ABSTRACT
OBJECTIVE: This study reports the gynecologic conditions in postmenopausal women (intact uterus on enrollment) in the National Surgical Adjuvant Breast and Bowel Project (NSABP) study of tamoxifen and raloxifene (STAR)/P-2 trial. STUDY DESIGN: This study, with a median follow-up period of 81 months, evaluated the incidence rates/risks of gynecologic conditions among women who were treated with tamoxifen and raloxifene. RESULTS: Compared with women who received tamoxifen therapy, women who received raloxifene therapy had a lower incidence of uterine cancer (relative risk, 0.55)/endometrial hyperplasia (relative risk, 0.19), leiomyomas (relative risk, 0.55), ovarian cysts (relative risk, 0.60), and endometrial polyps (relative risk, 0.30) and had fewer procedures performed. Women receiving tamoxifen therapy had more hot flashes (P < .0001), vaginal discharge (P < .0001), and vaginal bleeding (P < .0001). CONCLUSION: Our results suggest that tamoxifen has more of an estrogenic effect on the gynecologic reproductive organs. These effects should be considered in counseling women on options for breast cancer prevention.
Subject(s)
Breast Neoplasms/drug therapy , Breast Neoplasms/epidemiology , Leiomyoma/epidemiology , Raloxifene Hydrochloride/therapeutic use , Tamoxifen/therapeutic use , Uterine Neoplasms/epidemiology , Aged , Antineoplastic Agents, Hormonal/therapeutic use , Breast Neoplasms/prevention & control , Endometrial Hyperplasia/epidemiology , Endometrial Hyperplasia/prevention & control , Estrogen Antagonists/therapeutic use , Female , Follow-Up Studies , Hot Flashes/epidemiology , Humans , Incidence , Leiomyoma/prevention & control , Middle Aged , Ovarian Cysts/epidemiology , Ovarian Cysts/prevention & control , Polyps/epidemiology , Polyps/prevention & control , Postmenopause/drug effects , Risk Factors , Uterine Neoplasms/prevention & control , Vaginal Discharge/epidemiologyABSTRACT
BACKGROUND: Research on barriers to accrual has typically emphasized factors influencing participation after trial activation. PURPOSE: We sought to identify factors influencing trial design and accrual predictions prior to trial activation associated with sufficient accrual. METHODS: A 30-question web-based survey was sent to the study chair and lead statistician for all 248 phase III trials open in 1993-2002 by five Clinical Trials Cooperative Groups. Questions addressed prior trial experience, trial design elements, accrual predictions, and perceived accrual influences. Accrual sufficiency categorization was derived from Clinical Trials Cooperative Group records: sufficient accrual included trials closed with complete accrual or at interim analysis, insufficient accrual included trials closed with inadequate accrual. Responses were analyzed by respondent role (study chair/lead statistician) and accrual sufficiency. RESULTS: Three hundred and nine eligible responses were included (response rate, 63%; lead statisticians, 81%; and study chairs, 45%), representing trials with sufficient (63%) and insufficient accruals (37%). Study chair seniority or lead statistician experience was not linked to accrual sufficiency. Literature review, study chair's personal experience, and expert opinion within Clinical Trials Cooperative Group most commonly influenced control arm selection. Clinical Trials Cooperative Group experience most influenced accrual predictions. These influences were not associated with accrual sufficiency. Among respondents citing accrual difficulties (41%), factors negatively influencing accrual were not consistently identified. Respondents credited three factors with positively influencing accrual: clinical relevance of study, lack of competing trials, and protocol paralleling normal practice. LIMITATIONS: Perceptions of lead statisticians and study chairs may not accurately reflect accrual barriers encountered by participating physicians or patients. Survey responses may be subject to recall bias. CONCLUSION: Consistent factors explaining poor accrual were not identified, suggesting reasons for poor accrual are not well understood and warrant further study. Alternate strategies for accrual prediction are needed since Clinical Trials Cooperative Group experience is linked to successful and unsuccessful accrual.
Subject(s)
Biostatistics/methods , Clinical Trials, Phase III as Topic/methods , Data Collection , Humans , Internet , Medical Oncology , National Cancer Institute (U.S.) , Patient Participation , Patient Selection , Research Design , Surveys and Questionnaires , Therapeutic Equipoise , United StatesABSTRACT
The NSABP Study of Tamoxifen and Raloxifene (STAR), launched in 1999, compared tamoxifen with raloxifene in a population of healthy postmenopausal women at increased risk for breast cancer to determine the relative effects on the risk of invasive breast cancer. To be eligible for participation, a woman had to be healthy with at least a 5-year predicted breast cancer risk of 1.66% based on the Gail model or a history of lobular carcinoma in situ (LCIS) treated by local excision alone. All participants were at least 35 years of age and postmenopausal. Between July 1999 and November 2004, 19,747 participants were randomized to receive either tamoxifen (20 mg, plus placebo) or raloxifene (60 mg, plus placebo) daily for a 5-year period. The mean age of the participants was 58.5 years; 93% were white and 51.6% had a hysterectomy prior to entering the study. Of the women, 71% had one or more first degree female relatives (mother, sister, daughter) with a history of breast cancer and 9.2% of the women had a personal history of LCIS. A history of atypical hyperplasia of the breast was noted in 22.7% of the participants. The mean predicted 5-year risk of developing breast cancer among the study population was 4.03% (SD, 2.17%) with a lifetime predicted risk of 16%. The mean time of follow-up is 3.9 years (SD, 1.6 years). There was no difference between the effect oftamoxifen and the effect of raloxifene on the incidence of invasive breast cancer; there were 163 cases of invasive breast cancer in the tamoxifen-treated group and 168 cases in those women assigned to raloxifene (incidence 4.30 per 1,000 vs 4.41 per 1,000; RR 1.02; 95% CI, 082-1.28). There were fewer cases of noninvasive breast cancer (LCIS and ductal carcinoma in situ [DCIS]) in the tamoxifen group (57 cases) than in the raloxifene group (80 cases), although the difference is not yet statistically significant (incidence 1.51 vs 2.11 per 1,000; RR, 1.40; 95% CI, 0.98-2.00). There were 36 cases of uterine cancer with tamoxifen and 23 cases with raloxifene (RR, 0.63; 95% CI, 0.35-1.08).
Subject(s)
Breast Neoplasms/prevention & control , Estrogen Antagonists/therapeutic use , Raloxifene Hydrochloride/therapeutic use , Tamoxifen/therapeutic use , Female , HumansABSTRACT
The supplanting of radical mastectomy by simple mastectomy and then by lumpectomy plus radiation, the use of adjuvant therapy to alter the natural course of breast and colorectal cancer, the use of tamoxifen for the prevention of breast cancer, and the dramatic improvement in survival demonstrated with the use of the monoclonal antibody trastuzumab in women with HER2-positive breast cancer are all the direct results of research that has been carried out over the past 50 years by the National Surgical Adjuvant Breast and Bowel Project (NSABP). This National Cancer Institute-supported clinical cooperative trials group based in Pittsburgh, PA, currently has 200 member institutions and 700 satellite centers located throughout the United States, Canada, Puerto Rico, and Ireland. The NSABP's mandate is to conduct large randomized phase III trials to evaluate therapies designed to improve the treatment and prevention of breast and colorectal cancer. Over the past half century, the NSABP has entered more than 150,000 patients and participants into clinical studies that have changed the treatment of colorectal cancer and have revolutionized the treatment and prevention of breast cancer.
Subject(s)
Breast Neoplasms/therapy , Colorectal Neoplasms/therapy , Breast Neoplasms/pathology , Clinical Trials as Topic , Colorectal Neoplasms/pathology , Combined Modality Therapy , Humans , Lymph Node Excision , Mastectomy , Quality of Life , Tissue BanksABSTRACT
INTRODUCTION: Cancer clinical trials (CCT) provide much of the evidence for clinical guidelines and standards of care. But low levels of CCT participation are well documented, especially for minorities. METHODS AND MATERIALS: We conducted an online survey of 556 recruitment practices across the NRG Oncology network. Survey aims were 1) to learn how sites recruit minority/underserved populations; 2) to better understand the catchment areas of the NRG institutions; and 3) to aid in planning education programs for accrual of minority/underserved populations. RESULTS: The survey response rate was 34.9%. The most effective methods reported for recruiting minority/underserved participants were patient navigators (44.4%) and translators (38.9%). All institutions reported using a mechanism for eligibility screening and 71% of institutions reported using a screening/enrollment tracking system. CCT training was required at 78.1% and cultural competency training was required at 47.5% of responding institutions. Only 19.9% of sites used community partners to assist with minority recruitment and just 37.1% of respondents reported a defined catchment area. Sites reported very little race and ethnicity data. CONCLUSION: This NRG Oncology online survey provides useful data for improvements in trial enrollment and training to recruit minority/underserved populations to CCT. Areas for further investigation include web-based methods for recruitment and tracking, cultural competency training, definition of catchment areas, use of patient navigators, and community partnerships. The survey results will guide recruitment training programs.
ABSTRACT
CONTEXT: Tamoxifen is approved for the reduction of breast cancer risk, and raloxifene has demonstrated a reduced risk of breast cancer in trials of older women with osteoporosis. OBJECTIVE: To compare the relative effects and safety of raloxifene and tamoxifen on the risk of developing invasive breast cancer and other disease outcomes. DESIGN, SETTING, AND PATIENTS: The National Surgical Adjuvant Breast and Bowel Project Study of Tamoxifen and Raloxifene trial, a prospective, double-blind, randomized clinical trial conducted beginning July 1, 1999, in nearly 200 clinical centers throughout North America, with final analysis initiated after at least 327 incident invasive breast cancers were diagnosed. Patients were 19,747 postmenopausal women of mean age 58.5 years with increased 5-year breast cancer risk (mean risk, 4.03% [SD, 2.17%]). Data reported are based on a cutoff date of December 31, 2005. INTERVENTION: Oral tamoxifen (20 mg/d) or raloxifene (60 mg/d) over 5 years. MAIN OUTCOME MEASURES: Incidence of invasive breast cancer, uterine cancer, noninvasive breast cancer, bone fractures, thromboembolic events. RESULTS: There were 163 cases of invasive breast cancer in women assigned to tamoxifen and 168 in those assigned to raloxifene (incidence, 4.30 per 1000 vs 4.41 per 1000; risk ratio [RR], 1.02; 95% confidence interval [CI], 0.82-1.28). There were fewer cases of noninvasive breast cancer in the tamoxifen group (57 cases) than in the raloxifene group (80 cases) (incidence, 1.51 vs 2.11 per 1000; RR, 1.40; 95% CI, 0.98-2.00). There were 36 cases of uterine cancer with tamoxifen and 23 with raloxifene (RR, 0.62; 95% CI, 0.35-1.08). No differences were found for other invasive cancer sites, for ischemic heart disease events, or for stroke. Thromboembolic events occurred less often in the raloxifene group (RR, 0.70; 95% CI, 0.54-0.91). The number of osteoporotic fractures in the groups was similar. There were fewer cataracts (RR, 0.79; 95% CI, 0.68-0.92) and cataract surgeries (RR, 0.82; 95% CI, 0.68-0.99) in the women taking raloxifene. There was no difference in the total number of deaths (101 vs 96 for tamoxifen vs raloxifene) or in causes of death. CONCLUSIONS: Raloxifene is as effective as tamoxifen in reducing the risk of invasive breast cancer and has a lower risk of thromboembolic events and cataracts but a nonstatistically significant higher risk of noninvasive breast cancer. The risk of other cancers, fractures, ischemic heart disease, and stroke is similar for both drugs. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00003906.
Subject(s)
Breast Neoplasms/epidemiology , Breast Neoplasms/prevention & control , Raloxifene Hydrochloride/therapeutic use , Selective Estrogen Receptor Modulators/therapeutic use , Tamoxifen/therapeutic use , Adult , Aged , Cataract/epidemiology , Cause of Death , Double-Blind Method , Female , Fractures, Bone/epidemiology , Humans , Incidence , Middle Aged , Myocardial Ischemia/epidemiology , Risk , Thrombosis/epidemiology , Uterine Neoplasms/epidemiologyABSTRACT
Following up on the results of recent completed trials, several major breast cancer prevention trials are either underway or impending. In the Study of Tamoxifen and Raloxifene trial, eligible women are at least 35 years of age and postmenopausal, with either lobular carcinoma in situ or a 5-year risk of invasive breast cancer of at least 1.67%. The study will compare the ability of 5 years of tamoxifen or raloxifene to reduce the incidence of breast cancer. Subjects are randomly assigned to receive either 20 mg of tamoxifen or 60 mg of raloxifene daily. After 3 years of recruitment, 13647 women have been randomized (20.7% of those eligible). The median age of randomized women is 58 years (mean age, 58 years), and their median 5-year risk of breast cancer is 3.3% (mean 5-year risk of breast cancer, 4.0%). Hysterectomy was reported by 52.5% of the randomized women; lobular carcinoma in situ was reported by 8.4% of subjects before randomization. In the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-24 trial, 1804 women with ductal carcinoma in situ were randomly assigned tamoxifen after lumpectomy and radiation therapy. Women in the tamoxifen group had fewer breast cancer events at 5 years than did those on placebo (8.2% versus 13.4%, P = 0.0009). The proposed NSABP B-35 trial will have the same design as NSABP B-24 but will compare tamoxifen with anastrozole in postmenopausal women. Outcomes will include both ipsilateral and contralateral new breast cancer and recurrences, as well as the occurrence of regional and distant disease. Enrollment will begin in early 2003.
Subject(s)
Antineoplastic Agents, Hormonal/therapeutic use , Breast Neoplasms/prevention & control , Carcinoma in Situ/prevention & control , Carcinoma, Lobular/prevention & control , Raloxifene Hydrochloride/therapeutic use , Selective Estrogen Receptor Modulators/therapeutic use , Tamoxifen/therapeutic use , Chemotherapy, Adjuvant , Female , Humans , Mastectomy , Randomized Controlled Trials as TopicABSTRACT
The National Cancer Institute (NCI)-supported adult cooperative oncology research groups (now officially Network groups) have a longstanding history of participating in international collaborations throughout the world. Most frequently, the US-based cooperative groups work reciprocally with the Canadian national adult cancer clinical trial group, NCIC CTG (previously the National Cancer Institute of Canada Clinical Trials Group). Thus, Canada is the largest contributor to cooperative groups based in the United States, and vice versa. Although international collaborations have many benefits, they are most frequently utilized to enhance patient accrual to large phase III trials originating in the United States or Canada. Within the cooperative group setting, adequate attention has not been given to the study of cancers that are unique to countries outside the United States and Canada, such as those frequently associated with infections in Latin America, Asia, and Africa. Global collaborations are limited by a number of barriers, some of which are unique to the countries involved, while others are related to financial support and to US policies that restrict drug distribution outside the United States. This article serves to detail the cooperative group experience in international research and describe how international collaboration in cancer clinical trials is a promising and important area that requires greater consideration in the future.
Subject(s)
Biomedical Research/organization & administration , Clinical Trials as Topic , Cooperative Behavior , Internationality , Neoplasms , Africa , Asia , Canada , Humans , Latin America , National Cancer Institute (U.S.) , United StatesABSTRACT
Tamoxifen reduced the risk of invasive breast cancer by 49% among women at increased risk for breast cancer in the Breast Cancer Prevention Trial P-1, and raloxifene reduced breast cancer incidence by more than 70% in the Multiple Outcomes of Raloxifene Evaluation osteoporosis trial. These findings led the National Surgical Adjuvant Breast and Bowel Project to design and launch the Study of Tamoxifen and Raloxifene. Risk-eligible women are = 35 years of age and postmenopausal; they have either lobular carcinoma in situ (LCIS) or a 5-year risk of invasive breast cancer of at least 1.67% as determined by the Gail model. Participants are randomly assigned to receive either tamoxifen 20 mg or raloxifene 60 mg daily. The trial opened for accrual on July 1, 1999. After 32 months of recruitment at 194 clinical centers in North America, risk assessments have been performed in 107,855 women (83.8% white, 9.4% black, 3.8% Hispanic, 3.1% other race/ethnic groups). Of the eligible patients, 12,637 have been randomized (20.9% of risk-eligible women); the median age is 58 years (mean, 58 years), and the median 5-year risk of breast cancer is 3.3% (mean, 4.0%). LCIS was reported in 8.4% of women prior to randomization. Gail model risk was = 3.0% in 5 years for 59.3% of white women, 45.0% of black women, and 44.5% of Hispanic women. The trial will recruit a total of 22,000 postmenopausal women and is powered to demonstrate superior efficacy of either agent or their equivalence in reducing the incidence of primary breast
Subject(s)
Anticarcinogenic Agents/therapeutic use , Breast Neoplasms/etiology , Breast Neoplasms/prevention & control , Patient Participation/statistics & numerical data , Raloxifene Hydrochloride/therapeutic use , Selective Estrogen Receptor Modulators/therapeutic use , Tamoxifen/therapeutic use , Adult , Aged , Anticarcinogenic Agents/adverse effects , Breast Neoplasms/pathology , Female , Humans , Middle Aged , Neoplasm Invasiveness/prevention & control , Raloxifene Hydrochloride/adverse effects , Risk Assessment , Risk Factors , Selective Estrogen Receptor Modulators/adverse effects , Tamoxifen/adverse effectsABSTRACT
Mammographic breast density is an established risk factor for breast cancer. However, results are inconclusive regarding its use in risk prediction models. The current study evaluated 13,409 postmenopausal participants in the NSABP Study of Tamoxifen and Raloxifene. A measure of breast density as reported on the entry mammogram report was extracted and categorized according to The American College of Radiology Breast Imaging Reporting and Data System (BI-RADS) classifications. An increased risk of invasive breast cancer was associated with higher mammographic breast density (P < 0.001). The association remained significant after adjusting for age, treatment, and smoking history [HR 1.35, 95% confidence interval (CI): 1.16-1.58], as well as when added to a model including the Gail score (HR 1.33, 95% CI: 1.14-1.55). At five years after random assignment, time-dependent area under the curve (AUC) improved from 0.63 for a model with Gail score alone to 0.64 when considering breast density and Gail score. Breast density was also significant when added to an abbreviated model tailored for estrogen receptor-positive breast cancers (P = 0.02). In this study, high BI-RADS breast density was significantly associated with increased breast cancer risk when considered in conjunction with Gail score but provided only slight improvement to the Gail score for predicting the incidence of invasive breast cancer. The BI-RADS breast composition classification system is a quick and readily available method for assessing breast density for risk prediction evaluations; however, its addition to the Gail model does not seem to provide substantial predictability improvements in this population of postmenopausal healthy women at increased risk for breast cancer.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/etiology , Breast Neoplasms/prevention & control , Breast/cytology , Carcinoma/etiology , Carcinoma/prevention & control , Mammography , Breast/pathology , Breast Neoplasms/diagnosis , Breast Neoplasms/pathology , Carcinoma/diagnosis , Carcinoma/pathology , Cell Count , Combined Modality Therapy/statistics & numerical data , Female , Humans , Middle Aged , Neoplasm Invasiveness , Postmenopause , Predictive Value of Tests , Raloxifene Hydrochloride/administration & dosage , Randomized Controlled Trials as Topic/statistics & numerical data , Risk Factors , Tamoxifen/administration & dosageABSTRACT
High body mass index (BMI) has been associated with an increased risk for breast cancer among postmenopausal women. However, the relationship between BMI and breast cancer risk in premenopausal women has remained unclear. Data from two large prevention trials conducted by the National Surgical Adjuvant Breast and Bowel Project (NSABP) were used to explore the relationship between baseline BMI and breast cancer risk. The analyses included 12,243 participants with 253 invasive breast cancer events from the Breast Cancer Prevention Trial (P-1) and 19,488 participants with 557 events from the Study of Tamoxifen and Raloxifene (STAR). Both studies enrolled high-risk women (Gail score ≥ 1.66) with no breast cancer history. Women in P-1 were pre- and postmenopausal, whereas women in STAR (P-2) were all postmenopausal at entry. Using Cox proportional hazards regression, we found slight but nonsignificant increased risks of invasive breast cancer among overweight and obese postmenopausal participants in STAR and P-1. Among premenopausal participants, an increased risk of invasive breast cancer was significantly associated with higher BMI (P = 0.01). Compared with BMI less than 25, adjusted HRs for premenopausal women were 1.59 for BMI 25 to 29.9 and 1.70 for BMI 30 or more. Our investigation among annually screened, high-risk participants in randomized, breast cancer chemoprevention trials showed that higher levels of BMI were significantly associated with increased breast cancer risk in premenopausal women older than 35 years, but not postmenopausal women.
Subject(s)
Body Mass Index , Breast Neoplasms/diagnosis , Breast Neoplasms/prevention & control , Risk , Adult , Aged , Female , Humans , Middle Aged , Neoplasm Invasiveness , Obesity/complications , Postmenopause , Premenopause , Proportional Hazards Models , Raloxifene Hydrochloride/pharmacology , Randomized Controlled Trials as Topic , Tamoxifen/pharmacologyABSTRACT
The double-blind, prospective, National Surgical Adjuvant Breast and Bowel Project (NSABP) Breast Cancer Prevention Trial (BCPT) showed a 50% reduction in the risk of breast cancer for tamoxifen versus placebo, yet many women at risk of breast cancer do not adhere to the 5-year course. This first report of the rich BCPT drug adherence data examines predictors of adherence. Between June, 1992 and September, 1997 13,338 women at high risk of breast cancer were randomly assigned to 20 mg/d tamoxifen versus placebo; we analyzed the 11,064 enrolled more than 3 years before trial unblinding. Primary endpoint was full drug adherence (100% of assigned pills per staff report, excluding protocol-required discontinuation) at 1 and 36 months; secondary was adequate adherence (76%-100%). Protocol-specified multivariable logistic regression tested lifestyle factors, controlling for demographic and medical predictors. About 13% were current smokers; 60% were overweight/obese; 46% had moderate/heavy physical activity; 21%, 66%, 13% drank 0, 0-1, 1+ drinks per day, respectively; 91% were adequately adherent at 1 month; and 79% were at 3 years. Alcohol use was associated with reduced full adherence at 1 month (P = 0.016; OR = 0.79 1+ vs. 0), as was college education (P <0.001; OR = 0.78 vs. high school); age (P < 0.001; OR = 1.4 age 60+) and per capita household annual income (P < 0.001; OR = 1.2 per $30,000) with increased adherence. Current smoking (P = 0.003; OR = 0.75), age (P = 0.024, OR = 1.1), college education (P = 0.037; OR = 1.4), tamoxifen assignment (P = 0.031; OR = 0.84), and breast cancer risk (P <.001; OR = 1.5 high vs. low) predicted adequate adherence at 36 months. There were no significant associations with obesity or physical activity. Alcohol use and smoking might indicate a need for greater adherence support.
Subject(s)
Alcohol Drinking , Antineoplastic Agents, Hormonal/therapeutic use , Breast Neoplasms/prevention & control , Motor Activity , Obesity/epidemiology , Patient Compliance , Smoking , Tamoxifen/therapeutic use , Breast Neoplasms/epidemiology , Female , Humans , Life Style , Multivariate Analysis , Prospective Studies , Regression Analysis , Risk , United StatesABSTRACT
The selective estrogen-receptor modulator (SERM) tamoxifen became the first U.S. Food and Drug Administration (FDA)-approved agent for reducing breast cancer risk but did not gain wide acceptance for prevention, largely because it increased endometrial cancer and thromboembolic events. The FDA approved the SERM raloxifene for breast cancer risk reduction following its demonstrated effectiveness in preventing invasive breast cancer in the Study of Tamoxifen and Raloxifene (STAR). Raloxifene caused less toxicity (versus tamoxifen), including reduced thromboembolic events and endometrial cancer. In this report, we present an updated analysis with an 81-month median follow-up. STAR women were randomly assigned to receive either tamoxifen (20 mg/d) or raloxifene (60 mg/d) for 5 years. The risk ratio (RR; raloxifene:tamoxifen) for invasive breast cancer was 1.24 (95% confidence interval [CI], 1.05-1.47) and for noninvasive disease, 1.22 (95% CI, 0.95-1.59). Compared with initial results, the RRs widened for invasive and narrowed for noninvasive breast cancer. Toxicity RRs (raloxifene:tamoxifen) were 0.55 (95% CI, 0.36-0.83; P = 0.003) for endometrial cancer (this difference was not significant in the initial results), 0.19 (95% CI, 0.12-0.29) for uterine hyperplasia, and 0.75 (95% CI, 0.60-0.93) for thromboembolic events. There were no significant mortality differences. Long-term raloxifene retained 76% of the effectiveness of tamoxifen in preventing invasive disease and grew closer over time to tamoxifen in preventing noninvasive disease, with far less toxicity (e.g., highly significantly less endometrial cancer). These results have important public health implications and clarify that both raloxifene and tamoxifen are good preventive choices for postmenopausal women with elevated risk for breast cancer.
Subject(s)
Adenocarcinoma/prevention & control , Breast Neoplasms/prevention & control , Estrogens , Neoplasms, Hormone-Dependent/prevention & control , Raloxifene Hydrochloride/therapeutic use , Selective Estrogen Receptor Modulators/therapeutic use , Tamoxifen/therapeutic use , Adenocarcinoma/epidemiology , Adenocarcinoma/pathology , Adult , Aged , Aged, 80 and over , Breast Neoplasms/epidemiology , Breast Neoplasms/pathology , Cataract/chemically induced , Cataract/epidemiology , Double-Blind Method , Drug Utilization , Endometrial Neoplasms/chemically induced , Endometrial Neoplasms/epidemiology , Female , Follow-Up Studies , Fractures, Spontaneous/epidemiology , Fractures, Spontaneous/etiology , Fractures, Spontaneous/prevention & control , Humans , Incidence , Middle Aged , Myocardial Ischemia/epidemiology , Myocardial Ischemia/prevention & control , Neoplasm Invasiveness , Neoplasms, Hormone-Dependent/epidemiology , Neoplasms, Hormone-Dependent/pathology , Osteoporosis, Postmenopausal/complications , Osteoporosis, Postmenopausal/prevention & control , Raloxifene Hydrochloride/adverse effects , Raloxifene Hydrochloride/pharmacology , Risk , Selective Estrogen Receptor Modulators/adverse effects , Selective Estrogen Receptor Modulators/pharmacology , Tamoxifen/adverse effects , Tamoxifen/pharmacology , Thromboembolism/chemically induced , Thromboembolism/epidemiology , Uterus/pathologyABSTRACT
PURPOSE: This report describes interventions undertaken by the National Surgical Adjuvant Breast and Bowel Project (NSABP) to improve compliance with patient-reported outcome (PRO) assessments in the setting of multicenter cancer clinical trials. We describe the effectiveness of several interventions and of observational factors. METHODS: PRO submission rates were analyzed for the following three NSABP protocols: the Study of Raloxifene and Tamoxifen (STAR), B-32, and B-35. Institutions participating in protocol B-35 were randomly assigned to receive automated reminders of upcoming assessments or not. Compliance was analyzed with a logistic repeated measures mixed modeling. RESULTS: Compliance was high in the three protocols, with rates greater than 80% for nearly all time points. Institutions were a significant source of variability (P < .01). The largest institutions had the highest compliance in STAR (odds ratio [OR] = 0.68 for < 50 participants enrolled and OR = 0.82 for 50 to 99 participants enrolled v larger institutions; P < .001). Midsized institutions had highest compliance in B-32 (OR = 4.63 for 31 to 50 patients enrolled and OR = 3.12 for > 50 patients enrolled v small institutions; P = .007). Compliance increased with participant age in STAR (OR = 0.57, 0.89, and 1.01 for ages < 50, 50 to 60, and 60 to 70 years, respectively, v > 70 years; P < .001). Race was significant in B-32 (OR = 2.63 for white v nonwhite; P < .001) and in STAR (OR = 1.41 for white v nonwhite; P < .001). Treatment group was significant in B-32 (OR = 0.74; P = .006). The B-35 prospective reminder did not improve compliance significantly (P = .30), but in B-32, delinquency sanctions were significant (OR = 1.56; P = .007). CONCLUSION: Compliance in NSABP PRO studies is higher now than a decade ago. Results for compliance initiatives were mixed. Age and race are important factors, but institutional variation remains significant and largely unexplained.
Subject(s)
Clinical Trials as Topic/standards , Neoplasms/therapy , Patient Satisfaction , Quality of Life , Sickness Impact Profile , Treatment Outcome , Humans , Multicenter Studies as Topic/standards , Quality Indicators, Health CareABSTRACT
BACKGROUND: Initial findings from the National Surgical Adjuvant Breast and Bowel Project Breast Cancer Prevention Trial (P-1) demonstrated that tamoxifen reduced the risk of estrogen receptor-positive tumors and osteoporotic fractures in women at increased risk for breast cancer. Side effects of varying clinical significance were observed. The trial was unblinded because of the positive results, and follow-up continued. This report updates our initial findings. METHODS: Women (n = 13,388) were randomly assigned to receive placebo or tamoxifen for 5 years. Rates of breast cancer and other events were compared by the use of risk ratios (RRs) and 95% confidence intervals (CIs). Estimates of the net benefit from 5 years of tamoxifen therapy were compared by age, race, and categories of predicted breast cancer risk. Statistical tests were two-sided. RESULTS: After 7 years of follow-up, the cumulative rate of invasive breast cancer was reduced from 42.5 per 1000 women in the placebo group to 24.8 per 1000 women in the tamoxifen group (RR = 0.57, 95% CI = 0.46 to 0.70) and the cumulative rate of noninvasive breast cancer was reduced from 15.8 per 1000 women in the placebo group to 10.2 per 1000 women in the tamoxifen group (RR = 0.63, 95% CI = 0.45 to 0.89). These reductions were similar to those seen in the initial report. Tamoxifen led to a 32% reduction in osteoporotic fractures (RR = 0.68, 95% CI = 0.51 to 0.92). Relative risks of stroke, deep-vein thrombosis, and cataracts (which increased with tamoxifen) and of ischemic heart disease and death (which were not changed with tamoxifen) were also similar to those initially reported. Risks of pulmonary embolism were approximately 11% lower than in the original report, and risks of endometrial cancer were about 29% higher, but these differences were not statistically significant. The net benefit achieved with tamoxifen varied according to age, race, and level of breast cancer risk. CONCLUSIONS: Despite the potential bias caused by the unblinding of the P-1 trial, the magnitudes of all beneficial and undesirable treatment effects of tamoxifen were similar to those initially reported, with notable reductions in breast cancer and increased risks of thromboembolic events and endometrial cancer. Readily identifiable subsets of individuals comprising 2.5 million women could derive a net benefit from the drug.