Efficacy of medroxyprogesterone acetate treatment and retreatment for atypical endometrial hyperplasia and endometrial cancer

Transcription

1 doi: /jog J. Obstet. Gynaecol. Res. Vol. 44, No. 1: , January 2018 Efficacy of medroxyprogesterone acetate treatment and retreatment for atypical endometrial hyperplasia and endometrial cancer Satoshi Tamauchi 1, Hiroaki Kajiyama 1, Fumi Utsumi 1, Shiro Suzuki 1, Kaoru Niimi 1, Jun Sakata 1, Mika Mizuno 2, Kiyosumi Shibata 3 and Fumitaka Kikkawa 1 1 Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, 2 Department of Gynecologic Oncology, Aichi Cancer Center, and 3 Department of Obstetrics and Gynecology, Banbuntane Hotokukai Hospital, Fujita Health University, Nagoya, Japan Abstract Aim: Medroxyprogesterone acetate (MPA) is used to preserve fertility in patients with Grade 1 endometrial cancer without myometrial invasion (G1EA) and those with atypical endometrial hyperplasia (AEH). However, the efficacy of retreatment with MPA has not been sufficiently established for patients who experience recurrence but wish to retain their fertility. This study aimed to show the effectiveness of MPA treatment and retreatment for AEH and G1EA. Methods: A total of 39 patients received MPA treatment between 2005 and 2015, including nine with G1EA and 30 with AEH. The patients received high-dose (600 mg/day) MPA for 26 weeks. If a complete response was not achieved, MPA treatment was continued. After complete remission, if there was a recurrence, the patient was offered a choice of a hysterectomy or retreatment with MPA. The gynecologic and obstetric outcomes were retrospectively analyzed. Results: The median age was 34 years, and the median body mass index was 23.3 kg/m 2. The median follow-up period was 52 months. Complete response rates for the initial treatment were 89% for G1EA and 93% for AEH. Recurrence occurred in 88% of patients with G1EA (7/8) and 50% of those with AEH (14/28). Seven patients with G1EA and 11 with AEH received MPA retreatment, and 100% and 92% of these achieved a complete response. During the study period, a total of 14 pregnancies were recorded with 10 live births. Conclusion: MPA can be effective for G1EA and AEH treatment even when they recur. Key words: atypical endometrial hyperplasia, endometrial cancer, fertility-sparing therapy, high-dose medroxyprogesterone acetate. Introduction Endometrial cancer (EC) is typically a malignancy experienced by postmenopausal women, although young women under the age of 40 years account for 5 10% of cases. 1,2 Atypical endometrial hyperplasia (AEH) can be a precursor to EC, with 29% of cases reported as progressing to EC during a mean followup period of 13 years. 3 The standard treatment for EC is hysterectomy with bilateral oophorectomy; however, this procedure results in the permanent loss of the patient s fertility, which nulliparous patients can find hard to accept. For this reason, the use of highdose oral medroxyprogesterone acetate (MPA) as a Received: April Accepted: July Correspondence: Professor Hiroaki Kajiyama, Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya , Japan. kajiyama@med.nagoya-u.ac.jp 2017 Japan Society of Obstetrics and Gynecology 151

2 S. Tamauchi et al. fertility-sparing treatment for EC and AEH has attracted interest. Although oral progestin treatment including MPA can achieve a complete response in many patients, a high rate of recurrence has been reported. 4 Hysterectomy is often recommended to patients with recurrence, but almost all of these patients are reluctant to undergo the procedure following only a single relapse, with many requesting the readministration of MPA. Although Park et al. previously reviewed 73 cases with MPA retreatment, 5 obstetric outcomes were not described, and further accumulation of cases is still required. Therefore, in this study, we retrospectively analyzed the outcomes of patients with EC and AEH who underwent fertilitysparing treatment using daily oral MPA in our institution and evaluated the effectiveness of MPA therapy for primary and recurrent EC and AEH. Methods We retrospectively analyzed the data for patients who received MPA therapy for well-differentiated (Grade 1) endometrioid adenocarcinoma (G1EA) or AEH between 2005 and 2015 in Nagoya University Hospital. At the time of diagnosis, all pathology slides were reviewed by pathologists who specialized in gynecologic oncology at our institution. Our indications for MPA therapy for G1EA or AEH were as follows: (i) the patients were younger than 45 years and strongly wished to preserve their fertility; (ii) G1EA or AEH histology had been confirmed by dilation and curettage (D&C) biopsy; and (iii) when the pathology was EC, the lesions were shown to be confined to the endometrium by imaging examination, such as pelvic magnetic resonance imaging or chest abdominal enhanced computed tomography. Patients who matched these indications were fully informed about MPA therapy, which is not standard treatment for G1EA or AEH, and about the high risk of recurrence. In total, 39 patients were treated by MPA therapy with their agreement. Collection of patients data was approved by the institutional review board at Nagoya University Hospital. Treatment protocol Our standard dose of oral MPA was 600 mg/day, and dose reduction to 400 mg/day was considered when patients suffered from side-effects. In severely obese patients (body mass index [BMI] 40), dose increase to 800 mg/day was also considered. D&C biopsy was performed at the 26th week of treatment. Complete response (CR) was defined as the absence of any evidence in biopsy of hyperplasia or carcinoma. MPA therapy ended when CR was achieved. In cases where the disease remained stable or there was a partial response, MPA therapy was continued unless the patient changed her mind about undergoing a hysterectomy. If biopsy revealed that the disease had aggravated beyond the adaptation of fertility-sparing treatment, such as grade 2 endometrioid adenocarcinoma, MPA therapy was terminated and a hysterectomy, including bilateral salpingo-oophorectomy and pelvic lymphadenectomy, was performed. After achieving CR, patients were permitted to become pregnant. After MPA treatment, we performed aspiration biopsy every 3 months, as well as D&C if recurrence was suspected based on biopsy findings. In G1EA patients, recurrence was defined as the detection of AEH or G1EA. In the AEH group, recurrence was defined as the detection of only AEH. If recurrence was detected, the patient was again offered a hysterectomy and she selected her secondary treatment as either a hysterectomy or retreatment with MPA. In patients with recurrence, MPA was administrated for at least 12 weeks or more. In principle, D&C was performed to evaluate therapeutic effects, but the time of D&C was determined by the attending physician, and it differed for each patient. Statistical analysis All statistical analyses were performed with EZR (Saitama Medical Center, Jichi Medical University), a graphical user interface for R (The R Foundation for Statistical Computing). Data are presented as median values with ranges or as counts with percentages. Possible factors associated with recurrence, including age, BMI, time to initial CR, pregnancies after CR, and pathology, were investigated with univariate and multivariate analyses using a logistic regression, and odds ratios were calculated along with 95% confidence intervals (95%CI). The χ 2 -test was used to compare subgroups of the patients. A P-value less than 0.05 was considered statistically significant. Results Patient characteristics Background data for the 39 patients are shown in Table 1. The median age when starting MPA therapy was 34 years and the median follow-up period was Japan Society of Obstetrics and Gynecology

3 Medroxyprogesterone acetate rechallenge Table 1 Patients characteristics n % Age (years) Median (range) 34 (19 45) Follow-up (months) Median (range) 52 (16 128) Parity Nullipara Multipara Marital status at diagnosis Married Unmarried BMI Median (range) 23.3 ( ) Obese (BMI 25) Non-obese (BMI < 25) Histological type AEH G1EA Initial symptoms Irregular genital bleeding Menstrual abnormality Infertility Others AEH, atypical endometrial hyperplasia; BMI, body mass index; G1EA, grade 1 endometrial adenocarcinoma. 52 months. All but two of the patients were nulliparous. Thirty patients exhibited AEH and nine had a G1EA. Obese patients (BMI 25) accounted for 44% of the total. Two patients received reduced dose of MPA because of side-effects, such as headache. Only one severely obese patient received 800 mg/day of MPA. Treatment outcomes Table 2 shows the outcomes following MPA treatment. In total, 36 (92%) patients achieved CR with the initial MPA treatment: 28 patients with AEH and eight with G1EA. At the end of 26 weeks of treatment, six patients with AEH and six with G1EA still exhibited lesions and thus continued the MPA treatment. Patients with G1EA required significantly longer administration of MPA (P = ). Thereafter, 14 (50%) of the patients with AEH and seven (88%) of the patients with G1EA were diagnosed with recurrence. At that time, three patients decided to undergo hysterectomy, whereas the other 18 patients resumed MPA treatment. Ultimately, 17 patients achieved CR for a second time. In the multivariate analysis, the only parameter found to be an independent risk factor for recurrence was age, with younger patients at a significantly higher risk of recurrence (Table 3). Pregnancies after MPA treatment Details about pregnancies among the patients are presented in Table 4, and Table 5 summarizes the 10 patients who successfully delivered. Of the 19 patients who attempted to become pregnant after achieving CR, 12 achieved pregnancy, with two of these patients becoming pregnant twice. Pregnancies due to fertility treatment accounted for about 70% of the total. To date, there have been 10 live births. Four patients experienced recurrence before pregnancy, preserved their fertility by requesting the readministration of MPA, and successfully gave birth (Table 5). Conversely, two recurrences were recorded in patients who had successfully finished their pregnancies. The median number of D&C undergone by those who gave birth was three (range, 3 9). No cases of placenta accreta were recorded. Discussion We assessed the gynecologic and obstetric outcomes of 39 patients after high-dose oral MPA treatment at a Table 2 Summary of outcomes of MPA treatment Total (n = 39) AEH (n = 30) G1EA (n =9) n % n % n % CR by initial MPA treatment weeks >26 weeks Median time to first CR, weeks (range) 26 (10 63) 26 (10 63) 40 (26 53) Recurrence Median time to recurrence from CR, weeks 67 (10 283) 72 (10 283) 50 (24 272) (range) Retreatment by MPA CR by MPA retreatment Median time to second CR, weeks (range) 24 (12 63) 24 (12 63) 25 (12 32) AEH, atypical endometrial hyperplasia; CR, complete response; G1EA, grade 1 endometrial adenocarcinoma; MPA, medroxyprogesterone acetate Japan Society of Obstetrics and Gynecology 153

4 S. Tamauchi et al. Table 3 Recurrence predictive factors Recurrence (n) Univariate Multivariate + OR (95%CI) P-value OR (95%CI) P-value Time to primary CR (weeks) 1.01 ( ) ( ) Median BMI (kg/m 2 ) 1.05 ( ) ( ) Median Age (years) ( ) ( ) Median Pregnancy after CR 1.69 ( ) ( ) Yes 4 8 No Pathology 7 ( ) ( ) AEH G1EA 1 7 AEH, atypical endometrial hyperplasia; BMI, body mass index; CI, confidence interval; CR, complete response; G1EA, grade 1 endometrial adenocarcinoma; OR, odds ratio. Table 4 Pregnancy after CR Total (n = 34) AEH (n = 26) G1EA (n =8) n % n % n % Attempts to conceive Total number of pregnancies Natural conception Fertility treatment Miscarriage Live baby delivery Two patients achieved pregnancy twice. AEH, atypical endometrial hyperplasia; G1EA, grade 1 endometrial adenocarcinoma. Table 5 Obstetrics outcomes Pts. Age Histology (years) Method ofconception Time to CR (weeks) Time to pregnancy from CR (weeks) Numbers of D&C before delivery Recurrence before/after pregnancy Obstetrics complications 1 37 G1EA IUI / None 2 33 AEH IVF / Abortion, pprom 3 33 AEH IVF / CS due to CPD 4 31 AEH NC / + None 5 29 G1EA NC / None 6 28 AEH IVF / None 7 27 AEH NC / None 8 26 AEH NC / None 9 25 G1EA NC / + None AEH IVF / None Achieved pregnancy twice. AEH, atypical endometrial hyperplasia; CPD, cephalopelvic disproportion; CR, complete response; CS, cesarean section; D&C, dilation and curettage; G1EA, grade 1 endometrial adenocarcinoma; IUI, intrauterine insemination; IVF, in vitro fertilization; NC, Natural conception; pprom, preterm premature rupture of membrane. single institution. There were no cases of progressive recurrence or death. Although most patients experienced recurrence, the effectiveness of MPA therapy as a fertility-sparing treatment was demonstrated by the 10 live births. In this study, we determined that the indication for fertility-sparing treatment was an age less than 45 years. Actually, we experienced a case of pregnancy at age 46 years where the patient had overcome AEH by MPA therapy; however, it resulted in a miscarriage Japan Society of Obstetrics and Gynecology

5 Medroxyprogesterone acetate rechallenge Table 6 summarizes 12 previous reports 6 17 that have described outcomes for patients with AEH or G1EA treated with oral high-dose MPA. Combining these data, the rates of initial CR with MPA were 80.6% in AEH and 70.3% in G1EA. The results of the present study were superior in this respect. However, our rates of recurrence were higher than the overall rates across the previous studies, especially in G1EA. This may be due to our small sample size for G1EA and the relatively long period of follow-up. In the present study, 28% (10/36) of the patients successfully gave birth, which increased to 53% (10/19) when considering only the patients who attempted to conceive after achieving CR. These results were equivalent to or better than the pregnancy rate after CR across the previous studies of 35.2% (63/179). Age was shown to be an independent risk factor for recurrence in the present study. Younger patients are likely to wish to preserve their fertility and thus it is important to keep in mind that they may be at a higher risk of recurrence. Controversially, a previous study of oral progestin treatment for G1EA reported that BMI and pregnancy after CR were the significant factors that predicted recurrence-free survival after achieving CR of MPA therapy. 16 In this study, there was no significant difference in the pathology at diagnosis for AEH and G1EA. However, this may have been due to lack of cases, especially of G1EA. A further accumulation of cases is required to clarify the risk of recurrence. In this study, the recurrence criterion in the G1EA group was defined as the detection of AEH or G1EA. AEH was detected in six of the seven patients with recurrence in the G1EA group. As shown in Table 2, this may be the reason why the second time to CR was shorter than the first time to CR. One aim of this study was to confirm the efficacy of continued MPA therapy for patients who failed to achieve CR after 26 weeks of MPA treatment and retreatment with MPA for patients who experienced recurrence. No previous studies have reported an adverse relation between the time to CR and recurrence, 17 and our data supported this outcome. This provides evidence in support of continued MPA therapy in cases with a poor response to initial MPA treatment. When it is important for the patient to retain fertility, enduring treatment is necessary even when an initial response is unfavorable. However, Inoue et al. demonstrated that prolonged MPA treatment affected pregnancy outcomes through thinning of the endometrium. 18 This is an important dilemma Table 6 Patients characteristics, oncologic outcomes, and obstetric outcomes of MPA treatment for AEH and G1EA MPA dose (mg/day) AEH G1EA Others Live births n CR Rec n CR Rec n CR Rec Reference Median age, years (range) Kaku et al (20 42) Utsunomiya et al (26 38) Niwa et al (23 34) Ota et al (22 40) Ushijima et al (22 39) Minaguchi et al (19 37) Yamazawa et al (28 40) Hahn et al (21 43) NR Yu et al. 14 NR Fujiwara et al (21 42) Park et al. 16 NR NR Ohyagi-Hara et al ( ) Subtotal (80.8) 15 (25.4) (70.3) 72 (35.8) (35.2) Present study 34 (19 45) (93.3) 14 (50) 9 8 (88.9) 7 (87.5) ( ) Mean. AEH, atypical endometrial hyperplasia; CR, complete response; G1EA, grade 1 endometrial adenocarcinoma; MPA, medroxyprogesterone acetate; NR, not reported; Rec, recurrence Japan Society of Obstetrics and Gynecology 155

6 S. Tamauchi et al. regarding fertility preservation by MPA treatment. We believe that the present study combined with previous reports 5 will encourage the re-administration of MPA for patients who suffer recurrence, the efficacy of which had not previously been shown. Furthermore, 44% of our patients who gave birth after CR had experienced recurrence before their pregnancy. Because the main goal of MPA therapy is to preserve fertility, when there is no apparent progression, a considerable proportion of patients seek re-administration of MPA. Conversely, two cases of recurrence were recorded even in patients who had achieved childbirth. MPA treatment is not curative but only a temporary expedient before pregnancy; after achieving childbirth, a hysterectomy may be necessary. The present study has some limitations; the recurrence rate was higher than that observed in the literature and it had a retrospective design. Although the variety of progestins can be used for fertility-sparing treatment, only high-dose MPA was used in this study. In conclusion, we have shown the effectiveness of MPA treatment for AEH and G1EA. During the initial treatment, long-term administration was not associated with recurrence and the continuation of MPA treatment appeared to be effective in preserving patients fertility. When there was recurrence, retreatment with MPA appeared to be safe and effective. Disclosure The authors declare that they have no conflicts of interest. References 1. Gallup DG, Stock RJ. Adenocarcinoma of the endometrium in women 40 years of age or younger. Obstet Gynecol 1984; 64: Matsuda T, Marugame T, Kamo K, Katanoda K, Ajiki W, Sobue T. Cancer incidence and incidence rates in Japan in 2006: Based on data from 15 population-based cancer registries in the Monitoring of Cancer Incidence in Japan (MCIJ) project. Jpn J Clin Oncol 2012; 42: Kurman RJ, Kaminski PF, Norris HJ. 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