Original Research
Time Interval Between Endometrial Biopsy and Surgical Staging for Type I Endometrial Cancer Association Between Tumor Characteristics and Survival Outcome Koji Matsuo, MD, PhD, Neisha R. Opper, MPH, Marcia A. Ciccone, MD, Jocelyn Garcia, MD, Katherine E. Tierney, MD, Tsukasa Baba, MD, PhD, Laila I. Muderspach, MD, and Lynda D. Roman, MD OBJECTIVE: To examine whether wait time between endometrial biopsy and surgical staging correlates with tumor characteristics and affects survival outcomes in patients with type I endometrial cancer. METHODS: A retrospective study was conducted to examine patients with grade 1 and 2 endometrioid adenocarcinoma diagnosed by preoperative endometrial biopsy who subsequently underwent hysterectomybased surgical staging between 2000 and 2013. Patients who received neoadjuvant chemotherapy or hormonal treatment were excluded. Time interval and grade change between endometrial biopsy and hysterectomy were correlated to demographics and survival outcomes. RESULTS: Median wait time was 57 days (range 1–177 days) among 435 patients. Upgrading of the tumor to grade 3 in the hysterectomy specimen was seen in 4.7% of 321 tumors classified as grade 1 and 18.4% of 114 tumors classified as grade 2 on the endometrial biopsy, respectively. Wait time was not associated with grade change (P..05). Controlling for age, ethnicity, body habitus, medical comorbidities, CA 125 level, and stage, multivariable analysis revealed that wait time was not From the Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Los Angeles County Medical Center, and the Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California; and the Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan. Corresponding author: Koji Matsuo, MD, PhD, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Los Angeles County Medical Center, University of Southern California, 2020 Zonal Avenue, IRD520, Los Angeles, CA 90033; e-mail: [email protected]. Financial Disclosure The authors did not report any potential conflicts of interest. © 2015 by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0029-7844/15
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associated with survival outcomes (5-year overall survival rates, wait time 1–14, 15–42, 43–84, and 85 days or more; 62.5%, 93.6%, 95.2%, and 100%, respectively, P..05); however, grade 1 to 3 on the hysterectomy specimen remained as an independent prognosticator associated with decreased survival (5-year overall survival rates, grade 1 to 3 compared with grade change 1 to 1, 82.1% compared with 98.5%, P5.01). Among grade 1 preoperative biopsies, grade 1 to 3 was significantly associated with nonobesity (P5.039) and advanced stage (P5.019). CONCLUSION: Wait time for surgical staging was not associated with decreased survival outcome in patients with type I endometrial cancer. (Obstet Gynecol 2015;125:424–33) DOI: 10.1097/AOG.0000000000000636
LEVEL OF EVIDENCE: II
E
ndometrial cancer is the most common gynecologic malignancy in the United States.1 The majority of endometrial cancers possess type I histology highlighted by low-grade tumors and early-stage disease.2,3 Therefore, type I endometrial cancer is often curable with hysterectomy-based surgical treatment, generally with a good prognosis.2,4 Most cases of endometrial cancer are diagnosed by endometrial biopsy before surgery that enables both patients and care providers to have time to prepare for surgery, which is called the “wait time” for surgical staging. Wait time for surgical staging may reflect the spectrum of geographic and socioeconomic barriers, delays for medical clearance or optimization by specialists, or patient delays.5 The effect of wait time for surgical staging on survival outcome of endometrial cancer is controversial.
OBSTETRICS & GYNECOLOGY
Copyright ª by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
A recent population-based study concluded that longer wait time for surgical staging was associated with worse survival outcomes in uterine cancer.6 Others have found that type I endometrial cancers commonly progress very slowly in nature, and wait time for surgical staging in patients with endometrial cancer is not associated with survival outcomes.7–9 Therefore, whether wait time for surgical staging affects tumor progression is unclear. The aims of our study were to 1) examine the correlation of wait time for surgical staging and survival outcomes of patients with type I endometrial cancer and 2) evaluate the patterns and significance of tumor grade change between the endometrial biopsy and hysterectomy.
MATERIALS AND METHODS After institutional review board approval was obtained at the University of Southern California, an institutional database for endometrial cancer was searched.10 This electronic database collects consecutive gynecologic malignancies that are diagnosed and treated at Los Angeles County+University of Southern California Medical Center. This study followed the STROBE (STrengthening the Reporting of OBservational studies in Epidemiology) guideline for a retrospective cohort study. Eligibility criteria included women with grade 1 and 2 endometrioid adenocarcinoma of the endometrium diagnosed by endometrial biopsy before surgical staging: those patients subsequently underwent hysterectomy-based surgical staging between January 2000 and December 2013. Exclusion criteria were: neoadjuvant chemotherapy or hormonal treatment before hysterectomy, no preoperative biopsy demonstrating endometrial cancer, surgery, biopsy, or both at an outside hospital, lost to follow-up after endometrial biopsy, and mixed or nonendometrioid histology types on the endometrial biopsy. Among eligible cases, the following information was abstracted from the medical record: 1) clinical demographics at the time of endometrial biopsy for endometrial cancer diagnosis including age, ethnicity, body mass index (BMI, calculated as weight (kg)/ [height (m)]2), and medical comorbidities including hypertension, diabetes mellitus, and hypercholesterolemia; 2) tumor characteristics including tumor marker CA 125 level, grade, and histology from the endometrial biopsy as well as hysterectomy specimens and the International Federation of Gynecology and Obstetrics (FIGO) stage; and 3) survival data including disease-free survival and overall survival.
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Type I endometrial cancer was defined as grade 1 and 2 endometrioid adenocarcinoma.11,12 Wait time for surgical staging was defined as the time interval between the date of endometrial biopsy and the date of hysterectomy. Tumor grade was based on the FIGO system for endometrial cancer: 5% or less solid component for grade 1, 6–50% solid component for grade 2, and more than 50% solid component for grade 3.13 Grade change was defined as a change of FIGO grade between the diagnostic endometrial biopsy and hysterectomy. The grade changes were classified as: grade 1 to 1, grade 1 to 2, grade 1 to 3, grade 2 to 1, grade 2 to 2, and grade 2 to 3. All the histopathology slides from the endometrial biopsy and hysterectomy specimens were reviewed by pathologists with special expertise in gynecologic pathology at the time of cancer diagnosis and treatment. Disease-free survival was defined as the time interval between endometrial biopsy and the date of the first recurrence or last follow-up date. Overall survival was defined as the time interval between endometrial biopsy and the date of death resulting from endometrial cancer of last follow-up date. Data entry (deidentified) was performed by one of the coinvestigators (K.M., M.A.C., J.G., and K.E.T.), and the principal investigator examined all the medical records of collected data for accuracy, consistency, and quality (K.M.). To maximize the power of this study to examine the effects of wait time on survival outcome, three classifications of wait time for surgical staging based on its clinical relevance were tested in the analysis: 1) monthly grouping (1–28 days, 29–56 days, 57–84 days, and 85 days or more), 2) validation pattern of day intervals based on prior publication (1–14 days, 15– 42 days, 43–84 days, and 85 days or more),6 and 3) quartile pattern based on median value (1–25%ile, 26– 50%ile, 51–75%ile, and 76–100%ile). Among the three methods of wait time classification, grouping based on day intervals as reported in a prior publication6 was the most predictive for recurrence (area under the curve [AUC] 0.674, 95% confidence interval [CI] 0.571– 0.776) when compared with other methods (monthly grouping, AUC 0.663, 95% CI 0.556–0.770; and quartile pattern, AUC 0.662, 95% CI 0.566–0.759). Similar results were seen in predicting death event in that grouping based on day intervals per prior publication6 was the most sensitive method (AUC 0.691, 95% CI 0.570–0.811) followed by quartile pattern (AUC 0.674, 95% CI 0.567–0.791) and monthly grouping (AUC 0.671, 95% CI 0.541–0.801). Therefore, wait time was classified based on the prior publication (1–14 days, 15–42 days, 43–84 days, and 85 days or more) for our further analysis in the study.
Matsuo et al
Wait Time and Outcome of Endometrial Cancer
Copyright ª by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
425
Underwent hysterectomy for endometrial cancer (n=738)
Underwent upfront hysterectomy after preoperative biopsy for endometrial cancer (n=532)
Study exclusions (n=206) Neoadjuvant chemotherapy: 54 Hormonal therapy: 21 Surgery at outside institution: 51 Noncancer diagnosis in biopsy: 63 No preoperative biopsy: 17
Study exclusions (n=97) High-grade type in biopsy: 91 Mixed histology in biopsy: 4 Mucinous type in biopsy: 2 Underwent upfront hysterectomy after preoperative biopsy found type I endometrial cancer (n=435)
Grade 1 in biopsy (n=321)
Grade 2 in biopsy (n=114)
Wait time: preoperative biopsy to hysterectomy
Grade 1 in hysterectomy (n=240) (Grade 1→1)
Grade 2 in hysterectomy (n=66) (Grade 1→2)
Grade 3 in hysterectomy (n=15) (Grade 1→3)
Grade 1 in hysterectomy (n=26) (Grade 2→1)
Grade 2 in hysterectomy (n=67) (Grade 2→2)
Grade 3 in hysterectomy (n=21) (Grade 2→3)
Fig. 1. Selection criteria and study definition. Grade 1 and 2 refer to endometrioid adenocarcinoma histology type. Matsuo. Wait Time and Outcome of Endometrial Cancer. Obstet Gynecol 2015.
Because the previous large-scale populationbased study on this topic6 was performed in a population with universal access to health care and substantially different demographical and clinical characteristics, sample size was not calculated based on these results. Instead, sample size in this study was calculated based on the ability to detect at least a 0.20 correlation between wait time for surgical staging and both primary outcomes (disease-free survival and overall survival). With an a of 0.05 and 80% power, at least 153 patients were estimated to be required to detect this difference. The primary purpose of this study was to examine the effects of wait time on survival outcomes of endometrial cancer. A secondary purpose was to examine the effects of grade change between endometrial biopsy and hysterectomy on wait time and survival outcomes. Continuous variables were assessed for normality by Kolmogorov-Smirnov test expressed as mean (6standard deviation) or median (range) as appropriate. Statistical significances of continuous variables were examined by Student’s t test or
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Mann-Whitney U test as appropriate. Pearson’s correlation coefficient was used to examine nonnormally distributed continuous variables. Categorical or ordinal variables were examined by Fisher exact test or x2 test as appropriate expressed its magnitude of statistical significance with odds ratio (OR) and 95% CI. Receiver operator characteristic curve analysis was performed to determine the most sensitive method for wait time classification to predict survival event (recurrence and death) as comparing the values for AUC. Survival analysis was examined by Cox’s proportional hazard regression model for multivariable analysis expressed its magnitude of statistical significance with hazard ratio (HR) and 95% CI. In the multivariable model, a priori each covariate was selected for inclusion in any final model based on clinical relevance and effect in endometrial cancer: age (younger than 60 compared with 60 years or older), ethnicity (Hispanic compared with non-Hispanic), BMI (less than 30 compared with 30 or higher), hypertension (yes compared with no), diabetes mellitus (yes compared with no), and hypercholesterolemia (yes compared with
Wait Time and Outcome of Endometrial Cancer
OBSTETRICS & GYNECOLOGY
Copyright ª by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
no), CA 125 level (less than 35 compared with 35 international units/L or more), stage (I–II compared with III–IV), grade change between endometrial biopsy and hysterectomy (grade 1 to 1, 1 to 2, 1 to 3, 2 to 1, 2 to 2, and 2–3), and wait time for surgical staging (1–14, 15–42, 43–84, and 85 days or more). Kaplan-Meier method was used to plot survival curves. All tests were two-tailed, and P values of ,.05 were considered statistically significant in this study. SPSS 12.0 was used for statistical analysis.
RESULTS There were 738 women with endometrial cancer who underwent hysterectomy during the study period (Fig. 1). Of those, 206 (27.9%) patients were excluded as a result of: neoadjuvant chemotherapy (n554), surgery or biopsy at outside hospital (n551), progestin-based hormonal therapy before surgery (n521), noncancer diagnosis on preoperative endometrial biopsy (complex atypical hyperplasia, n558, and atrophic endometrium, n55), and no preoperative endometrial biopsy (n517). The remaining 532 patients had no treatment before surgical staging and had a histologic diagnosis of endometrial cancer by endometria biopsy before hysterectomy. Of these, 97 (18.2%) patients were excluded as a result of grade 3 endometrioid, serous, or clear cell type histology (n591); grade 1 mixed histology (n54); and grade 1 mucinous histology (n52). The remaining 435 patients with grade 1 and 2 endometrioid-type endometrial cancer diagnosed on preoperative endometrial biopsy who underwent subsequent hysterectomy-based surgical staging without any neoadjuvant chemotherapy or hormonal treatment comprised the study group. Patient demographics are shown in Table 1. The mean age was 52.2 years, and the majority of patients were Hispanic (70.6%), obese (BMI 30 or higher, 70.6%), had early-stage disease (stage I–II, 87.1%), and had grade 1 tumors on endometrial biopsy (73.8%). The median wait time for surgical staging was 57 days (range 1–177 days) in this cohort. The majority of wait times for surgical staging was between 43 and 84 days (57.7%). Approximately one sixth of women had a wait time for surgical staging more than 85 days or more (16.8%). Grade change between endometrial biopsy and hysterectomy was seen in 128 (29.4%) of 435 patients (Fig. 1). Recurrence and death resulting from endometrial cancer were seen in 25 (5.7%) and 17 (3.9%) patients, respectively. Median follow-up time of the cohort was 28.8 months. In bivariate analysis using Pearson’s correlation, a significant inverse association was found between wait time for surgical staging and disease-free survival of
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Table 1. Demographics of Patients With Type I Endometrial Cancer (N5435) Demographic Age at diagnosis (y) Younger than 60 60 or older Ethnicity Caucasian African American Hispanic Asian BMI (kg/m2) Less than 30 30 or higher Hypertension No Yes Diabetes mellitus No Yes Hypercholesterolemia No Yes CA 125 level (international units/L)* Less than 35 35 or more Stage† I II III IV Grade in endometrial biopsy 1 2 Grade in hysterectomy 1 2 3 Wait time (d) 1–14 15–42 43–84 85 or more
Value 52.2610 344 (79.1) 91 (20.9) 48 (11.0) 15 (3.4) 307 (70.6) 65 (14.9) 35.969.5 128 (29.4) 307 (70.6) 194 (44.6) 241 (55.4) 290 (66.7) 145 (33.3) 328 107 18 310 89
(75.4) (24.6) (3–4,656) (77.7) (22.3)
341 38 47 9
(78.4) (8.7) (10.8) (2.1)
321 (73.8) 114 (26.2) 266 133 36 57 14 97 251 73
(61.1) (30.6) (8.3) (1–177) (3.2) (22.3) (57.7) (16.8)
BMI, body mass index. Data are mean6standard deviation, n (%), or median (range). * Thirty-six missing data for preoperative CA 125 level. † Surgical staging.
20.120 (P5.012) and between wait time and overall survival of 20.148 (P5.002). Additional analyses showed that a quadric curve was the best overall fit for these data (see Appendix 1, available online at http://links.lww.com/AOG/A600). Contributing factors associated with wait time for surgical staging in patients with endometrial cancer were examined (Table 2). Among the variables examined in this study, Hispanic race (median wait time, Hispanic compared with non-Hispanic, 60 compared
Matsuo et al
Wait Time and Outcome of Endometrial Cancer
Copyright ª by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
427
Table 2. Contributing Factors for Wait Time in Type I Endometrial Cancer Wait Time (d) Factor Age at diagnosis (y) Younger than 60 60 or older Ethnicity Non-Hispanic Hispanic BMI (kg/m2) Less than 30 30 or higher Hypertension No Yes Diabetes mellitus No Yes Hypercholesterolemia No Yes Comorbidity extent* None or single Multiple CA 125 level (international units/L) Less than 35 35 or more Stage I–II III–IV Grade in biopsy 1 2 Grade change† Grade 1/1 Grade 1/2 Grade 1/3 Grade 2/1 Grade 2/2 Grade 2/3
n (%)
Wait Time (d)
1–14
15–42
43–84
85 or More
344 (79.1) 91 (20.9)
57 (1–177) 62 (6–139)
12 (3.5) 2 (2.2)
84 (24.4) 13 (14.3)
186 (54.1) 65 (71.4)
62 (18.0) 11 (12.1)
128 (29.4) 307 (70.6)
51 (2–177) 60 (1–162)
7 (5.5) 7 (5.5)
38 (29.7) 59 (19.2)
67 (52.3) 184 (59.9)
16 (12.5) 57 (18.6)
128 (29.4) 307 (70.6)
53 (3–139) 59 (1–177)
3 (2.3) 11 (3.6)
38 (39.7) 59 (19.2)
69 (53.9) 182 (59.3)
18 (14.1) 55 (17.9)
194 (44.6) 241 (55.4)
57 (8–135) 58 (1–177)
6 (3.1) 8 (3.3)
49 (25.3) 48 (19.9)
110 (56.7) 141 (58.5)
29 (14.9) 44 (18.3)
290 (66.7) 145 (33.3)
56.5 (1–177) 58 (2–162)
12 (4.1) 2 (1.4)
70 (24.1) 27 (18.6)
156 (53.8) 95 (65.5)
52 (17.9) 21 (14.5)
328 (75.4) 107 (24.6)
57 (1–162) 58 (2–177)
13 (4.0) 1 (0.9)
79 (24.1) 18 (16.8)
180 (54.9) 71 (66.4)
56 (17.1) 17 (15.9)
286 (65.7) 149 (34.3)
58 (1–162) 57 (2–177)
11 (3.8) 3 (2.0)
67 (23.4) 30 (20.1)
157 (54.9) 94 (63.1)
51 (17.8) 22 (14.8)
310 (77.7) 89 (22.3)
59.5 (2–162) 48 (1–177)
7 (2.3) 7 (7.9)
62 (20.0) 27 (30.3)
180 (58.1) 49 (55.1)
61 (19.7) 6 (6.7)
379 (87.1) 56 (12.9)
58 (2–177) 51.5 (1–139)
9 (2.4) 5 (8.9)
84 (22.2) 13 (23.2)
218 (57.5) 33 (58.9)
68 (17.9) 5 (8.9)
321 (73.8) 114 (26.2)
59 (1–177) 50.5 (3–139)
11 (3.4) 3 (2.6)
69 (21.5) 28 (24.6)
178 (55.5) 73 (64.0)
63 (19.6) 10 (8.8)
240 66 15 26 67 21
59 55.5 62 46 55 57
49 15 5 5 16 7
136 35 7 17 44 12
48 12 3 2 6 2
P .33 .001 .013
.28
.24
.23
.78
(55.2) (15.2) (3.4) (6.0) (15.4) (4.8)
(1–177) (2–138) (17–162) (3–94) (13–126) (1–177)
7 (4.9) 4 (6.1) 0 2 (7.7) 1 (1.5) 0
(20.4) (22.7) (33.3) (19.2) (23.9) (33.3)
(56.7) (53.0) (46.7) (65.4) (65.7) (57.1)
(20) (18.2) (20) (7.7) (9.0) (9.5)
Time Interval Between Endometrial Biopsy and Surgical Staging for Type I Endometrial Cancer Association Between Tumor Characteristics and Survival Outcome Koji Matsuo, MD, PhD, Neisha R. Opper, MPH, Marcia A. Ciccone, MD, Jocelyn Garcia, MD, Katherine E. Tierney, MD, Tsukasa Baba, MD, PhD, Laila I. Muderspach, MD, and Lynda D. Roman, MD OBJECTIVE: To examine whether wait time between endometrial biopsy and surgical staging correlates with tumor characteristics and affects survival outcomes in patients with type I endometrial cancer. METHODS: A retrospective study was conducted to examine patients with grade 1 and 2 endometrioid adenocarcinoma diagnosed by preoperative endometrial biopsy who subsequently underwent hysterectomybased surgical staging between 2000 and 2013. Patients who received neoadjuvant chemotherapy or hormonal treatment were excluded. Time interval and grade change between endometrial biopsy and hysterectomy were correlated to demographics and survival outcomes. RESULTS: Median wait time was 57 days (range 1–177 days) among 435 patients. Upgrading of the tumor to grade 3 in the hysterectomy specimen was seen in 4.7% of 321 tumors classified as grade 1 and 18.4% of 114 tumors classified as grade 2 on the endometrial biopsy, respectively. Wait time was not associated with grade change (P..05). Controlling for age, ethnicity, body habitus, medical comorbidities, CA 125 level, and stage, multivariable analysis revealed that wait time was not From the Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Los Angeles County Medical Center, and the Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California; and the Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan. Corresponding author: Koji Matsuo, MD, PhD, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Los Angeles County Medical Center, University of Southern California, 2020 Zonal Avenue, IRD520, Los Angeles, CA 90033; e-mail: [email protected]. Financial Disclosure The authors did not report any potential conflicts of interest. © 2015 by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0029-7844/15
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associated with survival outcomes (5-year overall survival rates, wait time 1–14, 15–42, 43–84, and 85 days or more; 62.5%, 93.6%, 95.2%, and 100%, respectively, P..05); however, grade 1 to 3 on the hysterectomy specimen remained as an independent prognosticator associated with decreased survival (5-year overall survival rates, grade 1 to 3 compared with grade change 1 to 1, 82.1% compared with 98.5%, P5.01). Among grade 1 preoperative biopsies, grade 1 to 3 was significantly associated with nonobesity (P5.039) and advanced stage (P5.019). CONCLUSION: Wait time for surgical staging was not associated with decreased survival outcome in patients with type I endometrial cancer. (Obstet Gynecol 2015;125:424–33) DOI: 10.1097/AOG.0000000000000636
LEVEL OF EVIDENCE: II
E
ndometrial cancer is the most common gynecologic malignancy in the United States.1 The majority of endometrial cancers possess type I histology highlighted by low-grade tumors and early-stage disease.2,3 Therefore, type I endometrial cancer is often curable with hysterectomy-based surgical treatment, generally with a good prognosis.2,4 Most cases of endometrial cancer are diagnosed by endometrial biopsy before surgery that enables both patients and care providers to have time to prepare for surgery, which is called the “wait time” for surgical staging. Wait time for surgical staging may reflect the spectrum of geographic and socioeconomic barriers, delays for medical clearance or optimization by specialists, or patient delays.5 The effect of wait time for surgical staging on survival outcome of endometrial cancer is controversial.
OBSTETRICS & GYNECOLOGY
Copyright ª by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
A recent population-based study concluded that longer wait time for surgical staging was associated with worse survival outcomes in uterine cancer.6 Others have found that type I endometrial cancers commonly progress very slowly in nature, and wait time for surgical staging in patients with endometrial cancer is not associated with survival outcomes.7–9 Therefore, whether wait time for surgical staging affects tumor progression is unclear. The aims of our study were to 1) examine the correlation of wait time for surgical staging and survival outcomes of patients with type I endometrial cancer and 2) evaluate the patterns and significance of tumor grade change between the endometrial biopsy and hysterectomy.
MATERIALS AND METHODS After institutional review board approval was obtained at the University of Southern California, an institutional database for endometrial cancer was searched.10 This electronic database collects consecutive gynecologic malignancies that are diagnosed and treated at Los Angeles County+University of Southern California Medical Center. This study followed the STROBE (STrengthening the Reporting of OBservational studies in Epidemiology) guideline for a retrospective cohort study. Eligibility criteria included women with grade 1 and 2 endometrioid adenocarcinoma of the endometrium diagnosed by endometrial biopsy before surgical staging: those patients subsequently underwent hysterectomy-based surgical staging between January 2000 and December 2013. Exclusion criteria were: neoadjuvant chemotherapy or hormonal treatment before hysterectomy, no preoperative biopsy demonstrating endometrial cancer, surgery, biopsy, or both at an outside hospital, lost to follow-up after endometrial biopsy, and mixed or nonendometrioid histology types on the endometrial biopsy. Among eligible cases, the following information was abstracted from the medical record: 1) clinical demographics at the time of endometrial biopsy for endometrial cancer diagnosis including age, ethnicity, body mass index (BMI, calculated as weight (kg)/ [height (m)]2), and medical comorbidities including hypertension, diabetes mellitus, and hypercholesterolemia; 2) tumor characteristics including tumor marker CA 125 level, grade, and histology from the endometrial biopsy as well as hysterectomy specimens and the International Federation of Gynecology and Obstetrics (FIGO) stage; and 3) survival data including disease-free survival and overall survival.
VOL. 125, NO. 2, FEBRUARY 2015
Type I endometrial cancer was defined as grade 1 and 2 endometrioid adenocarcinoma.11,12 Wait time for surgical staging was defined as the time interval between the date of endometrial biopsy and the date of hysterectomy. Tumor grade was based on the FIGO system for endometrial cancer: 5% or less solid component for grade 1, 6–50% solid component for grade 2, and more than 50% solid component for grade 3.13 Grade change was defined as a change of FIGO grade between the diagnostic endometrial biopsy and hysterectomy. The grade changes were classified as: grade 1 to 1, grade 1 to 2, grade 1 to 3, grade 2 to 1, grade 2 to 2, and grade 2 to 3. All the histopathology slides from the endometrial biopsy and hysterectomy specimens were reviewed by pathologists with special expertise in gynecologic pathology at the time of cancer diagnosis and treatment. Disease-free survival was defined as the time interval between endometrial biopsy and the date of the first recurrence or last follow-up date. Overall survival was defined as the time interval between endometrial biopsy and the date of death resulting from endometrial cancer of last follow-up date. Data entry (deidentified) was performed by one of the coinvestigators (K.M., M.A.C., J.G., and K.E.T.), and the principal investigator examined all the medical records of collected data for accuracy, consistency, and quality (K.M.). To maximize the power of this study to examine the effects of wait time on survival outcome, three classifications of wait time for surgical staging based on its clinical relevance were tested in the analysis: 1) monthly grouping (1–28 days, 29–56 days, 57–84 days, and 85 days or more), 2) validation pattern of day intervals based on prior publication (1–14 days, 15– 42 days, 43–84 days, and 85 days or more),6 and 3) quartile pattern based on median value (1–25%ile, 26– 50%ile, 51–75%ile, and 76–100%ile). Among the three methods of wait time classification, grouping based on day intervals as reported in a prior publication6 was the most predictive for recurrence (area under the curve [AUC] 0.674, 95% confidence interval [CI] 0.571– 0.776) when compared with other methods (monthly grouping, AUC 0.663, 95% CI 0.556–0.770; and quartile pattern, AUC 0.662, 95% CI 0.566–0.759). Similar results were seen in predicting death event in that grouping based on day intervals per prior publication6 was the most sensitive method (AUC 0.691, 95% CI 0.570–0.811) followed by quartile pattern (AUC 0.674, 95% CI 0.567–0.791) and monthly grouping (AUC 0.671, 95% CI 0.541–0.801). Therefore, wait time was classified based on the prior publication (1–14 days, 15–42 days, 43–84 days, and 85 days or more) for our further analysis in the study.
Matsuo et al
Wait Time and Outcome of Endometrial Cancer
Copyright ª by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
425
Underwent hysterectomy for endometrial cancer (n=738)
Underwent upfront hysterectomy after preoperative biopsy for endometrial cancer (n=532)
Study exclusions (n=206) Neoadjuvant chemotherapy: 54 Hormonal therapy: 21 Surgery at outside institution: 51 Noncancer diagnosis in biopsy: 63 No preoperative biopsy: 17
Study exclusions (n=97) High-grade type in biopsy: 91 Mixed histology in biopsy: 4 Mucinous type in biopsy: 2 Underwent upfront hysterectomy after preoperative biopsy found type I endometrial cancer (n=435)
Grade 1 in biopsy (n=321)
Grade 2 in biopsy (n=114)
Wait time: preoperative biopsy to hysterectomy
Grade 1 in hysterectomy (n=240) (Grade 1→1)
Grade 2 in hysterectomy (n=66) (Grade 1→2)
Grade 3 in hysterectomy (n=15) (Grade 1→3)
Grade 1 in hysterectomy (n=26) (Grade 2→1)
Grade 2 in hysterectomy (n=67) (Grade 2→2)
Grade 3 in hysterectomy (n=21) (Grade 2→3)
Fig. 1. Selection criteria and study definition. Grade 1 and 2 refer to endometrioid adenocarcinoma histology type. Matsuo. Wait Time and Outcome of Endometrial Cancer. Obstet Gynecol 2015.
Because the previous large-scale populationbased study on this topic6 was performed in a population with universal access to health care and substantially different demographical and clinical characteristics, sample size was not calculated based on these results. Instead, sample size in this study was calculated based on the ability to detect at least a 0.20 correlation between wait time for surgical staging and both primary outcomes (disease-free survival and overall survival). With an a of 0.05 and 80% power, at least 153 patients were estimated to be required to detect this difference. The primary purpose of this study was to examine the effects of wait time on survival outcomes of endometrial cancer. A secondary purpose was to examine the effects of grade change between endometrial biopsy and hysterectomy on wait time and survival outcomes. Continuous variables were assessed for normality by Kolmogorov-Smirnov test expressed as mean (6standard deviation) or median (range) as appropriate. Statistical significances of continuous variables were examined by Student’s t test or
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Mann-Whitney U test as appropriate. Pearson’s correlation coefficient was used to examine nonnormally distributed continuous variables. Categorical or ordinal variables were examined by Fisher exact test or x2 test as appropriate expressed its magnitude of statistical significance with odds ratio (OR) and 95% CI. Receiver operator characteristic curve analysis was performed to determine the most sensitive method for wait time classification to predict survival event (recurrence and death) as comparing the values for AUC. Survival analysis was examined by Cox’s proportional hazard regression model for multivariable analysis expressed its magnitude of statistical significance with hazard ratio (HR) and 95% CI. In the multivariable model, a priori each covariate was selected for inclusion in any final model based on clinical relevance and effect in endometrial cancer: age (younger than 60 compared with 60 years or older), ethnicity (Hispanic compared with non-Hispanic), BMI (less than 30 compared with 30 or higher), hypertension (yes compared with no), diabetes mellitus (yes compared with no), and hypercholesterolemia (yes compared with
Wait Time and Outcome of Endometrial Cancer
OBSTETRICS & GYNECOLOGY
Copyright ª by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
no), CA 125 level (less than 35 compared with 35 international units/L or more), stage (I–II compared with III–IV), grade change between endometrial biopsy and hysterectomy (grade 1 to 1, 1 to 2, 1 to 3, 2 to 1, 2 to 2, and 2–3), and wait time for surgical staging (1–14, 15–42, 43–84, and 85 days or more). Kaplan-Meier method was used to plot survival curves. All tests were two-tailed, and P values of ,.05 were considered statistically significant in this study. SPSS 12.0 was used for statistical analysis.
RESULTS There were 738 women with endometrial cancer who underwent hysterectomy during the study period (Fig. 1). Of those, 206 (27.9%) patients were excluded as a result of: neoadjuvant chemotherapy (n554), surgery or biopsy at outside hospital (n551), progestin-based hormonal therapy before surgery (n521), noncancer diagnosis on preoperative endometrial biopsy (complex atypical hyperplasia, n558, and atrophic endometrium, n55), and no preoperative endometrial biopsy (n517). The remaining 532 patients had no treatment before surgical staging and had a histologic diagnosis of endometrial cancer by endometria biopsy before hysterectomy. Of these, 97 (18.2%) patients were excluded as a result of grade 3 endometrioid, serous, or clear cell type histology (n591); grade 1 mixed histology (n54); and grade 1 mucinous histology (n52). The remaining 435 patients with grade 1 and 2 endometrioid-type endometrial cancer diagnosed on preoperative endometrial biopsy who underwent subsequent hysterectomy-based surgical staging without any neoadjuvant chemotherapy or hormonal treatment comprised the study group. Patient demographics are shown in Table 1. The mean age was 52.2 years, and the majority of patients were Hispanic (70.6%), obese (BMI 30 or higher, 70.6%), had early-stage disease (stage I–II, 87.1%), and had grade 1 tumors on endometrial biopsy (73.8%). The median wait time for surgical staging was 57 days (range 1–177 days) in this cohort. The majority of wait times for surgical staging was between 43 and 84 days (57.7%). Approximately one sixth of women had a wait time for surgical staging more than 85 days or more (16.8%). Grade change between endometrial biopsy and hysterectomy was seen in 128 (29.4%) of 435 patients (Fig. 1). Recurrence and death resulting from endometrial cancer were seen in 25 (5.7%) and 17 (3.9%) patients, respectively. Median follow-up time of the cohort was 28.8 months. In bivariate analysis using Pearson’s correlation, a significant inverse association was found between wait time for surgical staging and disease-free survival of
VOL. 125, NO. 2, FEBRUARY 2015
Table 1. Demographics of Patients With Type I Endometrial Cancer (N5435) Demographic Age at diagnosis (y) Younger than 60 60 or older Ethnicity Caucasian African American Hispanic Asian BMI (kg/m2) Less than 30 30 or higher Hypertension No Yes Diabetes mellitus No Yes Hypercholesterolemia No Yes CA 125 level (international units/L)* Less than 35 35 or more Stage† I II III IV Grade in endometrial biopsy 1 2 Grade in hysterectomy 1 2 3 Wait time (d) 1–14 15–42 43–84 85 or more
Value 52.2610 344 (79.1) 91 (20.9) 48 (11.0) 15 (3.4) 307 (70.6) 65 (14.9) 35.969.5 128 (29.4) 307 (70.6) 194 (44.6) 241 (55.4) 290 (66.7) 145 (33.3) 328 107 18 310 89
(75.4) (24.6) (3–4,656) (77.7) (22.3)
341 38 47 9
(78.4) (8.7) (10.8) (2.1)
321 (73.8) 114 (26.2) 266 133 36 57 14 97 251 73
(61.1) (30.6) (8.3) (1–177) (3.2) (22.3) (57.7) (16.8)
BMI, body mass index. Data are mean6standard deviation, n (%), or median (range). * Thirty-six missing data for preoperative CA 125 level. † Surgical staging.
20.120 (P5.012) and between wait time and overall survival of 20.148 (P5.002). Additional analyses showed that a quadric curve was the best overall fit for these data (see Appendix 1, available online at http://links.lww.com/AOG/A600). Contributing factors associated with wait time for surgical staging in patients with endometrial cancer were examined (Table 2). Among the variables examined in this study, Hispanic race (median wait time, Hispanic compared with non-Hispanic, 60 compared
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Wait Time and Outcome of Endometrial Cancer
Copyright ª by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
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Table 2. Contributing Factors for Wait Time in Type I Endometrial Cancer Wait Time (d) Factor Age at diagnosis (y) Younger than 60 60 or older Ethnicity Non-Hispanic Hispanic BMI (kg/m2) Less than 30 30 or higher Hypertension No Yes Diabetes mellitus No Yes Hypercholesterolemia No Yes Comorbidity extent* None or single Multiple CA 125 level (international units/L) Less than 35 35 or more Stage I–II III–IV Grade in biopsy 1 2 Grade change† Grade 1/1 Grade 1/2 Grade 1/3 Grade 2/1 Grade 2/2 Grade 2/3
n (%)
Wait Time (d)
1–14
15–42
43–84
85 or More
344 (79.1) 91 (20.9)
57 (1–177) 62 (6–139)
12 (3.5) 2 (2.2)
84 (24.4) 13 (14.3)
186 (54.1) 65 (71.4)
62 (18.0) 11 (12.1)
128 (29.4) 307 (70.6)
51 (2–177) 60 (1–162)
7 (5.5) 7 (5.5)
38 (29.7) 59 (19.2)
67 (52.3) 184 (59.9)
16 (12.5) 57 (18.6)
128 (29.4) 307 (70.6)
53 (3–139) 59 (1–177)
3 (2.3) 11 (3.6)
38 (39.7) 59 (19.2)
69 (53.9) 182 (59.3)
18 (14.1) 55 (17.9)
194 (44.6) 241 (55.4)
57 (8–135) 58 (1–177)
6 (3.1) 8 (3.3)
49 (25.3) 48 (19.9)
110 (56.7) 141 (58.5)
29 (14.9) 44 (18.3)
290 (66.7) 145 (33.3)
56.5 (1–177) 58 (2–162)
12 (4.1) 2 (1.4)
70 (24.1) 27 (18.6)
156 (53.8) 95 (65.5)
52 (17.9) 21 (14.5)
328 (75.4) 107 (24.6)
57 (1–162) 58 (2–177)
13 (4.0) 1 (0.9)
79 (24.1) 18 (16.8)
180 (54.9) 71 (66.4)
56 (17.1) 17 (15.9)
286 (65.7) 149 (34.3)
58 (1–162) 57 (2–177)
11 (3.8) 3 (2.0)
67 (23.4) 30 (20.1)
157 (54.9) 94 (63.1)
51 (17.8) 22 (14.8)
310 (77.7) 89 (22.3)
59.5 (2–162) 48 (1–177)
7 (2.3) 7 (7.9)
62 (20.0) 27 (30.3)
180 (58.1) 49 (55.1)
61 (19.7) 6 (6.7)
379 (87.1) 56 (12.9)
58 (2–177) 51.5 (1–139)
9 (2.4) 5 (8.9)
84 (22.2) 13 (23.2)
218 (57.5) 33 (58.9)
68 (17.9) 5 (8.9)
321 (73.8) 114 (26.2)
59 (1–177) 50.5 (3–139)
11 (3.4) 3 (2.6)
69 (21.5) 28 (24.6)
178 (55.5) 73 (64.0)
63 (19.6) 10 (8.8)
240 66 15 26 67 21
59 55.5 62 46 55 57
49 15 5 5 16 7
136 35 7 17 44 12
48 12 3 2 6 2
P .33 .001 .013
.28
.24
.23
.78
(55.2) (15.2) (3.4) (6.0) (15.4) (4.8)
(1–177) (2–138) (17–162) (3–94) (13–126) (1–177)
7 (4.9) 4 (6.1) 0 2 (7.7) 1 (1.5) 0
(20.4) (22.7) (33.3) (19.2) (23.9) (33.3)
(56.7) (53.0) (46.7) (65.4) (65.7) (57.1)
(20) (18.2) (20) (7.7) (9.0) (9.5)
