Jco 17/9

H e a l t h - R e l a t e d Q u a l i t y o f L i f e a n d T a m o x i f e n i n B r e a s t
C a n c e r P r e v e n t i o n : A R e p o r t F r o m t h e N a t i o n a l S u r g i c a l
A d j u v a n t B r e a s t a n d B o w e l P r o j e c t P - 1 S t u d y
By Richard Day, Patricia A. Ganz, Joseph P. Costantino, Walter M. Cronin, D. Lawrence Wickerham, and Bernard Fisher Purpose: This is the initial report from the health-
the MOS SF-36 summary physical and mental scores.
related quality of life (HRQL) component of the National
The mean number of symptoms reported was consis-
Surgical Adjuvant Breast and Bowel Project Breast Can-
tently higher in the tamoxifen group and was associ-
cer Prevention Trial. This report provides an overview of
ated with vasomotor and gynecologic symptoms. Signifi-
HRQL findings, comparing tamoxifen and placebo
cant increases were found in the proportion of women
groups, and advice to clinicians counseling women
on tamoxifen reporting problems of sexual functioning
about the use of tamoxifen in a prevention setting.
at a definite or serious level, although overall rates of
Patients and Methods: This report covers the base-
sexual activity remained similar.
line and the first 36 months of follow-up data on 11,064
Conclusion: Women need to be informed of the in-
women recruited over the first 24 months of the study.
creased frequency of vasomotor and gynecologic symp-
Findings are presented from the Center for Epidemiologi-
toms and problems of sexual functioning associated
cal Studies–Depression Scale (CES-D), the Medical Out-
with tamoxifen use. Weight gain and depression, two
comes Study 36-Item Short Form Health Status Survey
clinical problems anecdotally associated with tamoxi-
(MOS SF-36) and sexual functioning scale, and a symp-
fen treatment, were not increased in frequency in this
tom checklist.
trial in healthy women, which is good news that also
Results: No differences were found between pla-
needs to be communicated.
cebo and tamoxifen groups for the proportion of partici-
J Clin Oncol 17:2659-2669. ௠ 1999 by American
pants scoring above a clinically significant level on the
Society of Clinical Oncology.
CES-D. No differences were found between groups for
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 This report covers the baseline HRQL examination and the first 36 (NSABP) Breast Cancer Prevention Trial (P-1), a multicen- months of follow-up data on 11,064 women recruited over the first 24 ter, double-blinded, placebo-controlled clinical trial. The months (June 1, 1992, to May 31, 1994) of the study. This cohort of purpose of this report is to provide a concise overview of the women represents 82.6% of the total P-1 accrual (n ϭ 13,388).
Restrictions were imposed on the initial HRQL report for two reasons.
P-1 HRQL findings and an assessment of the effects of First, by limiting our attention to this cohort of women, we avoided the tamoxifen, when used as a preventative agent, on self- potential bias created by events beginning in March 1994,4,5 which reported symptoms and everyday physical, emotional, and resulted in a suspension of accrual to the P-1 study. Second, a focus on social functioning. Recommendations have been provided the first 36 months of data collection permitted improved control overtypes of missing HRQL data because all 11,064 participants should have that may be helpful to physicians involved in counseling completed the eight scheduled examinations before the disclosure of the women considering the use of tamoxifen in the setting of results of the trial in the spring of 1998.
The primary objective of the P-1 study was to evaluate whether 5 years of tamoxifen therapy would reduce the From the National Surgical Adjuvant Breast and Bowel Project incidence of invasive breast cancer in women at an increased (NSABP) Operations and Biostatistical Centers, Pittsburgh, PA, and risk for the disease. Secondary objectives were to assess the Jonsson Comprehensive Cancer Center, University of California Los incidence of ischemic heart disease, bone fractures, and other events, such as depression, that might be associated Submitted December 7, 1998; accepted April 22, 1999.
Supported by public health service grants from the National Cancer with the use of tamoxifen. Eligible participants were random- Institute (NCI-U10-CA-37377/69974) and a career development award ized either to 20 mg daily of tamoxifen or to a placebo for a from the Department of Defense (DAMD17-97-1-7058). Address reprint requests to Richard Day, PhD, Department of Detailed descriptions of the rationale, planning, and Biostatistics, Graduate School of Public Health, 130 DeSoto St,University of Pittsburgh, Pittsburgh, PA 15261; email rdfac@vms. design of the of the Breast Cancer Prevention Trial and the HRQL component of the P-1 study, as well as specific ௠ 1999 by American Society of Clinical Oncology. instruments, have been provided in separate reports.1-3 Journal of Clinical Oncology, Vol 17, No 9 (September), 1999: pp 2659-2669 Imputation procedures for missing items in otherwise complete scales were only used for eight SF-36 subscales, as recommended in the The 104-item P-1 HRQL Questionnaire3 was composed of the Center SF-36 scoring manual.9 No data imputation was carried out for other for Epidemiological Studies–Depression Scale (CES-D, 20 items), the scales, and incomplete scales were considered missing.6 Medical Outcomes Study (MOS) 36-Item Short Form Health StatusSurvey (SF-36, 36 items), the MOS sexual functioning scale (five items), and a symptom checklist (SCL, 43 items). The questionnairewas scheduled to be administered to all participants before randomiza- Table 1 lists the demographic, medical, and behavioral tion (baseline), at 3 months, at each succeeding 6-month examination characteristics of our participant cohort of 11,064 women by for the planned 5 years of treatment, and for 1 year after treatment was trial group. These data show that the women in the P-1 study were predominately white (96%), well educated (65% Նsome college), married (70%), professional and technically trained (68.2%), currently employed (64.9%), and reported a The P-1 study has multiple, complex levels of missing and incom- middle- to upper-middle class family income (median, plete data. In the case of self-administered instruments, such as the $35,000 to $49,999). None of the variables in Table 1 show a HRQL questionnaire, participants could leave items blank by error or striking imbalance between the two trial groups.
because they did not wish to answer the question.6 Beyond this, the Figure 1 charts the overall proportion and total numbers staffs of collaborating centers were generally unable to collect self- of women completing the HRQL questionnaire at each administered instruments on participants who quit taking pills becausethey no longer appeared for follow-up examinations, although many of examination. It provides a general measure of comparative these participants can still be observed for primary end points (eg, breast participant adherence with regard to the HRQL question- cancer and fractures). In addition, there are participants who did not naire in the two trial groups. Both trial groups showed a complete all of the scheduled follow-up HRQL questionnaires because consistent decline in HRQL adherence across the first 36 of the disclosure of the trial results in the spring of 1998,1 although they months of the study, averaging 4.2% per examination in the are still observed for primary end points. Finally, a small proportion ofparticipants (1.7%) were lost to follow-up, even for primary end points.
placebo group and 4.6% per examination in the tamoxifengroup. The proportion of HRQL-adherent participants wassmaller in the tamoxifen than in the placebo group at every one of the seven follow-up examinations (sign test, P ϭ The P-1 HRQL data set is composed of multiple HRQL instruments, .0078), with a maximum difference of 3.1% occurring at 36 each with its own psychometric properties and research history.3 This complexity is magnified by the fact that data distributions and patterns A number of demographic, clinical, and HRQL variables of missing data differ across the various instruments included in the were examined to investigate whether differences could be HRQL questionnaire. In addition, sample sizes are large, resulting in thepossibility of statistically significant findings for clinically negligible detected between the women who failed to complete the effects. All of these considerations argue for future detailed analyses of HRQL questionnaire at 36 months in the tamoxifen and the the data from each specific instrument. In this initial report, however, placebo groups. These variables included mean age (tamoxi- our aims were essentially descriptive in nature and emphasized basic fen ϭ 53.1 years v placebo ϭ 53.5 years) and mean RR (5.42 comparisons of the two trial groups. In making these comparisons, we v 5.43), treatment status (10.1% v 10.5% on treatment), seek to identify consistent differences, between the trial groups, usingsimple nonparametric procedures. The sign test7 is used to examine the breast cancer in a first-degree relative (76.89% v 78.40%), consistency of binary differences (Ϯ) between the two trial groups prior estrogen use (32.5% v 33.3%), mean maximum CES-D across time, independent of the magnitude of these differences. A score (12.52 v 12.46), and mean maximum number of one-sided alternative is routinely used because tamoxifen is expected to reported symptoms on the SCL (14.2 v 13.9). These have a negative effect on most short-term measures of HRQL.
comparisons suggested that participants who failed to com- Friedman’s test,7 implemented as a generalization of the paired signtest,8 was used as a nonparametric analog to the two-way analysis of plete the HRQL questionnaire in each group were similar variance when we wanted to block on a specific factor, such as age group. Positive findings, with regard to consistent differences between When, within a treatment group, the same variables were trial groups, were independently reviewed for magnitude to assess their used to compare HRQL adherent and nonadherent women, clinical and functional significance for the participants’ quality of life.
only the treatment status variable was different between the Clinical experience, as well as initial statistical investigations of the P-1 HRQL data set, suggested that the age of the study participants was two groups. A significantly greater proportion of HRQL- a key factor contributing to the observed distribution of HRQL adherent women in both groups remained on treatment measures. Hence, the results presented here from various HRQL (87.0% v 89.6%) compared with HRQL-nonadherent women instruments were routinely stratified by three age groups (35 to 49 years, (10.1% v 10.5%). In other words, adherence in the HRQL 50 to 59 years, and 60 years or older) that generally paralleled component of P-1 was largely a reflection of treatment menopausal status. Relative risks (RRs) or absolute differences in meancounts are presented in the tables to estimate differences in effect size adherence. This was because most collaborating centers did not have the staff resources to administer the HRQL HEALTH-RELATED QUALITY OF LIFE AND TAMOXIFEN Table 1. Demographic, Clinical, and Health Behavior Characteristics of P-1
Table 1. Demographic, Clinical, and Health Behavior Characteristics of P-1
HRQL Study Participants (N ؍ 11,064) (Cont’d)
HRQL Study Participants (N ؍ 11,064)
53.83 Ϯ 9.167 53.82 Ϯ 9.184 53.83 Ϯ 9.175 questionnaire via the telephone or mail to women who stopped treatment and failed to appear for their scheduled 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 condi- tions. 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 thetamoxifen group (184 women). When stopping their as- Fig 1. Proportion of participants
in the tamoxifen group and placebo
group completing HRQL question-
naire by examination (placebo, n ؍
5,537; tamoxifen, n ؍ 5,527). Fig-
ures on chart are the number of
women in the placebo/tamoxifen
groups completing the HRQL ques-
tionnaire and the difference be-
tween TAM and placebo groups in
terms of percent missing HRQL data.
signed treatment, participants in the placebo group were regard to the relationship between the two trial groups more likely to cite other nonmedical reasons, such as fear of emerged from the analysis of the five-item mental health side effects, change of mind, or desire to adopt an alternative subscale on the MOS SF-36 (not shown).
The results of the SF-36 are summarized using the Table 3 shows the proportion of P-1 participants, by age physical component summary (PCS) and mental component group and examination, who scored above the most fre- summary (MCS) scores12 and the eight SF-36 subscales. The quently used clinical cutoff (Ն 16) on the CES-D.10,11 The PCS and MCS scores represent aggregate measures that youngest age group (35 to 49 years) in both trial groups combine data from the eight subscales generally reported on consistently had the highest proportion of members scoring the SF-36. The PCS aggregates data from the Physical above the clinical cutoff, followed by the 50- to 59-year-old Functioning, Role-Physical, Bodily Pain, and General Health age group (Friedman test, P ϭ .001 tamoxifen and placebo).
subscales, while the MCS draws on data from the Vitality, The RRs listed in Table 3 show that, for all three age groups, Social Functioning, Role-Emotional, and Mental Health the magnitude of the differences is small, and there was no subscales. The PCS and MCS are scored using norm-based consistent excess of participants in the tamoxifen groupscoring above the clinical cutoff on the CES-D when Table 3. Proportion of Participants in Tamoxifen Arm With a Clinically
compared with the placebo group. Similar findings with Significant Score (м 16) on the CES-D by Age Group and Examination
Table 2. Reasons for Stopping Assigned Therapy by Participants
Not Completing Quality of Life Questionnaire
(Baseline to 36-Month Examination, n ؍ 3421)
12 months 0.128 0.937 0.122 0.999 0.096 0.989 0.116 0.968 18 months 0.139 0.892 0.126 0.918 0.101 0.929 0.123 0.908 30 months 0.142 0.978 0.107 0.961 0.104 0.934 0.120 0.959 HEALTH-RELATED QUALITY OF LIFE AND TAMOXIFEN methods; both component scores have a mean of 50 and a The youngest age group (35 to 49 years) had the greatest SD of 10 in the general United States (U.S.) population. This proportion of participants reporting vaginal discharge at means that the PCS and MCS can be meaningfully com- each examination (median, 35.5%; Friedman test, P Ͻ pared with one another, and their scores have a direct .001), and the oldest age group (Ն 60 years) reported the interpretation in relation to the distribution of scores in the greatest increase of vaginal discharge relative to the placebo controls (median RR, 3.05; Friedman test, P ϭ .005).
Figure 2 charts the PCS and MCS for the tamoxifen and Figure 4 summarizes the information from the five items placebo groups at each examination and by age group. As on the MOS sexual functioning scale. Figure 4A shows that expected, mean PCS declines across the age groups. At a greater proportion of participants in the tamoxifen group, follow-up examinations, the tamoxifen group was consis- as compared with the placebo group, reported being sexually tently lower on the PCS only in the 50- to 59-year-old age active during the 6 months before each follow-up examina- group (one-sided sign test, P ϭ .065). However, the absolute tion. Although apparently consistent (P ϭ .031), the abso- differences were small, approximating one tenth of an SD.
lute difference was small (mean, 0.78%) and may have been With regard to the MCS, all of the age groups scored above caused by chance. Figure 4B through 4E show that a small the mean MCS for the general U.S. population, and no but consistently larger percentage of participants in the consistent differences emerged between the two trial groups.
tamoxifen group reported a definite or serious problem in Figure 3 summarizes the overall data from eight subscales three of the four specific domains of sexual functioning 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 We observed in our earlier article3 that measuring the the 50- to 59-year-old age group, followed by the 35- to impact of new treatments on HRQL is particularly important 49-year-old and 60 years or older age groups (Friedman test, within the context of disease-prevention and health- P ϭ .001 tamoxifen and placebo). The participants in the promotion trials. Compared with patients suffering from tamoxifen group also reported a small but consistent excess clinically manifest disease, decrements in overall quality of in the mean number of symptoms (Ͻ one) reported at 19 of life are likely to have a much greater impact on the the 21 age-stratified follow-up examinations (3 to 36 months; subjective appraisal of treatment acceptability and the one-sided sign test, 35 to 49 years, P ϭ .0078; 50 to 59 years maintenance of long-term treatment adherence among high- and Ն 60 years, P ϭ .065) (Table 4).
risk but otherwise healthy individuals. This report covers the Table 5 provides information on the proportion of women initial HRQL findings from a large, multicenter chemopre- in the tamoxifen and placebo groups who reported symp- vention trial, which has shown that tamoxifen reduced the toms on the SCL at least once during the treatment period, ie, risk of invasive breast cancer in high-risk women by 49% the period excluding baseline but including the seven during the first 5 years of administration. Given the apparent follow-up examinations. The five symptoms with the great- clinical efficacy of tamoxifen in the prevention setting, it is est relative difference between the two trial groups are given important to assess whether the various secondary effects of for each age group, and the 10 symptoms with the greatest the drug might act to reduce this practical efficacy.13-15 relative difference are presented for all participants com- The cohort of women taking part in the P-1 study clearly was not representative of the general population. They were Tables 6 and 7 give detailed information, by age group predominately white, well educated, and middle class, with and examination, on the reported frequency of hot flashes a strong professional and technical orientation. The initial and vaginal discharge in the trial groups. The proportion of HRQL findings presented in this report must be assessed participants who reported hot flashes was elevated in all age within the context of the socioeconomic and cultural charac- groups of the tamoxifen group at every follow-up examina- tion. Among the participants in the tamoxifen group, the 50- The subcohort of women discussed in this report represent to 59-year-old age group had the largest proportion of 82.6% of the total study cohort. This subcohort was chosen women reporting hot flashes at each examination (median, to exclude potential biases, because of external factors 69.8%; Friedman test, P ϭ .001), but the youngest age group eventuating in the suspension of accrual in P-1, and to (35 to 49 years) showed the greatest relative increase in control for the amount and types of missing data. Despite proportion of women reporting hot flashes (median RR, this, we still lost 31.5% of our participants by the 36-month 1.50; Friedman test, P ϭ .011). Vaginal discharge was the follow-up examination. This proportion closely approxi- most consistently elevated symptom in the tamoxifen group.
mates the 10%-per-year loss to follow-up rate predicted at Fig 2. Mean scores by age group and examination on SF-36 physical and mental component scores (higher scores represent better quality of life).
HEALTH-RELATED QUALITY OF LIFE AND TAMOXIFEN Fig 3. Mean SF-36 subscale scores by examination.
Table 4. Mean Number of Total Symptoms Reported on Symptom Checklist by Age Group and Examination
Abbreviation: TAM, tamoxifen.
*Difference ϭ tamoxifen minus placebo.
the beginning of the P-1 trial and is similar in pattern and but, instead, to the prevalence of clinically significant number to the adherence data recently reported in a second affective distress that might be associated with a number of large, multicenter chemoprevention trial of hormone replace- specific psychiatric disorders. However, if tamoxifen use ment therapy for heart disease.16 We have shown that there is was associated with the onset of clinically diagnosable only a small difference in the proportion of nonadherent depression, we would have expected to see a consistent participants in the tamoxifen and placebo groups and that the excess of individuals scoring Ն 16 on the CES-D in the nonadherent women in both trial groups have generally tamoxifen group. No such consistent excess was observed.
similar key demographic, clinical, and HRQL variables.
These findings agreed with the data from the mental health Given these considerations, it seems unlikely that a maxi- mum difference of 3% in the HRQL follow-up rates between The MOS SF-36 served in this study as a measure of the two groups was sufficient to create a significant bias in overall HRQL. For this initial report, we have presented data from the SF-36 in terms of two high-level component HRQL adherence is closely related to treatment adher- scores12 and the eight basic subscales generally used in ence. Based on the reasons for quitting treatment, it would scoring this instrument.9 Neither of these two methods of seem that nonadherent women in both trial groups were summarizing the SF-36 data demonstrated any clinically those who were sensitive to the actual or possible occurrence significant differences between the tamoxifen and placebo of side effects caused by tamoxifen.
Much concern has been expressed about a potential The first clear signs of consistent differences between the relationship between tamoxifen use and the onset of depres- tamoxifen and placebo groups were observed in the SCL. In sion.17-21 Women who reported a history of depressive 19 out of 21 follow-up comparisons, the mean number of episodes or a history of treatment for nervous or mental symptoms reported on the SCL were consistently different disorders were not excluded from the trial. A brief eight-item by age group (50 to 59 years Ͼ 35 to 49 years Ͼ 60ϩ years) affective screening questionnaire based on the CES-D and and by trial group (tamoxifen Ͼ placebo). The absolute the Diagnostic Interview Schedule22 was part of the baseline differences between the trial groups were relatively small examination.23 Using data from this brief screening instru- and tended to be associated with the types of vasomotor, ment, local investigators were alerted to eligible participants gynecologic, and sexual functioning symptoms previously showing signs of potentially serious affective distress at the baseline examination and caution was advised regarding The data from the MOS sexual functioning scale indicate their enrollment onto the trial. However, women who that relatively small (Ͻ 4.0%) but consistent differences showed current signs of affective distress or depression were exist between the two groups in regard to the proportion of not routinely excluded from the trial.
women reporting definite or serious problems in at least With regard to the primary screening instrument used in three specific domains of sexual functioning, sexual interest, the follow-up examinations, it has been pointed out that ‘‘the arousal, and orgasm. These problems do not seem to be age items in. (the CES-D) are generally related to affective group specific. Despite these findings for specific domains distress but not to any particular psychiatric disorder.’’11 For of functioning, there is no evidence that these problems this reason, the numbers listed in Table 3 refer not to the result in a reduction of the overall proportion of women in prevalence of clinically diagnosable depressive disorders the tamoxifen group who are sexually active.
HEALTH-RELATED QUALITY OF LIFE AND TAMOXIFEN Table 5. Symptoms Reported at Least Once Between Months 3 and 36
Table 6. Proportion of Women Reporting Hot Flashes in Tamoxifen Arm and
With the Largest Relative Difference Between Trial Arms
RR Compared to Placebo Arm by Age Group and Examination
0.258 0.959 0.533 0.989 0.268 1.030 0.346 0.991 0.581 1.588 0.761 1.241 0.511 1.413 0.616 1.399 0.610 1.666 0.765 1.268 0.503 1.481 0.626 1.455 12 months 0.614 1.525 0.740 1.273 0.460 1.412 0.606 1.396 18 months 0.613 1.510 0.715 1.239 0.419 1.461 0.586 1.387 24 months 0.622 1.457 0.681 1.199 0.388 1.311 0.570 1.322 30 months 0.627 1.362 0.642 1.206 0.330 1.177 0.541 1.265 36 months 0.627 1.414 0.667 1.276 0.364 1.362 0.560 1.348 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 consider- ing tamoxifen therapy should include these points in the Disclosure of likely and unlikely symptoms should pre- pare 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 preven-tive therapy. In addition, the setting of preventive therapy Based on these data, we conclude that tamoxifen use is differs considerably from the treatment of breast cancer.
associated with an increase in specific vasomotor, gyneco- Therefore, if a woman experiences untoward symptoms logic, and sexual functioning symptoms. At the same time, after starting tamoxifen treatment, the medication can be we did not observe any evidence that overall physical and discontinued if the symptoms cannot be controlled or her emotional well being were significantly affected by these personal assessment of the risks and benefits changes.
differences in the frequency of symptoms. We also found noevidence on the CES-D or the SF-36 mental health scale foran association in any age group between tamoxifen use and Table 7. Proportion of Women Reporting Vaginal Discharge in Tamoxifen
an increase in the proportion of women reporting clinically Arm and RR Compared to Placebo Arm by Age Group and Examination
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 0.201 0.957 0.135 1.041 0.058 0.907 0.138 0.975 prevention? As demonstrated by the SCL data from the 0.379 1.549 0.308 2.023 0.275 3.665 0.326 1.972 placebo group of the trial, many symptoms experienced by 0.391 1.686 0.302 1.931 0.269 3.057 0.327 1.973 12 months 0.380 1.700 0.304 1.973 0.262 3.333 0.321 2.020 women who participated in this study are age and meno- 18 months 0.363 1.558 0.278 2.251 0.252 3.029 0.303 1.961 pause related and exist independent of the use of tamoxifen.
24 months 0.341 1.797 0.272 1.991 0.238 2.994 0.288 2.052 However, several symptoms are substantially more frequent 30 months 0.325 1.633 0.282 2.404 0.246 3.075 0.288 2.083 in women using tamoxifen; these include vasomotor symp- 36 months 0.316 1.671 0.264 2.332 0.241 3.096 0.277 2.095 toms (cold sweats, night sweats, and hot flashes), vaginal discharge, and genital itching. Women need to be informed Fig 4. Proportion of women in the tamoxifen group and placebo group reporting a definite or serious problem in past 4 weeks on MOS sexual functioning
scale (B through E, women who reported being sexually active in last 6 months).
HEALTH-RELATED QUALITY OF LIFE AND TAMOXIFEN The current report is a brief overview of the P-1 study HRQL data that focuses on important clinical and functional We thank Carol Redmond, DSc, University of Pittsburgh; Leslie implications of tamoxifen use for women’s overall HRQL. It Ford, MD, National Cancer Institute, Bethesda, MD; Carol Moinpour, will be supplemented in the future by a series of additional PhD, Southwest Oncology Group Statistical Center; John E. Ware, Jr,New England Medical Center, Boston, MA; David Cella, Northwestern methodologic and clinical reports that will provide in-depth University, Chicago, IL; Sheela Goshal and Wei Chen, NSABP analyses of the data obtained from each one of the several Biostatistical Center; and members of the NSABP Prevention Quality of 1. Fisher B, Costantino JP, Wickerham L, et al: Tamoxifen for the 15. Gorin MB, Day R, Costantino JP, et al: Long term tamoxifen prevention of breast cancer: A report from the NSABP P-1 study. J Natl citrate and potential ocular toxicity. Am J Ophthalmol 125:493-501, 2. Fisher B, Costantino J: Highlights of the NSABP Breast Cancer 16. Hulley S, Grady D, Bush T, et al: Randomized trial of estrogen Prevention Trial. Cancer Control 4:78-86, 1997 plus progestin for secondary prevention of coronary heart disease in 3. Ganz PA, Day R, Ware JE, et al: Base-line quality-of-life postmenopausal women. JAMA 280:605-613, 1998 assessment in the National Surgical Adjuvant Breast and Bowel Project 17. Cathacart CK, Jones SE, Pumroy CS, et al: Clinical recognition Breast Cancer Prevention Trial. J Natl Cancer Inst 87:1372-1382, 1995 and management of depression in node negative breast cancer patients 4. Fisher B, Redmond C: Fraud in breast cancer trials. N Engl J Med treated with tamoxifen. Breast Cancer Res Treat 27:277-281, 1993 18. Love RL, Cameron L, Connell BL, et al: Symptoms associated 5. Fisher B, Anderson S, Redmond C, et al: Reanalysis and results with tamoxifen treatment in postmenopausal women. Arch Intern Med after 12 years of follow-up in a randomized clinical trial comparing totalmastectomy with lumpectomy with or without irradiation in the treatment of breast cancer. N Engl J Med 333:1456-1461, 1995 19. Shariff S, Cumming CE, Lees A, et al: Mood disorder in women 6. Ganz PA, Day R, Costantino JP: Compliance with quality of life with early breast cancer taking tamoxifen, an estradiol receptor data collection in the NSABP breast cancer prevention trial. Stat Med antagonist: An unexpected effect? Ann N Y Acad Sci 761:365-368, 7. Daniel WW: Applied Non-Parametric Statistics. Boston, MA, 20. Moredo Anelli T, Anelli A, Tran KN, et al: Tamoxifen administra- tion is associated with a high rate of treatment-limiting symptoms in 8. Deshpande JV, Gore AP, Shanubhougue A: Statistical Analysis of male breast cancer patients. Cancer 74:74-77, 1994 Non-Normal Data. New York, NY, John Wiley & Sons, 1995 21. Pluss JL, Dibella NJ: Reversible central nervous system dysfunc- 9. International Resource Center for Health Care Assessment: How tion due to tamoxifen in a patient with breast cancer. Ann Intern Med to Score the SF-36 Health Status Survey. Boston, MA, New England 22. Robins LN, Helzer JE, Croughan J, et al: National Institute of 10. Radloff LS: The CES-D scale: A self-report depression scale for Health Diagnostic Interview Schedule: Its history, characteristics and research in the general population. Appl Psychol Meas 1:385-401, 1977 validity. Arch Gen Psychiatry 35:837-846, 1978 11. Roberts RE, Vernon SW: The Center for Epidemiologic Studies 23. Burnam MA, Wells KB, Leake B, et al: Development of a brief Depression Scale: Its use in a community sample. Am J Psychiatry screening instrument for detecting depressive disorders. Med Care 12. Ware JE, Kosinski M, Keller SD: SF-36 Physical and Mental Summary Scales: A User’s Manual (3rd Printing Revised). Boston, MA, 24. Fisher B, Dignam J, Bryant J, et al: Five versus more than five The Health Institute, New England Medical Center, 1994 years of tamoxifen therapy for breast cancer patients with negative 13. Fisher B: A commentary on endometrial cancer deaths in lymph nodes and estrogen receptor-positive tumors. J Natl Cancer Inst tamoxifen-treated breast cancer patients. J Clin Oncol 14:1027-1039, 25. Fisher B, Costantino J, Redmond C, et al: A randomized clinical 14. Fisher B, Costantino JP, Redmond CK, et al: Endometrial cancer trial evaluating tamoxifen in the treatment of patients with node- in tamoxifen-treated breast cancer patients: Findings from NSABP negative breast cancer who have estrogen-receptor-positive tumors. N B-14. J Natl Cancer Inst 86:527-537, 1994

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