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Urinary incontinence and other pelvic floor disorders after radiation therapy in endometrial cancer survivors
Accepted Manuscript Title: Urinary incontinence and other pelvic floor disorders after radiation therapy in endometrial cancer survivors Authors: Saya Segal, Gabriella John, Mary Sammel, Uduak Umoh Andy, Christina Chu, Lily A. Arya, Justin Brown, Kathryn Schmitz PII: DOI: Reference:
S0378-5122(16)30407-8 http://dx.doi.org/doi:10.1016/j.maturitas.2017.03.313 MAT 6789
To appear in:
Maturitas
Received date: Accepted date:
6-12-2016 10-3-2017
Please cite this article as: Segal Saya, John Gabriella, Sammel Mary, Andy Uduak Umoh, Chu Christina, Arya Lily A, Brown Justin, Schmitz Kathryn.Urinary incontinence and other pelvic floor disorders after radiation therapy in endometrial cancer survivors.Maturitas http://dx.doi.org/10.1016/j.maturitas.2017.03.313 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
1 Urinary incontinence and other pelvic floor disorders after radiation therapy in
endometrial cancer survivors Short title: Radiation treatment, incontinence, and other pelvic floor disorders in endometrial cancer survivors Saya Segal, MD, MSCE1; Gabriella John, MS2; Mary Sammel, ScD3; Uduak Umoh Andy, MD4; Christina Chu, MD5; Lily A. Arya, MD, MS4; Justin Brown, PhD3; Kathryn Schmitz, PhD, MPH3 1. Division of Female Pelvic Medicine and Reconstructive Surgery, Department of Obstetrics and Gynecology, and Division of Urology, Department of Surgery, Rutgers – Robert Wood Johnson Medical School, New Brunswick, NJ 2. Memorial Sloan‐Kettering Cancer Center, New York, NY 3. Center for Clinical Epidemiology and Biostatistics, and Department of Biostatistics and Epidemiology, University of Pennsylvania Perelman School of Medicine; Philadelphia, PA 4. Division of Urogynecology and Pelvic Reconstructive Surgery, Department of Obstetrics and Gynecology, University of Pennsylvania; Philadelphia, PA 5. Division of Gynecologic Oncology, Fox Chase Cancer Center, Philadelphia, PA Corresponding author: Saya Segal, MD, MSCE 125 Paterson Street, Room 2137 New Brunswick, NJ 08901
2 Phone: 732‐235‐7755 Fax: 732‐235‐7349 Email: [email protected] Highlights Endometrial cancer survivors report high rates of urinary and fecal incontinence. In women treated with radiation, age and body mass index (BMI) are associated with urinary leakage. Radiation therapy is not associated with de novo urinary or fecal incontinence. Sexual function in endometrial cancer survivors may be impaired by radiation therapy. Abstract: Objective: To investigate radiation therapy as a risk factor for urinary or fecal incontinence, pelvic organ prolapse, and sexual dysfunction in endometrial cancer survivors. Study Design: We performed a retrospective cohort study of endometrial cancer survivors. Data were collected using a mailed survey and the medical record. Validated questionnaires were used to generate rates of urinary incontinence and other pelvic floor disorders. The incidence rates of pelvic floor disorders were compared across groups with different exposures to radiation. Results: Of the 149 endometrial cancer survivors, 41% received radiation therapy. Fifty‐one percent of women reported urine leakage. The rates of urinary incontinence in women exposed and not exposed to vaginal brachytherapy (VBT) or whole‐pelvis radiation were 48% and 58%, respectively (p = 0.47). The incidence of fecal incontinence did not differ between groups, but the score for overall sexual function was significantly higher in women who did not undergo radiation therapy. On multivariable analysis, significant risk factors for urinary incontinence
3 were age (AOR 1.06 95% CI 1.02, 1.10) and BMI (AOR 1.07 95% CI 1.02, 1.11), but treatment with radiation was not significantly associated with urinary incontinence, or fecal incontinence (p>0.05). Age, BMI, and radiation exposure were independent predictors of decreased sexual function score (p<0.01). Conclusion: Local or regional radiation is not associated with urinary or fecal incontinence, but may contribute to sexual dysfunction in endometrial cancer survivors. Keywords: urinary incontinence; ; ; ; , fecal incontinence, radiation therapy, sexual dysfunction, endometrial cancer survivors Introduction Uterine cancer, specifically endometrial cancer, is the 4th most common cancer in women representing 7% of the new cancer diagnoses in 2016. The probability of diagnosis of invasive cancer of the uterus throughout a woman’s lifetime is approximately 2.8% based on data from 2010 to 2012. (1) Women diagnosed with endometrial cancer most often undergo hysterectomy and adjuvant radiation therapy is indicated for approximately 45% of these patients based on pathologic findings. (2) Pelvic teletherapy or external beam radiation therapy (EBRT) and vaginal brachytherapy (VBT) may affect the anatomy and function of pelvic organs including the bladder, bowel, and vagina, and may increase the risk for pelvic floor disorders. Prior studies suggest that radiation increases the risk of urinary and fecal incontinence in gynecologic cancer survivors.(3,4) However, these studies have not taken into account common risk factors for pelvic floor disorders and endometrial cancer such as aging, menopause, and obesity. Thus, the role of radiation as a risk factor for urinary incontinence, fecal incontinence, and sexual dysfunction in this population remains unclear.(5) The aim of this study was to
4 investigate radiation therapy as a risk factor for urinary incontinence and other pelvic floor disorders in endometrial cancer survivors. We hypothesized that women who were treated with radiation would have increased rates of urinary and fecal incontinence compared to women who underwent surgery alone. Materials and Methods: We obtained Institutional Review Board approval from the University of Pennsylvania prior to beginning this retrospective cohort study. Potential subjects were identified using fellow surgical case logs from 2008 to 2010 and ICD‐9 diagnosis codes 179.0 (malignant neoplasm of uterus, part unspecified) and 182.0 (malignant neoplasm of corpus uteri, except isthmus) to 182.8 (malignant neoplasm of other specified sites of body of uterus) from 2006 to 2010 electronic medical record query. Uterine corpus cancer survivors 20 years of age and older were included in the study if they were diagnosed between 2006 and 2010. Women who were unable to complete a written survey because of illiteracy, non‐English speaking, or had cognitive impairment were excluded. Death records were not searched prior to recruitment for this study. An initial letter of invitation requested the participation of survivors by completing and returning a mailed survey. Women who desired to opt out of participation were instructed to inform research personnel by phone. Passive assent was assumed if potential subjects did not call within two weeks after the first letter was sent. Those who passively agreed to participate were mailed a 30‐page survey packet and business reply envelope. A second copy of the survey was mailed to the women if no response was received two weeks after the 1st survey packet was mailed.(6) Letters that were returned without a forwarding addressed were marked as undeliverable. Notification by phone or mail that the addressee was deceased was also
5 recorded. The American Association for Public Opinion Research (AAPOR) unadjusted response rate was calculated. (7) The survey included demographic questions, including age, race/ethnicity, menopausal status, marital status, education, parity, height, weight, and medical history for tabulation of Charlson Comorbidity index (8). Uterine cancer characteristics including year of diagnosis, menopausal status at diagnosis, surgical staging (hysterectomy), histology, and treatment regimen were extracted from the electronic medical record. Endometrial cancer diagnosis was confirmed by pathology report in the electronic medical record and this data was used for univariate and multivariate analyses with urinary incontinence and pelvic floor disorder outcomes. In addition, clinical variables missing from survey data were replaced when available from the medical record. The survey contained validated, patient reported instruments to quantify symptoms of urinary incontinence (UI), fecal incontinence, pelvic organ prolapse and sexual dysfunction. UI was defined using the Incontinence Severity Index questionnaire (ISI). (9) The presence of any urinary incontinence is noted as a score > 0. Moderate to severe UI was defined as a score of at least 3 or greater, which corresponds to at least weekly or monthly leakage of more than drops of urine. (9,10,) Stress or urgency urinary incontinence predominant symptoms were measured by the Questionnaire for Urinary Incontinence Diagnosis (QUID). Stress urinary incontinence was defined as stress score of >/= 4 and urgency urinary incontinence was defined as an urge score of >/= 6 as described by the original validation paper. (11) Fecal incontinence was defined as at least monthly leakage of solid, liquid or mucous stool based on responses on the Fecal Incontinence Severity Index (FISI). (12)
6 The Pelvic Floor Distress Inventory (PFDI‐20) question number 3, “Do you usually have a bulge or something falling out that you can see or feel in the vaginal area?” was used to define symptomatic pelvic organ prolapse as described by previous studies. (13,14,15) Sexual function was measured by the Pelvic Organ Prolapse/Urinary Incontinence Sexual questionnaire (PISQ‐12). Responses are measured on a Likert scale with higher scores indicating better function. The maximum possible score of the PISQ is 48. The total PISQ score was calculated for each subject. The 9 general questions address sexual desire, orgasm, sexual excitement, satisfaction, pain, negative emotional reactions, and male partner sexual function. The remaining 3 items address restriction of sexual activity due to urinary or fecal incontinence and bulging in the vagina. The affirmative responses were compared to the negative responses. (16,17) The survey also included questions to assess if survivors had been diagnosed with urinary incontinence, pelvic organ prolapse, or fecal incontinence before their endometrial cancer diagnosis and treatment. The electronic medical record within the University of Pennsylvania Health System was searched to confirm if a pelvic floor disorder diagnosis was made prior to cancer treatment and these women were excluded from multivariable analysis. The primary exposure was radiation treatment with EBRT and/or VBT radiation for endometrial cancer. Radiation treatment was self‐reported in the survey packet. The electronic medical record was used to gather information regarding the type of radiation (EBRT and/or VBT) the women had received. For an analysis based on type of radiation exposure (VBT or EBRT), those that underwent any EBRT for endometrial cancer were analyzed in the EBRT group. The primary outcome of interest was urinary incontinence. Secondary outcomes were fecal incontinence,
7 symptoms of pelvic organ prolapse, the presence of any pelvic floor disorder (urinary or fecal incontinence, or pelvic organ prolapse), and sexual function score. Demographic data (age, BMI, parity, race, menopausal status, Charlson Comorbidity index, education, and marital status) were displayed using means and standard deviation or medians and interquartile ranges as appropriate. To test the association between radiation exposure and demographic and pelvic floor symptoms, unadjusted analyses using nonparametric tests were performed (Pearson Chi square, Fisher’s exact, or Wilcoxon rank sum). Multivariable linear and logistic regression models were used to test the association between radiation exposure and pelvic floor symptoms while adjusting for known risk factors for pelvic floor disorders. A potential confounder was considered within a multivariable model if associated with the primary or secondary outcomes with a P‐value of less than 0.2. (18) The multivariable models were tested for the presence of potential confounders by including the variable in the model if there was a change in odds ratio or regression coefficient for the radiation exposure of 15% or more. Model fit was tested using Akaike Information Criteria (AIC) statistic.(19) Data analysis was performed using STATA 12 IC software (College Station, TX) with a two‐tailed interpretation of test statics and a P‐value less than 0.05 considered statistically significant. Our sample size was calculated using a prevalence of urinary incontinence of 45% and 41% radiation exposure prevalence tabulated from a chart review of our institutions’ data prior to beginning this study.(20) We estimated a sample size of 125 women with endometrial cancer was needed to detect a relative risk of urinary incontinence of 1.6 or greater in women with and without radiation treatment with 80% power and type 1, alpha error of 5%. Results:
8 Demographics: Five‐hundred and forty surveys were mailed, and the survey was returned by 213 uterine cancer survivors. The calculated, unadjusted response rate was 43%.(6,7) The majority of the women in this cohort had a histological diagnosis of endometrioid adenocarcinoma (74.2%) and had stage 1 disease at the time of diagnosis. The uterine cancer pathology of the remaining women was papillary serous or clear cell (16.4%), sarcoma (3.8%), carcinosarcoma (3.8%), and undifferentiated (1.4%). Approximately seven percent of the cohort was treated for recurrent cancer. Endometrial Cancer Cohort Of the 158 endometrial cancer survivors, 149 had radiation exposure data available. The median BMI was 30, and approximately 24% of patients were diagnosed with premenopausal endometrial cancer. Eighty‐seven (58%) survivors did not undergo radiation therapy as treatment for endometrial cancer, and 28 (45%) of the exposed women underwent VBT alone, 34 (55%) were treated with EBRT, and 9 women had no exposure data available. There was no significant difference in clinical and socioeconomic status between the two groups. The median Charlson Comorbidity index was not significantly different between the exposed and unexposed groups. (8) Fewer respondents were diagnosed in 2006 to 2007 compared to 2008 to 2010, but this was not a significant difference when compared to radiation exposure (p=0.70). Hysterectomy was performed via laparotomy in 85(57%), and via minimally invasive techniques in 60(40%). The remaining women did not undergo surgery. (Table 1) Pelvic floor disorders
9 Urinary incontinence was reported by 80 (53%) of endometrial cancer survivors. Of these, 34(43%) of women reporting urine leakage had predominant stress urinary and 31(39%) had urgency urinary incontinence. Fecal incontinence was experienced by 70(46%) of the women in the endometrial cancer cohort. Solid and liquid stool leakage reported by 52(35%) and 43(29%) of survivors, respectively. A bothersome vaginal bulge suggestive of the presence of pelvic organ prolapse was reported by 7(5%) women in this cohort. No woman reported urogenital or gastrointestinal tract fistulas to the pelvic organs or radiation proctitis. There was no significant difference in the rate of urinary and fecal incontinence, and symptomatic pelvic organ prolapse among women exposed and unexposed to radiation (Table 2). Among the 149 endometrial cancer survivors in the cohort, 100 (67%) reported sexual activity in the 6 months prior to receiving the survey. Dyspareunia was reported by 34% of the sexually active cohort. Of the 100 sexually active survivors, the rates of affirmative responses to other sexual symptoms were as follows: 43% had sexual desire, 40% experienced orgasm during intercourse, and 28% felt sexually excited. Overall, 34% were satisfied with the variety of sexual activities and 19% had negative emotional reactions during sex. Restriction of sexual activity because of fear of leaking stool or urine was reported by 8%; urine leakage or vaginal bulge impaired sexual activity in 3% of the sexually active survivors. Twenty percent of women reported that their partner had a problem with erections with premature ejaculation in 7%. The item‐specific or median sexual function score was significantly lower in women exposed to radiation (Table 2). Predictors of pelvic floor disorders
10 Women with a history of UI, FI, or POP before their endometrial cancer treatment were not included in the multivariate analysis. Age and BMI were independently associated with moderate to severe urinary incontinence (ISI score ≥3, p<0.01). There was a 6% or 7% increase in odds of at least moderate urinary incontinence per unit increase in age or BMI, respectively. After controlling for risk factors for pelvic floor disorders (age, race, BMI, parity, Charlson Comorbidity Index, and menopausal status) exposure to radiation therapy was not a predictor of urinary or fecal incontinence and pelvic organ prolapse. In the model using at least monthly fecal incontinence as a dependent variable, age, BMI, and radiation were not significant risk factors. (Table 3). We also examined the relationship between radiation exposure and any pelvic floor disorder, defined as the presence of moderate to severe urinary incontinence or fecal incontinence or vaginal bulge symptoms. Overall, there was an increased odds of having any pelvic floor disorder with increasing age and BMI after controlling for radiation exposure (Table 3). Age, BMI, and radiation exposure were independent predictors of sexual function after controlling for menopause and for every unit increase in cofactors there was a 0.67, 0.26, or 7.30 unit decrease in sexual function score, respectively (p<0.01). An independent relationship between type of radiation exposure and urinary or fecal incontinence, sexual function score, or composite pelvic floor disorders was not noted. Comment: Our present study of endometrial cancer survivors, which had sufficient statistical power to detect an odds ratio of 1.6 or higher for UI, only age and BMI emerged as risk factors for de novo moderate to severe urinary incontinence. Radiation treatment was associated with decreased sexual function after adjustment for these other risk factors. The rates of stress or urgency
11 urinary incontinence, and fecal incontinence type did not differ significantly between women exposed and unexposed to radiation. Prior studies have reported that radiation is associated with urinary incontinence in uterine cancer survivors.(3,4) Erekson et al (2009) performed cross‐sectional study of endometrial cancer survivors of whom 52% reported at least moderate urinary incontinence symptoms. Approximately 36% of the patients reported having adjuvant radiation therapy, and an association was noted between urinary leakage and radiation therapy, but multivariate analysis was not performed controlling for known risk factors for urinary incontinence.(3) Nout RA et al (2011) surveyed long‐term quality of life outcomes of endometrial cancer survivors from the PORTEC‐1 trial exposed to EBRT compared to no radiation at median follow‐up of 13.3 years after treatment. EBRT was significantly associated with urinary and fecal incontinence after controlling only for age, arthropathy, and diabetes. (4) Of note, 30% of those exposed to EBRT underwent a regimen with parallel opposing fields, which has been shown to a higher rate of late complications when compared to the contemporary multiple field EBRT regimen.(4,21) The PORTEC‐2 trial evaluated long‐term bowel and bladder effects after EBRT or vaginal brachytherapy (VBT). Those in the EBRT group had worse fecal leakage and urinary urgency with comparable covariates of irritable bowel syndrome, diabetes, hypertension, and cardiovascular disease.(22). The late effects of traditional methods of EBRT have yet to be evaluated in our cohort and may negatively influence bladder function. (22) Age and obesity are well known risk factors for both endometrial cancer and pelvic floor disorders. (23, 24, 25) As our study population included endometrial cancer survivors, the majority of women in our cohort were obese (median BMI = 30 kg/m^2). Obese women are at increased risk for endometrial (uterine) cancer caused by excess endogenous estrogen produced
12 by peripheral adipose tissue. (26) In our study, advanced age and BMI emerged as predictors of moderate to severe urinary incontinence as noted on multivariate analysis. The interaction of risk factors for pelvic floor disorders may be best conceptualized using the lifespan approach including predisposing, inciting, and intervening factors with an accumulation of risk over time. (27, 28). Comorbidities which may be risk factors for pelvic floor disorders such as diabetes, connective tissue disease, heart disease, cerebrovascular disease, dementia, chronic obstructive pulmonary disease, hemiplegia, and renal disease were included in the multivariable models using the Charlson Comorbidity Index, but severity and duration of these diseases were not captured.(8) The Charlson Comorbidity Index may also serve as a surrogate marker for significant smoking history as several of the diseases are exacerbated by smoking.(8) Obstetric history, including delivery type or parity, was not significantly associated with pelvic floor disorders in this predominantly Caucasian and postmenopausal population of endometrial cancer survivors. The prevalence of pelvic floor disorders in our cohort is similar to previously reported rates in cancer survivors. (3,29) Leakage of urine was the most common pelvic floor disorder with 26% of the survivors reporting moderate to severe symptoms. This rate of clinically significant urinary incontinence in survivors is higher than the 16% rate previously reported in community dwelling women.(15) Similarly, fecal incontinence was very common in our cohort with about 47% of the survivors reporting fecal incontinence. A recent study by Rutledge et al reported similar rates of fecal incontinence (43%) in gynecologic cancer survivors.(29) This rate is higher than rates of fecal incontinence in community dwelling women.(15) Bothersome bulge symptoms attributable to pelvic organ prolapse were reported by only 5% of the women in this study. This may be lower than the true rate because the sensitivity of a questionnaire to measure symptoms of prolapse is low. (30) Alternatively,
13 external beam and vaginal brachytherapy may result in vaginal shortening and narrowing that may preclude the development of pelvic organ prolapse. (31) We report a high rate of sexual dysfunction in this population of uterine cancer survivors. Though 67% of the cohort reported sexual activity in the previous 6 months, 57% reported impaired sexual desire, 72% denied sexual excitement, and only 40% experienced orgasms during intercourse. Overall, 34% of survivors were satisfied with sexual activities. This rate is in agreement with the general rate of sexual dysfunction reported for gynecologic cancer survivors (29). The items contributing most to the low median sexual function score in our cohort of uterine cancer survivors were lack of sexual desire, excitement, and problems with orgasm. The presence of urinary or fecal incontinence and vaginal bulge interfering with intercourse was infrequently reported. Dyspareunia rates and sexual function scores were significantly different in women exposed and unexposed to VBT and/or EBRT. We found an association between declining sexual function with age, BMI, and radiation exposure. Another recent study did not find significant differences in sexual function of women treated with vaginal brachytherapy compared to surgery alone. (32) Long‐term outcomes of survivors treated with EBRT compared to no additional treatment did not show differences in sexual functioning or symptoms. (4) Our present study has a younger median age (65 vs. 75) and more sexually active women (67% vs. 24%) than prior studies.(4) Furthermore, at 5 years post‐radiation treatment, endometrial cancer survivors report impairment in sexual interest, activity, enjoyment, and vaginal dryness when compared to the general population. (33) Postoperative radiation therapy (EBRT or VBT) in women with endometrial cancer may induce vaginal changes and sexual impairment. (34) Sexual function in
14 women is multifactorial and further evaluation of psychosocial factors, post‐treatment effects, and comorbidities is warranted. There are strengths and limitations to our study. Though our sample size was small and retrospective in design, we took several measures to prevent bias. We used validated questionnaires for the diagnosis of pelvic floor disorders including sexual dysfunction. This response rate is similar to a 42% response rate to a mailed 16‐page survey among colon cancer survivors (6). Information bias is possible in this study, but to minimize this bias we verified exposure data obtained from the survivors using the medical record. The study was not powered to evaluate the association between type or regimen of radiation exposure for endometrial cancer treatment and pelvic floor symptoms. Recall bias is also possible and the medical record was screened for complaints of pelvic floor disorders preexisting cancer treatment, and corresponding pelvic symptoms may not have been captured. Finally, there is a potential for selection bias as women who returned the survey may be more likely to have pelvic floor symptoms. In conclusion, pelvic floor dysfunction is common in women treated for endometrial cancer. Similar to the general population, age and BMI are important risk factors for moderate to severe urinary incontinence in endometrial cancer survivors. Our study provides data that treatment with radiation may not be associated with an increased risk for de novo, post‐treatment pelvic floor disorders. Modifiable risk factors for pelvic floor disorders should be addressed by clinicians because of the high survivorship of this cancer and the potential negative effect on quality of life. Contributors All authors saw and approved the final version of the submitted manuscript.
15 Conflict of interest The authors declare that they have no conflict of interest. Funding The primary author was funded by a NIH T32 grant during the course of study design and data collection/analysis, and manuscript preparation. Ethical approval We obtained Institutional Review Board approval from the University of Pennsylvania prior to beginning this retrospective cohort study. Provenance and peer review This article has undergone peer review. Acknowledgement Dr. Saya Segal was supported by grant: T32HD007440‐17. References 1. Siegel R, Ward E, Miler KD, Jemal A SO. Cancer statistics, 2016; CA Cancer J Clin. 2016; 66: 7‐ 30 2. Delaney G, Jacob S, Barton M. Estimation of an optimal radiotherapy utilization rate for gynecologic carcinoma: part II—carcinoma of the endometrium. Cancer 2004; 101: 682, 3. Erekson EA, Sung VW, DiSilvestro PA, Myers DL. Urinary symptoms and impact on quality of life in women after treatment for endometrial cancer. Int Urogynecol J Pelvic Floor Dysfunct 2009; 20(2): 159‐163. 4. Nout RA, van de Poll‐Franse LV, Lybeert ML, et al. Long‐term outcome and quality of life of patients with endometrial carcinoma treated with or without pelvic radiotherapy in the post
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17 12. Rockwood TH, Church JM, Fleshman JW, Kane RL, Mavrantonis C, Thorson AG, Wexner SD, Bliss D, Lowry AC. Patient and surgeon ranking of the severity of symptoms associated with fecal incontinence. The fecal incontinence severity index. Diseases of the Colon and Rectum 1999; 42: 1525‐1531. 13. Barber MD, Walters MD, Bump RC. Short forms for two condition‐specific quality of life questionnaires for women with pelvic floor disorders (PFDI‐20 and PFIQ‐7). Am J Obstet Gynecol 2005; 193:103–113. 14. Rortveit G, Brown JS, Thom DH et al. Symptomatic pelvic organ prolapse: prevalence and risk factors in a population‐based, racially diverse cohort. Obstet Gynecol 2007; 109(6): 1396– 1403. 15. Nygaard I, Barber MD, Burgio KL, Kenton K, Meikle S, Schaffer J, Spino C, Whitehead WE, Wu J, Brody DJ; Pelvic Floor Disorders Network. Prevalence of symptomatic pelvic floor disorders in US women. JAMA 2008; 300: 1311‐6. 16. Rogers RG, Coates KW, Kammerer‐Doak D, Khalsa S, Qualis C. A short form of the pelvic organ prolapse/urinary incontinence sexual questionnaire (PISQ‐12). Int Urogynecol J Pelvic Floor Dysfunct 2003; 14: 164‐8.
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21 Table 1: DEMOGRAPHIC DATA OF ENDOMETRIAL CANCER SURVIVORS Variable
No radiation
Radiation therapy**
P value
(n= 87)
(n= 62)
Age (median)
63 (58 ‐67)
64 (58‐71)
0.32*
BMI (kg/m2)
30.8 (25.4‐37.5)
30.3 (25.4‐35.6)
0.64*
Parity (median, IQR¥)
2(1‐3)
2(0‐3)
0.40*
Caucasian Race,
76 (87.4)
54 (87.0)
0.97†
65 (74.7)
48 (77.4)
0.18†
2(2‐3)
2(2‐4)
0.99*
59 (67.8)
31 (50.0)
0.17†
21 (24.1)
13(21.0)
0.66†
Stage at diagnosis, n (%)
1
74 (85.1)
n (%) Menopausal at diagnosis, n (%) Charlson comorbidity index (median) Marital status , n(%) (married or living with partner) Education, n (%) (graduate of college or university)
22 2
4 (4.6)
46 (74.2)
3
6 (6.9)
6 (9.7)
4
0 (0)
8 (12.9)
0.27†
1 (1.6) Year of diagnosis, n (%)
2006
2007
9 (10.3)
9 (14.5)
0.70†
2008
13 (14.9)
9 (14.5)
2009
16 (18.4)
11 (17.7)
2010
23 (26.4)
19 (30.6)
26 (29.9)
14 (22.6)
Hysterectomy type, n(%)
Total Abdominal
Laparoscopic assisted‐Vaginal
46 (52.9)
39 (62.9)
0.35†
11 (12.6)
13 (21.0)
27 (31.0)
9 (14.5)
hysterectomy Robotic‐assisted
23 ¥
Interquartile range
*Wilcoxon ranksum †Chi square analysis **Vaginal brachytherapy and/or whole pelvis radiation Table 2. RELATIONSHIP BETWEEN EXPOSURE TO RADIATION AND PELVIC FLOOR DISORDERS IN ENDOMETRIAL CANCER SURVIVORS
Pelvic floor symptom
No radiation
Radiation therapy**
(n= 87)
(n= 62)
P value
24
Any urinary leakage, n (%)
50 (57.5)
30 (48.4)
0.47
24 (27.5)
14 (22.6)
0.78
21 (24.1)
13 (21.0)
0.81
23 (26.4)
8 (13.0)
0.13
3 (3.4)
4 (6.5)
0.33
42(48.3)
28 (45.2)
0.66
8 (9.2)
4(6.5)
0.38
Moderate to severe urinary incontinence, n (%)
Stress urinary incontinence, n (%)
Urgency urinary incontinence, n (%)
Pelvic organ prolapse (bulge), n (%)
Any fecal incontinence, n (%)
Mucous leakage
25 Liquid stool leakage Solid stool leakage
Sexual function score* (median, IQR)
29 (33.3)
14 (22.6)
0.29
32 (36.8)
20 (32.3)
0.31
32(16‐38)
21 (0‐34)
0.03
* Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire score (PISQ‐12) **Vaginal brachytherapy and/or whole pelvis radiation Table 3: ADJUSTED ODDS RATIOS FOR PELVIC FLOOR DISORDERS IN ENDOMETRIAL CANCER SURVIVORS: MULTIVARIATE ANALYSIS
Any urinary
Moderate to Stress
Urgency
Fecal
Sexual
Any
incontinenc
severe
urinary
incontinen
functio
pelvic
ce
n
floor
e
urinary
26 urinary
Age*
incontinenc
incontinen
incontinence e
ce
1.03 (0.99,
1.06 (1.02,
1.04 (1.01,
1.07 (1.02,
1.06)
1.10)
1.09)
1.13)
score
disord er†
‐‐
‐0.67
1.04
(‐0.99,
(1.01,
‐
1.08)
0.35)** Body
1.07 (1.02,
mass index*
Radiatio n therapy
1.07
1.05 (1.01,
(1.02 ,1.11)
1.09)
‐‐
0.75(0.32,1.7
‐‐
0.34
(0.13, 1.10)
2)
‐0.26
1.05
(‐0.51,
(1.01,
‐.02)**
1.09)
0.51(0.39,
‐7.30 (‐
0.56
1.60)
12.4, ‐
(0.27,1
1.11)
‐‐
‐‐
2.17)** .14)
*
* AOR and 95% CI (adjusted for age, race, BMI, parity, Charlson Comorbidity Index, and menopausal status) ** Linear regression coefficient and 95% CI † Moderate to severe urinary incon nence, fecal incon nence, or vaginal bulge symptoms
S0378-5122(16)30407-8 http://dx.doi.org/doi:10.1016/j.maturitas.2017.03.313 MAT 6789
To appear in:
Maturitas
Received date: Accepted date:
6-12-2016 10-3-2017
Please cite this article as: Segal Saya, John Gabriella, Sammel Mary, Andy Uduak Umoh, Chu Christina, Arya Lily A, Brown Justin, Schmitz Kathryn.Urinary incontinence and other pelvic floor disorders after radiation therapy in endometrial cancer survivors.Maturitas http://dx.doi.org/10.1016/j.maturitas.2017.03.313 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
1 Urinary incontinence and other pelvic floor disorders after radiation therapy in
endometrial cancer survivors Short title: Radiation treatment, incontinence, and other pelvic floor disorders in endometrial cancer survivors Saya Segal, MD, MSCE1; Gabriella John, MS2; Mary Sammel, ScD3; Uduak Umoh Andy, MD4; Christina Chu, MD5; Lily A. Arya, MD, MS4; Justin Brown, PhD3; Kathryn Schmitz, PhD, MPH3 1. Division of Female Pelvic Medicine and Reconstructive Surgery, Department of Obstetrics and Gynecology, and Division of Urology, Department of Surgery, Rutgers – Robert Wood Johnson Medical School, New Brunswick, NJ 2. Memorial Sloan‐Kettering Cancer Center, New York, NY 3. Center for Clinical Epidemiology and Biostatistics, and Department of Biostatistics and Epidemiology, University of Pennsylvania Perelman School of Medicine; Philadelphia, PA 4. Division of Urogynecology and Pelvic Reconstructive Surgery, Department of Obstetrics and Gynecology, University of Pennsylvania; Philadelphia, PA 5. Division of Gynecologic Oncology, Fox Chase Cancer Center, Philadelphia, PA Corresponding author: Saya Segal, MD, MSCE 125 Paterson Street, Room 2137 New Brunswick, NJ 08901
2 Phone: 732‐235‐7755 Fax: 732‐235‐7349 Email: [email protected] Highlights Endometrial cancer survivors report high rates of urinary and fecal incontinence. In women treated with radiation, age and body mass index (BMI) are associated with urinary leakage. Radiation therapy is not associated with de novo urinary or fecal incontinence. Sexual function in endometrial cancer survivors may be impaired by radiation therapy. Abstract: Objective: To investigate radiation therapy as a risk factor for urinary or fecal incontinence, pelvic organ prolapse, and sexual dysfunction in endometrial cancer survivors. Study Design: We performed a retrospective cohort study of endometrial cancer survivors. Data were collected using a mailed survey and the medical record. Validated questionnaires were used to generate rates of urinary incontinence and other pelvic floor disorders. The incidence rates of pelvic floor disorders were compared across groups with different exposures to radiation. Results: Of the 149 endometrial cancer survivors, 41% received radiation therapy. Fifty‐one percent of women reported urine leakage. The rates of urinary incontinence in women exposed and not exposed to vaginal brachytherapy (VBT) or whole‐pelvis radiation were 48% and 58%, respectively (p = 0.47). The incidence of fecal incontinence did not differ between groups, but the score for overall sexual function was significantly higher in women who did not undergo radiation therapy. On multivariable analysis, significant risk factors for urinary incontinence
3 were age (AOR 1.06 95% CI 1.02, 1.10) and BMI (AOR 1.07 95% CI 1.02, 1.11), but treatment with radiation was not significantly associated with urinary incontinence, or fecal incontinence (p>0.05). Age, BMI, and radiation exposure were independent predictors of decreased sexual function score (p<0.01). Conclusion: Local or regional radiation is not associated with urinary or fecal incontinence, but may contribute to sexual dysfunction in endometrial cancer survivors. Keywords: urinary incontinence; ; ; ; , fecal incontinence, radiation therapy, sexual dysfunction, endometrial cancer survivors Introduction Uterine cancer, specifically endometrial cancer, is the 4th most common cancer in women representing 7% of the new cancer diagnoses in 2016. The probability of diagnosis of invasive cancer of the uterus throughout a woman’s lifetime is approximately 2.8% based on data from 2010 to 2012. (1) Women diagnosed with endometrial cancer most often undergo hysterectomy and adjuvant radiation therapy is indicated for approximately 45% of these patients based on pathologic findings. (2) Pelvic teletherapy or external beam radiation therapy (EBRT) and vaginal brachytherapy (VBT) may affect the anatomy and function of pelvic organs including the bladder, bowel, and vagina, and may increase the risk for pelvic floor disorders. Prior studies suggest that radiation increases the risk of urinary and fecal incontinence in gynecologic cancer survivors.(3,4) However, these studies have not taken into account common risk factors for pelvic floor disorders and endometrial cancer such as aging, menopause, and obesity. Thus, the role of radiation as a risk factor for urinary incontinence, fecal incontinence, and sexual dysfunction in this population remains unclear.(5) The aim of this study was to
4 investigate radiation therapy as a risk factor for urinary incontinence and other pelvic floor disorders in endometrial cancer survivors. We hypothesized that women who were treated with radiation would have increased rates of urinary and fecal incontinence compared to women who underwent surgery alone. Materials and Methods: We obtained Institutional Review Board approval from the University of Pennsylvania prior to beginning this retrospective cohort study. Potential subjects were identified using fellow surgical case logs from 2008 to 2010 and ICD‐9 diagnosis codes 179.0 (malignant neoplasm of uterus, part unspecified) and 182.0 (malignant neoplasm of corpus uteri, except isthmus) to 182.8 (malignant neoplasm of other specified sites of body of uterus) from 2006 to 2010 electronic medical record query. Uterine corpus cancer survivors 20 years of age and older were included in the study if they were diagnosed between 2006 and 2010. Women who were unable to complete a written survey because of illiteracy, non‐English speaking, or had cognitive impairment were excluded. Death records were not searched prior to recruitment for this study. An initial letter of invitation requested the participation of survivors by completing and returning a mailed survey. Women who desired to opt out of participation were instructed to inform research personnel by phone. Passive assent was assumed if potential subjects did not call within two weeks after the first letter was sent. Those who passively agreed to participate were mailed a 30‐page survey packet and business reply envelope. A second copy of the survey was mailed to the women if no response was received two weeks after the 1st survey packet was mailed.(6) Letters that were returned without a forwarding addressed were marked as undeliverable. Notification by phone or mail that the addressee was deceased was also
5 recorded. The American Association for Public Opinion Research (AAPOR) unadjusted response rate was calculated. (7) The survey included demographic questions, including age, race/ethnicity, menopausal status, marital status, education, parity, height, weight, and medical history for tabulation of Charlson Comorbidity index (8). Uterine cancer characteristics including year of diagnosis, menopausal status at diagnosis, surgical staging (hysterectomy), histology, and treatment regimen were extracted from the electronic medical record. Endometrial cancer diagnosis was confirmed by pathology report in the electronic medical record and this data was used for univariate and multivariate analyses with urinary incontinence and pelvic floor disorder outcomes. In addition, clinical variables missing from survey data were replaced when available from the medical record. The survey contained validated, patient reported instruments to quantify symptoms of urinary incontinence (UI), fecal incontinence, pelvic organ prolapse and sexual dysfunction. UI was defined using the Incontinence Severity Index questionnaire (ISI). (9) The presence of any urinary incontinence is noted as a score > 0. Moderate to severe UI was defined as a score of at least 3 or greater, which corresponds to at least weekly or monthly leakage of more than drops of urine. (9,10,) Stress or urgency urinary incontinence predominant symptoms were measured by the Questionnaire for Urinary Incontinence Diagnosis (QUID). Stress urinary incontinence was defined as stress score of >/= 4 and urgency urinary incontinence was defined as an urge score of >/= 6 as described by the original validation paper. (11) Fecal incontinence was defined as at least monthly leakage of solid, liquid or mucous stool based on responses on the Fecal Incontinence Severity Index (FISI). (12)
6 The Pelvic Floor Distress Inventory (PFDI‐20) question number 3, “Do you usually have a bulge or something falling out that you can see or feel in the vaginal area?” was used to define symptomatic pelvic organ prolapse as described by previous studies. (13,14,15) Sexual function was measured by the Pelvic Organ Prolapse/Urinary Incontinence Sexual questionnaire (PISQ‐12). Responses are measured on a Likert scale with higher scores indicating better function. The maximum possible score of the PISQ is 48. The total PISQ score was calculated for each subject. The 9 general questions address sexual desire, orgasm, sexual excitement, satisfaction, pain, negative emotional reactions, and male partner sexual function. The remaining 3 items address restriction of sexual activity due to urinary or fecal incontinence and bulging in the vagina. The affirmative responses were compared to the negative responses. (16,17) The survey also included questions to assess if survivors had been diagnosed with urinary incontinence, pelvic organ prolapse, or fecal incontinence before their endometrial cancer diagnosis and treatment. The electronic medical record within the University of Pennsylvania Health System was searched to confirm if a pelvic floor disorder diagnosis was made prior to cancer treatment and these women were excluded from multivariable analysis. The primary exposure was radiation treatment with EBRT and/or VBT radiation for endometrial cancer. Radiation treatment was self‐reported in the survey packet. The electronic medical record was used to gather information regarding the type of radiation (EBRT and/or VBT) the women had received. For an analysis based on type of radiation exposure (VBT or EBRT), those that underwent any EBRT for endometrial cancer were analyzed in the EBRT group. The primary outcome of interest was urinary incontinence. Secondary outcomes were fecal incontinence,
7 symptoms of pelvic organ prolapse, the presence of any pelvic floor disorder (urinary or fecal incontinence, or pelvic organ prolapse), and sexual function score. Demographic data (age, BMI, parity, race, menopausal status, Charlson Comorbidity index, education, and marital status) were displayed using means and standard deviation or medians and interquartile ranges as appropriate. To test the association between radiation exposure and demographic and pelvic floor symptoms, unadjusted analyses using nonparametric tests were performed (Pearson Chi square, Fisher’s exact, or Wilcoxon rank sum). Multivariable linear and logistic regression models were used to test the association between radiation exposure and pelvic floor symptoms while adjusting for known risk factors for pelvic floor disorders. A potential confounder was considered within a multivariable model if associated with the primary or secondary outcomes with a P‐value of less than 0.2. (18) The multivariable models were tested for the presence of potential confounders by including the variable in the model if there was a change in odds ratio or regression coefficient for the radiation exposure of 15% or more. Model fit was tested using Akaike Information Criteria (AIC) statistic.(19) Data analysis was performed using STATA 12 IC software (College Station, TX) with a two‐tailed interpretation of test statics and a P‐value less than 0.05 considered statistically significant. Our sample size was calculated using a prevalence of urinary incontinence of 45% and 41% radiation exposure prevalence tabulated from a chart review of our institutions’ data prior to beginning this study.(20) We estimated a sample size of 125 women with endometrial cancer was needed to detect a relative risk of urinary incontinence of 1.6 or greater in women with and without radiation treatment with 80% power and type 1, alpha error of 5%. Results:
8 Demographics: Five‐hundred and forty surveys were mailed, and the survey was returned by 213 uterine cancer survivors. The calculated, unadjusted response rate was 43%.(6,7) The majority of the women in this cohort had a histological diagnosis of endometrioid adenocarcinoma (74.2%) and had stage 1 disease at the time of diagnosis. The uterine cancer pathology of the remaining women was papillary serous or clear cell (16.4%), sarcoma (3.8%), carcinosarcoma (3.8%), and undifferentiated (1.4%). Approximately seven percent of the cohort was treated for recurrent cancer. Endometrial Cancer Cohort Of the 158 endometrial cancer survivors, 149 had radiation exposure data available. The median BMI was 30, and approximately 24% of patients were diagnosed with premenopausal endometrial cancer. Eighty‐seven (58%) survivors did not undergo radiation therapy as treatment for endometrial cancer, and 28 (45%) of the exposed women underwent VBT alone, 34 (55%) were treated with EBRT, and 9 women had no exposure data available. There was no significant difference in clinical and socioeconomic status between the two groups. The median Charlson Comorbidity index was not significantly different between the exposed and unexposed groups. (8) Fewer respondents were diagnosed in 2006 to 2007 compared to 2008 to 2010, but this was not a significant difference when compared to radiation exposure (p=0.70). Hysterectomy was performed via laparotomy in 85(57%), and via minimally invasive techniques in 60(40%). The remaining women did not undergo surgery. (Table 1) Pelvic floor disorders
9 Urinary incontinence was reported by 80 (53%) of endometrial cancer survivors. Of these, 34(43%) of women reporting urine leakage had predominant stress urinary and 31(39%) had urgency urinary incontinence. Fecal incontinence was experienced by 70(46%) of the women in the endometrial cancer cohort. Solid and liquid stool leakage reported by 52(35%) and 43(29%) of survivors, respectively. A bothersome vaginal bulge suggestive of the presence of pelvic organ prolapse was reported by 7(5%) women in this cohort. No woman reported urogenital or gastrointestinal tract fistulas to the pelvic organs or radiation proctitis. There was no significant difference in the rate of urinary and fecal incontinence, and symptomatic pelvic organ prolapse among women exposed and unexposed to radiation (Table 2). Among the 149 endometrial cancer survivors in the cohort, 100 (67%) reported sexual activity in the 6 months prior to receiving the survey. Dyspareunia was reported by 34% of the sexually active cohort. Of the 100 sexually active survivors, the rates of affirmative responses to other sexual symptoms were as follows: 43% had sexual desire, 40% experienced orgasm during intercourse, and 28% felt sexually excited. Overall, 34% were satisfied with the variety of sexual activities and 19% had negative emotional reactions during sex. Restriction of sexual activity because of fear of leaking stool or urine was reported by 8%; urine leakage or vaginal bulge impaired sexual activity in 3% of the sexually active survivors. Twenty percent of women reported that their partner had a problem with erections with premature ejaculation in 7%. The item‐specific or median sexual function score was significantly lower in women exposed to radiation (Table 2). Predictors of pelvic floor disorders
10 Women with a history of UI, FI, or POP before their endometrial cancer treatment were not included in the multivariate analysis. Age and BMI were independently associated with moderate to severe urinary incontinence (ISI score ≥3, p<0.01). There was a 6% or 7% increase in odds of at least moderate urinary incontinence per unit increase in age or BMI, respectively. After controlling for risk factors for pelvic floor disorders (age, race, BMI, parity, Charlson Comorbidity Index, and menopausal status) exposure to radiation therapy was not a predictor of urinary or fecal incontinence and pelvic organ prolapse. In the model using at least monthly fecal incontinence as a dependent variable, age, BMI, and radiation were not significant risk factors. (Table 3). We also examined the relationship between radiation exposure and any pelvic floor disorder, defined as the presence of moderate to severe urinary incontinence or fecal incontinence or vaginal bulge symptoms. Overall, there was an increased odds of having any pelvic floor disorder with increasing age and BMI after controlling for radiation exposure (Table 3). Age, BMI, and radiation exposure were independent predictors of sexual function after controlling for menopause and for every unit increase in cofactors there was a 0.67, 0.26, or 7.30 unit decrease in sexual function score, respectively (p<0.01). An independent relationship between type of radiation exposure and urinary or fecal incontinence, sexual function score, or composite pelvic floor disorders was not noted. Comment: Our present study of endometrial cancer survivors, which had sufficient statistical power to detect an odds ratio of 1.6 or higher for UI, only age and BMI emerged as risk factors for de novo moderate to severe urinary incontinence. Radiation treatment was associated with decreased sexual function after adjustment for these other risk factors. The rates of stress or urgency
11 urinary incontinence, and fecal incontinence type did not differ significantly between women exposed and unexposed to radiation. Prior studies have reported that radiation is associated with urinary incontinence in uterine cancer survivors.(3,4) Erekson et al (2009) performed cross‐sectional study of endometrial cancer survivors of whom 52% reported at least moderate urinary incontinence symptoms. Approximately 36% of the patients reported having adjuvant radiation therapy, and an association was noted between urinary leakage and radiation therapy, but multivariate analysis was not performed controlling for known risk factors for urinary incontinence.(3) Nout RA et al (2011) surveyed long‐term quality of life outcomes of endometrial cancer survivors from the PORTEC‐1 trial exposed to EBRT compared to no radiation at median follow‐up of 13.3 years after treatment. EBRT was significantly associated with urinary and fecal incontinence after controlling only for age, arthropathy, and diabetes. (4) Of note, 30% of those exposed to EBRT underwent a regimen with parallel opposing fields, which has been shown to a higher rate of late complications when compared to the contemporary multiple field EBRT regimen.(4,21) The PORTEC‐2 trial evaluated long‐term bowel and bladder effects after EBRT or vaginal brachytherapy (VBT). Those in the EBRT group had worse fecal leakage and urinary urgency with comparable covariates of irritable bowel syndrome, diabetes, hypertension, and cardiovascular disease.(22). The late effects of traditional methods of EBRT have yet to be evaluated in our cohort and may negatively influence bladder function. (22) Age and obesity are well known risk factors for both endometrial cancer and pelvic floor disorders. (23, 24, 25) As our study population included endometrial cancer survivors, the majority of women in our cohort were obese (median BMI = 30 kg/m^2). Obese women are at increased risk for endometrial (uterine) cancer caused by excess endogenous estrogen produced
12 by peripheral adipose tissue. (26) In our study, advanced age and BMI emerged as predictors of moderate to severe urinary incontinence as noted on multivariate analysis. The interaction of risk factors for pelvic floor disorders may be best conceptualized using the lifespan approach including predisposing, inciting, and intervening factors with an accumulation of risk over time. (27, 28). Comorbidities which may be risk factors for pelvic floor disorders such as diabetes, connective tissue disease, heart disease, cerebrovascular disease, dementia, chronic obstructive pulmonary disease, hemiplegia, and renal disease were included in the multivariable models using the Charlson Comorbidity Index, but severity and duration of these diseases were not captured.(8) The Charlson Comorbidity Index may also serve as a surrogate marker for significant smoking history as several of the diseases are exacerbated by smoking.(8) Obstetric history, including delivery type or parity, was not significantly associated with pelvic floor disorders in this predominantly Caucasian and postmenopausal population of endometrial cancer survivors. The prevalence of pelvic floor disorders in our cohort is similar to previously reported rates in cancer survivors. (3,29) Leakage of urine was the most common pelvic floor disorder with 26% of the survivors reporting moderate to severe symptoms. This rate of clinically significant urinary incontinence in survivors is higher than the 16% rate previously reported in community dwelling women.(15) Similarly, fecal incontinence was very common in our cohort with about 47% of the survivors reporting fecal incontinence. A recent study by Rutledge et al reported similar rates of fecal incontinence (43%) in gynecologic cancer survivors.(29) This rate is higher than rates of fecal incontinence in community dwelling women.(15) Bothersome bulge symptoms attributable to pelvic organ prolapse were reported by only 5% of the women in this study. This may be lower than the true rate because the sensitivity of a questionnaire to measure symptoms of prolapse is low. (30) Alternatively,
13 external beam and vaginal brachytherapy may result in vaginal shortening and narrowing that may preclude the development of pelvic organ prolapse. (31) We report a high rate of sexual dysfunction in this population of uterine cancer survivors. Though 67% of the cohort reported sexual activity in the previous 6 months, 57% reported impaired sexual desire, 72% denied sexual excitement, and only 40% experienced orgasms during intercourse. Overall, 34% of survivors were satisfied with sexual activities. This rate is in agreement with the general rate of sexual dysfunction reported for gynecologic cancer survivors (29). The items contributing most to the low median sexual function score in our cohort of uterine cancer survivors were lack of sexual desire, excitement, and problems with orgasm. The presence of urinary or fecal incontinence and vaginal bulge interfering with intercourse was infrequently reported. Dyspareunia rates and sexual function scores were significantly different in women exposed and unexposed to VBT and/or EBRT. We found an association between declining sexual function with age, BMI, and radiation exposure. Another recent study did not find significant differences in sexual function of women treated with vaginal brachytherapy compared to surgery alone. (32) Long‐term outcomes of survivors treated with EBRT compared to no additional treatment did not show differences in sexual functioning or symptoms. (4) Our present study has a younger median age (65 vs. 75) and more sexually active women (67% vs. 24%) than prior studies.(4) Furthermore, at 5 years post‐radiation treatment, endometrial cancer survivors report impairment in sexual interest, activity, enjoyment, and vaginal dryness when compared to the general population. (33) Postoperative radiation therapy (EBRT or VBT) in women with endometrial cancer may induce vaginal changes and sexual impairment. (34) Sexual function in
14 women is multifactorial and further evaluation of psychosocial factors, post‐treatment effects, and comorbidities is warranted. There are strengths and limitations to our study. Though our sample size was small and retrospective in design, we took several measures to prevent bias. We used validated questionnaires for the diagnosis of pelvic floor disorders including sexual dysfunction. This response rate is similar to a 42% response rate to a mailed 16‐page survey among colon cancer survivors (6). Information bias is possible in this study, but to minimize this bias we verified exposure data obtained from the survivors using the medical record. The study was not powered to evaluate the association between type or regimen of radiation exposure for endometrial cancer treatment and pelvic floor symptoms. Recall bias is also possible and the medical record was screened for complaints of pelvic floor disorders preexisting cancer treatment, and corresponding pelvic symptoms may not have been captured. Finally, there is a potential for selection bias as women who returned the survey may be more likely to have pelvic floor symptoms. In conclusion, pelvic floor dysfunction is common in women treated for endometrial cancer. Similar to the general population, age and BMI are important risk factors for moderate to severe urinary incontinence in endometrial cancer survivors. Our study provides data that treatment with radiation may not be associated with an increased risk for de novo, post‐treatment pelvic floor disorders. Modifiable risk factors for pelvic floor disorders should be addressed by clinicians because of the high survivorship of this cancer and the potential negative effect on quality of life. Contributors All authors saw and approved the final version of the submitted manuscript.
15 Conflict of interest The authors declare that they have no conflict of interest. Funding The primary author was funded by a NIH T32 grant during the course of study design and data collection/analysis, and manuscript preparation. Ethical approval We obtained Institutional Review Board approval from the University of Pennsylvania prior to beginning this retrospective cohort study. Provenance and peer review This article has undergone peer review. Acknowledgement Dr. Saya Segal was supported by grant: T32HD007440‐17. References 1. Siegel R, Ward E, Miler KD, Jemal A SO. Cancer statistics, 2016; CA Cancer J Clin. 2016; 66: 7‐ 30 2. Delaney G, Jacob S, Barton M. Estimation of an optimal radiotherapy utilization rate for gynecologic carcinoma: part II—carcinoma of the endometrium. Cancer 2004; 101: 682, 3. Erekson EA, Sung VW, DiSilvestro PA, Myers DL. Urinary symptoms and impact on quality of life in women after treatment for endometrial cancer. Int Urogynecol J Pelvic Floor Dysfunct 2009; 20(2): 159‐163. 4. Nout RA, van de Poll‐Franse LV, Lybeert ML, et al. Long‐term outcome and quality of life of patients with endometrial carcinoma treated with or without pelvic radiotherapy in the post
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21 Table 1: DEMOGRAPHIC DATA OF ENDOMETRIAL CANCER SURVIVORS Variable
No radiation
Radiation therapy**
P value
(n= 87)
(n= 62)
Age (median)
63 (58 ‐67)
64 (58‐71)
0.32*
BMI (kg/m2)
30.8 (25.4‐37.5)
30.3 (25.4‐35.6)
0.64*
Parity (median, IQR¥)
2(1‐3)
2(0‐3)
0.40*
Caucasian Race,
76 (87.4)
54 (87.0)
0.97†
65 (74.7)
48 (77.4)
0.18†
2(2‐3)
2(2‐4)
0.99*
59 (67.8)
31 (50.0)
0.17†
21 (24.1)
13(21.0)
0.66†
Stage at diagnosis, n (%)
1
74 (85.1)
n (%) Menopausal at diagnosis, n (%) Charlson comorbidity index (median) Marital status , n(%) (married or living with partner) Education, n (%) (graduate of college or university)
22 2
4 (4.6)
46 (74.2)
3
6 (6.9)
6 (9.7)
4
0 (0)
8 (12.9)
0.27†
1 (1.6) Year of diagnosis, n (%)
2006
2007
9 (10.3)
9 (14.5)
0.70†
2008
13 (14.9)
9 (14.5)
2009
16 (18.4)
11 (17.7)
2010
23 (26.4)
19 (30.6)
26 (29.9)
14 (22.6)
Hysterectomy type, n(%)
Total Abdominal
Laparoscopic assisted‐Vaginal
46 (52.9)
39 (62.9)
0.35†
11 (12.6)
13 (21.0)
27 (31.0)
9 (14.5)
hysterectomy Robotic‐assisted
23 ¥
Interquartile range
*Wilcoxon ranksum †Chi square analysis **Vaginal brachytherapy and/or whole pelvis radiation Table 2. RELATIONSHIP BETWEEN EXPOSURE TO RADIATION AND PELVIC FLOOR DISORDERS IN ENDOMETRIAL CANCER SURVIVORS
Pelvic floor symptom
No radiation
Radiation therapy**
(n= 87)
(n= 62)
P value
24
Any urinary leakage, n (%)
50 (57.5)
30 (48.4)
0.47
24 (27.5)
14 (22.6)
0.78
21 (24.1)
13 (21.0)
0.81
23 (26.4)
8 (13.0)
0.13
3 (3.4)
4 (6.5)
0.33
42(48.3)
28 (45.2)
0.66
8 (9.2)
4(6.5)
0.38
Moderate to severe urinary incontinence, n (%)
Stress urinary incontinence, n (%)
Urgency urinary incontinence, n (%)
Pelvic organ prolapse (bulge), n (%)
Any fecal incontinence, n (%)
Mucous leakage
25 Liquid stool leakage Solid stool leakage
Sexual function score* (median, IQR)
29 (33.3)
14 (22.6)
0.29
32 (36.8)
20 (32.3)
0.31
32(16‐38)
21 (0‐34)
0.03
* Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire score (PISQ‐12) **Vaginal brachytherapy and/or whole pelvis radiation Table 3: ADJUSTED ODDS RATIOS FOR PELVIC FLOOR DISORDERS IN ENDOMETRIAL CANCER SURVIVORS: MULTIVARIATE ANALYSIS
Any urinary
Moderate to Stress
Urgency
Fecal
Sexual
Any
incontinenc
severe
urinary
incontinen
functio
pelvic
ce
n
floor
e
urinary
26 urinary
Age*
incontinenc
incontinen
incontinence e
ce
1.03 (0.99,
1.06 (1.02,
1.04 (1.01,
1.07 (1.02,
1.06)
1.10)
1.09)
1.13)
score
disord er†
‐‐
‐0.67
1.04
(‐0.99,
(1.01,
‐
1.08)
0.35)** Body
1.07 (1.02,
mass index*
Radiatio n therapy
1.07
1.05 (1.01,
(1.02 ,1.11)
1.09)
‐‐
0.75(0.32,1.7
‐‐
0.34
(0.13, 1.10)
2)
‐0.26
1.05
(‐0.51,
(1.01,
‐.02)**
1.09)
0.51(0.39,
‐7.30 (‐
0.56
1.60)
12.4, ‐
(0.27,1
1.11)
‐‐
‐‐
2.17)** .14)
*
* AOR and 95% CI (adjusted for age, race, BMI, parity, Charlson Comorbidity Index, and menopausal status) ** Linear regression coefficient and 95% CI † Moderate to severe urinary incon nence, fecal incon nence, or vaginal bulge symptoms