GOG 244-The lymphedema and gynecologic cancer (LEG) study: Incidence and risk factors in newly diagnosed patients

Highlights

• Lymphedema as defined by volume change ≥10% was found in 34% of endometrial, 35% of cervical, and 43% of vulvar patients.

• Regression analysis showed risk decreased with advanced age (p = 0.0467) and increased with a node count >8 (p = 0.033).

• Increase risk of lymphedema was not associated with radiation, advanced stage or other commonly reported risk factors.

• Final conclusions were weakened by 50% lost to follow-up and discrepancies in measurements identified in 32% of patients.

Abstract

Objectives

To evaluate the incidence and risk factors for lymphedema associated with surgery for gynecologic malignancies on GOG study 244.

Methods

Women undergoing a lymph node dissection for endometrial, cervical, or vulvar cancer were eligible for enrollment. Leg volume was calculated from measurements at 10-cm intervals starting 10 cm above the bottom of the heel to the inguinal crease. Measurements were obtained preoperatively and postoperatively at 4–6 weeks, and at 3-, 6-, 9-, 12-, 18-, and 24- months. Lymphedema was defined as a limb volume change (LVC) ≥10% from baseline and categorized as mild: 10–19% LVC; moderate: 20–40% LVC; or severe: >40% LVC. Risk factors associated with lymphedema were also analyzed.

Results

Of 1054 women enrolled on study, 140 were inevaluable due to inadequate measurements or eligibility criteria. This left 734 endometrial, 138 cervical, and 42 vulvar patients evaluable for LVC assessment. Median age was 61 years (range, 28–91) in the endometrial, 44 years (range, 25–83) in the cervical, and 58 years (range, 35–88) in the vulvar group. The incidence of LVC ≥10% was 34% (n = 247), 35% (n = 48), and 43% (n = 18), respectively. The peak incidence of lymphedema was at the 4–6 week assessment. Logistic regression analysis showed a decreased risk with advanced age (p = 0.0467). An exploratory analysis in the endometrial cohort showed an increased risk with a node count >8 (p = 0.033).

Conclusions

For a gynecologic cancer, LVC decreased with age greater than 65, but increased with a lymph node count greater than 8 in the endometrial cohort. There was no association with radiation or other risk factors.

Introduction

In 2012, when GOG 244-The Lymphedema and Gynecologic Cancer study was opened, a lymph node assessment was considered to be integral part of staging for endometrial, cervical and vulvar cancer patients and it remains so today [[1], [2], [3]]. These staging procedures are associated with lymphedema of the lower extremity (LLE), one of the most challenging complications associated with the diagnosis and treatment of a gynecologic cancer. It is commonly reported that an estimated 20% to 60% of gynecologic cancer patients will struggle with lymphedema [[4], [5], [6]]. The true incidence of lymphedema in the general population, as well as in gynecologic cancer patients, is difficult to determine in part because there are many way to measure it and therefore define it [7]. Most of the previous lymphedema analyses on patients with a gynecologic malignancy have been limited, largely retrospective, and frequently via a survey questionnaire [6,8,9]. In recent reports, LLE has been objectively measured as a change in bioimpedance [10,11] or a change in limb volume as compared to the opposite leg [10]. The various assessment and diagnostic methods in these published reports have been inconsistent, which contributes to the wide range in reported incidence.

Gynecologic Oncology Group (GOG) study 195, a randomized trial evaluating the use of a fibrin sealant in the inguinal incisions of vulvar cancer patients, was one of the initial efforts to prospectively evaluate for lymphedema in a gynecologic oncology population [12]. In that study, circumferential measurements were used to assess limb volume change (LVC), which was then used as a surrogate for lymphedema. Patients were evaluated for LVC as determined by three measurements in the lower, middle and upper leg, which were compared to preoperative baseline measurements. Although the study was negative for the use of a fibrin sealant to impact the incidence of lymphedema, GOG 195 identified that the incidence of lymphedema was 60–67% in the study and control arm, respectively. Concurrent with this high incidence of lymphedema was a concern that medical professional awareness of lower extremity lymphedema was less than awareness for upper extremity lymphedema as evidence by being less likely to receive an early referral to a lymphedema specialist [13]. These factors initiated a broader GOG interest in LLE and an intent to investigate lymphedema across a larger number of endometrial, cervical and vulvar cancer patients. Submersion with water displacement has been considered the gold standard for evaluating LVC, a surrogate for lymphedema [14]. The technique, however, is labor-intensive, complicated, and not available in many communities. More recently, sequential circumference measurements in the upper extremity have demonstrated excellent intra- and inter-observer reliability, and have yielded results statistically indistinguishable from those of the water displacement method [[15], [16], [17]]. The reported upper extremity correlation between the volumes measured with circumferential measurements and water displacement measurement is 0.99 [18]. The current study expanded on the experience from GOG-195 and increased the number of leg measurements from three locations along the limb to every 10 cm to improve the ability to detect a change in limb volume in the lower extremity. This study expanded on the clinical variables collected during GOG-195 to allow for any confounding or exploratory relationships to LLE. This study also incorporated patient self-reported symptoms associated with the development of LLE so that more than one method was used to assess patients. These self-reported symptoms have been well documented in the upper extremity lymphedema literature [19,20]. The Gynecologic Cancer Lymphedema Questionnaire (GCLQ) has an internal consistency reliability of 0.95 [21] and underwent additional adaptation and validation for inclusion in this trial.

The primary management of endometrial, cervical and vulvar cancer has included some type of regional nodal assessment that is commonly associated with increasing the risk of lymphedema [22]. It is believed that this surgical disruption of normal lymphatic channel causes a pooling of extracellular fluid distal to the dissection that is further complicated by the dependent position of the lower extremities. At the time it opened, this study incorporated gynecologic cancers where there was consensus in the nodal assessment such as the pelvic lymphadenectomy for cervical and endometrial cancer, and the inguinal lymphadenectomy for vulvar cancer [2,3,23]. Ovarian and other peritoneal malignancies were not included in this study as the role of primary retroperitoneal nodal assessment was less clear.

The primary objective of this study was to prospectively evaluate the incidence of LLE in patients undergoing primary surgery with a concurrent lymphadenectomy for a gynecologic malignancy of the cervix, endometrium, or vulva. Multiple variables were collected from the surgery and any adjuvant therapy to be analyzed for their relationship to lymphedema of the lower extremity.