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© 1999 American Society for Clinical Oncology Health-Related Quality of Life and Tamoxifen in Breast Cancer Prevention: A Report From the National Surgical Adjuvant Breast and Bowel Project P-1 StudyFrom the National Surgical Adjuvant Breast and Bowel Project (NSABP) Operations and Biostatistical Centers, Pittsburgh, PA, and Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA. Address reprint requests to Richard Day, PhD, Department of Biostatistics, Graduate School of Public Health, 130 DeSoto St, University of Pittsburgh, Pittsburgh, PA 15261; email rdfac{at}vms.cis.pitt.edu
PURPOSE: This is the initial report from the health-related quality of life (HRQL) component of the National Surgical Adjuvant Breast and Bowel Project Breast Cancer Prevention Trial. This report provides an overview of HRQL findings, comparing tamoxifen and placebo groups, and advice to clinicians counseling women about the use of tamoxifen in a prevention setting. PATIENTS AND METHODS: This report covers the baseline and the first 36 months of follow-up data on 11,064 women recruited over the first 24 months of the study. Findings are presented from the Center for Epidemiological Studies–Depression Scale (CES-D), the Medical Outcomes Study 36-Item Short Form Health Status Survey (MOS SF-36) and sexual functioning scale, and a symptom checklist. RESULTS: No differences were found between placebo and tamoxifen groups for the proportion of participants scoring above a clinically significant level on the CES-D. No differences were found between groups for the MOS SF-36 summary physical and mental scores. The mean number of symptoms reported was consistently higher in the tamoxifen group and was associated with vasomotor and gynecologic symptoms. Significant increases were found in the proportion of women on tamoxifen reporting problems of sexual functioning at a definite or serious level, although overall rates of sexual activity remained similar. CONCLUSION: Women need to be informed of the increased frequency of vasomotor and gynecologic symptoms and problems of sexual functioning associated with tamoxifen use. Weight gain and depression, two clinical problems anecdotally associated with tamoxifen treatment, were not increased in frequency in this trial in healthy women, which is good news that also needs to be communicated.
THIS IS THE INITIAL report of the findings from the health-related quality of life (HRQL) component of the National Surgical Adjuvant Breast and Bowel Project (NSABP) Breast Cancer Prevention Trial (P-1), a multicenter, double-blinded, placebo-controlled clinical trial. The purpose of this report is to provide a concise overview of the P-1 HRQL findings and an assessment of the effects of tamoxifen, when used as a preventative agent, on self-reported symptoms and everyday physical, emotional, and social functioning. Recommendations have been provided that may be helpful to physicians involved in counseling women considering the use of tamoxifen in the setting of prevention. The primary objective of the P-1 study was to evaluate whether 5 years of tamoxifen therapy would reduce the incidence of invasive breast cancer in women at an increased risk for the disease. Secondary objectives were to assess the incidence of ischemic heart disease, bone fractures, and other events, such as depression, that might be associated with the use of tamoxifen. Eligible participants were randomized either to 20 mg daily of tamoxifen or to a placebo for a planned 5 years. Detailed descriptions of the rationale, planning, and design of the of the Breast Cancer Prevention Trial and the HRQL component of the P-1 study, as well as specific instruments, have been provided in separate reports.1-3
Participant Cohort and HRQL Data This report covers the baseline HRQL examination and the first 36 months of follow-up data on 11,064 women recruited over the first 24 months (June 1, 1992, to May 31, 1994) of the study. This cohort of women represents 82.6% of the total P-1 accrual (n = 13,388). Restrictions were imposed on the initial HRQL report for two reasons. First, by limiting our attention to this cohort of women, we avoided the potential bias created by events beginning in March 1994,4,5 which resulted in a suspension of accrual to the P-1 study. Second, a focus on the first 36 months of data collection permitted improved control over types of missing HRQL data because all 11,064 participants should have completed the eight scheduled examinations before the disclosure of the results of the trial in the spring of 1998.
Instruments
Data Completeness
Statistical Analysis Clinical experience, as well as initial statistical investigations of the P-1 HRQL data set, suggested that the age of the study participants was a key factor contributing to the observed distribution of HRQL measures. Hence, the results presented here from various HRQL instruments were routinely stratified by three age groups (35 to 49 years, 50 to 59 years, and 60 years or older) that generally paralleled menopausal status. Relative risks (RRs) or absolute differences in mean counts are presented in the tables to estimate differences in effect size between the two groups. Imputation procedures for missing items in otherwise complete scales were only used for eight SF-36 subscales, as recommended in the SF-36 scoring manual.9 No data imputation was carried out for other scales, and incomplete scales were considered missing.6
Table 1 lists the demographic, medical, and behavioral characteristics of our participant cohort of 11,064 women by trial group. These data show that the women in the P-1 study were predominately white (96%), well educated (65%  some college), married (70%), professional and technically trained (68.2%), currently employed (64.9%), and reported a middle- to upper-middle class family income (median, $35,000 to $49,999). None of the variables in Table 1 show a striking imbalance between the two trial groups.
Figure 1 charts the overall proportion and total numbers of women completing the HRQL questionnaire at each examination. It provides a general measure of comparative participant adherence with regard to the HRQL questionnaire in the two trial groups. Both trial groups showed a consistent decline in HRQL adherence across the first 36 months of the study, averaging 4.2% per examination in the placebo group and 4.6% per examination in the tamoxifen group. The proportion of HRQL-adherent participants was smaller in the tamoxifen than in the placebo group at every one of the seven follow-up examinations (sign test, P = .0078), with a maximum difference of 3.1% occurring at 36 months.
A number of demographic, clinical, and HRQL variables were examined to investigate whether differences could be detected between the women who failed to complete the HRQL questionnaire at 36 months in the tamoxifen and the placebo groups. These variables included mean age (tamoxifen = 53.1 years v placebo = 53.5 years) and mean RR (5.42 v 5.43), treatment status (10.1% v 10.5% on treatment), breast cancer in a first-degree relative (76.89% v 78.40%), prior estrogen use (32.5% v 33.3%), mean maximum CES-D score (12.52 v 12.46), and mean maximum number of reported symptoms on the SCL (14.2 v 13.9). These comparisons suggested that participants who failed to complete the HRQL questionnaire in each group were similar cohorts of women. When, within a treatment group, the same variables were used to compare HRQL adherent and nonadherent women, only the treatment status variable was different between the two groups. A significantly greater proportion of HRQL-adherent women in both groups remained on treatment (87.0% v 89.6%) compared with HRQL-nonadherent women (10.1% v 10.5%). In other words, adherence in the HRQL component of P-1 was largely a reflection of treatment adherence. This was because most collaborating centers did not have the staff resources to administer the HRQL questionnaire via the telephone or mail to women who stopped treatment and failed to appear for their scheduled follow-up visits. By the 36-month examination, 3,421 women had stopped their assigned treatment and failed to fill out the HRQL questionnaire for at least 6 months. Table 2 lists the primary reasons these women gave for stopping treatment. The placebo and tamoxifen groups did not differ with regard to protocol-specified events, such as invasive breast cancer, depression, or deep vein thrombosis, or other medical reasons, such as anxiety disorders or cardiovascular conditions. Hot flashes were clearly the most frequently reported sign or symptom that caused women to stop their assigned treatment (251 women); they occurred most often in the tamoxifen group (184 women). When stopping their assigned treatment, participants in the placebo group were more likely to cite other nonmedical reasons, such as fear of side effects, change of mind, or desire to adopt an alternative therapy (eg, hormone replacement).
Table 3 shows the proportion of P-1 participants, by age group and examination, who scored above the most frequently used clinical cutoff (
The results of the SF-36 are summarized using the physical component summary (PCS) and mental component summary (MCS) scores12 and the eight SF-36 subscales. The PCS and MCS scores represent aggregate measures that combine data from the eight subscales generally reported on the SF-36. The PCS aggregates data from the Physical Functioning, Role-Physical, Bodily Pain, and General Health subscales, while the MCS draws on data from the Vitality, Social Functioning, Role-Emotional, and Mental Health subscales. The PCS and MCS are scored using norm-based methods; both component scores have a mean of 50 and a SD of 10 in the general United States (U.S.) population. This means that the PCS and MCS can be meaningfully compared with one another, and their scores have a direct interpretation in relation to the distribution of scores in the general U.S. population. Figure 2 charts the PCS and MCS for the tamoxifen and placebo groups at each examination and by age group. As expected, mean PCS declines across the age groups. At follow-up examinations, the tamoxifen group was consistently lower on the PCS only in the 50- to 59-year-old age group (one-sided sign test, P = .065). However, the absolute differences were small, approximating one tenth of an SD. With regard to the MCS, all of the age groups scored above the mean MCS for the general U.S. population, and no consistent differences emerged between the two trial groups. Figure 3 summarizes the overall data from eight subscales on which the component subscores are based.
Table 4 lists the mean number of symptoms reported on the 43-item SCL by age group and examination. The mean number of symptoms reported was consistently highest in the 50- to 59-year-old age group, followed by the 35- to 49-year-old and 60 years or older age groups (Friedman test, P = .001 tamoxifen and placebo). The participants in the tamoxifen group also reported a small but consistent excess in the mean number of symptoms (< one) reported at 19 of the 21 age-stratified follow-up examinations (3 to 36 months; one-sided sign test, 35 to 49 years, P = .0078; 50 to 59 years and
Table 5 provides information on the proportion of women in the tamoxifen and placebo groups who reported symptoms on the SCL at least once during the treatment period, ie, the period excluding baseline but including the seven follow-up examinations. The five symptoms with the greatest relative difference between the two trial groups are given for each age group, and the 10 symptoms with the greatest relative difference are presented for all participants combined.
Tables 6 and 7 give detailed information, by age group and examination, on the reported frequency of hot flashes and vaginal discharge in the trial groups. The proportion of participants who reported hot flashes was elevated in all age groups of the tamoxifen group at every follow-up examination. Among the participants in the tamoxifen group, the 50- to 59-year-old age group had the largest proportion of women reporting hot flashes at each examination (median, 69.8%; Friedman test, P = .001), but the youngest age group (35 to 49 years) showed the greatest relative increase in proportion of women reporting hot flashes (median RR, 1.50; Friedman test, P = .011). Vaginal discharge was the most consistently elevated symptom in the tamoxifen group. The youngest age group (35 to 49 years) had the greatest proportion of participants reporting vaginal discharge at each examination (median, 35.5%; Friedman test, P < .001), and the oldest age group (
Figure 4 summarizes the information from the five items on the MOS sexual functioning scale. Figure 4A shows that a greater proportion of participants in the tamoxifen group, as compared with the placebo group, reported being sexually active during the 6 months before each follow-up examination. Although apparently consistent (P = .031), the absolute difference was small (mean, 0.78%) and may have been caused by chance. Figure 4B through 4E show that a small but consistently larger percentage of participants in the tamoxifen group reported a definite or serious problem in three of the four specific domains of sexual functioning during the follow-up period.
We observed in our earlier article3 that measuring the impact of new treatments on HRQL is particularly important within the context of disease-prevention and health-promotion trials. Compared with patients suffering from clinically manifest disease, decrements in overall quality of life are likely to have a much greater impact on the subjective appraisal of treatment acceptability and the maintenance of long-term treatment adherence among high-risk but otherwise healthy individuals. This report covers the initial HRQL findings from a large, multicenter chemoprevention trial, which has shown that tamoxifen reduced the risk of invasive breast cancer in high-risk women by 49% during the first 5 years of administration. Given the apparent clinical efficacy of tamoxifen in the prevention setting, it is important to assess whether the various secondary effects of the drug might act to reduce this practical efficacy.13-15 The cohort of women taking part in the P-1 study clearly was not representative of the general population. They were predominately white, well educated, and middle class, with a strong professional and technical orientation. The initial HRQL findings presented in this report must be assessed within the context of the socioeconomic and cultural characteristics of the P-1 study cohort. The subcohort of women discussed in this report represent 82.6% of the total study cohort. This subcohort was chosen to exclude potential biases, because of external factors eventuating in the suspension of accrual in P-1, and to control for the amount and types of missing data. Despite this, we still lost 31.5% of our participants by the 36-month follow-up examination. This proportion closely approximates the 10%-per-year loss to follow-up rate predicted at the beginning of the P-1 trial and is similar in pattern and number to the adherence data recently reported in a second large, multicenter chemoprevention trial of hormone replacement therapy for heart disease.16 We have shown that there is only a small difference in the proportion of nonadherent participants in the tamoxifen and placebo groups and that the nonadherent women in both trial groups have generally similar key demographic, clinical, and HRQL variables. Given these considerations, it seems unlikely that a maximum difference of 3% in the HRQL follow-up rates between the two groups was sufficient to create a significant bias in our between-group comparisons. HRQL adherence is closely related to treatment adherence. Based on the reasons for quitting treatment, it would seem that nonadherent women in both trial groups were those who were sensitive to the actual or possible occurrence of side effects caused by tamoxifen. Much concern has been expressed about a potential relationship between tamoxifen use and the onset of depression.17-21 Women who reported a history of depressive episodes or a history of treatment for nervous or mental disorders were not excluded from the trial. A brief eight-item affective screening questionnaire based on the CES-D and the Diagnostic Interview Schedule22 was part of the baseline examination.23 Using data from this brief screening instrument, local investigators were alerted to eligible participants showing signs of potentially serious affective distress at the baseline examination and caution was advised regarding their enrollment onto the trial. However, women who showed current signs of affective distress or depression were not routinely excluded from the trial.
With regard to the primary screening instrument used in the follow-up examinations, it has been pointed out that "the items in... (the CES-D) are generally related to affective distress but not to any particular psychiatric disorder."11 For this reason, the numbers listed in Table 3 refer not to the prevalence of clinically diagnosable depressive disorders but, instead, to the prevalence of clinically significant affective distress that might be associated with a number of specific psychiatric disorders. However, if tamoxifen use was associated with the onset of clinically diagnosable depression, we would have expected to see a consistent excess of individuals scoring The MOS SF-36 served in this study as a measure of overall HRQL. For this initial report, we have presented data from the SF-36 in terms of two high-level component scores12 and the eight basic subscales generally used in scoring this instrument.9 Neither of these two methods of summarizing the SF-36 data demonstrated any clinically significant differences between the tamoxifen and placebo groups. The first clear signs of consistent differences between the tamoxifen and placebo groups were observed in the SCL. In 19 out of 21 follow-up comparisons, the mean number of symptoms reported on the SCL were consistently different by age group (50 to 59 years > 35 to 49 years > 60+ years) and by trial group (tamoxifen > placebo). The absolute differences between the trial groups were relatively small and tended to be associated with the types of vasomotor, gynecologic, and sexual functioning symptoms previously reported for tamoxifen.18,24,25 The data from the MOS sexual functioning scale indicate that relatively small (< 4.0%) but consistent differences exist between the two groups in regard to the proportion of women reporting definite or serious problems in at least three specific domains of sexual functioning, sexual interest, arousal, and orgasm. These problems do not seem to be age group specific. Despite these findings for specific domains of functioning, there is no evidence that these problems result in a reduction of the overall proportion of women in the tamoxifen group who are sexually active. Based on these data, we conclude that tamoxifen use is associated with an increase in specific vasomotor, gynecologic, and sexual functioning symptoms. At the same time, we did not observe any evidence that overall physical and emotional well being were significantly affected by these differences in the frequency of symptoms. We also found no evidence on the CES-D or the SF-36 mental health scale for an association in any age group between tamoxifen use and an increase in the proportion of women reporting clinically significant levels of affective distress and/or depression. How should clinicians integrate the results from the HRQL study data into decision-making and recommendations to women considering the use of tamoxifen in the setting of prevention? As demonstrated by the SCL data from the placebo group of the trial, many symptoms experienced by women who participated in this study are age and menopause related and exist independent of the use of tamoxifen. However, several symptoms are substantially more frequent in women using tamoxifen; these include vasomotor symptoms (cold sweats, night sweats, and hot flashes), vaginal discharge, and genital itching. Women need to be informed of these possible symptoms. Weight gain and depression, two clinical problems anecdotally associated with tamoxifen treatment in women with breast cancer, did not increase in frequency in this large placebo-controlled trial of healthy women. This is good news that must also be communicated to women. An informed discussion with a woman considering tamoxifen therapy should include these points in the risk/benefit discussion. Disclosure of likely and unlikely symptoms should prepare a woman for what she might experience and reduce her anxiety or concerns should she begin preventive therapy. Without the detailed evaluation of HRQL data obtained in the P-1 trial, we would not be able to provide this level of information and reassurance to women considering preventive therapy. In addition, the setting of preventive therapy differs considerably from the treatment of breast cancer. Therefore, if a woman experiences untoward symptoms after starting tamoxifen treatment, the medication can be discontinued if the symptoms cannot be controlled or her personal assessment of the risks and benefits changes. The current report is a brief overview of the P-1 study HRQL data that focuses on important clinical and functional implications of tamoxifen use for women's overall HRQL. It will be supplemented in the future by a series of additional methodologic and clinical reports that will provide in-depth analyses of the data obtained from each one of the several P-1 study HRQL instruments.
Supported by public health service grants from the National Cancer Institute (NCI-U10-CA-37377/69974) and a career development award from the Department of Defense (DAMD17-97-1-7058). We thank Carol Redmond, DSc, University of Pittsburgh; Leslie Ford, MD, National Cancer Institute, Bethesda, MD; Carol Moinpour, PhD, Southwest Oncology Group Statistical Center; John E. Ware, Jr, New England Medical Center, Boston, MA; David Cella, Northwestern University, Chicago, IL; Sheela Goshal and Wei Chen, NSABP Biostatistical Center; and members of the NSABP Prevention Quality of Life Committee.
1. Fisher B, Costantino JP, Wickerham L, et al: Tamoxifen for the prevention of breast cancer: A report from the NSABP P-1 study. J Natl Cancer Inst 90:1371-1388, 1998 2. Fisher B, Costantino J: Highlights of the NSABP Breast Cancer Prevention Trial. Cancer Control 4:78-86, 1997[Medline]
3.
Ganz PA, Day R, Ware JE, 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
4.
Fisher B, Redmond C: Fraud in breast cancer trials. N Engl J Med 330:1458-1460, 1994
5.
Fisher B, Anderson S, Redmond C, et al: Reanalysis and results after 12 years of follow-up in a randomized clinical trial comparing total mastectomy with lumpectomy with or without irradiation in the treatment of breast cancer. N Engl J Med 333:1456-1461, 1995 6. Ganz PA, Day R, Costantino JP: Compliance with quality of life data collection in the NSABP breast cancer prevention trial. Stat Med 17:613-622, 1998[Medline] 7. Daniel WW: Applied Non-Parametric Statistics. Boston, MA, PWS-Kent Publishing Co, 1990 8. Deshpande JV, Gore AP, Shanubhougue A: Statistical Analysis of Non-Normal Data. New York, NY, John Wiley & Sons, 1995 9. International Resource Center for Health Care Assessment: How to Score the SF-36 Health Status Survey. Boston, MA, New England Medical Center, 1991 10. Radloff LS: The CES-D scale: A self-report depression scale for research in the general population. Appl Psychol Meas 1:385-401, 1977
11.
Roberts RE, Vernon SW: The Center for Epidemiologic Studies Depression Scale: Its use in a community sample. Am J Psychiatry 140:41-46, 1983 12. Ware JE, Kosinski M, Keller SD: SF-36 Physical and Mental Summary Scales: A User's Manual (3rd Printing Revised). Boston, MA, The Health Institute, New England Medical Center, 1994
13.
Fisher B: A commentary on endometrial cancer deaths in tamoxifen-treated breast cancer patients. J Clin Oncol 14:1027-1039, 1996
14.
Fisher B, Costantino JP, Redmond CK, et al: Endometrial cancer in tamoxifen-treated breast cancer patients: Findings from NSABP B-14. J Natl Cancer Inst 86:527-537, 1994 15. Gorin MB, Day R, Costantino JP, et al: Long term tamoxifen citrate and potential ocular toxicity. Am J Ophthalmol 125:493-501, 1998[Medline]
16.
Hulley S, Grady D, Bush T, et al: Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 280:605-613, 1998 17. Cathacart CK, Jones SE, Pumroy CS, et al: Clinical recognition and management of depression in node negative breast cancer patients treated with tamoxifen. Breast Cancer Res Treat 27:277-281, 1993[Medline] 18. Love RL, Cameron L, Connell BL, et al: Symptoms associated with tamoxifen treatment in postmenopausal women. Arch Intern Med 151:1842-1847, 1991[Medline] 19. Shariff S, Cumming CE, Lees A, et al: Mood disorder in women with early breast cancer taking tamoxifen, an estradiol receptor antagonist: An unexpected effect? Ann N Y Acad Sci 761:365-368, 1995[Medline] 20. Moredo Anelli T, Anelli A, Tran KN, et al: Tamoxifen administration is associated with a high rate of treatment-limiting symptoms in male breast cancer patients. Cancer 74:74-77, 1994[Medline] 21. Pluss JL, Dibella NJ: Reversible central nervous system dysfunction due to tamoxifen in a patient with breast cancer. Ann Intern Med 101:652, 1984
22.
Robins LN, Helzer JE, Croughan J, et al: National Institute of Health Diagnostic Interview Schedule: Its history, characteristics and validity. Arch Gen Psychiatry 35:837-846, 1978 23. Burnam MA, Wells KB, Leake B, et al: Development of a brief screening instrument for detecting depressive disorders. Med Care 26:775-789, 1988[Medline]
24.
Fisher B, Dignam J, Bryant J, et al: Five versus more than five years of tamoxifen therapy for breast cancer patients with negative lymph nodes and estrogen receptor-positive tumors. J Natl Cancer Inst 88:1529-1542, 1996 25. Fisher B, Costantino J, Redmond C, et al: A randomized clinical trial evaluating tamoxifen in the treatment of patients with node-negative breast cancer who have estrogen-receptor-positive tumors. N Engl J Med 320:479-484, 1989[Abstract] Submitted December 7, 1998; accepted April 22, 1999. This article has been cited by other articles:
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ABSTRACT
INTRODUCTION
16) on the CES-D by Age Group and Examination
