Surgical orchiectomy and luteinizing hormone-releasing hormone agonists (LHRHa) are equally effective treatment for locally advanced or metastatic prostate cancer, but orchiectomy seems to be on the decline. Is this justified in the literature?

It is now 70 years since orchiectomy was shown to be an effective treatment for locally advanced or metastatic prostate cancer, and about 20 years since luteinizing hormone-releasing hormone agonists (LHRHa) were introduced into clinical practice. Both are equally effective forms of castration.[1] Over 90% of men with metastatic prostate cancer will respond for a median duration of about 12 months if treatment is instituted when the patient is symptomatic, or about 2 years if instituted earlier in the disease course. Inevitably, however, androgen resistance subsequently develops, and second-line treatments such as antiandrogens, steroids, chemotherapy, or radiation may provide useful palliation but have not been shown to further prolong survival.

The use of surgical castration has fallen in BC over the last decade—in 1995, 280 men underwent bilateral orchiectomy, compared with only 138 in 1999. Over the same time period the number of prescriptions of LHRHa for “permanent castration” has more than tripled. Is this change in practice justified?

A total of 10 randomized studies and two meta-analyses (see, for example, Seidenfeld and colleagues[2]) have shown that surgical castration is equivalent to medical castration (LHRHa) in terms of tumor control. The same randomized studies have also provided data on toxicity: cardiovascular events, impotence, hot flushes, and gynecomastia occur with the same frequency with both, which would be expected because the mechanism of these effects is largely as a result of castrate testosterone levels. Similarly, osteoporosis, muscle weakness, and cognitive impairment would also be expected to occur equally with both forms of treatment. However nausea, vomiting, and diarrhea are more frequent with LHRHa (5% v ~1%). Withdrawal from LHRHa occurs in 0% to 8.3% depending on the series. LHRHa are given as one to four depot injections monthly. Three products are available—buserelin, goserelin, and leuprolide. Their efficacy and tolerance appears identical.

If these treatments are broadly similar, what are patients’ preferences and experiences? The few studies that have addressed this issue suggest that most men, if properly informed about both options, would choose LHRHa (70% to 78%).[3] The reasons usually given for choosing LHRHa are that surgery is avoided, although more men felt that the surgical option was more convenient. Three months later both groups of patients were well satisfied with their decision—only 1% of patients felt they had made the wrong decision. A second, more recent study[4] looked at the impact on quality of life of both forms of treatment in men with advanced but nonmetastatic cancer. Those men who chose an LHRHa had a worse quality-of-life impact afterward than those who chose surgical castration (quality of life score 6.6 versus 7.8, P = 0.02). The largest quality-of-life study to date, from the US Prostate Cancer Outcomes Study,[5] showed that those men who chose LHRHa had increased worry about prostate cancer compared with orchiectomy (67% versus 51%, P = 0.004), possibly because the repeated visits for administration of the agents act as a reminder of the presence of the cancer. Additionally, LHRHa patients felt that their overall health was not as good, and they believed they were not free of cancer more often than those treated with orchiectomy. Satisfaction with treatment was equivalent in both groups (57% for orchiectomy and 54% for LHRHa), and over 90% would choose the same treatment again.

In favor of LHRHa is that the treatments are potentially reversible. For those men with nonmetastatic cancer this may be important, as ongoing studies addressing the possible role of intermittent hormone therapy may show a benefit in the future. However, intermittent therapy, where men typically spend 6 to 9 months alternating on and off the drug, is not of proven advantage in comparison with continuous treatment, and may be inferior. Randomized studies addressing this issue are unlikely to report within 5 years. Alternatives to either form of castration include the use of antiandrogen monotherapy (for example, flutamide or bicalutamide). However, these agents have been shown to be inferior to castration (medical or surgical) in those with metastatic cancer,[6] and their use as monotherapy for metastatic cancer is neither licensed in Canada, nor funded by the BC Cancer Agency.

Surgical orchiectomy is a simple procedure that can be done under local or general analgesic, as a day case procedure. Complications occur infrequently and are usually minor. It is an effective and well-tolerated treatment, comparable to LHRHa. For those men who are ready to accept the surgical castration (up to 30% of men who are presented with the option in an unbiased manner) its use should be encouraged. Additionally, there would be considerable cost savings to the taxpayer. The fee for bilateral orchiectomy is $139, the anesthetic fee is $75, and the daycare hospital charge is $540, for a one-time cost of $754. The annual cost per patient for LHRHa is about $5000. Current spending on LHRHa for metastatic prostate cancer exceeds $5 million annually in BC, so increased utilization of orchiectomy would lead to considerable savings. More importantly, those patients who chose orchiectomy may find superior quality of life compared with drug treatment.

References

1. Agency for Health Care Policy and Research. Relative effectiveness and cost-effectiveness of methods of androgen suppression in the treatment of advanced prostate cancer. In Evidence Report/Technology Assessment #4. Rockville, MD: US Department of Health and Human Services, 1999. Summary [10] Full Text [11]
2. Seidenfeld J, Samson DJ, Hasselblad V, et al. Single-therapy androgen supression in men with advanced prostate cancer: A systematic review and meta-analysis. Ann Internal Med 2000;132:566-577. PubMed Abstract [12] Full Text [13]
3. Cassileth BR, Soloway MS, Vogelzang NJ, et al. Patients’ choice of treatment in stage D prostate cancer. Urology 1989;33(suppl 5):57-62. PubMed Abstract [14]
4. Herr HW, O’Sullivan M. Quality of life of asymptomatic men with nonmetastatic prostate cancer on androgen deprivation therapy. J Urol 2000;163:1743-1746. PubMed Abstract [15] Full Text [16]
5. Potosky AL, Knopf K, Clegg LX, et al. Quality-of-life outcomes after primary androgen deprivation therapy: Results from the Prostate Cancer Outcomes Study. J Clin Oncol 2001;19:3750-3757. PubMed Abstract [17] Full Text [18]
6. Iversen P. Update of monotherapy trials with the new anti-androgen, Casodex (ICI 176,334). International Casodex Investigators. Eur Urol 1994;26(suppl 1):5-9. PubMed Abstract [19]

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Tom Pickles, MD, FRCPC and Gary Steinhoff, MD, FRPSC

Dr Pickles is a radiation oncologist at the BC Cancer Agency and chair of the Provincial Genito-Urinary Tumour Group. Dr Steinhoff is a Victoria urologist and the Urology Representative on the Provincial Genito-Urinary Tumour Group.