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Fertility-preserving treatment in young women with well-differentiated endometrial carcinoma and severe atypical hyperplasia of endometrium
Fertility-preserving treatment in young women with well-differentiated endometrial carcinoma and severe atypical hyperplasia of endometrium A retrospective study on 25 women (8 with endometrial carcinoma, 17 with severe endometrial atypical hyperplasia) under 35 years treated with progestin showed that six cases (75%) in the endometrial carcinoma (EC) group and 17 (100%) in the atypical hyperplasia (AH) group responded to the treatment, and among the 14 complete responders, 4 (40%) patients with AH had 7 pregnancies and 3 healthy deliveries. Given accurate pretreatment assessment, progestin therapy is a feasible management option to preserve fertility for young women with welldifferentiated endometrial carcinoma or severe atypical hyperplasia of endometrium. (Fertil Steril 2009;92:2122–4. 2009 by American Society for Reproductive Medicine.) Key Words: Endometrial carcinoma, severe endometrial atypical hyperplasia, fertility-preserving treatment, Progestin therapy, assisted reproductive technology
In recent years, the incidence of uterine endometrial carcinoma (EC) and atypical hyperplasia (AH) has increased among young women. According to our previous study, approximately 4% of ECs occurred in young women under the age of 35, and up to 88% of these young patients nulliparous (1). Hysterectomy adnexectomy is a standard treatment that cannot be accepted by patients who wish to preserve fertility. Multiple groups have reported that ECs were treated successfully with progesterone (2, 3). The purpose of this study is to share our experience in progestin therapy for young patients with EC or severe endometrial AH, and to evaluate its safety and efficacy. Twenty-five patients under 35 years (mean age 25.1 in EC, 29.9 in the AH group) were enrolled between 1991 and 2005, who were diagnosed with well-differentiated EC or severe endometrial AH. These patients were treated with progestin at Peking Union Medical College Hospital. The diagnosis were confirmed independently by two pathologists. Enrollment criteria included aged 35 years or younger, stage Ia well-differentiated EC or severe AH, patient has strong desire to preserve fertility, presence of progesMei Yu, M.D.a Jia-xin Yang, M.D.a Ming Wu, M.D.a Jing-he Lang, M.D.a Zhen Huo, M.D.b Keng Shen, M.D.a a Department of Obstetrics/Gynecology, Peking Union Medical College Hospital, Beijing, People’s Repulic of China b Department of Pathology, Peking Union Medical College Hospital, Beijing, People’s Republic of China Received April 25, 2008; revised May 29, 2009; accepted June 3, 2009; published online July 9, 2009. M.Y. has nothing to disclose. Y.-x.Y. has nothing to disclose. M.W. has nothing to disclose. J.-h.L. has nothing to disclose. Z.H. has nothing to disclose. K.S. has nothing to disclose. Reprint requests: Keng Shen, M.D., Department of Obstetrics/Gynecology, Peking Union Medical College Hospital, Shuaifuyan No. 1. Dongchen District, Beijing 100730, P.R. China (FAX: 8610-65212507; E-mail: [email protected]).
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terone receptor in the EC patient, and no contraindications to progestin. Enrolled patients were classified into two groups: 8 in EC group and 17 in AH group. All 25 patients agreed to participate by giving informed consent. Approval for this study was obtained from the institutional review board at Peking Union Medical College Hospital. In the EC group, pelvic ultrasonography, magnetic resonance imaging, chest roentgenogram, and serum CA125 were used for pretreatment assessment to rule out myometrial invasion or extrauterine metastases. Immunohistochemistry was applied to detect progesterone receptors (PgR). Twenty-two patients were initially treated with medroxyporgesterone acetate, and the other three patients with megestrol acetate or hydroxyprogesterone caproate. The dosage of medroxyporgesterone acetate was 250 to 500 mg/day in the EC group and 100 to 500 mg/day in the AH group. The progestin therapy was continued for at least 3 to 6 months after complete remission. Nonresponders were suggested to take hysterectomy if at least 3-month progestin treatment was proven to be of no effect. All patients were followed up by endometrial curettage at intervals of 3 months. Complete response (CR) was defined as absence of the lesion, partial response (PR) as histologic regression or endometrial deciduoid change, recurrence as presence of EC or AH after CR. In EC group (Table 1), six (75.0%) patients responded to the progestin therapy: five patients (62.5%) had CR and one patient (12.5%) had PR. The mean time to achieve CR was 6.4 months (range ¼ 3–10 months). Two (25.0%) no-responders were treated with total hysterectomy, which showed superficial myometrial invasion. The five patients with CR were followed up for an average of 31.8 months (range ¼ 5–90 months). One (20.0%) of them experienced recurrence at 30 months and underwent hysterectomy with superficial myometrial invasion. She was free of disease at follow-up of 55 months postoperation. In the AH group (Table 1), all of the 17 patients (100%) responded to progestin therapy, and 14 (82.4%) had CR. The mean time to achieve CR was 7.3 months (range ¼ 3–11 months). Three
Fertility and Sterility Vol. 92, No. 6, December 2009 Copyright ª2009 American Society for Reproductive Medicine, Published by Elsevier Inc.
0015-0282/09/$36.00 doi:10.1016/j.fertnstert.2009.06.013
TABLE 1 Effect of progestin therapy.
EC group AH group
N
Mean age
CR rate (n%)
8 17
25.1 29.9
5 (62.5) 14 (82.4)
PR rate (n%)
NR rate (n%)
Time to remission (month)
Recurrence rate (%)
Time to recurrence (month)
1 (12.5) 3 (17.6)
2 (25.0) 0 (0)
6.4 7.3
1 (20.0) 3 (21.4)
30 6–16
Note: EC ¼ endometrial carcinoma; AH ¼ atypical hyperplasia; CR ¼ complete response rate; PR ¼ partial response rate; NR ¼ nonresponse rate. Yu. Fertility-preserving treatment in your women. Fertil Steril 2009.
patients (17.6%) had PR. The 14 patients with CR were followed for an average of 34.6 months (range ¼ 7–114 months). Three (21.4%) of them experienced recurrence at 6, 11, and 16 months, respectively, after treatment. One patient underwent hysterectomy, which showed superficial myometrial invasion. The other two patients were retreated with progestin: one achieved a second CR and was free of disease at follow-up of 12 months; the other patient was still being treated. Fourteen patients attempted conception after CR. None of the four with EC got pregnant. In contrast, 4 of the 10 (40%) with AH achieved seven pregnancies. These four patients got pregnant 3 to 26 months after CR, and three of them each successfully delivered a healthy full-term baby and had been followed for 27 to 74 months after delivery without recurrence. The fourth patient was lost to follow-up shortly after being pregnant. Except for 1 patient with AH who got pregnant spontaneously, 13 patients used some kinds of assisted reproductive technology, such as ovulation induction. Three of them got pregnant successfully. One patient with a 7-year history of primary infertility and polycystic ovarian syndrome achieved pregnancy after a series of reproductive therapies, including superovulation with clomiphene and/or cyproterone (Diane-35), laparoscopic bilateral ovarian drilling, follicle-stimulation hormone injection, and ultrasound monitoring of ovulation. Progestin therapy is one of the most important fertilitypreserving treatments for patients with EC or AH. Progesterone as an anticancer therapy, which was combined with PgR to antagonize the effects of estrogen, was first reported in 1961 (4). In our review of literature published between 2001 and 2005, 42% to 100% of patients with EC responded to progestin with a recurrence rate of 20% to 89% (5–7). Ramirez et al. (8) reviewed 21 studies involving 81 patients with EC, with an initial response rate of 76%, recurrence rate of 24%. A multicenter phase II study (9) found 55% of EC cases and 82% of AH cases
got complete response and 47% recurred between 7 and 36 months. There is a broadly accepted opinion that 3 months is an appropriate interval period of evaluation, which is sufficient for progestin to show an obvious effect and to ensure prompt surgical treatment for nonresponders. Progestin treatment duration was suggested to continue at least for 6 months or until 2 months after remission (7). In the AH and EC groups of our study, the mean time to achieve CR was 6.4 and 7.3 months respectively. We recommend that progesterone be administered for at least 9 to 12 months. Strong positive association has been demonstrated between PgR status, and the response rate to the progestin treatment (10) response rates ranged from 60% to 72% for PgR-positive cases and from 12% to 19% for PgR-negative ones. It is suggested that progestin treatment should be taken in PgR-positive case. Recent studies indicated that tamoxifen may increase the sensitivity to progestin by promoting expression of PgR (11). This regimen may hold promise for patients with low expression of PgR. Pregnancy rate after conservative treatment with EC is quite variable from 25% to 80%. More assisted reproductive technology methods have been developed in the last 5 years to treat infertile women with EC or AH, such as in vitro fertilization (IVF), intracytoplasmic sperm injection, and embryo transfer (12–14). Gotlieb et al. (5) demonstrated that neither pregnancy nor assisted reproductive technology would worsen the prognosis of EC. Reproductive therapies should be taken as soon as possible after CR. If the patients fail to achieve pregnancy in 6 months, more effective methods, such as IVF, should be recommended. In conclusion, progestin therapy is a feasible management option for well-differentiated EC or severe AH in young women to preserve fertility. Assisted reproductive technologies are potential options to increase pregnancy rates for these cases after complete remission.
REFERENCES 1. Jin-song G, Keng S, Jing-he L, et al. Clinical analysis of endometrial carcinoma patients aged 45 years and younger. Chin J Obst Gynecol 2004;39: 159–61. 2. Randall TC, Kurman RJ. Progestin treatment of atypical hyperplasia and well-differentiated carcinoma of the endometrium in women under age 40. Obstet Gynecol 1997;90:434–40.
Fertility and Sterility
3. Kim YB, Holscheider CH, Ghosh K, Nieberg RK, Monyz FJ. Progestin alone as primary treatment of endometrial carcinoma in premenopausal women, report of seven cases and review of the literature. Cancer 1997;79:320–7. 4. Kelly RM, Baker WH. Progestational agents in the treatment of carcinoma of the endometrium. N Engl J Med 1961;264:216–22.
5. Gotlieb WH, Beiner ME, Shalmon B, Korach Y, Segal Y, Zmira N. Outcome of fertility-sparing treatment with progestins in young patients with endometrial cancer. Obstet Gynecol 2003;102: 718–25. 6. Ota T, Yoshida M, Kimura M, Kinoshita K. Clinicalpathologic study of uterine endometrial carcinoma in young women aged 40 years
2123
and younger. Int J Gynecol Cancer 2005;15: 657–62. 7. Niwa K, Tangami K, Lian Z, Onogi K, Mori H, Tamaya T. Outcome of fertility-preserving treatment in young women with endometrial carcinomas. BJOG 2005;112:317–20. 8. Ramirez PT, Frumovitz M, Bodurka DC, Sun CC, Levenback C. Hormonal therapy for the management of grade 1 endometrial adenocarcinoma: a literature review. Gynecol Oncol 2004;95:133–8. 9. Ushijima K, Yahata H, Yoshikawa H, Konishi I, Yasugi T, Saito T, et al. Multicenter phase II study of fertility-sparing treatment with medroxyprogesterone acetate for endometrial carcinoma and atyp-
2124
Yu et al.
Correspondence
ical hyperplasia in young women. J Clin Oncol 2007;25:2798–803. 10. Thigpen JT, Brady MF, Alvarez RD, Adelson MD, Homesley HD, Manetta A, et al. Oral medroxyprogesterone acetate in the treatment of advanced or recurrent endometrial carcinoma: a dose–response study by the gynecologic oncology group. J Clin Oncol 1999;17:1736–44. 11. Nola M, Jukic S, Ilic-Forko J, Babic D, Uzarevic B, Petrovecki M, et al. Effects of tamoxifen on steroid hormone receptors and hormone concentration and the results of DNA analysis by flow cytometry in endometrial carcinoma. Gynecol Oncol 1999;72: 331–6.
12. Yarali H, Bozdag G, Aksu T, Ayhan A. A successful pregnancy after intracytoplasmic sperm injection and embryo transfer in a patient with endometrial cancer who was treated conservatively. Fertil Steril 2004;81:214–6. 13. Piura B. Two successful pregnancies after in vitro fertilization and embryo transfer in a patient with endometrial atypical hyperplasia bordering on adenocarcinoma treated conservatively with high-dose progesterone. Gynecol Obstet Invest 2006;61:21–3. 14. Park JC, Cho CH, Rhee JH. A successful live birth through in vitro fertilization program after conservative treatment of FIGO grade I endometrial cancer. J Korean Med Sci 2006;21:567–71.
Vol. 92, No. 6, December 2009
In recent years, the incidence of uterine endometrial carcinoma (EC) and atypical hyperplasia (AH) has increased among young women. According to our previous study, approximately 4% of ECs occurred in young women under the age of 35, and up to 88% of these young patients nulliparous (1). Hysterectomy adnexectomy is a standard treatment that cannot be accepted by patients who wish to preserve fertility. Multiple groups have reported that ECs were treated successfully with progesterone (2, 3). The purpose of this study is to share our experience in progestin therapy for young patients with EC or severe endometrial AH, and to evaluate its safety and efficacy. Twenty-five patients under 35 years (mean age 25.1 in EC, 29.9 in the AH group) were enrolled between 1991 and 2005, who were diagnosed with well-differentiated EC or severe endometrial AH. These patients were treated with progestin at Peking Union Medical College Hospital. The diagnosis were confirmed independently by two pathologists. Enrollment criteria included aged 35 years or younger, stage Ia well-differentiated EC or severe AH, patient has strong desire to preserve fertility, presence of progesMei Yu, M.D.a Jia-xin Yang, M.D.a Ming Wu, M.D.a Jing-he Lang, M.D.a Zhen Huo, M.D.b Keng Shen, M.D.a a Department of Obstetrics/Gynecology, Peking Union Medical College Hospital, Beijing, People’s Repulic of China b Department of Pathology, Peking Union Medical College Hospital, Beijing, People’s Republic of China Received April 25, 2008; revised May 29, 2009; accepted June 3, 2009; published online July 9, 2009. M.Y. has nothing to disclose. Y.-x.Y. has nothing to disclose. M.W. has nothing to disclose. J.-h.L. has nothing to disclose. Z.H. has nothing to disclose. K.S. has nothing to disclose. Reprint requests: Keng Shen, M.D., Department of Obstetrics/Gynecology, Peking Union Medical College Hospital, Shuaifuyan No. 1. Dongchen District, Beijing 100730, P.R. China (FAX: 8610-65212507; E-mail: [email protected]).
2122
terone receptor in the EC patient, and no contraindications to progestin. Enrolled patients were classified into two groups: 8 in EC group and 17 in AH group. All 25 patients agreed to participate by giving informed consent. Approval for this study was obtained from the institutional review board at Peking Union Medical College Hospital. In the EC group, pelvic ultrasonography, magnetic resonance imaging, chest roentgenogram, and serum CA125 were used for pretreatment assessment to rule out myometrial invasion or extrauterine metastases. Immunohistochemistry was applied to detect progesterone receptors (PgR). Twenty-two patients were initially treated with medroxyporgesterone acetate, and the other three patients with megestrol acetate or hydroxyprogesterone caproate. The dosage of medroxyporgesterone acetate was 250 to 500 mg/day in the EC group and 100 to 500 mg/day in the AH group. The progestin therapy was continued for at least 3 to 6 months after complete remission. Nonresponders were suggested to take hysterectomy if at least 3-month progestin treatment was proven to be of no effect. All patients were followed up by endometrial curettage at intervals of 3 months. Complete response (CR) was defined as absence of the lesion, partial response (PR) as histologic regression or endometrial deciduoid change, recurrence as presence of EC or AH after CR. In EC group (Table 1), six (75.0%) patients responded to the progestin therapy: five patients (62.5%) had CR and one patient (12.5%) had PR. The mean time to achieve CR was 6.4 months (range ¼ 3–10 months). Two (25.0%) no-responders were treated with total hysterectomy, which showed superficial myometrial invasion. The five patients with CR were followed up for an average of 31.8 months (range ¼ 5–90 months). One (20.0%) of them experienced recurrence at 30 months and underwent hysterectomy with superficial myometrial invasion. She was free of disease at follow-up of 55 months postoperation. In the AH group (Table 1), all of the 17 patients (100%) responded to progestin therapy, and 14 (82.4%) had CR. The mean time to achieve CR was 7.3 months (range ¼ 3–11 months). Three
Fertility and Sterility Vol. 92, No. 6, December 2009 Copyright ª2009 American Society for Reproductive Medicine, Published by Elsevier Inc.
0015-0282/09/$36.00 doi:10.1016/j.fertnstert.2009.06.013
TABLE 1 Effect of progestin therapy.
EC group AH group
N
Mean age
CR rate (n%)
8 17
25.1 29.9
5 (62.5) 14 (82.4)
PR rate (n%)
NR rate (n%)
Time to remission (month)
Recurrence rate (%)
Time to recurrence (month)
1 (12.5) 3 (17.6)
2 (25.0) 0 (0)
6.4 7.3
1 (20.0) 3 (21.4)
30 6–16
Note: EC ¼ endometrial carcinoma; AH ¼ atypical hyperplasia; CR ¼ complete response rate; PR ¼ partial response rate; NR ¼ nonresponse rate. Yu. Fertility-preserving treatment in your women. Fertil Steril 2009.
patients (17.6%) had PR. The 14 patients with CR were followed for an average of 34.6 months (range ¼ 7–114 months). Three (21.4%) of them experienced recurrence at 6, 11, and 16 months, respectively, after treatment. One patient underwent hysterectomy, which showed superficial myometrial invasion. The other two patients were retreated with progestin: one achieved a second CR and was free of disease at follow-up of 12 months; the other patient was still being treated. Fourteen patients attempted conception after CR. None of the four with EC got pregnant. In contrast, 4 of the 10 (40%) with AH achieved seven pregnancies. These four patients got pregnant 3 to 26 months after CR, and three of them each successfully delivered a healthy full-term baby and had been followed for 27 to 74 months after delivery without recurrence. The fourth patient was lost to follow-up shortly after being pregnant. Except for 1 patient with AH who got pregnant spontaneously, 13 patients used some kinds of assisted reproductive technology, such as ovulation induction. Three of them got pregnant successfully. One patient with a 7-year history of primary infertility and polycystic ovarian syndrome achieved pregnancy after a series of reproductive therapies, including superovulation with clomiphene and/or cyproterone (Diane-35), laparoscopic bilateral ovarian drilling, follicle-stimulation hormone injection, and ultrasound monitoring of ovulation. Progestin therapy is one of the most important fertilitypreserving treatments for patients with EC or AH. Progesterone as an anticancer therapy, which was combined with PgR to antagonize the effects of estrogen, was first reported in 1961 (4). In our review of literature published between 2001 and 2005, 42% to 100% of patients with EC responded to progestin with a recurrence rate of 20% to 89% (5–7). Ramirez et al. (8) reviewed 21 studies involving 81 patients with EC, with an initial response rate of 76%, recurrence rate of 24%. A multicenter phase II study (9) found 55% of EC cases and 82% of AH cases
got complete response and 47% recurred between 7 and 36 months. There is a broadly accepted opinion that 3 months is an appropriate interval period of evaluation, which is sufficient for progestin to show an obvious effect and to ensure prompt surgical treatment for nonresponders. Progestin treatment duration was suggested to continue at least for 6 months or until 2 months after remission (7). In the AH and EC groups of our study, the mean time to achieve CR was 6.4 and 7.3 months respectively. We recommend that progesterone be administered for at least 9 to 12 months. Strong positive association has been demonstrated between PgR status, and the response rate to the progestin treatment (10) response rates ranged from 60% to 72% for PgR-positive cases and from 12% to 19% for PgR-negative ones. It is suggested that progestin treatment should be taken in PgR-positive case. Recent studies indicated that tamoxifen may increase the sensitivity to progestin by promoting expression of PgR (11). This regimen may hold promise for patients with low expression of PgR. Pregnancy rate after conservative treatment with EC is quite variable from 25% to 80%. More assisted reproductive technology methods have been developed in the last 5 years to treat infertile women with EC or AH, such as in vitro fertilization (IVF), intracytoplasmic sperm injection, and embryo transfer (12–14). Gotlieb et al. (5) demonstrated that neither pregnancy nor assisted reproductive technology would worsen the prognosis of EC. Reproductive therapies should be taken as soon as possible after CR. If the patients fail to achieve pregnancy in 6 months, more effective methods, such as IVF, should be recommended. In conclusion, progestin therapy is a feasible management option for well-differentiated EC or severe AH in young women to preserve fertility. Assisted reproductive technologies are potential options to increase pregnancy rates for these cases after complete remission.
REFERENCES 1. Jin-song G, Keng S, Jing-he L, et al. Clinical analysis of endometrial carcinoma patients aged 45 years and younger. Chin J Obst Gynecol 2004;39: 159–61. 2. Randall TC, Kurman RJ. Progestin treatment of atypical hyperplasia and well-differentiated carcinoma of the endometrium in women under age 40. Obstet Gynecol 1997;90:434–40.
Fertility and Sterility
3. Kim YB, Holscheider CH, Ghosh K, Nieberg RK, Monyz FJ. Progestin alone as primary treatment of endometrial carcinoma in premenopausal women, report of seven cases and review of the literature. Cancer 1997;79:320–7. 4. Kelly RM, Baker WH. Progestational agents in the treatment of carcinoma of the endometrium. N Engl J Med 1961;264:216–22.
5. Gotlieb WH, Beiner ME, Shalmon B, Korach Y, Segal Y, Zmira N. Outcome of fertility-sparing treatment with progestins in young patients with endometrial cancer. Obstet Gynecol 2003;102: 718–25. 6. Ota T, Yoshida M, Kimura M, Kinoshita K. Clinicalpathologic study of uterine endometrial carcinoma in young women aged 40 years
2123
and younger. Int J Gynecol Cancer 2005;15: 657–62. 7. Niwa K, Tangami K, Lian Z, Onogi K, Mori H, Tamaya T. Outcome of fertility-preserving treatment in young women with endometrial carcinomas. BJOG 2005;112:317–20. 8. Ramirez PT, Frumovitz M, Bodurka DC, Sun CC, Levenback C. Hormonal therapy for the management of grade 1 endometrial adenocarcinoma: a literature review. Gynecol Oncol 2004;95:133–8. 9. Ushijima K, Yahata H, Yoshikawa H, Konishi I, Yasugi T, Saito T, et al. Multicenter phase II study of fertility-sparing treatment with medroxyprogesterone acetate for endometrial carcinoma and atyp-
2124
Yu et al.
Correspondence
ical hyperplasia in young women. J Clin Oncol 2007;25:2798–803. 10. Thigpen JT, Brady MF, Alvarez RD, Adelson MD, Homesley HD, Manetta A, et al. Oral medroxyprogesterone acetate in the treatment of advanced or recurrent endometrial carcinoma: a dose–response study by the gynecologic oncology group. J Clin Oncol 1999;17:1736–44. 11. Nola M, Jukic S, Ilic-Forko J, Babic D, Uzarevic B, Petrovecki M, et al. Effects of tamoxifen on steroid hormone receptors and hormone concentration and the results of DNA analysis by flow cytometry in endometrial carcinoma. Gynecol Oncol 1999;72: 331–6.
12. Yarali H, Bozdag G, Aksu T, Ayhan A. A successful pregnancy after intracytoplasmic sperm injection and embryo transfer in a patient with endometrial cancer who was treated conservatively. Fertil Steril 2004;81:214–6. 13. Piura B. Two successful pregnancies after in vitro fertilization and embryo transfer in a patient with endometrial atypical hyperplasia bordering on adenocarcinoma treated conservatively with high-dose progesterone. Gynecol Obstet Invest 2006;61:21–3. 14. Park JC, Cho CH, Rhee JH. A successful live birth through in vitro fertilization program after conservative treatment of FIGO grade I endometrial cancer. J Korean Med Sci 2006;21:567–71.
Vol. 92, No. 6, December 2009