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Psychosocial Factors Associated With Withdrawal From the United Kingdom Collaborative Trial of Ovarian Cancer Screening After 1 Episode of Repeat Screening

Jenkins, Valerie DPhil*; Fallowfield, Lesley DPhil*; Langridge, Carolyn CChem*; Barrett, Jessica PhD; Ryan, Andy PhD; Jacobs, Ian FRCOG‡§; Kilkerr, Justine BA*; Menon, Usha FRCOG; Farewell, Vernon PhD

International Journal of Gynecological Cancer: October 2015 - Volume 25 - Issue 8 - p 1519–1525
doi: 10.1097/IGC.0000000000000507
Quality of Life

Objective: The United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) aims to establish the efficacy of 2 different ovarian cancer screening schedules. The psychosocial substudy examines the psychological factors associated with the screening program.

Methods: Women aged 50 to 75 years from 16 UK gynecologic centers randomized to annual multimodal screening or ultrasound screening (US) groups were followed up for 7 years. Psychosocial data from women who withdrew from the study after a repeat screen were examined.

Results: Sixteen percent (3499/21,733) of women requiring a repeat screening test in addition to annual screen withdrew from the study: 12.9% (1560/12,073) from the multimodal group and 20.1% (1939/9660) from the US group. An estimated relative risk of withdrawal is 1.46 (95% confidence interval, 1.36–1.56; P ≤ 0.001) for the US arm. High anxiety trait and increased psychological morbidity significantly influenced withdrawal, even when age, screening center, and group were taken into account (P < 0.001). The risk of withdrawal decreased significantly the longer a woman stayed in UKCTOCS, irrespective of the number of screens and intensity in the preceding year.

Conclusions: Withdrawal rate was greater in women undergoing US screening and in those who had repeats earlier in UKCTOCS. Having a high predisposition to anxiety, high current state anxiety, and above threshold general psychological morbidity all increased the withdrawal rate.

*Sussex Health Outcomes Research & Education in Cancer (SHORE-C), University of Sussex, Brighton, East Sussex, UK; †Public Health and Primary Care, University of Cambridge, Cambridge, UK; ‡Women’s Cancer, Institute for Women’s Health, University College London, London, UK; §Chancellery Building, UNSW, Sydney NSW, Australia; and ∥MRC Biostatistics Unit, Institute of Public Health, Cambridge, UK.

Address correspondence and reprint requests to Valerie Jenkins, DPhil, SHORE-C, BSMS, University of Sussex, Brighton, BN1 9RX, East Sussex, UK. E-mail: val@sussex.ac.uk.

Valerie Jenkins for and on behalf of UKCTOCS Trialists.

Declaration of conflicting interests: V.F. and J.B. have support from MRC (U105261167 and G0902100), and U.M. was supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. I.J. and U.M. have specified relationships to UCL Business and Abcodia Ltd in the commercial development of sample biobanks; their spouses, partners, or children have no financial relationships relevant to the submitted work. L.J.F., V.J., J.B., V.F., C.L., A.R., and J.K. have no nonfinancial interests that may be relevant to the submitted work.

Funding: Supported by Medical Research Council (G9901012) and the Eve Appeal Foundation.

Authors’ contributions: L.F., I.J., U.M., and VF devised the psychosocial study. C.L., A.R., and J.K. organized the data for analysis. V.F. and J.B. analyzed the data. V.J., L.J.F., and V.F. wrote the manuscript. I.J. and U.M. contributed to the manuscript. All authors read and commented on the final version. L.J.F. is the guarantor for the psychosocial data.

Details of ethics approval: The study was approved by the North West research ethics committee 20th June 2000 (MREC 00/8/34).

Trial registration: This study is registered as an International Standard Randomized Controlled Trial, No. ISRCTN22488978.

Received December 16, 2014

Received in revised form April 27, 2015

Accepted May 19, 2015

Ovarian cancer (OC) is the fourth highest common cause of cancer death in UK women.1 The United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) aims to establish the efficacy of 2 different screening schedules. If screening has a positive effect on mortality, then issues such as the acceptability of screening methods and identification of factors that might influence adherence to annual screening will be important factors in effective implementation.

Screening of healthy populations may have harms and benefits. Establishing the myriad of factors that might contribute to the acceptability of OC screening (OCS) and maintain regular attendance is therefore important. In UKCTOCS, women who experienced pain during a transvaginal ultrasound (TVS) scan were less likely to attend the following year’s scan compared with those not reporting pain.2 We have also shown that anxiety is not unduly raised in general in UKCTOCS, especially when compared with the variation in anxiety levels that occur over time within individuals. Anxiety decreased significantly with every year spent in the study and was lower in older women.3 The number of people diagnosed as having cancer at screening is relatively low, but a substantial proportion will experience false-positive results, which may increase anxiety and lead to withdrawal.4–6 One concern is that people who withdraw from screening programs or are lost to follow-up may experience higher levels of distress than those who remain in studies. There is some evidence of this in the National Cancer Institute’s Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial in which trial adherence was significantly better among participants who had received all normal results in the previous year’s screening tests than in those who received at least 1 abnormal result.7

In this article, we examine the association of anxiety, general psychological morbidity, and randomization group on withdrawal from UKCTOCS, after test results requiring a repeat screen. Knowledge that a screening test result is abnormal in any way might reasonably be expected to cause concern. If after further testing, the abnormality was shown to have been a false-positive result, this might produce relief or a loss of confidence in screening, or make individuals more anxious especially in those with a predisposition toward anxiety. Nonattendance or withdrawal from further screening could be the consequence.

A meta-analysis of breast cancer screening indicated that false positives had variable impacts on subsequent attendance for screening, with no significant relationship between false positives and reattendance in European women, decreased reattendance in Canadian women, and increased attendance in the United States.8 Furthermore, the type of screening and false positives might have a measurable effect; TVS is a more invasive procedure than a blood test, so one could hypothesise that false positives after additional scans might be more likely to foster withdrawal from further screening.

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METHODS

The design of the multicenter screening trial UKCTOCS and the psychosocial substudy has been described in detail elsewhere.3,9–11 The program involved 202,638 postmenopausal women from 13 UK screening centers randomized to a control group or annual screening in either (1) a multimodal (MM) group who had serum CA-125 interpreted via a Risk of Ovarian Cancer algorithm, followed if necessary by TVS scan as a second-line test, or (2) a TVS ultrasound screening (US) group. In addition to these tests, acceptability of screening and physical and psychological morbidity were measured after an abnormal screen and at annual screen, for 7 years postrandomization.

All women completed baseline questionnaires; thereafter, any women in the MM and US groups receiving abnormal results after annual screening were sent further psychosocial questionnaires after each abnormal screen requiring extra testing. If no abnormality was detected, women returned to annual screening (for a maximum of 7 years) while on study. If surgery for OC was needed, women had no further screening, but for non-OC or if ovaries were not removed at surgery, then women could continue in the study. More than 23,000 women from the MM and US groups in UKCTOCS had abnormal events at screening in the 7 years postrandomization.

Repeat screens were categorized as level 1 or 2. The level of the test after results of an abnormal annual screen depended on (a) the group (MM or US) and (b) the degree of invasiveness of the test. For example, a level 1 screen in the MM group was merely a repeat blood test in 3 months, whereas a level 2 screen was a repeat blood test and a TVS scan in 6 weeks. A level 1 screen for women in the US group was a repeat TVS by an experienced ultrasonographer in 3 months, and a level 2 screen was a repeat TVS by a senior ultrasonographer or consultant in 6 weeks.

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Study Measures

Participants provided sociodemographic details and highest education level, personal and family history of breast and OC, and use of oral contraception; these were obtained from the main UKCTOCS data set. Women also completed several questionnaires including the Spielberger State/Trait Anxiety Inventory (STAI)12 and the General Health Questionnaire 12 (GHQ-12).13

Trait anxiety was measured at baseline only and reflects an individual’s underlying predisposition toward anxiety. State anxiety measures how a person feels right now and was assessed at all other times together with the GHQ, which is a general psychological morbidity assessment.

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Statistical Methods

The psychosocial and basic demographic data of women who withdrew from the study at some point after their first repeat screen were compared with women having one or more repeat screens but not withdrawing subsequently. Women with no randomization date and those without baseline questionnaires (n = 410) were not included in the data set, as were 2 women without withdrawal dates. Withdrawals due to death (n = 364), any cancer diagnosis (n = 370), and removal of ovaries (n = 199) were censored. Also censored at withdrawal time were women who had surgery after an abnormal screen result (n = 1291), most of whom never returned to the screening program thereafter. Missing values for any variable led to the exclusion of that year’s information for the relevant women in analyses requiring that variable.

Scores from the 20 item STAI State questionnaire range from 20 to 80 and were treated as a continuous variable. The 12 item GHQ-12 scores range from 1 to 12 and were dichotomized, with at least 4 signifying probable psychological morbidity.

Withdrawal rates were examined through use of time-to-event analyses based on Cox relative risk regression model.14 Analysis results are presented as relative risk estimates with 95% confidence intervals (CIs) and significance levels (P values) for tests of relative risks being unity which corresponds to no effect. The planned duration of screening was 6 years. Because dates of screening during a year are irregular or fluctuate, a cutoff duration of 7 years was used in the analysis to avoid losing any sixth year screens. Women were thus censored at the time of their last annual screen if this occurred before 7 and at 7 years otherwise. Counts of withdrawals are given for illustrative purposes.

Both STAI and GHQ12 scores were updated at each annual screen if possible. Imputation using last value carried forward was applied for 2 years if necessary but thereafter treated as missing. Age and STAI scores were centered at their respective means, 35.9 and 61 years. Baseline scores for STAI trait were used to create a 3-level factored variable: low, medium, and high. Low and high anxiety were respectively defined as a STAI trait score lower or higher than 1 SD (10.1) from the sample mean (36.5), both calculated previously.11

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RESULTS

For the events sample of 21,733 women, 5723 withdrawals took place during the first 7 years of screening and after exclusions; 3,499 were available for analysis. Table 1 shows the participants’ characteristics at the time of the first screening event. Table 2 shows the withdrawal rates per center.

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Comparison of Withdrawal Rates in the Screening Groups

Of women with repeat testing, 12.9% (1560/12,073) withdrew in the MM arm and 20.1% (1939/9660) withdrew in the US arm. This led to an estimated relative risk of withdrawal of 1.44 (95% CI, 1.34–1.54; P ≤ 0.001) for the US arm vs the MM arm. Adjustment for center, through stratification, and age, through the inclusion of a continuous age variable, standardized at age 61 years, in the model, led to a relative risk estimate of 1.46 (95% CI, 1.36–1.56; P < 0.001) for the comparison of US and MM arms in this sample.

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Effects of other Factors

Tables 3 and 4 show the times to withdrawal of participants and withdrawal rates by year of entry into the events sample. Table 5 presents the results of the analyses. In single-factor analyses after adjustment for center, age, and randomization group, GHQ ≥ 4, current STAI state score (standardized at mean 35.9), a high STAI trait value, the level of the women’s last screen, and the maximum screening level experienced, along with randomization to the US arm, demonstrate very significant (P < 0.001) relationships to withdrawal rate. Other weaker but significant relationships were observed including having a perceived chance of OC of 1 in 10 (P = 0.01), having used hormone replacement therapy (HRT; P = 0.03), and with the year of the women’s first screening event (P = 0.01). There was no evidence of an ethnicity (white vs nonwhite) effect.

Multivariate analyses demonstrate that GHQ ≥ 4 and current STAI score retain their relationship when STAI trait is included in the model. High STAI trait retains a significant but less strong relationship to withdrawal when GHQ ≥ 4 is in the model, but low STAI trait does not. However, low STAI trait is significant and high STAI trait is not significant if STAI state is in the model and not GHQ ≥ 4. When both GHQ ≥ 4 and STAI state are in the model, then the significance of STAI trait dominates that of GHQ ≥ 4. There is also a suggestion that some increase in withdrawal rate may be associated with a low STAI trait (P = 0.10).

Also maintained in the multivariate analysis is the finding that an increased risk of withdrawal is associated with a woman last having level 1 or level 2 screens. However, if a woman has previously had a level 2 screen, it brings a reduced risk of withdrawal. It seems therefore that a recent event does increase the chance of withdrawal, but if a woman had a level 2 screen previously and stayed in the program, then subsequently the risk of withdrawal is reduced. There is no evidence for an interaction between past screening level and current level. Thus, relative to a woman whose last screen was an annual screen and who only ever had a level 1 screen previously, the risk of withdrawal is estimated to be increased by a factor of 1.32. For women who last had a level 1 and level 2 screen, respectively, it increased by a factor of 1.49. However, if a the previous screen was at level 2, the rate of withdrawal is estimated to be decreased by factors of 0.56, 0.74, and 0.83 if the woman last had an annual, a level 1, and a level 2 screen, respectively. Also maintained in the multivariate analysis is an increased risk of withdrawal for women who took HRT and a decreased risk the longer the woman has been in the screening program prior to their first screening event.

If interactions between randomization group and past screening level and between randomization group and current screening level are added to the multivariate model, then the former is highly significant (P < 0.001) and the latter has a suggestive significance level of P = 0.055. The estimated relative risk associated with level 1 and level 2 screen are 1.15 (CI, 0.94–1.40) and 1.35 (CI, 1.05–1.73), respectively, for the MM group but have the higher values of 1.54 (CI, 1.29–1.84) and 1.54 (CI, 1.31–1.80) for the US group. The estimated relative risk for a previous level 2 screen is 0.82 (CI, 0.67–1.00) and 0.46 (CI, 0.40–0.55) in the MM and US groups, respectively. There was no evidence of an interaction between randomization group and ethnicity (P = 0.37).

If the interaction between STAI state and last screen level is introduced into the multivariate model (c), then there is marginal evidence for an interaction (P = 0.07 on 2 df test). If a model is fit to the groups’ last level 1 and last level 2 classes together, then the interaction between this variable and STAI state is more significant (P = 0.026 on 1 df test). The magnitude of the interaction effect is relatively small with the estimated effect of a level 1 or level 2 screen corresponding to a relative risk of withdrawal of 1.38 for a STAI state score at its mean of 35.9 but of 1.51 if the STAI state score is 10 units higher.

Although not included in the multivariate model because it is potentially on the causal pathway to withdrawal, women also answered a question about the likelihood of returning for the following year’s screen. Available responses were “yes,” “unsure,” and “no.” As expected, the withdrawal rates in the next year varied greatly with the response to this question, with rates of 3% (2600/83,508), 23% (332/1447), and 41% (186/453) observed over all patient-year observations. A formal analysis of time to withdrawal, adjusting for group, age, and center leads to a relative risk of 5.4 (CI, 4.8–6.1) and 4.9 (CI, 4.1–5.7) for the “unsure” and “no” groups relative to the “yes” group. The unadjusted relative risk estimates were 6.1 (CI, 5.5–6.9) and 5.2 (CI, 4.5–6.1).

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DISCUSSION

Establishing the sensitivity and specificity of different types of screening is vital before initiating a population screening program, but it is also crucial to ascertain all potential factors that might influence participation and regular attendance. For example, a survey examining the acceptability of TVS scan within UKCTOCS showed that most women (72%) did not rate the procedure painful and only a small proportion (4%) felt embarrassed during the scan, but most shared apprehensions about the intrusive nature of the test. However, those who did rate TVS as uncomfortable and painful were less compliant with attendance at the following year’s scan compared with those who did not experience pain.2

The findings from this UKCTOCS analysis suggest that postmenopausal women who have experienced a screening event are more likely to withdraw from OCS programs using more invasive screening procedures such as TVS. High trait anxiety and increased psychological morbidity significantly influenced the rate of withdrawal, even when age, screening center, and screening group were taken into account. It is recognized that people who are anxious about their health are more likely to misinterpret health information; the likelihood of withdrawal from UKCTOCS increased in women with the incorrect perception that their chance of developing OC was as high as 1 in 10. The cognitive-behavioral theory of health anxiety predicts atypical responses in health anxious individuals when exposed to health-related information.15 Information is more likely to be viewed as personally threatening, and they are less likely to be reassured by medical investigations. This has been shown in a study of colorectal cancer screening. Health anxious people reported lower levels of reassurance after a clear test result than nonanxious participants, although the size of the effect was small.4

In the context of UKCTOCS, there was some evidence that a volunteer who was more anxious before annual screening and who then required additional screening because of a false-positive result was also more likely to withdraw from the program compared with someone less anxious having a false-positive result. As the experience of a “near miss” might heighten awareness of cancer and illness and increase anxiety, one might predict that an already anxious woman experiencing a number of false-positive results would be more likely to withdraw from screening. This supposition was not upheld by our results.

In an earlier study that examined the psychological sequelae associated with abnormal screen results for women in UKCTOCS, screening did not seem to raise anxiety, but psychological morbidity was slightly elevated by more invasive testing after annual screens. Anxiety in fact decreased with every year a volunteer stayed in the study.3 Likewise, in this withdrawal analysis, women were less likely to leave the study the later they experienced a repeat screening event during the 7 years of screening.

In the Psychological aspects of Familial Ovarian Cancer Screening Study, the main reasons for withdrawal from OCS before surgery were previous experience of UK FOCCSS Phase 1 screening, repeat tests during previous screens, higher cancer-specific distress, and a belief that aging caused OC.16 In this situation, where there is a familial risk of developing OC, it could be that having repeat tests heightened anxiety to such an extent that women decided to undergo risk-reducing surgery.

Similarly in the case of breast cancer screening programs, a false-positive result brings with it several disadvantages to the participant and provider. There is the cost related to the provision of further tests, biopsies to deliver a diagnosis, and the anxiety experienced by the participant that would never have happened in the absence of screening.4 An earlier study reported that despite having received a final clear result during routine breast screening, women who had undergone further investigations, for example, fine needle aspiration, surgical biopsy or been placed on early recall, suffered significantly greater adverse consequences at 1 month before their next routine breast screening appointment than did women who had received a clear result after their initial mammogram at their last routine breast screening.6 The authors concluded that undergoing further investigations did not necessarily motivate women to attend for their next routine appointment. Whether these women had a high anxiety trait characteristic is unknown.

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Strengths and Limitations

The primary strengths of the UKCTOCS psychosocial study are its size and, unlike much previous research in this area, its longitudinal design. Cross-sectional work does not permit the prospective detailed examination over time of putative psychosocial factors that might influence withdrawal from a screening program after at least 1 repeat screen. A limitation of the study is that those women who consent to participate in a trial of different screening modalities, which also included a control group, might be a self-selected population; however, the sociodemographic characteristics of the 202,638 volunteers in UKCTOCS seem to be wide ranging.

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Interpretation

There are no other OCS studies of comparable design and size with which to compare these UKCTOCS withdrawal results. What we have shown is that women with a high predisposition toward anxiety are more likely to drop out of screening, as do those who experience high anxiety after their most recent scan. Furthermore, the more invasive the initial screening procedure is, that is TVS, rather than a multimodal approach, the more likely withdrawal will be after a repeat scan or false-positive result.

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CONCLUSIONS

The United Kingdom Collaborative Trial of Ovarian Cancer Screening included a comprehensive psychosocial arm that has permitted an in-depth appraisal of not only the psychosocial harms and benefits of OCS but also some of the factors that might enhance or inhibit attendance and re attendance. Next year, the National Screening Committee is scheduled to review its policy on OCS in women after the UKCTOCS study against criteria that include psychosocial factors. These results should assist policy makers when considering the optimal screening methods and any accompanying educational resources, especially aimed at ameliorating anxiety.

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ACKNOWLEDGMENTS

The authors thank the many volunteers who participated in the trial, the clinicians and research nurses in the 16 centers, data monitors, managers, and other academic staff involved over the years, especially staff at SHORE-C, University of Sussex. The authors appreciate the help of UKCTOCS staff at UCL and the helpful comments from the UKCTOCS trialists and steering committee.

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REFERENCES

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Keywords:

Ovarian cancer; Population screening program; Withdrawal; Anxiety; Psychological morbidity; UKCTOCS

© 2015 by the International Gynecologic Cancer Society and the European Society of Gynaecological Oncology.