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© 2001 American Society for Clinical Oncology
Tamoxifen for the Prevention of Breast Cancer: Psychosocial Impact on Women Participating in Two Randomized Controlled TrialsCancer Research Campaign Psychosocial Oncology Group, University of Sussex; Imperial Cancer Research Fund, Lincoln’s Inn Fields, London; Royal Marsden National Health Services Trust, London; and Christie Hospital NHS Trust, Manchester, United Kingdom. Address reprint requests to Lesley Fallowfield, DPhil, CRC Psychosocial Oncology Group, School of Biological Sciences, University of Sussex, Brighton, BN1 9QG, United Kingdom; email: l.fallowfield@ bids.susx.ac.uk.
PURPOSE: The purpose of this study was to evaluate the psychosocial implications of tamoxifen versus placebo in women who are at increased risk of breast cancer. PATIENTS AND METHODS: The 488 women in the psychosocial study were recruited from participants in two placebo-controlled, double-blind, randomized, controlled trials that investigated the efficacy of tamoxifen in the prevention of breast cancer in women who are at high familial risk. During a 5-year period, repeated assessments were made of anxiety, psychological distress, and sexual functioning using standardized questionnaires before treatment at baseline and at 6-month intervals during the trial. RESULTS: Questionnaire completion over 5 years was good, with 71.1% of women returning at least 8 of 10 follow-up assessments. Although scores from individuals showed considerable fluctuation and variation over time, changes in anxiety, mood, and sexual functioning were not associated with treatment group. The number of symptoms reported at 48 months via a self-report cheklist were not associated with treatment group, but vasomotor symptoms were more frequent among tamoxifen-treated women. Symptoms of low energy, breast sensitivity, and visual blurring were reported most frequently in the placebo group. CONCLUSION: In general, these results are comparable to those from the National Surgical Adjuvant Breast and Bowel Project psychosocial study despite differences in study populations, methodology, and instruments. The long-term use of tamoxifen and other selective estrogen response modulators as preventive agents in high-risk groups has been questioned, but we found no evidence of treatment-related side effects that affect women’s psychosocial and sexual functioning.
RANDOMIZED TRIALS have been set up to test the efficacy of the antiestrogen tamoxifen in the prevention of breast cancer in women who are at high risk of developing the disease and to identify side effects that could offset any benefit in terms of cancer prevention.1-4 These prevention trials evolved from a series of adjuvant trials that emphasized the prophylactic effect of tamoxifen on disease recurrence and showed a reduction in the number of contralateral breast cancers in women with early stage disease.5 When the first chemoprevention trials were initiated, the toxicity of tamoxifen was thought to be minimal6,7; however, it was postulated that vasomotor changes resulting from tamoxifen use might affect mood and sexual functioning. The psychosocial impact of taking tamoxifen in a preventive setting had not been studied systematically when our study began, although a comparable study (National Surgical Adjuvant Breast and Bowel Project [NSABP]) began shortly afterward in United States.8,9 The NSABP study, which was stopped prematurely, found no increase in depression, effects on emotional well-being, or overall sexual activity associated with tamoxifen use but did find an associated increase in specific vasomotor and gynecologic symptoms and some problems with sexual functioning. This article describes the psychological well-being and sexual interest of 488 British women who are at high familial risk of breast cancer and who participated in two ongoing placebo-controlled, double-blind, randomized, controlled chemoprevention trials: the Royal Marsden Hospital tamoxifen randomized chemoprevention trial (TAMOPLAC)2 and the International Breast Cancer Intervention Study (IBIS).10 In both trials, participants were randomized to tamoxifen (20 mg) or an inert placebo to take daily for at least 5 years. We examined whether changes in psychological and sexual functioning were associated with the use of tamoxifen and compared participation, self-reported tablet adherence, and experience of symptoms between the women who were randomized to tamoxifen and the women who were randomized to placebo.
Recruitment Separate ethical approval for the psychosocial study was obtained, and the women who participated provided written informed consent. Consecutive women who were considering entry into the main trials were invited to join the psychological study. Data collection commenced in 1992 and was completed in 1999. Of the 550 women invited, 488 sent back baseline questionnaires: 416 women from TAMOPLAC and 72 from IBIS (Manchester center). Participants were sent postal questionnaires every 6 months for 5 years. Women were telephoned by the study coordinator shortly before questionnaires were sent out to discuss any queries and to check address details. Reminders were sent to nonresponders after 4 weeks.
Instruments
Data Completeness and Statistical Analysis There are many tests quoted in this article, and it is worth stressing that these have to be viewed with certain provisos. As an aid to better understanding, all P values and confidence intervals are quoted rather than introducing the problems and potential errors associated with formal adjustments for multiple comparisons.
Baseline Measurements Comparison between TAMOPLAC and IBIS trial participants. Women who were recruited from the TAMOPLAC trial (217 randomized to tamoxifen, 199 to placebo) were compared with the smaller group from the IBIS trial (37 randomized to tamoxifen, 35 to placebo) before the data were merged. Age, familial risk of breast cancer, use of HRT, and psychosocial characteristics were similar, but a larger proportion of the women from the TAMOPLAC trial were premenopausal compared with the IBIS women (53.4% [220 of 412] versus 37.7% [23 of 61]  2 = 5.2, df = 1, P = .02).
Comparison between women randomized to tamoxifen and placebo.
The women in the tamoxifen and placebo groups were well matched on age, risk-related family history, menopausal status, and use of HRT ( Table 1). Two thirds (67.4%) were younger than 50 years, 26.4% were between 50 and 59 years, and 6.1% were 60 years or older. Use of HRT before the trial was associated with age; 15.7% of the women who were younger than 50 years were using it compared with 34.3% of those who were 50 years or older (
The psychosocial characteristics of the tamoxifen and placebo groups were similar at trial entry (Table 1). Trait anxiety was associated with GHQ score. Almost three quarters (71.2% [89 of 125]) of the GHQ "cases" had a high trait anxiety score (equal or greater than 40) compared with 28.2% (98 of 348) of the others ( 2 = 71.3, df = 1, P < .001).
The "pleasure" score (a summary of desire, enjoyment, frequency, and satisfaction) and the "discomfort" score (aggregate of vaginal dryness and pain, discomfort during penetration) distributions suggest that sexually active women experienced a generally high level of sexual satisfaction and low discomfort (Table 1) at trial entry. Most (80.8% [286 of 354]) of these women described the frequency of sexual activity as "the same as usual," although this was more frequently reported by the women who were randomized to tamoxifen than the others (
Sexual activity was associated with age; 84.4% (271 of 321) of the women aged 30 to 49 years were active at trial entry compared with 64.9% (96 of 148) of the women aged 50 years or older (
Measurements Over Time Questionnaire completion. Almost three quarters (71.1% [347 of 488]) of participants returned at least 8 of 10 of their follow-up questionnaires, 46.9% (229 of 488) returned all. Twenty-six women did not return any questionnaires after baseline, but this includes 11 women who had withdrawn from the main trials. There was no difference between the treatment groups in their participation in the psychosocial study (random effects model: odds ratio [OR], 1.00; 95% confidence interval [CI], 0.68 to 1.49; Fig 1). Baseline data (age, menopausal status, whether sexually active, trait anxiety, and GHQ "caseness") were used to investigate the characteristics of the women who did not return questionnaires at various intervals during the trial (6 months, 1 year, 3 years, and 5 years). Failure to return questionnaires was not associated with any of these variables.
Self-reported tablet adherence. It is estimated that 38.2% (153 of 401, data missing for 87) of the psychosocial study participants stopped taking tablets before the end of the trial. Self-reported tablet adherence declined over time among the respondents in both groups, and there was a reduction in adherence associated with tamoxifen (random effects model: OR, 0.33; 95% CI, 0.19 to 0.57; Fig 2).
Psychological Morbidity The proportion of respondents who scored above the GHQ-30 threshold varied between 22% and 30% during the trial ( Fig 3). After adjustment for time on study and baseline GHQ score, there was a marginally significant effect favoring the tamoxifen-treated group (OR, 0.72; 95% CI, 0.53 to 1.00). Just over half (64 of 119) of the GHQ "cases" at 6 months were women who had also scored over the threshold at baseline. Becoming a new "case" at 6 months was not associated with treatment group; 13.2% (29 of 220) of the tamoxifen group did compared with 12.9% (26 of 201) of the placebo group, and only 42.6% of the new "cases" (20 of 47, data not available at 12 months for 8 women) scored over the threshold again 6 months later. Almost three quarters (72.4% [286 of 395]) of the women who returned five or more GHQ questionnaires during the trial scored over the GHQ threshold at least once. Scoring above the threshold repeatedly was associated with pretrial GHQ but not with treatment group; 41.3% (43 of 104) of the "cases" at baseline scored over the threshold on half or more of their follow-up questionnaires compared with 18.0% (52 of 289) of the others ( 2 = 22.8, df = 1, P < .001).
Anxiety. Differences between the treatment groups’ average anxiety scores at various points during the trial favored tamoxifen ( Fig 4), but these comparisons do not take baseline variation into account. Differences in anxiety level compared with baseline were estimated using a random effects linear model. The coefficient for the effect of treatment was not significant (P = .09).
The groups’ average anxiety scores did not vary much during the trial, but the scores of individual women fluctuated. Among the women who returned at least five follow-up questionnaires, one fifth (88 of 396) had a range of 30 or more points between their minimum and maximum anxiety scores and 30.8% (122 of 396) repeatedly scored highly (state anxiety equal or greater than 40 on at least 50% of their questionnaires). This was associated with trait anxiety but not with treatment group (54.9% with high trait anxiety [baseline score, 40 or more] had repeated high state anxiety scores compared with 15.9% of the others [ 2 = 64.3, df = 1, P < .001]). Sexual activity. Throughout the trial, approximately three quarters of the women who completed the SAQ were sexually active ( Fig 5) and there was no treatment effect (OR adjusting for baseline sexual activity status and time on study, 1.63; 95% CI, 0.86 to 3.08). Among those who described the frequency of sexual activity at trial entry "as usual," there was no association between a reduction in sexual activity during the trial and treatment group (adjusted OR, 1.04; 95% CI, 0.69 to 1.56). Comments that were written on questionnaires demonstrated a variety of factors that influenced sexual activity, such as family relationships, their own and their partner’s general health, and satisfaction with work. "Pleasure" from sexual activity (aggregate score) was not associated with treatment group (P = .09; Fig 6), and similar proportions of the sexually active women in both treatment groups experienced vaginal dryness (random effects model: OR, 0.56; 95% CI, 0.30 to 1.05; Fig 7) and pain or discomfort during penetration (random effects model: OR, 0.87; 95% CI, 0.49 to 1.57; Fig 8) during the study.
Symptoms. Women who returned questionnaires 48 months after joining the trial completed a symptom checklist, selecting those that had caused them problems since joining the trial ( Table 2). Most women (90% [314 of 347, data missing for 19]) reported at least one symptom that had caused a considerable problem (somewhat/quite a bit/very much). The number of problems reported was associated with anxiety; women whose trait anxiety score was under 40 reported a median of six symptoms compared with nine among those with a trait anxiety score of 40 or more (Mann-Whitney U test, P < .001). The number of symptoms reported was not associated with age or treatment group.
Problems with weight gain, joint pain, feeling bloated, night sweats, hot flushes, and low energy were reported by more than one third of respondents (Table 2). Women in the tamoxifen group were more likely to report vasomotor symptoms (night sweats, hot flushes, and cold sweats) and vaginal discharge, whereas members of the placebo group were more likely to report low energy, breast sensitivity or tenderness, and blurring of vision.
Changes in psychosocial well-being measured during a 5-year period were not associated with tamoxifen. Although women in the tamoxifen group were more likely to report vasomotor symptoms and vaginal discharge, these problems did not seem to have a major impact on either their measured psychological or their sexual well-being. Most of our results were similar to those from the parallel NSABP psychosocial study,9 which found no major quality-of-life differences between groups, despite increased vasomotor and gynecological symptoms. The specific but relatively small sexual functioning difficulties associated with tamoxifen reported in the NSABP study were not apparent in our sample. Furthermore, in common with the NSABP data, we found no effect of tamoxifen on overall sexual activity. Trial participants were self-selected women who are at high familial risk of breast cancer, but the baseline data suggest that they were fairly representative of the general population in terms of their psychological characteristics. The group’s average trait anxiety score was slightly higher than that of the published American female population norm13 but lower than that found among British women who have a family history of breast cancer and who were attending clinics for routine screening.18 The participants’ average GHQ score was slightly lower than the female average in a large British population study.19 Multidimensional Health Locus of Control scores were similar to published norms for persons engaged in preventive health behaviors.12 Participation in the psychosocial study was not associated with treatment group and remained high; almost three quarters returned questionnaires after 5 years. Although questionnaire completion and return remained high, women frequently missed occasional questionnaires. This is a common problem in longitudinal quality-of-life studies,20 making comparisons between groups at each follow-up difficult and sometimes misleading. Apart from the marginally significant results favoring the tamoxifen group from the GHQ, longitudinal analyses did not show any short- or long-term changes in anxiety, psychological distress, or sexual functioning associated with treatment group. It is important to reiterate that in the 5-year study follow-up, scores for individual women varied and fluctuated throughout the trial depending on other situational factors, eg, family relationships, general health, satisfaction with work. Many women had high scores occasionally, but those who were highly anxious or over the GHQ threshold at baseline were more likely than the others to have high scores repeatedly during the trial. The importance of distinguishing between premenopausal and postmenopausal women when investigating the risks and benefits of tamoxifen in prevention studies has been highlighted,21 but this study did not differentiate between women on this basis as a high proportion were perimenopausal. The analyses did not control for use of HRT during the study, another potentially confounding factor, because many women used it intermittently during the study. There was no evidence, however, that requirements for HRT differed between the tamoxifen and placebo groups. The data were analyzed on an intention-to-treat basis, but remaining in the psychosocial study and returning questionnaires was not analogous to taking tablets. The estimate of tablet adherence in this study was self-reported, which is considered to be reliable, as Powles et al2 found 96% agreement between volunteered history of compliance in relation to blood testing. As found in the NSABP study, tablet adherence decreased over time in both the tamoxifen and placebo groups. Noncompliance among participants in the psychosocial trial was comparable to the level previously reported in the TAMOPLAC trial.2 It is not surprising that tablet adherence declined over time in both groups as only approximately 50% of patients with chronic diseases take their medicines in therapeutically effective doses.22 Many women in this study were perimenopausal and may have attributed associated symptoms to the tablets. Participants were "at risk" rather than ill, and they may have been less willing to take tablets on a daily basis if they attributed side effects to them than were women who were taking tablets in a curative capacity and who may ignore "trivial" symptoms or side effects.17 As with NSABP study data, it is likely that the nonadherent women in both the tamoxifen and placebo groups were those most sensitive to either the actual or the possible occurrence of side effects caused by tamoxifen. Further data on tablet adherence will be available on completion of the IBIS and TAMOPLAC trials. The number of symptoms reported was not related to treatment group or age, but there was an association with anxiety. This finding complements previous research that found an association between symptom reporting and emotional and social distress in patients who had cancer.23 Women in the tamoxifen group were more likely to report vasomotor symptoms and vaginal discharge, whereas women in the placebo group were more likely to report low energy, breast sensitivity, and blurring of vision. Some of these differences may be due to chance as multiple comparisons were made. Interestingly, weight gain was the same in both groups. Reporting of symptoms was not a major end point in this psychosocial study, and only one assessment was made 48 months after trial entry, when women with major symptoms might have already withdrawn from the main trials. More comprehensive results relating to symptoms will be reported with the main findings from the TAMOPLAC and IBIS trials. Future psychological studies should also monitor symptoms at repeated intervals (cf NSABP study9) to examine when problems start and their duration and impact on psychosocial functioning. Generic psychosocial questionnaires may not be sensitive enough to detect the consequences of the symptoms reported, so additional assessments should be made. It may be possible to adapt the tools used to examine the impact of endocrine treatment on the quality of life in cancer patients.24 In general, our findings were comparable to those from the parallel NSABP psychosocial study,9 even though there were differences between the study populations, methodology, and instruments. The NSABP study was larger, participants were older, and HRT was not used during the trial. The psychosocial data in the NSABP study were also largely a reflection of treatment adherence as data collection coincided with clinic visits. Neither study found an association between psychological morbidity and tamoxifen. In both studies, women who were allocated to tamoxifen experienced an increased frequency of some vasomotor and gynecologic symptoms. Only the NSABP study reported differences in sexual functioning between the tamoxifen and placebo groups but acknowledged that the absolute differences were small and some might have been caused by chance. A healthy woman’s decision regarding tamoxifen use to prevent breast cancer will depend on her perception of the risk of cancer and other side effects. Much publicity has been generated by various groups that believe that tamoxifen is damaging. Our results are encouraging in that general psychological and sexual functioning did not seem to be affected adversely by tamoxifen. We await with interest further results from the main TAMOPLAC and IBIS trialsconcerning compliance, symptoms, and the effects of tamoxifen on breast cancer prevention.
This study was funded by the Cancer Research Campaign. L.J. Fallowfield conceived, designed, and supervised the study and wrote the original protocol with T. Powles, J. Cuzick, and A. Howell. A. Fleissig coordinated the final year of the study, carried out the data analysis, and wrote the first drafts of the paper. Independent statistical support was provided by R. Edwards. All authors contributed to the writing of the final paper. We thank Kathryn Thirlaway, Janice Osgood, and Andrea West for study coordination and data collection; Linda Onyemere for administrative support; Sue Ashley for help with the analysis; and Dan Altmann and Chris Wale for their advice. We also thank all of the women who took part in the study and the staff in the family history clinics, in particular Gareth Evans, Alywnne Tidy, and Rosemary Greenhalgh.
1. Fisher B, Costantino JP, Wickerham DL, et al: Tamoxifen for prevention of breast cancer: Report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 90: 1371-1388, 1998 2. Powles T, Eeles R, Ashley S, et al: Interim analysis of the incidence of breast cancer in the Royal Marsden Hospital tamoxifen randomised chemoprevention trial. Lancet 352: 98-101, 1998[Medline] 3. Veronesi U, Maisonneuve P, Costa A, et al: Prevention of breast cancer with tamoxifen: Preliminary findings from the Italian randomised trial among hysterectomised women. Lancet 352: 93-97, 1998[Medline] 4. Hutchings O, Evans G, Fallowfield L, et al: Effect of early American results on patients in a tamoxifen prevention trial (IBIS). International Breast Cancer Intervention Study. Lancet 352: 1222, 1998 (letter) 5. Cuzick J, Baum M: Tamoxifen and contralateral breast cancer. Lancet 2: 282, 1985[Medline] 6. Powles TJ, Tillyer CR, Jones AL, et al: Prevention of breast cancer with tamoxifen: An update on the Royal Marsden Hospital pilot programme. Eur J Cancer 26: 680-684, 1990
7.
Love RR, Cameron L, Connell BL, et al: Symptoms associated with tamoxifen treatment in postmenopausal women. Arch Intern Med 151: 1842-1847, 1991
8.
Ganz PA, Day R, Ware JE Jr, et al: Base-line quality-of-life assessment in the National Surgical Adjuvant Breast and Bowel Project Breast Cancer Prevention Trial. J Natl Cancer Inst 87: 1372-1382, 1995
9.
Day R, Ganz PA, Costantino JP, et al: Health-related quality of life and tamoxifen in breast cancer prevention: A report from the National Surgical Adjuvant Breast and Bowel Project P-1 study. J Clin Oncol 17: 2659-2669, 1999 10. Cuzick J: Chemoprevention of breast cancer with tamoxifen, in Hakama M, Beral V, Buiatti E, Faivre J, Parkin DM (eds): Chemoprevention in Cancer Control. Lyon, IARC, IARC scientific publication 136, 1996, pp 95-109 11. Fallowfield LJ, Rodway A, Baum M: What are the psychological factors influencing attendance, non-attendance and re-attendance at a breast screening centre? J R Soc Med 83: 547-551, 1990[Abstract] 12. Wallston KA, Wallston BS, DeVellis R: Development of the Multidimensional Health Locus of Control (MHLC) Scales. Health Educ Monogr 6: 160-170, 1978[Medline] 13. Spielberger CD, Gorsuch RL, Lusherie RE. STAI Manual (Form Y). Palo Alto, CA, Consulting Psychologists Press, 1983 14. Goldberg DP, Williams P: A user’s guide to the General Health Questionnaire. Windsor: NFER-Nelson, 1998 15. Thirlaway K, Fallowfield L, Cuzick J: The Sexual Activity Questionnaire: A measure of women’s sexual functioning. Qual Life Res 5: 81-90, 1996[Medline] 16. Stead ML, Crocombe WD, Fallowfield LJ: Sexual activity questionnaires in clinical trials: Acceptability to patients with gynaecological disorders. Br J Obstet Gynaecol 106: 50-54, 1999[Medline] 17. Hopwood P: Living with advanced breast cancer: Development and application of a clinical checklist for patients on endocrine therapy. Breast 7: 14-21, 1998 18. Thirlaway K, Fallowfield L, Nunnerley H, et al: Anxiety in women ‘at risk’ of developing breast cancer. Br J Cancer 73: 1422-1424, 1996[Medline] 19. Cox B, Blaxter M, Buckle ALJ, et al: The Health and Lifestyle Survey. Cambridge, Health Promotion Research Trust, 1987 20. Curran D, Molenberghs G, Fayers PM, et al: Incomplete quality of life data in randomized trials: Missing forms. Stat Med 17: 697-709, 1998[Medline]
21.
Love RR: Tamoxifen in healthy premenopausal and postmenopausal women: Different risks and benefits. J Natl Cancer Inst 86: 62-63, 1994 (letter) 22. Sackett DL, Snow JC: The magnitude of compliance and non-compliance, in Haynes RB, Taylor WD, Sackett DL (eds): Compliance in Health Care. Baltimore, MD, Johns Hoplins University Press 1979, pp 11-22 23. Koller M, Kussman J, Lorenz W, et al: Symptom reporting in cancer patients. The role of negative affect and experienced social stigma. Cancer 77: 983-995, 1996[Medline] 24. Fallowfield LJ, Leaity SK, Howell A, et al: Assessment of quality of life in women undergoing hormonal therapy for breast cancer: Validation of an endocrine symptom subscale for the Fact-B. Breast Cancer Res Treat 55: 189-199, 1999[Medline] Submitted June 8, 2000; accepted January 17, 2001.
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
