Letrozole for Postmenopausal Women with Breast Cancer

Pharmacology Watch

Letrozole (Femara) is a potent aromatase inhibitor that is used to treat women with metastatic breast cancer and, in a neoadjuvant role, for women who have failed tamoxifen. Aromatase inhibitors exert their effect by blocking the conversion of androgens to estrogens and reducing estrogen levels in tissue and plasma. Recently, letrozole was compared with tamoxifen for adjuvant therapy in postmenopausal women with steroid-hormone-receptor-positive breast cancer.

A total of 8010 women were randomized to 5 years of letrozole (4003) or tamoxifen (4007). After a median follow-up of 25.8 months, there were 351 events (local or distant recurrence) in the letrozole group and 428 events in the tamoxifen group, with 5-year disease-free survival estimates of 84% and 81.4%, respectively. Adverse effects of the drugs were different with tamoxifen, resulting in a higher rate of thromboembolism, endometrial cancer, and vaginal bleeding, while letrozole was associated with a higher incidence of skeletal and cardiac events and hypercholesterolemia.

The authors suggest that in women with endocrine-responsive breast cancer, adjuvant treatment with letrozole, as compared with tamoxifen, reduced the risk of recurrent disease (Thurlimann B, et al. A Comparison of Letrozole and Tamoxifen in Postmenopausal Women with Early Breast Cancer. N Engl J Med. 2005;353:2747-2757). In an accompanying editorial Sandra Swain, MD, from the National Cancer Institute, states that "all the evidence points to aromatase inhibitors as critically important for improving the outcome among postmenopausal women with breast cancer who have positive or negative lymph nodes and who are at a substantial risk for recurrent disease." (Swain SM, et al. Aromatase Inhibitors—A Triumph of Translational Oncology. N Engl J Med. 2005;353:2807-2809). Based on this study, the FDA has recently approved letrozole for adjuvant treatment (immediately after surgery) in postmenopausal women with hormone sense of breast cancer.

Do Antidepressants Increase Risk of Suicide?

An article in the January issue of the American Journal of Psychiatry asks "Is the FDA Warning About Antidepressants Wrong?" Researchers from Group Health Cooperative in the Pacific Northwest used population-based data to evaluate the risk of suicide death and serious suicide attempt in relation to the initiation of antidepressant treatment.

Computerized health plan records for over 65,000 patients with over 82,000 episodes of antidepressant treatment between 1992 and 2003 were reviewed. In the 6 months after initiation of antidepressant treatment, the risk of suicide was found be no higher than at any other time during treatment. The risk of suicide attempt was highest in the month before starting treatment, and declined progressively after starting medication. When newer drugs were compared to older drugs, an increase in suicidality was only seen with the older drugs.

The authors conclude that the risk of suicide during acute-phase antidepressant treatment is approximately 1 in 3000 treatment episodes, and the risk of serious suicide attempt is approximately one in 1000. Available data do not indicate significant increase in risk of suicide or serious suicide attempt after starting treatment with newer antidepressant drugs (Simon GE, et al. Suicide Risk During Antidepressant Treatment. Am J Psychiatry. 2006;163:41-47, available free at ajp.psychiatryonline.org). The study calls into question the March 2004 FDA public health advisory regarding worsening depression and suicidality in pediatric and adult patients being treated with 10 newer antidepressants (bupropion, citalopram, fluoxetine, fluvoxamine, mirtazapine, nefazodone, paroxetine, sertraline, escitalopram, and venlafaxine).

Can Viagra Improve Heart Function?

Concern still lingers regarding the safety of erectile dysfunction drugs in patients with heart failure. A new study from Australia suggests that sildenafil (Viagra) actually improves heart function in patients with systolic dysfunction. In a randomized, placebo-controlled, double-blind, 2-way crossover study, 20 patients with controlled left ventricular failure and ejection fractions < 35% received sildenafil 50 mg or matching placebo. Cardiac output was determined by Doppler echocardiography, aortic pressure waveform, and aortic and femoral arterial stiffness was also evaluated. With a peak effect at 60 minutes after administration, sildenafil resulted in an increase in cardiac index of 0.37 L/min, decrease in total systemic resistance, decreased aortic and lower limb pulse-wave velocity, and decreased wave reflection (all significant at P < .0001). The authors conclude that sildenafil improved cardiac performance by decreasing LV load, resulting in increased cardiac output and increase in exercise capacity in heart failure patients (Hirata K, et al. Effect of Sildenafil on Cardiac Performance in Patients with Heart Failure. Am J Cardiol. 2005;96:1436-1440).

Can Tamoxifen Increase Your Height?

Tamoxifen may increase height potential in short pubertal periods, according to new study in the journal Pediatrics. The study was a retrospective chart review of 7 boys with a mean age of 15 who took tamoxifen 10-20 mg twice a day for a mean of 26 months. Six of the boys were also receiving growth hormone. Tamoxifen significantly decreased the rate of skeletal maturation and improved predicted adult height without negative effects on sexual maturation. Skeletal maturation was determined by review of bone radiographs by independent endocrinologists. The authors state that "additional evaluation of this therapy is now required to determine if the increase in predicted adult height results in a clinically significant increase in final adult height." (Kreher NC, et al. The Use of Tamoxifen to Improve Height Potential in Short Pubertal Boys. Pediatrics. 2005;116:1513-1515).

A Dramatic Increase of Clostridium difficile

Clostridium difficile is increasing in frequency and severity in both hospital and community settings. Widespread use of acid suppressing proton pump inhibitors (PPIs) and H2 receptor agonists (H2RAs) may be a contributing factor, according to new study. Two population-based, case-control studies from England reviewed all 1672 cases of C. difficile reported between 1994 and 2004, while a second study looked at cases defined as community acquired. All cases were matched 10 controls. The incidence of C. difficile increased dramatically between 1994 and 2004. The adjusted rate ratio of C. difficile associated disease with current use of PPIs was 2.9 (95% CI, 2.4-3.4) and, with H2RAs, the rate ratio was 2.0 (95% CI, 1.6-2.7). The authors conclude that the use of acid-suppressive therapy is associated with an increase risk of community-acquired C. difficile. Parenthetically, they also found an increased risk associated with use of nonsteroidal anti-inflammatory drugs (JAMA. 2005;294:2943-3048).

FDA Actions

The FDA has approved Bristol-Myers Squibb's abatacept (Orencia) for the treatment of rheumatoid arthritis. The drug, which is produced by recombinant DNA technology, is a T cell costimulation modulator. It is approved for patients with moderately-to-severely active rheumatoid arthritis who had an inadequate response to one or more DMARDs, including TNF antagonists. It may be used as monotherapy or with other non-TNF inhibitor DMARD. Abatacept is administered as a 30-minute IV infusion at 0, 2, and 4 weeks, then every 4 weeks thereafter.

The FDA and GlaxoSmithKline have issued a "Dear Doctor" letter regarding rare reports of macular edema in patients receiving rosiglitazone (Avandia). The majority of the cases involved concurrent peripheral edema and, in the majority of cases, macular edema improved with discontinuation of the drug. Macular edema presents as blurred or distorted vision, decrease color sensitivity, and decreased dark adaptation.

This supplement was written by William T. Elliott, MD, FACP, Chair, Formulary Committee, Kaiser Permanente, California Division; Assistant Clinical Professor of Medicine, University of California-San Francisco. In order to reveal any potential bias in this publication, we disclose that Dr. Elliott reports no consultant, stockholder, speaker’s bureau, research, or other financial relationships with companies having ties to this field of study. Questions and comments, call: (404) 262-5416. E-mail: leslie.hamlin@thomson.com.