Home Journal Excerpts Tamoxifen Prevention of breast cancer with tamoxifen: preliminary findings from the Italian randomised trial among hysterectomised women.
Prevention of breast cancer with tamoxifen: preliminary findings from the Italian randomised trial among hysterectomised women. PDF Print E-mail
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Saturday, 11 July 1998 00:00
“Background: Tamoxifen is a candidate chemopreventive agent in breast cancer, although the drug may be associated with the development of endometrial cancer. Therefore we did a trial in hysterectomised women of tamoxifen as a chemopreventive.”

“Methods: In October, 1992, we started a double-blind placebo-controlled, randomised trial of tamoxifen in women (mainly in Italy) who did not have breast cancer and who had had a hysterectomy. Women were randomised to receive tamoxifen 20 mg per day or placebo, both orally for 5 years. The original plan was to follow the intervention phase by 5 years' follow-up. In June, 1997, the trialists and the data-monitoring committee decided to end recruitment primarily because of the number of women dropping out of the study. Recruitment ended on July 11, 1997, and the study will continue as planned. The primary endpoints are the occurrence of and deaths from breast cancer. This preliminary interim analysis is based on intention-to-treat.”

“Findings: 5408 women were randomised; participating women have a median follow-up of 46 months for major endpoints. 41 cases of breast cancer occurred so far; there have been no deaths from breast cancer. There is no difference in breast-cancer frequency between the placebo (22 cases) and tamoxifen (19) arms. There is a statistically significant reduction of breast cancer among women receiving tamoxifen who also used hormone-replacement therapy during the trial: among 390 women on such therapy and allocated to placebo, we found eight cases of breast cancer compared with one case among 362 women allocated to tamoxifen. Compared with the placebo group, there was a significantly increased risk of vascular events and hypertriglyceridaemia among women on tamoxifen.”

“Interpretation: Although this preliminary analysis has low power, in this cohort of women at low-to-normal risk of breast cancer, the postulated protective effects of tamoxifen are not yet apparent. Women using hormone-replacement therapy appear to have benefited from use of tamoxifen. There were no deaths from breast cancer recorded in women in the study. It is essential to continue follow-up to quantify the long-term risks and benefits of tamoxifen therapy”

“However, side-effects of Tamoxifen include an increased occurrence of endometrial cancer.”

“In June, 1997, the trialists and the data-monitoring committee decided to end recruitment because of the number of women dropping out of the study and the side-effect profile of tamoxifen.”

“The decision to recruit only hysterctomised women was based on the consideration that tamoxifen could produce an additional risk of endometrial cancer.”

“56 women experienced 64 events of thrombophlebitis, phelbothrombosis, or embolus (or a combination) during the course of this study: 18 women on placebo and 38 on tamoxifen (p=0..0053). 42 events were superficial phlebitis, with nine women having a diagnosis of deep-vein thrombosis, six on tamoxifen and three on placebo.”

“There were 14 documented cerebrovascular ischaemic events: five on placebo and nine on tamoxifen (p=0.27). All five confirmed strokes occurred in the tamoxifen arm. Based on the incidence of stroke in Italy, it was estimated that the number of strokes seen in this study was less than to be expected in a group of women this age. (After the "freezing" of the data set, there was a further stroke and one transient ischaemic attack, both in women on placebo).”

“Hypertriglyceridaemia was not looked for specifically at each follow-up visit, and the study relies on self-reports from patients and physicians and subsequent confirmation from laboratory findings. 17 women in the study had hypertriglyceridaemia: two on placebo and 15 on tamoxifen (p=0.0013). This information almost certainly underestimates the occurrence of hypertriglyceridaemia in women in the study.”

“The principal investigators were concerned about the large numbers of women withdrawing from the study, the unexpected finding with hypertriglyceridaemia, the findings about vascular events, and the number of well women complaining about the side-effects of tamoxifen.”

“The excess of hypertriglyceridaemia seen in women receiving tamoxifen in our study appears to be occurring among women in whom a diagnosis of hypertriglyceridaemia has not previously been made. Although this is still a rare event, and it may be being underestimated by the lack of direct focused question and examination in the follow-up visits, the relative risk is large.”

“The NSABP-14 trial showed a significant advantage to women who received tamoxifen for 5 years in the adjuvant setting. Women on tamoxifen were then radomised to either further 5 years of tamoxifen or placebo. Through 4 years after the reassignment of tamoxifen-treated patients to continued therapy or placebo, advantages in disease-free survival (92 vs 86%, p=0.003) and distant-disease-free survival (96 vs 90%, p=0.01) were found for those who discontinued tamoxifen. Survival was 96% for those who discontinued the drug compared with 94% for those who continued the drug (p=0.08). These data could be interpreted as being compatible with the hypothesis that long-term tamoxifen therapy is associated with a more aggressive form of breast-cancer recurrence. It is essential to monitor the mortality rate from breast cancer among women receiving tamoxifen prophylactically. Otherwise there is a risk that well women may be prescribed tamoxifen when experience of long-term effects is lacking in such a population.”

“In conclusion, tamoxifen was not significantly protective against breast cancer in women at normal or slightly reduced risk of the disease, at least in the duration of our follow-up. Women using hormone-replacement therapy benefited from tamoxifen administration: these preliminary findings require further investigation of the impact of antioestrogens on users of such therapy. Whether the action is limited to women receiving hormone-replacement therapy transdermally or is present also in women using oral treatment should also be investigated. It is notable that no deaths from breast cancer have yet been observed in the entire cohort and a much longer follow-up will be needed to quantify the impact of tamoxifen use on breast-cancer mortality and other long-term risks and benefits of tamoxifen therapy.”


Veronesi U, Maisonneuve P, Costa A, Sacchini V, Maltoni C, Robertson C, Rotmensz N, and Boyle P., "Prevention of breast cancer with tamoxifen: preliminary findings from the Italian randomised trial among hysterectomised women. Italian Tamoxifen Prevention Study", The Lancet, July 11, 1998, Vol. 352, Num. 0, pp. 93-97

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