Integration of perioperative reduction treatment with lymphaticovenular anastomosis for the management of lower extremity lymphedema

INTRODUCTION

The mainstay of lymphedema treatment is complex decongestive therapy (CDT). CDT is a conservative treatment method that includes compression therapy, manual lymph drainage, remedial exercise, and skin care, and it has been proven to be effective in reducing edema^[1-4]. However, studies have shown that the effectiveness of CDT is dependent on residual lymphatic function^[5,6]. Furthermore, CDT does not address functional insufficiency in the lymphatic drainage system^[7]. In contrast, microsurgical treatments, including lymphaticovenular anastomosis (LVA) and vascularized lymph node transfer, increase lymph drainage routes and boost lymphatic drainage, which all play an essential role in improving intrinsic lymphatic function^[7].

Studies have indicated the importance of compression therapy after LVA^[7-9]; however, no general consensus has been reached regarding when to start and what to combine in the early postoperative period^[10]. In general, CDT consists of two phases: a reduction phase, followed by a maintenance phase^[1-3,11]. Most patients are likely to undergo LVA surgery during their maintenance phase^[12,13]. According to the literature, after LVA surgery, patients typically resume and continue maintenance treatment, including compression therapy, after 1-4 weeks of postoperative interruption^[7,9,10]. However, to our knowledge, no study has reported an integration of conservative therapy in the early postoperative period, especially within 1 week after LVA.

In the early postoperative period, we hypothesized that reduction treatment could be performed more efficiently with a boosted lymphatic drainage through the LVA. Based on this hypothesis, we adopted reduction treatment in the early postoperative period after LVA surgery in October 2015. This study aimed to clarify the efficacy of the integration of LVA and perioperative reduction treatment (PORT), in the search for an optimal combination of surgery and conservative therapy for lymphedema, by retrospectively reviewing our experience treating patients with lower extremity lymphedema.

METHODS

We conducted a retrospective chart review of 134 consecutive patients with lower extremity lymphedema who were treated with LVA, by the same surgeon (FO), at two affiliated hospitals, Saitama Medical Center and Tochigi Cancer Center, between 2014 and 2018. The exclusion criteria were as follows: follow-up period of less than 1 year and patients who did not undergo appropriate compression therapy before and after LVA surgery. Patients with insufficient response to CDT or those whose clinical improvement plateaued following CDT were indicated for LVA surgery. PORT, which included compression therapy and remedial exercise, has been adopted in our clinical practice since October 2015 for use during the early postoperative period immediately following LVA. Prior to this, no additional perioperative intervention had been provided for patients who underwent LVA. In both cases, all patients who underwent LVA surgery wore elastic stockings as baseline maintenance therapy preoperatively for some duration (more than 1 year on average) and resumed wearing the stockings 1 week postoperatively. This study’s cohort was divided into two patient groups: patients who underwent PORT following LVA surgery (PORT group) and patients who underwent no additional perioperative intervention after LVA surgery during the early postoperative period (control group). The edema reduction effect was compared between the two groups. This study was conducted in accordance with the Declaration of Helsinki and was approved by the Institutional Review Board of Saitama Medical University (#1483) and Tochigi Cancer Center (#21-C004).

RESULTS

The baseline characteristics and demographics of patients who underwent LVA surgery with and without perioperative reduction therapy are summarized in Table 1. The current study included 116 patients with lower extremity lymphedema. Six patients (5%) presented with primary lymphedema and 110 patients (95%) developed lymphedema secondary to cancer therapy. Among these, 65 patients (56%) were treated with LVA surgery without perioperative reduction therapy, whereas 51 patients (44%) were treated with LVA followed by perioperative reduction therapy.

Overall, there was a significant difference between the two unmatched groups at the distribution in clinical stage (P = 0.03). That is, all the patient in PORT group were classified as stage II, whereas control group included 6 (9.2%) and 1 (1.5%) patients of stage I and III, respectively. Other covariates, including age, BMI, sex, etiology, institute of treatment, LEL index at the first visit, previous radiotherapy/LVA, and duration of preoperative conservative therapy, showed a slight difference between the two groups, although this was not statistically significant.

After propensity score matching, patients in each group were evenly matched for age, BMI, sex, etiology, clinical stage, institute of treatment, LEL index at the first visit, previous radiotherapy/LVA, and duration of preoperative conservative therapy. PORT group demonstrated significantly lower LEL indices at 1 year postoperatively than at 1 month preoperatively (P < 0.001), whereas the control group did not (P = 0.14). Patients who underwent PORT had a significantly higher reduction in LEL index than those in the control group (14.7 vs. 6.7; P = 0.03) [Table 2]. We did not experience any unfavorable complications in our cohort related to PORT, including hemorrhage, wound infection, and wound dehiscence.

Case presentation

A 63-year-old female patient had bilateral lower extremity lymphedema secondary to cervical cancer and had undergone over 5 years of compression therapy using elastic stockings [Figure 1A]. Preoperative lymphoscintigraphy showed extensive dermal backflow in the right lower leg, right thigh, and left thigh [Figure 2A]. The patient underwent LVA surgery followed by PORT of the right lower extremity during her 7-day hospital stay. After she was discharged from the hospital, compression therapy with elastic stockings was continued. A remarkable improvement in the LEL index, by up to 20.9, was noticeable 1 year postoperatively [Figure 1B]. Lymphoscintigraphy at 6 months after treatment demonstrated a significant reduction in dermal backflow in the right lower extremity [Figure 2B].

Figure 1. An illustrative case of a 63-year-old woman with bilateral lower extremity lymphedema who underwent perioperative reduction treatment following LVA. (A) 1 month before LVA; (B) 1 year after LVA for the right lower extremity. A remarkable improvement of edema in the right lower extremity was noted. LVA: Lymphaticovenular anastomosis.

Figure 2. Comparison of lymphoscintigraphy before and after the treatment. (A) 1 month before LVA; (B) 6 months after LVA. Note that the dermal backflow over the right lower leg and the thigh diminished and the lymphatic pathways became distinct after LVA followed by perioperative reduction treatment. LVA: Lymphaticovenular anastomosis.

DISCUSSION

This study demonstrated that the treatment efficacy of LVA surgery followed by PORT was significantly higher than that of LVA with no combined therapy in the early postoperative period.

According to Filippetti et al.^[17], the benefits of CDT are generated by improving lymph drainage while preventing venous pressure from rising. Studies have shown that a good response to CDT is correlated with a higher remaining lymphatic function^[5,6]. Therefore, those findings suggest that the basic principle of CDT depends on the remaining lymphatic system. Given that the microsurgical treatment of lymphedema could play a role in improving the intrinsic deteriorated lymphatic function^[7,18], it could be hypothesized that CDT, especially reduction treatment, would be more effective, with improved remaining lymphatic function after LVA surgery.

LVA is a microsurgical treatment that redirects excess lymph fluid from the interstitial space to the venous circulation through the bypasses. For better improvement with LVA, lymphatic pressure needs to be higher than venous pressure^[10,12,19]. In an experimental study, Gloviczki et al.^[20] reported that the main problems responsible for occlusion of LVAs were low lymphatic flow, low pressure gradient across the anastomosis, and venous reflux. They mentioned that lymph flow eventually diminished as the anastomosis gradually reduced lymphatic pressure, which usually deteriorates in lymphedema in the first place. According to a systematic review conducted by Tourani et al.^[21], the overall long-term patency rate of LVA was discouraging in animal studies due to the gradual decline of the pressure gradient across the anastomosis and the eventual thrombosis due to venous reflux. Similarly, several clinical studies have reported that venous reflux diminished the surgical outcome with LVA^[22] and caused occlusion of the anastomotic site over time^[23].

Tourani et al.^[21] mentioned possible technical ideas to overcome the decrease in lymphatic pressure and thrombus formation from venous reflux at the anastomoses; however, they did not include a physiotherapeutic approach. In other words, muscle pumping under compression therapy can amplify lymphatic flow^[20,24,25]. Chen et al.^[26] observed that immediate limb compression following LVA prevented venous backflow by augmenting lymphatic pressure. Likewise, according to Olszewski et al.^[25], muscle contraction in the lower leg increased lymphatic pressure and could play an important role as a driving force for lymph flow. They observed that lymphatic pressure could rise as much as 100 mmHg during muscle contraction under compression therapy and that the optimal compression pressure was 40 mmHg. It can be hypothesized that this amplified lymphatic flow yielded by muscle pumping under compression therapy could boost bypass flow and overcome venous reflux. Thus, we presumed that LVA followed by reduction treatment in the early postoperative period would be more beneficial than LVA with maintenance treatment resumed after a certain period of interruption.

Generally, LVA is indicated when conservative therapy is proven to be insufficient or plateaued^[12,13]. Studies have reported that the previous compression therapy, namely maintenance treatment, should be restarted one month postoperatively^[7,9,10,27]. We believe that this may be a loss of great opportunity for another reduction treatment because the lymphatic-venous pressure gradient and the boosted lymphatic function could be optimal in the early postoperative period with the bypasses. Our findings support the possibility of improving lymphedema more efficiently by combining PORT with LVA. We aimed at the highest interface pressure the patient could tolerate by exerting 20-60 mmHg using compression therapy, as reported in previous studies^[1,25]. Additionally, we demonstrated that physical exercise under compression could be combined efficiently and safely as an integral part of PORT. Without a doubt, patients should continue maintenance treatment at home after discharge from the hospital to maintain the reduction in edema.

As previous studies have reported low rates of complications for LVA surgery, such as infection and lymphorrhea^[27], our clinical protocol was not accompanied by those complications perioperatively. Undoubtedly, care must be taken to avoid shear stress on the anastomotic site when patients apply compression garments or bandages^[28] in the early postoperative period. In addition, remedial exercise is not considered harmful for anastomotic sites unless they are exposed to a traumatic external force. Several review studies have shown that the hospital stay after LVA surgery can be as short as 1 day^[29], and patients are assumed to return to their normal daily life. It is presumed that our exercise protocol activity during hospital stay is no more than daily activities. Thus, our study may support the safety of reduction treatment in the early postoperative period.

Our study has some limitations. First, we cannot separately determine the exact efficacy of LVA and that of perioperative reduction treatment because edema reduction after LVA should be an integrated effect of both LVA and CDT. Therefore, further investigation should clarify whether our enhanced treatment efficacy can be attributed to the effect of LVA itself under augmentation with PORT or the effect simply added by CDT. Second, we did not address the long-term patency of LVA. Accordingly, whether perioperative reduction therapy can impact the patency of LVA should be elucidated in future studies. Third, our assessment only focused on the edema reducing effect with the suggested lymphedema treatment. Since lymphedema is often comorbid with acute or chronic inflammation as well as fluid accumulation, further investigation regarding the efficacy of the suggested combined treatment on reducing inflammation is needed.

In conclusion, our study demonstrated that LVA surgery plus PORT yielded significantly greater edema reduction than LVA alone in the early postoperative period. Based on our findings, it would be highly beneficial to combine reduction treatment during the early postoperative period after LVA surgery to maximize treatment outcomes because the surgical outcomes of LVA alone can be diverse. To our knowledge, our study is the first to describe a combination of LVA and PORT. We believe that this study will contribute to the development of an optimal treatment strategy for patients with lymphedema.