New Data on Tamoxifen for Early Breast Cancer Shake Certainty About Stopping Treatment After 5 Years

The latest data, published in the December 18th issue of the Journalof the National Cancer Institute, reopen a question that affects millionsof women worldwide: whether to continue tamoxifen beyond 5 years aftersurgery for early-stage breast cancer.

Douglass Tormey, MD, PhD, et al, writing for the US Eastern CooperativeOncology Group (ECOG) about a study of tamoxifen (Nolvadex) use extendedbeyond 5 years, report very early ECOG data that give the first hint infavor of more than 5 years' duration of tamoxifen therapy. A certain subsetof women in that study--ie, those who test positive for tumor cells withestrogen receptors--showed a longer time to disease relapse with more than5 years of tamoxifen, a statistically significant advantage.

The other newly published paper reports early data from a study of 2vs 5 of years of tamoxifen by the British Cancer Research Campaign BreastCancer Trials Group. These data suggest that the longer duration is morebeneficial.

Editorial Questions 1995 NCI Announcement

In an editorial accompanying these first reports from two major, ongoingtamoxifen clinical trials, Professor Richard Peto, Oxford University, statesthat "it may have been unwise" for a 1995 announcement by theUS National Cancer Institute (NCI) "...to have concluded so definitelythat 5 years of treatment is enough...."

The announcement states that "...all available evidence indicatesthat 5 years of tamoxifen is a reasonable standard...." Peto saysthat much of the evidence used for that determination was available onlybecause it appeared to be negative--ie, it suggested that taking tamoxifenfor more than 5 years is more dangerous than beneficial--and had been releasedearlier than intended on that account. The ECOG evidence, which Peto viewsas "apparently favorable," was unavailable until now preciselybecause it is positive [and its release could therefore follow a longer,natural course under the scientific process].

In his editorial, Peto analyzes and compares the newly published resultsand the more mature--but still preliminary, in his view--tamoxifen resultspublished in the November 6th issue of the Journal of the National CancerInstitute. That issue contains a paper by the Swedish Breast Cancer CooperativeGroup (2 vs 5 years of tamoxifen; the longer duration showing better resultsat this point in follow-up) and a paper by Fisher et al for the US NationalSurgical Breast and Bowel Project (NSABP)

B-14 study (no tamoxifen vs 5 years and 5 vs 10 years; 5 years' durationappearing optimal at this point in follow-up). The NSAPB B-14 study, alludedto above, was stopped and preliminary data were released earlier than intended:More recurrences of breast cancer were seen among patients assigned to10 years of tamoxifen than among those receiving 5 years, making it appearthat, although 5 years is clearly beneficial, the risks associated withlonger therapy outweigh the benefits.

Peto, however, stresses that if the suggested hazard were real, theECOG results should likewise show an adverse trend, which is not the case."...The ECOG data tend, if anything, to favor more than 5 years oftreatment," he says. But he finds that neither set of data is "statisticallyconvincing" on its own. According to Peto, as-yet insufficient follow-uptime is the chief reason that it is inappropriate to try to synthesizethe data from the four trials through a formal meta-analysis, "andthe early findings in such trials may be therapeutically misleading."In their paper on the ECOG study, Tormey et al point out differences inpatient populations among the studies that could explain the apparent discrepanciesin results.

No Definitive Conclusion About Long-Term Survival Yet Available

Peto says direct and indirect comparisons suggest an advantage for 5years of tamoxifen over 2 years, although "a definitive conclusionabout long-term survival may not be possible until at least the year 2000.But neither direct nor indirect comparisons can yet address the questionof whether substantially more than 5 years of adjuvant tamoxifen treatmentwill yield better long-term survival."

Longer follow-up of NSABP B-14, the ECOG study, and a Scottish trialof 5 years vs longer will help, he says, but trials that are still recruitingpatients need to enroll much larger numbers. If "really large-scalerecruitment" can be achieved before the year 2000, "then [thesestudies] will yield preliminary findings in 2005 and reliable findingsin 2010," he claims.

In the meantime, Peto believes that the current results from the fourtrials reported in the Journal will likely foster agreement "....that5 years of tamoxifen is a reasonable standard." He maintains, however,that "...they should also foster continuing disagreement as to whetherlonger treatment is promising...."

He concludes that the scientific process "is frustratingly slow,but eventually it is reliable, and it needs to be."