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Complications of Androgen Deprivation Therapy: Prevention and Treatment

Complications of Androgen Deprivation Therapy: Prevention and Treatment

For the past 60 years, the treatment of advanced prostate cancer has consisted of depriving cancer cells of androgens.[1] The key premise of androgen ablation is that most prostate carcinoma cell growth is initially androgen-dependent. The androgen receptor expressed by these cells binds dihydrotestosterone, which is then transported into the nucleus, leading to a cascade of events that induce cellular growth. If androgen is removed, cellular death ensues via apoptosis of the androgen-sensitive cells. Development of Antiandrogens
The initial strategy for inducing serum testosterone levels similar to those following castration was either orchiectomy or estrogen therapy. The latter approach was abandoned because of life-threatening cardiovascular toxicity. In the early 1980s, luteinizing hormone-releasing hormone (LHRH) agonists and antiandrogens were introduced. This was followed by total androgen blockade (ie, using an LHRH agonist plus an antiandrogen), and more recently, intermittent hormone therapy. As is true of most antineoplastic therapies, success with antiandrogen therapy was first achieved in patients with metastatic disease. The first Veterans Administration Cooperative Urological Research Group study in 1967 demonstrated that orchiectomy was associated with a 1-year survival of 73% and a 5-year survival of 35% in stage IV prostate cancer patients, compared with 66% and 2%, respectively, in patients receiving placebo.[2] Orchiectomy also resulted in subjective improvement in pain symptoms and performance status, compared with placebo. Recent studies have demonstrated a beneficial result using early hormonal ablation. In 1997, the Medical Research Council found that early hormonal ablation in patients with locally advanced or asymptomatic metastatic prostate cancer prolonged survival compared with delayed treatment when the patient became symptomatic.[3] More recently, Radiation Therapy Oncology Group trial 8610 demonstrated that patients with T2-4 tumors, with or without pelvic lymph node involvement, had improved local control (12% advantage) and disease- free survival (12% advantage), as well as a reduction in the incidence of distant metastases (11% advantage) and disease-specific mortality (8% advantage) with radiation plus combined androgen blockade (goserelin [Zoladex] + flutamide) vs radiation therapy alone.[4] Thus, androgen deprivation therapy (ADT) is being used to treat increasing numbers of patients with early prostate cancer. Adverse Effects
Androgen deprivation therapy is not free of serious side effects. These have been increasingly recognized and are comprehensively reviewed by Drs. Holzbeierlein, Castle, and Thrasher. Side effects include hair loss, hot flashes, fatigue, anemia, lipid and body mass changes, sexual dysfunction, decrease in cognitive function, and osteoporosis. Indeed, these side effects can deleteriously affect quality of life and, at times, can even be life-threatening. One recent concern is that long-term treatment with ADT may result in osteoporosis.[ 5] Decreased bone mineral density usually occurs in men treated with ADT. This is accompanied by a substantial increase in fracture risk among castrated prostate cancer patients compared with age-matched controls.[ 6] Hip fractures in elderly patients are associated with a 25% chance of 30-day mortality. The rate of bone loss after initiation of ADT can be retarded with either oral or intravenous bisphosphonate therapy.[7] Conclusions
Sixty years later, we continue to learn about the optimal ways to use androgen deprivation for the benefit of our patients. Much work remains to be performed to better define patients who will benefit most from hormone deprivation therapy. In addition, we are becoming aware of the risks of this form of therapy and how to counteract and prevent the toxicities associated with extreme hormone deprivation over a prolonged period of time.

Disclosures

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

References

1. Huggins C, Hodges C: Studies on prostate cancer. I. The effect of castration, of estrogen, and androgen injection on serum phosphatases in metastatic carcinoma of the prostate. Cancer Res 1:293-297, 1941.
2. The Veterans Administration Cooperative Urological Research Group: Treatment and survival of patients with cancer of the prostate. Surg Gynecol Obstet 124:1011-1017, 1967.
3. Kirk D: Immediate vs deferred hormone treatment for prostate cancer. How safe is androgen deprivation? Medical Research Council Prostate Cancer Working Party Investigators Group. Br J Urol 86(suppl):220, 2000.
4. Pilepich MV, Winter K, John MJ, et al: Phase III radiation therapy oncology group (RTOG) trial 8610 of androgen deprivation adjuvant to definitive radiotherapy in locally advanced carcinoma of the protate. Int J Radiat Oncol Biol Phys 50:1243-1252, 2001.
5. Daniell HW: Osteoporosis after orchiectomy for prostate cancer. J Urol 157:439-444, 1997.
6. Melton LJ 3rd, Alothman KI, Khosla S, et al: Fracture risk following bilateral orchiectomy. J Urol 169:1747-1750, 2003.
7. Smith MR, Eastham J, Gleason DM, et al: Randomized controlled trial of zoledronic acid to prevent bone loss in men receiving androgen deprivation therapy for nonmetastatic prostate cancer. J Urol 169:2008-2012, 2003.
 
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