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Safety of Exemestane in the Intergroup Exemestane Study

For the Intergroup Exemestane Study, Imperial College London, Hammersmith Hospitals Trust, London, UK

Judith M. Bliss, Emma Hall

For the Intergroup Exemestane Study, The Institute of Cancer Research, Sutton, Surrey, UK

To the Editor:

In the September 15, 2004, letter to the Editor,¹ Dr Mouridsen raised issues over the safety profile of exemestane, as described by us in the Intergroup Exemestane Study (IES).² He also made cross-study comparisons with other large adjuvant trials evaluating the use of aromatase inhibitors in the treatment of postmenopausal patients with hormone-sensitive early breast cancer. Our initial response is to caution against such comparisons where the study design (ie, sequential treatments v monotherapy), use of comparator treatments (ie, tamoxifen or placebo), and time between breast cancer diagnosis and randomization (ie, 0 to 5 years) differ so widely between the trials. In particular, comparisons that cite absolute benefits and risks identified in each trial are not helpful due to differing underlying event rates (eg, changing relapse rates as the time from diagnosis increases) and consequences of withdrawal of pretreatment with other endocrine agents (ie, tamoxifen).

In response to his comments relating to the safety profile of exemestane as shown in IES, we would remind readers that due to the large number of types of adverse events analyzed, a P value of .01 was adopted to indicate results reliable enough to be considered statistically significant. The same criterion for reporting adverse events was used in the reporting of the MA17 trial.³ Dr Mouridsen's letter seems to focus on adverse events where the results do not satisfy this criterion (eg, P = .05) and where the results must at best therefore be considered hypothesis generating.

Dr Mouridsen draws particular attention to the bone data. His subjective description of the magnitude of bone loss associated with the different aromatase inhibitors is unhelpful and not substantiated by the data, particularly in light of the study design issues described earlier. Tamoxifen is known to protect bone⁴; hence, withdrawal of tamoxifen is likely, in itself, to contribute to the modest and nonsignificant increase in fracture rate observed in patients who switch to exemestane, particularly in this instance where the comparator arm is continuing to receive tamoxifen. As an investigator in the IES, Dr Mouridsen is aware of the bone subprotocol in which a subset of patients have undergone detailed bone mineral density assessments. Early results from this subprotocol have been released.⁵ For longer-term assessment, when any early effect of tamoxifen withdrawal can be excluded, we will have to await further follow-up.

Dr Mouridsen discusses other side effects where comparison between the treatment groups was presented. The only one of these cited events, however, in which a statistically reliable difference was observed, was diarrhea, which has been previously reported with the use of exemestane.⁵ Weight gain was not included in the New England Journal of Medicine article since it did not meet the criteria for inclusion. From this, the reader may conclude that it was reported in less than 10% of patients and differed by less than 1% between the treatment arms. Contrary to the suggestion in Dr Mouridsen's letter, there were no significant differences in terms of incidence of or mortality from cardiovascular disease. An important note in the interpretation of causes of death is that only intercurrent deaths (deaths that occur before the occurrence of a breast cancer–related event) are prescribed a specific cause. Hence, given the differential rate of first events between the treatment groups due to the increased efficacy of the tamoxifen-exemestane sequence, patients who switched to exemestane will, on average, be "at risk" of dying from an intercurrent death with prescribed cause for longer than those on the tamoxifen monotherapy arm. In a population in which the average age at randomization was 64 years, this could lead to apparently spurious differences in the incidence of other causes of death, particularly those that are common in this age group.

As for MA17, the goal of the IES New England Journal of Medicine publication was early release of the efficacy data. We understand that each of the large trials (IES, MA17, and ATAC) plan to publish a more in-depth analysis of safety and tolerability in due course. For IES, such an analysis will discuss time-related incidence of adverse event reporting postrandomization, treatment emergent events, and the prevalent comorbidities pre-existing in this patient population.

Authors' Disclosures of Potential Conflicts of Interest

The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Consultant: R. Charles Coombes, Pfizer. Honoraria: R. Charles Coombes, Pfizer; Judith Bliss, Pfizer. Research Funding: R. Charles Coombes, Pfizer; Judith Bliss, Pfizer. Other Remuneration: Judith Bliss, Pfizer. For a detailed description of these categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section of Information for Contributors found in the front of every issue.

REFERENCES

1. Mouridsen HT: Exemestane following tamoxifen in postmenopausal women with primary breast cancer. J Clin Oncol 22:3833-3834, 2004[Free Full Text]

2. Coombes RC, Hall E, Gibson LJ, et al: A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med 350:1081-1092, 2004[Abstract/Free Full Text]

3. Goss PE, Ingle JN, Martino S, et al: A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med 349:1793-1802, 2003[Abstract/Free Full Text]

4. Powles T: Effect of tamoxifen on bone mineral density measured by dual-energy x- ray absorptiometry in healthy premenopausal and postmenopausal women. J Clin Oncol 4:78-84, 1996

5. Coleman RE, Banks LM, Hall E, et al: The Intergroup Exemestane Study: 1 year results of the bone sub-protocol. Breast Cancer Res Treat 88:S35, 2004 (suppl 1)

6. Lonning PE, Bajetta E, Murray R, et al: Activity of exemestane in metastatic breast cancer after Failure of nonsteroidal aromatase inhibitors: A phase II trial. J Clin Oncol 18:2234-2244, 2000[Abstract/Free Full Text]

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