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Journal of Clinical Oncology, Vol 26, No 9 (March 20), 2008: pp. 1537-1543 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.13.6739 Psychological and Clinical Factors Implicated in Decision Making About a Trial of Low-Dose Tamoxifen in Hormone Replacement Therapy Users
From the Medical Oncology Unit, Galliera Hospital; Biostatistics Unit, Department of Health Sciences; Health Psychology Unit, Department of Educational Sciences, University of Genoa, Genoa; Prevention and Cancer Genetics Unit, European Institute of Oncology, Milan, Italy; and Cancer Epidemiology Center, The Cancer Council Victoria, Melbourne, Victoria, Australia Corresponding author: Andrea Decensi, MD, Division of Medical Oncology, E.O. Ospedali Galliera, Mura delle Cappuccine 14, 16128 Genoa, Italy; e-mail: andrea.decensi{at}galliera.it
Purpose To assess the sociodemographic, health-related, and psychological factors that influence the decision of women on hormone replacement therapy (HRT) to participate in a phase III trial of low-dose tamoxifen. Patients and Methods Clinical and psychological factors were assessed in 265 women who accepted and 192 women who refused to participate in a proposed trial. Health-related and sociodemographic factors included age, Gail risk, body mass index, education, current HRT use, regular mammographic screening, smoking habit, physical activity, alcohol use, concern about adverse effects, and physician recommendation. Psychological factors included breast cancer–related worry, absolute and comparative cancer risk perception, anxiety, and depression.
Results The most frequent reasons for entry were willingness to participate in a research program (60%), the need/desire to receive frequent medical care (58%), and the desire to contribute to medical knowledge (44%); whereas reasons for refusal included fear of medication abuse (33%), concern about adverse effects (31%), and physician advice against enrollment (24%). In a logistic model, after adjusting for current HRT use, the trial participation was directly associated with satisfaction with clearly explained study objectives (odds ratio [OR] = 9.33; 95% CI, 4.04 to 21.55) and inversely associated with high breast cancer worry (OR = 0.15; 95% CI, 0.03 to 0.77) and age Conclusion Participation in a chemoprevention trial among HRT users is associated with a younger age, no breast cancer worry, and satisfaction with health care providers, suggesting a condition of psychological well-being as a promoting factor and emphasizing the importance of thorough counseling at study presentation.
The concept of health has evolved over the last two decades, with more emphasis now given to the notion of health promotion rather than to the prevention of disease. Health care strategies have, as a consequence, mutated from reactive to proactive, with individuals becoming responsible for their well-being through behaviors directed towards disease prevention, health promotion, and improvement of quality of life.1,2 Adherence to a cancer prevention trial is a paradigm of health promotion behavior, inasmuch as participants are required to possess a strong sense of awareness and an ability to carefully assess risks and benefits. The decision also entails the individual's willing control of her own life to achieve a state of well-being and an enhanced quality of life.3 This is particularly true for hormone replacement therapy (HRT) for menopausal symptoms, where the trade-off between risks and benefits has been subject to debate after the controversial results of clinical trials.4,5 The decision-making process about participating in a cancer chemoprevention trial is poorly understood. Despite evidence of efficacy ensuing from large trials,6 tamoxifen use for breast cancer risk reduction in clinical practice has thus far been limited.7 This paradox reflects a distinct difference between the experimental setting and the real life clinical uptake of results. With regard to breast cancer prevention, a few studies have shown that medical variables, such as a positive family history,8 a history of biopsies,9 or the presence of cytologic atypia,10 were important factors for taking tamoxifen, whereas another study showed that worry about breast cancer was the most important factor prompting the theoretical intention to start chemoprevention.11 In the present work, we explored the sociodemographic, clinical, and psychological factors that influenced the decision-making process about participating in a phase III trial of tamoxifen at a low dose in women undergoing or considering HRT for menopausal symptoms.12 Our main hypothesis was that an elevated risk perception or worry about breast cancer was associated with trial participation. Additional exploratory objectives were to determine whether anxiety, depression, counseling satisfaction, Gail risk, and at-risk lifestyle factors were associated with trial participation.
Participants Participants in the psychosocial study were postmenopausal healthy women currently on or about to start HRT for the treatment of menopausal symptoms who were eligible for an ongoing double-blind, placebo-controlled, phase III trial to assess the efficacy of tamoxifen 5 mg/d administered for 5 years in women undergoing HRT. The rationale and main study characteristics of the HRT Opposed by Low-Dose Tamoxifen (HOT) study and the results of a phase II dose-ranging trial have previously been described.12,13 The study was conducted in two centers, the European Institute of Oncology, Milan, and the Galliera Hospital, Genoa, Italy. The institutional review board of each site approved the protocol, and all women gave their informed consent.
Study Procedures
Measures Health-related and lifestyle variables. These included age at menopause, 5-year Gail risk of breast cancer (%),15 body mass index (kg/m2), current use and duration of HRT, regular mammographic screening (never, one to two times, or every 1 to 2 years), smoking habit (never, former, or current), physical activity (< 3, 3 to 6, > 6 h/wk), use of any medication (sometimes v regular), and alcohol use (< five, five to 10, 11 to 20, or > 20 glasses a week). Participant satisfaction. Satisfaction with various aspects of the decision-making process was assessed with six questions using a 5-point Likert scale (1, strongly agree; 2, agree; 3, neither agree nor disagree; 4, disagree; and 5, strongly disagree), as previously described.16 Reasons for participating or refusing to participate in the trial. The main reasons for participating or not in the study were partly prespecified and partly open in an unpublished questionnaire adopted in the Italian Randomized Tamoxifen Prevention Trial.17 Reasons for participation included willingness to take part in a research program, willingness to contribute to increased medical knowledge, desire to receive frequent medical care, physician's advice (family doctor or gynecologist), relative's advice, and other reasons. Reasons for refusal included refusal to take medications, fear of tamoxifen adverse effects, physician advice against participation (family doctor or gynecologist), excessive trial duration, no faith in clinical trials, family problems, geographic inaccessibility, relative's advice against participation, and other reasons. More than one answer was allowed. Self-reported psychological variables. Worry about developing breast cancer was the study's main outcome measure and was assessed by the following question: "How worried are you about getting breast cancer in the next 5 years?" Responses were "not at all worried," "slightly worried," "somewhat worried," "worried," and "very worried." Risk perception and breast cancer worry were assessed as previously described.9,11 Perception of absolute breast cancer risk was assessed using standard verbal and numerical measures within the span of 5 years. For the verbal measures, women were asked, "How likely are you to get breast cancer in the next 5 years?" Responses were "very unlikely," "unlikely," "50/50 chance," "likely," and "very likely." For the numerical measures, women were asked, "On a scale from 0 to 100, with 0 indicating certain not to happen and 100 indicating certain to happen, how likely are you to get breast cancer in the next 5 years?" Perceptions of comparative breast cancer risk were assessed through the following question: "Compared with other women your age, what are the odds that you will get breast cancer in the next 5 years?" Responses were "much below average," "below average," "same average risk as other women my age," "above average," and "much above average." Anxiety and depression were assessed using the Hospital Anxiety and Depression Scale.18,19
Objectives
Sample Size
Statistical Methods A logistic regression model was used to test the association between the outcome and all sociodemographic, health-related, satisfaction, and psychological factors, and the likelihood ratio test was used to assess the statistical significance. An initial baseline model was constructed with all clinically and statistically significant factors. Because of the high correlation between anxiety, depression, and risk perception variables, to avoid collinearity, a single model for each psychological factor was built, adding one by one each variable to the baseline model. The Akaike Information Criterion was used to choose the best model.20 All analyses were conducted using STATA software (version 9; STATA Corp, College Station, TX). Two-tailed probabilities were reported, and P = .05 was used to define nominal statistical significance.
From September 1, 2001 to May 31, 2004, 1,457 women received counseling about the trial characteristics. Of these eligible women, 496 (34.0%) were entered onto the trial, whereas 961 (66%) refused to participate. Immediately after trial entry or refusal, all 1,457 women received by mail a preprinted, self-reported psychosocial questionnaire, to which 457 (31.4%) replied; 265 replies (53.4%) were from women who participated in the trial, and 192 (20.0%) were from women who refused to participate in the trial. The participant flow diagram is depicted in Figure 1.
Because of the limited response rate to the questionnaire among women who refused to participate in the trial, we compared the age distribution of the women who completed the questionnaire with that of the respective study population (ie, women who had been asked to participate in the HOT trial) separately for randomly assigned and non–randomly assigned women and found no difference, suggesting that the participants on study were representative of the whole population invited (both P > .3). The main sociodemographic and health-related characteristics of the women related to trial entry are listed in Table 1. A younger age and current HRT use were significantly associated with trial participation. The mean age was 56 ± 5 years in participating women versus 58 ± 6 years in decliners (t test, P < .001). Among trial participants, current HRT users totaled 87.5% compared with 53.4% among decliners (P < .001). All other sociodemographic and health-related factors of trial participants and decliners, including education, 5-year Gail risk, and lifestyle risk factors, did not differ significantly in univariate analyses.
Satisfaction of women after counseling is listed in Table 2. The top two highest degrees of satisfaction with clearly explained study objectives were claimed by 96.4% of trial participants and 70.1% of decliners (P < .001). Likewise, satisfaction with answering all questions was reported by 95.5% of participants compared with 73.8% of decliners (P < .001).
Psychological factors related to trial decision are listed in Table 3. Worry about breast cancer was the only factor significantly associated with trial refusal, inasmuch as 28.1% of participants claimed not to be worried at all compared with 18.5% of the decliners, whereas 10.2% of the participants were worried or very worried about breast cancer compared with 13.8% of the decliners (odds ratio [OR] for trial participation = 0.54; 95% CI, 0.31 to 0.95). We found a similar association, although not statistically significant, between numerical risk perception and trial participation (women  60 points v  30 points, OR = 0.54; 95% CI, 0.25 to 1.14). Interestingly, objective risk by the Gail model was associated with absolute risk perception expressed in a verbal way (r = 0.15, P = .003) but not with worry of breast cancer (r = 0.02, P = .6). Of the nine women who were very worried and declined the trial, six were current HRT users. Neither anxiety nor depression was significantly associated with the decision to participate in the trial.
The multivariate logistic regression model of all factors related to the trial participation decision is summarized in Table 4. The probability of accepting to participate in the trial, adjusted for current HRT use, was significantly associated with participant satisfaction for understanding study objectives (OR = 9.33; 95% CI, 4.04 to 21.55), high level of worry for breast cancer (OR = 0.15; 95% CI, 0.03 to 0.77), and age 60 years (OR = 0.40; 95% CI, 0.22 to 0.73). There was no significant association between breast cancer worry and age or alcohol intake. In addition, the presence of at least two lifestyle risk factors (including smoking, obesity, and no physical exercise) and no high alcohol consumption reached marginal statistical significance in the multivariate model. Participant satisfaction with answering all questions was also highly significantly associated with trial participation when substituted in the model in place of clarity of study objectives (OR = 6.45; 95% CI, 2.90 to 14.37). Notably, objective breast cancer risk determined with the Gail model was not associated with the decision to participate in the trial (P = .6). We also fitted the logistic model only for current HRT users, and the estimates did not change significantly (data not shown).
Table 5 lists the most frequent reasons for entry or refusal as claimed by the women. Among trial participants, the most frequently declared reasons were willingness to participate in a research program (60%), need for frequent medical care (58%), and contribution to increase medical knowledge (44%). Among trial decliners, the most frequent reasons for refusal included fear of medication abuse (33%), concern about adverse effects (31%), and physician advice against participation (24%).
Cancer chemoprevention trials have proven to be difficult medical experiments because they are mostly conducted in people who, albeit at increased risk for a given neoplasm, are unaffected. Despite the recent accomplishments in breast and prostate cancer prevention,6,21 the use of tamoxifen or finasteride for these indications has not been successful.7 First, we explored whether worry for breast cancer was the main reason for taking tamoxifen and not related to the objective risk, as previously suggested,11 because this would have important implications in terms of risk assessment, communication, and counseling. Second, we sought to provide clues about the characteristics of the women who actually accepted the trial compared with those who declined it to understand to what extent our results could be generalized. Our data show that participation in the chemoprevention trial of low-dose tamoxifen in HRT users was quite high, attaining about a third of the eligible population, and was associated with participant satisfaction of study personnel, lower breast cancer worry and risk perception, and younger age. There was no significant association of trial decision making with clinical variables, such as objective risk of breast cancer, or additional psychological factors, such as anxiety and depression. Our results differ from those of Bastian et al,11 who surveyed 1,273 women by telephone and showed that women's theoretical interest in chemoprevention was claimed by 23% of the sample and derived more from worries about getting breast cancer than from objective risk factors. Additional factors associated with interest in chemoprevention were elevated cancer risk perception, current HRT use, and smoking status. An explanation for the different conclusions may be related to the studies’ different settings, inasmuch as we studied women after direct counseling and actual trial participation or refusal and not by telephone interview on theoretical intentions. In addition, Bastian et al11 interviewed women who were unaware of tamoxifen as the study medication, whereas women in our protocol were fully informed of the potential risks and benefits of the drug, even at a lower dose. Our results contrast with our original hypothesis because they indicate that an increased worry about cancer and enhanced risk perception were inhibitory factors for trial participation, suggesting a proactive attitude towards health promotion as an important factor of trial participation.22 Furthermore, we suggest that women who are more worried and have a higher risk perception of illness may develop a defensive attitude that tends to avoid preventive measures. In support of this hypothesis, a lower degree of worry about cancer is also a predictor for women's participation in genetic research programs.23 Nevertheless, the finding of an association between low breast cancer worry and greater trial participation, which is rather counterintuitive based on most theories of behavior change, needs to be replicated before any substantive meaning can be placed. Our results differ slightly from those of Bober et al,9 who found that women at higher risk according to the Gail model opting for chemoprevention had elevated levels of anxiety and worry about breast cancer and perceived themselves at greater risk compared with those declining chemoprevention. This difference in psychological concerns may be related to the different risk selection criteria, inasmuch as women who choose HRT tend to have a high level of self-competence in terms of risk/benefit assessment and may not overestimate risks of breast cancer, as suggested by the high correlation between risk perception and objective risk by the Gail model. Similar to our study, however, undecided women were less satisfied about the level of information, and women with a more autonomous motivational style felt more satisfied with their treatment decision.9 Our results confirm that chemoprevention trials are hampered by a number of complexities, one of which is related to the potential gap between research participants and the general population. In our study, the women who actually accepted to participate in the trial were, compared with the women who refused, less worried about breast cancer, and this effect was not influenced by HRT use. Although a strong belief in clinical research was considered a reason to participate, our findings are limited by the use of prespecified questions to assess the reasons for trial participation that may be influenced by the women's willingness to give socially desirable responses rather than measuring actual psychological reasons for entering the trial. So far, the uptake of the results of large prevention trials in clinical practice has been limited in the United States.7 The causes for these limitations are unclear, although a number of reasons have been advocated,24 including poor commercial appeal of approved study medications,25 liability issues of pharmaceuticals,26 fear of adverse events,27 and scarce faith in and lack of time for risk assessment and counseling by physicians.28 The latter reason seems to be quite important in our study, given the strong association between entry onto the trial and satisfaction with answering all questions and clarity of explanation of study objectives by the study personnel. Although it is unknown whether the presence of a physician rather than a different health professional was an extra value, our findings indicate that a dedicated caregiver-participant relationship is a critical component for an elevated participation. Nevertheless, our data, as well those of Bober et al9 and Heisey et al,22 indicate that at-risk women do not overwhelmingly reject the option of chemoprevention, as suggested in previous studies.27,29 In conclusion, participation in our breast cancer chemoprevention trial of tamoxifen in HRT users is associated with a younger age, low breast cancer worry, and satisfaction with health care providers. This last factor underlines the importance of careful counseling at study presentation. These results may help to identify those who are more likely to accept the results of chemoprevention intervention, as well as to increase the efficiency of future trials.
The author(s) indicated no potential conflicts of interest.
Conception and design: Gabriella Rondanina, Gianluca Severi, Bernardo Bonanni, Andrea Decensi Administrative support: Andrea Decensi Provision of study materials or patients: Gabriella Rondanina, Clara Varricchio, Irene Feroce, Bernardo Bonanni, Andrea Desensi Collection and assembly of data: Gabriella Rondanina, Clara Varricchio, Irene Feroce Data analysis and interpretation: Gabriella Rondanina, Matteo Puntoni, Gianluca Severi, Andrea Decensi Manuscript writing: Gabriella Rondanina, Matteo Puntoni, Gianluca Severi, Andrea Decensi Final approval of manuscript: Gabriella Rondanina, Matteo Puntoni, Gianluca Severi, Clara Varricchio, Anna Zunino, Irene Feroce, Bernardo Bonanni, Andrea Decensi
Supported by Grant No. BCTR01-00537 from the S. Komen Breast Cancer Foundation, a grant from the Italian Health Ministry (Ricerca Finalizzata), a fellowship from Gruppo Bancario Credito Valtellinese and the European School of Oncology, and a contract from the Italian Foundation for Cancer Research. Presented in part at the 4th Annual American Association for Cancer Research Conference Frontiers in Cancer Prevention Research, November 11-15, 2006, Boston, MA. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Engel GL: The need for a new medical model: A challenge for biomedicine. Science 196:129-136, 1977 2. Schwartz GE: Testing the biopsychosocial model: The ultimate challenge facing behavioral medicine? J Consult Clin Psychol 50:1040-1053, 1982[CrossRef][Medline] 3. Matarazzo JD: Behavioral health and behavioral medicine: Frontiers for a new health psychology. Am Psychol 35:807-817, 1980[CrossRef][Medline] 4. Hulley S, Grady D, Bush T, et al: Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women: Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA 280:605-613, 1998 5. Rossouw JE, Anderson GL, Prentice RL, et al: Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results from the Women's Health Initiative randomized controlled trial. JAMA 288:321-333, 2002 6. Cuzick J, Powles T, Veronesi U, et al: Overview of the main outcomes in breast-cancer prevention trials. Lancet 361:296-300, 2003[CrossRef][Medline] 7. Zielinski SL: Despite positive studies, popularity of chemoprevention drugs increasing slowly. J Natl Cancer Inst 96:1410-1412, 2004 8. Lovegrove E, Rumsey N, Harcourt D, et al: Factors implicated in the decision whether or not to join the tamoxifen trial in women at high familial risk of breast cancer. Psychooncology 9:193-202, 2000[CrossRef][Medline] 9. Bober SL, Hoke LA, Duda RB, et al: Decision-making about tamoxifen in women at high risk for breast cancer: Clinical and psychological factors. J Clin Oncol 22:4951-4957, 2004 10. Goldenberg VK, Seewaldt VL, Scott V, et al: Atypia in random periareolar fine-needle aspiration affects the decision of women at high risk to take tamoxifen for breast cancer chemoprevention. Cancer Epidemiol Biomarkers Prev 16:1032-1034, 2007 11. Bastian LA, Lipkus IM, Kuchibhatla MN, et al: Women's interest in chemoprevention for breast cancer. Arch Intern Med 161:1639-1644, 2001 12. Decensi A, Galli A, Veronesi U: HRT opposed to low-dose tamoxifen (HOT study): Rationale and design. Recent Results Cancer Res 163:104-111, 2003[Medline] 13. Decensi A, Gandini S, Serrano D, et al: A randomized dose-ranging trial of tamoxifen at low doses in hormone replacement therapy users. J Clin Oncol 25:4201-4209, 2007 14. Lerman C, Daly M, Sands C, et al: Mammography adherence and psychological distress among women at risk for breast cancer. J Natl Cancer Inst 85:1074-1080, 1993 15. Gail MH, Costantino JP, Bryant J, et al: Weighing the risks and benefits of tamoxifen treatment for preventing breast cancer. J Natl Cancer Inst 91:1829-1846, 1999 16. Man-Son-Hing M, Laupacis A, O'Connor AM, et al: A patient decision aid regarding antithrombotic therapy for stroke prevention in atrial fibrillation: A randomized controlled trial. JAMA 282:737-743, 1999 17. Veronesi U, Maisonneuve P, Rotmensz N, et al: Tamoxifen for the prevention of breast cancer: Late results of the Italian Randomized Tamoxifen Prevention Trial among women with hysterectomy. J Natl Cancer Inst 99:727-737, 2007 18. Zigmond AS, Snaith RP: The Hospital Anxiety and Depression Scale. Acta Psychiatr Scand 67:361-370, 1983[Medline] 19. Bjelland I, Dahl AA, Haug TT, et al: The validity of the Hospital Anxiety and Depression Scale: An updated literature review. J Psychosom Res 52:69-77, 2002[CrossRef][Medline] 20. Burnham KP, Anderson DR: Model Selection and Multimodel Inference: A Practical Information-Theoretic Approach (ed 2). New York, NY, Springer, 2004 21. Thompson IM, Goodman PJ, Tangen CM, et al: The influence of finasteride on the development of prostate cancer. N Engl J Med 349:215-224, 2003 22. Heisey R, Pimlott N, Clemons M, et al: Women's views on chemoprevention of breast cancer: Qualitative study. Can Fam Physician 52:624-625, 2006 23. Helmes AW, Bowen DJ, Bowden R, et al: Predictors of participation in genetic research in a primary care physician network. Cancer Epidemiol Biomarkers Prev 9:1377-1379, 2000 24. Herberman RB, Pearce HL, Lippman SM, et al: Cancer chemoprevention and cancer preventive vaccines—A call to action: Leaders of diverse stakeholder groups present strategies for overcoming multiple barriers to meet an urgent need. Cancer Res 66:11540-11549, 2006 25. Veronesi U, Maisonneuve P, Decensi A: Tamoxifen: An enduring star. J Natl Cancer Inst 99:258-260, 2007 26. Tanne JH: Court awards claimant 13.5m dollars in rofecoxib lawsuit. BMJ 332:927, 2006 27. Melnikow J, Paterniti D, Azari R, et al: Preferences of Women Evaluating Risks of Tamoxifen (POWER) study of preferences for tamoxifen for breast cancer risk reduction. Cancer 103:1996-2005, 2005[CrossRef][Medline] 28. Rouch D, Mayer I, Truica C: Barriers to chemoprevention of breast cancer with tamoxifen. J Clin Oncol 23:108s, 2005 (suppl 16S; abstr 1010) 29. Port ER, Montgomery LL, Heerdt AS, et al: Patient reluctance toward tamoxifen use for breast cancer primary prevention. Ann Surg Oncol 8:580-585, 2001[Medline] Submitted July 27, 2007; accepted November 29, 2007.
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 or Fisher's exact test analyses. 
