Endometrial cancer is the leading gynecologic malignancy in the United States, with approximately 47,130 women diagnosed in 2012.1 Many of these cancers arise from complex hyperplasia and 75–80% of cancers are diagnosed at an early stage.1,2 For patients with low-grade disease, total hysterectomy with bilateral salpingo-oophorectomy, radiation therapy, or both achieves a 5-year survival rate of 75–90%.3–5 Although these data support surgery as an effective treatment, the role of surgery is a less viable option for patients with comorbid perioperative risks or the desire for fertility preservation. It is estimated that two-thirds of the U.S. population is overweight or obese.6 Researchers estimate that in 50 years, the incidence of diabetes in women will increase 179–351%.7 In addition to being a risk factor for developing disease, obesity and diabetes predispose patients to many additional comorbidities and surgical complications.
Although most patients diagnosed with endometrial hyperplasia or cancer are postmenopausal, 5–30% of patients are premenopausal and thus fertility preservation may be an important factor when considering options for therapy.8 With the high rates of obesity in younger women, it is not difficult to imagine increasing rates of endometrial cancer in premenopausal patients. As more women require or request nontraditional treatment modalities, alternative treatments including hormone therapy are being considered. Hormone therapy has long been used for recurrent disease.9,10 In addition, recent data suggest that progestins can be successful as sole treatment in early-stage disease.11,12 It is thought that endometrial hyperplasia and carcinoma often result from unbalanced estrogen levels as a result of obesity (endogenous) or exogenous exposures. Progestin is thought to induce signaling pathways that inhibit cell transformation and cancer progression.13 Hormone treatments have been available as oral agents; however, there is an increasing interest in the use of the long-term levonorgestrel-releasing intrauterine system. Treatment using the levonorgestrel-releasing intrauterine system minimizes some of the undesirable effects of the other progestational compounds.
Today, physicians are charged with the task of using less traditional methods to treat nonsurgical candidates. These patients may not be surgical candidates either by medical necessity or by choice. We evaluated our experience in women with complex hyperplasia and stage I endometrial cancer who received primary hormone therapy to better understand the rates of disease regression, persistence, and progression.
MATERIALS AND METHODS
After obtaining University of North Carolina institutional review board approval, the records of all patients with a diagnosis of endometrial hyperplasia or early-stage endometrioid (International Federation of Gynecology and Obstetrics [FIGO] grade 1–2) cancer who received primary hormone therapy between January 1999 and July 2011 were reviewed. Patients were identified and cross-referenced using University of North Carolina gynecology disposition tumor board records and the University of North Carolina tumor registry. University of North Carolina Obstetrics and Gynecology departmental International Classification of Diseases, 9th Revision billing codes for levonorgestrel-releasing intrauterine system treatment by gynecologic oncology providers were also assessed to ensure comprehensive patient identification. Patients were not enrolled in a formal protocol and thus treatment regimens, including oral progesterone dosages, were typically at the discretion of the treating physician. The patients in this study were limited to those felt to have clinical stage I disease and patients did not routinely undergo magnetic resonance imaging or other assessments of deep myometrial invasion.
Patients who underwent definitive surgery, curative radiation therapy, or chemotherapy as part of their primary therapy were excluded. In addition, patients with a concurrent or prior diagnosis of breast or ovarian cancer were also excluded from analysis regardless of breast cancer hormone receptor status and subsequent breast or ovarian cancer treatment. Patients who received hormone therapy before a definitive diagnosis of hyperplasia or cancer were also excluded. Cancer patients with histology other than endometrioid adenocarcinoma were excluded. Patient without follow-up after initiation of hormone therapy were excluded.
Medical records were reviewed and relevant data extracted. Data obtained included patient demographic information (age at diagnosis, race, body mass index, calculated as weight (kg)/[height (m)]2), hyperplasia or tumor characteristics (grade, histologic cell type), disease outcomes (regression, progression, recurrence of disease, or both at each follow-up visit), and use of salvage therapy if any. For patients who pursued nonoperative management because of interest in fertility preservation, subsequent fertility outcomes were also recorded. Clinical endometrial cancers were staged based on the FIGO staging system at the time of diagnosis.14,15 All patients with the diagnosis of cancer underwent tumor board review as part of standard institutional practice where patient cases are reviewed with gynecologic oncology providers and pathology subspecialists. Endometrial hyperplasia was classified based on pathology reports using the Standard International Society of Gynecological Pathologists and World Health Organization criteria.16 Estrogen and progesterone receptor status was not analyzed because these data are not routinely acquired on endometrial biopsy or dilation and curettage (D&C) samples at our institution and were not available for the majority of patients. All patients received progestin hormone therapy, either systemically (eg, megestrol, medroxyprogesterone, oral contraceptive pills) or locally ([levonorgestrel-releasing intrauterine system). Follow-up was standardized to conservative surveillance, which included endometrial biopsy approximately every 3 months. Treatment regimen was at the discretion of the treating physician, but in general, patients who were found to have progressive or recurrent disease on follow-up biopsy were typically monitored closely for an additional 3 months at which point patients either continued on surveillance or received definitive surgery with curative intent.
Patient factors were compared initially between therapy subgroups among patients with the same histologic diagnosis, ie, hyperplasia and carcinoma. Patient factors were then compared between patients with hyperplasia and carcinoma among all treatment modalities. Gynecologic pathologists interpreted all pathology; however, there was no formal central review for the purposes of this study. Disease status at each follow-up time point was determined by endometrial sampling, either by office biopsy or D&C. Follow-up status was categorized as pathologic disease regression, persistence, or progression as compared with initial pathology at diagnosis. Although tissue samples were not submitted for confirmatory pathology, gynecologic pathologists reviewed each sample. Disease status was assessed at each follow-up as compared with initial pathology, and overall disease response at the time of last follow-up is as listed in Table 1. In brief, disease regression, persistence, and progression were defined as no evidence of disease (“negative biopsy”), persistent hyperplasia or cancer, or transformation to cancer or increase in grade (“positive biopsy”) as compared with initial biopsy before initiation of treatment, respectively. Overall disease response was defined as complete response, initial response or recurrence, or no response based on pattern of disease regression, persistence, or progression, respectively, over the entire patient follow-up time. For those who achieved response, time to response was defined as the time from initial biopsy or treatment initiation to first negative biopsy. Initial response or recurrence was defined as a disease regression with at least one positive biopsy after regression. Time to recurrence was defined as time from initial biopsy or treatment initiation to the first positive biopsy after a negative biopsy after 3 months of treatment. Time to event analysis was plotted using Kaplan-Meier analysis.
Comparisons were performed using a Student’s t test, Fisher’s exact test, χ2 test, Kaplan-Meier analysis, and two-tailed Wilcoxon signed-rank test. All statistical tests were two-sided and P<.05 was considered significant. JMP software was used for all statistical analyses.
Between 1999 and 2011, 186 patients who received primary hormone therapy for endometrial hyperplasia or cancer were identified and all pertinent data were obtained. Several patients were excluded at the beginning of analysis. Twelve patients (6%) were excluded secondary to initiation of treatment before definitive pathologic diagnosis. Six (3%) patients were found to have prior or concurrent breast cancer and two (1%) patients were found to have prior or concurrent ovarian cancer. Nine (5%) patients were lost to follow-up after initiation of treatment. Two (1%) patients were scheduled to receive hormones but underwent surgery, radiation, or both at the time of onset of hormone treatment. One (less than 1%) patient with a diagnosis of complex hyperplasia was found to be pregnant at the scheduled time of hormone therapy induction and thus was not included in this analysis. One (less than 1%) patient on pathology review was found to have endometrial sarcoma and was thus excluded. The distribution of the remaining 153 evaluable patients is presented in Figure 1.
Baseline patient histologies and treatment characteristics are presented in Table 2. The average age at diagnosis for all patients was 49.6 years (range 22–92 years) with the majority of patients presenting with postmenopausal bleeding (57% [87 of 153]). Most patients were diagnosed with hyperplasia and among these, most received traditional, systemic hormone therapy as compared with levonorgestrel-releasing intrauterine system therapy. Overall, the most common reasons cited for hormone therapy were medical comorbidities (46%) and fertility (21%) with subsets as listed in Table 2. Oral progesterone dosage and regimen were made at the discretion of the treating physician and ranged from 20 to 160 mg once to three times daily. Reasons for using a levonorgestrel-releasing intrauterine system compared with systemic therapy were often based on patient preference, side effect profile, and health care provider concerns of compliance. Distribution of patient factors between patients who received the levonorgestrel-releasing intrauterine system compared with systemic therapy for both those with hyperplasia and cancer was in general well balanced. There was a significant increase in median body mass index overall among patients who received systemic therapy as compared with the levonorgestrel-releasing intrauterine system, 36.1 compared with 50.8 (P<.001) and 40.6 compared with 50.6 (P=.035) for patients with hyperplasia and carcinoma, respectively.
Disease outcome at time of last follow-up for all patients is listed in Table 2. Time to first biopsy showing persistent or progressive disease obtained after 3 months of treatment is shown in Figure 2. Despite positive biopsies at the earlier time points, many patients had negative biopsies at the later time points. In addition, although health care providers attempted to standardize surveillance at 3-month intervals, patients returned for a varied number of visits at varied time points. In an attempt to compare patient subgroups, assessments were binned into four different follow-up intervals: 3–6 months, 6–9 months, 9–12 months, and greater than 12 months. Bin intervals were chosen as 3 months because this was the goal interval between follow-up appointments for posttreatment surveillance. Several patients had more than one follow-up assessment during each interval with some having different biopsy results within an interval time. Disease outcome for each bin was thus chosen based on the results at the latest biopsy during that interval. Outcomes based on treatment modality were compared between patients with hyperplasia and cancer as in Table 3. There was no significant difference in outcomes based between patients who received systemic hormones and the levonorgestrel-releasing intrauterine system among patients with cancer at all time points. For patients with hyperplasia, outcomes were not significantly different except during the 9- to 12-month assessment when those who received systemic hormones were less likely to have disease persistence or progression compared with patients who had levonorgestrel-releasing intrauterine systems. At the time of curative surgery, 17 patients were considered to have disease regression, 17 patients had disease persistence, and nine patients had disease progression.
When considering therapeutic response, there was no difference in complete response, initial response, or no response or progression rate between treatment modalities for each patient subgroup. Patients with cancer had significantly higher rates of recurrence and no response or progression with significantly shorter time to recurrence as compared with patients with hyperplasia. Patients with hyperplasia had complete response rates of 66–70% but recurrence rates of 11–23%, whereas those with cancer had complete response rates of 6–13% with recurrence rates of 19–30%. One patient with complex hyperplasia and three patients with adenocarcinoma, all treated with systemic hormones, eventually died with their disease. Three patients with cancer had persistent cancer found on all follow-up biopsies. The patient originally diagnosed with hyperplasia underwent surgery as part of treatment for cancer. Two patients with cancer eventually underwent local radiation therapy. One of the patients with cancer continually refused salvage radiation therapy and eventually died of disease. The extent of disease for the remainder of patients with disease at last pathologic uterine follow-up ranged from hyperplasia to FIGO grade 3.
Thirty-two (21%) patients cited fertility preservation as part of their decision to choose hormone rather than surgical management or radiation therapy. Fertility outcomes for patients who chose conservative management for fertility perseveration were low, as shown in Table 4. Of those patients interested in fertility preservation, six patients pursued assisted reproductive technology and three patients achieved pregnancy. Sixteen (52%) of patients who chose fertility preservation went on to receive curative surgery at some point in their follow-up. Although the majority of patients with hyperplasia were free of disease, either hyperplasia or cancer at final pathologic assessment, 64% of patients with cancer on initial biopsy had hyperplasia or cancer at the time of curative surgery.
This study is one of a growing number of studies, including a few prospective and phase II trials currently enrolling or nearing completion that address the use of primary hormone therapy for treatment of hyperplasia and early-stage endometrial cancer.17–20 Because patients are increasingly unwilling or unable to undergo surgery, alternative treatments are increasingly important. In general, our findings parallel a formal review by Gunderson et al and a smaller meta-analysis by Baker et al.11,21 In their analyses of 359 patients, Gunderson et al observed a complete response rate of 65.8% and 48.2% in patients with hyperplasia and cancer, respectively. We observed a complete response rate of 66–70% in patients with hyperplasia. Complete response rate in our patients with cancer was decreased at 6–13%, which may be the result of the decision to transition to curative surgical or radiation therapy earlier. In general, patients with cancer had increased time to response as compared with patients with hyperplasia and a higher percentage of patients with persistent disease.
There was no demonstrable difference in outcomes between women receiving a levonorgestrel-releasing intrauterine system compared with systemic hormones as seen in other studies21 despite the 100% compliance afforded by implanted devices, which releases a daily local dose of 20 micrograms of levonorgestrel. In contrast, systemic therapy can affect the hypothalamic–pituitary axis, altering the body's pituitary estrogen release. Health care providers can also add oral progestin therapy when there may be concern that local therapy alone may not adequately address endogenous estrogen burden in the more obese woman. However, such a treatment regimen requires patient compliance and follow-up. The decision between oral progesterone and the levonorgestrel-releasing intrauterine system was based in many cases on patient preference, although compliance and cost were considered. When choosing the modality of therapy, the levonorgestrel-releasing intrauterine system may be preferred for many health care providers due to patient compliance.
Our data highlight a difficulty encountered when treating patients with conservative treatment, because patient biopsy results at different follow-up time points varied widely. Although women with cancer were more likely to have persistent disease, they too demonstrated sporadic biopsy results, making the functional significance of negative biopsies unclear. Although some suggest a median of 9 months is necessary to see regression, our data and others suggest that the effect of individual factors, tumor-specific factors, and possibly hormone modality may make this a moving target.11,22 Results of a prospective study of women (n=12) with endometrial cancer reported a patient with repeated negative biopsies at 6 and 9 months but positive for carcinoma at 12 months.23 Further complicating the picture, reported data show significant differences in interobserver interpretation of tissue for endometrial atypical hyperplasia and cancer, both underestimating and overestimating disease status.24,25 More data are needed to determine the accuracy of pathologic assessment in the setting of pretreatment compared with posttreatment biopsies. In addition to differences in tissue assessment, some argue the merits of diagnostic tools such as D&C in acquiring such tissues in the context of malignancy.26,27 Surveillance schedules may depend on a patient and health care provider's ability to undergo in-office biopsy compared with D&C. In-office biopsy with a levonorgestrel-releasing intrauterine system every 3 months is a relatively uncomplicated cost-conscious method to consider. This acknowledged, appropriate clinical judgment is imperative and patients at significant concern for progressive disease should be treated accordingly.
Given the small patient population and low numbers of attempted pregnancies in this retrospective study, it is difficult to draw conclusions regarding a woman's ability to achieve pregnancy in this setting. Gunderson et al reported that 36% of 315 patients achieved pregnancy at least once with similar rates among patients with hyperplasia and those with cancer.28 Investigators note that desire to retain reproductive potential does not always lead to posttreatment fertility attempts. We observed three pregnancies, which likely underestimates the actual pregnancy rate because we are a tertiary referral center and patients may have pursued subsequent obstetric care elsewhere. Despite the fact that many patients had favorable responses to treatment, like others, we observed recurrent disease or eventual surgery in patients who chose hormones for fertility preservation.12,29 Furthermore, we observed one cancer-related death in a woman who elected fertility-sparing conservative therapy and did not have an initial complete response, but rather positive biopsies over more than 18 months of follow-up. These data highlight the need for continued vigilance and realistic discussions regarding potential disease mortality.
Although this study is one of the larger studies of patients who received hormone therapy for complex atypical hyperplasia and early-stage endometrial cancer, there are limitations. The study design is limited by the retrospective nature of the study, lack of randomization, and small patient numbers, which limit the power and conclusions of subgroup analysis. Patients were treated according to best practices and follow-up was attempted at appropriate points. Although pathology was not formally rereviewed, all samples underwent initial review by gynecology-specialized pathologists and cases of cancer were presented as part of a formal tumor board. Our data are further limited given the long timeframe of the study and potential changes in management that may have occurred. There is potential selection bias, because patients who were surgical candidates were counseled regarding surgery as the best known treatment. Patients with poor performance status or at risk for loss to follow-up may have been preferentially selected for levonorgestrel-releasing intrauterine system treatments. In addition, this study performed in a tertiary care setting has limited follow-up because many patients may have followed up at outside institutions. The data reported represent patient outcomes at the time of last follow-up. With these limitations acknowledged, we believe our approach was reasonable, as complete as possible, and most likely represents “the real-world” experience. These data contribute to the available literature for patients and health care providers seeking alternative treatments to traditional surgery.
Early results of phase II prospective studies using levonorgestrel-releasing intrauterine system report a12-month response rate of 58% with stratified response rates of 85% and 33% in patients with hyperplasia and early-stage endometrial cancer, respectively.17–20 With these results acknowledged, 42% of patients still had stable or persistent disease at 12 months, slightly higher than literature reported rates, but closer to the 50–75% observed in our patients with cancer.11 Investigators argue response could be predicted by the presence of exogenous progesterone effect and reduction in PS6 protein expression at 3 months.
Recently, high-throughput molecular techniques have been used to identify patients who might be at increased risk of recurrence or who might benefit from adjuvant therapies. The aggregate results of genomic, metabolomics, or proteomic analyses, in addition to demographic factors, help create a signature of disease and may, in turn, be exploited to better understand prognoses and guide treatment. Prospective analysis of proliferation markers in 12 patients treated with a levonorgestrel-releasing intrauterine system saw significant reduction in S6 phosphorylation and a trend toward higher baseline Ki67 expression between responders compared with nonresponders.20 Preliminary work investigating adjuvant metformin therapy to reduce progestin resistance indicates that metformin affects expression of glyoxalase I, stimulates AMPK phosphorylation, decreases phosphorylation of S6 proteins, and affects molecules along the mammalian target of rapamycin pathway.30,31 Although these results underline the importance of the mammalian target of rapamycin pathway, the therapeutic potential of metformin remains uncertain. More study is needed to identity other potential therapies and confirm the use of metformin in the adjuvant setting.
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© 2013 by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.
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