Perhaps the greatest drug ever developed for the treatment of cancer is tamoxifen. Since it was introduced about 30 years ago, it has probably saved hundreds of thousands of lives. Its main use has been in the adjuvant setting to prevent recurrence. Early on it was used to treat cancer that had become widespread, but now it is used less because most women have had the drug before the disease spread; in these instances it didn’t prevent the spread.
It has been known for decades that breast cancer in many women was sensitive to hormone treatment. Removing the ovaries in younger women could cause the cancer to melt away. Likewise, high doses of estrogen could produce the same effect in older women. Eventually tamoxifen was synthesized. This is a chemical that looks like estrogen and interacts with a molecule in the breast cancer cell called the estrogen receptor. About two-thirds of breast cancers have estrogen receptors and can be treated with tamoxifen.
But tamoxifen has side effects. The major ones are that it causes women to have a higher chance of developing blood clots and also cancer of the uterus. Still these are minor problems compared to its extraordinary success rate. But they are problems and when a substitute for tamoxifen came along, it quickly became the drug of choice.
Actually there are several new drugs, all called aromatase inhibitors. They only work in postmenopausal women because they block the production of those women’s normal but small (about 10 percent of premenopausal women) supply of estrogen. The drugs won’t block estrogen production from the ovaries, so are ineffective in younger women.
Many studies showed they might be even more effective than tamoxifen. Yet, they too have side effects. Without that small amount of estrogen, women are at higher risk for osteoporosis and bone fractures. Tamoxifen actually strengthens bones. Women on these drugs also have a greater risk of heart attacks. And, although not a danger, many women will experience joint pain like a friend of mine who had to stop the drug. Finally, although head to head studies of tamoxifen and aromatase inhibitors showed that the aromatase inhibitors were more likely to slow the cancer down, they did not save more lives than tamoxifen.
So at the end of the day there is not much to choose between these two drugs. They each have their problems (by the way, these problems except for the joint pain are not very common) but are both equally effective at saving women’s lives. So what is a woman to do?
There may be an answer. This month (September 7), researchers published an article in the Journal of the National Cancer Institute that compared all the head to head studies on these two drugs that they thought worthwhile. After describing all the problems I mentioned, they concluded that the best approach and the one that showed the most lives saved was to use both drugs. They recommend starting with tamoxifen for two or three years and then switching to aromatase inhibitors for two or three years.
More lives saved and fewer side effects. As the editorial writers in this issue said, “don’t ditch the switch”. This may be the best approach.
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4 comments:
Dr. Kattlove.
In your day, did they know much about the chemosensitizing effect of tamoxifen? Tamoxifen acts as an antagonist in breast and conversely an agonist in uterus. Agonist (potentiating) effects at high doses.
In cell function analysis, high-dose tamoxifen has been turning up with very nice responses. It turns up synergistic (cooperative) in brain tumors, lung cancer, ovarian cancer and the like.
Navelbine is often potentiated by high-dose tamoxifen on in vitro testing. At concentrations of 2.5 micromolar or greater significantly inhibits the P-glycoprotein (gatekeeper in the blood-brain barrier) multidrug resistant membrane pump, as well as inhibiting protein kinase C (preventing the increase in vascular resistance).
Is this something that has been known only in the last twenty years?
We knew about its agonist effect in the uterus, but no about any chemosensitizing effect. Navelbine was introduced after I left practice. Of course, on ust be careful about chemosensitization because in addition to amplifying the beneficial effects, this can increase side effects. One example is adriamycin and radiation therapy.
A clinician friend involved with cell function analysis, has studied high-dose tamoxifen with a great many drugs. High-dose tamoxifen putatively inhibits p-glycoprotein and/or protein kinase c. Gefitinib putatively inhibits anti-apoptotic pathways. Both of these agents potentiate vinorelbine more than they have been found to potentiate any other drug. Report outs from assays have shown synergy between gefintinib, tamoxifen, vinorelbine, a very active regimen. There is an old JNCI paper by Trump et al from Duke, with vinblastine + high-dose tamoxifen, in which much higher doses of high-dose tamoxifen were used, with modest toxicity.
Around the globe, cancer research is hitting new milestones in earlier detections of several types of cancers including those of the lung tissues. New tests performed such as developing advances in cat scans and chest x-rays are improving early detection. Some clinical studies are finding even better more pronounced results in studying the sputum, or mucus of the lung. This test can find cancer cell signatures not yet visible on other scans increasing ones survival and over all health maintenance in fighting early stage cancers. Hospitals for Lung cancer in Germany
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