Androgen Deprivation Therapy in High-Risk Prostate Cancer

Androgen deprivation therapy (ADT) has been shown to be beneficial in combination with radiotherapy (RT) vs RT alone in multiple phase III randomized trials treating patients with high-risk prostate cancer. Drs. Fang, Merrick, and Wallner have concisely summarized the data in Table 1 of their article. The Radiation Therapy Oncology Group trial RTOG 86-10 has demonstrated that as little as 4 months of ADT in combination with RT can delay the time to development of metastatic disease by up to 8 years, compared with RT alone.[1] What’s more, longer durations of ADT (ie, 28 to 36 months) are superior to shorter durations (4 to 6 months), as evidenced by the results of RTOG 92-02 and the European Organisation for Research and Treatment of Cancer trial EORTC 22961. Therefore, a long-term duration of ADT (ie, 24 to 36 months) is an accepted standard of care in combination with RT for patients with high-risk disease.

While the benefits of ADT are clear, the specific mechanism of action is not. Whether the predominant action of ADT is to potentiate the local effects of RT or eliminate subclinical micrometastasis has not been determined. This raises the question, as Fang et al. discuss, whether ADT may obviate the need for dose-escalated RT, or, conversely, whether dose-escalated RT may obviate the need for long-term ADT. RT dose escalation (ie, 78 Gy) has been shown to improve prostate cancer survival.[2] Currently, there is only one ongoing trial that explores this question in intermediate-risk patients. RTOG 08-15 will compare dose-escalated RT alone (eg, 79.2 Gy delivered in 1.8 Gy fractions) vs dose-escalated RT with 6 months ADT. Given the results of RTOG 92-02 and EORTC 22961, shorter courses of ADT are unlikely to be tested in high-risk patients. Instead, additional adjuvant therapies have been explored. RTOG 05-21 randomized high-risk patients to RT and long-term ADT with or without adjuvant docetaxel (Taxotere) chemotherapy and its results are eagerly awaited.

As Fang et al. discuss, excess cardiac morbidity has been associated with ADT. Interestingly, the evidence for this interaction has arisen from comparisons of radiation therapy (RT) versus RT + ADT in which the duration of ADT has been short (ie, 6 months). RTOG 85-31 and EORTC 22863,[3] which have both employed long-term ADT, have shown no excess risk of cardiac morbidity. The explanation for this inconsistency is unclear. It implies however, that shortening ADT from 24–36 months to 6 months may not reduce the excess risk of cardiac morbidity. Prospective trials, which characterize cardiovascular risk factors better, are needed to improve our understanding of the relationship between ADT use, ADT duration, and cardiac mortality risk.

As an aside, it is important to note that the “duration” of ADT (ie, 4, 6, 28, 36 months) relates to the months of pharmacologic action of the luteinizing-hormone-releasing hormone agonist and is different from the length of time that the testosterone level is suppressed. The recovery of serum testosterone following ADT varies greatly; it can take as long as 1 year, and sometimes recovery does not occur. Therefore, the “true” duration of ADT is longer than the planned duration. Ideally, ADT duration is measured as a function of testosterone recovery and not duration of therapy.

Unfortunately, specific risk factors that may preclude administration of ADT with RT are lacking. There is consensus that pretreatment cardiac testing or intervention is unlikely to clarify the issue. Therefore, the decision as to whether the benefits of ADT outweigh the risks is made between the radiation oncologist and patient. Men with congestive heart failure or myocardial infarction induced by coronary artery disease appear to have approximately twice the risk for mortality when receiving ADT.[4] For patients with cardiac disease who are receiving ADT, appropriate secondary preventive measures as recommended by the American Heart Association include statin therapy to lower low-density lipoprotein cholesterol; antihypertensive therapies to lower blood pressure; and, in patients with diabetes mellitus, glucose-lowering therapies to reduce glucose and glycosylated hemoglobin levels to recommended levels.[5] All patients with cardiovascular disease should be taking aspirin (generally at a dosage of 81 mg/d) unless there is a strong contraindication to doing so, and smokers should be strongly encouraged to stop.[5]

Financial Disclosure:The author has no significant financial interest of other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

References

1. Roach M, III, Bae K, Speight J, et al: Short-term neoadjuvant androgen deprivation therapy and external-beam radiotherapy for locally advanced prostate cancer: Long-term results of RTOG 8610. J Clin Oncol 26:585-591, 2008.

2. Kuban DA, Levy LB, Cheung MR, et al: Long-term failure patterns and survival in a randomized dose-escalation trial for prostate cancer. Who dies of disease? Int J Radiat Oncol Biol Phys (in press).

3. Bolla M, Collette L, Van Tienhoven G, et al: Ten-year results of long term adjuvant androgen deprivation with goserelin in patients with locally advanced prostate cancer treated with radiotherapy: A phase III EORTC study. Int J Radiat Oncol Biol Phys 72:S30-S31, 2008.

4. Nanda A, Chen M-H, Braccioforte MH, et al: Hormonal therapy use for prostate cancer and mortality in men with coronary artery disease-induced congestive heart failure or myocardial infarction. JAMA 302:866-873, 2009.

5. Levine GN, D’Amico AV, Berger P, et al: Androgen-deprivation therapy in prostate cancer and cardiovascular risk: A science advisory from the American Heart Association, American Cancer Society, and American Urological Association: Endorsed by the American Society for Radiation Oncology. CA Cancer J Clin 60:194-201, 2010.