In several previous entries I have discussed the issue of risks vs. benefits regarding this or that medical therapy, generally use of some medication where sufficient data have not been obtained to determine long-term risks. The other day, I was going through my pile of New England Journal of Medicine (NEJM) issues from January-June 2011, working on a continuing education program offered by the journal (it “forces” me to actually read each of the issues which come weekly), I spied a short article that I had not noticed previously, entitled ,”Long-term effects of in utero exposures- the DES story,” written by Annekathryn Goodman, John Schorge, and Michael Greene, all professors at Harvard Medical School in Boston and serves as an important reminder about the importance of assessing “risk vs. benefit” for medical therapies.
The Diethylstilbesterol (DES) story
DES is a synthetic nonsteroidal estrogen that was developed in the late 1930s. It was widely used as a supplement to cattle feed (to fatten them up) and in humans as estrogen replacement therapy and for treatment of prostate and breast cancers. In the late 1940s, one study showed that DES could prevent miscarriage if given early in pregnancy. Other studies had shown no benefit, yet DES was widely used for quite a long time despite very convincing data that accumulated showing no benefit with respect to miscarriages. Eventually, doctors got the message and use of DES faded away. Then, in 1971, the NEJM published results from a very scary study performed by Herbst et al., showing an association between DES use during pregnancy and development of a rare vaginal cancer (clear-cell adenocarcinoma) many years later in female offspring of these mothers. I still remember when the news hit. I was a pediatric resident physician and doing my pediatric endocrinology rotation. Even back then I was reading the NEJM regularly (I have been a regular subscriber since 1965). I remember the many discussions we all had about the data. As it turned out, by the early 1990s, 431 cases of the rare cancer had been identified in young women exposed to DES in utero. The median age of cancer diagnosis was 19 years. We now know that the mechanism for the development of the cancer was probably drug-induced abnormal development of the Mullerian ducts (these ducts develop into the uterus, fallopian tubes, and a bit of the vagina). It was all a nightmare for the mothers, the young women, and the physicians involved in their care.
What did we learn from the DES catastrophe?
I am not certain what the collective “we” learned from the DES story. I do know what I learned- that all medical treatments, be they procedures or medications, have risks and benefits. Many times we know what the potential benefits are for a given treatment, but do not know what the risks might be. Thus, it is always important to consider and to weight unknown risks vs. the potential benefits. This is no easy task but it needs to be done and physicians who do not do this, do a disservice to their patients. The potential benefit of a given treatment must be compelling enough to counter the unknown risks of the therapy, whatever the therapy might be. We (here I mean the collective “we”), keep learning this lesson over and over. Just this week, I read an article (and two accompanying editorials) in the NEJM entitled ” Stenting versus aggressive medical therapy for intracranial arterial stenosis.” In summary, the study showed that stenting was associated with many more deaths than the medical therapy. As it turned out, the stenting procedure was approved by the FDA in 2005 after a small non-randomized study showed benefit from the stenting vs. medical therapy. Now the “experts” are moaning and groaning about the fact that FDA approval for the stenting procedure was probably inappropriate given the very limited data and that a large randomized trial should have been performed, which as it turns out was the substance of the current NEJM article. Then there is the story about the “metal-on-metal” hip replacement devices that is turning out to be another medical therapy catastrophe (see “Medical Devices-balancing regulation and innovation, ” written by Curfman GD and Redberg RF in this week’s NEJM). I could go on and on. We as caregivers all need to go back and review the DES story and understand why we need to learn as much as possible about risks and benefits of any given therapy/device before we “jump in.” Obviously, if a patient faces certain death and a new therapy comes along, it would not be appropriate to “sit on one’s hands.” But, few new medical treatments meet that urgency standard. Pressures from device manufacturers and pharmaceutical companies and the researchers who either developed or tested the treatments, should not trump the need for careful unbiased assessment of the risks and benefits of the proposed treatment.
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