Jewish World Review Feb. 24, 2003 / 22 Adar I, 5763

Tamoxifen & Benign Breast Disease

By Robert A. Wascher, M.D., F.A.C.S.

http://www.NewsAndOpinion.com | Tamoxifen has been shown in large studies to effectively reduce the incidence of hormonally responsive breast cancers by nearly 50% in women who are at high risk of developing the disease.

The current issue of the Journal of the National Caner Institute contains a very interesting study that evaluated the impact of tamoxifen on benign breast disease, as well. The overwhelming majority of breast biopsies performed in the United States result in a diagnosis of benign breast lesions.

The authors of this study hypothesized that tamoxifen's ability to block the stimulatory effects of estrogen on the female breast might also reduce the risk of developing benign breast masses.

A total of 13,203 women who had previously participated in a large tamoxifen breast cancer prevention study were included in the current analysis. The researchers evaluated the incidence of biopsies for breast lesions that turned out to be benign in women who received tamoxifen, and in those who received a placebo pill only.

This retrospective study determined that the women who had received tamoxifen had a 28% reduction in the risk of developing non-cancerous breast tumors. The types of benign breast tumors that were favorably influenced by tamoxifen included cysts, fibrocystic disease, and fibroadenomas. Compared with the group receiving a placebo, the tamoxifen group also underwent 29% fewer breast biopsies. This reduction in the risk of benign breast tumors and biopsies occurred primarily in premenopausal women less than 50 years of age.

This study suggests a potential prevention role for tamoxifen in women with a predisposition towards not only malignant breast lesions, but also in at least some women with a high incidence of benign breast lesions that require biopsy to exclude cancer. Some of the benign lesions that appear to be favorably impacted upon by tamoxifen are, in themselves, associated with a slight increase in the risk of developing breast cancer.

These include ductal hyperplasia and metaplasia, as well as fibroadenomas. The potential risks of tamoxifen, however, must be carefully weighed against its benefits. Some of the risks associated with tamoxifen, although quite uncommon, can include such potentially life-threatening complications as stroke, blood clots in the veins, and uterine cancer.

Nonetheless, this study provides an intriguing look at the effects of tamoxifen on the premenopausal breast, and may lead to the development of other anti-estrogen drugs with better safety profiles than tamoxifen. Such drugs are already undergoing early clinical testing, and may have an important role to play in the prevention of both benign and malignant breast disease in high-risk women.

NEW RECOMMENDATION ON DIGITALIS DOSING

Digitalis is one of the oldest medications in continuous use by physicians. Digitalis is derived from the Foxglove plant, and has been prescribed for a variety of maladies since the 18th century. It is still used by contemporary physicians to improve cardiac function in patients with congestive heart failure (CHF), and to regulate abnormally fast heart rates in patients with cardiac arrhythmias.

Although this medication is still frequently prescribed, recent studies have called into question its effectiveness in preventing cardiac complications and death. Now, a new study in the current issue of the Journal of the American Medical Association takes a look at clinical outcomes in patients associated with various blood levels of this medication.

A total of 3,782 male patients with CHF were treated with varying doses of digitalis, and an additional 2,611 patients with CHF took placebo pills. The group taking digitalis was further divided into 3 subgroups, based upon the levels of digitalis in their blood (0.5-0.8 ng/ml, 0.9-1.1 ng/ml, 1.2 ng/ml or greater).

The authors then looked at the incidence of death among all of the study volunteers.

The study determined that patients with the lowest blood levels of digitalis (0.5-0.8 ng/ml) also had the lowest death rate among all of the patient groups in the study, including the placebo group. At the same time, patients with the highest levels of digitalis in their blood (1.2 ng/ml or greater) had the highest mortality rates.

This study suggests that achieving relatively low blood levels of digitalis appear to provide the greatest protection against premature death in patients with CHF, while increasing blood levels of digitalis are associated with a greater risk of dying.

The authors, therefore, suggest that patients (and men in particular) taking digitalis should have their doses optimized to obtain blood levels in the range of 0.5 to 0.8 ng/ml. If you are currently taking digitalis for CHF, you should consult with your physician prior to making any changes in your daily digitalis dose. Under no circumstances should you alter your digitalis intake without the assistance and advice of your physician.

CREUTZFELDT-JAKOB DISEASE & THE NOSE

Creutzfeldt-Jakob Disease (CJD) is a member of the family of diseases caused by protein particles called prions. The spontaneous variety of CJD is extremely rare, occurring in less than one per million people. While 10-15% of cases of CJD are thought to be inherited, the remaining cases fall within the "sporadic" category. Sporadic CJD has been eclipsed in recent years by the development of bovine spongiform encephalopathy (BSE), more commonly called "mad cow disease."

These and other related diseases fall within the transmissible spongiform encephalopathy (TSE) category of prion-mediated brain disease, and are characterized by the very gradual onset, often over many years, of progressive dementia and wasting, followed by death.

The exact mechanism whereby spontaneous CJD is transmitted is not clear. While occasional cases are thought to have been passed along to patients receiving transplanted tissue from other patients already infected with CJD, the majority of cases arise by unknown mechanisms. An intriguing study in the current issue of the New England Journal of Medicine builds upon previous studies that have shown the presence of the CJD-causing prions in the olfactory lobes of patients who have died of this illness.

The authors performed autopsies on 9 patients with documented sporadic CJD, and evaluated the brain (including the olfactory lobes), the thin plate of bone (the cribriform plate) through which the olfactory nerves travel from the nasal cavity to the olfactory lobes, the lining of the nose (mucosa) containing the receptors for smell (olfaction), and the lining of the trachea and lungs.

All of these tissues were analyzed for the presence of the CJD prion, in an effort to identify possible sites of initial infection by the deadly protein particles.

In all 9 patients, the CJD prions were shown to be present in the olfactory receptor cells lining the upper nasal cavity, the olfactory nerves leading from the nasal cavity to the olfactory lobes of the brain, and in the olfactory lobes as well. However, the lining of the respiratory tract did not contain any of the prions. As a control, identical autopsy studies were performed on 11 deceased people without a history of CJD.

No CJD prions were identified in any of the tissues in these control patients. The implications of these findings are very significant, for they suggest that sporadic CJD may find entry into the brain via the nasal cavity, but not through the respiratory tract. This study also suggests that patients suspected of having sporadic CJD might be able to undergo biopsy of the nasal lining rather than the current standard of undergoing a biopsy of their brain through holes drilled into the skull.

While the precise mechanism whereby sporadic CJD is introduced into a new host is not answered by this study, it strongly suggests that the route of infection is likely to be via the nasal cavity, with subsequent spread of prions throughout the brain.

RADIOLOGIST EXPERIENCE & ACCURACY OF MAMMOGRAM INTERPRETATION

In the surgical world, there is ample evidence that patients undergoing complex surgical procedures tend to have a better outcome in the hands of surgeons with the most experience in performing such operations. Thus, it would seem logical that the interpretation of mammograms would be more accurate among older and more experienced radiologists. According to a new study in the Journal of the National Cancer Institute, this may not be so.

Previous studies have shown that radiologists who, in general, review high volumes of mammograms tend to identify subtle abnormalities more frequently than low-volume radiologists. However, these studies have been limited in their scope, and in the numbers of radiologists evaluated. In the current study, 110 radiologists around the United States were asked to review the mammograms of 148 randomly selected women.

After controlling for potentially confounding variables, the study determined that neither the current volume of mammograms reviewed nor the radiologists' number of years of experience in reading mammograms were statistically associated with accuracy.

Instead, the study found that radiologists who most recently completed their training produced the most accurate readings! Additional factors that correlated with accurate mammogram results included the designation of a radiographic center as a comprehensive breast imaging center (and, in particular, the frequent performance of mammograms and mammogram-guided needle biopsies at the facility), and centers where each mammogram was reviewed by at least two radiologists.

While the findings of this study have met with understandable disbelief among many experts, it is not surprising that busy comprehensive breast diagnostic centers tend to do a better job of accurately interpreting mammograms than smaller multi-specialty radiology centers. As for the finding that recently trained radiologists may have an edge over their older colleagues, much speculation abounds as to the possible reasons behind this finding.

In an accompanying editorial, women are advised to obtain their annual mammograms at a single facility so as to allow for comparisons between current and previous mammogram films. It is also suggested that women who are still menstruating undergo mammography during the first half of their menstrual cycle, when the breast tissue is least dense.

REGULAR REST BREAKS & THE RISK OF INDUSTRIAL ACCIDENTS

A new study in the journal Lancet confirms what common sense should already dictate: accidents within industrial work environments can be reduced by scheduling all workers for brief regular rest breaks. The authors of this study reviewed accident records from a large engineering company over a period of 3 years.

By studying 2-hour blocks of work periods, the study identified a two-fold increase in the risk of industrial accidents in the last half hour of the 2-hour shift when compared to the first half hour. At the same time, there was no apparent difference in the incidence of accidents among the three 2-hour work shifts present in each workday.

The implications of these findings are that periods of continuous work for as little as 2 hours are associated with a significant increase in the risk of industrial accidents. When brief regular breaks are scheduled at 2-hour intervals, no further increase in accidents rates are seen during the course of the workday in industrial work environments.

MORE DATA ON THE INCIDENCE OF GI SIDE EFFECTS WITH SELECTIVE COX-2 NSAIDs

A recently published study called into question the belief that the COX-2-specific nonsteroidal anti-inflammatory drugs (NSAIDs) (e.g., Vioxx and Celebrex) are safer for the GI tract than the non-specific anti-inflammatory drugs (e.g., ibuprofen, Motrin, Naprosyn, Indocin, aspirin, etc.). In the journal Gastroenterology, this question is evaluated in a large-scale prospective study.

A total of 8,076 patients with rheumatoid arthritis were randomly assigned to take either Vioxx (50 mg per day) or Naprosyn (500 mg twice a day) for at least 1 year. The rate of serious GI events was then assessed, including GI bleeding, perforation of the stomach or intestine, obstruction of the stomach, or diverticulitis (inflammation of the colon).

The study found that the rate of serious GI events was 54% lower among patients taking the selective COX-2 inhibitor than was seen in the group taking Naprosyn. This rather large and prospective study appears to rather convincingly substantiate the premise that COX-2-selective NSAIDs are associated with a reduced incidence of upper and lower GI tract complications when compared to their non-selective cousins.

JWR contributor Dr. Robert A. Wascher is a senior research fellow in molecular & surgical oncology at the John Wayne Cancer Institute in Santa Monica, CA. Comment by clicking here.