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Abstract
Objective A number of patients with atypical endometrial hyperplasia and endometrial cancer have not yet given birth when they relapse after achieving complete response with initial fertility-preserving treatment. Often such patients still have a strong desire for fertility preservation; however, there are limited reports in the related literature on the efficacy of fertility-preserving retreatment in patients with relapse. This study intends to evaluate the safety and efficacy of fertility-preserving retreatment in patients with atypical endometrial hyperplasia and endometrial cancer after recurrence following initial fertility-preserving treatment.
Methods Data from 110 patients with atypical endometrial hyperplasia and endometrial cancer who received fertility-preserving treatment in the Department of Obstetrics and Gynecology, Peking University People's Hospital (December 2005 to September 2019) were collected, and a retrospective analysis was performed on the clinical characteristics, histopathology results, and outcomes of 25 patients with recurrence.
Results 25 patients (9 with atypical endometrial hyperplasia and 16 with endometrial cancer) received fertility-preserving retreatment. After a median treatment duration of 5 months (range 3–18), 21 patients (84%, 21/25) achieved complete response and 4 patients (16%, 4/25) had a partial response. The median follow-up time was 19.5 months (range 8–76), and a total of 8 patients (38.1%, 8/21) relapsed. The time from retreatment to complete response for endometrial cancer was significantly longer than that for atypical endometrial hyperplasia (7.5 vs 3 months; p=0.007). Among the 21 patients who achieved complete response, 12 patients had a desire for fertility, among whom 8 patients had a successful pregnancy (66.7%, 8/12) and 6 patients experienced term birth (1 patient with natural pregnancy and 5 patients with assisted reproductive technology). Six patients (50%, 6/12) delivered 6 full-term babies.
Conclusion The response rate is high and obstetrical outcomes are favorable after fertility-preserving retreatment in patients with recurrence of atypical endometrial hyperplasia and endometrial cancer.
- uterine cancer
- endometrial neoplasms
- endometrial hyperplasia
- neoplasm recurrence
- local
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HIGHLIGHTS
A complete response of 84% was noted after fertility-preserving retreatment in patients with recurrence of atypical endometrial hyperplasia and endometrial cancer.
The relapse rate was 38% after fertility-preserving retreatment.
Long-term maintenance treatment is recommended if there is no pregnancy desired after complete response from initial treatment.
Introduction
The 2018 global cancer statistics showed 382 069 new cases of endometrial cancer (2.1%) and 89 929 deaths (0.9%).1 Based on the statistics, approximately 6.5% of patients were between the ages of 20 and 44 years, and 70–88% had not given birth.2 Although the efficacy of high-dose progesterone in the treatment of early endometrioid adenocarcinoma has been confirmed, a certain recurrence rate also exists. It has been reported that the complete response rate of patients with atypical endometrial hyperplasia and endometrial cancer treated with fertility-preserving treatment is up to 50–80%, and the recurrence rate is up to 24–40%.3–8 A number of patients with atypical endometrial hyperplasia and endometrial cancer have not yet given birth when they relapse after achieving complete response with initial fertility-preserving treatment, and often such patients still have a strong desire for fertility preservation. Therefore, our center retrospectively analyzed the oncologic outcomes and obstetrical outcomes of fertility-preserving retreatment in patients with recurrence of atypical endometrial hyperplasia and endometrial cancer after initial fertility-preserving treatment, and evaluated the safety and efficacy of the retreatment.
Methods
The data of 110 patients with atypical endometrial hyperplasia and endometrial cancer who underwent fertility-preserving treatment in the Department of Obstetrics and Gynecology, Peking University People's Hospital (December 2005 to September 2019) were collected, and a retrospective analysis was performed in 25 patients with recurrent disease.
Pretreatment Evaluation
The enrollment criteria were as follows: (1) patients ≤45 years with a desire to preserve fertility; (2) patients with endometrioid adenocarcinoma, grade 1 or grade 2 (G1/G2); (3) patients with tumor localized to the endometrium confirmed by transvaginal ultrasonography and pelvic magnetic resonance imaging (MRI), and with no equivocal deeper myometrial invasion, extrauterine extension, or lymph node metastasis; (4) patients with no contraindications to progesterone treatment (drug allergy, thromboembolic disease, moderate to severe liver and kidney dysfunction, coagulation dysfunction); (5) expression of progestin receptors; and (6) fertility function assessed before treatment with no irreversible infertility disorders. The pathological tissues of all patients were obtained by hysteroscopic endometrial biopsy. The pathological diagnoses were reviewed by two gynecological oncology pathologists, and the histological diagnoses and progestin receptor expression levels were reported. All patients were informed regarding the treatment-related risks prior to treatment. The protocol was approved by the Independent Ethics Committee of Peking University People’s Hospital (approval number: 2016PHB054-01). All patients agreed to participate in this study and to undergo fertility-preserving treatment by providing informed consent.
Treatment Protocol and Response Evaluation
The main treatments were progesterone therapy including: single oral medroxyprogesterone acetate/megestrol acetate or in combination with levonorgestrel intrauterine system/gonadotropin releasing hormone agonist every 3 months (Table 1). At the end of each treatment cycle, endometrial biopsy under hysteroscopy was performed for histopathological examination to evaluate for response. Complete response was defined as no atypical endometrial hyperplasia or endometrioid carcinoma; partial response as presence of residual atypical hyperplasia or carcinoma with degeneration or atrophy of endometrial glands; no change or stable disease was defined as pathology consistent with that prior to treatment with no changes; progressive disease as pathology more severe than on previous evaluation, and/or the scope of invasion was greater; and recurrence as when hysteroscopic curettage was performed during the follow-up period and there was atypical endometrial hyperplasia or endometrioid adenocarcinoma confirmed after complete response from fertility-preserving treatment.
Fertility-preserving retreatment regimen after recurrence of endometrial atypical hyperplasia and endometrial cancer
Consolidation therapy was performed 12 weeks following complete response closely, and the therapy regimen was the same as before. At the completion of consolidation therapy, if the patient had no desire for pregnancy, a maintenance therapy was performed: low-dose progesterone, such as dydrogesterone tablets 20–40 mg/day or progesterone capsules 100–200 mg/day for the last 12 days during the second half of the menstrual cycle, combination oral contraceptives, or levonorgestrel intrauterine system. Follow-up was performed every 3 months during maintenance therapy. When pregnancy was desired, a natural pregnancy of 3–6 months was expected, and when pregnancy attempts failed, assisted reproductive technology was performed. Alternatively, patients could go to a fertility center directly for assisted reproductive technology.
Statistical Analysis
Data are presented as median values with ranges or as counts with percentages, and the χ2 test was used to compare the differences between groups. If the expected value was <5, Fisher’s exact χ2 test was adopted. Cox regression analysis was adopted to analyze the factors affecting the efficacy. A p value <0.05 was considered statistically significant, and tests were performed using Statistical Package for the Social Sciences (SPSS) for Windows (version 25.0; International Business Machines (IBM) Corp, Armonk, NY, USA).
Results
Clinical Characteristics
In this study, there were 93 (84.5%) patients who had a complete response after initial treatment, 27 (29%) patients had a recurrence after a median follow-up of 14 months (range 3–81), and the recurrence rate of endometrial cancer was significantly higher than that of atypical endometrial hyperplasia (40.5% vs 21.4%; p=0.022). However, there were 25 patients who chose fertility-preserving retreatment. There were nine (36%) patients with atypical endometrial hyperplasia, 15 (60%) patients with endometrial cancer (stage IA, G1), and one (4.0%) patient with endometrial cancer (stage IA, G2). The general information of these 25 patients with recurrence is shown in Table 2.
General conditions of patients with recurrence of atypical endometrial hyperplasia and endometrial cancer
Treatment Outcomes
Among the 25 patients who chose fertility-preserving retreatment after a median treatment of 5 months (range 3–18), 21 (84%) patients achieved a complete response and four (16%) patients achieved a partial response (Figure 1 and Table 1). Among the nine patients with recurrent atypical endometrial hyperplasia and the 16 patients with recurrent endometrial cancer after fertility-preserving retreatment, all nine patients with atypical endometrial hyperplasia had a complete response and 12 (75%) patients with endometrial cancer had a complete response. The time from retreatment to complete response for endometrial cancer was significantly longer than that for atypical endometrial hyperplasia (7.5 vs 3 months; p=0.007) (Table 3). The total median follow-up time was 61 months (range 3–104) with no deaths.
Retreatment outcomes of patients with recurrent atypical endometrial hyperplasia and endometrial cancer. CR, complete response; PR, partial response; SD, stable disease.
Tumor outcomes of fertility-preserving treatment after recurrence of atypical endometrial hyperplasia and endometrial cancer
In this study, 22 patients were treated with oral progesterone (medroxyprogesterone acetate/megestrol acetate), and the others received the following regimen: one patient with grade 1 endometrial cancer had a complete response after 6 months of treatment with a gonadotropin releasing hormone agonist alone for the combination of adenomyosis and polycystic ovarian syndrome; one patient with grade 1 endometrial cancer had a complete response after 14 months of treatment with medroxyprogesterone acetate combined with a gonadotropin releasing hormone agonist for MRI evidence of superficial myometrial invasion; and one patient with grade 1 endometrial cancer had a complete response after 6 months of treatment with a gonadotropin releasing hormone agonist combined with the levonorgestrel intrauterine device for abnormal liver function.
As shown in Table 4, the rates of complete response in the retreatment group and the initial treatment group were 84% and 85.5%, respectively (p=0.95), and the times to complete response were 5 and 3 months, respectively (p=0.88). The time to complete response for atypical endometrial hyperplasia and endometrial cancer after initial treatment was 8.1±9.9 months and 10.6±7.4 months, respectively (p=0.95), and the time to complete response after retreatment was 3.7±1.4 months and 8.7±5.3 months, respectively (p=0.007). The time to complete response for patients with endometrial cancer after initial treatment and retreatment was 6.3±5.2 months and 8.7±5.3 months, respectively (p=0.46), and the time to complete response for atypical endometrial hyperplasia was 6.3±5.4 months and 3.7±1.4 months, respectively (p=0.045).
Tumor outcomes of patients with atypical endometrial hyperplasia and endometrial cancer after recurrence in the retreatment group and the initial treatment group
In patients with recurrent disease and with fertility-preserving retreatment, the median follow-up time was 19.5 months (range 8–76), and eight patients (38.1%, 8/21) developed re-recurrence. Among these, three patients chose to receive a third round of fertility-preserving treatment, and then two patients had a complete response. The time from the second complete response to re-recurrence was significantly longer than the time from the first complete response to recurrence (29.3±20.8 vs 11.7±4.3 months, p=0.045). The median time between instances of recurrences was 29 months (range 12–84).
Univariate analysis of recurrence correlation showed that histopathological type (atypical endometrial hyperplasia/endometrial cancer, p=0.05), patients without consolidation therapy (p=0.001), and patients without maintenance therapy (p<0.0001) were associated with recurrence. Cox analysis on the single variable affecting the efficacy of fertility-preserving retreatment showed that both the histopathological type (atypical endometrial hyperplasia/endometrial cancer) (p=0.007) and the time from retreatment to complete response (p=0.007) had significant effects on whether complete response could be achieved again. In this study, seven patients underwent surgery. The median follow-up time was 30 months (range 1–73) after the operation, and all postoperative patients survived disease-free, as shown in Table 1.
Pregnancy Outcomes
Among the 21 patients with complete response after recurrence, 12 patients attempted to get pregnant, and of these eight patients had a successful pregnancy (66.7%, 8/12); there were six full-term pregnancies (one patient with a natural pregnancy and five patients with assisted-reproductive technology). Six (50%, 6/12) patients delivered six full term babies: four patients underwent delivery via Cesarean section and two patients via vaginal delivery. All newborns had Apgar scores of 10 at birth.
Patients with atypical endometrial hyperplasia and endometrial cancer delivered three live births, respectively. There were no statistically significant differences in the pregnancy rate of patients with recurrent atypical endometrial hyperplasia and endometrial cancer after fertility-preserving retreatment (80% vs 57.1%; p=0.37), and there were no significant differences in the live birth rate (50% vs 42.9%; p=0.57), as shown in online supplemental Table 1. There were no significant differences in the pregnancy rate (66.7% vs 72.4%; p=0.84) or live birth rate (50% vs 58.6%; p=0.54) between those who recurred and those who did not. There were no significant differences in the pregnancy rate (70.7% vs 66.7%; p=0.57) or live birth rate (56.1% vs 50%; p=0.65) when comparing pregnancy outcomes between the initial treatment and the retreatment groups after recurrence, as shown in online supplemental Table 2.
Supplemental material
Supplemental material
Discussion
In this study, the total complete response rate of fertility-preservation retreatment after recurrence was 84% (21/25). The treatment outcomes of patients with endometrial cancer were worse than those of patients with atypical endometrial hyperplasia, which was likely because the treatment for endometrial cancer requires tumor reversal, from cancer to atypical hyperplasia to hyperplasia and finally to benign, so it may take longer to achieve a response. The conservative retreatment regimen after recurrence is similar to the initial treatment, which is still mainly based on progesterone therapy; however, whether to add combination therapy or adjuvant therapy can be decided according to the general conditions of patients, the type of recurrence pathology, the responsiveness of the progesterone receptor, and the complications of the patients.
The re-recurrence rate in this study was 38.1% (8/21), and the time of complete response to re-recurrence was significantly longer than that of the first recurrence (29.3±20.8 vs 11.7±4.3 months), indicating that fertility-preserving retreatment still has a risk of recurrence. Hysterectomy is recommended after childbearing is complete, and further attention should be paid to the importance of maintenance therapy if patients do not attempt pregnancy. In this study, univariate analysis showed that the presence or absence of consolidation therapy and maintenance therapy were closely related to the reduction of recurrence, suggesting that consolidation therapy and maintenance therapy may reduce the risk of recurrence after complete response is achieved. Perri et al9 reported that three of five patients with re-recurrence chose to receive progesterone therapy again and all responded. In this study, three of eight patients with re-recurrence chose conservative retreatment, two of whom achieved a complete response and one of whom had achieved a partial response; five patients underwent surgery, and after a median follow-up time of 30 months, all were disease-free. Although all the reports have contained small sample sizes, this exploratory treatment could provide more than one treatment option for these types of patients.
In this study, the pregnancy rate and the live birth rate of fertility-preserving retreatment after recurrence were 66.7% and 50%, respectively, which were high compared with those reported in the literature. In this study, 52% of patients had primary infertility, and 12% of patients had polycystic ovarian syndrome. Therefore, it is suggested that patients with a desire for pregnancy should be referred to the fertility center as soon as they achieve a complete response to shorten the time to pregnancy. In our study, there were no significant differences in the pregnancy rate (66.7% vs 72.4%; p=0.84) or live birth rate (50.6% vs 58.6%; p=0.54) between the recurrent and non-recurrent groups (Online supplemental table 3). These results suggest that fertility-preserving retreatment after recurrence could also achieve a high pregnancy rate and live birth rate. However, due to the small sample size, it may not show a statistical difference in the pregnancy rate (80% vs 57.1%; p=0.37) or live birth rate (60% vs 42.9%; p=0.57) between patients with atypical endometrial hyperplasia and endometrial cancer. These results indicated that both atypical endometrial hyperplasia and endometrial cancer patients with recurrence of fertility-preserving retreatment may have a live birth.
Some have questioned the feasibility and safety of conservative retreatment after recurrence. Reports of retreatment after recurrence are limited. Tamauchi et al10 reported that the complete response rates of 18 patients with recurrence (11 with atypical endometrial hyperplasia and seven with endometrial cancer) after medroxyprogesterone acetate retreatment were 91% and 100%, respectively, with 14 pregnancies and 10 live births. A single-center retrospective study by Yamagami et al11 in Japan analyzed 82 patients with recurrence (28 with atypical endometrial hyperplasia and 54 with endometrial cancer), and the complete response rates of atypical endometrial hyperplasia and endometrial cancer after progesterone retreatment were 96.4% and 98.1%, respectively. Park et al12 reported on 33 patients with recurrence (13 with atypical endometrial hyperplasia and 20 with endometrial cancer), and after progesterone retreatment, 28 (85%) patients achieved a complete response, five patients delivered six full-term babies, and the median follow-up time was 51 months with no deaths.
This study supplements reference data to limited relevant studies. However, the relatively small sample size and retrospective nature of our study are the limitations. Thus, a further prospective large-sample study is required to test our speculation.
In conclusion, a satisfactory complete response rate and a relatively high pregnancy rate and live birth rate may be achieved with fertility-preserving retreatment in patients with recurrence of atypical endometrial hyperplasia or endometrial cancer as shown in our study. It must be emphasized that long-term maintenance therapy is recommended if there is no desire to conceive after achieving complete response after the initial treatment, and close follow-up is required during treatment. Once complete response is achieved, those with a desire to conceive should be referred to a fertility center as soon as possible.
Supplementary materials
Supplementary Data
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Footnotes
Contributors All authors worked collaboratively as a team. Corresponding author JLW is in charge of the program and directed this original article. YJH was responsible for writing this article. YQW and RZ provided help with the revision. All authors are in agreement will all aspects of the final manuscript.
Funding This work was supported by the National Key Technology R&D Program of China (nos.2019YFC1005200 and 2019YFC1005201).
Competing interests None declared.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information.