Peritoneal closure does not reduce the incidence of postoperative lower limb lymphedema after lymphadenectomy for uterine cancers during the first three years after surgery: a single-blinded randomized controlled trial in multiple facilities

doi:10.21203/rs.3.rs-4346452/v1

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Peritoneal closure does not reduce the incidence of postoperative lower limb lymphedema after lymphadenectomy for uterine cancers during the first three years after surgery: a single-blinded randomized controlled trial in multiple facilities

https://doi.org/10.21203/rs.3.rs-4346452/v1

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Objective

Lower limb lymphedema (LLL) that occurs after lymphadenectomy for gynecologic malignancies significantly reduces the quality of life of the patients. Although it has long been considered that opening of the retroperitoneum reduces LLL, there have been no randomized studies to date aimed solely to determine whether opening of the retroperitoneum is more favorable than closing for preventing LLL.

Methods

The subjects were a total of 200 patients with either cervical or endometrial cancer who were enrolled for surgery in 11 institutes. Primary endpoint is the cumulative incidence of LLL during 3 years after surgery, compared between “surgery with no retroperitoneal closure (open)” and “surgery with retroperitoneal closure (closed)”. Secondary endpoint is the frequency of the appearance of lymphocysts.

Results

No significant difference in the incidence of postoperative LLL between the open and closed groups (24/98 and 25/95, respectively. P = 0.77) was observed. However, a higher risk of lymphocyst formation was detected during the initial postoperative period in the closed group (36/98 and 54/95, respectively. P = 0.005).

Conclusion

There was no significant difference in the incidence of postoperative LLL between the open and closed groups. However, to prevent the development of lymphocysts, the retroperitoneum should be open rather than closed at the time of surgery for uterine cancers that include retroperitoneal lymph node dissection. Since lymphocyst formation could be a known risk factor of LLL, the favorable outcomes in the incidence of postoperative LLL in the open group might be revealed with longer term investigation.

uterine cervical cancer

endometrial cancer

lymphadenectomy

retroperitoneum

lymphedema

lymphocyst

Lymphedema is a type of edema caused by the inhibition of lymph flow, owing to congenital dysplasia, secondary compression, stenosis, or obstruction of the lymph vessels and nodes. [1] It is primarily observed in the limbs, and is divided into primary lymphedema with an unknown cause, and secondary lymphedema with a known cause. [2, 3] Limb lymphedema mostly occurs as a complication that is unavoidable to some extent after radical surgery for cancers, including breast, uterine, and prostate, involving lymph node dissection or radiation therapy. [4–7] More than 80% of patients with lymphedema develop the condition after treatment for gynecological cancers, such as breast and uterine cancers. The progression of lymphedema not only causes psychological distress owing to its appearance and gait disturbance, but may also cause complications of recurrent phlegmon or lymphangitis, because congested lymph provides an optimal medium for bacterial proliferation. These complications exacerbate the lymphedema, which then further promotes bacterial proliferation, and may initiate a vicious cycle. With further persistence of the congestion of lymph flow, it may induce secondary fibrosis or connective tissue hyperplasia, resulting in elephantiasis-like or scleroderma-like changes. Some patients have been reported to develop granuloma-like changes rather than fibrosis, and edematous interstitial granulomatosis is typical of these changes. In addition, lymphangiosarcoma (Stewart-Treves syndrome) may develop, though very rarely, as a delayed complication, and this type of sarcoma has been reported to enlarge rapidly, metastasize early to organs including the lungs, and have a poor prognosis. [8]

We previously performed a retrospective analysis on 694 gynecological cancer patients (301 with endometrial cancer, 258 with cervical cancer, and 135 with ovarian cancer) who underwent retroperitoneal lymph node dissection during the previous 3 years. The incidences of lower limb lymphedema (LLL) were 38% in those with cervical cancer and 29% in those with endometrial cancer who did not undergo postoperative radiation therapy, whereas the incidences in patients who underwent postoperative radiation therapy were 48% and 37%, respectively. [9]

Although the outcomes of cancer treatment have improved, avoiding these postoperative complications and improving the QOL of patients are still urgently required. However, no surgical procedure with a possible preventive effect on lymphedema has been established. [10] This study was designed on the basis that lymphedema may be prevented prophylactically in uterine cancer patients undergoing lymph node dissection, who are a high-risk group for lymphedema, by a new procedure, namely, guiding the lymph in deep pelvic areas into the peritoneal cavity by not closing the retroperitoneum when suturing after hysterectomy. Although this procedure has been reported previously [11], an evaluation in a randomized controlled clinical trial with a higher evidence level is necessary. Therefore, the present study aimed to confirm the usefulness of this new procedure in a multicenter single-blinded randomized controlled trial using the conventional procedure of surgery with retroperitoneal closure as the control.

Trial overview

This trial was conducted from August 2008 to June 2010 at The Jikei University Kashiwa Hospital, Niigata Cancer Center Hospital, and other hospitals in Japan (total of 11 facilities, supplementary table 1). Also, this study was registered in the University Hospital Medical Information Network (UMIN) Clinical Trials Registry, as UMIN000001248, and the registration date was 07/14/2008. Medical Research Support, Co., Ltd. is a data management company for clinical trials and conducted this research hereinafter as an independent data center. The trial was a randomized, single-blinded study, and was approved by the institutional ethics committee, and written informed consent was provided. An independent data and safety monitoring board reviewed the records of the recruited patients for adverse events at annual meetings.

Inclusion and exclusion criteria

Eligibility criteria were as follows: 1) patients who were due to undergo resection for cervical cancer (squamous cell carcinoma or adenocarcinoma of surgical stage up to IIb) with pelvic lymph node dissection, or 2) patients who were due to undergo resection for uterine endometrial cancer with at least pelvic lymph node dissection (site of lymph node dissection not specified), and 3) those aged 20 years or older and younger than 70 years in a performance status (PS) of 0–1, who submitted written informed consent

Exclusion criteria were as follows: 1) patients with primary lymphedema or a history of lymphedema owing to causes such as wound infection, or 2) patients judged by the physician to be unsuitable for participation in the study for other reasons, such as the presence of marked varices in the leg and a history of treatments for varices.

Treatment procedures

A minimization method with a random component was used to balance the groups with respect to the following adjustment factors: study site, age ( > = 56 or < 56 years), presence or absence of psoriasis of foot, cervical or endometrial cancer. Surgery with no retroperitoneal closure (open group): In suturing the abdomen after hysterectomy followed by retroperitoneal lymphadenectomy, Seprafilm (Kaken Pharmaceutical Co., Ltd., Tokyo, Japan), which was intended to reduce the incidence, extent, and severity of postoperative adhesions, was applied (maximum of 2 sheets) to keep the retroperitoneum open to guide lymph retained in the deep areas of the pelvis into the peritoneal cavity.

Surgery with retroperitoneal closure (closed group): After hysterectomy followed by retroperitoneal lymphadenectomy, the retroperitoneum was closed by the conventional suturing method.

Common procedures: Two drains were inserted into the paravesical spaces, which led the lymph fluid out of the abdominal wall by applying negative pressure using a low-pressure suction bag (SB bag), and were removed within 7 days. The vaginal stump was closed. Pelvic lymph node dissection was performed in all patients, and para-aortic lymphadenectomy was performed if necessary. The contents of the dissected lymph nodes were recorded in detail. After lymph node dissection, ligation was performed only on the cephalic side, and the pelvic side was left open. However, ligation was performed if bleeding was observed, and the ligation site was recorded.

Endpoints and assessments

Primary endpoint: The cumulative incidence of LLL during the 3 years after surgery was compared between the open group (surgery with no retroperitoneal closure), and the closed group (surgery with retroperitoneal closure). LLL was diagnosed by a physician according to the definition/standards used in this study.

Secondary endpoints: The degree of LLL, association between the postoperative frequency of the appearance of lymphocysts and incidence of LLL, and the association between tinea pedis and the occurrence of LLL.

Statistical analysis

The intended number of subjects was 180 eligible patients, consisting of 90 allotted to the open group and 90 allotted to the closed group. The probability of the occurrence of LLL as a postoperative complication after the conventional procedure was assumed to be 34%, and that after surgery with no retroperitoneal closure to be 15%. The necessary number of patients calculated by assuming the frequency of type I errors to be 5% and the power to be 80% was 84 for each group, and 168 in total. Therefore, at least 180 patients were judged to be necessary, considering dropouts. The allocation was performed by the minimization method, according to a manual prepared separately. The allocation factors were facility, uterine cervical/endometrial cancer, age of 55 years and younger or 56 years and older, and the presence or absence of tinea pedis.

From August 2008 to June 2010, we identified 200 patients who underwent surgery for uterine cancer with retroperitoneal lymph node dissection, with or without peritoneal closure. The patients underwent screening and 193 met the inclusion criteria (98 in the open group, comprising patients in whom the retroperitoneum was left open, and 95 in the closed group, comprising patients in whom the retroperitoneum was closed) (Fig. 1). No significant differences in the baseline characteristics between these 2 groups were found, except for the number of patients who underwent radical dissection of the lateral inguinal lymph nodes (Table 1). Kaplan-Meier curves of the time to death demonstrated that there was no significant difference between these two groups in the follow-up period. (Fig. 2)

The primary endpoint was comparison of the cumulative incidence of LLL during the 3 years after surgery between the open group and the closed group. As shown in Table 2, the cumulative incidence of LLL within 3 years after the operation was 24 out of 98 in the open group and 25 out of 95 in the closed group (Table 2). Whereas there was no significant difference in the development of LLL between these two groups (P = 0.77, Fig. 4), a higher incidence of lymphocyst formation from the initial period after surgery in the closed group was observed (36/98 vs. 54/95, P = 0.005, Table 2). Furthermore, it should be noted that this difference was caused by lymphocyst formation in the initial period (less than 1 month after surgery), and the difference persisted thereafter (Fig. 3). This result suggests that to keep the retroperitoneum open has an advantage in preventing lymphocyst formation. Whether or not removal of the regional lymph nodes in the femoral inguinal region is a crucial factor in the surgical treatment of uterine cancers is an important issue. In this trial, however, we found that there was no significant difference in postoperative LLL formation between the open and closed groups, regardless of whether radical dissection of the lateral inguinal lymph nodes was observed (12/42 vs. 14/55, P = 0.731, Table 1). This result suggests that the dissection of lymph nodes in the femoral inguinal region does not affect the frequency of LLL formation.

This single-blinded randomized controlled clinical trial was conducted to evaluate the usefulness of surgery with no retroperitoneal closure, which is expected to reduce the incidence and severity of LLL following surgery for cervical and endometrial cancers. The incidence of LLL in the 3 years following surgery as the primary endpoint was compared between patients who underwent surgery with and without retroperitoneal closure. We found that there was no difference between the open and closed groups regarding the overall survival rate and incidence of lymphedema in the patients. Lymphocyst formation as the secondary endpoint tended to be lower in the open group than that in the closed group from the initial period after surgery.

A previous non-randomized control trial by another group showed that the open group had much less lymphedema formation than the closed group [11]. Our results, on the other hand, indicated that the open and closed groups show almost no difference. To further clarify these results, follow-up of the patients for an additional 5 to 10 years is expected to be required.

It has been reported previously that radical dissection of regional lymph nodes in the femoral inguinal region may increase lymphedema in patients [12]. In addition, we have discussed the possibility that dissection of the external inguinal lymph nodes may cause severe lymphedema of the lower limbs [13–15]. To clarify whether radical inguinal lymph node dissection increases the risk of LLL or not, it is necessary to compare the patients in a randomized controlled trial. The results of our randomized controlled trial demonstrated that there is no difference in the incidence of LLL with or without radical inguinal lymph node dissection. Although the small number of patients who underwent radical inguinal lymph node dissection or possibly the short follow-up period duration may have affected the results, our results indicate that dissection of the external inguinal lymph nodes may not be a factor affecting LLL.

We conclude that open surgery is more favorable than closed surgery for cervical and endometrial cancers, as lymphocyst formation can be prevented by open surgery. Clinicians and patients should consider the results of this study when making treatment decisions.

Ethical approval and consent to participate

This study was conducted in accordance with the Declaration of Helsinki and was approved by the Ethics Committee of The Jikei University School of Medicine, Japan on the approved number 19-188-5119. Regarding the trial registration, this study was registered in the University Hospital Medical Information Network (UMIN) Clinical Trials Registry, as UMIN000001248. Registered date was 07/14/2008. Clinical data were collected after informed written consent was obtained from all human participants.

Funding

This research was supported by a grant from the Ministry of Health, Labour and Welfare Third Research Project on General Strategy Against Cancer, Japan, in which the reference number is 201313022A.

Data Availability

The data that support the findings of this study are available from the corresponding author upon request.

Author contribution

Hiroshi Sasaki planned and performed entire study. HS and Tomoki Yokochi wrote the manuscript. Hideki Ishikawa conducted the statistical analysis. Hiroshi Tanabe, Hirokuni Takano, Naotake Tanaka, Syoji Kodama, Minoru Akiyama, Nobutaka Yoshida, Kazuhiro Takehara, and HS collected the data.

Consent for publication

Written informed consent was obtained from all participants.

Competing interests

The authors declare no competing interests.

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Table 1 and 2 are available in the Supplementary Files section.

No competing interests reported.

LLLTable1.pptx
Table 1. Background characteristics of the patients. Baseline demographic and clinical characteristics of the patients in the open and closed groups before surgery are shown. Also, clinical characteristics of the patients in the open and closed groups after surgery are shown.
LLLTable2.pptx
Table 2. Results of the surgery and adverse events. Results of the surgery and adverse events are shown.
SupplementaryTable.pptx

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You are reading this latest preprint version

Peritoneal closure does not reduce the incidence of postoperative lower limb lymphedema after lymphadenectomy for uterine cancers during the first three years after surgery: a single-blinded randomized controlled trial in multiple facilities

Status:

Version 1

Abstract

Objective

Methods

Results

Conclusion

Figures

Introduction

Methods

Trial overview

Inclusion and exclusion criteria

Treatment procedures

Endpoints and assessments

Statistical analysis

Results

Discussion

Conclusion

Declarations

References

Tables

Additional Declarations

Supplementary Files

Status:

Version 1