Risk factors for late-onset lower limb lymphedema after gynecological cancer treatment: A multi-institutional retrospective study

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Abstract

Introduction

Late-onset lower limb lymphedema (LLL) is a significant clinical challenge for physicians dealing with patients that undergo treatment involving the pelvic cavity. We aimed to clarify the prevalence of and risk factors for late-onset LLL after treatment for gynecological cancer.

Methods

We conducted a multicenter retrospective study using records of cases in which LLL diagnosed by physical findings and measurement of limbs girths. Patients with LLL after treatment for uterine cervical, endometrial, and ovarian cancer were sequentially enrolled. We examined the timing of LLL onset and the associations between the time to onset and clinical characteristics, including age, type of cancer, lymphadenectomy sites, and performance of radiotherapy. We also investigated the risk factors for late-onset LLL and their effects on the cumulative incidence of late-onset LLL.

Results

In total, 711 patients fulfilled the required criteria. Mean age of was 50.2 years old and median follow-up period was 5.05 years. More than half of them (50.5%) presented with LLL ≥5 years after undergoing treatment for gynecological cancer. A substantial number of patients (29.4%) developed LLL ≥10 years after undergoing treatment for gynecological cancer. Being aged <50 years [(odds ratio (OR): 1.919, P = 0.001), cervical cancer (OR: 1.912, P = 0.001), and radiotherapy (OR: 1.664, P = 0.017) were identified as significant risk factors for late-onset LLL in multivariate logistic regression analysis.

Conclusions

A substantial number of patients present with LLL ≥5 years after receiving treatment for gynecological malignancies. Clinicians are required to identify high-risk patients and inform them of the risk of late-onset LLL.

Introduction

Lower limb lymphedema (LLL) is one of the most disabling and debilitating complications of treatment for gynecological cancer [1]. It is characterized by lymphatic fluid accumulation in the interstitium, resulting from an injury to the lymphatic vessels or the obstruction of lymphatic channels or nodes caused by treatment, such as surgical procedures involving lymphadenectomy [2]. The prevalence of LLL after gynecological cancer treatment reportedly ranges from 5% to 58% [[1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11]]. The marked variation in the prevalence of LLL after gynecological cancer treatment is caused by differences in the observational period among studies and the absence of standard diagnostic criteria. The clinical presentations of LLL are usually chronic and progressive, and LLL ultimately leads to a reduction in quality of life [[12], [13], [14]].

Focusing on the period from treatment to the onset of LLL, it has been reported that some patients developed LLL ≥10 years after receiving treatment for gynecological cancer [5,7]. In contrast, most of the literature focuses on LLL that develops early in the follow-up period; however, late-onset LLL is a significant clinical challenge for physicians that deal with patients that undergo surgery involving the pelvic cavity. In ordinary clinical practice, most patients that do not exhibit any evidence of cancer recurrence stop visiting healthcare institutions after 5–10 years of follow-up. Therefore, a substantial number of cases of late-onset LLL might be missed due to the current clinical situation. To detect as many cases of LLL as possible, even after post-cancer-treatment follow-up, we need to be able to identify high-risk patients and inform them of the possibility of late-onset LLL to implement possible interventions such as lymphaticovenular anastomosis [15,16], and creating perforator flap [17]. In this study, we aimed to evaluate the prevalence of and risk factors for late-onset LLL after gynecological cancer treatment and to assess the associations between clinical variables and the timing of LLL onset.

Section snippets

Materials and methods

We conducted a multicenter retrospective study using the records of 7 medical institutions (Toyota Memorial Hospital, Hirota Internal Medicine Clinic, Nagumo Clinic Fukuoka, Northern Fukushima Medical Center, Limbs Tokushima Clinic, Iwate Prefectural Miyako Hospital, and the Cancer Institute Hospital of the Japanese Foundation for Cancer Research) for the period from April 2002 to November 2014. Every institution follows the recommendations of the National Lymphedema Network who require a

Results

In total, 711 patients with LLL who visited one of the 7 institutions during the study period fulfilled the required criteria. The mean age of the patients was 50.2 years old. ISL stages I, II, late in II, and III were noted in 6 (0.8%), 634 (89.2%), 65 (9.1%) and 6 (0.8%) patients, respectively. One hundred and ninety-five (27.4%) patients received radiotherapy. The baseline characteristics of the eligible cases are listed in Table 1. The patients’ characteristics were also stratified into

Discussion

In the present study, more than half of the examined cases of LLL were categorized as late-onset LLL. Moreover, approximately 30% of LLL developed ≥10 years after treatment for gynecological cancer. This indicates that a substantial number of patients develop LLL 5–10 years after undergoing treatment for gynecological cancer. We also confirmed that being aged <50 years, having a history of cervical cancer rather than endometrial or ovarian cancer, and receiving radiotherapy were independent

Funding sources

This study was supported by JSPS KAKENHI, Grant Number 26293463.

Declaration of competing interest

None declared.

Acknowledgment

We express our appreciation to the seven medical institutions that contributed to our study. We also express our sincere gratitude to Dr. Koji Tamakoshi, who contributed to the design of this study and the statistical analysis with patience and knowledge.

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