A prospective longitudinal observational multicenter study, the Lymphoedema After Surgery of Endometrial Cancer (LASEC) trial, was conducted between June 2014 and January 2018. Fifteen hospitals in Sweden participated; four university, seven central and four county hospitals. Sweden is divided into 21 administrative regions that take care of healthcare. All regions are affiliated with one of the seven university hospitals in the country. In addition to caring for patients in their own regional catchment areas, the university hospitals also care for referral patients from the regions connected to the university hospital who need highly specialized care. EC surgery that includes lymphadenectomy is generally considered as highly specialized care and consequently, these patients are referred to university hospital facilities whereas women with EC that is not considered to require lymphadenectomy are treated at the local hospital.

Women diagnosed with apparent early-stage EC and assigned for primary surgery were eligible for the study. After oral and written consent was obtained, the participants underwent surgery and adjuvant oncological treatment according to the recommendations of the Swedish National Guidelines for Endometrial Cancer (SNGEC) [1]. The Regional Ethics Board of Linköping University (Dnr 2013/373-31) approved the study. The study was performed in accordance with the Declaration of Helsinki.

The flowchart, the inclusion and exclusion criteria, power estimation, clinical data, and postoperative follow-up have previously been published and described in detail [18].

The EC was preoperatively categorized as low- or high-risk as described in the SNGEC [1] and by Stålberg et al. [21]. The guidelines recommend laparoscopic surgery when possible [1]. The surgical method (open or minimally invasive (i.e., laparoscopic, or robotic-assisted laparoscopic surgery)) was accordingly decided by the surgeon with the patient’s consent. The surgery comprised total hysterectomy (TH) and bilateral salpingo oophorectomy (BSOE) with pelvic and para-aortic lymphadenectomy on women categorized as having high-risk EC, whereas TH and BSOE without lymphadenectomy were performed on women categorized as having low-risk EC.

The lymphadenectomy was intended to comprise resection of the lymph nodes on the pelvic sidewalls from the inguinal ligament distally, and para-aortic cranially to the level of the left renal vein. The extent of the lymphadenectomy was modified by the surgeon intraoperatively, depending on co-morbidity and aggravated intraabdominal surgical conditions.

All participants underwent assessments preoperatively (baseline) and one year after surgery with systematic circumference measurement of the legs from a fixed point above the malleolus to the groin at four cm intervals, enabling calculation of leg volume according to the cone model described by Sitzia [22]. The estimated leg volume was adjusted for body mass index (BMI) in order to obtain a standardized measure of leg volume for the determination of lymphedema. The volume change in BMI-standardized leg volume from baseline to one year was classified as “lymphedema” if the increase was $\ge$10% in at least one of the legs, according to the International Society of Lymphology definition [23], and as “no lymphedema” if the increase was 10% in both legs.

The calculations of costs followed the structure of a cost analysis [24]. The calculation of hospital costs was based on the Cost-Per-Patient (CPP) principles [25]. CPP is a method of estimating healthcare costs per care contact and patient that has been developed and used within Swedish healthcare for more than two decades to describe and calculate costs for various care services. In this study, the 2020 CPP list from the university hospital in Linköping was used. The prices in the CPP list for treatment of EC were based on the costs of 128 women treated in 2020 for EC in the university hospital in Linköping, Sweden.

The costs per unit related to the treatment of EC were identified in the CPP list. Table 1 presents the list of costs per unit for the variables: hospital stay, surgery time, post-anesthesia care unit, histopathology analysis, unplanned outpatient visits within six weeks after discharge, readmissions within one year after surgery, attributed to conditions related to the primary surgery, with or without concomitant surgery. Overhead costs such as development, rent for premises, and reinvestigations of standard equipment are equally distributed in all CPP costs.

All costs are reported in Swedish crowns (SEK). The average exchange rates in November 2022 were £1 = 12.3605 SEK; €1 = 10.7972 SEK, and $\$$1 = 10.5417 SEK according to the Swedish Central Bank [26].

The statistical analyses were performed using the software TIBCO Statistica™, version 13.5 (TIBCO Software Inc, Palo Alto, CA, USA). Continuous data are expressed as median and (interquartile range (IQR)) or mean and (standard deviation), as appropriate, and nominal data are described as number and (frequency in percent). Comparison between groups with continuous data was performed with Mann-Whitney U-test or Kruskal-Wallis analysis of variance, and correspondingly were Pearson Chi-square test or Fisher’s exact test used, as appropriate when comparing categorical data. The level of significance was set at p 0.05. The ordinary p-values associated with two-tailed tests of group differences are reported. Accordingly, adjustments for multiple comparisons, for instance Bonferroni adjustment, can be applied ad libitum if necessary.

Table 3 presents the hospital costs associated with surgical treatment including lymphadenectomy compared with treatment without lymphadenectomy.

The total mean cost for surgical treatment of EC within one year was 118,205 SEK (43,116 SEK) when lymphadenectomy was performed and 70,451 SEK (31,138 SEK), when lymphadenectomy was not performed, an increase in costs for lymphadenectomy of 71%. This increase in costs for treatment including lymphadenectomy compared with treatment without lymphadenectomy was mainly attributed to higher costs for the hospital stay (102%), surgery costs (49%), unplanned outpatient visits (97%), and readmissions with or without concomitant surgery (156% and 71%, respectively).

The hospital stay and operation time were significantly longer for women who underwent lymphadenectomy compared with those without lymphadenectomy (median 4.0 days (2–5 days) vs. 2.0 (1–2 days); p 0.0001, and median 176 min (140–246 min) vs. 85 min (64–107) min, p 0.0001, respectively) (Table 2), which influenced the costs for hospital stay and surgery substantially (Table 3). Compared with the group without lymphadenectomy, a significantly higher proportion of women in the lymphadenectomy group had unplanned outpatient visits (40% (46/116) vs. 20% (24/119), p 0.01), but no significant differences were seen when analyzing the proportions of readmissions within one year, readmissions requiring surgery and readmissions without surgery, or number of readmissions (among readmitted women) (Table 2).

The total hospital costs of surgery in relation to the occurrence of lymphedema are presented in Table 4.

The total mean hospital cost for surgery within one year for a woman treated for EC who developed lymphedema within one year of surgery was 115,099 SEK (44,593 SEK) and for the women who did not develop lymphedema the mean cost was 91,793 SEK (44,062 SEK), that is a 25% higher total hospital cost for those who developed lymphedema.

The higher hospital costs were mainly attributed to higher costs for the hospital stay (22%), surgery (19%), unplanned outpatient visits (42%), and readmissions requiring surgery (322%).

However, the length of hospital stay, operation time and proportions of women with unplanned outpatient visits or readmissions did not differ between the women who developed lymphedema and those who did not (Table 2). In contrast, the proportion of women who were readmitted and required surgery among those women who developed lymphedema was significantly higher than in women without lymphedema who were readmitted and required surgery (18% (4/22) vs. 4% (9/209), p = 0.03) (Table 2). This significant difference was not maintained between the groups with and without lymphedema who were readmitted but did not require surgery. The number of readmissions was higher among those women who developed lymphedema, although the difference did not reach statistical significance (p = 0.05, Mann-Whitney U-test (adjusted for ties)).

The risk classification of EC for using lymphadenectomy was based on the preoperative evaluation whereas the decision on adjuvant oncologic therapy was made postoperatively after the pathology report. Adjuvant oncologic treatment was offered if more than one unfavorable prognostic risk factor was revealed in the pathology report. The high-risk histopathology types (endometrioid adenocarcinoma International Federation of Gynecology and Obstetrics (FIGO) grade III, serous-, clear cell-, adenosquamous, squamous- and undifferentiated carcinomas, and carcinosarcoma) are more likely to reveal more than one prognostic risk factor, even independent of lymph node metastasis. Thus, for obvious reasons, the high-risk EC patients more often received adjuvant oncologic therapy than the low-risk EC patients did. However, the low-risk EC patients also received adjuvant oncologic therapy when the pathology report revealed unfavorable prognostic factors. Nearly two-thirds of the women who had lymphadenectomy received adjuvant oncologic treatment, and of the women without lymphadenectomy more than one-tenth received adjuvant treatment.

Since lymphadenectomy per se has not been shown to improve the prognosis of EC but is used exclusively for tailoring the postoperative treatment, it is important to analyze hospital costs, in particular in societies where health care is not individually funded. The question raised by this study is whether lymphadenectomy can be justified based on health economic considerations. As lymphadenectomy contributes substantially to increased intra- and postoperative morbidity including lymphedema, which creates costs for the health care service and impairs patients’ HRQoL substantially, lymphadenectomy cannot be assessed as cost-effective in general.

Given the fact that a significant proportion of the high-risk EC patients received adjuvant oncological treatment, independent of lymph node metastasis, and lymphadenectomy per se is not considered to contribute to improved survival, the most important questions would be what the total hospital costs amount to, given that all high-risk EC patients receive adjuvant oncologic treatment instead of lymphadenectomy in order to avoid the adverse side effects of the extended surgery and lymphedema, and whether such a change in treatment will affect survival and HRQoL. However, these questions will most likely never be answered since the Swedish national guidelines have been changed since this study and now recommend the use of the sentinel node technique instead of complete lymphadenectomy [28]. The clinical rationale for using sentinel node mapping in endometrial cancer and the drawbacks have recently been presented in a review article by Bogani et al. [29]. In the conclusion they highlighted the need of more evidence for the therapeutic benefits of identifying low-volume disease (i.e., micrometastasis or isolated tumor cells) in sentinel node mapping. All evidence in the review was based on clinical outcome variables but nothing was reported on HRQoL or patient-reported experience measures (PREM) or patient-reported outcome measures (PROM), nor was the effect of a false negative detection rate of sentinel node metastasis of 3–5% reported in a systematic review and meta-analysis by Fan et al. [30] discussed. Thus, future research should focus on the impact of sentinel node on HRQoL, PREM and PROM, the development of lymphedema, and the related health economic aspects. However, the new molecular and genomic classification of EC will probably influence how EC will be treated surgically and oncologically in the future and will probably render lymph node diagnostics redundant.