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The purpose of patient education is to equip the patient decisions for her own treatment-- NOT to convince her doctor of the validity of her decisions. --MH |
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Dr. Eric Winer from Dana Farber Cancer Institute VIDEO From 2010: Aromatase Inhibitors as adjuvant therapy offer no survival value. |
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10-year analysis of the ATAC trial: wrong conclusion?
Ian F Tannock
The 10-year analysis of the Arimidex, Tamoxifen, Alone or in Combination (ATAC)
trial1 continues to show a difference in its primary endpoint of disease-free survival,
which favours anastrozole as adjuvant treatment for postmenopausal women with
hormone-responsive breast cancer. Ultimately, however, clinical trials have two aims:
either to show improvement in survival, or in its quality. Anastrozole has failed to meet
these criteria when compared with tamoxifen.
The choice of disease-free survival as the primary endpoint in trials assessing
adjuvant therapy was presumably made with the expectation that early differences in
this endpoint would predict later differences in overall survival. The 10-year analysis
of the ATAC trial invalidates this assumption—overall survival remains similar
in the two groups. With no improvement in survival, the choice between
adjuvant anastrozole and tamoxifen should depend on which drug has better
safety and tolerability. The investigators claim that safety criteria support
anastrozole. This conclusion is made on the basis of comparisons of treatment-related
serious adverse events, which were more common in those receiving tamoxifen than in
those receiving anastrozole (14·3% vs 9·2%). In the ATAC trial, serious adverse
events were defined in a standard way but there was no prespecified checklist.
Whether an event was treatment related depended on the judgment of the treating
physician, creating bias because side-effects due to tamoxifen were recognised better
at the start of the ATAC trial than were those due to anastrozole. Long-term
experience with new agents has found that adverse events that are not recognised as
side-effects of therapy in early trials might later prove to be treatment related.2 For
example, increased fractures, which were later associated with aromatase inhibitors,
were not originally recognised as treatment related.
An important omission is reference to the secondary analysis of ATAC data by the US
Food and Drug Administration,3 which required that a warning be added to the drug
label to indicate that “anastrozole may be linked to an increased risk for ischemic
cardiovascular events in women with pre-existing ischemic heart disease”. Other
evidence supports a higher incidence of cardiac events in women receiving aromatase
inhibitors4 than in those receiving tamoxifen, possibly due to tamoxifen's protective
effect, or to increased serum cholesterol in women receiving aromatase inhibitors.5 In
the ATAC trial, fewer deaths after recurrence of breast cancer were counterbalanced
by more deaths with no recurrence in the anastrozole group. Tamoxifen is a safer
drug than anastrazole.
Tolerability and compliance are different from safety. A past review of side-effects in
the ATAC trial indicated that 13 patients receiving anastrozole and six receiving
tamoxifen withdrew because of arthralgias. Compliance is a problem for both drugs,
but post-trial studies have shown high rates of arthralgia and sexual dysfunction
associated with aromatase inhibitors, and rates of non-adherence and discontinuation
up to 40%.6 In the ATAC trial, absence of a prespecified checklist including these side-
effects would probably lead to under-reporting of such data.
In my opinion, it is more appropriate to conclude from these data that tamoxifen should
remain the preferred drug for most postmenopausal patients with hormone-receptor
positive breast cancer.
The author declared no conflicts of interest. I thank Eitan Amir, Philippe Bedard, and
Bostjan Seruga for helpful discussion during preparation of this commentary.
References
1 Cuzick J, Sestak I, Baum M, et alfor the ATAC/LATTE investigators. Effect of anastrozole and tamoxifen as
adjuvant treatment for early-stage breast cancer: 10-year analysis of the ATAC trial. Lancet Oncol 2010; 11: 1135-
1141. Summary | Full Text | PDF(395KB) | CrossRef | PubMed
2 Seruga B, Sterling L, Wang L, Tannock IF. Reporting of serious adverse drug reactions of targeted cancer agents
in pivotal phase III clinical trials. J Clin Oncol 2011; 29: 174-185. CrossRef | PubMed
3 US Food and Drug Administration. Highlights of prescribing information. http://www.accessdata.fda.
gov/drugsatfda_docs/label/2009/020541s024s025lbl.pdf. (accessed Jan 05, 2011).
4 Amir E, Ocana A, Niraula S, Carlsson L, Seruga B. Toxicity of adjuvant endocrine therapy in postmenopausal
breast cancer patients. 33rd Annual San Antonio Breast Cancer Symposium; San Antonio, TX, USA; Dec 8—12,
2010. S2—7 (abstr).
5 Monnier A. Effects of adjuvant aromatase inhibitor therapy on lipid profiles. Expert Rev Anticancer Ther 2006; 6:
1653-1662. PubMed
6 Hershman DL, Kushi LH, Shao T, et al. Early discontinuation and nonadherence to adjuvant hormonal therapy in
a cohort of 8,769 early-stage breast cancer patients. J Clin Oncol 2010; 28: 4120-4128. CrossRef | PubMed
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