Cancer Treatment Today

Androgens play a prominent role in the development, maintenance and progression of prostate cancer. The introduction of androgen deprivation therapies into the treatment paradigm for prostate cancer patients has resulted in a wide variety of benefits ranging from a survival advantage for those with clinically localized or locally advanced disease, to improvements in symptom control for patients with advanced disease.

The continued responsiveness of prostate cancer to hormonal therapy after progression on ADT is supported by multiple observations:

Men who originally had undergone castration or treatment with a GnRH agonist may have a response following the subsequent addition of an antiandrogen.
The discontinuation of antiandrogens in men who progressed after complete androgen blockade may provide objective benefit in 15 to 20 percent of patients (the antiandrogen withdrawal response).
Agents that suppress adrenal androgen production may induce objective regressions and symptomatic benefit, even in men who are refractory to ADT.
The administration of androgens can cause a worsening of disease in men with castrate-resistant prostate cancer. This was illustrated in a trial in which men given androgens along with chemotherapy had a shorter survival than those given chemotherapy alone.

There are no trials that directly address the utility of continued testicular androgen deprivation in men with castrate-resistant prostate cancer. However, the Eastern Cooperative Oncology Group (ECOG) did perform a multivariate analysis of 341 patients with castrate-resistant prostate cancer who were treated in four clinical trials and found that continued testicular androgen suppression was associated with a median survival benefit of two to six months. Although a review of 205 men treated in five Southwest Oncology Group (SWOG) trials did not demonstrate a survival benefit, the applicability of these data are limited since 84 percent of the men had undergone orchiectomy.

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Hussain M, Wolf M, Marshall E, et al. Effects of continued androgen-deprivation therapy and other prognostic factors on response and survival in phase II chemotherapy trials for hormone-refractory prostate cancer: a Southwest Oncology Group report. J Clin Oncol 1994; 12:1868.
Bubley GJ, Carducci M, Dahut W, et al. Eligibility and response guidelines for phase II clinical trials in androgen-independent prostate cancer: recommendations from the Prostate-Specific Antigen Working Group. J Clin Oncol 1999; 17:3461.
Winquist E, Waldron T, Berry S, et al. Nonhormonal systemic therapy in men with hormone-refractory prostate cancer: A Clinical Practice Guideline, 2005 www.cancercare.on.ca/pdf/pebc3-15s.pdf (Accessed on April 18, 2011).
Basch EM, Somerfield MR, Beer TM, et al. American Society of Clinical Oncology endorsement of the Cancer Care Ontario Practice Guideline on nonhormonal therapy for men with metastatic hormone-refractory (castration-resistant) prostate cancer. J Clin Oncol 2007; 25:5313.

Importantly, these studies analyzed use of GnRH agonists and did not evaluate serum testosterone levels. Discontinuation of GnRH agonist therapy results in highly variable recovery of testosterone with some men never recovering normal pituitary/gonadal function despite discontinuation of GnRH agonist treatment.

Guidelines from the Prostate Specific Antigen Working Group recommended that all patients who have not undergone surgical castration should be continued on testicular androgen suppression as a protocol eligibility criterion in phase II studies. In addition, the Cancer Care Ontario Practice guidelines, which have been endorsed by the American Society of Clinical Oncology (ASCO), recommend that maintenance gonadal androgen suppression (drugs like Lupron) be continued during chemotherapy,