Abstract
Objective:
Pelvic floor dysfunction is a common adverse effect of uterine cancer treatment. In this study, we compared patient-reported outcomes regarding pelvic floor dysfunction among uterine cancer survivors after hysterectomy and bilateral salpingo-oophorectomy; surgery and brachytherapy; or surgery and external beam radiotherapy with or without brachytherapy vs. women who had a hysterectomy for benign indications.
Methods:
We used the validated, 20-item Pelvic Floor Distress Inventory to assess lower urinary distress, colorectal distress, and pelvic organ prolapse dysfunction in each treatment group. Pelvic floor dysfunction-related quality of life in these domains was compared across treatment modalities with the Pelvic Floor Impact Questionnaire-7. Treatment type, body mass index, comorbidities, and number of vaginal births were obtained from medical records. A zero-inflated negative binomial regression model was used to assess the association of treatment regimens and covariates relative to the non-cancer cohort.
Results:
A total of 309 surveys were analyzed; patients’ median age at surgery was 57 years (range, 20–87) and median age at survey completion was 66 years (range, 34–92). Most participants reported experiencing at least 1 symptom of pelvic floor dysfunction (75% by Pelvic Floor Distress Inventory-20, 76% by Pelvic Floor Impact Questionnaire-7). Type of treatment had no effect on overall pelvic floor dysfunction on multivariate analysis (all p>0.05). Worse urinary-related symptoms were associated with higher body mass index at surgery (OR=1.41), higher age at time of survey (OR=1.07), and higher numbers of vaginal births (OR = 1.43) (all p<0.05).
Conclusions:
Overall pelvic floor dysfunction did not significantly vary by treatment modality. Our findings suggest complex interactions among age, body mass index, and parity as to how uterine cancer treatment affects pelvic-floor quality of life that should be considered in the choice of treatment strategy and patient counseling.
Keywords: Hysterectomy, Radiotherapy, Quality of life, Uterine cancer, Pelvic Floor Dysfunction, Incontinence
PRECIS
Treatment modality for uterine cancer survivors did not significantly alter pelvic floor dysfunction when other common co-morbidities including BMI, age, and number of vaginal births were factored.
INTRODUCTION
Uterine cancer is the most common gynecologic cancer in the United States, with approximately 66,750 new cases and 12,290 deaths each year.1 Uterine cancer is the second most prevalent cancer among women in the United States, with an estimated 807,860 survivors,2 and its incidence continues to rise by approximately 1% per year.3 Treatment is often multimodal and can include surgery, radiation (brachytherapy or external-beam), chemotherapy, or a combination depending on stage, histology, and other risk factors.4 Prolonged survivorship underscores the importance of documenting long-term side effects among survivors, particularly pelvic floor dysfunction and its resulting effects on quality of life (QoL).
Pelvic floor dysfunction includes multiple symptoms including pelvic organ prolapse, colorectal–anal distress, and urinary incontinence. Pelvic floor issues are relatively common, even among women without gynecologic cancer; 1 in 4 women in the United States is estimated to have at least one pelvic floor disorder, most commonly urinary incontinence.5 Uterine cancer and its treatment can result in further pelvic floor dysfunction due to damage to vascular, neurological, muscular, and connective tissue.6,7 Pelvic floor dysfunction after treatment of uterine cancer has been assessed to some degree, but most studies have focused on other gynecologic cancers, aggregate all gynecologic cancers, focus on surgical details, or assess relatively small patient groups.8–13
The objective of this study was to assess and compare pelvic floor dysfunction and corresponding QoL among uterine cancer survivors after different forms of treatment, including surgery alone (hysterectomy and bilateral salpingo-oophorectomy), surgery with vaginal brachytherapy, and surgery with external-beam radiation therapy; these were compared against those from a cohort of patients who had undergone surgery for benign indications.
METHODS
This study was a single-institution, cross-sectional, survey study (National Clinical Trial 04634617) in which patients with uterine cancer were grouped according to common treatment paradigms: surgery only; surgery and brachytherapy; and surgery and external beam radiation therapy (Appendix 1). The control group consisted of women who underwent hysterectomy and bilateral salpingo-oophorectomy for benign indications. Patients were contacted via a combination of email, calling, and standard mail (Appendix 2). The cancer cohorts included uterine cancer survivors that had been treated from 2006–2017 with at least 1-year follow up, no recurrence, and no other malignancies. The non-cancer cohort were women receiving care at the institution’s cancer prevention clinic from January 2017 and June 2020 who had a hysterectomy and bilateral salpingo-oophorectomy at any point in their history. Adjuvant radiation treatment following surgery consisted of high-dose rate vaginal brachytherapy to 30 Gy in 5 fractions or external beam radiation to 45–50.4 Gy in 25–28 fractions and brachytherapy to 10 Gy in 2 fractions. Concurrent chemotherapy typically consisted of cisplatin 40 mg/m2 weekly for 5–6 cycles.
Study measures included the Pelvic Floor Distress inventory-20 (Appendix 3) to assess pelvic floor dysfunction and the Pelvic Floor Impact Questionnaire-7 (Appendix 4) which is a corresponding survey to assess impact of pelvic floor dysfunction symptoms on QoL.14 Both instruments use subscales in three domains: urinary, colorectal, and prolapse symptoms. Each subscale is scored from 0–100 and summed for a total score of 300; higher scores represent worse symptoms or greater impact on QoL. Additional demographic and treatment variables were collected including age and body mass index (BMI), smoking history, number of vaginal births, and Charlson comorbidity index.15
Descriptive statistics were used to summarize patient characteristics. Cohort comparisons were tested initially with the Kruskal-Wallis test, an omnibus test, and a one-way ANOVA, where appropriate; findings found to be significant on the omnibus test (p<0.05) were followed by pair-wise comparisons using the Wilcoxon rank-sum test and a Bonferroni-corrected p-value of <0.0083. Categorical variables were compared by using chi-squared or Fisher’s exact tests as appropriate. A zero-inflated negative binomial regression model, which includes both a logit component (comparing a zero response to a non-zero) and a negative binomial (comparing mean response score) was used for univariate and multivariate modeling. Detailed methodology including study design, survey design, and statistical analysis is further elaborated in Appendix 1. In accordance with the journal’s guidelines, we will provide our data for the reproducibility of this study in other centers if such is requested.
RESULTS
Patient and treatment characteristics
Of 852 eligible patients who were contacted, 309 (36%) questionaries were returned and available for analysis: 64 surgery-only, 77 brachytherapy, 96 external beam, and 72 non-cancer (Appendix 2). Most women were White (88%) and had no history of smoking (73%). Other characteristics are summarized in Table 1. Median age at survey completion was 66 years (range, 34–92) and differed among the various treatment groups: surgery-only 66 (range, 41–89); brachytherapy 68 (range, 45–90); external beam 68 (range, 34–92); and non-cancer 62 (range, 45–78) (p<0.003). The median age at the time of surgery also differed among groups: surgery-only 58 years, brachytherapy 62 years, external beam 61 years, and non-cancer 43 years (p=0.0001). The BMI values differed among groups at both surgery and survey completion: median BMI at surgery was 29 kg/m2 (surgery-only 33 kg/m2, brachytherapy 28 kg/m2, external beam 28 kg/m2, and non-cancer 27 kg/m2; P<0.001) and median BMI at survey completion was 28 kg/m2 (surgery-only 32 kg/m2, brachytherapy 28 kg/m2, external beam 28 kg/m2, non-cancer 26 kg/m2 (p<0.001)). The number of vaginal births per patient differed across cohorts, with an overall median of 1 (surgery-only 1, brachytherapy 2, external beam 0, non-cancer 1, p=0.018). No significant differences were noted among cohorts in race (p=0.34), smoking history (p=0.59), Charlson comorbidity index (p=0.19), or cups of caffeine consumed daily (p=0.77).
Table 1.
Patient characteristics by treatment group
| Non-CA | HS | BT | EBRT | P value | Total | |
|---|---|---|---|---|---|---|
|
| ||||||
| Age at Surgery | n=62 | n=64 | n=77 | n=95 | N=298 | |
| Mean ± SD | 43.8 ± 8.7 | 58.1 ± 9.2 | 62.0 ± 8.6 | 60.6 ± 10.4 | <0.001a | 57.0 ± 11.6 |
| Median (Min to Max) | 43 (20–64)1,2,3 | 58 (32–76)1 | 62 (37–83)2 | 62 (27–87)3 | <0.001b | 58 (20–87) |
| Age at Survey Completion | n=72 | n=64 | n=77 | n=96 | N=309 | |
| Mean ± SD | 62.7 ± 8.2 | 66.0 ± 9.6 | 68.1 ± 8.4 | 66.4 ± 10.9 | 0.006a | 65.9 ± 9.6 |
| Median (Min to Max) | 62 (45–78)1,2 | 66 (41–89) | 68 (45–90)1 | 68 (34–92)2 | 0.003b | 66 (34–92) |
| BMI at Surgery | n=69 | n=64 | n=75 | n=93 | N=301 | |
| Mean ± SD | 27.9 ± 5.65 | 34.6 ± 10.0 | 31.0 ± 8.8 | 30.5 ± 8.9 | <0.001a | 30.9 ± 8.8 |
| Median (Min to Max) | 27 (19–41)1 | 33 (19–66)1,2 | 28 (18–68) | 28(18–56)2 | 0.001b | 29(18–68) |
| BMI at Survey Completion | n=65 | n=64 | n=77 | n=96 | N=302 | |
| Mean ± SD | 26.8 ± 5.6 | 33.4 ± 9.9 | 29.9 ± 8.4 | 29.8 ± 8.1 | <0.001a | 29.9 ± 8.4 |
| Median (Min to Max) | 26 (20–42)1 | 32 (19–61)1 | 28 (19–64) | 28 (17–54) | 0.001b | 28 (17–64) |
| Time from Surgery to Survey Completion | n=62 | n=64 | n=77 | n=95 | N=298 | |
| Mean ± SD | 18.8 ± 10.0 | 8.0 ± 3.3 | 6.3 ± 3.5 | 6.2 ± 3.1 | <0.001a | 9.2 ± 7.3 |
| Median (Min to Max) | 18 (2–45)1,2,3 | 7. (3–14)1,4,5 | 6 (1–17)2,4 | 6 (2–14)3,5 | <0.001b | 7 (1–45) |
| Race (n, %) | ||||||
| White | 61 (95.3) | 54 (84.4) | 65 (87.8) | 78 (84.8) | 0.341d | 258 (87.8) |
| Black | 1 (1.6) | 4 (6.3) | 4 (5.4) | 3 (3.3) | 12 (4.1) | |
| Other | 2 (3.1) | 6 (9.4) | 5 (6.8) | 11 (12.0) | 24 (8.2) | |
| Smoking History (n, %) | ||||||
| No | 48 (73.9) | 48 (76.2) | 50 (66.7) | 69 (74.2) | 0.592c | 215 (72.6) |
| Yes | 17 (26.2) | 15 (23.8) | 25 (33.3) | 24 (25.8) | 81 (27.4) | |
| Charlson Comorbidity Index | n=64 | n=56 | n=66 | n=86 | N=272 | |
| Mean ± SD | 0.6 ± 1.1 | 0.9 ± 1.1 | 0.7 ± 1.3 | 0.9 ± 1.6 | 0.410a | 0.8 ± 1.3 |
| Median (Min to Max) | 0 (0–5) | 0.5 (0– 4) | 0 (0– 8) | 0 (0–7) | 0.192b | 0 (0–8) |
| No. Vaginal Births | n=61 | n=56 | n=63 | n=87 | N=267 | |
| Mean ± SD | 1.5 ± 1.4 | 1.4 ± 1.4 | 1.5 ± 1.3 | 0.9 ± 1.1 | 0.017a | 1.3 ± 1.3 |
| Median (Min to Max) | 1 (0–6) | 1 (0–5) | 2 (0–5)1 | 0 (0–4)1 | 0.018b | 1 (0–6) |
| Daily Caffeine Consumption, cups | n=64 | n=54 | n=66 | n=86 | N=270 | |
| Mean ± SD | 2.3 ± 1.2 | 2.4 ± 2.2 | 2.4 ± 1.8 | 2.5 ± 1.7 | 0.897a | 2.4 ± 1.7 |
| Median (Min to Max) | 2 (0–6) | 2 (0–10) | 2 (0–8) | 2 (0–9) | 0.786b | 2 (0–10) |
| Histology (n, %) | ||||||
| Endometrioid | 0 (0) | 63 (98.4) | 48 (62.3) | 62 (64.6) | <0.001d | 173 (73.0) |
| Serous | 0 (0) | 1 (1.6) | 12 (15.6) | 4 (4.2) | 17 (7.2) | |
| Clear Cell | 0 (0) | 0 (0) | 4 (5.2) | 5 (5.2) | 9 (3.8) | |
| Mixed | 0 (0) | 0 (0) | 10 (13.0) | 18 (18.8) | 28 (11.8) | |
| Sarcoma | 0 (0) | 0 (0) | 3 (3.9) | 4 (4.2) | 7 (3.0) | |
| Undifferentiated | 0 (0) | 0 (0) | 0 (0) | 2 (2.1) | 2 (0.8) | |
| Squamous Cell | 0 (0) | 0 (0) | 0 (0) | 1 (1.0) | 1 (0.4) | |
| Chemotherapy (n, %) | ||||||
| No | 0 (0) | 63 (98.4) | 51 (66.2) | 17 (17.9) | <0.001d | 131 (55.5) |
| Yes | 0 (0) | 1 (1.6) | 26 (33.8) | 78 (82.1) | 105 (44.5) | |
| EBRT Method (n, %) | ||||||
| 3D | 0 (0) | 0 (0) | 0 (0) | 1 (1.1) | *** | 1 (1.1) |
| IMRT | 0 (0) | 0 (0) | 0 (0) | 34 (38.6) | 34 (38.6) | |
| Type of Surgery (n, %) | ||||||
| MIS Combined | 0 (0) | 1 (1.6) | 0 (0) | 0(0) | <0.001d | 1 (0.4) |
| MIS Laproscopic | 3 (12) | 25 (39.1) | 26 (33.8) | 42(43.8) | 96 (36.6) | |
| MIS Robot | 0 (0) | 27 (42.2) | 37 (48.1) | 31(32.3) | 95 (36.3) | |
| Open Procedure | 22 (88) | 11 (17.2) | 14 (18.2) | 23(24.0) | 70 (26.7) | |
P-values computed using one-way ANOVA
P-values computed using Kruskal-Wallis test
P-values computed using chi-square test
P-values computed using Fisher’s exact test
no statistical comparison was conducted
For continuous variables, matching numerical superscripts were used to indicate significant pair-wise comparisons using a Wilcoxon rank-sum test exact P value <0.0083=0.05/6
Abbreviations: Non-CA, treated with hysterectomy and bilateral salpingo-oophorectomy for benign conditions; HS, hysterectomy and bilateral salpingo-oophorectomy; BT, brachytherapy; SD, standard deviation; EBRT, external beam radiation therapy (with or without brachytherapy); BMI, body mass index; IMRT, intensity-modulated radiation therapy; MIS, minimally invasive surgery.
The median time from surgery to survey completion was 7 years (range, 1–45): benign surgery 19 years (range, 2–45), surgery-only 7 years (range, 3–14), brachytherapy 6 years (range, 1–17), and external beam 6 years (range, 2–14). Most uterine cancers were endometrioid (73%, n=173). Less than half of the patients (45%, n=105) received concurrent chemotherapy.
Pelvic Floor Distress Index-20
The presence of any pelvic floor dysfunction symptom (a non-zero score) was reported in 76% of patients (142/186), and the median total Pelvic Floor Distress Index-20 score was 25 (IQR 4–25) (Figure 1; Appendix 5). Overall, urinary tract symptoms were the most common (median 13 [IQR 0–29]), followed by colorectal-anal distress (6 [0–19]), then uterovaginal prolapse (0 [0–8]). The external beam cohort had the highest median overall score at 41 (range, 9–82), indicating the highest burden of pelvic floor dysfunction symptoms, followed by the benign surgery group (29 [range, 6–65]), surgery-only (23 [range, 4–52]), then brachytherapy (12 [range, 0–50]). In a subset analysis of the role of surgical technique, there was no significant difference between those treated with an open, laparoscopic, or robotic procedure (Appendix 6). A similar subset analyzing use of chemotherapy was negative (Appendix 7)
Figure 1.
Summary and subscale score box plots for the Pelvic Floor Distress Inventory-20 survey by treatment group
The logit component of the zero-inflated negative binomial regression analysis was used to model the probability of achieving any positive score, i.e., any pelvic floor symptoms at all, versus a zero score, i.e., no pelvic floor symptoms. Univariable analyses indicated that neither treatment type nor any other variable were significant for overall score (all p>0.05, Table 2). Compared with the control group, the brachytherapy cohort was 64% less likely to report any symptoms of colorectal distress (odds ratio [OR]=0.36, p=0.009). Variables associated with likelihood of reporting urinary incontinence symptoms included elevated BMI at surgery (OR per 5-year increments=1.25, p=0.019), or current BMI (OR per 5-year increments=1.27, p=0.013), and number of vaginal births (OR per birth=1.30, p=0.033). No variables were independently associated with the presence of pelvic floor prolapse scores. Upon multivariable analysis, BMI at surgery (OR=1.4, p=0.003) and number of vaginal births (OR=1.43, p=0.009) remained significant for the presence of urinary incontinence symptoms (Table 3).
Table 2.
ZINB regression for univariable analysis of PFDI-20 and PFIQ-7 subscores
| PFDI-20 | |||||||||
|
|
|||||||||
| UDI-6 [lower urinary distress] | CRAD-8 [colorectal distress] | POPDI-6 [pelvic organ prolapse distress] | Summary | ||||||
|
|
|||||||||
| Model | Characteristic | Est | P value | Est | P value | Est | P value | Est | P value |
|
| |||||||||
| Study Cohort | |||||||||
| Negative Binomial | Brachy vs. Control | 0.92 | 0.595 | 0.81 | 0.257 | 0.71 | 0.054 | 0.73 | 0.106 |
| EBRT +/− Brachy vs. Control | 1.44 | 0.012 | 0.89 | 0.457 | 0.87 | 0.371 | 1.07 | 0.712 | |
| Surgery-only vs. Control | 1.05 | 0.745 | 0.78 | 0.147 | 0.94 | 0.735 | 0.80 | 0.278 | |
| Logistic Model | Brachy vs. Control | 0.56 | 0.152 | 0.36 | 0.009 | 0.62 | 0.189 | 0.59 | 0.269 |
| EBRT +/− Brachy vs. Control | 0.91 | 0.820 | 1.03 | 0.944 | 0.87 | 0.677 | 1.27 | 0.649 | |
| Surgery vs. Control | 1.10 | 0.829 | 0.71 | 0.407 | 0.86 | 0.692 | 0.96 | 0.944 | |
| Current BMI | |||||||||
| Negative Binomial | 5-unit increase | 1.04 | 0.279 | 1.01 | 0.877 | 1.02 | 0.664 | 1.02 | 0.560 |
| Logistic Model | 5-unit increase | 1.27 | 0.013 | 1.09 | 0.309 | 1.00 | 0.977 | 1.18 | 0.153 |
| BMI at Surgery | |||||||||
| Negative Binomial | 5-unit increase | 1.04 | 0.169 | 1.02 | 0.542 | 1.03 | 0.410 | 1.02 | 0.532 |
| Logistic Model | 5-unit increase | 1.25 | 0.019 | 1.03 | 0.677 | 1.02 | 0.787 | 1.26 | 0.077 |
| Age at Survey Completion | |||||||||
| Negative Binomial | 5-unit increase | 1.06 | 0.046 | 1.07 | 0.016 | 1.01 | 0.710 | 1.07 | 0.040 |
| Logistic | 5-unit increase | 1.01 | 0.905 | 0.94 | 0.348 | 1.01 | 0.932 | 0.90 | 0.254 |
| Age at Surgery | |||||||||
| Negative Binomial | 5-unit increase | 1.06 | 0.021 | 1.04 | 0.146 | 0.99 | 0.730 | 1.04 | 0.237 |
| Logistic Model | 5-unit increase | 1.00 | 0.979 | 0.89 | 0.064 | 0.98 | 0.758 | 0.92 | 0.307 |
| Charlson Comorbidity Index | |||||||||
| Negative Binomial | unit increase | 1.09 | 0.059 | 1.12 | 0.035 | 1.01 | 0.792 | 1.10 | 0.111 |
| Logistic Model | unit increase | 1.14 | 0.281 | 1.09 | 0.431 | 1.10 | 0.369 | 1.14 | 0.412 |
| No. Vaginal Births | |||||||||
| Negative Binomial | unit increase | 1.05 | 0.320 | 1.10 | 0.068 | 1.12 | 0.030 | 1.12 | 0.070 |
| Logistic Model | unit increase | 1.30 | 0.033 | 1.16 | 0.189 | 1.04 | 0.690 | 1.26 | 0.130 |
| Daily Caffeine Consumption, cups | |||||||||
| Negative Binomial | unit increase | 0.98 | 0.592 | 1.03 | 0.381 | 1.03 | 0.448 | 1.00 | 0.954 |
| Logistic Model | unit increase | 1.07 | 0.427 | 0.93 | 0.360 | 0.88 | 0.120 | 0.97 | 0.795 |
| Smoking History | |||||||||
| Negative Binomial | unit increase | 0.87 | 0.285 | 0.83 | 0.189 | 1.03 | 0.824 | 0.77 | 0.110 |
| Logistic Model | unit increase | 1.20 | 0.582 | 1.11 | 0.745 | 0.80 | 0.443 | 1.51 | 0.342 |
| Time from Surgery to Survey Completion | |||||||||
| Negative Binomial | 5 unit increase | 0.98 | 0.605 | 1.03 | 0.462 | 1.03 | 0.483 | 1.04 | 0.386 |
| Logistic Model | 5 unit increase | 1 | 0.998 | 1.24 | 0.05 | 1.07 | 0.423 | 1.03 | 0.815 |
|
|
|||||||||
| PFIQ-7 | |||||||||
|
|
|||||||||
| UIQ [urinary] | CRAIQ [colorectal] | POPIQ [prolapse] | Summary | ||||||
|
|
|||||||||
| Est | P value | Est | P value | Est | P value | Est | P value | ||
|
|
|||||||||
| Treatment Types | |||||||||
| Negative Binomial | Brachy vs. Control | 1.10 | 0.727 | 1.31 | 0.402 | 0.86 | 0.781 | 0.96 | 0.878 |
| EBRT +/− Brachy vs. Control | 1.39 | 0.107 | 1.12 | 0.423 | 1.74 | 0.152 | 1.47 | 0.087 | |
| Surgery vs. Control | 1.06 | 0.805 | 0.81 | 0.446 | 1.76 | 0.243 | 0.92 | 0.760 | |
| Logistic Model | Brachy vs. Control | 0.47 | 0.046 | 0.32 | 0.011 | 0.49 | 0.263 | 0.45 | 0.026 |
| EBRT +/− Brachy vs. Control | 1.36 | 0.340 | 1.57 | 0.187 | 1.90 | 0.170 | 1.42 | 0.285 | |
| Surgery vs. Control | 0.77 | 0.486 | 0.75 | 0.467 | 0.86 | 0.787 | 0.91 | 0.794 | |
| Current BMI | |||||||||
| Negative Binomial | 5-unit increase | 0.99 | 0.872 | 0.92 | 0.127 | 0.82 | 0.061 | 0.94 | 0.259 |
| Logistic Model | 5-unit increase | 1.22 | 0.008 | 0.96 | 0.625 | 0.92 | 0.466 | 1.11 | 0.165 |
| BMI at Diagnosis/Surgery | |||||||||
| Negative Binomial | 5-unit increase | 1.01 | 0.784 | 0.97 | 0.539 | 0.87 | 0.141 | 0.98 | 0.713 |
| Logistic Model | 5-unit increase | 1.20 | 0.010 | 0.96 | 0.563 | 0.90 | 0.373 | 1.08 | 0.257 |
| Age | |||||||||
| Negative Binomial | 5-unit increase | 0.97 | 0.429 | 0.97 | 0.450 | 0.95 | 0.457 | 0.96 | 0.378 |
| 5-unit increase | 1.04 | 0.564 | 1.01 | 0.935 | 0.84 | 0.063 | 0.99 | 0.917 | |
| Age at Surgery | |||||||||
| Negative Binomial | 5-unit increase | 1.00 | 0.984 | 0.97 | 0.455 | 0.94 | 0.367 | 0.97 | 0.524 |
| Logistic Model | 5-unit increase | 1.03 | 0.631 | 0.99 | 0.861 | 0.89 | 0.133 | 0.99 | 0.823 |
| Charlson Comorbidity Index | |||||||||
| Negative Binomial | unit increase | 0.93 | 0.306 | 1.04 | 0.703 | 1.13 | 0.422 | 0.96 | 0.611 |
| Logistic Model | unit increase | 1.24 | 0.038 | 1.09 | 0.436 | 1.20 | 0.145 | 1.30 | 0.029 |
| No. Vaginal Births | |||||||||
| Negative Binomial | unit increase | 1.06 | 0.435 | 1.13 | 0.140 | 0.89 | 0.400 | 1.07 | 0.370 |
| Logistic Model | unit increase | 1.05 | 0.594 | 0.98 | 0.862 | 0.97 | 0.811 | 1.00 | 0.964 |
| Daily Caffeine Consumption, cups | |||||||||
| Negative Binomial | unit increase | 0.94 | 0.322 | 1.07 | 0.400 | 1.06 | 0.634 | 0.96 | 0.556 |
| Logistic Model | unit increase | 0.97 | 0.738 | 0.94 | 0.433 | 0.92 | 0.519 | 0.98 | 0.792 |
| Smoking History | |||||||||
| Negative Binomial | unit increase | 0.94 | 0.752 | 1.05 | 0.821 | 1.00 | 0.996 | 0.91 | 0.664 |
| Logistic Model | unit increase | 0.90 | 0.723 | 0.97 | 0.909 | 1.15 | 0.733 | 1.06 | 0.821 |
| Time from Surgery to Survey Completion | |||||||||
| Negative Binomial | 5 unit increase | 0.92 | 0.207 | 1.01 | 0.912 | 1.04 | 0.756 | 0.98 | 0.764 |
| Logistic Model | 5 unit increase | 0.97 | 0.713 | 1.02 | 0.829 | 0.97 | 0.801 | 0.99 | 0.868 |
Abbreviations: EBRT, external beam radiation therapy; Brachy, brachytherapy; Control, patients treated with hysterectomy and bilateral salpingo-oophorectomy for non-cancerous conditions; ZINB, zero-inflated negative binomial; PFID-20, Pelvic Floor Distress Inventory; PFIQ-7, Pelvic Floor Impact Questionnaire
Table 3.
ZINB regression for multivariate analysis of PFDI-20 and PFIQ-7 subscores
| PFDI-20 | |||||||
|
|
|||||||
| UDI-6 [urinary] | CRAD-8 [colorectal distress] | Summary | |||||
|
|
|||||||
| Model | Characteristic | Est | P value | Est | P value | Est | P value |
|
| |||||||
| Study Cohort | |||||||
| Negative Binomial | Brachy vs. Control | 0.82 | 0.246 | 0.67 | 0.123 | ||
| EBRT +/− Brachy vs. Control | 1.33 | 0.082 | 0.69 | 0.112 | |||
| Surgery vs. Control | 0.79 | 0.206 | 0.61 | 0.039 | |||
| Logistic Model | Brachy vs. Control | 0.46 | 0.104 | 0.71 | 0.547 | ||
| EBRT +/− Brachy vs. Control | 1.07 | 0.89 | 1.96 | 0.241 | |||
| Surgery vs. Control | 0.67 | 0.462 | 1.41 | 0.553 | |||
| BMI at Diagnosis/Surgery | |||||||
| Negative Binomial | 5-unit increase | 1.07 | 0.055 | ||||
| Logistic Model | 5-unit increase | 1.41 | 0.003 | ||||
| Current Age | |||||||
| Negative Binomial | 5-unit increase | 1.07 | 0.031 | 1.09 | 0.014 | ||
| Logistic Model | 5-unit increase | 1.07 | 0.436 | 0.9 | 0.194 | ||
| Charlson Comorbidity Index | |||||||
| Negative Binomial | 5-unit increase | 1.11 | 0.064 | ||||
| Logistic Model | 5-unit increase | 1.07 | 0.541 | ||||
| No. Vaginal Births | |||||||
| Negative Binomial | unit increase | 1.08 | 0.104 | ||||
| Logistic Model | unit increase | 1.43 | 0.009 | ||||
| Time from surgery to Survey Completion | |||||||
| Negative Binomial | 5-unit increase | 0.95 | 0.371 | ||||
| Logistic Model | 5-unit increase | 1.27 | 0.127 | ||||
|
|
|||||||
| PFIQ-7 | |||||||
|
|
|||||||
| UIQ [urinary] | Summary | ||||||
|
|
|||||||
| Est | P value | Est | P value | ||||
|
|
|||||||
| Study Cohort | |||||||
| Negative Binomial | Brachy vs. Control | 0.91 | 0.749 | 0.95 | 0.859 | ||
| EBRT +/− Brachy vs. Control | 1.26 | 0.295 | 1.47 | 0.099 | |||
| Surgery vs. Control | 0.95 | 0.865 | 0.72 | 0.242 | |||
| Logistic Model | Brachy vs. Control | 0.29 | 0.003 | 0.33 | 0.004 | ||
| EBRT +/− Brachy vs. Control | 0.96 | 0.911 | 1.17 | 0.651 | |||
| Surgery vs. Control | 0.39 | 0.03 | 0.73 | 0.424 | |||
| BMI at Diagnosis/Surgery | |||||||
| Negative Binomial | 5-unit increase | 1.02 | 0.747 | ||||
| Logistic Model | 5-unit increase | 1.3 | 0.002 | ||||
| Charlson Comorbidity Index | |||||||
| Negative Binomial | unit increase | 0.91 | 0.196 | 0.97 | 0.744 | ||
| Logistic Model | unit increase | 1.21 | 0.072 | 1.28 | 0.034 | ||
Abbreviations: EBRT, external beam radiation therapy; Brachy, brachytherapy; Control, patients treated with hysterectomy and bilateral salpingo-oophorectomy for non-cancerous conditions; ZINB, zero-inflated negative binomial; PFID-20, Pelvic Floor Distress Inventory; PFIQ-7, Pelvic Floor Impact Questionnaire.
The negative binomial component of the zero-inflated negative binomial regression was used to compare means between treatment cohorts. Univariable modeling indicated that treatment type was not associated with overall pelvic floor dysfunction score (all p>0.05) (Table 3). The only variable associated with worsened overall pelvic floor dysfunction symptoms was age at survey completion (regression mean square=1.07, p=0.04). Receipt of external beam was associated with a higher urinary incontinence symptom score (1.44, p=0.012). In addition, both age at surgery and age at survey completion were associated with worse urinary symptoms (1.06; p=0.021; 1.06, p=0.046, respectively). Number of vaginal births was associated with worse prolapse scores (1.12, p=0.03). Current age and Charlson comorbidity index predicted higher colorectal scores (1.07, p=0.016; 1.12, p=0.035, respectively). Multivariable analysis showed that worsened urinary and colorectal symptoms persisted for those with elevated age (1.07 (p=0.031) and 1.09 (p=0.014), respectively) (Table 3).
Pelvic Floor Impact Questionnaire −7 (QoL Assessment)
The presence of any effect from pelvic floor dysfunction on patient QoL (i.e., a non-zero score) was reported by 45% of patients (131/294), with a median total score of 0 (IQR 0–19; Table 2) (Figure 2, Appendix 5). Among the Pelvic Floor Impact Questionnaire subscales, most scores were elevated by urinary incontinence, followed by colorectal distress, then prolapse. Among treatment cohorts, the external beam patients had the highest median score (5 [0–31]), with the other cohorts sharing a median of 0. In a subset analysis of the role of surgical techniques on QoL, there was no significant difference in our data between those treated with different procedures. Those treated with chemotherapy were more likely to report symptoms of colorectal distress (p=0.045) (Appendix 7).
Figure 2.
Summary and subscale score box plots for the Pelvic Floor Impact Questionnaire—short form 7 survey by treatment group
The logit component of the zero-inflated negative binomial regression found the brachytherapy cohort to have a statistically lower likelihood of reporting any decrease in QoL secondary to pelvic floor dysfunction than the non-cancer cohort (OR=0.45, p=0.026, Table 2); specifically, they were 53% less likely to report urinary symptoms causing decreased QoL (OR=0.47, p=0.046) and 68% less likely to report colorectal symptoms causing decreased QoL (OR=0.32, p=0.011). Elevated Charlson comorbidity index score was associated with an increased likelihood of decreased QoL (OR=1.30, p=0.029). Factors associated with increased likelihood of reporting urinary incontinence-related QoL issues included BMI at surgery (OR=1.200, p=0.01), current BMI (OR=1.220, p=0.008), and Charlson comorbidity index (OR=1.24, pP=0.038). No variables were independently associated with the colorectal or prolapse subscale scores. On multivariable logistic analysis, the brachytherapy cohort continued to be less likely to report QoL impairments secondary to pelvic floor dysfunction (OR=0.33, p=0.04) relative to the non-cancer group. Increased Charlson comorbidity scores were associated with a higher likelihood of reporting QoL impairments (OR=1.28, p=0.034). The brachytherapy and surgery-only treatment cohorts were associated with decreased likelihood of QoL impairments secondary to urinary symptoms (OR=0.29, p=0.03; OR=0.39, p=0.03, respectively), whereas having a high BMI at surgery was associated with an increased likelihood of reporting worse QoL secondary to urinary symptoms (OR=1.3, p=0.002).
The negative binomial component of the zero-inflated negative binomial regression indicated that no covariates, including treatment type, were related to the total score or the subscale scores of the Pelvic Floor Impact Questionnaire-7 (Table 2).
DISCUSSION
Summary of Main Results
Overall, we found that participants across the cancer treatment groups had similar pelvic floor dysfunction scores compared with the control benign surgery group and that the brachytherapy cohort had superior total QoL scores compared with the control group on multivariable analysis. The only significant difference found amongst treatment group was the surgery-only cohort reporting decreased colorectal distress. Patients with higher BMI at time of surgery, higher age, and higher number of vaginal births were more likely to have urinary incontinence-related symptoms. Elevated age was also associated with worsened colorectal distress.
When examining QoL associated with pelvic floor dysfunction symptoms, worse overall scores were related to elevated Charlson comorbidity scores. High BMI at surgery was associated with worse urinary-incontinence–related score.
Results in the Context of Published Literature
Uterine cancer treatment may alter pelvic floor dysfunction due to disruptions to muscle, fascia, blood vessels, and nervous tissue in the bony pelvis that constitute the pelvic floor. The pelvic-floor musculature is important for maintaining fecal continence, urinary continence, and overall support and pelvic-organ stability.16 Connective tissue serves to support and suspend pelvic organs.17 Neuroregulatory systems contract and relax the musculature to maintain fecal/urinary continence and guard against prolapse.16 Hysterectomies have independently shown to detrimentally affect pelvic floor dysfunction.18,19 While the precise mechanism by which hysterectomies result in pelvic floor dysfunction is multifactorial, direct damage to uterosacral ligaments20 and harm to autonomic fibers resulting in progressive weakening of pelvic floor smooth muscle are thought to be at play.
Many studies have assessed the association between uterine cancer and pelvic floor dysfunction,8–13 but the role of radiotherapy specifically has been less explored. Longitudinal assessments of gynecologic cancer patients undergoing radiotherapy have shown that acute adverse toxicities are common during treatment and shortly afterward, but these improved rapidly after treatment.21,22 In PORTEC-1,23 a trial that compared outcomes among patients with endometrial cancer treated with whole-pelvis external beam radiation or observation after surgery, the 15-year QoL assessment found increased urinary incontinence, urinary urgency, fecal incontinence, and overall worse physical function in the external beam group.24 However, that study included patients treated from 1987–1995 and thus involved surgical and radiation techniques that are now considered suboptimal. In the follow-up study PORTEC-2,25 a trial that assessed patients with endometrial cancer treated with adjuvant pelvic radiation or vaginal brachytherapy after surgery, 5-year analyses showed that the brachytherapy cohort experienced significantly lower symptom scores for diarrhea, fecal leakage, and limitation in activity due to bowel symptoms.26 Similarly, among our findings, the brachytherapy cohort had the lowest mean colorectal symptom score as compared to the external beam and surgery-only group.
Strengths and Weaknesses
This study had several strengths, among them the inclusion of a control group treated with hysterectomy for benign conditions. Although several studies have compared patients with age-matched controls, our analysis is unique in that a non-cancer cohort, who underwent surgery similar to our cancer cohort, was used. Additionally, this study had strict inclusion/exclusion criteria, such as excluding those without recurrence, which allowed us to focus on treatment variables without the influence of recurrence on QoL. We were also able to control for common covariates associated with pelvic floor dysfunction, including number of vaginal births and BMI. Finally, our study was strengthened by having all cancer patients treated at a single institution, which limited variability in treatment practices.
The central limitation of this research was the cross-sectional nature, which did not allow us to establish baseline pelvic floor dysfunction or follow trends in outcomes. Also, not all cohorts were evenly balanced with the control group having a lower median age, the surgery-only cohort having an increased BMI, and the different times from surgery to survey completion. These differences may affect surgical technique, surgical complications, post-op recovery, or obscure temporal onset of pelvic floor dysfunction sequelae which may affect findings. Additionally, relatively few participants were non-White. While studies assessing race as a factor in non-malignancy-associated pelvic floor dysfunction have shown mixed results, and we found no differences in race composition across cohorts, the low preponderance of non-White participants may affect the generalizability of our results. 27–31 Another shortcoming includes uncaptured variables that may impact pelvic floor dysfunction including details of the surgical excision or use of therapeutic interventions including pharmaceutical agents, pelvic floor physiotherapy, or corrective surgeries. Lastly, our study had relatively low response rate (36%). While this is lower than expected, this falls in line with similar previously reported studies.32 This reduction in sample size results in loss of precision and hinders our ability to conduct reliable subgroup analysis. Thus, this remains a major limitation and non-responder bias must be considered when abstracting these findings.
Implications for Practice and Future Research
With radiation as a key component in the treatment of uterine cancer, this research aimed to delineate the differential effects of radiation modalities on uterine cancer survivors and suggests some of the underlying mechanisms by which radiotherapy affects pelvic floor dysfunction. Research assessing the effect of radiotherapy on pelvic floor anatomy has been limited. One study in prostate cancer patients who underwent pelvic radiotherapy used magnetic resonance imaging before and after treatment to visualize changes in the periurethral and levator ani muscles found detrimental effects on urethral length and muscular fibrotic changes.33 Another study in prostate cancer patients treated with external-beam radiation showed direct radiation dose-effect relationships with regard to bowel and bladder incontinence.34 In a cross-sectional study of 15 patients with cervical or endometrial cancer, treatment with radiotherapy was associated with decreases in anal resting pressure (p=0.05) and maximum squeeze pressure (p=0.07) and increased rectal sensory perception (desire to defecate based on rectal distension) relative to control subjects (p<0.05).35
With this context in mind, it is not surprising that our brachytherapy cohort had less severe pelvic floor symptoms relative to the external beam cohort, as brachytherapy is an inherently more localized treatment. In our final multivariate analysis, however, the only significant difference found was decreased colorectal distress when compared to the control cohort. While this may possibly simply reflect sampling error rather than a true finding it is suggestive that at the minimum there was no significant worsening of pelvic floor symptoms with radiotherapy. Overall, our findings suggest that radiotherapy may not be singularly detrimental to pelvic floor dysfunction particularly when used locally, and that the underlying effect of radiotherapy on the pelvic floor is inherently complex and necessitates further study.
Conclusions
Our study findings highlight the complexity by which treatment modality can affect pelvic floor function in uterine cancer survivors. Although overall pelvic floor dysfunction was not statistically worse after multimodality cancer therapy than after surgery for benign conditions, other potential factors including number of vaginal births, BMI, and patient co-morbidities must be taken into account. These are important to consider when counseling patients on treatment-related side effects and their risk of pelvic floor dysfunction.
Supplementary Material
RESEARCH HIGHLIGHTS.
Pelvic floor dysfunction is a common complaint for uterine cancer survivors
Treatment modality did not differentially impact overall pelvic floor dysfunction or pelvic floor dysfunction-related quality of life
Elevated BMI, older age, and increased number of vaginal births were associated with worse urinary incontinence
Key Message.
What is already known on this topic: Pelvic-floor dysfunction is a common adverse effect of uterine cancer treatment; however, little has been explored on the differential effect of various treatment modalities.
What this study adds: We found no significant difference in pelvic floor dysfunction between patients treated with hysterectomy alone, adjuvant brachytherapy, or adjuvant external beam radiation as compared to a cohort of women who underwent hysterectomy for benign indications when factoring in common pelvic floor dysfunction-related covariates including body mass index and number of vaginal births.
How this study might affect research, practice or policy: When discussing and counseling pelvic floor dysfunction risks for uterine cancer patients, emphasis should be given to patient demographic risks (body mass index, age, parity) rather than treatment modality.
Acknowledgments:
The authors thank Christine F. Wogan, MS, ELS, from MD Anderson’s Division of Radiation Oncology for editorial assistance.
Funding:
Supported in part by Cancer Center Support (Core) Grant P30 CA016672 from the National Cancer Institute, National Institutes of Health, to The University of Texas MD Anderson Cancer Center.
Footnotes
Disclosures: Dr. Lin reports funding from AstraZeneca and Pfizer for investigator-initiated clinical trials. The other authors report no proprietary or commercial conflicts of interest with respect to any product mentioned or concept discussed in the present work.
Data Availability Statement:
Research data are stored in an institutional repository and will be shared upon reasonable request to the corresponding author.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
Research data are stored in an institutional repository and will be shared upon reasonable request to the corresponding author.