Abstract
Treatment for gynecologic cancer is associated with sexual dysfunction, that may present during and/or after treatment. The aim of this study was to investigate the risk of sexual dysfunction among gynecologic cancer survivors compared to cancer-free women in a population-based cohort study.
We identified a cohort of 4,863 endometrial, ovarian and cervical cancer survivors diagnosed between 1997–2012 in the Utah Cancer Registry. Up to five cancer-free women were matched to cancer survivors (N=22,693). We used ICD-9 codes to identify sexual dysfunction. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for sexual dysfunction with adjustment for potential confounders.
Approximately 6.6% of gynecologic cancer survivors had sexual dysfunction diagnoses 1–5 years after cancer diagnosis. Gynecologic cancer survivors had higher risks of overall sexual dysfunction (HR: 2.51, 95% CI: 2.16, 2.93), dyspareunia (HR: 3.27, 95% CI: 2.63, 4.06) and vaginal dryness (HR: 2.63, 95% CI: 2.21, 3.12) compared to a general population of women, 1–5 years after cancer diagnosis. Sexual dysfunction was associated with advance cancer stage (HRRegional vs. Localized: 1.61, 95% CI:1.19, 2.31), radiation therapy (HR: 1.73, 95% CI: 1.29, 2.31), and chemotherapy (HR: 1.80, 95% CI: 1.30, 2.50).
This large cohort study confirms that there is an increased risk of sexual dysfunction among gynecologic cancer survivors when compared to the general population. Further investigation is needed to address the risk factors for sexual dysfunction and to improve patient-provider communication, diagnosis, documentation, and treatment of sexual dysfunction among gynecologic cancer survivors.
Keywords: Sexual dysfunction, sexual health, gynecologic cancer, ovarian cancer, endometrial cancer, cervical cancer, survivors
Introduction
Gynecologic cancers account for 116,760 new cases diagnosed each year in the United States, and is comprised of cancers of the cervix, fallopian tube, ovary, uterus, vagina and vulva.[1] Annually 34,080 women die from these diseases.[1] Gynecologic cancers are treated with various approaches including surgery, chemotherapy, radiation therapy, or multimodal therapy.[2] Cancer treatments can lead to adverse health outcomes including physical, psychological, and sexual.[3, 4] While certain symptoms (i.e. nausea, radiation dermatitis) present and subside during treatment,[5, 6] sexual dysfunction may present during treatment and can last months to years after treatment.[7, 8]
Sexual symptoms include both issues with sexuality and sexual function. Sexuality encompasses a woman’s ability to engage in sexual activity, but also includes issues related to femininity, reproduction, appearance, and intimacy.[9] Female sexual function includes the domains of desire, arousal, lubrication, orgasm, satisfaction and pain/discomfort.[10] Sexual function directly impacts the ability to engage in sexual activity including intercourse and stimulation [10] and may have an impact on intimate relationships, physical and psychological health, and quality of life.[11–14] Previous studies reported that a range of 10% to 89% of women treated for gynecological cancer have at least one sexual function symptom, ranging in duration from 3 months to 10 years after cancer diagnosis.[15–25] However, most studies included less than 300 cancer patients and were cross-sectional or hospital-based. Previous hospital-based studies on risk factors among gynecologic cancer patients reported that radiation therapy and adjuvant chemotherapy were associated with self-reported sexual dysfunction, such as vaginal changes, low sexual desire, sexual arousal disorder, orgasmic disorder, and sexual pain disorder.[26, 27] No population-based studies have been conducted on the association between oophorectomy and sexual dysfunction among gynecologic cancer survivors. A cross-sectional study reported no association between sexual functioning and the levels of serum hormone among ovarian cancer survivors (n=287).[28]
The purpose of this study was to describe and compare the incidence of sexual dysfunction among gynecologic cancer survivors and cancer-free women based on ICD-9 codes, and to examine the risk factors for sexual dysfunction among gynecologic cancer survivors.
Methods
Data source
The study design was a population-based cohort study. Our study was based on the Utah Population Database (UPDB) which links data from hospital electronic medical records (EMR), statewide healthcare facility data, driver licenses, voter registration, family history records, residential histories, birth and death certificates, and the Utah Cancer Registry for the population of the state of Utah. The Utah Cancer Registry has been part of the NCI’s Surveillance Epidemiology and End Results (SEER) program since 1973 and maintains cancer patients’ records in Utah beginning in 1966. The sources of hospital EMRs were the University of Utah and Intermountain Healthcare hospitals, the two major healthcare systems in Utah.[29, 30] The statewide healthcare facility data included data on inpatient, emergency department, and ambulatory surgery encounters provided by all Utah licensed hospitals and free standing ambulatory surgical centers.[31] The statewide healthcare facility data for ambulatory surgery is available since 1996, and the encounter records for inpatient discharge are available since 1996 regardless of payers (uninsured, private insurance, Medicaid, Medicare, Public Employee Health Plans (PEHP)).
Study population
Women 18 years of age or older who were diagnosed with a first primary gynecologic cancer in Utah between 1997 and 2012 were identified by the Utah Cancer Registry. Gynecologic cancer diagnosis was classified according to the International Classification of Diseases for Oncology, Version 3 (ICD-O-3 code: ovarian cancer, C56.9; endometrial cancer, C54.0-C55.9; cervical cancer: C53.0-C53.9). Cases were excluded if they died or were lost to follow-up within a year of cancer diagnosis (N=833) or had no match for women from the general population (N=1). Given that the goal of this investigation was to evaluate the impact of cancer treatment on sexual dysfunction over time, we did not include patients whose follow-up time was within a year of their cancer diagnosis (Figure 1). Our final cohort included 4,863 gynecologic cancer survivors (1,165 ovarian cancer survivors, 2,946 endometrial cancer survivors, 752 cervical cancer survivors). The last known date of residence in Utah was determined using linked records from UPDB. Outcome data were available through July 15, 2016. In order to calculate baseline comorbidity scores, we restricted the year of diagnosis from 1997, due to the availability of high quality electronic health records from 1996.
Figure 1.
Flow of inclusion and exclusion criteria
Gynecologic cancer survivors were matched with up to five cancer-free women from the general population by birth year and birth state (Utah/non-Utah). We matched for birth state because individuals who were born in Utah may have more detailed health records over their lifespan than Utah residents who grew up in other states. The baseline date was defined as the date of cancer diagnosis for cancer survivors. For women from the general population, the baseline date was defined as the date of cancer diagnosis for the cancer survivor that the individual was matched to. Similar to the criteria for gynecologic cancer survivors, we excluded subjects who had a follow-up period of one year or less. Our final sample included 22,693 women from the Utah general population (comparison group for ovarian cancer survivors: 5,561, for endometrial cancer survivors: 14,053, for cervical cancer survivors: 3,079).
The current study was approved by the Institutional Review Board of the University of Utah, and the Resource for Genetic and Epidemiologic Research, the oversight committee for the Utah Population Database.
Study Variables
Information on the date of cancer diagnosis, tumor characteristics, and first-course cancer treatment for the gynecologic cancer survivors was obtained from the Utah Cancer Registry. Information about comorbidities and sexual function symptoms was obtained from the Utah statewide healthcare facility data as well as EMR data. We used ICD-9 codes to identify sexual dysfunction including dyspareunia, vaginal dryness/atrophic vaginitis, decreased libido, lack of arousal (female sexual arousal disorder), lack of orgasm (female orgasmic disorder), other sexual dysfunction (Supplementary Table 1 shows the ICD codes used). The coverage rates were 97.9% for the ovarian cancer cohort, 97.8% for the endometrial cohort, and 98.7% for the cervical cancer cohort.
Statistical analysis
Demographic factors between gynecologic cancer survivors and cancer-free women were compared, along with clinical characteristics of the gynecologic cancer survivors. Individuals who did not have documented ICD-9 codes for sexual dysfunction were censored at death, last known residence date in Utah, or July 15, 2016 (the last date of follow up across the 3 gynecologic cancers), whichever came first. We evaluated the risk of sexual dysfunction 1 to 5 years and >5 years after cancer diagnosis or the baseline date. Women diagnosed with the outcome of interest before baseline were considered to have prevalent disease and were excluded from the analyses for that outcome. Cox proportional hazards models stratified on matched groups were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for incident sexual dysfunction outcomes with adjustment for potential confounding factors, such as race/ethnicity, baseline body mass index (BMI), and baseline Charlson Comorbidity Index (CCI). Potential confounding factors were chosen a priori based on three properties of confounders determined by causal diagrams.[32] BMI was included as a potential confounding factor because women who are obese were more likely to report sexual dysfunction[33] and obesity is also associated with an increased risk of gynecologic cancers, especially low-grade endometrial cancers.[34] Ethnicity was included as a potential confounding factor because ethnicity is associated with differences in the risk of sexual dysfunction and ethnicity is associated with cervical cancer incidence.[27, 35] The CCI was calculated using health records data prior to the baseline.[36] The proportional hazards assumption was tested for each Cox proportional hazards model by including interactions between the predictors and time in the model. For models where the assumption was violated, we used flexible parametric survival models with restricted cubic splines to estimate the HR.[37, 38]
We calculated BMI from self-reported height and weight, which was obtained from the Utah driver license data at least one year prior to the baseline. Approximately 27.6% of the gynecologic cancer survivors and 22.8% of the general population had missing information for baseline BMI. Thus, for individuals with missing BMI, we imputed the value using a linear regression model with cancer diagnosis, baseline CCI, race, and age at baseline as covariates. Hazard ratios with and without the imputed BMI were compared to assure that the inferences did not change. The estimates without imputed BMI were used if the inference with imputation was different from the estimate without imputation. Analyses were performed using SAS software (version 9.4, SAS Institute, Cary, NC).
Results
Demographic and Clinical Characteristics
The final cohort included 4,863 women diagnosed with gynecologic cancer and 22,693 cancer-free women from the general population. The gynecologic cancer survivors had more persons of Hispanic ethnicity, especially for cervical cancer (Hispanic among ovarian cancer survivors: 7.6%, endometrial cancer survivors: 6.9%, cervical cancer survivors: 21.7%, Table 1). Ovarian and endometrial cancer survivors had a higher baseline CCI score and higher BMI compared to their respective general population cohorts (Table 1). The cervical cancer cohort was younger, with 69.9% of women diagnosed with cancer at 18–50 years of age. In terms of clinical characteristics, 22.5% of the ovarian cancer survivors were diagnosed at the localized stage (Table 2), whereas 79.7% of endometrial cancer survivors and 61.2% of cervical cancer survivors were diagnosed at the localized stage. More than 90% of ovarian and endometrial cancer survivors had surgery. Approximately 26.5% of endometrial cancer survivors and 42.6% of cervical cancer survivors received radiotherapy, but only 1.0% of ovarian cancer survivors had radiotherapy as first-course treatment. The percent of patients receiving chemotherapy was 67.0% for ovarian cancer survivors, 8.5% for endometrial cancer survivors, and 29.3% cervical cancer survivors.
Table 1.
Demographic characteristics among gynecologic cancer survivors and women from the general population
| Ovarian cancer, n(%) | General population, n(%) | Endometrial cancer, n(%) | General population, n(%) | Cervical cancer, n(%) | General population, n(%) | ||||
|---|---|---|---|---|---|---|---|---|---|
| N=1,165 | N=5,561 | P-valueb | N=2,946 | N=14,053 | P-valueb | N=752 | N=3,079 | P-valueb | |
| Age at cancer diagnosis | 0.998 | 0.956 | 0.991 | ||||||
| 18–50 | 342 (29.4) | 1,644 (29.6) | 602 (20.4) | 2,923 (20.8) | 526 (69.9) | 2,157 (70.1) | |||
| 51–60 | 299 (25.7) | 1,427 (25.7) | 881 (29.9) | 4,225 (30.1) | 124 (16.5) | 512 (16.6) | |||
| 61–70 | 269 (23.1) | 1,284 (23.1) | 814 (27.6) | 3,,834 (27.3) | 62 (8.2) | 255 (8.3) | |||
| 71+ | 255 (21.9) | 1,206 (21.7) | 649 (22.0) | 3071 (21.9) | 40 (5.3) | 155 (5.0) | |||
| Race | <0.001 | <0.001 | 0.002 | ||||||
| White | 1,131 (97.1) | 5,164 (92.9) | 2,795 (94.9) | 12,904 (91.8) | 695 (92.4) | 2898 (94.1) | |||
| AIAN | 13 (1.1) | 56 (1.0) | 41 (1.4) | 140 (1.0) | ~ (~) | 18 (0.6) | |||
| Asian | ~ (~) | 102 (1.8) | 24 (0.8) | 374 (2.7) | 14 (1.9) | 14 (0.5) | |||
| NH/OPI | ~ (~) | 31 (0.6) | 58 (2.0) | 64 (0.5) | ~ (~) | ~ (~) | |||
| Black or African American | ~ (~) | 17 (0.3) | 11 (0.4) | 38 (0.3) | ~ (~) | ~ (~) | |||
| Otherc | ~ (~) | 191 (3.4) | 17 (0.6) | 533 (3.8) | 32 (4.3) | 136 (4.4) | |||
| Ethnicity | 0.032 | 0.024 | <0.001 | ||||||
| Non-Hispanic | 1,076 (92.4) | 5,229 (94.0) | 2,742 (93.1) | 13,233 (94.2) | 589 (78.3) | 2795 (90.8) | |||
| Hispanic | 89 (7.6) | 332 (6.0) | 204 (6.9) | 820 (5.8) | 163 (21.7) | 284 (9.2) | |||
| Baseline Charlson Comorbidity Index | 0.019 | <0.001 | 0.352 | ||||||
| 0 | 762 (65.4) | 3,847 (69.2) | 1,803 (61.2) | 9,323 (66.3) | 572 (76.1) | 2,355 (76.5) | |||
| 1 | 240 (20.6) | 963 (17.3) | 624 (21.2) | 2,712 (19.3) | 117 (15.6) | 510 (16.6) | |||
| 2+ | 163 (14.0) | 751 (13.5) | 519 (17.6) | 2,018 (14.4) | 63 (8.4) | 214 (7.0) | |||
| Baseline body mass index a | 0.051 | <0.001 | 0.208 | ||||||
| <18.5 kg/m2 | 39 (3.3) | 131 (2.4) | 26 (0.9) | 286 (2.0) | 24 (3.2) | 95 (3.1) | |||
| 18.5 to 24.9 kg/m2 | 565 (48.5) | 2,809 (50.5) | 747 (25.4) | 6,799 (48.4) | 426 (56.6) | 1,827 (59.3) | |||
| 25 to 29.9 kg/m2 | 334 (28.7) | 1,662 (29.9) | 874 (29.7) | 4,397 (31.3) | 194 (25.8) | 684 (22.2) | |||
| 30+ kg/m2 | 227 (19.5) | 959 (17.2) | 1,299 (44.1) | 2,571 (18.3) | 108 (14.4) | 473 (15.4) | |||
| First degree family history of any cancer | 0.033 | 0.058 | <0.001 | ||||||
| No | 713 (61.2) | 3,587 (64.5) | 1,837 (62.4) | 9,022 (64.2) | 548 (72.9) | 2,023 (65.7) | |||
| Yes | 452 (38.8) | 1,974 (35.5) | 1,109 (37.6) | 5,031 (35.8) | 204 (27.1) | 1,056 (34.3) | |||
Abbreviation: AIAN, American Indian/Alaska Native, NH/OPI, Native Hawaiian/other Pacific Islander
Imputed body mass index
p for chi-square
multiple races, unknown
Counts and percentage are suppressed if fewer than 11
Table 2.
Clinical characteristics of gynecologic cancer survivors, diagnosed from 1997 to 2012
| Ovarian cancer, n(%) | Endometrial cancer, n(%) | Cervical cancer, n(%) | |
|---|---|---|---|
| N=1,165 | N=2,946 | N=752 | |
| Cancer Stage | |||
| Localized | 262 (22.5) | 2,349 (79.7) | 460 (61.2) |
| Regional | 202 (17.3) | 489 (16.6) | 260 (34.6) |
| Distant | 701 (60.2) | 108 (3.7) | 32 (4.3) |
| Year of cancer diagnosis | |||
| 1997 to 2000 | 267 (22.9) | 591 (20.1) | 192 (25.5) |
| 2001 to 2004 | 278 (23.9) | 667 (22.6) | 181 (24.1) |
| 2005 to 2008 | 296 (25.4) | 744 (25.3) | 192 (25.5) |
| 2009 to 2012 | 324 (27.8) | 944 (32.0) | 187 (24.9) |
| Surgery * | |||
| No | 78 (6.7) | 70 (2.4) | 199 (26.5) |
| Yes | 1,087 (93.3) | 2,876 (97.6) | 553 (73.5)a |
| Radiation therapy * | |||
| No | 1,149 (98.6) | 2,152 (73.0) | 432 (57.4) |
| Yes | 12 (1.0) | 782 (26.5) | 320 (42.6) |
| Unknown | ~ (~) | 12 (0.4) | ~ (~) |
| Chemotherapy * | |||
| No | 344 (29.5) | 2,685 (91.1) | 532 (70.7) |
| Yes | 780 (67.0) | 249 (8.5) | 220 (29.3) |
| Unknown | 41 (3.5) | 12 (0.4) | ~ (~) |
Counts and percentage are suppressed if fewer than 11
Included loop electrical excision procedure (LEEP) and cryotherapy that were usually office procedures
First course cancer treatment
Risks of sexual dysfunction
Approximately 6.6% of gynecologic cancer survivors had sexual dysfunction diagnoses 1–5 years after cancer diagnosis (Table 3). In addition, gynecologic cancer survivors had a higher risk of sexual dysfunction compared to the general population 1–5 year after cancer diagnosis (HR, 2.51, 95% CI: 2.16, 2.93, Table 3). Specifically, the risk was 2.76-fold for ovarian cancer survivors (95% CI: 2.02, 3.76), 2.35-fold for endometrial cancer survivors (95% CI: 1.88, 2.92), 2.72-fold for cervical cancer survivors (95% CI: 1.89, 3.92) compared to their respective general population cohorts. Gynecologic cancer survivors had an increased risk of dyspareunia and vaginal dryness/atrophic vaginitis (dyspareunia, HR, 3.27, 95% CI: 2.63, 4.06; vaginal dryness/atrophic vaginitis, HR, 2.63, 95% CI: 2.21, 3.12). No gynecologic cancer survivors were diagnosed with lack of orgasm (ICD-9 diagnosis code: 302.73), and <5 gynecologic cancer survivors were diagnosed with ICD codes on decreased libido, lack of arousal, and other sexual dysfunction (data not shown). We did not observe an increased risk of sexual dysfunction diagnoses among gynecologic cancer survivors >5 years after cancer diagnosis compared to the respective general population cohorts (Supplementary Table 2).
Table 3.
Sexual dysfunction among gynecologic cancer survivors and women from the general population 1 to 5 years after cancer diagnosisa
| Gynecologic cancer survivorsc | General population | Stratified by cancer sites | ||||||
|---|---|---|---|---|---|---|---|---|
| Ovarian cancer survivors | General population | Endometrial cancer survivors | General population | Cervical cancer survivors | General population | |||
| n, % | n, % | n, % | n, % | n, % | n, % | n, % | n, % | |
| Sexual function symptoms (included dyspareunia, vaginal dryness, decreased libido, lack of arousal, unspecified sexual dysfunction) | ||||||||
| Yes | 261 (6.6) | 498 (2.9) | 60 (5.7) | 126 (2.7) | 151 (6.4) | 297 (2.8) | 50 (8.8) | 75 (3.5) |
| No | 3,700 (93.4) | 16,794 (97.1) | 984 (94.3) | 4,556 (97.3) | 2,195 (93.6) | 10,163 (97.2) | 521 (91.2) | 2,075 (96.5) |
| Hazard Ratio (95% CI)b | 2.51 (2.16, 2.93) * | 2.76 (2.02, 3.76) * | 2.35 (1.88, 2.92) | 2.72 (1.89, 3.92) * | ||||
| Dyspareunia | ||||||||
| Yes | 141 (3.3) | 216 (1.1) | 34 (3.1) | 62 (1.2) | 74 (2.9) | 114 (1.0) | 33 (5.3) | 40 (1.6) |
| No | 4,117 (96.7) | 19,113 (98.9) | 1,074 (96.9) | 5,102 (98.8) | 2,453 (97.1) | 11,612 (99.0) | 590 (94.7) | 2,399 (98.4) |
| Hazard Ratio (95% CI)b | 3.27 (2.63, 4.06) * | 3.20 (2.10, 4.88) * | 3.03 (2.16, 4.24) | 3.33 (2.08, 5.33) * | ||||
| Vaginal Dryness/Atrophic Vaginitis | ||||||||
| Yes | 208 (4.7) | 391 (2.0) | 43 (4.0) | 84 (1.7) | 133 (4.9) | 261 (2.1) | 32 (4.7) | 46 (1.7) |
| No | 4,246 (95.3) | 19,437 (98.0) | 1,045 (96.0) | 4,875 (98.3) | 2,554 (95.1) | 11,962 (97.9) | 647 (95.3) | 2,600 (98.3) |
| Hazard Ratio (95% CI)b | 2.63 (2.21, 3.12) * | 3.43 (2.26, 5.22) | 2.49 (2.00, 3.09) * | 3.13 (1.86, 5.24) | ||||
Abbreviation: NA, not applicable; HR, hazard ratio; CI, confidence interval
Excluded subjects who had the outcome of interest before 1-year of follow-up
Models adjusted for matching factors (birth year and birth state), race/ethnicity, baseline body mass index, baseline Charlson Comorbidity Index, cancer site, where appropriate.
Combined women from ovarian, endometrial, and cervical cancer cohorts.
Proportional hazards assumption not met; flexible cubic splines model was used.
Risk factors for sexual dysfunction
Age, baseline CCI, baseline BMI, and ethnicity were not associated with the risk of sexual dysfunction among gynecologic cancer survivors (Table 4). We observed that regional cancer stage, radiotherapy and chemotherapy were associated with an elevated risk of sexual dysfunction among gynecologic cancer survivors. The association between radiation therapy and sexual dysfunction was observed among ovarian cancer survivors (HR, 5.84, 95% CI:1.79, 19.12) and endometrial cancer survivors (HR, 1.63, 95% CI: 1.15, 2.29). When we compared the risk of sexual dysfunction among endometrial cancer survivors treated with brachytherapy to endometrial cancer survivors treated with external beam radiation, we did not observe an association (data not shown). For chemotherapy, an increased risk of sexual dysfunction was observed among ovarian cancer survivors (HR, 2.02, 95% CI: 1.07, 3.82). We observed an inverse association between surgery and sexual dysfunction among cervical cancer survivors (HR, 0.48, 95% CI: 0.25, 0.91).
Table 4.
Risk factors for sexual dysfunction among gynecologic cancer survivors 1 to 5 years after cancer diagnosis
| Gynecologic cancer survivorsg | Stratified by cancer sites | |||
|---|---|---|---|---|
| Ovarian cancer survivors | Endometrial cancer survivors | Cervical cancer survivors | ||
| HR (95% CI) | HR (95% CI) | HR (95% CI) | HR (95% CI) | |
| Age at cancer diagnosis a | ||||
| 18–50 | Reference | Reference | Reference | Reference |
| 51–60 | 1.11 (0.80, 1.54) | 0.98 (0.52, 1.86) | 1.01 (0.64, 1.61) | 1.70 (0.88, 3.29) |
| 61–70 | 1.22 (0.86, 1.72) | 0.89 (0.44, 1.78) | 1.30 (0.82, 2.04) | 1.12 (0.38, 3.26) |
| 71+ | 0.66 (0.42, 1.03) | 0.51 (0.21, 1.25) | 0.72 (0.41, 1.27) | NA |
| Baseline Charlson Comorbidity Index b | ||||
| 0 | Reference | Reference | Reference | Reference |
| 1 | 0.96 (0.69, 1.33) | 0.90 (0.46, 1.77) | 1.03 (0.68, 1.58) | 0.77 (0.32, 1.86) |
| 2+ | 1.32 (0.92, 1.88) | 1.05 (0.45, 2.44) | 1.41 (0.91, 2.16) | 1.42 (0.53, 3.80) |
| Baseline body mass index (BMI) c | ||||
| <18.5 kg/m2 | 1.99 (0.79, 5.00)f | 2.19 (0.76, 6.29) | 1.77 (0.43, 7.36) | 2.23 (0.65, 7.65) |
| 18.5 to 24.9 kg/m2 | Reference | Reference | Reference | Reference |
| 25 to 29.9 kg/m2 | 1.22 (0.84, 1.78)f | 1.18 (0.63, 2.18) | 0.99 (0.63, 1.55) | 1.04 (0.51, 2.11) |
| 30+ kg/m2 | 1.32 (0.91, 1.91)f | 1.01 (0.50, 2.05) | 1.13 (0.75, 1.71) | 1.57 (0.74, 3.32) |
| Ethnicity d | ||||
| Non-Hispanic | Reference | Reference | Reference | Reference |
| Hispanic | 0.93 (0.61, 1.43) | 0.59 (0.18, 1.89) | 0.97 (0.51, 1.86) | 1.09 (0.56, 2.14) |
| Cancer Stage e | ||||
| Localized | Reference | Reference | Reference | Reference |
| Regional | 1.61 (1.19, 2.16) | 2.08 (0.97, 4.43) | 1.47 (0.99, 2.18) | 1.58 (0.77, 3.24)f |
| Distant | 1.44 (0.91, 2.29) | 1.58 (0.80, 3.13) | 1.29 (0.47, 3.50) | 3.82 (0.81, 18.02)f |
| Surgery e | ||||
| No | Reference | Reference | Reference | Reference |
| Yes | 0.76 (0.46, 1.24) | 2.35 (0.32, 17.28) | 1.53 (0.38, 6.21) | 0.48 (0.25, 0.91) |
| Radiation therapy e | ||||
| No | Reference | Reference | Reference | Reference |
| Yes | 1.73 (1.29, 2.31) | 5.84 (1.79, 19.12) | 1.63 (1.15, 2.29) | 1.53 (0.84, 2.80) |
| Chemotherapy e | ||||
| No | Reference | Reference | Reference | Reference |
| Yes | 1.80 (1.30, 2.50) | 2.02 (1.07, 3.82) | 1.45 (0.83, 2.52) | 1.73 (0.86, 3.48)f |
Abbreviation: NA, not applicable; HR, hazard ratio; CI, confidence interval
Models adjusted for race/ethnicity, baseline BMI, baseline Charlson Comorbidity Index
Models adjusted for age at cancer diagnosis, baseline BMI, race/ethnicity
Models adjusted for age at cancer diagnosis, race/ethnicity, baseline Charlson Comorbidity Index
Models adjusted for age at cancer diagnosis, baseline BMI, baseline Charlson Comorbidity Index
Models adjusted for age at cancer diagnosis, baseline BMI, baseline Charlson Comorbidity Index, race/ethnicity
Non-imputed BMI was used
Additionally adjusted for cancer sites
Discussion
In this population-based cohort study, we included 4,863 women with gynecologic cancers and 22,693 matched cancer-free women to investigate the risk of sexual dysfunction after cancer diagnosis. The risk of sexual dysfunction documented by ICD-9 codes was 2.51-fold among women with gynecologic cancers compared to a general population of women (95% CI: 2.16, 2.93). When we compared the risk of sexual dysfunction among women in each cancer site to their cancer-free women, the risk of sexual dysfunction was 2.76-fold among ovarian cancer survivors (95% CI: 2.02, 3.76), 2.35-fold among endometrial cancer survivors (95% CI: 1.88, 2.92), and 2.72-fold among cervical cancer survivors (95% CI: 1.89, 3.92).
Compared to patient-reported outcomes in the literature [15, 16, 39], our results showed that dyspareunia and vaginal dryness were less frequently recorded in the diagnosis codes. For example, compared to 2.9% for dyspareunia and 4.9% for vaginal dryness based on the ICD-9 diagnosis codes from our study, Aerts and colleagues [16] reported that 24%−39% of endometrial cancer survivors experienced dyspareunia and vaginal dryness among 84 endometrial cancer survivors who had surgery. We found decreased libido, lack of arousal, and overall sexual dysfunction were rarely diagnosed via ICD-9 codes by providers, while other studies observed these issues among 20–50% of cancer patients via patient-reported outcomes.[15, 16, 39–41] Anorgasmia, or difficulty with orgasms, was never documented as a diagnosis in our study. Women frequently reported these in the literature in some studies at a high prevalence [42–44], with as many as 60% of patients after adjuvant intravaginal radiotherapy [43] or high-dose-rate brachytherapy [44]. Our study used ICD-9 codes and had a population-based study design compared to the previous studies. The low proportion of sexual dysfunction identified in our study may be due to using ICD codes instead of questionnaires to ascertain sexual dysfunction. In addition, ICD codes of sexual dysfunction may not be reported if there were barriers in communication between the patient and provider and subsequent diagnosis of sexual function symptoms. During follow-up care, clinicians may focus on cancer recurrence and not sexual function in gynecologic cancer patients due to the goal of improving survival. Both cancer survivors and clinicians reported barriers to communication on sexual function symptoms during and after treatment for gynecologic cancer.[45–48] The reported lack of communication on sexual function symptoms may lead to delays in the diagnosis of sexual dysfunction and effective treatment leading to prolonged symptom experience and impacts on quality of life.
Our results were similar to previous studies in terms of worse sexual function outcomes among gynecologic cancer patients compared to healthy women.[15, 16, 26, 41, 43, 49] Although previous studies reported worse sexual function after 5 years of cancer diagnosis compared to cancer-free women [50, 51], we did not observe an increased risk of sexual dysfunction among gynecologic cancer survivors >5 years after cancer diagnosis. One potential explanation is that previous studies had a cross-sectional study design that obtained prevalent outcomes. Thus, women may develop sexual dysfunction <5 years after cancer diagnosis but report it >5 years after cancer diagnosis and the timing of sexual dysfunction developed was ambiguous when using prevalent outcomes. The positive association between sexual dysfunction and gynecologic cancer >5 years after cancer diagnosis could be overestimated in the studies using prevalent outcomes. Another reason could be that patients were likely to visit the clinic for their sexual dysfunction less after more years since cancer diagnosis. Therefore, the incidence of sexual dysfunction among gynecologic cancer survivors >5 years after cancer diagnosis could be lower and the HRs of sexual dysfunction among gynecologic cancer survivors compared to the general population could be underestimated in our study.
We observed that radiation therapy treatment was associated with an increased risk of sexual dysfunction among both endometrial and ovarian cancer survivors, while chemotherapy was associated with an increased risk of sexual dysfunction among ovarian cancer survivors. Consistent with our study, an increased risk of sexual dysfunction due to radiotherapy and chemotherapy was observed among gynecologic cancer survivors in a previous study that included cervix, uterine, vaginal and vulvar carcinoma.[27] Because radiation therapy is not common among ovarian cancer patients, the risk of sexual dysfunction may be hard to detect with a small sample size. Thus, this may be why there are very few studies that examined the risk of radiotherapy on sexual dysfunction among ovarian cancer survivors. The decreased risk of sexual dysfunction among cervical cancer survivors who had surgery (HR, 0.48, 95% CI: 0.25, 0.91) could be related to the improvement of severe symptoms (such as bleeding, pain, etc.) after the surgery. The percentage of Hispanic ethnicity was high among cervical cancer survivors (21.7%). It may reflect the high incidence of cervical cancer in this population. The cervical cancer incidence rate among Hispanic women overall in the US is 30% higher than among non-Hispanic whites.[1]
While we reported some important results, our study has a few limitations. We used ICD codes as a proxy for sexual dysfunction but the codes may not be sufficient to capture the detailed information on the sexual dysfunction. Thus, the percentage of sexual dysfunction was likely underestimated by our method. Although cancer survivors may have more of a chance to report sexual dysfunction during follow-up care than the general population, the impact may be limited due to the strong focus on no evidence of disease (NED) or recurrence during follow-up care. Some important factors such as whether the woman was sexually active was not available from our data set. The strength of association between sexual dysfunction and gynecological cancer diagnosis was likely underestimated because the HR might be higher among sexually active women. Hysterectomy history before baseline was not available. However, hysterectomy may not be a risk factor for sexual dysfunction [52–54] according to at least some previous studies. Finally, ICD-9 coding errors are possible; however we expect that coding errors would be nondifferential between gynecologic cancer survivors and the general population, and nondifferential misclassification may lead to bias toward the null. While these limitations exist, we analyzed data from a large cohort, and provided valuable information regarding potential issues in provider documentation of sexual function among gynecologic cancer that is important in clinical practice.
The strengths of our study include the population-based design, large sample size, and longitudinally documented sexual dysfunction from ICD codes. The risk of sexual dysfunction among gynecologic cancer survivors in the current study may be more generalizable than previous studies since our analyses were based on a population-based cohort. Most of the previous studies included only early-stage cancer patients with a limited sample size (N<300).[17, 50, 55–58] We included more than 4,000 gynecologic cancer survivors diagnosed from 1997 to 2012 with all cancer stages. Recall bias or self-report bias is not an issue in our study because we used ICD codes from statewide healthcare facility data and EMR to ascertain sexual dysfunction from cancer diagnosis to the end of follow-up.
In conclusion, gynecological cancer patients had a higher risk of sexual dysfunction than women without gynecological cancer; however, the incidence identified in our study was very low in comparison to patient reports. Further work is needed to address the risk factors of sexual dysfunction and to improve patient-provider communication, diagnosis, documentation, and treatment of sexual dysfunction in gynecologic cancer survivors.
Supplementary Material
Acknowledgements:
We thank the Pedigree and Population Resource of the Huntsman Cancer Institute, University of Utah (funded in part by the Huntsman Cancer Foundation) for its role in the ongoing collection, maintenance and support of the Utah Population Database (UPDB). We also acknowledge partial support for the UPDB through grant P30 CA2014 from the National Cancer Institute, University of Utah and from the University of Utah’s Program in Personalized Health and Center for Clinical and Translational Science. We thank the University of Utah Center for Clinical and Translational Science (CCTS) (funded by NIH Clinical and Translational Science Awards), the Pedigree and Population Resource, University of Utah Information Technology Services and Biomedical Informatics Core for establishing the Master Subject Index between the Utah Population Database, the University of Utah Health Sciences Center and Intermountain Health Care.
Funding:
This work was supported by grants from the NIH (NCI R21 CA185811, R03 CA159357, M.Hashibe, PI; NINR T32NR013456, K Mooney, PI), the Huntsman Cancer Institute, Cancer Control and Population Sciences Program (HCI Cancer Center Support Grant P30CA042014), and a NCRR grant (R01 RR021746, G. Mineau, PI) with additional support from the Utah State Department of Health and the University of Utah.
Footnotes
Ethics approval The current study was approved by the Institutional Review Board of the University of Utah, and the Resource for Genetic and Epidemiologic Research, the oversight committee for the Utah Population Database.
Conflict of interest The authors declare no competing interests.
Conflict of interest:
The authors declare no conflicts of interest.
Data Availability
The data that support the findings of this study are available upon request with appropriate approval from the UPDB oversight committee, the Resource for Genetic and Epidemiologic Research (RGE), and IRB approval.
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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
The data that support the findings of this study are available upon request with appropriate approval from the UPDB oversight committee, the Resource for Genetic and Epidemiologic Research (RGE), and IRB approval.