The Long-term Impact of Post-Operative Oral Contraceptive Recommendations After Laparoscopic Cystectomy of Endometrioma on the Incidence of Endometrioma Recurrence and Ovarian Cancer Development

doi:10.21203/rs.3.rs-2834252/v1

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The Long-term Impact of Post-Operative Oral Contraceptive Recommendations After Laparoscopic Cystectomy of Endometrioma on the Incidence of Endometrioma Recurrence and Ovarian Cancer Development

https://doi.org/10.21203/rs.3.rs-2834252/v1

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Background

Previous studies have shown the ovarian carcinoma after laparscopic cystectomy of endometrioma arises through the recurrence of endometrioma. Then it can be assumed that reduction of ovarian endometrioma recurrence through postoperative medication can lead prevention of carcinogenesis. Therefore, this study aimed to evaluate the long-term impact of oral contraceptive (OC) recommendation after laparoscopic cystectomy of endometrioma on the incidence of endometrioma recurrence and ovarian cancer development.

Methods

This retrospective study included 546 patients who underwent laparoscopic cystectomy of ovarian endometrioma at a tertiary referral hospital to evaluate the OC recommendation following laparoscopic cystectomy of endometrioma introduced after the year 2005.

Results

This study included 218 patients in the pre-recommendation group and 328 patients in the post-recommendation group. Patient characteristics (age, gravida, parity at surgery, comorbidity of uterine fibroids and adenomyosis, revised American Society for Reproductive Medicine score, cyst size, and bilateral involvement) were comparable between the groups. Postoperative OC was recommended to be started and continued for at least 2 years in 3.2% of patients in the pre-recommendation group and 38.7% of patients in the post-recommendation group. The endometrioma recurrence rate was significantly lower in the post-recommendation group (3.8% per year) than in the pre-recommendation group (6.8% per year, p < .001). The incidence of ovarian cancer was lower in the post-recommendation group (0.063% per year) than in the pre-recommendation group (0.248% per year), although this difference was not significant. None of the patients who had used OC for > 2 years developed ovarian cancer.

Conclusions

Introduction of the postoperative OC recommendation after laparoscopy significantly reduced the recurrence rate of endometrioma, and tended to reduce the incidence of ovarian cancer.

Cohort study

Endometriosis

Excision: Laparoscopy

Ovarian neoplasms

Endometriosis affects approximately 10% of women of reproductive age¹ and can cause severe chronic pelvic pain and infertility². Endometriosis can arise in various parts of the human body³, but endometriosis of the ovaries (ovarian endometrioma) accounts for approximately 55% of the cases⁴.

Although hormonal therapy can relieve symptoms in most cases of endometrioma^5,6, surgical treatment is indicated when hormonal therapy is not effective or when the patient wants to conceive^7,8. Fertility preserving surgery, i.e., laparoscopic cystectomy of endometrioma, is preferred over adnexectomy, and is the recommended line of treatment for female infertility, regardless of symptoms⁹.

Despite their benign character, endometriomas can develop into malignant lesions¹⁰. We previously conducted a study of 121 patients who underwent laparoscopic cystectomy of endometrioma and reported that 24.9% of patients developed ovarian endometrioma recurrence and 0.82% developed ovarian cancer in 4 years after laparoscopy. In all cases, ovarian cancer is developed from recurrent endometrioma¹¹.

Later in 2005, our institution introduced the "postoperative oral contraceptive (OC) recommendation", which recommended the use of OC after laparoscopic cystectomy of endometrioma. We found that the postoperative OC recommendation significantly decreased the recurrence rate of endometrioma in 2 years¹². Later, similar results had been reported by other groups, however, no studies have focused on the effect of long-term OC administration on reduction of endometria recurrence and carcinogenesis resulting from endometria¹³. Therefore, this study aimed to investigate the long-term impact of OC recommendation after laparoscopic cystectomy of endometrioma on the incidence of endometrioma recurrence and development of ovarian cancer.

The study protocol was approved by the institutional review board (the University of Tokyo IRB number is 3128-6). The inclusion criteria for this study were as follows: 1) age less than 40 years at the time of surgery, 2) not seeking pregnancy immediately after surgery, and 3) the size of endometrioma larger than 4 cm in diameter at the time of surgery. No exclusion criteria were set.

In 2005, a recommendation of postoperative OC for at least 2 years was introduced for all patients (age < 40, not seeking pregnancy) who underwent the cystectomy of endometrioma at our institute. During laparoscopy, every patient was routinely provided with the following information: i) recurrence rate and risk factors that we analyzed in our previous study¹⁴, ii) known side-effects, risks, benefits of OC supported by conclusive evidence, and iii) the possible benefits of reducing or delaying recurrence¹². Their decision to use OC was voluntary. Women who chose to use OC were given a cyclic regimen of OC starting within 3 months after the laparoscopy, a majority of them were given a monophasic OC containing ethinyl-estradiol (0.035 mg) and norethisterone (1.0 mg), and some were administered ethinyl-estradiol (0.030 mg) and drospirenone (3 mg).

In this before-after study, a total of 546 patients were included. Among them, 218 patients had undergone laparoscopic cystectomy of endometrioma prior to the introduction of OC recommendation, between 1995 and 2004 (the pre-recommendation group), and 328 patients after the introduction of OC recommendation, between 2005 and 2014 (the post-recommendation group). Their prognosis was evaluated separately in June 2013 and September 2019 for the pre-recommendation and post-recommendation groups, respectively. This study was carried out in accordance with The Code of Ethics of the World Medical Association (Declaration of Helsinki). Before the surgical procedure, informed consent was obtained from all patients.

Surgical procedure

Endometriomas were excised using a laparoscopic technique as described in the previous studies^12,14. After inspection of the pelvis, adhesions of the ovary were removed. The capsule of the cyst was removed by stripping it from the healthy ovarian tissue, followed by excision or coagulation of peritoneal implants of endometriosis using surgical scissors or bipolar electro-coagulation, respectively.

Detection of post-operative recurrence and ovarian cancer

After surgery, patients were periodically followed up every 3–6 months, and transvaginal ultrasonography was performed. The diagnosis criteria for the recurrence of endometrioma was similar to our previous studies^12,14, i.e., a cyst was considered recurrent, if the typical feature of the cyst was greater than 2 cm in diameter and was detected during repeated follow-up examinations using transvaginal ultrasonography¹⁵. The management of recurrent cysts was based on the size of the lesion and patients' age. Ovarian cancer was histopathologically diagnosed after the evaluation of surgically removed specimens.

Statistical analysis

Patient characteristics (age at the first laparoscopy, gravida, parity, comorbidity of adenomyosis, comorbidity of uterine fibroids, revised American Society for Reproductive Medicine (rASRM) score, bilateral/unilateral involvement, postoperative observation period, postoperative OC treatment, postoperative pregnancy, recurrence of endometrioma, and development of ovarian cancer) between the two groups, the pre-recommendation group, and the post-recommendation group, were compared using the Student's t-test, Mann–Whitney U test, and Fisher's exact test. Statistical analyses were performed using JMP Pro version 15.0 software (SAS Institute Inc., Cary, NC, USA). A P-value of < .05 was considered significant.

Patients' Background at Laparoscopy, Laparoscopic Findings, and Postoperative Conditions

As indicated in Table 1, the patients' background at the time of laparoscopic surgery was comparable between the pre-recommendation and the post-recommendation groups. The mean age of the two groups was not significantly different (31.6 ± 4.5 versus 31.7 ± 4.4, mean ± SD, pre-recommendation and the post-recommendation group, respectively). The proportions of nulligravida and nulliparous women were also comparable between the two groups. There was also no significant difference in laparoscopic findings, including, the comorbidity of uterine fibroids and adenomyosis, rASRM score, endometrioma cyst size, and the percentage of bilateral involvement between the two groups. There was significant difference (p < .001) regarding postoperative medication intake with 3.2% in the pre-recommendation group, and 38.7% in the post-recommendation group using OC after the surgery. The mean duration of OC use was 2.0 ± 12.4 months in the pre-recommendation group and 22.0 ± 28.5 months in the post-recommendation group. Moreover, for the patients who had been on OC for more than 2 years, the mean duration of OC medication was 48.9 ± 29.1 months. There were no cases of OC-related fatal complications such as thrombosis in both the groups. One patient in the pre-recommendation group developed mild hepatic dysfunction and OC was discontinued. In the post-recommendation group, of the three patients who discontinued OC, two were because of mild hepatic dysfunction and one was because of the diagnosis of breast cancer. The rate of post-operative pregnancy was comparable between the two groups (17.9% in the pre-recommendation group versus 13.7% in the post-recommendation group, respectively).

Table 1

Clinical characteristics of both groups
Analysis items	Pre-recommendation group (n = 218)	Post-recommendation group (n = 328)	p value
Patient background at laparoscopy
Age, mean ± SD	31.6 ± 4.5 y	31.7 ± 4.4 y	NS ^†
Gravida			NS ^‡
0	78.9%	80.8%
1	11.5%	14.3%
≧2	9.6%	4.9%
Parity			NS ^‡
0	87.1%	88.1%
1	6.9%	10.1%
≧2	6.0%	1.8%
Laparoscopic findings
Comorbidity of adenomyosis	7.3%	7.6%	NS ^§
comorbidity of uterine fibroids	21.6%	25.6%	NS ^§
rASRM score	42 (28–65) *	42 (28–72)	NS ^‡
Largest cyst diameter	6 cm (5–7) *	6 cm (5–7)	NS ^‡
Bilateral involvement	37.6%	36.3%	NS ^§
Postoperative conditions
Postoperative observation period (Month)	59 (12–119) *	45 (15–93)	NS ^‡
Postoperative OC ( ≧ 2 year )	3.2%	38.7%	< .001 ^†
Postoperative pregnancy	39 (17.9%) ^‖	45 (13.7%) ^‖	NS ^§
Recurrence of ovarian endometrioma	58 (26.6%) ^‖	51 (15.6%) ^‖	< .005 ^§
The ratio of endometrioma recurrence /postoperative observation periods (%/year)	6.8	3.8	< .001 ^¶
Development of ovarian cancer	3 (1.4%) ^‖	1 (0.3%) ^‖	NS ^§
The ratio of ovarian cancer development /postoperative observation periods (%/year)	0.248	0.063	NS ^¶
* Median (Interquartile Range), † t-test, ‡ Mann–Whitney U test, § Fisher's exact test, ‖Number (%), ¶ Statistical hypothesis testing, NS: p < 0.05; rASRM: revised American Society for Reproductive Medicine; SD: standard deviation; OC: oral contraceptive

The recurrence rate of endometrioma in both groups

The overall recurrence rate of endometrioma was significantly lower in the post-recommendation group than in the pre-recommendation group (15.6% versus 26.6%, respectively, p < .005). There was also a significant difference in the annual rate of ovarian endometrioma recurrence during the postoperative observation period (3.8%/year versus 6.8%/year, respectively, p < .001).

The incidence of ovarian cancer development in both groups

During the postoperative follow-up period, three patients in the pre-recommendation group and one patient in the post-recommendation group were diagnosed with ovarian cancer (1.4% versus 0.3%, respectively, p = .31). The incidence of ovarian cancer development/postoperative observation period was 0.063%/year in the post-recommendation group, which was lower than in the pre-recommendation group (0.248%/year), although the difference was not statistically significant (p = .43). Three patients who developed ovarian cancer in the pre-recommendation group did not use postoperative OC. The patient who developed ovarian cancer in the post-recommendation group had started postoperative OC regimen but discontinued it before 2 years. None of the patients who had used OC for more than 2 years developed ovarian cancer.

Details of the Patients Who Developed Ovarian Cancer: three in the pre-recommendation group and one in the post-recommendation group

The details of the patients who developed ovarian cancer following surgery: three in the pre-recommendation group (PRE1, 2, 3) and one in the post-recommendation group (POST1) are presented in Table 2. The age of four ovarian cancer patients at the time of laparoscopy ranged from 31 to 38 years. The size of endometriomas was 5–10 cm in diameter, and the rASRM scores ranged from 38 to 56 points. All patients who were diagnosed with ovarian cancer had experienced a recurrence of the endometrioma prior to developing ovarian cancer. The time elapsed between surgery and the recurrence of endometrioma ranged from 41 to 159 months. The age of patients at the diagnosis of ovarian cancers was 42–44 years. Histologically, three were clear cell carcinoma (PRE 1, PRE3, and POST1) and one (PRE2) was carcinosarcoma. All cancerous lesions were considered to have originated from endometriosis, as the direct contiguity of tumors with endometriosis was confirmed. According to the International Federation of Gynecology and Obstetrics classification, the postsurgical stages were Ia in one case (PRE1), Ic in two cases (PRE3 and POST1), and IIIc (PRE2) in one case.

Table 2

The details of patients with ovarian cancer after cystectomy
Analysis items	PRE1	PRE2	PRE3	POST1
Age at the first surgery (laparoscopic excision)	38 y	31 y	31 y	38 y
rASRM score	38	52	56	46
Maximum cyst diameter	6 cm	10 cm	5 cm	7 cm
Postoperative pregnancy	No	No	No	No
Duration of postoperative OC treatment	N.A.	N.A.	N.A.	1 y 3 m
Recurrence of ovarian endometrioma	Yes	Yes	Yes	Yes
Period between first surgery and the recurrence	3 y 5 m	12 y 3 m	13 y 3 m	4 y 7 m
Age at the development of ovarian cancer	42 y	44 y	44 y	43 y
Histology of ovarian cancer	CCC	CS	CCC	CCC
FIGO staging classification	Ⅰa	Ⅲc	Ⅰc	Ⅰc

N.A.; not applicable, CCC; clear cell cancer, CS; carcinosarcoma; OC: oral contraceptive; rASRM: revised American Society for Reproductive Medicine; FIGO: International Federation of Gynecology and Obstetrics classification

In the present study, we evaluated the long-term impact of postoperative OC recommendation on the incidence of endometrioma recurrence, and ovarian cancer after laparoscopic cystectomy of endometrioma. First, we observed a significant increase in the percentage of patients who continued OC for > 2 years and a significant decrease in endometrioma recurrence after the introduction of the recommendation. Second, we found that the annual incidence of ovarian cancer during follow-up decreased after the recommendation, although the difference was not statistically significant. Lastly, none of the patients who took OC for > 2 years after laparoscopy developed ovarian cancer.

The percentage of patients who took OC at least once during the observation period increased from 3.2% (7/218) before the introduction of the postoperative OC recommendation to 66.8% (219/328) post introduction, which was consistent with our previous small sample study¹². Additionally, 3.2% and 38.7% of patients in the pre-recommendation and post-recommendation groups, respectively, used OC for > 2 years. Accordingly, the recurrence rate of endometrioma in our patients almost halved, from 26.6–15.6%, with the use of OC, which is comparable with the findings of another study¹². In the present study, the median observation period was 4.9 years in the pre-recommendation group and 3.8 years in the post-recommendation group, demonstrating that OC recommendation is effective in reducing the recurrence rate, even when the observation period is extended beyond 2 years.

This study also showed that there was a trend toward a decrease in the incidence of ovarian cancer after the post-operative OC recommendation. With the use of OC, the incidence of ovarian cancer decreased regardless of the presence of endometriosis, which is thought to be related to the suppression of ovulation. The inhibitory effect of OC is proportional to the duration of intake, with a 36% and 44% reduction in cancer incidence reported for women who used OC for ≥ 5 years and ≥ 10 years, respectively¹⁵. In the current study, the annual incidence of ovarian cancer during follow-up was reduced by 76.4%, and because this reduction was greater than that in the above-mentioned general population, there may be a specific mechanism by which OC inhibits carcinogenesis in patients after laparoscopic surgery for endometrioma.

Overall, 134 patients across both groups (24.5%) consumed OC for > 2 years and none of them developed ovarian cancer during the observation period. Among the four patients who developed ovarian cancer, three did not take OC after surgery and one discontinued its use before 2 years, and all four patients had a recurrence of ovarian endometrioma before the development of ovarian cancer. Taniguchi et al. also reported similar results, in that the six cases of ovarian cancer development after cystectomy of endometrioma were observed in cases where hormonal therapies were not administered for more than 6 months¹⁶. Considering this information, together with our present results, it appears that long-term use of postoperative OC is important to prevent the development of cancer.

There are several limitations of this study. First, considering the low incidence (0.7%) of ovarian cancer in patients with ovarian endometrioma¹⁷, the number of patients included may not have been sufficient to find a statistically significant difference. Based on our current results it is estimated that about 9 times the current number of patients enrolled in our study, or 4960 patients, would be required to see a statistically significant difference. The second limitation is the short follow-up period of this study. Considering that the median observation period is 5 years and the average age at first surgery is 31 years, ovarian cancer is likely to develop later than this observation period. Therefore, further long-term follow-up studies should be conducted. In this study, we conducted a historical study comparing outcomes before and after the introduction of the postoperative OC recommendation. Therefore, the possibility of unaccounted factors affecting the results cannot be ruled out. A randomized control trial of non-OC use and OC use groups was not conducted because postoperative OC usage is now standard care, and it would not be ethical to set up a non-OC use group.

In summary, this study found that the introduction of the postoperative OC recommendation after laparoscopy significantly reduced the recurrence rate of endometrioma, and tended to reduce the incidence of ovarian cancer. Future multi-center studies with a larger number of cases and a longer observation period are required to obtain conclusive evidence on whether postoperative OC usage prevents the development of ovarian cancer after laparoscopic cystectomy of endometrioma.

OC, oral contraceptive

PRE, pre-recommendation group

POST, post-recommendation group

Ethics approval and consent to participate: This study was granted approval by the institutional review board (the University of Tokyo IRB: 3128-7) and it conforms to the provisions of the Declaration of Helsinki. Need for Informed consent was waived by the institutional review board in the University of Tokyo.

Consent for publication: Not applicable.

Availability of data and materials: The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Competing interests: Authors declare no Conflicts of Interests for this article.

Funding: This research was supported by AMED under Grant Number JP21gk0210023

Statement of prior presentation: The summary of this study was presented in 41^stannual conference of Japan society of endometriosis.

Authors’ contributions

Conception and Design: EM, MT, and KK, Acquisition of data: EM, GI, ES, AT, TM, HH, TH, MH, YH, and OW-H, Analysis and Interpretation of data: EM and MT, Drafting of the manuscript: EM, MT, and KK, Obtaining funding: KK, Supervision: YO

Acknowledgements: The authors appreciate Dr. Ichiro Arakawa for his kind advice on statistical analysis.

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No competing interests reported.

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The Long-term Impact of Post-Operative Oral Contraceptive Recommendations After Laparoscopic Cystectomy of Endometrioma on the Incidence of Endometrioma Recurrence and Ovarian Cancer Development

Status:

Version 1

Abstract

BACKGROUND

METHODS

Surgical procedure

Detection of post-operative recurrence and ovarian cancer

Statistical analysis

RESULTS

Patients' Background at Laparoscopy, Laparoscopic Findings, and Postoperative Conditions

The recurrence rate of endometrioma in both groups

The incidence of ovarian cancer development in both groups

DISCUSSION

Abbreviations

Declarations

References

Additional Declarations

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