Endometrial cancer in women younger than 40 years represents approximately 5% of all cases.1 The occurrence of the disease in women of reproductive age is related to long-term unopposed estrogen exposure, as in cases with polycystic ovary syndrome or other ovulation disorders. Atypical complex endometrial hyperplasia is a precancerous lesion and it can progress to endometrial cancer in several years.2 Some of such cases might include endometrial cancer but cannot be detected at the first diagnosis.
The standard treatment of endometrial cancer in the early stage or atypical complex endometrial hyperplasia (EC/ACEH) includes hysterectomy and bilateral salpingo-oophorectomy. However, many patients younger than 40 years have no children at the diagnosis of the disease. They cannot accept the standard therapy and desire to preserve fertility. Recently, high-dose medroxyprogesterone acetate is reported as effective fertility-preserving therapy for early stage endometrial cancer and atypical complex endometrial hyperplasia.3 Successful pregnancies after conservative treatment have been reported and most of them are the results of infertility treatment including assisted reproductive technology (ART).4
However, ovulation induction or controlled ovarian stimulation for infertility treatment can induce hyperestrogenic status, which might be implicated in the progression or recurrence of the disease. In the previous reports regarding successful pregnancies, several recurrent cases have been reported.4,5 However, there has not been enough evidence about the influence of infertility treatment on the recurrence after conservative therapy for EC/ACEH.
Therefore, we retrospectively reviewed the clinical courses of 36 cases after complete response with high-dose medroxyprogesterone acetate. The purpose of this study was to assess the pregnancy rate after infertility treatment and the influence on the recurrence of EC/ACEH.
This retrospective study was approved by the institutional review board of the University of Tokyo. We evaluated the patients with EC/ACEH who achieved complete response after high-dose medroxyprogesterone acetate and were followed up at the University of Tokyo hospital from January 1996 to January 2012.
After careful examination using ultrasound scan and magnetic resonance imaging to rule out the cases with myometrial invasion or adnexal involvement, total endometrial curettage was performed to determine the initial pathological diagnosis. Cases diagnosed as grade 1, stage Ia endometrial cancer, or atypical complex endometrial hyperplasia (FIGO classification in 1988), who were younger than 40 years and desired to preserve fertility were eligible for conservative treatment. They were given oral high-dose medroxyprogesterone acetate (600 mg/d) for 26 weeks. At 8, 16, and 26 weeks, cytodiagnosis or biopsy of the endometrium was conducted to check the efficacy of the treatment. Complete response was diagnosed when any hyperplastic or cancerous lesion was pathologically absent. Total endometrial curettage or hysteroscopic resection was performed again when the specimen showed remaining lesion. Cases diagnosed as progressive disease at any point stopped conservative treatment and hysterectomy was recommended. After 26 weeks, cases diagnosed as complete response received cyclic estrogen and progestin therapy for another 6 months to confirm complete response was maintained. Cases free of disease for 6 months could choose to attempt pregnancy. The patients who did not wish childbearing soon after achieving complete response continued cyclic estrogen and progestin or progestin only.
We recommended starting ovulation induction for women who wish to conceive soon after achieving complete response. Ovulation induction using clomiphene citrate or human menopausal gonadotropin, combined with timed intercourse or intrauterine insemination was initiated for the patients who had no history of infertility because many of them had ovulation disorder. The patients with other infertility factors, history of infertility treatment, or history of recurrence of EC/ACEH, were recommended to undergo ART to attain pregnancy as soon as possible. Oral contraceptive pills were given in the intervening cycles between ovulation induction cycles. The patients who no longer wish to conceive either after successful pregnancy or giving up infertility treatment were recommended to take oral contraceptive pills as long as any sign of recurrence was not detected or to undergo hysterectomy.
Characteristics of the patients, whether they underwent infertility treatment, conceived, or relapsed, and the interval from complete response to recurrence or pregnancy were retrospectively investigated. The duration of infertility was defined as the time from the first infertility treatment cycle to conception. The observational period [mean (SD)], from complete response to the latest follow-up, was 91.4 (46.2) months. Statistical analysis was performed using JMP 9 (SAS Institute, Cary, NC). The characteristics of the 2 groups—those with or without infertility treatment—were compared using Cochrane-Cox test. The characteristics of the 3 groups—those with infertility treatment resulting in live birth, those not resulting in live birth, and those without infertility treatment—were compared using Kruskal-Wallis test. The rate of recurrence was analyzed using Kaplan-Meier curve. The influence of infertility treatment and resulting live birth on recurrence was evaluated with log-rank test.
Thirty-six patients who achieved complete response after high-dose medroxyprogesterone acetate for 26 weeks followed by cyclic estrogen-progestin therapy for 6 months were eligible for this retrospective analysis. The age [mean (SD)] at the first diagnosis was 30.9 (5.8) years. Twenty-three cases were diagnosed as endometrial cancer and 13 cases as atypical complex endometrial hyperplasia. Only 1 woman had a child and all the others were nulliparous at the initial diagnosis. Body mass index (BMI) [mean (SD)] was 22.4 (4.5) kg/m2 and 3 of 36 cases were obese (BMI ≥ 30 kg/m2). Twenty-three cases had clinical background of irregular menstruation or amenorrhea.
Twenty-six of 36 patients desired to conceive soon after complete response and all of them underwent infertility treatment. Ten patients did not desire to conceive soon and continued to take oral conceptive pills. The characteristics and pregnancy outcomes of the 2 groups are shown in Table 1. The age at the first diagnosis, the ratio of endometrial cancer, BMI, and the ratio of patients with irregular menstruation were not significantly different between the 2 groups.
Eighteen (69.2%) of 26 patients who underwent infertility treatment conceived, and 16 of them delivered healthy babies. Live birth rate per patient was 61.5% and the duration [mean (SD)] of infertility was 12.2 (10.3) months. Fourteen (87.5%) of 16 successful cases conceived within 2 years. Of 23 women with history of irregular menstruation, 17 underwent infertility treatment, and 14 of them underwent ART. Meanwhile, 9 of 13 patients with regular menstruation underwent infertility treatment, and 7 of them underwent ART. In total, 21 women underwent ART, and 13 of them achieved live birth.
To investigate the relationship among infertility treatment, resulting pregnancy, and recurrence, we sorted the patients into 3 groups—women with infertility treatment resulting in live birth (group A), those not achieving live birth (group B), and those without infertility treatment (group C). Characteristics and oncologic outcomes of the 3 groups are shown in Table 2. The ratio of endometrial cancer and the duration to achieve complete response, both of which could be related to early recurrence of the disease, were not significantly different among the 3. Of 16 patients in group A, only 3 (18.8%) patients experienced recurrence, whereas 7 (70.0%) of 10 patients in group B did. In total, 10 (38.5%) of 26 patients who underwent infertility treatment experienced recurrence. Seven (70.0%) of 10 cases in group C experienced recurrence despite continuous administration of estrogen and progestin or progestin only. The recurrence rate of women in group A was significantly lower than that in group B or C (P < 0.05). The median time from complete response to recurrence was 20, 13, and 23 months in groups A, B, and C, respectively, not significantly different. Two of 3 women in group A, all 7 cases in group B and 5 of 7 patients in group C experienced recurrence within 2 years.
Of 17 recurrent cases, 9 patients underwent hysterectomy and 8 cases desired to preserve fertility. After close check-up with ultrasound scanning and magnetic resonance imaging, they were given an additional high-dose medroxyprogesterone acetate therapy for 6 months. All 8 cases achieved complete response again. Five women attempted to conceive, and 2 of them achieved successful pregnancies after ART.
The remaining 1 case with recurrence in group A relapsed 45 months after complete response, 19 months after live birth and during oral estrogen and progestin therapy. She underwent hysterectomy.
Kaplan-Meier recurrence free curve of the 3 groups is shown in Figure 1A. Log-rank test analysis revealed that there is a significant difference of recurrence rate among the 3 groups (P < 0.01).
Kaplan-Meier recurrence free curve of those with or without live birth is shown in Figure 1B. Log-rank test analysis revealed that the recurrence rate of women with live birth (group A) is significantly lower than that of those without live birth, irrespective of infertility treatment (group B + group C) (P < 0.01).
Kaplan-Meier curve of those with or without any infertility treatment is shown in Figure 1C. Disease-free rates in both groups were apparently similar within 2 years. In the group with infertility treatment, recurrence after 2 years occurred in only 1 case, and disease-free rate remained at the level of 62%, whereas that in the group without any infertility treatment declined to 16.7%. However, log-rank test analysis revealed that there was no statistically significant difference between the 2 groups (P = 0.17).
The overall recurrence rate of group B (cases with infertility treatment not resulting in live birth) and group C (cases without infertility treatment) was the same (7/10, 70.0%). Although the disease-free rate in group B declined in a shorter period than that in group C, log-rank test analysis revealed that there was no statistically significant difference (Fig. 1A).
To investigate the relationship between the kind of infertility treatment and recurrence, clinical courses of 26 women who underwent any infertility treatment were investigated, regardless of whether pregnancy was obtained or not. Thirteen of them underwent ovulation induction other than ART at the beginning, including 8 women who proceeded to ART. Five of 13 patients experienced recurrence, 4 during clomiphene citrate administration and 1 during hMG administration. Of 18 women who underwent ART, excluding 3 patients who were submitted to ART after recurrence, 4 patients experienced recurrence. There was not a statistically significant difference of recurrence rate between ART and non-ART treatment groups.
Between 4 patients who experienced recurrence during ART and 14 patients who did not during ART, there was not a statistically significant difference of peak estradiol on day of hCG administration (2783 vs 3011 pg/mL) or maximum hMG dose during 1 cycle (1950 vs 2967 IU).
To the best of our knowledge, this is the first report comparing the recurrence rate of endometrial cancer or atypical complex endometrial hyperplasia between the patients with and without infertility treatment after conservative management.
Only a few studies have assessed the influence of infertility treatment on the development of endometrial cancer.6 In the previous 2 cohort studies of infertile women, standardized incidence ratio for endometrial cancer was higher among women with infertility treatment than those with no treatment.7,8 Althuis et al9 showed that clomiphene citrate might increase endometrial cancer risk. However, most of the patients in their studies undergoing infertility treatment have ovulatory dysfunction, which is a well-known risk factor for the incidence of endometrial cancer.7 Chao et al10 compared clinical outcomes of those who achieved pregnancy after conservative treatment of endometrial carcinoma between cases with and without in vitro fertilization. The rate of metastasis or recurrence was not increased in cases with in vitro fertilization. However, those who failed to conceive or did not desire to conceive were not included in their study. Therefore, the role of ovulation induction drugs in the development of endometrial cancer remains to be fully elucidated.
Recently, many women younger than 40 years diagnosed as EC/ACEH desire to preserve fertility and choose conservative treatment. Several both successful pregnant and recurrent cases after conservative treatment have been reported but there have been no data regarding the influence of infertility treatment on the recurrence of endometrial cancer.
The recurrence rate after conservative treatment of endometrial cancer or atypical complex endometrial hyperplasia is reported to be 33.8% to 47% according to the multicenter trial in Japan3 and previous reviews.11,12 Mean duration to recurrence is 20 to 47.9 months.3,11 In this study, including 26 patients undergoing infertility treatment and 10 patients who had continuous estrogen and progestin pills, the overall recurrence rate was 47.2%, a comparable result to previous reports. Kaplan-Meier analysis revealed that there is no apparent difference of recurrence rate between the 2 groups within 2 years after initiating infertility treatment (Fig. 1C). After 2 years, recurrence occurred more often among the women without infertility treatment, probably because live births after infertility treatment had inhibitory effects on the recurrence, as shown in Figure 1B. Log-rank test analysis revealed no significance possibly because of the small number of patients. The overall recurrence rate was 70% in cases without pregnancy regardless of whether they were treated with infertility treatment, although the disease-free rate in cases with infertility treatment seemed to decline in a shorter period. Clinical backgrounds related to recurrence, such as pathological diagnosis and the duration to achieve complete response were not significantly different between these groups (Table 2). The recurrence risk seemed not to be influenced by the kind of infertility treatment, peak estradiol level, or total gonadotropin dose per cycle in our limited number of cases. These results indicate that ovulation induction drugs seem not to increase the recurrence rate. To confirm the favorable effect of infertility treatment on the recurrence of EC/ACEH in the long-term, a larger scale study including a large number of pregnant women will be necessary.
We did not use tamoxifen or letrozole for ovulation induction drugs in this study. These drugs have been reported to be useful in ovulation induction at the same time as antitumor effect against estrogen-sensitive cancer.13,14 They can induce follicle growth with relatively low estradiol levels, and may be useful as ovulation induction drugs in cases with infertility treatment after conservative therapy for endometrial cancer.
We achieved a high live birth rate per patient (61.5%) for the patients who desire to conceive after conservative treatment. Thirteen (81.3%) of 16 successful cases achieved live birth after ART. In the previous results regarding clinical pregnancies, successful pregnancy rate per patient was around 50%, and most of the cases were treated with infertility treatment.4,5,15–17 In these reports, 12 (54.5%) of 22 successful cases conceived after ART (data not shown in 1 report). We recommended undergoing ART soon after achieving complete response for the patients with other infertility factors, history of infertility treatment, or history of recurrence. Our treatment protocol could achieve a high live birth rate compared with the previous reports.
Additional medroxyprogesterone acetate therapy for recurrence achieved good response rate in this study. Ushijima et al3 reported medroxyprogesterone acetate therapy was conducted again for 8 in 14 recurrent cases and 6 cases achieved initial response, but lesion recurred in 5 patients. We here showed 2 successful pregnant cases after recurrence and additional medroxyprogesterone acetate therapy. Both cases experienced recurrence after infertility treatment other than ART. After complete response again, they underwent ART and achieved successful pregnancy. Only a few pregnant cases after recurrence have been reported so far.18,19 Our result shows that conservative therapy for recurrent EC/ACEH and subsequent infertility treatment is feasible in carefully selected patients.
Recurrence after successful delivery is considered to be rare. We here report a patient who relapsed 19 months after normal singleton delivery with clomiphene citrate therapy. Elizur et al4 reported a recurrent case 12 months after delivery and Niwa et al16 also reported 2 recurrent cases 18 and 51 months after delivery, respectively. After finishing breastfeeding, we need to recommend prompt initiation of cyclic estrogen and progesterone therapy and close follow-up in the same way as before pregnancy.
In summary, our results suggest that hyperestrogenic state after controlled ovarian stimulation or ovulation induction does not increase the overall recurrence of EC/ACEH after conservative treatment and that women with live birth has significantly lower risk of recurrence than those without live birth. Therefore, improvement of pregnancy rate with the aid of infertility treatment including ART can improve long-term prognosis of EC/ACEH.
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