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Regarding the Influence of Adjuvant Suppression Therapy for Prostate Cancer on the Frequency and Timing of Fatal Myocardial Infarction: How Real Is the Risk?

Department of Radiation Oncology, University of California, San Francisco Cancer Center at Mount Zion, San Francisco, CA

To the Editor:

Dr D'Amico and his colleagues have made tremendous contributions to the study of prostate cancer. They popularized a number of concepts, including the use of risk groups to analyze outcomes, the importance of prostate-specific antigen doubling time, and the effect of the percent of positive cores as a prognostic factor. None of these concepts were based on prospective randomized trials, but rather they arose from hypothesis-generating studies. Thus, hypothesis-generating research has been one of the hallmarks of their major contributions. However, this article entitled "Influence of Androgen Suppression Therapy for Prostate Cancer on the Frequency and Timing of Fatal Myocardial Infarction" troubles me.¹ The authors concluded that short-term hormone therapy significantly increased the risk of fatal myocardial infarctions (MIs), and this risk was not related to the duration of hormone therapy. In my opinion, these counterintuitive conclusions are unsupported by the data they provided.

First was the somewhat arbitrary decision to use a cutoff at age 65 years. This seems unjustified since the median age in this cohort was approximately 70 years. The authors justified this age cutoff by extrapolating from a surgical series. This is a big stretch for men treated with external beam radiotherapy (EBRT) and androgen deprivation therapy (ADT). If the end point is fatal MIs and the patients at greatest risk are older, why not use the median of the population at risk? Most Radiation Therapy Oncology Group trials included patients with a median age of 70 years, and, in my opinion, this would have been an appropriate cut point.²

For somewhat arbitrary reasons, the authors chose to combine the risk of fatal MIs associated with 6 months of ADT and EBRT without ADT (EBRT alone) in their Figure 1, while they also chose to combine the risk of fatal MIs associated with 3 months of ADT and 6 to 8 months of ADT in Figure 2. Their argument for separating these data into separate figures was that "The median follow-up time for men in the Canadian study compared with men in the US study was significantly shorter (4.8 v 6.7 years) ...".

View larger version (19K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Cumulative incidence of fatal myocardial infarctions after random assignment for men treated on the Trans-Tasman Radiation Oncology Group and US studies (solid lines) and Trans-Tasman and Canadian studies (dashed lines) reported by D'Amico et al.1 Figure generated by combining data provided Figures 1 and 2 of their article. Men younger than 65 years are excluded because of low rates of fatal myocardial infarctions. ADT, androgen deprivation therapy.

Their argument is based on a very small number of events. When one reviews their Figure 1, one sees that the maximum difference in the risk of cardiovascular disease was approximately 2.5% at 2 years for patients who received 6 months of hormone therapy compared with none. However, if one combines the data from both of the figures (Figs 1 and 2) in their paper as I have done below in my Figure 1, they would reach a different conclusion. My conclusion after reviewing the combined data is that the differences in the risk of fatal MIs at 2 years alluded to by these authors actually represents "statistical noise."

As shown in this Figure, the maximum difference in the risk of fatal MIs appears to be on the order of 1.5% higher among patients who receive 3 months or 6 to 8 months of ADT compared with patients treated with radiation alone. With longer follow-up, the curves cross, and after 8 years, it appears that patients who receive no ADT had twice the risk of having fatal MI as that of men who received 3 months or 6 to 8 months of ADT. Should we then (as a hypothesis-generating exercise) hypothesize that short-term ADT reduced the risk of fatal MIs? I think not.

There is no question that long-term ADT can induce a so-called "metabolic syndrome." This is not up for debate; however, their conclusions go too far. This hypothesis-generating analysis is problematic from both its statistical design as well as their counterintuitive interpretation. They argue that although the physiologic changes associated with ADT are clearly reversible, there does not appear to be a relationship between duration of ADT and fatal MIs.

Based on the most recently updated analysis of the first phase III trial evaluating the role of ADT combined with EBRT (Radiation Therapy Oncology Group Trial 8610), we saw no evidence that ADT was associated with an increased risk of fatal MIs.³ In addition, with the addition of only 4 months of ADT to EBRT, we saw a 1.4-year longer median survival time (8.7 v 7.3 years, P = .05), and on multivariate analysis, noted a 50% improvement in the cause-specific survival and freedom from metastases (P = .01). I consider these data far more reliable for assessing the risk and benefit ratios for elderly men undergoing short-term ADT and EBRT than any hypothesis-generating study.

The readers should exercise caution when considering the conclusions derived from hypothesis-generating research, particularly when it might encourage them to make treatment recommendations that fly in the face of high-level evidence.⁴

AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure 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 in Information for Contributors.

Employment or Leadership Position: None Consultant or Advisory Role: Mack Roach III, AstraZeneca (C) Stock Ownership: None Honoraria: Mack Roach III, AstraZeneca Research Funding: None Expert Testimony: Mack Roach III, AstraZeneca (C) Other Remuneration: None

REFERENCES

1. D'Amico AV, Denham JW, Crook J, et al: Influence of androgen suppression therapy for prostate cancer on the frequency and timing of fatal myocardial infarctions. J Clin Oncol 25:2420-2425, 2007[Abstract/Free Full Text]

2. Roach M III, DeSilvio M, Lawton C, et al: Phase III trial comparing whole-pelvic versus prostate-only radiotherapy and neoadjuvant versus adjuvant combined androgen suppression: Radiation Therapy Oncology Group 9413. J Clin Oncol 21:1904-1911, 2003[Abstract/Free Full Text]

3. Roach M, Bae K, Speight J, Wet al: Short-term neoadjuvant androgen deprivation therapy and external beam radiotherapy for locally advanced prostate cancer: Long-term results of RTOG 8610 a phase III prospective randomized trial. J Clin Oncol (in press)

4. Speight JL, Roach M III: Radiotherapy in the management of clinically localized prostate cancer: Evolving standards, consensus, controversies and new directions. J Clin Oncol 23:8176-8185, 2005[Abstract/Free Full Text]

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