Preventive Tamoxifen Dangerous, Unnecessary, says Physician

As the saying goes, "An ounce of prevention is worth a pound of cure." There's a caveat implicit in that old saw, of course. In preventive medicine, the last thing anyone wants is for the "ounce of prevention" to be as bad as the condition they're trying to avoid.

Several years ago, in an effort to head off breast cancer in women at very high risk for the disease, a few surgeons convinced healthy women to undergo complete double mastectomies. This practice, which amounted to medical mutilation (and which was not based on any clinical evidence that cancer might not appear in tissues other than the breast), has fallen out of favor. Now another preventive strategy has emerged, the use of tamoxifen citrate as preventive chemotherapy.

Today, September 2, the U.S. Food and Drug Administration's Advisory Committee on Oncologic Drugs will review Zeneca Pharmaceutical's New Drug Application (NDA) for tamoxifen citrate (Nolvadex), "for the prevention of breast cancer in (healthy) women at high risk." Zeneca's claims are based on a National Cancer Institute preliminary, short-term study (and no peer-reviewed publication), in which the drug was given to 13,000 healthy, high-risk women.

The trial was terminated prematurely in view of the reduction in the incidence of breast cancer in all tamoxifen treated age groups. However, serious and sometimes fatal complications, including uterine cancer and pulmonary embolism, were seen in 2.2% of postmenopausal women, among whom the incidence of breast cancer was reduced by 1.7%. Zeneca's data shows that the incidence of breast cancer was reduced in all women in the study by 45%.

However, according to Samuel S. Epstein, Professor of Environmental Medicine at the University of Illinois School of Public Health (Chicago, IL), the brevity of the trial prevented recognition of other delayed serious health risks. Of particular concern to Epstein is tamoxifen's potent carcinogenicity. Rats given doses equivalent to those used in the trial have developed liver cancer. Disturbingly, women in the trial were not informed of the clear evidence of these risks. The absence of reported liver cancer in women treated with tamoxifen for breast cancer is hardly reassuring, as relatively few women have been treated for over 5 years and followed up for a further 20 years (before which the development of liver cancer would be most unlikely). Additionally, Epstein questions whether tamoxifen actually reduces the incidence of breast cancer or merely delays its onset by treating small, undetected tumors. Two articles published on July 11, 1998 in The Lancet reported no evidence of breast cancer prevention by tamoxifen in two major European trials.

In an August 17 written statement, which will be read into the record at the September 2 Advisory Committee Hearing, Epstein concluded:

NCI's preliminary April 6 report on the prevention of breast cancer by tamoxifen has still not yet been finalized and published in a scientific journal. The Advisory Committee should also consider the propriety of Zeneca's NDA as it is based, in part, on data which have not been made fully available to the public although the underlying (NCI) research was funded by the public. Furthermore, the claimed evidence for chemoprevention has been discredited by two subsequent scientific publications. Of as great concern is the well documented evidence of short term life-threatening complications, and also risks of delayed fatal complications, evidence for which has been trivialized and suppressed by NCI. Based on these scientific and ethical considerations, the Advisory Committee is urged to deny approval of Zeneca's NDA.

Strong words on an emotionally charged issue.

Chemoprevention is a tricky business. As with all chemotherapies, one must weigh the benefits vs. the risks. Tamoxifen clearly offers extended life and improved quality of life for women with life-threatening and early-stage breast cancer. These women, unfortunately, are far more concerned with their health in five or twenty months than five or twenty years.

Although only bits and pieces of its data were made public, Zeneca is obviously onto something: the European studies aside, there is little doubt that tamoxifen reduces breast cancer in women at risk. The question is, does this risk reduction justify the chronic administration of chemotherapeutic agents to healthy women? And, by analogy, might other chemotherapeutic drugs be administered prophylactically to individuals predisposed to other types of cancer? No one is in a position to say without decades-long clinical trials.

Long before such trials are planned, much less completed, genetic testing may answer the two critical questions:

• Who is susceptible to (what types of) cancer?
• Who will benefit from what drugs?

When we have that capability, which is no more than five or ten years away, we may very well be able to identify patients for whom tamoxifen (or some other drug) would prevent breast cancers close to 100% of the time. For those women the answer to the question, "to take, or not to take?" will be clear.

Comments? Email me at
adepalma@pharmaceuticalonline.com

Angelo DePalma
Managing Editor, Pharmaceutical Online