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Tamoxifen: A Brief overview. It is now almost three decades since Tamoxifen was first proven in a clinical trial to provide a survival benefit to patients with early breast cancer. This trial was published by Michael Baum in the Lancet in 1983 (Lancet II) (8347): 450. The study showed an improved survival amongst patients treated with adjuvant Tamoxifen after mastectomy for early breast cancer. Prior to that Tamoxifen has been available for the treatment of advanced “breast cancer” since 1973. Tamoxifen is an antagonist of the estrogen receptor in breast tissue via its active metabolite, Hydroxy Tamoxifen. In other tissues such as the endometrium and bone, it behaves as an agonist, and hence Tamoxifen may be regarded as a mixed antagonist/agonist. Tamoxifen’s tissue selective action directly lead to the formulation of the concept of selective estrogen receptor modulators (SERMs). (Perez et-al Mayo Clinic Proceedings Volume 75(8) page 821, 2000). In the late 1950's, pharmaceutical companies were actively researching a newly discovered class of anti-estrogen compounds in the hope of developing a “morning after” contraceptive pill. Arthur L Walpole was a reproductive endocrinologist who lead such a team at Alderley Park Research Laboratories of ICI pharmaceuticals. It was there in 1966 that Dora Richardson first synthesised Tamoxifen, then known as ICI-46,474. The compound was never shown to have value in human contraception, and for some years there was no further research, owing to patent rights being denied in the US, and the absence of any approval for the marketing of this agent. A link between estrogen and breast cancer had been known for many years, and the first clinical study took place at the Christie Hospital in 1971 showing a convincing effect of Tamoxifen in advanced breast cancer. A proven benefit was shown in a further study carried out at the Queen Elizabeth Hospital Birmingham, reported by Harold Ward in 1973, and finally Tamoxifen became available as a proven treatment for late stage breast cancer, in 1973. The results of the clinical trial performed by Professor Michael Baum showing the improved survival in the adjuvant setting in early breast cancer was published a decade later in 1983, and this was confirmed in further studies, most notable being the meta-analysis of the Oxford based early breast cancer trialists’ collaboration group showing that Tamoxifen saved lives in early breast cancer, published in the Lancet 1998. Tamoxifen is a non-steroidal agent with potent anti-estrogenic properties which compete with estrogen for binding sites in breasts and other tissues. Tamoxifen causes cells to remain in the G0 and G1 phases of the cell cycle. Because it prevents malignant and pre-cancer cells from dividing but does not cause cell death, Tamoxifen is regarded as cytostatic rather than cytocidal. Tamoxifen is currently used for the treatment of both early and advanced estrogen receptor positive breast cancer patients in both pre and post menopausal women. Additionally, it is the most common hormone treatment for male breast cancer. It has also been approved by the FDA for the prevention of breast cancer in women at high risk for developing the disease. It has also been approved as prophylaxis, for the reduction of contralateral breast cancer.
Comparative studies have been performed in the last 15 years, assessing the value of alternative anti-estrogen therapies. In 2006 the large STAR clinical study concluded that Raloxifene is equally effective in the prophylaxis against breast cancer, reducing the incidence of breast cancer to the same degree as Tamoxifen. Raloxifene does not carry the risk of neither thrombotic episodes, nor uterine cancer, as seen with Tamoxifen. Raloxifene has no proven role in the adjuvant setting in the management of breast cancer. Recent studies have shown without doubt, that aromatase inhibitors have superceded Tamoxifen in the management of breast cancer. This pertains to the neoadjuvant, advanced, and early breast cancer settings. (ATAC trial, ABCSG trial, ARNO trial and the BIG1-98 trial). There is some evidence to support the initial treatment with Tamoxifen for a 2-3 year period followed by further treatment with an aromatase inhibitor (Intergroup Exemestane Study (IES)). AI’s are unsuitable in the premenopausal patient, owing to the mechanism of action of the AI, and hence Tamoxifen remains the gold standard for the treatment of ER positive premenopausal patients requiring anti estrogen therapy in the adjuvant setting. In post menopausal ER positive patients, an AI would be the treatment of choice, Tamoxifen being required in patients who are unsuitable for an AI, particularly on the basis of significant osteoporosis. The side effects of Tamoxifen relate to the increased risk of endometrial cancer and of cardiovascular and thrombotic events. The risk of endometrial cancer may be doubled or quadrupled, once treatment is continued beyond five years. Hence Tamoxifen is typically not prescribed beyond five years. Tamoxifen is regarded as a partial agonist on the endometrial mucosa, and its link to endometrial cancer is now beyond question. The American Cancer Society lists Tamoxifen as a known carcinogen. Tamoxifen carries the increased risk of thromboembolism, particularly enhanced following major surgery or periods of immobility. There are numerous other potential side effects of Tamoxifen, the more important ones being enhanced menopausal symptoms, possible memory loss, reduced libido, and fatty change of the liver. A beneficial side effect of Tamoxifen is the prevention of bone loss, by acting as an estrogen agonist, thereby inhibiting osteoclastic action and hence osteoporosis. The ATAC ten year trial data is now available, assessing and comparing Arimidex alone (an AI), Tamoxifen alone or in combination with Arimidex. The ten year data was made available at the 12th Milan Breast Cancer Conference in June 2010. The long term superior efficacy of Anastrozole (Arimidex) over Tamoxifen has been proven. Also, the treatment benefits of Anastrozole have now been shown to extend at least five years beyond treatment cessation. Whereas the aromatase inhibitor group of drugs remain the gold standard for the treatment of ER positive early breast cancer patients in the adjuvant setting, Tamoxifen has a definite place in our armamentarium against this disease, and has a proven survival benefit in the management of early breast cancer.
Note - As with all medical issues the best advice is to be seen by medical professionals. Skin abrasions from asphalt, better know to cyclists as Road Rash, can be very serious if not taken care of promptly and properly. When treated properly, Road Rash can heal very fast, cutting very little into your training. This article will help you in the care for these injuries. First, you will ne
The gastro-intestinal tract in systemic sclerosis Professor László Czirják Department of Immunology and Rheumatology, University of Pécs, Pécs, Hungary Systemic sclerosis (SSc) is a disease abnormality affecting the vessels and the connective tissue. Besides the skin, joints, muscles, several internal organs can also be involved in SSc including the gastrointestinal tract (GI).