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National patterns of care and fertility outcomes for reproductive-aged women with endometrial cancer or atypical hyperplasia
Original Research 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55
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GYNECOLOGY
National patterns of care and fertility outcomes for reproductive-aged women with endometrial cancer or atypical hyperplasia Q10
Ross F. Harrison, MD; Weiguo He, PhD; Shuangshuang Fu, PhD; Hui Zhao, PhD; Charlotte C. Sun, DrPH, MPH; Rudy S. Suidan, MD, MS; Terri L. Woodard, MD; J. Alejandro Rauh-Hain, MD, MPH; Shannon N. Westin, MD, MPH; Sharon H. Giordano, MD, MPH; Larissa A. Meyer, MD, MPH
BACKGROUND: Although it is uncommon, the incidence of endometrial
cancer and atypical hyperplasia among reproductive-aged women is increasing. The fertility outcomes in this population are not well described. OBJECTIVE: We aim to describe the patterns of care and fertility outcomes of reproductive-aged women with endometrial cancer or atypical hyperplasia. MATERIALS AND METHODS: A cohort of women aged 45 years with endometrial cancer or atypical hyperplasia diagnosed in 2000 to 2014 were identified in Truven Marketscan, an insurance claims database of commercially insured patients in the United States. Treatment information, including use of progestin therapy, hysterectomy, and assisted fertility services, was identified and collected using a combination of Common Procedural Terminology codes, International Classification of Diseases codes, and National Drug Codes. Pregnancy events were identified from claims data using a similar technique. Patients were categorized as receiving progestin therapy alone, progestin therapy followed by hysterectomy, or standard surgical management with hysterectomy alone. Multivariable logistic regression was performed to assess factors associated with receiving fertility-sparing treatment. RESULTS: A total of 4007 reproductive-aged patients diagnosed with endometrial cancer or atypical hyperplasia were identified. The majority of these patients (n ¼ 3189; 79.6%) received standard surgical management. Of the 818 patients treated initially with progestins, 397 (48.5%) subsequently underwent hysterectomy, whereas 421 (51.5%) did not. Patients treated with progestin therapy had a lower median age than those who received standard surgical management (median age, 36 vs 41 years; P < .001). The proportion of patients receiving progestin therapy increased significantly over the observation period, with 24.9% treated at
E
ndometrial carcinoma is uncommon in reproductive-aged women, with only about 7% of new diagnoses occurring in women under the age of 44 years.1 For both endometrial cancer and
Cite this article as: Harrison RF, He W, Fu S, et al. National patterns of care and fertility outcomes for reproductive-aged women with endometrial cancer or atypical hyperplasia. Am J Obstet Gynecol 2019;XX:x.exx.ex. 0002-9378/$36.00 ª 2019 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.ajog.2019.05.029
least initially with progestin therapy in 2014 (P < .001). Multivariable analysis shows that younger age, a diagnosis of atypical hyperplasia diagnosis rather than endometrial cancer, and diagnosis later in the study period were all associated with a greater likelihood of receiving progestin therapy (P < .0001). Among the 421 patients who received progestin therapy alone, 92 patients (21.8%; 92/421) had 131 pregnancies, including 49 live births for a live birth rate of 11.6%. Among the 397 patients treated with progestin therapy followed by hysterectomy, 25 patients (6.3%; 25/397) had 34 pregnancies with 13 live births. The median age of patients who experienced a live birth following diagnosis during the study period was 36 years (interquartile range, 3338). The use of some form of assisted fertility services was observed in 15.5% patients who were treated with progestin therapy. Among patients who experienced any pregnancy event following diagnosis, 54% of patients used some form of fertility treatment. For patients who experienced a live birth following diagnosis, 50% of patients received fertility treatment. Median time to live birth following diagnosis was 756 days (interquartile range, 5251077). Patients treated with progestin therapy were more likely to experience a live birth if they had used assisted fertility services (odds ratio, 5.9; 95% confidence interval, 3.410.1; P < .0001). CONCLUSION: The number of patients who received fertility-sparing treatment for endometrial cancer or atypical hyperplasia increased over time. However, the proportion of women who experience a live birth following these diagnoses is relatively small. Key words: endometrial cancer, endometrial hyperplasia, fertility,
fertility conservation, fertility-sparing treatment, oncofertility, health services research
atypical hyperplasia, hysterectomy is part of standard surgical management.24 However, uterine-sparing treatment is an option for women diagnosed at a young age who desire fertility preservation. The Society of Gynecologic Oncology describes an ideal candidate for conservative treatment as a woman who strongly desires fertility-sparing management with a well-differentiated (grade 1) tumor, no evidence of myometrial invasion (stage 1A), no contraindications for medical management, and acceptance of nonstandard cancer treatment.2,5
Historically, oral progestin therapy has been the primary management strategy for women with endometrial cancer who desire fertility preservation.2 Reported initial response rates to progestins are estimated to be 7090%, although the optimal dose and progestin formulation is uncertain.6 The use of the levonorgestrel-releasing intrauterine device (LNG-IUD) has been associated with regression rates in women with atypical hyperplasia as high as 90%.7 In a recent case series from the University of Texas MD Anderson Cancer Center, responses to
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AJOG at a Glance Why was this study conducted? This study was performed to examine national patterns of care for reproductiveaged women with endometrial cancer or atypical hyperplasia. Desire for fertility is an important clinical indication for pursuing nonsurgical management. However, the fertility outcomes in this group of patients is not well described, apart from retrospective single-institution reviews. Key findings From 1999 to 2014, the proportion of reproductive-aged women with endometrial cancer or atypical hyperplasia who received fertility-conserving treatment increased significantly. Younger age, diagnosis later in the study period, and a diagnosis of atypical hyperplasia as opposed to cancer were all associated with an increased likelihood of receiving fertility-sparing treatment, at least initially. However, less than 12% of patients experienced a live birth following fertilitysparing treatment. What does this add to what is known? This analysis provides a broader perspective on the use over time of fertilitysparing treatment for reproductive-aged women with endometrial cancer or atypical hyperplasia. With certain limitations considered, it offers a populationbased estimate of the proportion of women who may experience a live birth following fertility-conserving treatment.
treatment with an LNG-IUD were seen in 67% of patients with grade 1 and 75% of patients with grade 2 endometrial cancer of endometrioid histology.8 Although these findings may suggest that progestin therapy is a reasonable alternative treatment strategy in patients who desire fertility preservation, increased disease-specific mortality is seen in young women with endometrial cancer treated with progestin therapy compared with hysterectomy.9,10 Furthermore, approximately 2040% of patients experience recurrent disease after an initial response.6,11,12 Much of the literature published regarding the fertility outcomes of young women with endometrial cancer or atypical hyperplasia who received fertility-sparing management has been limited to single-institution retrospective reviews at academic institutions or meta-analyses of these reports.6,1113 Our objective was to describe patterns of care in the treatment of young women diagnosed with endometrial cancer or atypical hyperplasia, and to estimate their fertility outcomes from a population-level perspective using a national insurance claims database.
Materials and Methods We performed a retrospective cohort study by analyzing data from the Truven Health MarketScan Research Database (IBM Watson Health, Cambridge, MA), a commercial database of patient-level information derived from health insurance claims. Since 1995, this database has collected enrollment data, hospital admission records, outpatient services, and outpatient prescription drug claims for 250 million health insurance beneficiaries from more than 300 employersponsored health plans, including feefor-service coverage, fully capitated and partially capitated health plans, preferred provider organizations, indemnity plans, health maintenance organizations, and other managed caretype insurance. In the most recent data year, the MarketScan databases contained information on 43.6 million covered individuals.14 Insurance claims from 1998 to 2016 were analyzed for this study. Eligibility for inclusion into our study cohort was all women aged 45 years diagnosed with endometrial cancer (International Classification of Diseases [ICD]9-CM 182.0; ICD-10-CM
C54.x) or atypical hyperplasia (ICD-9CM 621.33; ICD-10-CM N85.02) between 1999 and 2014 (Figure 1). ½F1 Outpatient diagnoses were included only if the codes appeared 2 or more times with at least 30 days between claims. Inpatient diagnoses were included if a single claim was observed. Patients were restricted to those who had continuous coverage for at least 12 months before and 24 months after diagnosis (n ¼ 6941 excluded). An algorithm was applied to remove prevalent cases from the analysis (n ¼ 724 excluded). Patients identified with endometrial cancer or atypical hyperplasia without any corresponding treatment information (eg, no claims for either hysterectomy or progestin therapy) were also removed (n ¼ 1116 excluded). Our primary objective was to estimate the proportion of reproductive-aged patients with endometrial carcinoma or atypical hyperplasia receiving progestin therapy alone, progestin therapy followed by hysterectomy, or definitive surgical management with hysterectomy alone. Secondary objectives included the following: determination of factors associated with progestin therapy; estimation of pregnancy events that occurred after a diagnosis of endometrial carcinoma or atypical hyperplasia; and the use of assisted fertility services, including use of ovulation induction and in vitro fertilization, after diagnosis of endometrial cancer or atypical hyperplasia. Variables for patient characteristics were collected for analysis, including age at diagnosis, year of diagnosis, geographic location, and insurance plan type. Comorbidity was estimated using the Klabunde-modified Charlson Comorbidity Index score using claims in the 12 months before the diagnosis of endometrial cancer/hyperplasia.15,16 Treatment information, including receipt of progestin therapy, hysterectomy, and assisted fertility services, was identified in claims data by using a combination of International Statistical Classification of Diseases and Related Health Problems (ICD), revision 9 and 10 diagnosis codes; Common Procedural Q1 Terminology (CPT) codes; ICD-9/10
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FIGURE 1
Cohort identification for reproductive-aged patients with endometrial cancer or atypical hyperplasia
At least 2 outpatient claims or at least 1 inpatient for endometrial cancer (ICD-9-CM 182.0; ICD-10CM C54.x) or atypical hyperplasia (ICD-9-CM 621.33; ICD-10-CM N85.02) was required for initial study inclusion. This figure depicts the process by which the final analyzed sample was selected from the MarketScan Commercial Database, as well as the rationale and number of patients excluded at different points in the cohort selection. Harrison et al. Fertility conservation and pregnancy outcomes in young women with endometrial cancer or hyperplasia. Am J Obstet Gynecol 2019.
Original Research
subdivided into the following 3 treatment categories: patients receiving progestin therapy alone (eg, fertility-sparing treatment); progestin therapy followed by hysterectomy; or hysterectomy alone. Fertility outcomes were categorized as any pregnancy event and live births. For consistency with other investigations regarding this patient population, live birth rate was defined as number of live births observed divided by the number of patients receiving fertility-sparing treatment or progestin therapy followed by hysterectomy.6,12 Descriptive statistics (means, medians, and standard deviations of continuous variables and frequencies of discrete variables) of patients’ sociodemographic and clinical characteristics were calculated. The c2 test (for discrete variables) or F test (for group means) or KruskalWallis test (for medians) was used to assess differences between patients’ characteristics and therapies. Multivariable logistic regression was performed to assess factors associated with receipt of progestin therapy. A subset of patients was treated with progestin therapy initially but subsequently underwent hysterectomy. As a sensitivity analysis, we repeated multivariate logistic regression after reassigning patients away from the fertility-sparing treatment group if they underwent hysterectomy after <2 months (60 days) of progestin therapy. Our rationale was that determining the intent of a given treatment is difficult with insurance claims data, and that patients who would be excluded by this criterion would more likely represent patients who received progestins for indications other than fertility conservation (eg, amelioration of bleeding symptoms). All analyses were conducted with SAS statistical software (version 9.3; SAS Institute, Cary, NC). This project was approved by our Institutional Review Board (PA 14-0796).
Results procedure codes; and National Drug Codes (NDC) (Supplementary Table 1). Similarly, pregnancy events, including live birth, spontaneous abortion, and ectopic pregnancy were identified using
a combination of ICD-9/10 diagnosis codes, Common Procedural Terminology (CPT) codes, and ICD-9/10 procedure codes (Supplementary Table 1). The cohort of identified patients was
With the Marketscan database, we identified 4007 women 45 years old who were diagnosed with endometrial cancer (3137; 78.3%) or atypical hyperplasia (870; 21.7%) between 2000
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TABLE 1
Patient characteristics (N [ 4007) Treatment category Progestin therapy only (421/4007; 10.5%)
Characteristics
Progestin therapy followed by hysterectomy (397/4007; 9.9%)
Hysterectomy only (3189/4007; 79.6%)
Total ¼ 4007, P valuec n (%) <.001
Age at diagnosis, y 18e29
72 (17.1)
29 (7.3)
83 (2.6)
184 (4.5)
30e34
107 (25.4)
82 (20.7)
287 (9.0)
476 (11.9)
35e39
122 (29.0)
122 (30.7)
764 (24.0)
1008 (25.2)
40e45
120 (28.5)
164 (41.3)
2055 (64.4)
37.7 (5.2)
40.1 (4.5)
<.0001d
39.4 (5)
41 (38e44)
<.0001
41 (37e43)
Mean age, y (SD)
35.4 (6)
Median age, y (IQR)
36 (31e40)
Median duration of follow-up, y (IQR)
4.1 (3.1e5.9)
38 (34e42) 4.7 (3.4e6.6)
4.5 (3.2e6.6)
2339 (58.4)
<.001
e
4.5 (3.2e6.5)
<.001
Diagnosis group Endometrial cancer
216 (51.3)
302 (76.1)
2619 (82.1)
3137 (78.3)
Atypical hyperplasia
205 (48.7)
95 (23.9)
570 (17.9)
870 (21.7) <.001
Year of diagnosis 2000e2004
a
25 (5.9)
26 (6.5)
365 (11.4)
416 (10.4)
2005
16 (3.8)
19 (4.8)
163 (5.1)
198 (4.9)
2006
17 (4.0)
21 (5.3)
257 (8.1)
295 (7.4)
2007
21 (5.0)
19 (4.8)
250 (7.8)
290 (7.2)
2008
49 (11.6)
50 (12.6)
373 (11.7)
472 (11.8)
2009
57 (13.5)
67 (16.9)
415 (13.0)
539 (13.5)
2010
51 (12.1)
51 (12.8)
402 (12.6)
504 (12.6)
2011
49 (11.6)
42 (10.6)
336 (10.5)
427 (10.7)
2012
51 (12.1)
45 (11.3)
241 (7.6)
337 (8.4)
2013
49 (11.6)
42 (10.6)
233 (7.3)
324 (8.1)
2014
36 (8.6)
15 (3.8)
154 (4.8)
205 (5.1)
Region
b
.029
Northeast
92 (22.5)
77 (19.8)
542 (17.4)
711 (18.2)
North Central
94 (23.0)
92 (23.7)
776 (24.9)
962 (24.6)
150 (36.8)
138 (35.5)
1273 (40.9)
1561 (39.9)
72 (17.6)
82 (21.1)
521 (16.7)
675 (17.3)
259 (85.8)
276 (84.1)
2372 (86.6)
2907 (86.3)
43 (14.2)
52 (15.8)
368 (13.4)
463 (13.7)
South West Charlson Comorbidity Index
f
.045
0 1 Patient’s relationship to primary beneficiary
<.001
g
Employee
280 (66.5)
286 (72.0)
2052 (64.3)
2618 (65.3)
Spouse
127 (30.2)
109 (27.5)
1115 (35.0)
1351 (33.7)
Harrison et al. Fertility conservation and pregnancy outcomes in young women with endometrial cancer or hyperplasia. Am J Obstet Gynecol 2019.
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ajog.org 447 448 449 450 451 452 453 454 455 456 457 458 459 460 461 462 463 464 465 466 467 468 ½T1 469 470 471 472 473 474 475 476 477 478 479 480 481 482 483 484 485 486 487 488 489 490 491 492 493 494 495 496 497 ½F2 498 499 500 501 502
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Original Research
503 504 TABLE 1 505 Patient characteristics (N [ 4007) (continued) 506 Treatment category 507 508 Progestin therapy Hysterectomy followed by Progestin therapy 509 Total ¼ 4007, only (3189/4007; hysterectomy only (421/4007; 510 P valuec n (%) 79.6%) (397/4007; 9.9%) 10.5%) Characteristics 511 Insurance 0.116 512 513 HMO 62 (14.7) 80 (20.2) 498 (15.6) 640 (16.0) 514 PPO 261 (62.0) 217 (54.7) 1909 (59.9) 2387 (59.6) 515 Other 98 (23.3) 100 (25.2) 782 (24.5) 980 (24.5) 516 HMO, health maintenance organization; IQR, interquartile range; PPO, preferred provider organization; SD, standard deviation. 517 a For the years 2000e2004, <11 patients were identified in certain treatment groups per year. These years were grouped together to protect patient privacy; b A total of 98 patients were excluded 518 because of unknown region; c P values were derived using the c2 test for comparing differences among the 3 treatment groups; d P values were derived using the F test for comparing means among 519 the 3 treatment groups; e P values were derived using the KruskalWallis test for comparing medians among the 3 treatment groups; f A total of 637 patients were excluded because of missing comorbidity scores. For patients in the progestin therapy only and the progestin therapy followed by hysterectomy treatment categories, <11 patients were identified with a Charlson Comorbidity 520 Index score of 2. These patients were grouped with patients with a score of 1 to protect patient privacy; g To protect patient privacy, the frequency of patients who were the child of or had other 521 relationship to the primary beneficiary (total n ¼ 38) is not shown, as <11 patients identified in certain treatment groups. Harrison et al. Fertility conservation and pregnancy outcomes in young women with endometrial cancer or hyperplasia. Am J Obstet Gynecol 2019. 522 523 524 and 2014 (Table 1, Figure 1). Median treated with an LNG-IUD (175/818), Of patients who received progestin ther525 follow-up for patients identified was 4.5 alone or in combination with other apy alone, 20.9% of patients (88/421) 526 years (interquartile range [IQR], progestins. received fertility treatments. Of patients 527 3.26.5). From this cohort, 3189 Of the cohort treated with progestin who had any pregnancy or specifically a 528 (79.6%) received definitive surgical therapy with or without hysterectomy, live birth during the study period, 54% 529 management and 818 (20.4%) received 117 patients experienced 165 pregnan- (63/117) and 50% (31/62) of patients 530 progestin therapy either alone or fol- cies during the observation period received fertility treatments, respectively. 531 lowed by hysterectomy. Of the patients (Table 2). Among the 421 patients Of the patients who received fertility ½T2 532 in the subcohort initially treated with receiving fertility-sparing treatment, 92 treatment and experienced any preg533 progestin therapy, 48.5% (397/818) patients (21.8%; 92/421) had 131 preg- nancy event, 79% (50/63) used in vitro 534 subsequently underwent hysterectomy, nancies. Of these patients who were fertilization. Patients treated with pro535 whereas 51.5% (421/818) did not. The treated exclusively with progestins, 49 gestin therapy were 5.9 times more likely 536 median time from diagnosis to hyster- patients had live births for a live birth to experience a live birth if they also had 537 ectomy in the patients initially treated rate of 11.6% (49/421). Among the 397 received some form of fertility treatment 538 with progestins but who subsequently patients treated with progestin therapy (95% confidence interval [CI], 3.410.1; 539 underwent hysterectomy was 168 days followed by hysterectomy, 25 patients P < .0001). 540 (IQR, 55727). After excluding pa- (6.3%; 25/397) had 34 pregnancies. Of Both univariate and multivariable 541 tients who underwent hysterectomy those, 13 patients had live births for a live analysis revealed that younger age, 542 after <2 months of progestin therapy, birth rate of 3.3% (13/397). The live diagnosis of atypical hyperplasia, and 543 the median time from diagnosis to birth rate for the entire cohort of patients diagnosis later in the observation 544 hysterectomy in this group was 380 who received progestin treatment with period were associated with a greater 545 days (IQR, 142959). Patients who or without hysterectomy was 7.6% (62/ likelihood of receiving progestin ther546 underwent definitive surgical manage- 818). The median age of patients who apy at least initially (Table 4). Patients ½T4 547 ment were older and more likely to experienced a live birth during the study aged <25 years were 9.5 times more 548 have endometrial cancer than atypical period was 36 years (IQR, 3338). The likely to receive progestin therapy 549 hyperplasia (P < .001) (Table 1). A median time from diagnosis to first compared to those aged 4045 years 550 greater proportion of patients diag- pregnancy event was 413 days (IQR, (odds ratio [OR], 9.5; 95% CI, 551 nosed later in the study period received 262758). The median time from diag- 3.625.1; P < .0001). Women with 552 fertility-sparing treatment (P <.001) nosis to live birth was 756 days (IQR, atypical hyperplasia were 2.6 times 553 (Figure 2). In the final year of the study 5251077). more likely to initially receive progestin 554 In the group of patients treated with therapy compared with those diagnosed period, 24.9% of patients were treated 555 with progestin therapy, at least initially. progestin therapy with or without hys- with endometrial cancer (OR, 2.7; CI, 556 Of the patients treated with progestin terectomy, 15.5% of patients (127/818) 2.23.2; P < .0001). Analyzing the 557 period into 5-year ½T3 therapy at least initially, 21.4% were utilized assisted fertility services (Table 3). observation 558 MONTH 2019 American Journal of Obstetrics & Gynecology FLA 5.6.0 DTD YMOB12697_proof 10 June 2019 7:46 pm ce
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615 616 617 Reproductive-aged patients with endometrial cancer or atypical hyperplasia receiving progestin therapy 618 619 620 621 622 623 624 625 626 627 628 629 630 631 632 633 634 635 636 The y-axis indicates percentage of patients diagnosed with endometrial cancer or atypical hyperplasia in a given year in each treatment group. Patients 637 treated with only hysterectomy are not shown. Fertility-sparing treatment is defined as treatment with progestin therapy alone. Patients diagnosed in 638 1999 are not shown because of washout algorithm to exclude prevalent cases. Cases from 2000 are not shown, as only 22 patients were identified as 639 meeting inclusion criteria for analysis; 18% (4/22) received fertility-sparing treatment. This figure depicts a statistically significant increasing trend in the 640 proportion of patients who were treated with progestin therapy in each subsequent year of the observation period. The total group of patients treated with 641 progestins is divided into those treated with progestin therapy alone (blue) and progestin therapy followed by hysterectomy (orange). 642 Harrison et al. Fertility conservation and pregnancy outcomes in young women with endometrial cancer or hyperplasia. Am J Obstet Gynecol 2019. 643 644 intervals, a diagnosis of endometrial CI, 1.12.1; P ¼ .0002). These factors Comment 645 cancer or atypical hyperplasia between remained significant predictors of Principal findings 646 2009 and 2014 was associated with an receiving fertility-sparing treatment af- In our study, the use of progestin therapy 647 approximately 47% increased likelihood ter the sensitivity analysis of reassigning for reproductive-aged women diagnosed 648 of receiving progestin therapy, at least patients who underwent hysterectomy with endometrial cancer or atypical hy649 initially, compared to those diagnosed after <2 months of progestin therapy perplasia became more common over 650 between 1999 and 2004 (OR, 1.5; 95% was performed (Table 5). the study period. Patients diagnosed ½T5 651 near the end of the study period were 652 nearly 75% more likely to receive pro653 TABLE 2 gestin therapy. As would be expected, the 654 Fertility events among patients receiving progestin therapy youngest patients in our study cohort 655 and those with atypical hyperplasia were 656 Total cohort much more likely to receive progestin initially managed Progestin 657 therapy than the oldest patients. Among with fertility therapy followed Progestin 658 patients who received fertility conservaconservation by hysterectomy therapy alone 659 n ¼ 818 n ¼ 397 n ¼ 421 tion, we observed a live birth rate of 660 <12%. Most of the pregnancy events Patients 92 25 117 661 experiencing any that occurred following a diagnosis of 662 pregnancy, n endometrial cancer or atypical hyper663 49 13 62 plasia occurred in the context of assisted Patients 664 experiencing live fertility services. 665 birth, n 666 Q3 Live birth rate, % 11.6% 3.3% 7.6% Meaning 667 Our findings are consistent with prior Live birth rate defined as proportion of patients experiencing a live birth (numerator) divided by patients in treatment category 668 (denominator). population-based analyses of the treat669 Harrison et al. Fertility conservation and pregnancy outcomes in young women with endometrial cancer or hyperplasia. ment of young women with endometrial Am J Obstet Gynecol 2019. 670 cancer that have shown an increase in the FIGURE 2
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Original Research
GYNECOLOGY
TABLE 3
Use of assisted fertility services Patients using assisted fertility services
Patients not using assisted fertility services
Endometrial cancer
Hyperplasia with atypia
Endometrial cancer
Hyperplasia with atypia
Total, n
151 (3.8)
69 (1.7)
2986 (74.5)
801 (20)
4007
Patients who received progestin therapya, n (%)
79 (9.7)
48 (5.9)
439 (53.7)
252 (30.8)
818
Patients who received fertility-sparing treatmentb, n (%)
47 (11.2)
41 (9.7)
169 (40.1)
164 (39)
421
Patients who experienced any pregnancy, n (%)
35 (29.9)
28 (23.9)
27 (23.1)
27 (23.1)
117
Patients who experienced a live birth, n (%)
18 (29)
13 (21)
15 (24.2)
16 (25.8)
62
Entire cohort, n (%)
All values represent frequencies followed by row percentages in parentheses, unless otherwise indicated. a Includes patients who received progestin therapy exclusively and those who also subsequently underwent hysterectomy; b Includes patients who were treated with progestin therapy only. Harrison et al. Fertility conservation and pregnancy outcomes in young women with endometrial cancer or hyperplasia. Am J Obstet Gynecol 2019.
use of progestin therapy over time.9,10 This trend may relate to increased awareness and interest in this treatment strategy by clinicians for women in this age group. Using the National Cancer Database, Ruiz et al found that the proportion of endometrial cancer patients who were treated with progestin therapy increased from 2.4% in 2004 to 5.9% in 2014.10 We observed that nearly 25% of our cohort received progestin therapy, with or without subsequent hysterectomy, during the final year of our study period. This difference in estimates may be accounted for at least partially by the inclusion of patients with atypical hyperplasia in our analysis, who we found were more likely to be treated with progestin therapy compared to those with endometrial cancer. In addition, Ruiz et al included patients aged 4549 years, an age group in which the incidence of endometrial cancer and atypical hyperplasia is relatively higher and patients are more likely to be treated surgically than medically.10 Greenwald et al reported similar findings from an analysis using the Surveillance, Epidemiology, and End Results (SEER) database.9 Both analyses found that women receiving nonsurgical treatment for endometrial cancer were at an increased risk for cancer-specific mortality.9,10 Both of these investigations identified a greater number of
reproductive-aged women with endometrial cancer than in this report. The discrepancy in the number of patients identified in our study vs these reports reflects differences in data sources, methodology, and inclusion criteria. As fertility preservation may be an important factor in pursuing uterinesparing treatment, the fertility-related outcomes reported here offer context for what may be seen as the benefit for avoiding or deferring hysterectomy. We found that a pregnancy or a live birth was an uncommon event in women following an endometrial cancer or atypical hyperplasia diagnosis. In our cohort, we observed a live birth rate of 11.6% among those women pursuing fertility-conserving therapy. In a systematic review by Gallos et al, the live birth rate in women receiving fertilitysparing treatment for endometrial cancer or atypical hyperplasia was 26% and 28%, respectively.6 In a more recent review, Wei et al reported a live birth rate of 1420%.12 Some of the difference in the live birth rate estimated by those reviews and this study may be due to patient population differences. Those reports include patients receiving uterinesparing treatment exclusively for the purpose of fertility preservation. Our methodology does not allow us to discriminate and to exclude patients who received uterine-sparing treatment for
reasons other than fertility preservation. Other common rationales for nonsurgical treatment include medical infirmity, advanced age, or patient preference to avoid surgery. However, as patients in our cohort were by definition young, and as few had significant medical comorbidities, the live birth rate that we report may better reflect the real-world likelihood of live birth for patients following a diagnosis of endometrial cancer or atypical hyperplasia. Although we are limited in our ability to definitively determine the proportion of patients in this study who sought pregnancy, these data may suggest a more limited reproductive potential for reproductive-aged patients with endometrial cancer or atypical hyperplasia. More than half of the pregnancies achieved in this study occurred in the context of fertility treatment. Given this, individualized assessment of each patient’s likelihood to achieve pregnancy should be carefully incorporated into shared decision making when fertility-sparing treatment is considered. Advancing age and obesity—well-established risks shared by endometrial cancer and impaired fertility—are clinical factors immediately available to a gynecologic oncologist counseling a patient regarding her reproductive potential and treatment that may affect it.1719 Collaboration with a fertility specialist may be a highly valuable
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TABLE 4
Factors associated with receiving progestin therapy (N [ 4,007) Multivariable
Univariate OR
P value
95% CI
OR
P value
95% CI
<.0001
Age at diagnosis, y
<.0001
40e45 <25
8.0
4.2
15.4
9.5
3.6
25.1
25e29
9.0
6.4
12.8
10.0
6.9
14.4
30e34
4.8
3.8
5.9
4.9
3.9
6.2
35e39
2.3
1.9
2.8
2.3
1.9
2.8
<.0001
Diagnosis group
<.0001
Endometrial cancer Atypical hyperplasia
2.7
2.2
3.2
2.7
2.2
3.2
<.0001
Year of diagnosis
.0002
1999e2004 2005e2008
1.5
1.0
2.0
1.0
0.7
1.4
2009e2014
2.2
1.6
3.0
1.5
1.1
2.0
Region
.0194
.0132
South Northeast
1.4
1.1
1.7
1.4
1.1
1.8
North Central
1.1
0.9
1.3
1.2
0.9
1.5
West
1.3
1.0
1.6
1.4
1.1
1.8
Unknown
1.2
0.7
2.0
1.4
0.8
2.4
Insurance
.4756
Study strengths and weaknesses .6431
HMO Other
0.9
0.7
1.1
0.9
0.7
1.2
PPO
0.9
0.7
1.1
0.9
0.7
1.1
Charlson Comorbidity Index
.2799
.4077
0 1
1.1
0.8
1.4
1.1
0.9
1.5
2
0.6
0.3
1.2
0.7
0.3
1.4
<.0001
Relationship to the Primary Beneficiary
.0112
Employee Spouse
0.8
0.6
0.9
0.8
0.6
0.9
Child/Other
2.6
1.4
5.1
0.9
0.3
2.5
CI, confidence interval; HMO, health maintenance organization; OR, odds ratio; PPO, preferred provider organization. a P values are based on Wald test. Harrison et al. Fertility conservation and pregnancy outcomes in young women with endometrial cancer or hyperplasia. Am J Obstet Gynecol 2019.
addition to the evaluation of an individual patient’s reproductive potential, as referral may offer clarity in terms of the potential for pregnancy with and without various forms of assisted reproductive
With increased use of uterine-sparing treatment, questions regarding longerterm management of these patients also arise. As stated above, 2 population-level analyses of young endometrial cancer patients found an increased risk of cancer-specific mortality among patients who received fertility-sparing treatment.9,10 Durable responses to progestin therapy are suboptimal, with up to 40% of patients experiencing disease recurrence.6,11 The true rate may be higher still, given that the proportion of patients who will experience a relapse increases with time as women remain at risk. For women with atypical hyperplasia, the Royal College of Obstetricians and Gynaecologists recommends hysterectomy after initial uterine-sparing treatment “once fertility is no longer required,” because of the high recurrence risk.21 Nearly 90% of gynecologic oncologists surveyed would recommend hysterectomy once childbearing was completed for women initially treated with uterinepreservation.22
technology. Notably, the American Society of Clinical Oncology recommends that physicians “should refer patients who express an interest in fertility preservation to reproductive specialists.”20
To our knowledge, this analysis is the first that examines the fertility outcomes of patients with endometrial cancer or atypical hyperplasia using a national-level sample. We identified a large number of reproductive-aged patients with these diagnoses with a median follow-up time of 4.5 years, likely a satisfactory observation period to examine these fertility endpoints. However, our study has several important limitations. First, our analysis does not capture oncologic outcomes or information regarding adjuvant treatment, both of which could affect fertility potential. We cannot estimate the effectiveness of progestin therapy compared with standard therapy. As stated previously, we cannot ascertain what proportion of patients received uterine-sparing treatment for the purpose of fertility conservation as opposed to other clinical indications. We cannot determine what proportion of patients who received fertility conservation subsequently tried to become pregnant. We cannot determine the reason why
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some patients who were initially managed with progestin therapy subsequently underwent hysterectomy. Koskas et al found that the number of patients who will respond to progestin therapy seems to plateau at approximately 80% at 12 months after the start of treatment.23 It is possible that some of the patients initially treated with progestins subsequently underwent hysterectomy for treatment failure, recurrence, or disease progression. Although our analysis did not limit the observation period, patients changing insurance providers may have been lost to follow-up if their new insurance carrier did not report into the MarketScan database. The 24-month requirement of continuous coverage after diagnosis was designed to mitigate this. We may have underestimated pregnancy events in our study population, especially for those diagnosed in the final years of the study who may have experienced pregnancy after the end of the observation period or for those who had miscarriages that did not require medical services. The use of assisted fertility services may also have been underestimated. In many parts of the United States, these services are not a standard health insurance benefit, and so a claim for these may have not been submitted for reimbursement. The generalizability of these findings may be limited to persons who are uninsured or underinsured. Finally, selection and treatment bias are inherent limitations of retrospective investigations, and this analysis is not exempt from that.
Conclusion In summary, this study offers a real-world perspective on the use of fertilityconserving treatment in patients diagnosed with endometrial cancer and atypical hyperplasia. We observed more widespread use of this treatment strategy across the study period. The live birth rate in these women was lower than some estimates currently available in the literature, and most pregnancies in this cohort occurred in the context of assisted fertility services. This observation underscores the need to evaluate each patient’s reproductive potential when
Original Research
TABLE 5
Factors associated with receiving progestin therapy (sensitivity analysis reassigning patients who underwent hysterectomy after £2 months of progestin treatment) (N [ 4007) Univariate OR
Multivariable
P value
95% CI
OR
P value
95% CI
<.0001
Age at diagnosis, y
<.0001
40e45 <25 25e29
9.0 4.7 17.2
11.9
12.4 8.7 17.7
30e34
5.6 4.5
7.1
35e39
2.8 2.3
3.5
4.4 32.5
14.7 10.1 21.3 6.0
4.7
7.7
2.9
2.3
3.5
<.0001
Diagnosis group
<.0001
Endometrial cancer Atypical hyperplasia
3.3 2.8
4.0
3.5
2.9
4.2
<.0001
Year of diagnosis
.0046
1999e2004 2005e2008
1.8 1.2
2.5
1.1
0.8
1.7
2009e2014
2.6 1.8
3.6
1.5
1.0
2.2
Region
.0131
.0029
South Northeast
1.5 1.2
1.8
1.6
1.3
2.1
North Central
1.1 0.9
1.3
1.2
0.9
1.5
West
1.2 1.0
1.6
1.3
1.0
1.7
Unknown
1.4 0.8
2.3
1.6
0.9
2.9
Insurance
.435
.7102
HMO Other
0.9 0.7
1.1
0.9
0.7
1.2
PPO
1.0 0.8
1.2
1.0
0.8
1.3
Charlson Comorbidity Index
.272
.4253
0 1
1.0 0.8
1.4
1.1
0.8
1.5
2
0.5 0.2
1.2
0.6
0.3
1.4
Relationship to primary beneficiary
.0006
.0508
Employee Spouse
0.8 0.7
1.0
0.8
0.6
1.0
Child/Other
2.6 1.3
5.0
0.8
0.3
2.5
CI, confidence interval; HMO, health maintenance organization; OR, odds ratio; PPO, preferred provider organization. a P values are based on Wald test. Harrison et al. Fertility conservation and pregnancy outcomes in young women with endometrial cancer or hyperplasia. Am J Obstet Gynecol 2019.
exploring fertility conservation, as uterine-sparing treatment may be associated with greater cancer-specific
mortality. An individualized assessment of a patient’s chance to achieve pregnancy should facilitate shared decision making
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and ensure that the choice to pursue fertility-preserving treatment is well informed. n References 1. Noone AM, Howlader N, Krapcho M, et al. SEER Cancer Statistics Review, 1975-2015. Bethesda, MD: National Cancer Institute; 2018. 2. Group SGOCPECW, Burke WM, Orr J, et al. Endometrial cancer: a review and current management strategies: part II. Gynecol Oncol 2014;134:393–402. 3. Group SGOCPECW, Burke WM, Orr J, et al. Endometrial cancer: a review and current management strategies: part I. Gynecol Oncol 2014;134:385–92. 4. Trimble CL, Method M, Leitao M, et al. Management of endometrial precancers. Obstet Gynecol 2012;120:1160–75. 5. Rodolakis A, Biliatis I, Morice P, et al. European Society of Gynecological Oncology Task Force for Fertility Preservation: Clinical recommendations for fertility-sparing management in young endometrial cancer patients. Int J Gynecol Cancer 2015;25:1258–65. 6. Gallos ID, Yap J, Rajkhowa M, Luesley DM, Coomarasamy A, Gupta JK. Regression, relapse, and live birth rates with fertility-sparing therapy for endometrial cancer and atypical complex endometrial hyperplasia: a systematic review and metaanalysis. Am J Obstet Gynecol 2012;207:266. 7. Gallos ID, Shehmar M, Thangaratinam S, Papapostolou TK, Coomarasamy A, Gupta JK. Oral progestogens vs levonorgestrel-releasing intrauterine system for endometrial hyperplasia: a systematic review and metaanalysis. Am J Obstet Gynecol 2010;203:547. 8. Pal N, Broaddus RR, Urbauer DL, et al. Treatment of low-risk endometrial cancer and complex atypical hyperplasia with the levonorgestrel-releasing intrauterine device. Obstet Gynecol 2018;131:109–16. 9. Greenwald ZR, Huang LN, Wissing MD, Franco EL, Gotlieb WH. Does hormonal therapy for fertility preservation affect the survival of young women with early-stage endometrial cancer? Cancer 2017;123:1545–54. 10. Ruiz MP, Huang Y, Hou JY, et al. All-cause mortality in young women with endometrial cancer receiving progesterone therapy. Am J Obstet Gynecol 2017;217:669.
11. Gunderson CC, Fader AN, Carson KA, Bristow RE. Oncologic and reproductive outcomes with progestin therapy in women with endometrial hyperplasia and grade 1 adenocarcinoma: a systematic review. Gynecol Oncol 2012;125:477482. 12. Wei J, Zhang W, Feng L, Gao W. Comparison of fertility-sparing treatments in patients with early endometrial cancer and atypical complex hyperplasia: a meta-analysis and systematic review. Medicine (Baltimore) 2017;96:e8034. 13. Chae SH, Shim SH, Lee SJ, Lee JY, Kim SN, Kang SB. Pregnancy and oncologic outcomes after fertility-sparing management for early stage endometrioid endometrial cancer. Int J Gynecol Cancer 2019;29:77–85. 14. IBM Corporation. IBM MarketScan Research Databases for Health Services Researchers. Available at: https://www.ibm.com/ downloads/cas/6KNYVVQ2. 2018. Accessed May 7, 2019. 15. Klabunde CN, Harlan LC, Warren JL. Data sources for measuring comorbidity: a comparison of hospital records and Medicare claims for cancer patients. Med Care 2006;44: 921–8. 16. Klabunde CN, Potosky AL, Legler JM, Warren JL. Development of a comorbidity index using physician claims data. J Clin Epidemiol 2000;53:1258–67. 17. Gambadauro P. The reproductive prognosis of women considering fertility preservation for early stage endometrial cancer. Arch Gynecol Obstet 2019 [Epub ahead of print]. 18. Practice Committee of the American Society for Reproductive Medicine. Obesity and reproduction: a committee opinion. Fertil Steril 2015;104:1116–26. 19. American College of O, Gynecologists Committee on Gynecologic P, Practice C. Female age-related fertility decline. Committee Opinion No. 589. Fertil Steril 2014;101:633–4. 20. Oktay K, Harvey BE, Partridge AH, et al. Fertility preservation in patients with cancer: ASCO clinical practice guideline update. J Clin Oncol 2018;36:1994–2001. 21. Gynaecologists RCoOa. Green-top Guideline No. 67: management of endometrial Hyperplasia. 2016:1-30. 22. La Russa M, Zapardiel I, Halaska MJ, et al. Conservative management of endometrial cancer: a survey amongst European
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clinicians. Arch Gynecol Obstet 2018;298: 1064 373–80. 1065 23. Koskas M, Uzan J, Luton D, Rouzier R, Darai E. Prognostic factors of oncologic and 1066 reproductive outcomes in fertility-sparing 1067 management of endometrial atypical hyper1068 plasia and adenocarcinoma: systematic re1069 view and meta-analysis. Fertil Steril 2014;101: 1070 Q4 Q5 785–94.
Author and article information From the Department of Gynecologic Oncology and Reproductive Medicine (Drs Harrison, Sun, Suidan, Woodard, Rauh-Hain, Westin, and Meyer), Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX; Department of Health Services Research (Drs He, Fu, Zhao, and Giordano), Division of Cancer Prevention and Population Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX. Received March 31, 2019; revised May 15, 2019; accepted May 17, 2019. Outside the scope of the current work, C.C.S. reports research support from AstraZeneca. Outside the scope of the current work, S.N.W. reports research support from ArQule, AstraZeneca, Bayer, Clovis Oncology, Cotinga Pharmaceuticals, Novartis, Roche/Genentech, and Q9 Tesaro. Outside of the scope of the current work, S.N.W. reports consulting fees from AstraZeneca, Clovis Oncology, MediVation, Merck, Ovation, Pfizer, Roche/ Genentech, Takeda, and Tesaro. Outside the scope of the current work, L.A.M. reports research support from AstraZeneca. The other authors report no conflict of interest. Financial support for this research investigation was provided in part by grant funding to the following individuals or organizations: R.H., National Institutes of Health T32 grant (#5T32 CA101642); L.M., National Cancer Institute K award (#K07 CA201013); S.W., National Cancer Institute SPORE for Uterine Cancer (2P50 CA098258-13) and Andrew Sabin Family Fellowship; S.G., CPRIT RP160674; Susan Komen SAC150061; MD Anderson Cancer Center: National Cancer Institute Cancer Center Support Grant (P30 CA016672). The investigation described in this manuscript was presented in part by during the International Gynecologic Cancer Society Global Meeting in Lisbon, Portugal, Oct. 2931, 2016, and the 50th Society of Gynecologic Oncology Annual Meeting in Honolulu, HI, March 1519, 2019. Corresponding author: Larissa A. Meyer, MD, MPH. [email protected]
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Original Research
SUPPLEMENTARY TABLE 1
Medical classification codes used for identification of outcomes of interest Endometrial cancer ICD-9-CM 182.0; ICD-10-CM C54.x Atypical hyperplasia ICD-9-CM 621.33; ICD-10-CM N85.02 Miscarriage CPT 59812-59866; ICD-9-CM 634.xx; ICD-10-CM O03.xx; ICD-10-PCS 10A00ZZ, 10A03ZZ, 10A04ZZ Ectopic pregnancy ICD-9-CM 633.xx; ICD-10-CM O00.xx Pregnancy CPT 7680176817; ICD-9-CM V22.x, V23.x, 650, 651xx; ICD-10-CM Z33.x, Z34.x, Z36.2, O09.x, O30.x, O31.x, O35.x, O36.x Delivery CPT 5940059410, 5951059525, 5961059614; ICD-9-CM 74.x, 72.x, ICD-10-PCS 10D00Z1, 10D00Z0, 10D00Z2, 0W8NXZZ, 10D07Z5, 10D07Z4, 10D07Z3 Assisted fertility services and in vitro fertilization CPT 58322, 5897058976, 8925089291, 8933589356; ICD-9-CM 65.91, 256.1, 628.0, V26.81; ICD-10-CM N97.x, Z31.83; ICD-10-PCS 0U90xx, 0U91xx, 0UDNxxx; HCPCS S4011S4042, S4989, J0725, J1620, J1675, S0132, S0122, S0126, S0128, J3355, J9202, J9217, J9218, J9219, J1950 Hysterectomy CPT 58150, 58180, 58200, 58210, 5854158548, 5855058554, 5857058573, 5895358956, 59100; ICD-9-CM 68.x; ICD-10-PCS 0UT9xxx, 0UTC0ZZ, 0UTC4ZZ, 0UTC7ZZ, 0UTC8ZZ, 0UT40ZZ, 0UT44ZZ, 0UT47ZZ, 0UT48ZZ; HCPCS S2900 Use of ovulation induction agents Letrozole, clomiphene citrate, tamoxifen citrate, follitropin, menotropin, urofollitropin, chorionic gonadotropin, choriogonadotropin alfa, cetrorelix acetate, triptorelin, ganirelix acetate Use of progestin therapy Megestrol acetate, medroxyprogesterone acetate, levonorgestrel intrauterine device CPT, Current Procedural Terminology; HCPCS, Healthcare Common Procedure Coding System; ICD, International Classification of Diseases. Harrison et al. Fertility conservation and pregnancy outcomes in young women with endometrial cancer or hyperplasia. Am J Obstet Gynecol 2019.
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National patterns of care and fertility outcomes for reproductive-aged women with endometrial cancer or atypical hyperplasia Q10
Ross F. Harrison, MD; Weiguo He, PhD; Shuangshuang Fu, PhD; Hui Zhao, PhD; Charlotte C. Sun, DrPH, MPH; Rudy S. Suidan, MD, MS; Terri L. Woodard, MD; J. Alejandro Rauh-Hain, MD, MPH; Shannon N. Westin, MD, MPH; Sharon H. Giordano, MD, MPH; Larissa A. Meyer, MD, MPH
BACKGROUND: Although it is uncommon, the incidence of endometrial
cancer and atypical hyperplasia among reproductive-aged women is increasing. The fertility outcomes in this population are not well described. OBJECTIVE: We aim to describe the patterns of care and fertility outcomes of reproductive-aged women with endometrial cancer or atypical hyperplasia. MATERIALS AND METHODS: A cohort of women aged 45 years with endometrial cancer or atypical hyperplasia diagnosed in 2000 to 2014 were identified in Truven Marketscan, an insurance claims database of commercially insured patients in the United States. Treatment information, including use of progestin therapy, hysterectomy, and assisted fertility services, was identified and collected using a combination of Common Procedural Terminology codes, International Classification of Diseases codes, and National Drug Codes. Pregnancy events were identified from claims data using a similar technique. Patients were categorized as receiving progestin therapy alone, progestin therapy followed by hysterectomy, or standard surgical management with hysterectomy alone. Multivariable logistic regression was performed to assess factors associated with receiving fertility-sparing treatment. RESULTS: A total of 4007 reproductive-aged patients diagnosed with endometrial cancer or atypical hyperplasia were identified. The majority of these patients (n ¼ 3189; 79.6%) received standard surgical management. Of the 818 patients treated initially with progestins, 397 (48.5%) subsequently underwent hysterectomy, whereas 421 (51.5%) did not. Patients treated with progestin therapy had a lower median age than those who received standard surgical management (median age, 36 vs 41 years; P < .001). The proportion of patients receiving progestin therapy increased significantly over the observation period, with 24.9% treated at
E
ndometrial carcinoma is uncommon in reproductive-aged women, with only about 7% of new diagnoses occurring in women under the age of 44 years.1 For both endometrial cancer and
Cite this article as: Harrison RF, He W, Fu S, et al. National patterns of care and fertility outcomes for reproductive-aged women with endometrial cancer or atypical hyperplasia. Am J Obstet Gynecol 2019;XX:x.exx.ex. 0002-9378/$36.00 ª 2019 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.ajog.2019.05.029
least initially with progestin therapy in 2014 (P < .001). Multivariable analysis shows that younger age, a diagnosis of atypical hyperplasia diagnosis rather than endometrial cancer, and diagnosis later in the study period were all associated with a greater likelihood of receiving progestin therapy (P < .0001). Among the 421 patients who received progestin therapy alone, 92 patients (21.8%; 92/421) had 131 pregnancies, including 49 live births for a live birth rate of 11.6%. Among the 397 patients treated with progestin therapy followed by hysterectomy, 25 patients (6.3%; 25/397) had 34 pregnancies with 13 live births. The median age of patients who experienced a live birth following diagnosis during the study period was 36 years (interquartile range, 3338). The use of some form of assisted fertility services was observed in 15.5% patients who were treated with progestin therapy. Among patients who experienced any pregnancy event following diagnosis, 54% of patients used some form of fertility treatment. For patients who experienced a live birth following diagnosis, 50% of patients received fertility treatment. Median time to live birth following diagnosis was 756 days (interquartile range, 5251077). Patients treated with progestin therapy were more likely to experience a live birth if they had used assisted fertility services (odds ratio, 5.9; 95% confidence interval, 3.410.1; P < .0001). CONCLUSION: The number of patients who received fertility-sparing treatment for endometrial cancer or atypical hyperplasia increased over time. However, the proportion of women who experience a live birth following these diagnoses is relatively small. Key words: endometrial cancer, endometrial hyperplasia, fertility,
fertility conservation, fertility-sparing treatment, oncofertility, health services research
atypical hyperplasia, hysterectomy is part of standard surgical management.24 However, uterine-sparing treatment is an option for women diagnosed at a young age who desire fertility preservation. The Society of Gynecologic Oncology describes an ideal candidate for conservative treatment as a woman who strongly desires fertility-sparing management with a well-differentiated (grade 1) tumor, no evidence of myometrial invasion (stage 1A), no contraindications for medical management, and acceptance of nonstandard cancer treatment.2,5
Historically, oral progestin therapy has been the primary management strategy for women with endometrial cancer who desire fertility preservation.2 Reported initial response rates to progestins are estimated to be 7090%, although the optimal dose and progestin formulation is uncertain.6 The use of the levonorgestrel-releasing intrauterine device (LNG-IUD) has been associated with regression rates in women with atypical hyperplasia as high as 90%.7 In a recent case series from the University of Texas MD Anderson Cancer Center, responses to
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GYNECOLOGY
AJOG at a Glance Why was this study conducted? This study was performed to examine national patterns of care for reproductiveaged women with endometrial cancer or atypical hyperplasia. Desire for fertility is an important clinical indication for pursuing nonsurgical management. However, the fertility outcomes in this group of patients is not well described, apart from retrospective single-institution reviews. Key findings From 1999 to 2014, the proportion of reproductive-aged women with endometrial cancer or atypical hyperplasia who received fertility-conserving treatment increased significantly. Younger age, diagnosis later in the study period, and a diagnosis of atypical hyperplasia as opposed to cancer were all associated with an increased likelihood of receiving fertility-sparing treatment, at least initially. However, less than 12% of patients experienced a live birth following fertilitysparing treatment. What does this add to what is known? This analysis provides a broader perspective on the use over time of fertilitysparing treatment for reproductive-aged women with endometrial cancer or atypical hyperplasia. With certain limitations considered, it offers a populationbased estimate of the proportion of women who may experience a live birth following fertility-conserving treatment.
treatment with an LNG-IUD were seen in 67% of patients with grade 1 and 75% of patients with grade 2 endometrial cancer of endometrioid histology.8 Although these findings may suggest that progestin therapy is a reasonable alternative treatment strategy in patients who desire fertility preservation, increased disease-specific mortality is seen in young women with endometrial cancer treated with progestin therapy compared with hysterectomy.9,10 Furthermore, approximately 2040% of patients experience recurrent disease after an initial response.6,11,12 Much of the literature published regarding the fertility outcomes of young women with endometrial cancer or atypical hyperplasia who received fertility-sparing management has been limited to single-institution retrospective reviews at academic institutions or meta-analyses of these reports.6,1113 Our objective was to describe patterns of care in the treatment of young women diagnosed with endometrial cancer or atypical hyperplasia, and to estimate their fertility outcomes from a population-level perspective using a national insurance claims database.
Materials and Methods We performed a retrospective cohort study by analyzing data from the Truven Health MarketScan Research Database (IBM Watson Health, Cambridge, MA), a commercial database of patient-level information derived from health insurance claims. Since 1995, this database has collected enrollment data, hospital admission records, outpatient services, and outpatient prescription drug claims for 250 million health insurance beneficiaries from more than 300 employersponsored health plans, including feefor-service coverage, fully capitated and partially capitated health plans, preferred provider organizations, indemnity plans, health maintenance organizations, and other managed caretype insurance. In the most recent data year, the MarketScan databases contained information on 43.6 million covered individuals.14 Insurance claims from 1998 to 2016 were analyzed for this study. Eligibility for inclusion into our study cohort was all women aged 45 years diagnosed with endometrial cancer (International Classification of Diseases [ICD]9-CM 182.0; ICD-10-CM
C54.x) or atypical hyperplasia (ICD-9CM 621.33; ICD-10-CM N85.02) between 1999 and 2014 (Figure 1). ½F1 Outpatient diagnoses were included only if the codes appeared 2 or more times with at least 30 days between claims. Inpatient diagnoses were included if a single claim was observed. Patients were restricted to those who had continuous coverage for at least 12 months before and 24 months after diagnosis (n ¼ 6941 excluded). An algorithm was applied to remove prevalent cases from the analysis (n ¼ 724 excluded). Patients identified with endometrial cancer or atypical hyperplasia without any corresponding treatment information (eg, no claims for either hysterectomy or progestin therapy) were also removed (n ¼ 1116 excluded). Our primary objective was to estimate the proportion of reproductive-aged patients with endometrial carcinoma or atypical hyperplasia receiving progestin therapy alone, progestin therapy followed by hysterectomy, or definitive surgical management with hysterectomy alone. Secondary objectives included the following: determination of factors associated with progestin therapy; estimation of pregnancy events that occurred after a diagnosis of endometrial carcinoma or atypical hyperplasia; and the use of assisted fertility services, including use of ovulation induction and in vitro fertilization, after diagnosis of endometrial cancer or atypical hyperplasia. Variables for patient characteristics were collected for analysis, including age at diagnosis, year of diagnosis, geographic location, and insurance plan type. Comorbidity was estimated using the Klabunde-modified Charlson Comorbidity Index score using claims in the 12 months before the diagnosis of endometrial cancer/hyperplasia.15,16 Treatment information, including receipt of progestin therapy, hysterectomy, and assisted fertility services, was identified in claims data by using a combination of International Statistical Classification of Diseases and Related Health Problems (ICD), revision 9 and 10 diagnosis codes; Common Procedural Q1 Terminology (CPT) codes; ICD-9/10
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FIGURE 1
Cohort identification for reproductive-aged patients with endometrial cancer or atypical hyperplasia
At least 2 outpatient claims or at least 1 inpatient for endometrial cancer (ICD-9-CM 182.0; ICD-10CM C54.x) or atypical hyperplasia (ICD-9-CM 621.33; ICD-10-CM N85.02) was required for initial study inclusion. This figure depicts the process by which the final analyzed sample was selected from the MarketScan Commercial Database, as well as the rationale and number of patients excluded at different points in the cohort selection. Harrison et al. Fertility conservation and pregnancy outcomes in young women with endometrial cancer or hyperplasia. Am J Obstet Gynecol 2019.
Original Research
subdivided into the following 3 treatment categories: patients receiving progestin therapy alone (eg, fertility-sparing treatment); progestin therapy followed by hysterectomy; or hysterectomy alone. Fertility outcomes were categorized as any pregnancy event and live births. For consistency with other investigations regarding this patient population, live birth rate was defined as number of live births observed divided by the number of patients receiving fertility-sparing treatment or progestin therapy followed by hysterectomy.6,12 Descriptive statistics (means, medians, and standard deviations of continuous variables and frequencies of discrete variables) of patients’ sociodemographic and clinical characteristics were calculated. The c2 test (for discrete variables) or F test (for group means) or KruskalWallis test (for medians) was used to assess differences between patients’ characteristics and therapies. Multivariable logistic regression was performed to assess factors associated with receipt of progestin therapy. A subset of patients was treated with progestin therapy initially but subsequently underwent hysterectomy. As a sensitivity analysis, we repeated multivariate logistic regression after reassigning patients away from the fertility-sparing treatment group if they underwent hysterectomy after <2 months (60 days) of progestin therapy. Our rationale was that determining the intent of a given treatment is difficult with insurance claims data, and that patients who would be excluded by this criterion would more likely represent patients who received progestins for indications other than fertility conservation (eg, amelioration of bleeding symptoms). All analyses were conducted with SAS statistical software (version 9.3; SAS Institute, Cary, NC). This project was approved by our Institutional Review Board (PA 14-0796).
Results procedure codes; and National Drug Codes (NDC) (Supplementary Table 1). Similarly, pregnancy events, including live birth, spontaneous abortion, and ectopic pregnancy were identified using
a combination of ICD-9/10 diagnosis codes, Common Procedural Terminology (CPT) codes, and ICD-9/10 procedure codes (Supplementary Table 1). The cohort of identified patients was
With the Marketscan database, we identified 4007 women 45 years old who were diagnosed with endometrial cancer (3137; 78.3%) or atypical hyperplasia (870; 21.7%) between 2000
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TABLE 1
Patient characteristics (N [ 4007) Treatment category Progestin therapy only (421/4007; 10.5%)
Characteristics
Progestin therapy followed by hysterectomy (397/4007; 9.9%)
Hysterectomy only (3189/4007; 79.6%)
Total ¼ 4007, P valuec n (%) <.001
Age at diagnosis, y 18e29
72 (17.1)
29 (7.3)
83 (2.6)
184 (4.5)
30e34
107 (25.4)
82 (20.7)
287 (9.0)
476 (11.9)
35e39
122 (29.0)
122 (30.7)
764 (24.0)
1008 (25.2)
40e45
120 (28.5)
164 (41.3)
2055 (64.4)
37.7 (5.2)
40.1 (4.5)
<.0001d
39.4 (5)
41 (38e44)
<.0001
41 (37e43)
Mean age, y (SD)
35.4 (6)
Median age, y (IQR)
36 (31e40)
Median duration of follow-up, y (IQR)
4.1 (3.1e5.9)
38 (34e42) 4.7 (3.4e6.6)
4.5 (3.2e6.6)
2339 (58.4)
<.001
e
4.5 (3.2e6.5)
<.001
Diagnosis group Endometrial cancer
216 (51.3)
302 (76.1)
2619 (82.1)
3137 (78.3)
Atypical hyperplasia
205 (48.7)
95 (23.9)
570 (17.9)
870 (21.7) <.001
Year of diagnosis 2000e2004
a
25 (5.9)
26 (6.5)
365 (11.4)
416 (10.4)
2005
16 (3.8)
19 (4.8)
163 (5.1)
198 (4.9)
2006
17 (4.0)
21 (5.3)
257 (8.1)
295 (7.4)
2007
21 (5.0)
19 (4.8)
250 (7.8)
290 (7.2)
2008
49 (11.6)
50 (12.6)
373 (11.7)
472 (11.8)
2009
57 (13.5)
67 (16.9)
415 (13.0)
539 (13.5)
2010
51 (12.1)
51 (12.8)
402 (12.6)
504 (12.6)
2011
49 (11.6)
42 (10.6)
336 (10.5)
427 (10.7)
2012
51 (12.1)
45 (11.3)
241 (7.6)
337 (8.4)
2013
49 (11.6)
42 (10.6)
233 (7.3)
324 (8.1)
2014
36 (8.6)
15 (3.8)
154 (4.8)
205 (5.1)
Region
b
.029
Northeast
92 (22.5)
77 (19.8)
542 (17.4)
711 (18.2)
North Central
94 (23.0)
92 (23.7)
776 (24.9)
962 (24.6)
150 (36.8)
138 (35.5)
1273 (40.9)
1561 (39.9)
72 (17.6)
82 (21.1)
521 (16.7)
675 (17.3)
259 (85.8)
276 (84.1)
2372 (86.6)
2907 (86.3)
43 (14.2)
52 (15.8)
368 (13.4)
463 (13.7)
South West Charlson Comorbidity Index
f
.045
0 1 Patient’s relationship to primary beneficiary
<.001
g
Employee
280 (66.5)
286 (72.0)
2052 (64.3)
2618 (65.3)
Spouse
127 (30.2)
109 (27.5)
1115 (35.0)
1351 (33.7)
Harrison et al. Fertility conservation and pregnancy outcomes in young women with endometrial cancer or hyperplasia. Am J Obstet Gynecol 2019.
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Original Research
503 504 TABLE 1 505 Patient characteristics (N [ 4007) (continued) 506 Treatment category 507 508 Progestin therapy Hysterectomy followed by Progestin therapy 509 Total ¼ 4007, only (3189/4007; hysterectomy only (421/4007; 510 P valuec n (%) 79.6%) (397/4007; 9.9%) 10.5%) Characteristics 511 Insurance 0.116 512 513 HMO 62 (14.7) 80 (20.2) 498 (15.6) 640 (16.0) 514 PPO 261 (62.0) 217 (54.7) 1909 (59.9) 2387 (59.6) 515 Other 98 (23.3) 100 (25.2) 782 (24.5) 980 (24.5) 516 HMO, health maintenance organization; IQR, interquartile range; PPO, preferred provider organization; SD, standard deviation. 517 a For the years 2000e2004, <11 patients were identified in certain treatment groups per year. These years were grouped together to protect patient privacy; b A total of 98 patients were excluded 518 because of unknown region; c P values were derived using the c2 test for comparing differences among the 3 treatment groups; d P values were derived using the F test for comparing means among 519 the 3 treatment groups; e P values were derived using the KruskalWallis test for comparing medians among the 3 treatment groups; f A total of 637 patients were excluded because of missing comorbidity scores. For patients in the progestin therapy only and the progestin therapy followed by hysterectomy treatment categories, <11 patients were identified with a Charlson Comorbidity 520 Index score of 2. These patients were grouped with patients with a score of 1 to protect patient privacy; g To protect patient privacy, the frequency of patients who were the child of or had other 521 relationship to the primary beneficiary (total n ¼ 38) is not shown, as <11 patients identified in certain treatment groups. Harrison et al. Fertility conservation and pregnancy outcomes in young women with endometrial cancer or hyperplasia. Am J Obstet Gynecol 2019. 522 523 524 and 2014 (Table 1, Figure 1). Median treated with an LNG-IUD (175/818), Of patients who received progestin ther525 follow-up for patients identified was 4.5 alone or in combination with other apy alone, 20.9% of patients (88/421) 526 years (interquartile range [IQR], progestins. received fertility treatments. Of patients 527 3.26.5). From this cohort, 3189 Of the cohort treated with progestin who had any pregnancy or specifically a 528 (79.6%) received definitive surgical therapy with or without hysterectomy, live birth during the study period, 54% 529 management and 818 (20.4%) received 117 patients experienced 165 pregnan- (63/117) and 50% (31/62) of patients 530 progestin therapy either alone or fol- cies during the observation period received fertility treatments, respectively. 531 lowed by hysterectomy. Of the patients (Table 2). Among the 421 patients Of the patients who received fertility ½T2 532 in the subcohort initially treated with receiving fertility-sparing treatment, 92 treatment and experienced any preg533 progestin therapy, 48.5% (397/818) patients (21.8%; 92/421) had 131 preg- nancy event, 79% (50/63) used in vitro 534 subsequently underwent hysterectomy, nancies. Of these patients who were fertilization. Patients treated with pro535 whereas 51.5% (421/818) did not. The treated exclusively with progestins, 49 gestin therapy were 5.9 times more likely 536 median time from diagnosis to hyster- patients had live births for a live birth to experience a live birth if they also had 537 ectomy in the patients initially treated rate of 11.6% (49/421). Among the 397 received some form of fertility treatment 538 with progestins but who subsequently patients treated with progestin therapy (95% confidence interval [CI], 3.410.1; 539 underwent hysterectomy was 168 days followed by hysterectomy, 25 patients P < .0001). 540 (IQR, 55727). After excluding pa- (6.3%; 25/397) had 34 pregnancies. Of Both univariate and multivariable 541 tients who underwent hysterectomy those, 13 patients had live births for a live analysis revealed that younger age, 542 after <2 months of progestin therapy, birth rate of 3.3% (13/397). The live diagnosis of atypical hyperplasia, and 543 the median time from diagnosis to birth rate for the entire cohort of patients diagnosis later in the observation 544 hysterectomy in this group was 380 who received progestin treatment with period were associated with a greater 545 days (IQR, 142959). Patients who or without hysterectomy was 7.6% (62/ likelihood of receiving progestin ther546 underwent definitive surgical manage- 818). The median age of patients who apy at least initially (Table 4). Patients ½T4 547 ment were older and more likely to experienced a live birth during the study aged <25 years were 9.5 times more 548 have endometrial cancer than atypical period was 36 years (IQR, 3338). The likely to receive progestin therapy 549 hyperplasia (P < .001) (Table 1). A median time from diagnosis to first compared to those aged 4045 years 550 greater proportion of patients diag- pregnancy event was 413 days (IQR, (odds ratio [OR], 9.5; 95% CI, 551 nosed later in the study period received 262758). The median time from diag- 3.625.1; P < .0001). Women with 552 fertility-sparing treatment (P <.001) nosis to live birth was 756 days (IQR, atypical hyperplasia were 2.6 times 553 (Figure 2). In the final year of the study 5251077). more likely to initially receive progestin 554 In the group of patients treated with therapy compared with those diagnosed period, 24.9% of patients were treated 555 with progestin therapy, at least initially. progestin therapy with or without hys- with endometrial cancer (OR, 2.7; CI, 556 Of the patients treated with progestin terectomy, 15.5% of patients (127/818) 2.23.2; P < .0001). Analyzing the 557 period into 5-year ½T3 therapy at least initially, 21.4% were utilized assisted fertility services (Table 3). observation 558 MONTH 2019 American Journal of Obstetrics & Gynecology FLA 5.6.0 DTD YMOB12697_proof 10 June 2019 7:46 pm ce
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Original Research
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615 616 617 Reproductive-aged patients with endometrial cancer or atypical hyperplasia receiving progestin therapy 618 619 620 621 622 623 624 625 626 627 628 629 630 631 632 633 634 635 636 The y-axis indicates percentage of patients diagnosed with endometrial cancer or atypical hyperplasia in a given year in each treatment group. Patients 637 treated with only hysterectomy are not shown. Fertility-sparing treatment is defined as treatment with progestin therapy alone. Patients diagnosed in 638 1999 are not shown because of washout algorithm to exclude prevalent cases. Cases from 2000 are not shown, as only 22 patients were identified as 639 meeting inclusion criteria for analysis; 18% (4/22) received fertility-sparing treatment. This figure depicts a statistically significant increasing trend in the 640 proportion of patients who were treated with progestin therapy in each subsequent year of the observation period. The total group of patients treated with 641 progestins is divided into those treated with progestin therapy alone (blue) and progestin therapy followed by hysterectomy (orange). 642 Harrison et al. Fertility conservation and pregnancy outcomes in young women with endometrial cancer or hyperplasia. Am J Obstet Gynecol 2019. 643 644 intervals, a diagnosis of endometrial CI, 1.12.1; P ¼ .0002). These factors Comment 645 cancer or atypical hyperplasia between remained significant predictors of Principal findings 646 2009 and 2014 was associated with an receiving fertility-sparing treatment af- In our study, the use of progestin therapy 647 approximately 47% increased likelihood ter the sensitivity analysis of reassigning for reproductive-aged women diagnosed 648 of receiving progestin therapy, at least patients who underwent hysterectomy with endometrial cancer or atypical hy649 initially, compared to those diagnosed after <2 months of progestin therapy perplasia became more common over 650 between 1999 and 2004 (OR, 1.5; 95% was performed (Table 5). the study period. Patients diagnosed ½T5 651 near the end of the study period were 652 nearly 75% more likely to receive pro653 TABLE 2 gestin therapy. As would be expected, the 654 Fertility events among patients receiving progestin therapy youngest patients in our study cohort 655 and those with atypical hyperplasia were 656 Total cohort much more likely to receive progestin initially managed Progestin 657 therapy than the oldest patients. Among with fertility therapy followed Progestin 658 patients who received fertility conservaconservation by hysterectomy therapy alone 659 n ¼ 818 n ¼ 397 n ¼ 421 tion, we observed a live birth rate of 660 <12%. Most of the pregnancy events Patients 92 25 117 661 experiencing any that occurred following a diagnosis of 662 pregnancy, n endometrial cancer or atypical hyper663 49 13 62 plasia occurred in the context of assisted Patients 664 experiencing live fertility services. 665 birth, n 666 Q3 Live birth rate, % 11.6% 3.3% 7.6% Meaning 667 Our findings are consistent with prior Live birth rate defined as proportion of patients experiencing a live birth (numerator) divided by patients in treatment category 668 (denominator). population-based analyses of the treat669 Harrison et al. Fertility conservation and pregnancy outcomes in young women with endometrial cancer or hyperplasia. ment of young women with endometrial Am J Obstet Gynecol 2019. 670 cancer that have shown an increase in the FIGURE 2
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Original Research
GYNECOLOGY
TABLE 3
Use of assisted fertility services Patients using assisted fertility services
Patients not using assisted fertility services
Endometrial cancer
Hyperplasia with atypia
Endometrial cancer
Hyperplasia with atypia
Total, n
151 (3.8)
69 (1.7)
2986 (74.5)
801 (20)
4007
Patients who received progestin therapya, n (%)
79 (9.7)
48 (5.9)
439 (53.7)
252 (30.8)
818
Patients who received fertility-sparing treatmentb, n (%)
47 (11.2)
41 (9.7)
169 (40.1)
164 (39)
421
Patients who experienced any pregnancy, n (%)
35 (29.9)
28 (23.9)
27 (23.1)
27 (23.1)
117
Patients who experienced a live birth, n (%)
18 (29)
13 (21)
15 (24.2)
16 (25.8)
62
Entire cohort, n (%)
All values represent frequencies followed by row percentages in parentheses, unless otherwise indicated. a Includes patients who received progestin therapy exclusively and those who also subsequently underwent hysterectomy; b Includes patients who were treated with progestin therapy only. Harrison et al. Fertility conservation and pregnancy outcomes in young women with endometrial cancer or hyperplasia. Am J Obstet Gynecol 2019.
use of progestin therapy over time.9,10 This trend may relate to increased awareness and interest in this treatment strategy by clinicians for women in this age group. Using the National Cancer Database, Ruiz et al found that the proportion of endometrial cancer patients who were treated with progestin therapy increased from 2.4% in 2004 to 5.9% in 2014.10 We observed that nearly 25% of our cohort received progestin therapy, with or without subsequent hysterectomy, during the final year of our study period. This difference in estimates may be accounted for at least partially by the inclusion of patients with atypical hyperplasia in our analysis, who we found were more likely to be treated with progestin therapy compared to those with endometrial cancer. In addition, Ruiz et al included patients aged 4549 years, an age group in which the incidence of endometrial cancer and atypical hyperplasia is relatively higher and patients are more likely to be treated surgically than medically.10 Greenwald et al reported similar findings from an analysis using the Surveillance, Epidemiology, and End Results (SEER) database.9 Both analyses found that women receiving nonsurgical treatment for endometrial cancer were at an increased risk for cancer-specific mortality.9,10 Both of these investigations identified a greater number of
reproductive-aged women with endometrial cancer than in this report. The discrepancy in the number of patients identified in our study vs these reports reflects differences in data sources, methodology, and inclusion criteria. As fertility preservation may be an important factor in pursuing uterinesparing treatment, the fertility-related outcomes reported here offer context for what may be seen as the benefit for avoiding or deferring hysterectomy. We found that a pregnancy or a live birth was an uncommon event in women following an endometrial cancer or atypical hyperplasia diagnosis. In our cohort, we observed a live birth rate of 11.6% among those women pursuing fertility-conserving therapy. In a systematic review by Gallos et al, the live birth rate in women receiving fertilitysparing treatment for endometrial cancer or atypical hyperplasia was 26% and 28%, respectively.6 In a more recent review, Wei et al reported a live birth rate of 1420%.12 Some of the difference in the live birth rate estimated by those reviews and this study may be due to patient population differences. Those reports include patients receiving uterinesparing treatment exclusively for the purpose of fertility preservation. Our methodology does not allow us to discriminate and to exclude patients who received uterine-sparing treatment for
reasons other than fertility preservation. Other common rationales for nonsurgical treatment include medical infirmity, advanced age, or patient preference to avoid surgery. However, as patients in our cohort were by definition young, and as few had significant medical comorbidities, the live birth rate that we report may better reflect the real-world likelihood of live birth for patients following a diagnosis of endometrial cancer or atypical hyperplasia. Although we are limited in our ability to definitively determine the proportion of patients in this study who sought pregnancy, these data may suggest a more limited reproductive potential for reproductive-aged patients with endometrial cancer or atypical hyperplasia. More than half of the pregnancies achieved in this study occurred in the context of fertility treatment. Given this, individualized assessment of each patient’s likelihood to achieve pregnancy should be carefully incorporated into shared decision making when fertility-sparing treatment is considered. Advancing age and obesity—well-established risks shared by endometrial cancer and impaired fertility—are clinical factors immediately available to a gynecologic oncologist counseling a patient regarding her reproductive potential and treatment that may affect it.1719 Collaboration with a fertility specialist may be a highly valuable
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GYNECOLOGY
TABLE 4
Factors associated with receiving progestin therapy (N [ 4,007) Multivariable
Univariate OR
P value
95% CI
OR
P value
95% CI
<.0001
Age at diagnosis, y
<.0001
40e45 <25
8.0
4.2
15.4
9.5
3.6
25.1
25e29
9.0
6.4
12.8
10.0
6.9
14.4
30e34
4.8
3.8
5.9
4.9
3.9
6.2
35e39
2.3
1.9
2.8
2.3
1.9
2.8
<.0001
Diagnosis group
<.0001
Endometrial cancer Atypical hyperplasia
2.7
2.2
3.2
2.7
2.2
3.2
<.0001
Year of diagnosis
.0002
1999e2004 2005e2008
1.5
1.0
2.0
1.0
0.7
1.4
2009e2014
2.2
1.6
3.0
1.5
1.1
2.0
Region
.0194
.0132
South Northeast
1.4
1.1
1.7
1.4
1.1
1.8
North Central
1.1
0.9
1.3
1.2
0.9
1.5
West
1.3
1.0
1.6
1.4
1.1
1.8
Unknown
1.2
0.7
2.0
1.4
0.8
2.4
Insurance
.4756
Study strengths and weaknesses .6431
HMO Other
0.9
0.7
1.1
0.9
0.7
1.2
PPO
0.9
0.7
1.1
0.9
0.7
1.1
Charlson Comorbidity Index
.2799
.4077
0 1
1.1
0.8
1.4
1.1
0.9
1.5
2
0.6
0.3
1.2
0.7
0.3
1.4
<.0001
Relationship to the Primary Beneficiary
.0112
Employee Spouse
0.8
0.6
0.9
0.8
0.6
0.9
Child/Other
2.6
1.4
5.1
0.9
0.3
2.5
CI, confidence interval; HMO, health maintenance organization; OR, odds ratio; PPO, preferred provider organization. a P values are based on Wald test. Harrison et al. Fertility conservation and pregnancy outcomes in young women with endometrial cancer or hyperplasia. Am J Obstet Gynecol 2019.
addition to the evaluation of an individual patient’s reproductive potential, as referral may offer clarity in terms of the potential for pregnancy with and without various forms of assisted reproductive
With increased use of uterine-sparing treatment, questions regarding longerterm management of these patients also arise. As stated above, 2 population-level analyses of young endometrial cancer patients found an increased risk of cancer-specific mortality among patients who received fertility-sparing treatment.9,10 Durable responses to progestin therapy are suboptimal, with up to 40% of patients experiencing disease recurrence.6,11 The true rate may be higher still, given that the proportion of patients who will experience a relapse increases with time as women remain at risk. For women with atypical hyperplasia, the Royal College of Obstetricians and Gynaecologists recommends hysterectomy after initial uterine-sparing treatment “once fertility is no longer required,” because of the high recurrence risk.21 Nearly 90% of gynecologic oncologists surveyed would recommend hysterectomy once childbearing was completed for women initially treated with uterinepreservation.22
technology. Notably, the American Society of Clinical Oncology recommends that physicians “should refer patients who express an interest in fertility preservation to reproductive specialists.”20
To our knowledge, this analysis is the first that examines the fertility outcomes of patients with endometrial cancer or atypical hyperplasia using a national-level sample. We identified a large number of reproductive-aged patients with these diagnoses with a median follow-up time of 4.5 years, likely a satisfactory observation period to examine these fertility endpoints. However, our study has several important limitations. First, our analysis does not capture oncologic outcomes or information regarding adjuvant treatment, both of which could affect fertility potential. We cannot estimate the effectiveness of progestin therapy compared with standard therapy. As stated previously, we cannot ascertain what proportion of patients received uterine-sparing treatment for the purpose of fertility conservation as opposed to other clinical indications. We cannot determine what proportion of patients who received fertility conservation subsequently tried to become pregnant. We cannot determine the reason why
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some patients who were initially managed with progestin therapy subsequently underwent hysterectomy. Koskas et al found that the number of patients who will respond to progestin therapy seems to plateau at approximately 80% at 12 months after the start of treatment.23 It is possible that some of the patients initially treated with progestins subsequently underwent hysterectomy for treatment failure, recurrence, or disease progression. Although our analysis did not limit the observation period, patients changing insurance providers may have been lost to follow-up if their new insurance carrier did not report into the MarketScan database. The 24-month requirement of continuous coverage after diagnosis was designed to mitigate this. We may have underestimated pregnancy events in our study population, especially for those diagnosed in the final years of the study who may have experienced pregnancy after the end of the observation period or for those who had miscarriages that did not require medical services. The use of assisted fertility services may also have been underestimated. In many parts of the United States, these services are not a standard health insurance benefit, and so a claim for these may have not been submitted for reimbursement. The generalizability of these findings may be limited to persons who are uninsured or underinsured. Finally, selection and treatment bias are inherent limitations of retrospective investigations, and this analysis is not exempt from that.
Conclusion In summary, this study offers a real-world perspective on the use of fertilityconserving treatment in patients diagnosed with endometrial cancer and atypical hyperplasia. We observed more widespread use of this treatment strategy across the study period. The live birth rate in these women was lower than some estimates currently available in the literature, and most pregnancies in this cohort occurred in the context of assisted fertility services. This observation underscores the need to evaluate each patient’s reproductive potential when
Original Research
TABLE 5
Factors associated with receiving progestin therapy (sensitivity analysis reassigning patients who underwent hysterectomy after £2 months of progestin treatment) (N [ 4007) Univariate OR
Multivariable
P value
95% CI
OR
P value
95% CI
<.0001
Age at diagnosis, y
<.0001
40e45 <25 25e29
9.0 4.7 17.2
11.9
12.4 8.7 17.7
30e34
5.6 4.5
7.1
35e39
2.8 2.3
3.5
4.4 32.5
14.7 10.1 21.3 6.0
4.7
7.7
2.9
2.3
3.5
<.0001
Diagnosis group
<.0001
Endometrial cancer Atypical hyperplasia
3.3 2.8
4.0
3.5
2.9
4.2
<.0001
Year of diagnosis
.0046
1999e2004 2005e2008
1.8 1.2
2.5
1.1
0.8
1.7
2009e2014
2.6 1.8
3.6
1.5
1.0
2.2
Region
.0131
.0029
South Northeast
1.5 1.2
1.8
1.6
1.3
2.1
North Central
1.1 0.9
1.3
1.2
0.9
1.5
West
1.2 1.0
1.6
1.3
1.0
1.7
Unknown
1.4 0.8
2.3
1.6
0.9
2.9
Insurance
.435
.7102
HMO Other
0.9 0.7
1.1
0.9
0.7
1.2
PPO
1.0 0.8
1.2
1.0
0.8
1.3
Charlson Comorbidity Index
.272
.4253
0 1
1.0 0.8
1.4
1.1
0.8
1.5
2
0.5 0.2
1.2
0.6
0.3
1.4
Relationship to primary beneficiary
.0006
.0508
Employee Spouse
0.8 0.7
1.0
0.8
0.6
1.0
Child/Other
2.6 1.3
5.0
0.8
0.3
2.5
CI, confidence interval; HMO, health maintenance organization; OR, odds ratio; PPO, preferred provider organization. a P values are based on Wald test. Harrison et al. Fertility conservation and pregnancy outcomes in young women with endometrial cancer or hyperplasia. Am J Obstet Gynecol 2019.
exploring fertility conservation, as uterine-sparing treatment may be associated with greater cancer-specific
mortality. An individualized assessment of a patient’s chance to achieve pregnancy should facilitate shared decision making
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and ensure that the choice to pursue fertility-preserving treatment is well informed. n References 1. Noone AM, Howlader N, Krapcho M, et al. SEER Cancer Statistics Review, 1975-2015. Bethesda, MD: National Cancer Institute; 2018. 2. Group SGOCPECW, Burke WM, Orr J, et al. Endometrial cancer: a review and current management strategies: part II. Gynecol Oncol 2014;134:393–402. 3. Group SGOCPECW, Burke WM, Orr J, et al. Endometrial cancer: a review and current management strategies: part I. Gynecol Oncol 2014;134:385–92. 4. Trimble CL, Method M, Leitao M, et al. Management of endometrial precancers. Obstet Gynecol 2012;120:1160–75. 5. Rodolakis A, Biliatis I, Morice P, et al. European Society of Gynecological Oncology Task Force for Fertility Preservation: Clinical recommendations for fertility-sparing management in young endometrial cancer patients. Int J Gynecol Cancer 2015;25:1258–65. 6. Gallos ID, Yap J, Rajkhowa M, Luesley DM, Coomarasamy A, Gupta JK. Regression, relapse, and live birth rates with fertility-sparing therapy for endometrial cancer and atypical complex endometrial hyperplasia: a systematic review and metaanalysis. Am J Obstet Gynecol 2012;207:266. 7. Gallos ID, Shehmar M, Thangaratinam S, Papapostolou TK, Coomarasamy A, Gupta JK. Oral progestogens vs levonorgestrel-releasing intrauterine system for endometrial hyperplasia: a systematic review and metaanalysis. Am J Obstet Gynecol 2010;203:547. 8. Pal N, Broaddus RR, Urbauer DL, et al. Treatment of low-risk endometrial cancer and complex atypical hyperplasia with the levonorgestrel-releasing intrauterine device. Obstet Gynecol 2018;131:109–16. 9. Greenwald ZR, Huang LN, Wissing MD, Franco EL, Gotlieb WH. Does hormonal therapy for fertility preservation affect the survival of young women with early-stage endometrial cancer? Cancer 2017;123:1545–54. 10. Ruiz MP, Huang Y, Hou JY, et al. All-cause mortality in young women with endometrial cancer receiving progesterone therapy. Am J Obstet Gynecol 2017;217:669.
11. Gunderson CC, Fader AN, Carson KA, Bristow RE. Oncologic and reproductive outcomes with progestin therapy in women with endometrial hyperplasia and grade 1 adenocarcinoma: a systematic review. Gynecol Oncol 2012;125:477482. 12. Wei J, Zhang W, Feng L, Gao W. Comparison of fertility-sparing treatments in patients with early endometrial cancer and atypical complex hyperplasia: a meta-analysis and systematic review. Medicine (Baltimore) 2017;96:e8034. 13. Chae SH, Shim SH, Lee SJ, Lee JY, Kim SN, Kang SB. Pregnancy and oncologic outcomes after fertility-sparing management for early stage endometrioid endometrial cancer. Int J Gynecol Cancer 2019;29:77–85. 14. IBM Corporation. IBM MarketScan Research Databases for Health Services Researchers. Available at: https://www.ibm.com/ downloads/cas/6KNYVVQ2. 2018. Accessed May 7, 2019. 15. Klabunde CN, Harlan LC, Warren JL. Data sources for measuring comorbidity: a comparison of hospital records and Medicare claims for cancer patients. Med Care 2006;44: 921–8. 16. Klabunde CN, Potosky AL, Legler JM, Warren JL. Development of a comorbidity index using physician claims data. J Clin Epidemiol 2000;53:1258–67. 17. Gambadauro P. The reproductive prognosis of women considering fertility preservation for early stage endometrial cancer. Arch Gynecol Obstet 2019 [Epub ahead of print]. 18. Practice Committee of the American Society for Reproductive Medicine. Obesity and reproduction: a committee opinion. Fertil Steril 2015;104:1116–26. 19. American College of O, Gynecologists Committee on Gynecologic P, Practice C. Female age-related fertility decline. Committee Opinion No. 589. Fertil Steril 2014;101:633–4. 20. Oktay K, Harvey BE, Partridge AH, et al. Fertility preservation in patients with cancer: ASCO clinical practice guideline update. J Clin Oncol 2018;36:1994–2001. 21. Gynaecologists RCoOa. Green-top Guideline No. 67: management of endometrial Hyperplasia. 2016:1-30. 22. La Russa M, Zapardiel I, Halaska MJ, et al. Conservative management of endometrial cancer: a survey amongst European
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Author and article information From the Department of Gynecologic Oncology and Reproductive Medicine (Drs Harrison, Sun, Suidan, Woodard, Rauh-Hain, Westin, and Meyer), Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX; Department of Health Services Research (Drs He, Fu, Zhao, and Giordano), Division of Cancer Prevention and Population Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX. Received March 31, 2019; revised May 15, 2019; accepted May 17, 2019. Outside the scope of the current work, C.C.S. reports research support from AstraZeneca. Outside the scope of the current work, S.N.W. reports research support from ArQule, AstraZeneca, Bayer, Clovis Oncology, Cotinga Pharmaceuticals, Novartis, Roche/Genentech, and Q9 Tesaro. Outside of the scope of the current work, S.N.W. reports consulting fees from AstraZeneca, Clovis Oncology, MediVation, Merck, Ovation, Pfizer, Roche/ Genentech, Takeda, and Tesaro. Outside the scope of the current work, L.A.M. reports research support from AstraZeneca. The other authors report no conflict of interest. Financial support for this research investigation was provided in part by grant funding to the following individuals or organizations: R.H., National Institutes of Health T32 grant (#5T32 CA101642); L.M., National Cancer Institute K award (#K07 CA201013); S.W., National Cancer Institute SPORE for Uterine Cancer (2P50 CA098258-13) and Andrew Sabin Family Fellowship; S.G., CPRIT RP160674; Susan Komen SAC150061; MD Anderson Cancer Center: National Cancer Institute Cancer Center Support Grant (P30 CA016672). The investigation described in this manuscript was presented in part by during the International Gynecologic Cancer Society Global Meeting in Lisbon, Portugal, Oct. 2931, 2016, and the 50th Society of Gynecologic Oncology Annual Meeting in Honolulu, HI, March 1519, 2019. Corresponding author: Larissa A. Meyer, MD, MPH. [email protected]
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Original Research
SUPPLEMENTARY TABLE 1
Medical classification codes used for identification of outcomes of interest Endometrial cancer ICD-9-CM 182.0; ICD-10-CM C54.x Atypical hyperplasia ICD-9-CM 621.33; ICD-10-CM N85.02 Miscarriage CPT 59812-59866; ICD-9-CM 634.xx; ICD-10-CM O03.xx; ICD-10-PCS 10A00ZZ, 10A03ZZ, 10A04ZZ Ectopic pregnancy ICD-9-CM 633.xx; ICD-10-CM O00.xx Pregnancy CPT 7680176817; ICD-9-CM V22.x, V23.x, 650, 651xx; ICD-10-CM Z33.x, Z34.x, Z36.2, O09.x, O30.x, O31.x, O35.x, O36.x Delivery CPT 5940059410, 5951059525, 5961059614; ICD-9-CM 74.x, 72.x, ICD-10-PCS 10D00Z1, 10D00Z0, 10D00Z2, 0W8NXZZ, 10D07Z5, 10D07Z4, 10D07Z3 Assisted fertility services and in vitro fertilization CPT 58322, 5897058976, 8925089291, 8933589356; ICD-9-CM 65.91, 256.1, 628.0, V26.81; ICD-10-CM N97.x, Z31.83; ICD-10-PCS 0U90xx, 0U91xx, 0UDNxxx; HCPCS S4011S4042, S4989, J0725, J1620, J1675, S0132, S0122, S0126, S0128, J3355, J9202, J9217, J9218, J9219, J1950 Hysterectomy CPT 58150, 58180, 58200, 58210, 5854158548, 5855058554, 5857058573, 5895358956, 59100; ICD-9-CM 68.x; ICD-10-PCS 0UT9xxx, 0UTC0ZZ, 0UTC4ZZ, 0UTC7ZZ, 0UTC8ZZ, 0UT40ZZ, 0UT44ZZ, 0UT47ZZ, 0UT48ZZ; HCPCS S2900 Use of ovulation induction agents Letrozole, clomiphene citrate, tamoxifen citrate, follitropin, menotropin, urofollitropin, chorionic gonadotropin, choriogonadotropin alfa, cetrorelix acetate, triptorelin, ganirelix acetate Use of progestin therapy Megestrol acetate, medroxyprogesterone acetate, levonorgestrel intrauterine device CPT, Current Procedural Terminology; HCPCS, Healthcare Common Procedure Coding System; ICD, International Classification of Diseases. Harrison et al. Fertility conservation and pregnancy outcomes in young women with endometrial cancer or hyperplasia. Am J Obstet Gynecol 2019.
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