Endometrial cancer is the most common cancer of the female genital tract and the fourth most common female cancer in the United States, with 47,130 new cases and 8,010 deaths projected in 2012.1 In Korea, it is the third most common cancer of the female genital tract and the twelfth most common female cancer, with 1,562 new cases and 210 deaths estimated in 2008.2 Although the incidence of endometrial cancer in the United States has been stable for the past 20 years,3 it is rapidly increasing in Asian countries, including Korea, Japan, and Taiwan.2,4,5
Approximately 3–14% of all endometrial cancers are diagnosed in women younger than age 40 years who might want to preserve their fertility, and the incidence of endometrial cancer in this age group is increasing.6,7 Because current standard treatment, including hysterectomy and bilateral salpingo-oophorectomy, might not be acceptable for women who want to retain their fertility, many of these women are being managed conservatively with oral progestin. The long-term oncologic outcomes8 and pregnancy outcomes9 after progestin treatment have been reported to be promising. The indication for progestin treatment has been limited to endometrioid adenocarcinoma with stage IA, grade 1 differentiation without myometrial invasion.10–14 Although women with grade 2–3 differentiation with or without superficial myometrial invasion also may want to preserve their fertility, the feasibility, safety, and outcomes of progestin treatment in these patients are not yet known. The aim of this study was to estimate the oncologic and pregnancy outcomes after progestin treatment of women of reproductive age with endometrioid adenocarcinoma with stage IA, grade 1 differentiation with superficial myometrial invasion or stage IA, grade 2–3 differentiation with or without superficial myometrial invasion.
MATERIALS AND METHODS
This was a multicenter retrospective cohort study. After obtaining the approval of the Institutional Review Board of each participating center (a representative Institutional Review Board was the Asan Medical Center Institutional Review Board), the medical records of women of reproductive age with early stage endometrial cancer who received fertility-sparing management with oral progestin between 1996 and 2012 were reviewed. The inclusion criteria of this study were as follows: women of reproductive age (age 40 or younger years) who strongly wanted to preserve their fertility; stage IA endometrial cancer, as defined by the 2008 International Federation of Obstetrics and Gynecology (FIGO) staging system; endometrioid adenocarcinoma; grade 2–3 differentiation or superficial myometrial invasion, defined as invasion less than half of the myometrium, as indicated by magnetic resonance imaging (MRI); and no evidence of ovarian tumors or lymph node metastasis in imaging studies. Patients with atypical hyperplasia and patients with stage IA, grade 1 endometrial adenocarcinoma without myometrial invasion were excluded. Stage IA was defined as tumor confined to the corpus uteri with no or less than half myometrial invasion according to the 2008 FIGO staging system.15 The stage of endometrial cancer is determined by the pathologic diagnosis made after surgical staging procedures including hysterectomy, bilateral salpingo-oophorectomy, lymph node dissection, and peritoneal washing cytology. However, because the patients in this study received conservative management, the stage was determined by MRI. Myometrial invasion and stage can be assessed with MRI with a fairly high degree of accuracy.16–18 Grade of differentiation was determined by the 1989 FIGO grading system as follows: grade 1, 5% or less of the tumor shows a solid growth pattern; grade 2, 6–50% of the tumor shows a solid growth pattern; and grade 3, more than 50% of the tumor shows a solid growth pattern.19 Notable nuclear atypia, which is inappropriate for the architectural grade, raised a grade 1 or grade 2 tumor by one grade.19 The diagnosis of endometrial cancer and grade of differentiation were performed by dilatation and curettage biopsy or hysteroscopic biopsy of the endometrium, and the depth of myometrial invasion was determined by MRI before treatment in all patients. All available pathology slides were reviewed by the pathologist specializing in gynecologic oncology in each of the contributing centers.
During progestin treatment, a response assessment occurred every 3 months using dilatation and curettage biopsy or hysteroscopic biopsy of the endometrium. Hysteroscopic biopsies were performed under general anesthesia in an operating room. Suspicious lesions were removed during these procedures, but endometrial curettage was not performed simultaneously. The response determination was based on the pathology report for these endometrial biopsies. All patients underwent this assessment during their treatment period, and there were no missing response assessment data. The response was classified as follows: complete response; the absence of evidence of hyperplasia or carcinoma; partial response, residual hyperplasia, or carcinoma with a degenerating and atrophic endometrial gland; stable disease; a persistent lesion; and progressive disease, progression to a higher-grade lesion, or clinically progressive disease, including extrauterine disease or lymph node metastasis.
After achieving a complete response, the patients were followed-up every 3–6 months. At each follow-up visit, history, physical examination, and transvaginal ultrasonography were performed. At some follow-up points in some women, MRI was performed instead of transvaginal ultrasonography. Whenever the recurrence of endometrial cancer was suspected because of symptoms or imaging study, dilatation and curettage biopsy or hysteroscopic biopsy of the endometrium was performed. The imaging criteria frequently used to proceed with endometrial biopsy was as follows: any space-occupying lesion in the endometrial cavity; irregular endometrial wall with fluid collection; and an endometrial lesion invading or protruding into the myometrium in the endometrial cavity. Currently, we do not recommend routine follow-up endometrial biopsy after achieving complete response because the positive rate for this procedure is low and its frequent application may cause intrauterine adhesion and adversely affect fertility. None of the patients in our study underwent office endometrial biopsy for surveillance after treatment. Although office endometrial biopsy is reported to be as accurate as endometrial curettage in the diagnosis of endometrial cancer, its efficacy in surveillance or as a treatment-response evaluation is not known. In addition, office endometrial biopsy has no effect on the removal of space-occupying lesions in the endometrial cavity in contrast to endometrial curettage or hysteroscopic biopsy.
Student t test or Mann-Whitney U test was used to compare the mean values of groups, depending on the normality of the distribution of continuous variables (determined by the Kolmogorov-Smirnov test). The analysis of variance test was used to compare the mean values of three groups. The χ2 test was used to compare the frequency distribution of categorical variables between groups, unless at least one frequency was less than five; if so, Fisher exact test was used. The disease-free survival time (months) was calculated from the date complete remission was achieved to the date of relapse or censoring. Survival curves and rates were calculated according to the Kaplan-Meier method and the log-rank test was used to compare the difference of survival rates between groups in univariable survival analysis. Cox proportional hazards model was used for multivariable survival analysis that included the factors that were significant in univariable survival analysis. The P values were calculated by using the two-sided test, and P<.05 was regarded as being statistically significant. Statistical analysis was performed by using SPSS for Windows.
A total of 204 patients with stage IA endometrial cancer who tried oral progestin treatment during the study period were reviewed. Of them, 156 patients did not meet the inclusion criteria. The remaining 48 patients who met the inclusion criteria were included in this study. Table 1 lists their characteristics. The median age was 30 years (range 23–40 years) and 46 patients (95.8%) were nulliparous. The patients were divided into three groups on the basis of the grade of differentiation and the presence of myometrial invasion as follows: group 1, patients with stage IA, grade 2–3 differentiation without superficial myometrial invasion (n=17); group 2, patients with stage IA, grade 1 differentiation with superficial myometrial invasion (n=23); and group 3, patients with stage IA, grade 2–3 differentiation with superficial myometrial invasion (n=8).
Fourteen patients (29.2%) received daily oral megestrol acetate and 34 patients (70.8%) received daily oral medroxyprogesterone acetate. The daily median dose of megestrol acetate was 160 mg/d (range 40–240 mg/d) and the daily median dose of medroxyprogesterone acetate was 500 mg/d (range 80–1,000 mg/d). A complete response, partial response, and stable disease were seen in 37 (77.1%; 95% confidence interval [CI] 63.3–86.9%), 1 (2.1%; 95% CI 0.01–11.9%), and 10 patients (20.8%; 95% CI 11.5–34.4%), respectively. The median time to complete response was 17 weeks (range 9–51 weeks). The median duration of progestin treatment for 37 patients who achieved complete response was 10 months (range 3–20 months). Patients who did not achieve a complete response underwent definitive surgical treatment after the median duration of progestin treatment of 9 months (range 6–20 months). The response rates according to grade of differentiation and myometrial invasion are shown in Table 2. The complete response rates were 76.5% (95% CI 52.2–91%), 73.9% (95% CI 53.2–87.7%), and 87.5% (95% CI 50.8–99.9%) for groups 1, 2, and 3, respectively (P=.731). Univariable analysis showed that age (30 years or younger compared with older than 30 years), medical comorbidity, parity (0 compared with 1), history of infertility, polycystic ovary syndrome, irregular menstruation, grade of disease (1 compared with 2–3), myometrial invasion on MRI (absent compared with present), progestin type (megestrol acetate compared with. medroxyprogesterone acetate), and progestin dose (less than 500 mg/d compared with 500 or more mg/d) were not predictive of treatment failure (Table 3). Only body mass index (calculated as weight (kg)/[height (m)]2) of 25 or more was associated significantly with a higher risk of treatment failure (odds ratio 7.39, 95% CI 1.39–39.27) (Table 3).
The median follow-up time of the 37 patients who had complete response was 48 months (range 7–136 months). Four patients received a low-dose cyclic oral progestin as a maintenance treatment after achieving complete remission. There were no follow-up losses, and compliance rate was 100%. Of the 37 patients who had a complete response, 21 women (57%) underwent routine follow-up endometrial biopsy after demonstrating complete response. The median number of additional endometrial biopsies for these patients was 3 (range 1–6). Sixteen of 37 patients who achieved complete response (43.2%; 95% CI 28.7–59.1%) had recurrent disease. The median time to recurrence was 20 months (range 7–69 months). The recurrent disease was atypical complex hyperplasia in 2 patients and stage IA, grade 1, 2, or 3 endometrioid adenocarcinoma confined to the uterus in 11, 1, and 2 patients, respectively. Three patients underwent definitive surgical treatment, and 13 patients received progestin treatment again at recurrence. Of 13 patients who tried progestin retreatment, two patients underwent definitive surgical treatment because of absence of response, nine showed complete response again, and two were still receiving progestin retreatment at the time of writing this article. Of five patients who underwent definitive surgical treatment, one patient had atypical hyperplasia, three patients had stage IA, grade 1 endometrioid adenocarcinoma without myometrial invasion, and one patient had stage IA, grade 3 endometrioid adenocarcinoma with myometrial invasion, which was determined from hysterectomy specimens. At the time of this analysis, all patients who tried initial progestin treatment (n=48) were alive without evidence of disease, excluding two patients who were still receiving progestin retreatment. None had extrauterine spread of disease. The 5-year recurrence-free survival rate was 52% (95% CI 34–71%), and the median recurrence-free survival time was 69 months (95% CI 32–106 months) for 37 patients who achieved complete response. Recurrence rates in 37 patients who achieved complete response were 23.1% (95% CI 7.5–50.9%), 47.1% (95% CI 26.2–69%), and 71.4% (95% CI 35.2–92.4%) for groups 1, 2, and 3, respectively (P=.104). Their median times to recurrence were 19 (range 8–20), 18 (range 7–69), and 34 (range 14–48) months, respectively (P=.515), and their 5-year recurrence-free survival rates were 73% (95% CI 47–99%), 56% (95% CI 31–81%), and 19% (95% CI 0–52%), respectively (P=.359) (Fig. 1). Univariable analysis showed that recurrence-free survival was not associated with age (30 years or younger compared with older than 30 years), body mass index (less than 25 compared with 25 or more), medical comorbidity, parity (0 compared with 1), polycystic ovary syndrome, irregular menstruation, grade of disease (1 compared with 2–3), myometrial invasion on MRI (absent compared with present), progestin type (megestrol acetate compared with medroxyprogesterone acetate), progestin dose (less than 500 mg/d compared with 500 or more mg/d), progestin treatment duration (less than 10 months compared with more than 10 months), time to complete remission (less than 17 weeks compared with 17 or more weeks), maintenance treatment, or infertility treatment. Only a history of infertility (odds ratio 0.20, 95% CI 0.06–0.69; P=.011) and pregnancy (odds ratio 0.26, 95% CI 0.07–0.93; P=.038) were significantly associated with recurrence-free survival. In multivariable analysis, however, none of these variables were significantly associated with recurrence-free survival.
In total, 22 patients tried to conceive after achieving complete response, and 12 of these patients received infertility treatment. The median time to pregnancy trial after achieving complete response was 1 month (range, 1–25 months). Twelve patients (55%; 95% CI 34.7–73.1%) achieved 14 pregnancies, including one twin pregnancy. Eight of these patients (67%) received infertility treatment. There were four spontaneous abortions (29%; 95% CI 11.3–55%), one ectopic pregnancy (7%; 95% CI 0.01–33.5%), one preterm delivery (7%; 95% CI 0.01–33.5%), and eight full-term deliveries (57%; 95% CI 32.6–78.7%). Thus, nine patients gave birth to 10 healthy newborns. There were no congenital anomalies. Of 12 patients who had a successful pregnancy, two patients underwent prophylactic hysterectomy after achieving their planned family and tumors were not detected in the hysterectomy specimens. One patient had a recurrence of disease after giving birth and underwent surgery. The remaining nine patients are alive without recurrence.
According to the literature, conservative management of patients with stage IA, grade 1 differentiation without myometrial invasion by using oral progestin results in complete response rates that range between 67% and 80%.10–14 A recent meta-analysis showed that the response rate of these patients was 72% (95% CI 62–80%).11 The recurrence rates of these patients after achieving complete remission ranged between 19% and 34%.10–14 Therefore, approximately 50% of these patients show a durable complete response to progestin treatment. However, the complete response rates and recurrence rates of patients with stage IA, grade 2–3 differentiation with or without superficial myometrial invasion are not yet clear. In the present series, patients with stage IA, grade 2–3 differentiation without myometrial invasion had a complete remission rate of 76.5% and a recurrence rate of 23.1%; thus, approximately 59% of these patients had a durable complete response to progestin treatment. These results are comparable with those of patients with stage IA, grade 1 differentiation without myometrial invasion. Therefore, progestin treatment may be safe in patients with stage IA, grade 2–3 differentiation without myometrial invasion.
The complete response rate (73.9%) of patients with stage IA, grade 1 differentiation with superficial myometrial invasion was comparable with that of patients with stage IA, grade 1 differentiation without myometrial invasion. Although the recurrence rate of the former patients (47.1%) was somewhat higher and the durable response rate (39%) was slightly lower than the rates of patients with stage IA, grade 1 differentiation without myometrial invasion, progestin treatment also may be a reasonable treatment option for patients with stage IA, grade 1 differentiation with superficial myometrial invasion.
In patients with stage IA, grade 2–3 differentiation with superficial myometrial invasion, the complete response rate (87.5%) was similar to that of patients with stage IA, grade 1 differentiation without myometrial invasion. The recurrence rate (71.4%) was very high; thus, the durable complete response rate was very low in these patients (25%). Therefore, progestin treatment in these patients cannot be routinely recommended. However, none of the patients had progression of disease during progestin treatment or follow-up after achieving a complete response. All recurrent disease was confined to the uterus and no one died of the disease. Although the durable complete response rate of the patients with stage IA, grade 2–3 differentiation with superficial myometrial invasion was rather low, it seems that progestin treatment in these patients does not worsen the prognosis. Furthermore, approximately 80% of the patients who tried to conceive succeeded in giving birth to healthy newborns. Therefore, progestin treatment in these patients may be administered on an individual basis after careful discussion with patients about the benefits and risks of this treatment. Because patients with deep myometrial invasion (more than half of the myometrium) were not included in this study, we cannot assume that progestin treatment is safe in such patients.
A recent study suggested that maintenance treatment with low-dose cyclic progestin or a progestin-releasing intrauterine device was significantly associated with decreased recurrence after achieving complete response to progestin treatment.8 Maintenance treatment can be recommended for patients with superficial myometrial invasion after they achieve a complete response to progestin treatment until they try to conceive.
In the literature, there are reports of 14 patients with stage IA, grade 2–3 differentiation without myometrial invasion who underwent conservative management (Table 4).20–26 Ten of these patients (71%) had a complete response, and 3 of the 10 patients (30%) who achieved complete response had recurrent disease. These results are consistent with the results of the present study. Thus, conservative management of patients with stage IA, grade 2–3 differentiation without myometrial invasion is effective and safe. However, patients with stage IA, grade 1 differentiation with superficial myometrial invasion or stage IA, grade 2–3 differentiation with superficial myometrial invasion who were treated conservatively could not be found in the literature.
After conservative management for endometrial hyperplasia or cancer, there is no established surveillance strategy. Periodic imaging modalities such as transvaginal ultrasonography and endometrial biopsy are the most frequently adopted surveillance tools. However, standard imaging criteria are still lacking for the surveillance of these patients.12,14
The limitations of the present study are its retrospective design and the small number of cases that were included. Notably, the number of cases of higher-grade disease that would be of interest when considering oncologic safety issues is particularly small. In the present series, a three-tiered FIGO system was used to grade the histology of the tumor. A recent study has reported poor interobserver reproducibility in distinguishing between grade 1 and grade 2 disease, but a better degree of agreement in this regard for grade 3 disease.27 This previous finding may be pertinent to the interpretation of our current results.
In conclusion, conservative management with oral progestin can be a reasonable treatment option for patients with stage IA, grade 2–3 differentiation without myometrial invasion and patients with stage IA, grade 1 differentiation with superficial myometrial invasion. The complete response rate of patients with stage IA, grade 2–3 differentiation with superficial myometrial invasion also was substantially high and oral progestin treatment did not impair the prognosis of these patients. However, the routine use of this treatment in these patients cannot be justified because of the high recurrence rate. Therefore, this treatment should be applied on an individual basis, and caution is required in patients with stage IA, grade 2–3 differentiation with superficial myometrial invasion.
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© 2013 by The American College of Obstetricians and Gynecologists.
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