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. Author manuscript; available in PMC: 2021 Jan 1.
Published in final edited form as: Gynecol Oncol. 2019 Nov 21;156(1):131–139. doi: 10.1016/j.ygyno.2019.10.026

Prospective Follow-up of Quality of Life for Participants Undergoing Risk-Reducing Salpingo-Oophorectomy or Ovarian Cancer Screening in GOG-0199: An NRG Oncology/GOG Study

Phuong L Mai 1,*, Helen Q Huang 2, Lari B Wenzel 3, Paul K Han 4, Richard P Moser 5, Gustavo C Rodriguez 6, John Boggess 7, Thomas J Rutherford 8, David E Cohn 9, Noah D Kauff 10, Kelly-Anne Phillips 11, Kelly Wilkinson 12, Robert M Wenham 13, Chad Hamilton 14, Matthew A Powell 15, Joan L Walker 16, Mark H Greene 17, Martee L Hensley 18
PMCID: PMC6980744  NIHMSID: NIHMS1544428  PMID: 31759774

Abstract

Background

Risk-reducing salpingo-oophorectomy (RRSO) and ovarian cancer screening (OCS) are management options for women at increased risk of ovarian cancer. Long-term effects of these interventions on quality of life (QOL) are not well understood.

Methods

GOG-0199 is a prospective cohort study of women at increased ovarian cancer risk who chose either RRSO or OCS as their risk management intervention. At study entry, 6, 12, 24 and 60 months of follow-up, participants completed the QOL questionnaire, which included the Medical Outcome Study Short Form-36, the Impact of Events Scales, the Center for Epidemiological Studies Depression Scale, the State-Trait Anxiety Inventory, the Functional Assessment of Cancer Therapy – Endocrine Subscale, and the Sexual Activity Questionnaire. QOL measures were compared between the RRSO and OCS cohort at baseline and over time.

Results

Five-hundred-sixty-two participants in the RRSO cohort and 1,010 in the OCS completed the baseline and at least one follow-up questionnaire. At baseline, participants selecting RRSO reported lower health-related QOL (HRQOL), greater ovarian cancer-related stress, greater anxiety, and more depressive symptomatology, which improved during follow-up, especially for ovarian cancer-related stress. Screening was not found to adversely impact HRQOL. Hormone-related menopausal symptoms worsened and sexual functioning declined during follow-up in both cohorts, but more so among participants who underwent RRSO.

Conclusions

HRQOL improved after surgery among women who chose RRSO and remained stable among participants undergoing screening. The adverse effects of RRSO and screening on short-term and long-term sexual activity and sexual functioning warrant consideration in the decision-making process for high-risk women.

Introduction

Ovarian cancer (OC) risk is significantly increased in certain hereditary cancer syndromes, such as the Hereditary Breast/Ovarian Cancer syndrome (1, 2), and Lynch syndrome (3, 4). Family history of OC, especially in first-degree relatives, has also been shown to be associated with increased risk (5). Risk management options for high-risk women are limited and uncertainties regarding these options remain. For BRCA1 and BRCA2 (BRCA1/2) mutation carriers, risk-reducing salpingo-oophorectomy (RRSO) has been shown to reduce ovarian/fallopian tube cancer incidence as well as cancer-specific and overall mortality, and is considered the most effective ovarian cancer risk management option (6–8). However, the efficacy of RRSO on risk reduction for women at increased risk based on personal and/or family cancer history, but who have no detectable germline pathogenic variant in known susceptibility genes, is not established. Moreover, RRSO is a major and irreversible intervention, often with significant short-term consequences, particularly symptoms related to estrogen deprivation and sexual dysfunction (9–14), and potential long-term morbidity and cardiovascular mortality risk, in pre-menopausal women due to the sequelae of premature menopause (15). Nonetheless, most studies of high-risk women undergoing RRSO have shown that short-term and long-term overall quality of health quality (QOL) was not adversely affected (9, 10, 16–18). For women who reported acute decreases in QOL after RRSO, these effects generally resolved within 12 months (19). Prospective long-term follow-up data on QOL after RRSO are limited. A recent small study showed that high-risk women who underwent RRSO reported more sexual discomfort and urogenital symptoms, but no differences in anxiety, depression, or body image, compared with age- and risk-matched controls, at 3 years’ follow-up (20).

Although ovarian cancer screening (OCS) with periodic transvaginal ultrasound and serum CA125 measurements is often utilized as a risk management option, its effectiveness for high-risk women has not been demonstrated, and routine screening is not recommended (21–23). The need for testing over many years, and frequent false-positive screening results, may increase anxiety (24, 25). However, a study of average-risk women showed that serial CA-125 determinations did not incur any clinically significant psychological morbidity from repeat testing following abnormal screening results (26). For some high-risk women, participating in a screening program may decrease emotional distress due to reassurance from negative test results, or a sense of satisfaction from a proactive approach to risk management. However, the acceptability and long-term effects of OCS on QOL are unknown.

In this study, women considered to be at increased risk of OC based on family history of ovarian cancer or at least 20% probability of carrying a BRCA1 or BRCA2 pathogenic variant chose either RRSO or OCS at enrollment and were followed prospectively for five years. A primary study objective was to determine whether overall health-related QOL (HRQOL), depression, cancer-related stress, anxiety, menopausal symptoms, and sexual functioning differed at baseline and over time between women undergoing OCS and those who elected RRSO at baseline.

Methods

Study Population

GOG-0199 is a multi-institution, prospective cohort study. At enrollment, participants chose either RRSO (27) or OCS (28) utilizing the Risk of Ovarian Cancer Algorithm (ROCA), an experimental screening methodology (29). Participants in the OCS cohort were screened according to ROCA (29), with CA-125 measurements and ROCA score calculations every 3 months and annual transvaginal ultrasound (TVUS). The ROCA score reflects the probability of harboring ovarian cancer (normal risk: <1%; intermediate risk: 1–10%; and elevated risk: >10%). Additional follow-up, including repeat CA-125 measurements, TVUS, and/or evaluation by a gynecologist oncologist or the study site Principal Investigator, was determined by the ROCA score. Participants who elected RRSO underwent the protocol-defined procedure within 90 days of enrollment. Hysterectomy was performed electively per patient and physician discretion. Participants in the RRSO cohort had CA-125 measurements and ROCA score calculations every 6 months during the study prospective follow-up period. Participants in the OCS cohort had the option to cross-over to the RRSO cohort post-enrollment, either electively or as prompted by screening results or clinical findings. Detailed eligibility criteria have been published previously (30). In brief, women aged ≥ 30, with no previous history of ovarian/fallopian tube/peritoneal cancer and had at least one intact ovary, were eligible if they or a close relative carried a BRCA1/2 pathogenic variant, or if they had a personal and/or family history of BC and/or OC that conferred an increased OC risk, or ≥20% probability of carrying a BRCA1/2 pathogenic variant based on the BRCAPRO model (31). The study opened to accrual 6/16/2003 and closed on 11/3/2006. Participants were followed prospectively for 5 years. By design, it was considered that 1,600 participants would provide a sufficiently representative sample for the QOL study endpoints. Thus, only participants enrolled prior to April 24, 2006 were asked to complete a QOL questionnaire at study entry, and at 6, 12, 24 and 60 months of follow-up.

All participants signed informed written informed consent for GOG Protocol 0199; NCI Protocol 02-C-0268; NCT-00043472 which were approved by institutional review boards at the National Cancer Institute, GOG and 151 GOG institutions (US, Australia).

Sociodemographic and Cancer History Information

We collected information on age, race, menopausal status, marital status, education, self reported BRCA1/2 mutation status, personal history of BC, personal history of any cancer, and family history of BC, pre-menopausal BC, and OC. Self-reported mutation status at the time of enrollment was used in this analysis, since this measure best reflected participants’ understanding of their mutation status.

Quality of Life Instruments

The QOL questionnaire included validated instruments to assess overall QOL, anxiety, depression, frequency of menopausal symptoms, and sexual functioning. The questionnaire was completed by participants at each indicated time-point, except for the time-point(s) that occurred after an off-study event, including cancer diagnosis (except non-melanoma skin cancers), pregnancy, withdrawal from participation, or death, or after loss to follow-up.

(1). The Medical Outcome Study Short Form-36 (MOS SF-36)

The MOS SF-36 is a validated 36-item patient-reported outcome measure designed to assess HRQOL across all medical conditions, consisting of eight subscales measuring general health perceptions, physical functioning, role limitations due to physical health problems, role limitations due to emotional problems, bodily pain, vitality, social functioning, general mental health, and one item evaluating the change in health (32). Each subscale score was computed by summing subscale items and transforming the total to a 0–100 scale, where higher scores indicated better HRQOL.

(2). The Impact of Events Scale (IES)

The IES provides a quantitative measure of the impact of OC-related stress. It is a validated 15-item self-report instrument focusing on intrusive thoughts and avoidance associated with a stressor, in this case OC risk and its associated management options (33, 34). The overall score (range 0–75) was calculated based on the individual responses. Higher scores indicated more stress. The overall score was also used to classify participants’ level of stress as subclinical (<9 points), mild (9–25 points), moderate (26–43 points), or severe (≥44 points), delineating levels of clinical significance.

(3). The Center for Epidemiology Studies Depression Scale (CES-D)

The CES-D is a 20-item instrument used to assess depressive symptoms, including depressive mood and feelings of helplessness, over the previous 7 days. Responses were summed to provide an overall score (range 0–60). A score of 16 or higher is indicative of significant depressive symptomatology (35).

(4). Speilberger State-Trait Anxiety Inventory (STAI)

The STAI consists of two 20-item subscales which measure state and trait anxiety (36). State anxiety is a transitory emotional response to a stressful situation and reflected how the individual felt at the time the instrument was administered. Trait anxiety reflected a stable predisposition to anxiety as determined by personality pattern. Scores for each sub-scale ranged from 20 to 80, with higher scores indicating greater anxiety.

(5). The Functional Assessment of Cancer Therapy – Endocrine Subscale (FACT-ES)

The FACT-ES is a validated 18-item scale designed to measure hormone-related symptoms (37) over the 7 days prior to completing the instrument. An overall total score was calculated by summing the individual score for each item (range 0–72). Higher scores represented fewer hormone-related symptoms.

(6). The Sexual Assessment Questionnaire (SAQ)

The SAQ is a 14-item questionnaire designed to capture information regarding variation in sexual functioning in three parameters: pleasure from intercourse, pain from intercourse, and change of sexual habit (38). The sexual pleasure (range 0–18) and discomfort (range 0–6) subscale scores were calculated by summing the item scores after the negative items were reversed. Higher scores indicated better sexual functioning.

Statistical Analysis

Participants were included if they completed the baseline questionnaire and ≥1 follow-up questionnaire(s). Participants in the OCS cohort who had RRSO during follow-up were censored at the time of RRSO, and their post-RRSO QOL assessments were excluded from the analysis.

Sociodemographic characteristics, health-related factors, and personal and family cancer history were compared between the RRSO and OCS cohorts, using chi-square and t-tests for categorical and continuous variables, respectively.

Questionnaire completion rate was calculated at each time-point using the number of participants expected to complete the assessment for that time-point as the denominator, and was compared between the two cohorts using the generalizing estimating equations for repeated measures. A logit link for the binomial distribution was used to model the completeness status (yes/no) and an unstructured working correlation matrix was used to model the correlation of the repeated measures from the same subject.

For baseline QOL measures, a general linear model was used to examine the differences between the two cohorts with adjustment for age, previous BC (yes/no), mutation status at baseline (carrier/non-carrier/unknown), and contraceptive use (current/previous use/never). For measures reported over time, a linear mixed model was used to assess the group differences over time, adjusting for baseline scores and age. The time-points were treated as categorical, and the covariance matrix for repeated measures was assumed to be unstructured. To reflect the observed covariance pattern of the QOL scores, the ‘empirical’ variance was used in estimating the precision of parameter estimates. The interaction between time-points and study cohort was tested first for the constant group difference over time. If the interaction effect was not statistically significant, an overall group difference was evaluated by an average of estimates from each time-point together with a 99% confidence interval. To adjusting for multiple testing and limit the overall type I error, the Sidak method 1-(1-unadjust_p)18 was used to adjust the group difference p-values for each measure.

All analyses were performed using the SAS software, version 9.4 (SAS Institute Inc., Cary, NC).

Results

One-thousand-seven-hundred-eighty participants enrolled prior to April 24, 2006. One-hundred-eleven participants in the OCS and 97 participants in the RRSO cohort were excluded (Figure 1). Questionnaire completion rates declined over time, with more participants in the OCS cohort completing the questionnaires at each time-point compared with the RRSO cohort (p<0.001, Table 1).

Figure 1:

Figure 1:

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CONSORT diagram

Table 1:

Questionnaire completion at each time-point by cohort

Assessment time Status of PROs assessment RRSO Screening
Baseline Expected 659 1121
 Received and Valid 638(97%) 1082(97%)
 Received but with Insufficient answer 6 12
 Missed without reasons 15 27
6 Months Death (cumulative) 0 1
Cancer diagnosis 18 7
Withdrew consent 3 8
Pregnancy 0 2
Expected 638 1103
 Received and Valid 528(83%) 952(86%)
 Received but with Insufficient answer 4 13
 Patient refusal 8 6
 Missed without reasons 98 132
12 Months Death (cumulative) 0 1
Cancer diagnosis (cumulative) 23 19
Withdrew consent (cumulative) 20 30
Pregnancy (cumulative) 0 6
Expected 616 1065
 Received and Valid 492 (80%) 907 (85%)
 Received but with Insufficient answer 8 7
 Patient refusal 15 19
 Missed without reasons 101 132
24 months Death (cumulative) 2 2
Cancer diagnosis (cumulative) 33 41
Withdrew consent (cumulative) 39 65
Pregnancy (cumulative) 0 15
Expected 585 998
 Received and Valid 424(72%) 799(80%)
 Received but with Insufficient answer 1 5
 Patient refusal 31 49
 Missed Without reasons 129 145
60 months Death (cumulative) 8 16
Cancer diagnosis (cumulative) 51 63
Withdrew consent (cumulative) 67 145
Pregnancy (cumulative) 0 33
Expected 533 864
 Received and Valid 313(59%) 586(68%)
 Received but with Insufficient answer 1 7
 Patient refusal 102 130
 Missed Without reasons 117 141
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RRSO: risk-reducing salpingo-oophorectomy; OCS: ovarian cancer screening

Participants in the RRSO cohort were older than those in the OCS cohort (48.6 years vs. 47.6 years, p=0.038) and were more likely to report being a BRCA1 or BRCA2 mutation carrier, have a personal history of BC, and to not be using contraceptive at the time of enrollment (Table 2).

Table 2:

Baseline characteristics

Patient characteristic RRSO (n=562)
 OCS (n=1010)
 P-value
N % N %
Age group
 30–39 96 17.08 274 27.13
 40–49 239 42.53 321 31.78
 50–59 170 30.25 301 29.80 <0.001
 60–69 47 8.36 100 9.90
 ≥70 10 1.78 14 1.39
Race
 White 540 96.1 977 96.7
 Black 16 2.9 20 2.0 0.51
 Other/Not Specified 6 1.1 13 1.3
Menopausal status
 Pre-menopausal 315 56.1 610 60.4 0.09
 Menopausal 247 44.0 400 39.6
Ashkenazi Parent
 Yes 108 19.2 222 22.0
 No 410 73.0 732 72.5 0.12
 Unknown/Not specified 44 7.8 56 5.5
Self-reported mutation status
 Known carrier 267 47.5 160 15.8
 Known non-carrier 49 8.7 196 19.4
 Tested but results unknown 47 8.4 57 5.6 <0.001
 Not tested 193 34.3 583 57.7
 Unknown 6 1.1 14 1.4
Previous breast cancer
 Yes 313 55.7 419 41.5 <0.001
 No 249 44.3 591 58.5
Parity
 Nulliparous 155 27.6 307 30.4 0.66
 Parous 407 72.4 702 69.6
Hormone therapy currently
 Yes 100 17.8 188 18.6
 No 462 82.2 819 81.1 0.40
 Unknown 3 0.3
Contraceptive use
 Yes, currently 38 6.8 127 12.6
 Yes, not currently 390 69.4 637 63.1 0.001
 Never used 134 23.8 246 24.4
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RRSO: risk-reducing salpingo-oophorectomy; OCS: ovarian cancer screening

(1). The Medical Outcome Study Short Form-36 (MOS SF-36)

At baseline, participants in the RRSO cohort had significantly lower Physical Functioning, Social Functioning, Role Functioning_Physical, and Role Functioning_Emotional subscale scores than OCS participants. The baseline scores did not differ significantly between the two cohorts for the Bodily Pain, Mental Health, Vitality, and General Health subscales (Table 3).

Table 3:

Least Square Means differences at baseline

QOL Instruments RRSO OCS RRSO-OCS p-value*
Mean (SD) Mean (SD) LS-Means* Difference (95% CI)
The Medical Outcome Study Short Form-36
Physical functioning 86.4 (19.7) 90.6 (15.5) −3.6 (−5.5 to −1.7) <0.001
Role functioning_physical 77.8 (36.9) 86.4 (28.5) −7.4 (−10.9 to −3.9) <0.001
Role functioning_emotional 80.3 (35.6) 86.5 (28.6) −5.1 (−8.6 to −1.6) 0.004
Social functioning 82.0 (23.7) 88.0 (19.3) −5.6 (−7.9 to −3.2) <0.001
Bodily pain 76.1 (25.6) 77.6 (22.5) −1.4 (−4.0 to 1.2) 0.30
Mental health 74.3 (17.1) 75.4 (15.5) −0.87 (−2.7 to 0.9) 0.34
Vitality 59.7 (21.7) 61.2 (20.5) −1.7 (−4.0 to 0.6) 0.14
General health 73.9 (19.4) 75.4 (18.5) −0.97 (−3.1 to 1.1) 0.36
The Impact of Events Scales
Overall score 16.4 (15.3) 10.4 (13.2) 5.5 (4.0 to 7.0) <0.001
Intrusion 7.4 (8.0) 4.2 (6.0) 3.1 (2.4 to 3.9) <0.001
Avoidance 9.0 (8.6) 6.2 (8.1) 2.4 (1.4 to 3.3) <0.001
Center for Epidemiological Studies Depression Scale
CES-D 9.6 (9.9) 8.1 (8.5) 1.4 (0.4 to 2.4) 0.006
State-Trait Anxiety Inventory
State of Anxiety 46.0 (12.0) 44.2 (11.0) 1.9 (0.6 to 3.1) 0.004
Trait of Anxiety 41.9 (10.7) 41.2 (10.0) 0.6 (−0.3 to 2.0) 0.15
The Functional Assessment of Cancer Therapy – Endocrine Subscale
FACT-ES 60.1 (8.3) 60.7 (8.2) −0.9 (−1.8 to 0.05) 0.06
Sexual Activity Questionnaire
Pleasure 11.6 (4.7) 12.2 (4.4) −0.4 (1.0 to 0.2) 0.2
Discomfort 4.1 (2.0) 4.3 (1.9) −0.2 (−0.4 to 0.1) 0.16
Habit 0.7 (0.6) 0.9 (0.6) −0.04 (−0.16 to −0.002) 0.05
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RRSO: risk-reducing salpingo-oophorectomy; OCS: ovarian cancer screening

*

Least-Square Means difference and p-values were from a fitted linear model with adjustment for patient’s age, status of previous breast cancer (yes/no), mutation status (carrier/non-carrier/unknown), and contraceptive use (current/previous/never) at baseline.

Over time, the group difference did not vary significantly for any subscales, and there were no significant group differences in HRQOL as assessed by any MOS SF-36 subscale (Supplemental Figure S1 and Table 4). However, the group differences were significantly larger in participants age 50 years and younger for the bodily pain (−4.5 (−7.4 to −1.6) vs. 0.2 (−3.3 to 3.5), pinteraction=0.007) and vitality (−4.0 (−6.4 to −1.6) vs. 0.8 (−2.1 to 3.6), pinteraction=0.001) subscales, with those in the OCS group reported better QOL than those in the RRSO group in these aspects.

Table 4:

Overall group differences between RRSO and OCS

QOL Instruments LS-Means group difference (99% CI) Adjusted p-value* Unadjusted p-values for interaction
The Medical Outcome Study Short Form-36
Physical functioning 0.09 (−1.3 to 1.48) 1.0 0.4
Role functioning_physical −0.09 (−3.06 to 2.89) 1.0 0.6
Role functioning_emotional −0.41 (−3.34 to 2.51) 1.0 0.4
Social functioning −0.15 (−2.33 to 2.03) 1.0 0.05
Bodily pain −2.11 (−4.37 to 0.15) 0.3 0.5
Mental health −0.37 (−1.92 to 1.18) 1.0 0.3
Vitality −1.61 (−3.53 to 0.31) 0.4 0.06
General health −1.28 (−2.86 to 0.31) 0.5 0.1
The Impact of Events Scales
Overall score −4.27 (−5.32 to −3.21) <0.001 0.6
Intrusion −1.75 (−2.21 to −1.29) <0.001 0.8
Avoidance −2.2 (−2.9 to −1.53) <0.001 0.3
Center for Epidemiological Studies Depression Scale
CES-D 0.08 (−0.79 ∼ 0.95) 1.0 0.02
State-Trait Anxiety Inventory
State of Anxiety −0.7 (−1.74 to 0.34) 0.8 0.7
Trait of Anxiety 0.32 (−0.56 to 1.2) 1.0 0.2
The Functional Assessment of Cancer Therapy – Endocrine Subscale
FACT-ES −2.6 (−3.37 to −1.83) <0.001 0.008
Sexual Activity Questionnaire
Pleasure −0.93 (−1.48 to −0.37) <0.001 0.2
Discomfort −1.06 (−1.34 to −0.78) <0.001 0.2
Habit −0.11 (−0.18 to −0.04) <0.001 0.2
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RRSO: risk-reducing salpingo-oophorectomy; OCS: ovarian cancer screening

*

p-values for testing least squares means differences estimated from the fitted mixed model adjusting for baseline score, age at enrollment, assessment time, and interaction between time and groups, and adjusted for multiple testing using Sidak method.

(2). The Impact of Events Scale (IES)

At baseline, participants in the RRSO cohort reported higher IES Global score and Intrusion and Avoidance subscale scores than those in the OCS cohort (Table 3). The IES global scores declined significantly during follow-up (p<0.001), most notably within 6 months after RRSO (Supplemental Figure S2A). After adjusting for the baseline score, the patients in the RRSO cohort reported a statistically significantly lower global and component scores compared with the OCS cohort (Table 4). There were no significant changes in the group differences over time (pinteraction=0.6). The reduction in the overall global score was largest among participants who had tested positive for a BRCA mutation prior to enrollment (positive: (−6.3 (−8.5 to −4.1) vs. negative: −5.0 (−7.6 to −2.4) vs. unknown: −3.5 (−5.0 to −2.0); pinteraction=0.02).

At baseline, more participants in the RRSO cohort reported clinically significant levels (i.e., IES global score ≥ 9) of OC-related stress (60% vs 41%, p<0.001). In general, during follow-up, participants in the RRSO group were less likely to report clinical levels of OC-related stress (odds ratio=0.42; 99%CI=0.31 to 0.57; padjusted<0.001). Over time, the percentages of patients with clinical levels of stress declined in both groups (ptime<0.001), but the difference between the two groups remained unchanged (pinteraction=0.2, Supplemental Figure S2B).

(3). The Center for Epidemiology Studies Depression Scale (CES-D)

At baseline, the RRSO cohort scored 1.4 points higher on the CES-D than the OCS cohort (p=0.006, Table 3), and more participants scored ≥16, the threshold suggestive of clinical depression (21% vs 15%, p=0.007). The group difference in the CES-D scores did not change significantly during follow-up (pinteraction=0.02, Supplemental Figure S3A), with an estimated overall difference between the two cohorts of 0.8 (Table 4). No overall difference between the two cohort by mutation status was observed (data not shown). There was no difference in the percentages of participants with clinical depression between the two groups (padjusted=1.0, Supplemental Figure S3B).

(4). Speilberger State-Trait Anxiety Inventory (STAI)

At baseline, participants in the RRSO cohort reported higher STAI-State scores than, and similar STAI-Trait score to, those in the OCS cohort (Table 3). The two subscale scores did not change significantly over time (STAI-State, pinteraction=0.7; STAI-Trait, pinteraction=0.2, Supplemental Figure S4), and there were no significant overall group differences in either subscale between the RRSO and OCS cohorts during follow-up (Table 4). There was no difference in either subscales between the two cohort by mutation status (data not shown).

(5). The Functional Assessment of Cancer Therapy – Endocrine Subscale (FACT-ES)

At baseline, participants in both groups reported similar levels of menopausal symptoms (Table 3). Over time, however, the FACT-ES scores declined significantly in the RRSO cohort, reflecting worsening menopausal symptomatology (p<0.001, Supplemental Figure S5), with significant changes between group differences across the time-points (pinteraction=0.008), and an estimated overall group difference of −2.6 (Table 4). The greatest difference between the two groups occurred at 24 months (RRSO vs OCS: −3.07, 99%CI=−4.1 to −2.04; padjusted <0.001). By 60 months, the difference had decreased to −1.55 (99%CI=−2.72 to −0.38; padjusted<0.011).

(6). The Sexual Assessment Questionnaire (SAQ)

Sexual functioning, as measured by reported pleasure from intercourse, pain from intercourse, and change of sexual habit, was evaluated among patients who reported engaging in sexual activities at the assessment time points. Approximately 70% of participants (391 in the RRSO and 711 in the OCS cohort) reported on measures related to sexual health at baseline, vs 65%, 62%, 53% and 37% at 6, 12, 24, and 60 months, respectively.

SAQ_Pleasure

The SAQ_Pleasure subscale scores were not statistically different between the two groups at baseline (Table 3); however, the scores declined significantly in both cohorts during follow-up (ptime<0.001, Supplemental Figure S6A), with significant differences between the two cohorts at each of the time-points (RRSO scoring worse), and an overall group difference of −0.93 (Table 4). These group differences did not vary significantly over time (pinteraction=0.2).

SAQ_Discomfort

The SAQ_Discomfort scores were not different between the RRSO and OCS cohorts at baseline (Table 3). The SAQ_Discomfort subscale scores declined significantly during follow-up (ptime<0.001, Supplemental Figure S6B), with an estimated overall group difference between the two cohorts of −1.06 (RRSO scoring worse) (Table 4). The group difference did not vary significantly over time (pinteraction=0.2).

SAQ_Habit

At baseline, SAQ_Habit subscale scores were 0.08 units lower for the RRSO group compared with the OCS group (Table 3). Over time, participants in the RRSO cohort continued to have lower scores than participants in the OCS cohort, with an estimated overall group difference of −0.11 (Table 4). The group differences (pinteraction=0.2) did not change significantly over time (Supplemental Figure S6C).

Discussion

In this study of women who selected either RRSO or OCS as the option for managing increased OC risk, we collected information on QOL using various metrics at baseline and prospectively for 5 years. Approximately 48% of participants in the RRSO cohort reported themselves to have a BRCA pathogenic variant, compared with 16% in the OCS cohort, which might explain in part the lower baseline QOL measures in the RRSO cohort. At baseline, participants selecting RRSO reported lower HRQOL as indicated by the SF-36, greater OC-related stress, greater anxiety, and more depressive symptomatology – suggesting that OC-related worry might have had a stronger impact on their overall well-being compared with participants who chose OCS. At 6 months after enrollment, these scores had improved to levels either similar to or exceeding those reported by participants in the OCS cohort. The improvement was strongest for OC-related stress, especially among those who were known to have a BRCA pathogenic variant at enrollment. Throughout the study, among those age 50 years and younger, participants the RRSO reported higher bodily pain and lower vitality than participants in the OCS, suggesting that RRSO had a greater impact on these aspects of the HRQOL among younger individuals. Although the financial burden of RRSO was not formally assessed in this study, its impact might not have substantially affected QOL, as evidenced by the improvement in the RRSO cohort’s QOL at the 6-month timepoint. Similarly, frequent blood draw and ROCA measurements could potentially result in substantial financial burden; however, this did not appear to have adversely affected the QOL in this study. Furthermore, serial CA-125 determinations among average-risk women has been shown to not associated with clinically significant psychological morbidity from repeat testing (26). Thus, although the impact of interval ROCA measurement after RRSO cannot be quantified, it was unlikely to be significant, as there was still an overall improvement in QOL in this cohort. Subsequent measures over time showed that QOL as measured by the SF-36, IES, STAI, and CES-D were either similar in both groups or better in the RRSO cohort, possibly due to their post-surgical reduction in cancer worry.

More participants in the OCS cohort than in the RRSO cohort had not undergone genetic testing prior to enrollment. Not knowing their BRCA mutation status might have an impact on the participants’ perception of cancer risk and cancer worries. However, QOL measures at baseline were adjusted by BRCA mutation carrier status, and the linear mixed model used to assess differences in the repeated measures over time was adjusted for baseline scores. Thus, it is unlikely that not knowing their mutation status influenced the findings regarding QOL measures over the study duration.

Previous studies among individuals with a BRCA pathogenic variants unaffected with cancer showed that general QOL was not permanently affected by their management choices (39). Although frequent screening and the consequent need for additional testing to evaluate false-positive findings have been associated with elevated anxiety levels among high-risk women (24, 25), we hypothesized that participating in an active, long-term screening program might decrease emotional distress by helping women feel proactive in their care and reassured by normal screening tests. Our data suggest that long-term, frequent screening did not adversely impact the HRQOL among participants undergoing OCS.

Hormone-related menopausal symptoms and self-reported sexual functioning were similar between the two study groups at baseline. However, compared with women in the OCS cohort, participants in the RRSO cohort reported worsened menopausal symptoms, reduced sexual pleasure, more intercourse-related discomfort, and less frequent sexual activity during follow-up, which reached a nadir at 6-months, and then stabilized after 24 months. Similar findings on the effect of RRSO on sexual activity and sexual functioning have been reported previously (12, 20, 40). While hormone replacement therapy (HRT) appears to ameliorate post-RRSO sexual discomfort compared with nonusers (40) high-risk women may have concerns about cancer risks associated with HRT. However, more recently data showed that HRT after RRSO was safe in women with a BRCA1 pathogenic variant without a personal history of breast cancer (41). In this study, 18% of participants in the RRSO cohort reported HRT use prior to and after surgery. No participants who were not already on HRT started taking it after RRSO. Unfortunately, we did not collect data on why HRT was not utilized, and approximately 56% of the participants in the RRSO cohort had a prior history of breast cancer, which would have precluded HRT use. It is likely that for women with a BRCA1 pathogenic variant with no previous history of breast cancer, the use of HRT would have lowered the worsening in menopausal symptoms and sexual functioning.

Our study has some limitations. Questionnaire response rates declined significantly over time, as is typical in long-term studies, with ~60% of the eligible participants completing the questionnaire at 60 months. Our results could have been biased if participants with worse QOL disproportionately did not complete the questionnaire. Efforts were made to reduce the burden related to data collection. The form was mailed to participants, who could return it by mail or in person at their annual visit. These measures might have facilitated our achieving a reasonable 5-year response rate in this large cohort. Second, ~96% of the participants were white, which might limit our ability to apply these findings to other racial/ethnic groups, and it is not clear how changes in QOL might differ between whites and non-whites.

The study’s large sample size, broad recruitment base (including many community oncology programs), and the inclusion of individuals at increased OC risk, either due to a BRCA1/2 pathogenic variant or a positive family-history, increase the representativeness and applicability of our findings. The QOL data were collected prospectively, using validated psychometric instruments, over a 5-year period. Thus, the findings reflect the long-term effect of RRSO and OCS on women at increased OC risk, an area in which currently available data are limited.

Our data showed that cancer worry and depression symptomatology decreased, and general HRQOL improved, soon after surgery among women undergoing RRSO, and remained stable during the 5-year follow-up. Screening, on the other hand, did not significantly impact long-term QOL. It is reassuring to demonstrate that concerns regarding the psychological and emotional burdens of an intensive OCS program might not be justified. Although there is no effective ovarian cancer screening regimen available, this knowledge might be useful in future efforts to establish such a regimen. Women who elected RRSO reported worsening menopausal symptoms and poorer sexual activity and sexual functioning scores. Issues regarding the effect of surgery on short-term and long-term sexual activity and sexual functioning should be discussed thoroughly in the decision-making process. However, current understanding of medical management post-RRSO, including the judicious use of hormone therapy, should be part of the discussion. These data can inform the discussions with women at increased OC risk regarding their decision about RRSO.

Supplementary Material

1

Supplemental Figure S1: The Medical Outcome Study Short Form-36

Supplemental Figure S2: The Impact of Event Scale

Supplemental Figure S3: The Center for Epidemiology Studies Depression Scale

Supplemental Figure S4: Speilberger State-Trait Anxiety Inventory

Supplemental Figure S5: The Functional Assessment of Cancer Therapy – Endocrine Subscale

Supplemental Figure S6: The Sexual Assessment Questionnaire

RESEARCH HIGHLIGHTS.

  • Ovarian cancer screening did not adversely impact health-related Quality of Life

  • Health-related QOL improved during follow-up for participants selecting RRSO

  • Ovarian cancer-related stress improved after RRSO

  • No adverse effects of RRSO or OCS on psychological and emotional well-being

Acknowledgment

The research of Drs. Phuong L. Mai and Mark H. Greene was supported by the Intramural Research Program of the US National Cancer Institute, and by support services contracts with Westat Inc., Contract #s HHSN261200109D, HHSN261200655004C and HHSN261201300003C. GOG-0199 was supported by NCI Grants No. CA 27469 to the Gynecologic Oncology Group (GOG) Administrative Office and Tissue Bank, No. CA37517 to the GOG Statistical and Data Center, and by NCI Community Clinical Oncology Program Grant No. CA101165 as well as NRG Oncology (1U10 CA180822) and NRG Operations (U10CA180868). Dr. Hensley is supported in part by the MSK Cancer Center Support Grant P30 CA008748. KAP is an Australian National BC Foundation Practitioner Fellow.

The following Gynecologic Oncology Group member institutions participated in the primary treatment studies: Roswell Park Cancer Institute; University of Alabama at Birmingham; Duke University Medical Center; Walter Reed Army Medical Center; University of Minnesota Medical School; Mount Sinai School of Medicine; University of Mississippi Medical Center; Colorado Gynecologic Oncology Group PC; University of California at Los Angeles; University of Cincinnati; University of North Carolina School of Medicine; University of Iowa Hospitals and Clinics; University of Texas Southwestern Medical Center at Dallas; Indiana University School of Medicine; Wake Forest University School of Medicine; University of California Medical Center at Irvine; Tufts-New England Medical Center; Rush-Presbyterian–St. Luke’s Medical Center; Magee Women’s Hospital of the University of Pittsburgh Medical Center; University of New Mexico; The Cleveland Clinic Foundation; Washington University School of Medicine; Memorial Sloan-Kettering Cancer Center; Cooper Hospital/University Medical Center; Columbus Cancer Council; MD Anderson Cancer Center; University of Massachusetts Medical School; Fox Chase Cancer Center; Women’s Cancer Center; University of Oklahoma; University of Virginia Health Sciences Center; University of Chicago; Tacoma General Hospital; Thomas Jefferson University Hospital; Mayo Clinic; Case Western Reserve University; Tampa Bay Cancer Consortium; Gynecologic Oncology Network; Ellis Fischel Cancer Center; Fletcher Allen Health Care; Australia New Zealand Gynaecological Group; Yale University School of Medicine; University of Wisconsin Hospital; National Cancer Institute – Clinical Genetics Branch; The Hospital of Central Connecticut at New Britain General Hospital; and the Community Clinical Oncology Program.

CONFLICTS OF INTEREST

Dr. Kelly Wilkinson received payment for lectures, including service on speakers bureaus from Tessaro-Speakers Bureau.

Dr. Robert Wenham received an institutional grant for conducting research from the GOG. He also served as a consultant for Tesaro as a DSMB Chair and Genentech on the Advisory Board. He received grants/grants pending from Merck for investigator initiation of study. He also received payment for lectures, including service on speakers bureaus from Genentech, Tesaro, Clovis and J&J.

Dr. Matthew Powell served as a consultant for Roche/Genentech, Merck, Clovis Oncology, Tesaro, and AstraZeneca. He also received payment for lectures, including service on speakers bureaus from Roche/Genentech, AstraZeneca, Clovis Oncology, Tesaro and Merck.

Dr. Lari Wenzel was a consultant for Janssen, Lilly and EMD Serona.

Footnotes

All other co-authors have no conflicts of interest to declare.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

1

Supplemental Figure S1: The Medical Outcome Study Short Form-36

Supplemental Figure S2: The Impact of Event Scale

Supplemental Figure S3: The Center for Epidemiology Studies Depression Scale

Supplemental Figure S4: Speilberger State-Trait Anxiety Inventory

Supplemental Figure S5: The Functional Assessment of Cancer Therapy – Endocrine Subscale

Supplemental Figure S6: The Sexual Assessment Questionnaire

NIHMS1544428-supplement-1.docx (351.5KB, docx)

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