hospitalization and multiple outpatient visits with associated high costs to the health system [6, 7]. Due to the high complication rate following ILND [8], there is a need for new evidence-based strategies to reduce the risk of complications.

Incisional Negative-pressure Wound Therapy (iNPWT) is a mechanical treatment modality, which has been shown to facilitate wound healing through vacuum-assisted closure [9]. The vacuum package consists of a single-use, battery-powered device and a dressing, which can be applied to the surgical field after the incision has been closed. Biomechanical studies have shown that iNPWT treatment leads to removal of interstitial fluid and increased blood and lymph flow which may in turn decreases the risk of seroma and lymphedema [10‐12]. The risk of postoperative seroma and SSI following other surgical procedures has been shown to be halved by the prophylactic use of iNPWT [13]. However, it remains to be investigated as to whether the same technique can be used to reduce complications after ILND.

The aim of this study is to investigate the value of iNPWT in reducing complications following ILND, when applied to the surgical field immediately after macroscopic complete removal of all malignancy [14, 15].

All analysis will be conducted on the intention-to-treat principle using STATA (StataCorp, College Station, TX, USA). Baseline variables are used to describe the characteristics of the trial participants. Continuous variables are summarized as mean and standard deviation or as median and interquartile range (25th to 75th percentiles) if the distribution is asymmetrical. Categorical variables are summarized as numbers and percentages. The categorical variables will be compared between groups with chi-squared test or Fisher’s exact test depending on the number of events. The continuous variables will be compared between groups using an unpaired t test or Mann-Whitney depending on data representation. A two-sided P value of less than 0.05 will be considered significant and reported with a 95% confidence interval when applicable

The primary outcome is the proportion of patients with at least one seroma aspiration and will be compared between groups using chi-squared test or Fisher’s exact test, depending on the number of events.

The secondary outcomes consist of categorical and continuous variables. SSI, wound dehiscence, wound necrosis, hematoma, reoperation, lymphedema and regional recurrence will be sampled as categorical variables and compared between groups. The cumulative volume and number of seroma aspirations, volume of collected lymph fluid, days until drain removal, quality of life scores, length of hospitalization and re-admission times will be registered as continuous variables and compared between groups.

Subgroup analyses of patients with iliac LND will be conducted as removal of these more proximal and deeper lymph nodes require extensive surgery beyond the inguinal boundary. Patients requiring this additional surgery may be at an increased risk of additional morbidity such as lymphedema, and recurrence.

The purpose of this trial is to evaluate the efficacy and oncological safety of iNPWT for the prevention of the clinically relevant morbidities after ILND. In addition, this study is an advancement of trial methodology for assessment of postoperative outcomes after lymph node excisions. The study is expected to generate valuable new information in the possible prevention of postoperative complications and improve recovery following cancer treatment.

Lymph node dissection is associated with considerable morbidity and selection of appropriate patients is of importance. For melanoma patients with a low lymph-node-tumor burden (micrometastases in sentinel nodes), the MSLT-II trial showed no additional 3-year survival for complete dissection when compared to observation and delayed lymph node dissection in case the patient later revealed regional metastases [2]. While a long-term survival comparison is still pending, complete dissection provides better regional disease control and could be advocated for patients with a greater tumor burden, and the general opinion is that patients with larger metastases should still undergo lymph node dissection if no evidence of distant metastases. Patients undergoing dissection of the groin lymph nodes are particularly prone to postoperative morbidity and previous studies have suggested conservative and minimally invasive ILND protocols [22, 23] however, these have yet to achieve broad acceptance due to the risk of compromising oncological safety. In this study, the ILND procedure is performed according to the national guidelines in Denmark, and, therefore, does not vary between study groups. Because iNPWT may increase tissue vascularization, the device is only applied when all malignancy has been excised. Thus, it is presumed that there will be no difference in regional recurrence between intervention and control groups. The safety and tolerability of iNPWT for other indications has been well established for many years. Reported discomforts related to its use has been associated to bandage removal, which is similar to the discomfort following regular postoperative dressing removal [13, 24]. This minor discomfort is, however, insignificant compared to the potential benefit of iNPWT application.

The outcomes investigated in this study were chosen due to their relevance to clinical practice and postoperative complications were defined as the need for treatment. The primary outcome, seroma, is often the first sign of a problematic wound-healing trail and prevention may, therefore, in turn, prevent some of the frequent subsequent complications. During the planning of the study, blinding and the use of a sham iNPWT device was considered, but not found feasible due to the nature of the intervention, which exerts a vacuum on the wound. The study will be conducted in accordance with the published protocol and positive, negative and inconclusive results on the short-term complications will be published, when all patients have completed their 3-month follow-up visits. A separate publication on the long-term lymphedema evaluation and regional recurrence will be published, when all patients have completed their 2-year follow-up. All publications derived from this study will adhere to the Vancouver author convention.

Prevention of diseases can be more efficient than treatment if the preventive intervention is more cost-effectiveness than the treatment [25, 26]. In this study, a relatively inexpensive device may prevent several outpatient and inpatient appointments and treatment-related costs. The results from this trial will, therefore, elucidate the efficacy and safety of prophylactic iNPWT treatment in prevention of the major short- and long-term postoperative complications following ILND. Regardless of the outcome, this study will benefit the patients by providing a solid foundation for future research in the field of prophylactic wound care treatment after lymph node dissection for cancer in general, possibly also in other regions such as the axilla and the neck.

At the time of manuscript submission, the trial is not yet actively enrolling participants.