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Educational Supplement: Appendix
Duration
of Adjuvant Hormonal Treatment
Christina
Davies, MBChB, M.Sc.
Summary.
Large trials of 10 years versus 5 years of adjuvant tamoxifen therapy
are still in progress. Other large trials have shown that 7 to 8
years of adjuvant tamoxifen treatment are significantly better than
2 to 3 years, with much of the additional benefit emerging after
year 5. Large trials have also shown that 5 years of tamoxifen is
significantly better than 2 to 3 years. Whatever the hormonal treatment
to be used, large-scale randomized evidence is needed as to whether
the duration of hormonal therapy should in general be at least 10
years, or whether 7.5 years, or even 5 years, can suffice.
Five years
of tamoxifen versus a shorter period. In trials of tamoxifen
versus no tamoxifen and of one tamoxifen duration versus another
duration (shorter versus longer), the overview has demonstrated
that for women with potentially hormone-sensitive disease, tamoxifen
is of substantial benefit (EBCTCG, unpublished data, 2000). Five
years of tamoxifen appears to be better than shorter regimens at
least in terms of recurrence, although this has not been shown so
far to be translated into a survival benefit. A French trial of
7 to 8 years of tamoxifen versus 2 to 3 years also shows that, with
regard to recurrence, longer is better (Delozier, Spielmann, Mace-Lesech,
et al., 1997). However, there is inadequate randomized evidence
about the effects of prolonging tamoxifen beyond 7 to 8 years. Five
years of tamoxifen increases endometrial cancer mortality, and this
adverse effect increases with a longer duration of tamoxifen (EBCTCG,
2000; EBCTCG, 1998). In addition, tamoxifen causes a slight increase
in the risk of pulmonary embolus (EBCTCG, 2000; EBCTCG, 1998). But
tamoxifen reduces the risk of new cancers in the opposite breast,
and this effect is also increased with longer duration (EBCTCG,
2000; EBCTCG, 1998). There was no evidence of an effect on mortality
from causes other than breast or endometrial cancer. In terms of
the 10-year incidence of new cancers, the extra number of endometrial
cancers caused by tamoxifen is smaller than the number of new cancers
prevented in the opposite breast; the overall net survival benefit
is 30 times greater than the hazard.
Five years
of tamoxifen versus a longer period. The question of the value
of 5 years of tamoxifen versus a longer period is still unanswered
in terms of recurrence and survival. So far, that question has not
been properly studied, either through indirect comparisons of duration
between trials of tamoxifen versus no tamoxifen, or through direct
comparisons in trials which compare, within the same study, 5 years
of tamoxifen versus longer treatment (EBCTCG, 2000; Peto, 1996;
Swain, 1996). Concerns have been expressed about resistance to tamoxifen
with more prolonged treatment, but the mechanisms of resistance
are poorly understood and, more importantly, this concern has not
been supported by randomized evidence. The current trials are of
insufficient sizeeven in combinationto detect the moderately
sized difference that might exist. The three directly randomized
comparisons of 5 years versus 10 years of adjuvant tamoxifen that
started long enough ago to have produced some results have now ended
(Tormey, Gray, Falkson, 1996; Stewart, Forrest, Everington, et al.,
1996; Fisher, Dignam, Bryant, et al., 1996). All three (known colloquially
as ECOG, Scottish Cancer Trial, and NSABP B-14) involved only small
numbers of breast cancer recurrence or death after year 5. It remains
quite possible, based on current evidence, to hope for additional
benefit from longer treatment, and the results from the French trial
support this (Delozier, Spielmann, Mace-Lesech, et al., 1997).
The need
for large-scale randomized evidence. Studies assessing the optimal
duration of adjuvant tamoxifen need to be much larger than has generally
been recognized. Small-scale studies carry the substantial risk
of getting the wrong answer because their results are unduly influenced
by favorable or unfavorable random fluctuations. That is particularly
the case if frequent interim analyses are carried out before sufficient
numbers of events have been allowed to occur. As a consequence,
chance blips, suggesting either benefit or hazard, are
then inappropriately emphasized.
The need
for long-term followup. Tamoxifen has a substantial carry-over
benefit, with fewer recurrences seen for a few years after the end
of the treatment period. This means that, in trials of tamoxifen
versus no tamoxifen, the benefits of tamoxifen are enhanced compared
with the no tamoxifen arm, but in trials of longer versus shorter
tamoxifen there may be little additional benefit apparent during
the first few years of continued treatment due to the carry-over
benefit in women in the shorter tamoxifen arm of the trial. Any
worthwhile benefit will emerge later on, provided that the study
is large enough. This means that in trials of longer versus shorter
treatment, long-term followup is required, because the expected
balance of risks and benefits may change during the followup period.
If the question of 5 years versus 10 years is going to be reliably
answered, tens of thousands of women may need to be randomized and
followed up for at least 10 years. It will probably not be until
2005, or more likely 2010, that there will be sufficient randomized
evidence on 5 versus 10 years of tamoxifen to merit a review by
the EBCTCG.
Current large-scale
trials of 5 versus 10 years of tamoxifen. ATLAS and aTTom are
both large-scale randomized trials of longer versus shorter hormonal
therapy to assess reliably the effects of an extra 5 years of tamoxifen
in women who have had some years of treatment and for whom there
is uncertainty as to whether they should stop or continue (Rea,
Poole, Gray, 1998). About 20,000 women will be randomized, usually
after about 5 years of tamoxifen, to either stop tamoxifen or to
continue it for 5 more years. The main analyses in ATLAS and aTTom
will be of all-cause mortality, but they will also provide information
on cause-specific mortality and on nonfatal but important events.
If, by 2010, patients show improved long-term survival with 10 years
of tamoxifen, this result will save thousands of lives annually,
and will be relevant to the use of hormonal therapies in general.
By November 2000, more than 7,000 women will have entered ATLAS,
making it the largest-ever study of tamoxifen duration. Some 4,000
have been randomized in aTTom. Still, many thousands more need to
be studied in randomized trials to obtain reliable answers about
treatment of an extra 5 years with tamoxifen.
Conclusion.
There is now reliable evidence that 7 to 8 years of tamoxifen is
better than shorter regimens in women with hormone-sensitive breast
cancer. There is insufficient evidence to draw reliable conclusions
about whether 10 years of tamoxifen compared with 5 years confers
additional benefits. ATLAS and aTTom, in combination with the trials
of 5 years versus longer adjuvant tamoxifen that have now ended,
should help to answer this question, but it is unlikely that a reliable
answer will emerge before 2010.
References
Delozier T,
Spielmann J, Mace-Lesech M, Janvier M, et al. Short-term versus
lifelong adjuvant tamoxifen in early breast cancer: a randomised
trial (TAM-01). [abstract]. Proc Am Soc Clin Oncol 1997. Abstract.
Early Breast
Cancer Trialists Collaborative Group (EBCTCG). Tamoxifen for
early breast cancer: an overview of the randomised trials. Lancet
1998;351:1451-67. Abstract.
Early Breast
Cancer Trialists Collaborative Group, 2000. Unpublished data.
Fisher B, Dignam J, Bryant J, DeCillis A, Wickerham DL, Wolmark
N, et al. Five versus more than five years of tamoxifen therapy
for breast cancer patients with negative lymph nodes and estrogen
receptor-positive tumors. J Natl Cancer Inst 1996;88:1529-42. Abstract.
Peto R. Five
years of tamoxifenor more? J Natl Cancer Inst 1996;88:1791-3.
Rea D, Poole C, Gray R. Adjuvant tamoxifen: how long before we know
how long? BMJ 1998;316:1518-9. No Abstract Available.
Rea D, Poole C, Gray R. Adjuvant tamoxifen: how long before we
know how long? BMJ 1998;316:1518-9. Abstract.
Stewart HJ,
Forrest AP, Everington D, McDonald CC, Dewar JA, Hawkins RA, et
al. Randomised comparison of 5 years of adjuvant tamoxifen with
continuous therapy for operable breast cancer. Br J Cancer 1996;74:297-9.
Abstract.
Swain SM. Tamoxifen:
the long and short of it. J Natl Cancer Inst 1996;88:1510-2. No
Abstract Available.
Tormey DC, Gray
R, Falkson HC. Postchemotherapy adjuvant tamoxifen therapy beyond
five years in patients with lymph node-positive breast cancer. [Eastern
Cooperative Oncology Group]. J Natl Cancer Inst 1996;88:1828-33.
Abstract.
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