Oncologic and Reproductive outcomes with progestin therapy in women with endometrial hyperplasia and grade 1 Adenocarcinoma: A systematic review

Gynecologic Oncology 125 (2012) 477–482

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Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno

Review

Oncologic and Reproductive outcomes with progestin therapy in women with endometrial hyperplasia and grade 1 Adenocarcinoma: A systematic review Camille C. Gunderson a,⁎, Amanda Nickles Fader a, b, Kathryn A. Carson c, Robert E. Bristow d a

Johns Hopkins Medical Institutions, Baltimore, MD, USA Greater Baltimore Medical Center, Baltimore, MD, USA Johns Hopkins School of Public Health, Baltimore, MD, USA d University of California Irvine Medical Center, Orange, CA, USA b c

a r t i c l e

i n f o

a b s t r a c t Objective. The objective of this review was to analyze published contemporary oncologic and reproductive outcomes in women with endometrial hyperplasia or cancer undergoing medical management with progestin therapy. Methods. A systematic review of oncologic and pregnancy outcomes in women with complex atypical hyperplasia or grade 1 adenocarcinoma was performed using a comprehensive search of the MEDLINE literature. English language studies published from 2004 to 2011 which utilized hormonal therapy were identified using key words endometrial hyperplasia, endometrial cancer, fertility preservation, hormone and progestin therapy. Fisher's exact test was used to calculate statistical differences. Results. Forty-five studies with 391 study subjects were identified. The median age was 31.7 years. Therapies included medroxyprogesterone (49%), megestrol acetate (25%), levonorgestrel intrauterine device (19%), hydroxyprogesterone caproate (0.8%), and unspecified/miscellaneous progestins (13.5%). Overall, 344 women (77.7%) demonstrated a response to hormonal therapy. After a median follow up period of 39 months, a durable complete response was noted in 53.2%. The complete response rate was significantly higher for those with hyperplasia than for women with carcinoma (65.8% vs. 48.2%, p = .002). The median time to complete response was 6 months (range, 1–18 months). Recurrence after an initial response was noted in 23.2% with hyperplasia and 35.4% with carcinoma during the study periods (p = .03). Persistent disease was observed in 14.4% of women with hyperplasia and 25.4% of women with carcinoma (p = .02). During the respective study periods, 41.2% of those with hyperplasia and 34.8% with a history of carcinoma became pregnant (p = .39), with 117 live births reported. Conclusion. Based on this systematic review of the contemporary literature, endometrial hyperplasia has a significantly higher likelihood of response (66%) to hormonal therapy than grade 1 endometrial carcinoma (48%). Disease persistence is more common in women with carcinoma (25%) compared to hyperplasia (14%). Reproductive outcomes do not seem to differ between the cohorts. © 2012 Elsevier Inc. All rights reserved.

Article history: Received 30 November 2011 Accepted 4 January 2012 Available online 11 January 2012 Keywords: Endometrial hyperplasia Endometrial carcinoma Progestin therapy Disease persistence Reproductive outcomes

Contents Introduction . . . Methods . . . . . Results . . . . . Discussion . . . . Conflict of interest Acknowledgment . References . . . .

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⁎ Corresponding author at: Johns Hopkins Hospital, Department of Gynecology and Obstetrics, 600 North Wolfe Street, Phipps 279, Baltimore, MD 21287, USA. Fax: + 1 410 502 6683. E-mail address: [email protected] (C.C. Gunderson). 0090-8258/$ – see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2012.01.003

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Introduction Endometrial carcinoma is the most frequently occurring gynecologic malignancy in the United States with approximately 44,000 new cases in 2011 [1]. It is predominantly a disease of postmenopausal women; however, greater than 25% of cases occur in premenopausal women. An even larger proportion of premenopausal women is diagnosed with complex atypical hyperplasia, a known precursor of endometrial carcinoma [2]. The standard treatment for endometrial carcinoma is a total extrafascial hysterectomy, bilateral salpingo-oophorectomy (BSO), and pelvic and para-aortic lymph node assessment [3]. However, in spite of oncologic risk, this definitive approach may be undesirable in select women who wish to maintain their fertility. Prior studies have described the feasibility and safety of treating women with endometrial hyperplasia or early-stage, low grade carcinoma with high-dose progestin therapy to allow for future fertility [4–9]. Reversal of endometrial hyperplasia or cancer by progestin therapies is believed to occur through activation of progesterone receptors, resulting in stromal decidualization and subsequent thinning of the endometrial lining. In 2004, Ramirez et al. published a review of 81 women with grade 1 endometrial carcinoma who were managed with hormonal treatment [6]. Seventy-six percent responded to therapy, and 58% had no evidence of recurrence at the time of publication. This review highlighted the efficacy and safety of continuous progestin therapy in the treatment of low grade endometrial carcinoma but was limited by relatively short follow-up periods, a small number of subjects, and exclusion of women with endometrial hyperplasia. Therefore, the objective of this manuscript is to analyze the contemporary oncologic and reproductive outcomes in conservatively treated women with either endometrial hyperplasia or carcinoma and to determine if there are differences in hormonal response and fertility rates and between these cohorts. Methods An electronic literature search via the MEDLINE database was performed to identify published English language articles addressing hormonal treatment of women with a histologic diagnosis of complex atypical hyperplasia or grade 1 adenocarcinoma of the endometrium. Key words searched include endometrial hyperplasia, endometrial cancer, fertility preservation, hormone and progestin therapy. Previous reviews by other authors have adequately characterized the data prior to 2004; thus, we limited the search to reports published between January 2004 and March 2011. The search was further narrowed by limiting articles cited to only those reporting on human subjects. Manuscripts identified in the MEDLINE search were crossreferenced to retrieve all relevant articles. A total of 329 articles were identified. We excluded studies that described progestin treatment in the following settings: grade 2 or 3 endometrial adenocarcinoma, advanced stage endometrial carcinoma, non-endometrioid histology, progestin use combined with surgical therapy and progestin use in conjunction with other hormonal agents. Studies which did not stratify results to allow interpretation of hyperplasia with or without atypia were also excluded, as were review articles, abstracts, and letters. The results of the identified studies were carefully evaluated to determine relevance to this review. After these exclusions, a total of 45 studies encompassing 391 subjects were utilized. Demographic data extracted from each study included age, diagnosis, type of hormonal agent, route of hormone administration, and method and timing of interval endometrial re-evaluation. Information pertaining to oncologic outcomes was recorded including response rates, and particularly, percentage of women achieving a complete response, timing of complete response, number of women with complete response who later experienced a recurrence, and

number of women with persistent or progressive disease. Complete response was defined as complete regression of atypia or carcinoma upon sampling after hormone administration. Data regarding reproductive outcomes was also collected including number of study subjects who became pregnant and number of live births; however, this information was not reported in all studies. Study quality was assessed utilizing a modified Newcastle–Ottawa Study Assessment Scale (Table 1), which emphasized study design and ascertainment of outcome based on length of follow up [10]. Descriptive as well as pooled analyses of main outcome measures were performed. For calculations of median age and follow up times, individual data were used if the study reported these values. Otherwise, each subject in the study was assumed to be the reported mean or median value for the respective study. Some studies did not provide any information and therefore were not included in the overall median estimates. Statistical analyses were performed using SAS version 9.22 (SAS Institute, Inc., Cary, NC). The literature was critically appraised in order to determine the influence of any bias. Results Forty-five studies with 391 study subjects were identified. Five studies were prospective, and the remainder were retrospective series (n = 20) or case reports (n = 20). (Tables 2 and 3) One hundred eleven women had a histologic diagnosis of complex atypical hyperplasia, and 280 women had grade 1 adenocarcinoma of the endometrium. The median age for the overall cohort was 31.7 years (range 19–80 years); however, in nine studies, individual ages were not reported [11–19]. Two of these studies (17 women) included other subjects in the summary age measure and therefore were not used in the calculation [16,17]. Progestin agents administered included medroxyprogesterone acetate, megestrol acetate, levonorgestrel intrauterine system, intramuscular 17-hydroxyprogesterone, oral contraceptive pills, norethisterone, dihydrogesterone, and natural progesterone. Eight studies utilized a combination of progestin agents [11,12,20–25]. Forty nine percent of women received medroxyprogesterone, 25% megestrol acetate and 19% of women were treated with the intrauterine levonorgestrel system. Seven percent of subjects received oral progestins of unspecified type. Oral natural progesterone was given to 5.3% of women, and intramuscular progesterone was administered to 0.8% of women. One subject each received oral contraceptive pills, norethisterone and dihydrogesterone. Notably, one study did not specify the progestin that was utilized [26], and 32/391 women received a combination of progestin therapies. Forty percent of women underwent repeat endometrial sampling every three months with either endometrial curettage or office endometrial biopsy. Two studies re-evaluated endometrial histology at one month intervals [27,28], and six studies repeated endometrial sampling six to seven months after initiation of hormonal therapy [20,21,29–32]. One case series of six women with carcinoma did not specify the exact timing at which the endometrium was re-sampled [33]. Nine studies reported variable sampling intervals, such as every three to four months, every three to six months, every two to four months, or gradually increasing sampling periods from every one to three to six months [11,16,17,19,26,34–37].

Table 1 Description of quality assessment of studies on safety and efficacy of hormone therapy in the treatment of complex atypical hyperplasia or grade 1 endometrial carcinoma. Quality categories

High

Moderate

Low

Study design Ascertainment of outcome

Prospective Follow-up for at least 5 years

Prospective Follow-up for > 1 and b5 years

Retrospective Short follow-up of b 1 year

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479

Table 2 Outcomes in women with complex atypical hyperplasia. Study

# of women

# with CAH

Treatment

Regression

Relapse

Number of subjects achieving pregnancy

Live births

Median follow up time (months)

Ercan 2010 [22] Fujiwara 2009 [51] Han 2009 [34] Yu 2009 [13]

1 6 10 25

1 3 3 17

1 2 3 14

0 1 0 3

1 2 2 4

2 3 1 3

18 65 54 34.6 mean (range 7–114)

Signorelli 2009 [15]

21

10

1

5

5

8

98

Kresowick 2008 [31] Varma 2008 [16] Qi 2008 [29] Wildemeersch 2007 [17] Ushijima 2007 [18] Wheeler 2007 [35] Minaguchi 2007 [36] Chang 2006 [44] Rubatt 2005 [25] Yasuda 2004 [32] Tjalma 2004 [19]

1 9 2 8 45 44 31 2 1 1 8

1 9 2 8 17 18 12 1 1 1 7

MPA, megestrol, IUD MPA MPA or megestrol MPA, megestrol, or hydroxyprogesterone caproate “Natural progesterone” (200 mg daily) IUD IUD IUD IUD MPA Oral progestin or IUD MPA MPA Megestrol x3 months then OCP MPA IUD

0 4 2 7 14 10 7 1 0 0 7

0 2 0 0 3 2 4 0 1 1 0

0 n/a 2 n/a 7 n/a 5 n/a 0 0 n/a

0 n/a 2 n/a 5 n/a 4 n/a 0 0 n/a

6 24 Unknown 32 47.9 11 42 12 30 36 29

CAH = complex atypical hyperplasia; MPA = medroxyprogesterone acetate; IUD = levonorgestrel intrauterine device; n/a = not applicable; OCP = oral contraceptive pills.

Overall, the median follow up time was available for 359 subjects with both atypical hyperplasia and carcinoma and was 39 months (range, 2–138 months). In all, 304 women (77.7%) demonstrated a complete response. Median time to complete response in studies where time to response was reported was 6.0 months (n = 226 subjects; range, 1–18 months). A total of 208 women (53.2%) demonstrated a complete response with no evidence of recurrence. Ninety six women (24.6%) exhibited an initial response but eventually developed a recurrence. The median time to recurrence was 24 months (range, 4–72 months); however, this was only individually reported for nine subjects. Eighty seven women (22.2%) did not respond to hormonal therapy and were diagnosed with persistent disease. Data regarding surgical management and pathologic diagnosis was inconsistently reported. When stratified by disease type, the durable complete response rate was significantly higher in women with complex atypical hyperplasia (65.8%) compared to those with carcinoma (48.2%; p = .002). (Table 4) The rate of initial response in women with complex atypical hyperplasia was also significantly higher (85.6%), compared to those with carcinoma (74.6%; p = 0.03). Disease recurrence was more likely to occur in the carcinoma cohort (35.4%) than the hyperplasia group (23.2%; p = .03). Further, persistent disease was noted in only 14.4% of women with complex atypical hyperplasia compared with 25.4% of those with carcinoma (p = .02). No statistically significant difference in response was noted between the oral and intrauterine agents (50.8% vs. 67.6%, p = .07). Thirty eight studies provided pregnancy data. Of the 315 subjects in these studies, 114 (36.2%) became pregnant at least once. Forty one percent of women with complex atypical hyperplasia and 34.8% of women with carcinoma became pregnant (p= .39). These women conceived both spontaneously and via assisted reproductive technologies. Data on spontaneous versus assisted-pregnancies were not consistently reported, and therefore, percentage of pregnancies resulting from assisted reproductive technologies could not be calculated. Of the 114 women who became pregnant, 117 live births occurred. Data were not specifically recorded regarding the percentage of pregnancies resulting in live births. Moreover, although the participating women desired to retain reproductive potential, not all attempted conception after achieving a complete response. Five prospective studies were identified with the remainder composed of retrospective studies and case series and reports. Only one study was considered of “high quality” as outlined by the study assessment criteria in Table 1 (which included study design and length of follow-up period) [10,15]. The four other prospective studies had shorter follow-up periods and are thus considered of “medium quality”

[16,18,36,38]. The forty retrospective studies are either case series or reports and are thus of “low quality” [11–14,17,19–35,37,39–55]. Discussion Hysterectomy may not be an acceptable option for young women diagnosed with complex atypical hyperplasia or endometrial carcinoma if they wish to maintain their fertility. Although hormonal management of complex atypical hyperplasia and low-grade, apparent early-stage endometrial carcinoma has been utilized for fifty years, high quality data regarding the efficacy and safety of this approach is nevertheless lacking [56]. To our knowledge, the current study is the most comprehensive systematic review of contemporary data evaluating the efficacy of hormonal treatment for these conditions with respect to both oncologic and reproductive outcomes. Our study also stratified response rates by diagnosis. The overall response rate for endometrial neoplasia was similar to that noted by Ramirez et al. and other investigators [4–9]. However, durable response rate for atypical hyperplasia (65.8%) was significantly higher than for endometrial carcinoma (48.2%; p = .002). Although it is well recognized that a significant proportion of women with atypical hyperplasia harbors underlying carcinoma, the results of this review underscore the biologic difference in responsiveness to hormonal treatment of the two entities [57]. These data have important clinical utility and will allow clinicians to tailor their counseling of young women with endometrial neoplasia who wish to defer surgical management. Unfortunately, there is no definitive consensus regarding the optimal progestin regimen and duration, and most studies assessed in this review did not report long follow-up times post-hormonal treatment. Progestin therapy has an impact on the endometrial cells as early as 10 weeks after initiation of treatment, but most recognize the need for a minimum of 3 months of treatment before assessing for a response with endometrial hyperplasia and even longer for endometrial cancer [55,58,59]. Randall and Kurman previously reported that the median length of progestin treatment required for regression is nine months [4]. Thus, some clinicians use this time frame in determining responsiveness to progestin therapy. Obese and anovulatory women have been shown to require longer periods of progestin therapy to attain a complete response, but individual response time is variable [9]. Thus, type and duration of hormonal management should be individually tailored. Definitive treatment with hysterectomy/BSO (and staging if necessary) should be performed in women after completion of childbearing or if an appropriate response to hormone therapy was not achieved. Rates of synchronous ovarian

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Table 3 Outcomes in women with endometrial carcinoma. Study

# of women

# with EC

Therapy

Perri 2011 [11]

27

27

Cade 2010 [20] Mao 2010 [55] Fujiwara 2009 [51] Hahn 2009 [12] Vandenput 2009 [40] Sodano 2009 [41] Bozdag 2009 [26] Han 2009 [34] Yu 2009 [13]

16 6 6 35 1

16 6 3 35 1

Megestrol, MPA, IUD, norethisterone, hydroxy-progesterone MPA, IUD, or both MPA or megestrol MPA MPA or megestrol IUD

1 4 10 25

1 4 7 8

Fambrini 2009 [46] Eftekhar 2009 [14] Signorelli 2009 [15]

1 21 21

1 21 11

Hoekstra 2008 [53] Takahashi 2008 [50] Wu 2008 [27] Ushijima 2007 [18] Hurst 2008 [42] Topuz 2008 [39] Shamshirsaz 2007 [23] Wheeler 2007 [35]

1 1 1 45 1 1 1

1 1 1 28 1 1 1

Megestrol Not specified Megestrol or MPA Megestrol, MPA, or hydroxy-progesterone caproate IUD Megestrol Natural progesterone (200 mg daily) Megestrol MPA Megestrol MPA Megestrol Megestrol Megestrol and MPA

44

26

Oral progestin or IUD

Yamazawa 2007 [38] Gurgan 2007 [43] Minaguchi 2007 [36] Cormio 2006 [52] Yahata 2006 [54] Park 2006 [37] Chang 2006 [44] Piura 2006 [24] Dhar 2005 [49] Ferrandina 2005 [48] Yang 2005 [33] Ota 2005 [47] Demirol 2005 [30] Niwa 2005 [28] Nakao 2004 [45] Yarali 2004 [21] Tjalma 2004 [19]

9

9

MPA

1 31

1 19

Not specified MPA

1 8 1 2 1 4 1

1 8 1 1 1 4 1

6 12 1 10 2 1 8

6 12 1 10 2 1 1

Regression

Relapse

Number of subjects achieving pregnancy

Live births

Median follow up time (months)

9

15

14

19

57.4

9 4 1 22 0

1 0 1 9 1

3 3 2 10 0

4 3 1 12 0

27 (mean) 50 49 39 19

1 4 7 5

0 0 0 1

1 3 6 0

1 6 3 0

39 Unknown 47 Unknown

1 15 2

0 3 4

0 5 4

0 2 8

36 42 98

0 0 0 12 0 1 0

0 1 1 7 1 0 0

0 n/a 1 4 0 1 0

0 n/a 1 4 0 1 0

6 26 28 47.9 96 20 36

11

1

n/a

n/a

5

2

4

3

10 (premenopausal, n = 21); 19 (postmenopausal, n = 5) 35

0 10

0 5

0 3

0 1

6 35

Megestrol MPA Megestrol MPA MPA and Megestrol IUD Dihydrogesterone

0 0 1 1 0 1 0

1 7 0 0 1 0 1

0 3 1 n/a 1 n/a 1

0 2 1 n/a 2 n/a 1

36 76.5 40 12 120 21 21

Megestrol MPA Not specified Megestrol MPA Megestrol and MPA IUD

2 3 1 3 2 1 1

2 2 0 7 0 0 0

2 4 1 6 2 1 n/a

2 3 1 5 2 1 n/a

48.8 44 Unknown 48 51 22 29

EC = endometrial carcinoma; MPA = medroxyprogesterone acetate; IUD = levonorgestrel intrauterine device; n/a = not applicable.

malignancy are as high as 25% in women less than 45 years of age [60]. The danger of concomitant adnexal malignancy and the considerable risk of disease recurrence mandate close follow-up and definitive surgical therapy if so indicated. Prior to commencement of progestin therapy, it is crucial to exclude extrauterine disease. Minimum radiologic assessment includes pelvic ultrasound and magnetic resonance imaging (MRI) of the pelvis to rule out adnexal involvement and myometrial invasion. Some clinicians also recommend computed tomography (CT) of the abdomen and pelvis to thoroughly evaluate for metastatic disease. Multiple agents, including oral, intramuscular, and intrauterine, have been described with varying success rates [4,7–9,58,59]. Less data exists in the literature appraising the levonorgestrel containing IUD as compared to oral agents since it is a newer drug. Montz et al. describe a 75% complete response rate at one year in twelve women with grade 1 endometrial cancer [59]. However, a small series by Dhar et al. raised concern about the efficacy of single agent progestin

releasing IUD; this was notably a much older and co-morbid population compared to our study group and thus perhaps not comparable [49]. Currently, there are few other prospective studies which

Table 4 Composite oncologic and reproductive outcomes. Initial response

Complete response

Complete response with recurrence

Persistent/ progressive disease

Proportion achieving pregnancy

Number of live births

CAH

85.6%

65.8%

23.2%

14.4%

28

EC

74.6%

48.2%

35.4%

25.4%

p-value

0.03

0.002

0.03

0.02

28/111 (41%) 86/280 (34.8%) 0.39

CAH: complex atypical hyperplasia. EC: endometrial carcinoma.

89 n/a

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evaluate sole use of intrauterine progesterone in the setting of endometrial cancer, and thus one should consider addition of an oral progestin when using a progestin releasing IUD. The association between the excessive estrogen of obesity and endometrial carcinogenesis coupled with the growing obesity epidemic in the United States suggest that the incidence of endometrial neoplasia will likely increase in the coming years. Therefore, fertility sparing treatment may become increasingly more relevant. Knowledge regarding efficacy and risks of progestin treatment is paramount; limited information is currently understood regarding the effect on delayed childbearing. Non-progestin hormonal therapies such as metformin are increasingly being described in the literature for select women [61]. Those most likely to benefit from metformin include women with obesity, polycystic ovarian syndrome and/or insulin resistance, and women with progestin resistance. Weight loss with subsequent reduction of androgen to estrone conversion and normalization of hyperinsulinemia contribute to the therapeutic effect of metformin [61,62]. Limitations of this study include the retrospective nature of the review and thus inherent reporting and observational biases, lack of long term follow up data for most studies, and inconsistent reporting of reproductive outcomes. Additionally, details of treatment and surgical pathology were often not available, and there was no centralized pathology review. As most included studies were not of “high quality,” a large prospective or randomized study comparing the efficacy of hormonal agents and associated reproductive outcomes is warranted. In conclusion, with intensive vigilance to detect disease persistence or recurrence, hormonal management appears to be a safe and moderately effective option in women diagnosed with endometrial neoplasia who are motivated to retain their reproductive potential. The results of this contemporary systematic review indicate an increased likelihood of response and decreased risk of disease persistence with progestin treatment of complex atypical hyperplasia compared with treatment of endometrial carcinoma. Additionally, the pregnancy rates and number of live births reported in the above studies suggest that a short interval of treatment with progestin therapy in premenopausal women may allow for reasonable fecundity. Despite these findings, women must be made aware that hysterectomy remains the standard of care for atypical endometrial hyperplasia and endometrial cancer. Women opting for hormonal treatment of these conditions should be extensively counseled regarding the risks including a lack of response or even progression of disease while on hormonal therapy. Documentation of informed consent should reflect these discussions and patient understanding. Further evaluation with larger prospective or randomized trials with uniform hormonal therapy is necessary to define the most effective treatment regimen and further stratify women according to risk of treatment failure. As the original predisposing factors for endometrial malignancy often persist, long term follow-up is essential. Conflict of interest statement The authors declare that there are no conflicts of interest.

Acknowledgment Grant support: Kathryn A. Carson's work on this manuscript was supported by Johns Hopkins Institute for Clinical and Translational Research grant number UL1RR025005 from the National Institutes of Health/National Center for Research Resources. Dr. Robert E. Bristow was supported by a grant from the Queen of Hearts Foundation. References [1] Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ. Cancer statistics, 2009. CA Cancer J Clin 2009;59:225–49. [2] Gallup DG, Stock RJ. Adenocarcinoma of the endometrium in women 40 years of age or younger. Obstet Gynecol 1984;64:417–20.

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