Han, Aera R.; Kwon, Yong-Soon; Kim, D. Y.; Kim, J. H.; Kim, Y. M.; Kim, Y. T.; Nam, J. H.
The treatment of choice for patients with early-stage endometrial cancer is hysterectomy with bilateral oophorectomy. Many younger patients do not want to choose this treatment, however, because they desire to become pregnant. After the first reported successful pregnancies that were found to occur after progestative treatment of patients with well-differentiated endometrial adenocarcinoma,1 there have been many reports of fertility-preserving therapies for endometrial cancer in young women.
Although the safety and efficacy of fertility-preserving therapy have been demonstrated,2,3 there have been only a few case reports regarding successful pregnancies after treatment.4-8 To date, there is no consensus regarding the method of follow-up.
We describe our findings in 11 young women (<40 years old) who were treated in our institute for 10 years with progestin and serial dilatation and curettage (D&C) as primary treatment of endometrial cancer or atypical complex hyperplasia and who then sought to become pregnant. This is the second study for fertility-preserving therapy in endometrial cancer. The previous study was focused on treatment efficacy.9 In this study, we evaluated their pregnancy outcomes and postpartum follow-ups.
MATERIALS AND METHODS
We retrospectively reviewed the charts of 11 women with endometrial cancer or atypical complex hyperplasia who had been treated with progestin and serial D&C as primary fertility-preserving therapies at Asan Medical Center from January 1997 to October 2007. For inclusion in the study, women were required to be younger than 40 years old, to have pathologically confirmed endometrial complex hyperplasia with atypia or endometrioid adenocarcinoma of grade 1 or 2 differentiation, to not have deep myometrial invasion on magnetic resonance imaging (MRI) or ultrasonography (USG), to have a strong desire to preserve fertility, to have received extensive counseling regarding the possibility of tumor recurrence or progression, and to have undergone assisted reproductive technology (ART) after remission. One of the 11 patients did not undergo ART and was excluded, leaving a total of 10 women as the patient cohort.
Treatment and Follow-up
All patients were treated with megestrol acetate ([MA] Megace 80-160 mg/d) or medroxyprogesterone acetate ([MPA] Farutal 500-1000 mg/d or Provera 20 mg/d), which was continued to pathological remission. Endometrial curettage was performed every 3 to 6 months as a modality for treatment and follow-up. All patients underwent TV-USG or endometrial cytology after remission and after delivery.
The mean age at diagnosis was 32 years (range, 26-37 years). Of the 10 women, 8 were nulliparous, one was primiparous, and one had undergone 2 spontaneous abortions after ovulation induction. The TV-USG showed that 8 patients had polycystic ovaries.
Six patients were diagnosed with early endometrial cancer or atypical complex hyperplasia during infertility workup, 3 were diagnosed after irregular vaginal bleeding, and one was diagnosed by an abnormal USG finding during her early pregnancy. Of the 10 patients, 7 were diagnosed with endometrioid adenocarcinoma by D&C at a local clinic; all slides were reviewed by the Pathology Department of our institute. Two women presented with grade II differentiation and 5 with grade I. Three patients were underdiagnosed with complex hyperplasia without atypia at a local clinic. These patients were referred to our institute and underwent repeat D&C. They were rediagnosed with endometrial complex hyperplasia with atypia.
Of the 8 women who underwent MRI, one was suspected of having superficial myometrial invasion, with the other 7 having no evidence of myometrial invasion by imaging analyses. Carbohydrate antigen 125 levels were measured in 8 women to rule out other abnormalities; all 8 were within the reference range (6.6-32.8 U/mL) (Table 1).
Treatment and Response
Of the 10 patients, 9 received high-dose progestin therapy; 7 received MA (Megace) 80 to 160 mg/d, and 2 received MPA (Farutal) 500 to 1000 mg/d. The remaining patient received low-dose progestin therapy, consisting of MPA (Provera) 20 mg/d for 2 weeks and no medication for 2 weeks. All patients underwent repeat D&C every 3 to 6 months (Table 2). Nine of the 10 patients underwent D&C 3 to 4 months after starting progestin therapy and every 3 to 4 months thereafter; the remaining patient underwent a D&C 6 months after medication started and every 6 months thereafter. The average number of D&C before ART was 3.6. One patient, who experienced uterine synechia after frequent D&C, was treated with hysteroscopic adhesiolysis. Eight patients were in pathological remission at initial D&C, and the other 2 achieved remission after 9 and 18 months, respectively.
Progestin therapy and D&C were continued for 6 months after remission, except for the 2 women who stopped progestin after reaching remission and immediately tried to become pregnant using ART.
Pregnancy Trials and Outcomes
All 10 patients tried to get pregnant with ART, 6 with controlled ovarian hyperstimulation (COH), with or without intrauterine insemination (IUI), and 4 with in vitro fertilization and embryo transfer (IVF-ET). Assisted reproductive technology was performed 1 to 6 times until successful intrauterine pregnancy (IUP) and is still continuing in 2 women.
Of the 10 women, 8 achieved IUP and 1 had an ectopic pregnancy, which was treated with methotrexate (Table 3). Of the 8 women with successful IUP, 6 had live births (cases 1, 2, 3, 5, 7, and 8) by vaginal or cesarean delivery. The other 2 women (cases 4 and 6) experienced pregnancy losses because of cervical incompetence during the second trimester.
Postpartum Follow-up and Present Status of Original Disease
Nine of the 10 patients have been followed up for 13 to 75 months (mean, 46.8 months) with regular TV-USG, with or without endometrial cytology. The 10th patient, who lost her baby because of preterm labor, has been lost to follow-up. Of the 9 women who were available for follow-up, 8 showed no evidence of tumor recurrence. One patient, who was suspected of recurrence on MRI, underwent laparoscopy-assisted vaginal hysterectomy, but this showed no evidence of cancerous tissue. Pathological examination showed only focally myometrial invasion of chorionic villi, suggestive of placenta accreta.
Of the 8 patients who achieved IUP, 7 have been followed for 9 to 51 months (mean, 21 months). Three of these patients are continuing treatment with low-dose progestin and are undergoing regular routine follow-up. One woman is trying to have a second child using ART.
About 2% to 14% of women with endometrial cancer are younger than 40 years.10,11 Endometrial cancer in younger patients is commonly correlated with polycystic ovarian syndrome and irregular menstruation, and anovulation, obesity, and hypertension have been shown to be risk factors.10,11 Endometrial cancer in younger women is believed to have less myometrial invasion, to be well differentiated, and to have a higher dependence on hormone.11 Because many of these younger women wish to have children, they have received various fertility-preserving therapies with hormone, especially progesterone.
Progestins have long been used as palliative treatment in patients with advanced or recurrent endometrial adenocarcinoma.12 Response rates to primary therapy with progestins are 83% to 94% for women with atypical complex hyperplasia and 57% to 75% for women with early-stage endometrial adenocarcinoma.10 Treatment protocols have used progestin alone, repeated endometrial curettage and application of progestins, and primary hysteroscopic resection of endometrial lesions, followed by adjuvant progestin therapy.2,13,14 The most frequently used progestins are MA and MPA. Primary therapy for our patients consisted of progestin and serial D&C, with 7 patients receiving MA and 3 given MPA. All patients showed a good response and attained remission.
The optimal time to evaluate initial response to progestin is not clear, and many studies reported initial D&C 3 months after. Normal endometrial findings have been reported after 10 weeks of treatment with MPA.15 In contrast, Ramirez et al16 reported remission as long as 15 months of treatment. We found that the mean time to remission was 5.5 months, but 1 patient required 18 months of continuous progestin therapy to attain remission. Continuous progestin therapy should be considered in nonresponders to initial D&C. Total duration of treatment has been reported to range from 3 to 18 months.4 We found that the mean duration of treatment was 10.5 months and that it was continued for a mean of 6 months after attaining remission.
Although natural conception can occur after conservative treatment of endometrial cancer,4 ART is frequently required because younger endometrial cancer patients commonly have coincident polycystic ovarian syndrome or chronic anovulation. Although the risks of high levels of estrogen induced by ovulation induction drugs are unknown in these patients, there is no evidence that ovulation induction agents, including clomiphene citrate, were associated with a higher risk of endometrial carcinoma.17 In addition, 1 woman who was directly treated with ovulation induction agents rather than with progesterone had a good outcome.5
A successful triplet pregnancy was reported in a woman who underwent gamete intrafallopian transfer after conservative treatment of endometrial cancer.18 Other methods of ART include IVF after COH, oocyte donation and intracytoplasmic sperm injection and ET.6-8 We found that 1 patient had a successful IUP with COH only. Of the 7 IVF-ETs, 3 resulted in successful IUPs. Of the 12 IUIs, 4 resulted in successful IUPs; this included 1 woman who underwent 5 IUIs, none of which was successful. This patient later underwent COH-IUI, which resulted in a successful IUP. By comparison with other reports about ART of general infertile patients, our IUP success rate was relatively high.19,20
No consensus currently exists regarding postpartum follow-up and management of these patients, although hysterectomy is recommended as soon as possible after delivery.21 If this is not possible, regular D&C and pelvic USG are recommended, and endometrial cytology can be considered. It is a noninvasive and simple procedure in an outpatient clinic, and Kondo et al22 reported that endometrial cytology can detect endometrial malignancy with 80% sensitivity. Diagnostic hysteroscopy also can be considered, but it is not an appropriate tool for follow-ups. Because there is a controversy regarding hysteroscopy increasing intraperitoneal tumor cell dissemination,23 we used TV-USG and endometrial cytology for routine postpartum follow-up; women with abnormal findings underwent diagnostic D&C or pelvic MRI. In one of our patients, recurrence was suspected after postpartum TV-USG, and the abnormal results of the latter were confirmed by pelvic MRI. Laparoscopy-assisted vaginal hysterectomy was performed, which showed no evidence of cancer tissue.
Oral contraceptives (OCPs) and cyclic progestins have been used to inhibit tumor recurrence.13 The combination of OCP and high-potency progestins has been found to decrease the risk of endometrial cancer by 5-fold, and the combination of OCP and low-potency progestins by 2.5-fold.24 Three of our patients have been taking low-dose oral progestins, one in combination OCP and 2 as MA 5 mg/d. One patient received an intrauterine device after delivery. Intrauterine devices containing slow-release levonorgestrel have been successful in the treatment of women with presumed stage Ia grade 1 endometrial cancer at high risk for perioperative morbidity.25
Although fertility-preserving therapy may be successful, this treatment may lead to tumor recurrence. For example, the recurrence rate after complete remission has been reported to be 46% to 50% after a relatively long-term follow-up.2 In contrast, recurrences were rare after term delivery.26 In agreement with the latter study, we observed no tumor recurrences after delivery, although the number of patients was small and the follow-up time was short. Our findings support the negative correlation between number of full-term pregnancies and incidence of endometrial cancer27 and suggest that early pregnancy after remission has benefits.
Continuous progestin treatment plus serial D&C could lead to uterine synechia, which can contribute to infertility. In our study, 1 patient presented with amenorrhea for 5 months after her third D&C. This patient, who was diagnosed with uterine synechia, was treated by hysteroscopic adhesiolysis. These findings support immediately attempting to become pregnant after the first pathological remission.
Patient selection can enhance the efficacy and safety of fertility-preserving therapy. Response rates to fertility-preserving therapy have been found to depend on tumor differentiation, being 37% for patients with grade 1 tumors, 23% for grade 2, and 9% for grade 3.28 In addition, achievement of complete remission was positively correlated with the expression of progesterone receptor.29 Of our patients, none had an ovarian malignancy, only 2 patients had grade 2 tumors, and only one (case 10) was assessed for progesterone receptor, which was strongly positive. Pretreatment counseling about the risks of conservative therapy is necessary, along with careful evaluation of initial tumor stage and grade, the existence of any other gynecologic malignancies, and the expression of hormonal receptors.
In summary, we have shown here that fertility-preserving therapy can be a good option in well-selected patients with early-stage low-grade endometrial cancer or atypical complex hyperplasia. Pregnancy should be attempted using various forms of ART as soon as possible after achieving remission. Prospective randomized trials in larger numbers of patients and with longer follow-up times are clearly warranted.30
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