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Patients with early-stage hormone-receptor-positive breast cancer may benefit from 10 years of adjuvant treatment with an aromatase inhibitor, according to a new study.

Researchers performed a phase 3, double-blind, placebo-controlled trial in patients treated for early hormone-receptor-positive breast cancer to determine whether extended therapy with an aromatase inhibitor had an effect on disease-free survival. The current standard of care is 5 years of aromatase inhibitor monotherapy up front or after tamoxifen therapy. Study results were published online June 5 by the New England Journal of Medicine.

A total of 1,918 women who had already received 4.5 to 6 years of adjuvant therapy with an aromatase inhibitor, in most cases preceded by tamoxifen, were enrolled in the study. Up to 2 years after completing aromatase inhibitor treatment, patients were randomly assigned to receive 2.5 mg of letrozole or placebo orally once daily for an additional 5 years. Nine hundred fifty-nine patients were assigned to each group. The median age of included patients was 65.1 years. Adherence to the study regimen was 62.5% in the letrozole group and 62.3% in the placebo group.

During a median follow-up of 6.53 years, 67 women in the letrozole group and 98 patients in the placebo group experienced disease recurrence or contralateral breast cancer, and 100 patients in each group died. The 5-year rate of disease-free survival was 95% (95% CI, 93% to 96%) with letrozole and 91% (95% CI, 89% to 93%) with placebo (hazard ratio for recurrence or contralateral disease, 0.66), while the 5-year rate of overall survival was 93% (95% CI, 92% to 95%) and 94% (95% CI, 92% to 95%), respectively (hazard ratio, 0.97). Annual rate of contralateral breast cancer was 0.21% (95% CI, 0.32% to 0.67%) in the letrozole group and 0.49% (95% CI, 0.32% to 0.67%) in the placebo group (hazard ratio, 0.42).

No significant between-group differences in quality of life were noted, but patients in the letrozole group had a higher rate of bone-related adverse effects (i.e., bone pain, bone fractures, and new-onset osteoporosis). Overall, 5.4% of patients in the letrozole group and 3.7% in the placebo group discontinued treatment because of toxic effects of the study drug.

The authors noted that their data on adherence may have limited validity because they relied on patient-self report. However, they concluded that based on their results, adjuvant therapy with an aromatase inhibitor for 5 years after initial treatment is "safe and beneficial" for postmenopausal patients with hormone-receptor-positive early-stage breast cancer. The authors wrote that although hazard ratios for disease progression and contralateral disease were similar with different durations of exposure to tamoxifen and they observed no interaction effects between the study regimen and previous tamoxifen exposure, "it is likely that the benefits of treatment, toxic effects, and quality of life differ among these groups."

They concluded that the decision about prolonged therapy should be based "largely on the extent of its effect on [the patient] in terms of toxic effects and quality of life, the extent to which bone mineral density is maintained, as indicated by sequential scans, and the patient's individual risk of disease recurrence."

The authors of an accompanying editorial wrote, "The reduction in contralateral breast cancers and the favorable safety profile seen with letrozole ... provide support for the use of aromatase inhibitors for chemoprevention in clinical practice." They noted that the lack of effect of extended therapy on survival is to be expected because most of the patients in the study were randomly assigned to treatment about 10 years after their initial diagnosis and were past the peak recurrence risk.

"In any event, avoiding a new diagnosis of invasive breast cancer is a benefit in itself," the editorialists wrote. They noted, however, that clinicians and breast cancer patients should consider the absence of a survival effect as they weigh the risks and benefits of long-term adjuvant therapy.

Lisa M. Schwartz, MD, MS; Steven Woloshin, MD, MS; Eugene Zheng, BA; Tony Tse, PhD; and Deborah A. Zarin, MD

Background: Pharmaceutical companies and other trial sponsors must submit certain trial results to ClinicalTrials.gov. The validity of these results is unclear.

Purpose: To validate results posted on ClinicalTrials.gov against publicly available U.S. Food and Drug Administration (FDA) reviews on Drugs@FDA.

Data Sources: ClinicalTrials.gov (registry and results database) and Drugs@FDA (medical and statistical reviews).

Study Selection: 100 parallel-group, randomized trials for new drug approvals (January 2013 to July 2014) with results posted on ClinicalTrials.gov (15 March 2015).

Data Extraction: 2 assessors extracted, and another verified, the trial design, primary and secondary outcomes, adverse events, and deaths.

Results: Most trials were phase 3 (90%), double-blind (92%), and placebo-controlled (73%) and involved 32 drugs from 24 companies. Of 137 primary outcomes identified from ClinicalTrials.gov, 134 (98%) had corresponding data at Drugs@FDA, 130 (95%) had concordant definitions, and 107 (78%) had concordant results. Most differences were nominal (that is, relative difference <10%). Primary outcome results in 14 trials could not be validated. Of 1927 secondary outcomes from ClinicalTrials.gov, Drugs@FDA mentioned 1061 (55%) and included results data for 367 (19%). Of 96 trials with 1 or more serious adverse events in either source, 14 could be compared and 7 had discordant numbers of persons experiencing the adverse events. Of 62 trials with 1 or more deaths in either source, 25 could be compared and 17 were discordant.

Limitation: Unknown generalizability to uncontrolled or crossover trial results.

Conclusion: Primary outcome definitions and results were largely concordant between ClinicalTrials.gov and Drugs@FDA. Half the secondary outcomes, as well as serious events and deaths, could not be validated because Drugs@FDA includes only “key outcomes” for regulatory decision making and frequently includes only adverse event results aggregated across multiple trials.

Primary Funding Source: National Library of Medicine.

Mark S. Lachs, MD, MPH; Jeanne A. Teresi, EdD, PhD; Mildred Ramirez, PhD; Kimberly van Haitsma, PhD; Stephanie Silver, MPH; Joseph P. Eimicke, MS; Gabriel Boratgis, MPH; Gail Sukha, BA; Jian Kong, MS; Alexandra M. Besas, RN; Maria Reyes Luna, AS; and Karl A. Pillemer, PhD

Background: Resident-to-resident elder mistreatment (R-REM) in nursing homes can cause physical and psychological injury and death, yet its prevalence remains unknown.

Objective: To estimate the prevalence of physical, verbal, and sexual R-REM in nursing home residents and subgroups.

Design: 1-month observational prevalence study.

Setting: 5 urban and 5 suburban New York state nursing homes.

Participants: 2011 residents in 10 facilities randomly selected on the basis of size and location; 83% of facilities and 84% of eligible residents participated.

Measurements: R-REM was identified through resident interviews, staff interviews, shift coupons, observation, chart review, and accident or incident reports.

Results: 407 of 2011 residents experienced at least 1 R-REM event; the total 1-month prevalence was 20.2% (95% CI, 18.1% to 22.5%). The most common forms were verbal (9.1% [CI, 7.7% to 10.8%]), other (such as invasion of privacy or menacing gestures) (5.3% [CI, 4.4% to 6.4%]), physical (5.2% [CI, 4.1% to 6.5%]), and sexual (0.6% [CI, 0.3% to 1.1%]). Several clinical and contextual factors (for example, lower versus severe levels of cognitive impairment, residing on a dementia unit, and higher nurse aide caseload) were associated with higher estimated rates of R-REM.

Limitations: Most facilities were relatively large. All R-REM cases may not have been detected; resident and staff reporting may be subject to recall bias.

Conclusion: R-REM in nursing homes is highly prevalent. Verbal R-REM is most common, but physical mistreatment also occurs frequently. Because R-REM can cause injury or death, strategies are urgently needed to better understand its causes so that prevention strategies can be developed.

Primary Funding Source: National Institute on Aging.

Torsten Dahlén, MD; Gustaf Edgren, MD, PhD; Mats Lambe, MD, PhD; Martin Höglund, MD, PhD; Magnus Björkholm, MD, PhD; Fredrik Sandin, MSc; Anders Själander, MD, PhD; Johan Richter, MD, PhD; Ulla Olsson-Strömberg, MD, PhD; Lotta Ohm, MD, PhD; Magnus Bäck, MD, PhD; Leif Stenke, MD, PhD, on behalf of the Swedish CML Group and the Swedish CML Register Group*

Background: Tyrosine kinase inhibitors (TKIs) have increased survival dramatically for patients with chronic myeloid leukemia (CML), but continuous administration of these drugs may elicit long-term toxicity.

Objective: To investigate the incidence of vascular events in patients with CML treated with first- and second-generation TKIs.

Design: Retrospective cohort study using nationwide population-based registries.

Setting: Sweden.

Patients: All patients diagnosed with chronic-phase CML in Sweden from 2002 to 2012 and treated with a TKI, and 5 age- and sex-matched control individuals per patient.

Measurements: Relative risks, expressed as incidence rate ratios comparing patients with control individuals, were calculated. Events per 1000 person-years were assessed in interdrug comparisons.

Results: 896 patients, 94.4% with documented TKI treatment, were followed for a median of 4.2 years. There were 54 arterial and 20 venous events in the CML cohort, corresponding to relative risks of 1.5 (95% CI, 1.1 to 2.1) and 2.0 (CI, 1.2 to 3.3), respectively. The event rate for myocardial infarction was higher in patients treated with nilotinib or dasatinib (29 and 19 per 1000 person-years, respectively) than in those receiving imatinib (8 per 1000 person-years), although data are limited and the CIs were wide and overlapped. Among 31 patients treated with a TKI who had myocardial infarction, 26 (84%) had at least 1 major cardiac risk factor diagnosed before the event occurred.

Limitations: Patients may have been exposed to multiple TKIs. Data on second- and third-generation TKIs were limited.

Conclusion: An increased risk for arterial and venous vascular events was seen in patients with CML treated with a TKI. Further study is needed to determine whether the risk for myocardial infarction increases with second-generation drugs.

Primary Funding Source: No external funding.