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Prostate Cancer Treatment (Professional) (cont.)

Treatment Option Overview

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

State-of-the-art treatment in prostate cancer provides prolonged disease-free survival for many patients with localized disease but is rarely curative in patients with locally extensive tumor. Even when the cancer appears clinically localized to the prostate gland, a substantial fraction of patients will develop disseminated tumor after local therapy with surgery or radiation therapy. This development is the result of the high incidence of clinical understaging, even with current diagnostic techniques. Metastatic tumor is currently not curable.

Surgery is usually reserved for patients in good health who elect surgical intervention.[1,2,3] Tumors in these patients should be confined to the prostate gland (stage I and stage II). Prostatectomy can be performed by the perineal or retropubic approach. The perineal approach requires a separate incision for lymph node dissection. Laparoscopic lymphadenectomy is technically possible and accomplished with much less patient morbidity.[4] For small, well-differentiated nodules, the incidence of positive pelvic nodes is less than 20%, and pelvic node dissection may be omitted.[5] With larger, less differentiated tumors, a pelvic lymph node dissection is more important. The value of pelvic node dissection (i.e., open surgical or laparoscopic) is not therapeutic but spares patients with positive nodes the morbidity of prostatectomy. Radical prostatectomy is not usually performed if frozen section evaluation of pelvic nodes reveals metastases; such patients should be considered for entry into existing clinical trials or receive radiation therapy to control local symptoms. The role of preoperative (neoadjuvant) hormonal therapy is not established.[6,7]

Following radical prostatectomy, pathological evaluation stratifies tumor extent into organ-confined, specimen-confined, and margin-positive disease. The incidence of disease recurrence increases when the tumor is not specimen-confined (extracapsular) and/or the margins are positive.[8,9,10] Results of the outcome of patients with positive surgical margins have not been reported. Patients with extraprostatic disease are suitable candidates for clinical trials. Trials such as RTOG-9601 included the evaluation of postoperative radiation delivery, cytotoxic agents, and hormonal treatment using luteinizing hormone-releasing hormone (LHRH) agonists and/or antiandrogens.

Cryosurgery is a surgical technique under development that involves destruction of prostate cancer cells by intermittent freezing of the prostate tissue with cryoprobes, followed by thawing.[11][Level of evidence: 3iiiC];[12,13][Level of evidence: 3iiiDiv] Cryosurgery is less well established than standard prostatectomy, and long-term outcomes are not as well established as with prostatectomy or radiation therapy. Serious toxic effects include bladder outlet injury, urinary incontinence, sexual impotence, and rectal injury. Impotence is common. (For more information on impotence, refer to the PDQ summary on Sexuality and Reproductive Issues.) The frequency of other side effects and the probability of cancer control at 5 years' follow-up have varied among reporting centers, and series are small compared with surgery and radiation therapy.[12,13]

Candidates for definitive radiation therapy must have a confirmed pathological diagnosis of cancer that is clinically confined to the prostate and/or surrounding tissues (stage I, stage II, and stage III). Patients should have a computed tomographic scan negative for metastases, but staging laparotomy and lymph node dissection are not required. Prophylactic radiation therapy to clinically or pathologically uninvolved pelvic lymph nodes does not appear to improve overall survival (OS) or prostate cancer–specific survival as seen in the RTOG-7706 trial, for example.[14][Level of evidence: 1iiA] In addition, patients considered poor medical candidates for radical prostatectomy can be treated with an acceptably low complication rate if care is given to the delivery technique.[15] Long-term results with radiation therapy are dependent on stage. A retrospective review of 999 patients treated with megavoltage radiation therapy showed cause-specific survival rates to be significantly different at 10 years by T-stage: T1 (79%), T2 (66%), T3 (55%), and T4 (22%).[16] An initial serum prostate-specific antigen (PSA) level higher than 15 ng/mL is a predictor of probable failure with conventional radiation therapy.[17] Several randomized studies have demonstrated an improvement in freedom from biochemical (PSA-based) recurrence with higher doses of radiation therapy (78 Gy–79 Gy) as compared to conventional doses (68 Gy–70 Gy).[18,19,20][Level of evidence: 1iiDiii] The higher doses were delivered using conformal techniques. None of the studies demonstrated a cause-specific survival benefit to higher doses; however, an ongoing study through the Radiation Therapy Oncology Group will be powered for OS.

Interstitial brachytherapy has been employed in several centers, generally for patients with T1 and T2 tumors. Patients are selected for favorable characteristics, including low Gleason score, low PSA level, and stage T1 to T2 tumors. Information and further study are required to better define the effects of modern interstitial brachytherapy on disease control and quality of life and to determine the contribution of favorable patient selection to outcomes.[21][Level of evidence: 3iiiDiv] Information about ongoing clinical trials is available from the NCI Web site.

There is interest in the use of novel radiation techniques (e.g., intensity-modulated radiation therapy, proton-beam therapy, cyber knife) for the treatment of prostate cancer. Although proton therapy could theoretically improve the therapeutic ratio of prostate radiation, allowing for an increase in dose to the tumor without a substantial increase in side effects, no randomized controlled trials have been conducted to compare its efficacy and toxicity with those of other forms of radiation therapy.

Asymptomatic patients of advanced age or with concomitant illness may warrant consideration of careful observation without immediate active treatment.[22,23,24] One population-based study with 15 years of follow-up (mean observation time = 12.5 years) has shown excellent survival without any treatment in patients with well-differentiated or moderately well-differentiated tumors clinically confined to the prostate, irrespective of age.[8] None of these men were detected by PSA screening, since PSA was not available at the time. The patient cohort was followed for a mean of 21 years after initial diagnosis.[25] The risk of prostate cancer progression and prostate cancer death persisted throughout the follow-up period. By the end of follow-up, 91% of the cohort had died; 16% had died of prostate cancer. A second, smaller population-based study of 94 patients with clinically localized prostate cancer managed by a watch and wait strategy gave very similar results at 4 to 9 years of follow-up.[26] In a selected series of 50 stage C patients, 48 of whom had well-differentiated or moderately well-differentiated tumors, the prostate cancer–specific survival rates at 5 and 9 years were 88% and 70%, respectively.[9]

In the United States, as in other settings with widespread PSA screening, the results of conservative management of localized prostate cancer are particularly favorable. In a population-based Surveillance, Epidemiology and End Results (SEER) Medicare-linked database, 14,516 men with localized prostate cancer (T1 or T2 prostate cancer) who were diagnosed from 1992 to 2002 were followed while undergoing conservative management (i.e., no surgery or radiation for at least 6 months) for a median of 8.3 years.[27] The median age at diagnosis was 78 years. At 10 years, the prostate cancer–specific mortality rates were 8.3%, 9.1%, and 25.6% for men with well-differentiated, moderately differentiated, and poorly differentiated tumors, respectively. Corresponding risks of dying of other causes were 59.8%, 57.2%, and 56.6%.[27][Levels of evidence: 3iA, 3iB]

Another population-based observational study of men with clinically localized prostate cancer diagnosed in the PSA-screening era has also been reported, with a median follow-up of 8.2 years.[28] A nationwide Swedish cohort of 6,849 men aged 70 or younger with T1 or T2 prostate cancer, Gleason scores of 7 or lower, and serum PSA levels of lower than 20 ng/mL was followed after an initial strategy of surveillance (N = 2,021), radical prostatectomy (N = 3,399), or radiation therapy (N = 1,429). The cumulative risk of prostate cancer–specific death at 10 years was 3.6% in the initial surveillance group and 2.7% in the curative intent groups (i.e., 2.4% and 3.3% in the prostatectomy and radiation therapy groups, respectively). The 10-year risk of dying from non–prostate-cancer causes was 19.2% in the surveillance group versus 10.2% in the curative intent group, respectively, showing evidence of selection of less healthy patients for surveillance on average.[28][Levels of evidence: 3iA, 3iB]

Tumor pathological characteristics of 222 men in that cohort who followed an initial strategy of surveillance but underwent deferred prostatectomy at a median of 19.2 months (10th –90th percentile, 9.2–45.5 months) were compared to those who underwent immediate prostatectomy.[29] There were no differences between the groups in extraprostatic extension or tumor margin positivity. Although the Gleason scores at radical prostatectomy were higher in the surveillance groups than in the immediate prostatectomy group, this occurred concurrently with a national training effort in prostate tumor pathology evaluation that led to the upgrading of tumor specimens. Therefore, the investigators concluded that the delay in prostatectomy in the surveillance group artifactually led to assignment of higher tumor grades.

Many men with screen-detected prostate cancer are candidates for active surveillance, with definitive therapy reserved for signs of tumor progression. In a retrospective analysis from four of the centers of the European Randomized Study of Screening for Prostate Cancer (ERSPC), 616 men (mean age 66.3 years) in the screening arm represented between 27% and 38% of the men diagnosed with prostate cancer in the trial. The 616 men met the following criteria for active surveillance:[30]

  • PSA =10 ng/mL.
  • PSA density <0.2 ng/mL.
  • Tumor stage T1c/T2.
  • Gleason score =3 + 3 = 6.
  • =2 positive biopsy cores.

With a median follow-up of 3.91 years, the 10-year prostate cancer–specific survival rate was 100%. By 7.75 years, 50% of men had received active treatment; however, 55.8% of these men received treatment despite continued favorable PSA and PSA–doubling time. The OS rate at 10 years was 77%.[30][Level of evidence: 3iiB]

Since the early 1980s, a dramatic increase has occurred in the rates of radical prostatectomy in the United States for men aged 65 to 79 years (5.75-fold rise from 1984 to 1990). Wide geographic variation is seen with these rates.[31] A structured literature review of 144 papers has been done in an attempt to compare the following three primary treatment strategies for clinically localized prostate cancer:[32]

  • Radical prostatectomy.
  • Definitive radiation therapy.
  • Watchful waiting.

The authors concluded that poor reporting and selection factors within all series precluded a valid comparison of efficacy for the three management strategies. In another literature review of a case series of patients with palpable, clinically localized disease, the authors found that 10-year prostate cancer–specific survival rates were best in radical prostatectomy series (about 93%), worst in radiation therapy series (about 75%), and intermediate with deferred treatment (about 85%).[33] Because it is highly unlikely that radiation therapy would worsen disease-specific survival, the most likely explanation is that selection factors affect choice of treatment. Such selection factors make comparisons of therapeutic strategies imprecise.[34] A retrospective analysis of outcomes of men demonstrated a 10-year disease-specific survival rate of 94% for expectant management for Gleason score 2 to 4 tumors and 75% for Gleason score 5 to 7 tumors;[35] this is similar to a previous study using the Surveillance, Epidemiology, and End Results database with survival rates of 93% and 77%, respectively.[36]

Radical prostatectomy has been compared to watchful waiting in men with early-stage disease (i.e., clinical stages T1b, T1c, or T2) in a randomized clinical trial performed in Sweden in the pre-PSA screening era.[37,38] Only about 5% of the men in the trial had been diagnosed by PSA screening. The estimated overall mortality difference after 12 years between the radical prostatectomy and watchful waiting arms of the study was not statistically significant: 32.7% versus 39.8%, P = .09; see Figure 1.[39][Level of evidence: 1iiA]
Scandinavian Prostate Cancer Group-4 study; flow diagram shows participants randomly allocated to radical prostatectomy versus watchful waiting within 12 months, results of follow-up after 12 months and to the end of year 2006, and an analysis according to intention to treat.
Figure 1. Scandinavian Prostate Cancer Group-4 (SPCG-4) study. Trial flow diagram of the 695 men randomly assigned in the SPCG-4 study. RT equals radiation therapy; RP equals radical prostatectomy. Copyright A. Bill-Axelson 2008. Published by Oxford University Press. All rights reserved.

In a post hoc subset analysis, there was a statistically significant difference in overall mortality favoring prostatectomy for men aged 65 years and younger: 21.9% versus 40.2%, P = .004 (relative risk [RR] of death = 0.59; 95% confidence interval [CI], 0.41–0.85).[38] In contrast, for men aged 65 years or older, the overall mortality at 12 years for the prostatectomy and watchful waiting arms was 42% versus 39.3%; P = 0.81 (RR of death = 1.04; 95% CI, 0.77–1.40). Overall prostate cancer–specific mortality in the full trial at 12 years favored prostatectomy: 12.5% versus 17.9%, P = .03; RR = 0.65; 95% CI, 0.45–0.94; see Figure 2.[39][Level of evidence: 1iiB]
Scandinavian Prostate Cancer Group-4 study cumulative incidence; six line graphs show the cumulative incidence of six different endpoints in the radical prostatectomy and watchful waiting groups. The probability of a given endpoint is shown on the y-axis, and time (from 0-12 years) is shown on the x-axis. Endpoints include overall mortality, prostate cancer death, metastases, local progression, the use of hormonal treatment, and the use of other palliative treatment. Higher cumulative incidence of each endpoint is shown in the watchful waiting group, with statistically significant differences shown for all endpoints except overall mortality. 95% confidence intervals are shown at 4, 6, and 8 years of follow-up.
Figure 2. Cumulative incidence with 95% confidence intervals (CIs) at 4, 8, and 12 years of endpoints for all patients. A) Overall mortality: relative risk (RR) equals 0.82; 95% CI, 0.65–1.03; P equals .09. B) Prostate cancer (PC) death: RR equals 0.65; 95% CI, 0.45–0.94; P equals .03. C) Metastases: RR equals 0.65; 95% CI, 0.47–0.88; P equals .006. D) Local progression: RR equals 0.36; 95% CI, 0.27–0.47; P less than .001. E) Hormonal treatment: RR equals 0.54; 95% CI, 0.44 –0.68; P less than .001. F) Other palliative treatment: RR equals 0.63; 95% CI, 0.41–0.97; P equals .04. P values (two-sided) were calculated using Gray's test. Copyright A. Bill-Axelson 2008. Published by Oxford University Press. All rights reserved.

Results from the Prostate Intervention Versus Observation Trial (PIVOT-1), a randomized trial in the United States that compared radical prostatectomy with watchful waiting, have not been reported. The PIVOT used overall mortality as its primary endpoint. (Refer to the Stage II Prostate Cancer treatment section of this summary for more information.)

Cryotherapy is also under evaluation for the treatment of localized prostate cancer. There is limited evidence on its efficacy and safety compared to the more commonly used local therapies, and the technique is evolving in an attempt to reduce local toxicity and normal tissue damage (see below). The quality of evidence on efficacy is low, currently limited to case series of relatively small size, short follow-up, and surrogate outcomes of efficacy.[40]

Surgical Complications

Complications of radical prostatectomy can include urinary incontinence, urethral stricture, impotence, [41] and the morbidity associated with general anesthesia and a major surgical procedure. (For more information on impotence, refer to the PDQ summary on Sexuality and Reproductive Issues.) An analysis of Medicare records on 101,604 radical prostatectomies performed from 1991 to 1994 showed a 30-day operative mortality rate of 0.5%, a rehospitalization rate of 4.5%, and a major complication rate of 28.6%; over the study period, these rates decreased by 30%, 8%, and 12%, respectively.[42] Prostatectomies done at hospitals where fewer prostatectomies were performed were associated with higher rates of 30-day postoperative mortality, major acute surgical complications, longer hospital stays, and higher rates of rehospitalization than those done at hospitals where more prostatectomies were performed. Morbidity and mortality rates increase with age.[31,43] Comorbidity, especially underlying cardiovascular disease and a history of stroke, accounts for a portion of the age-related increase in 30-day mortality. In a cohort of all men with prostate cancer who underwent radical prostatectomy from 1990 to 1999 in Ontario, 75-year-old men with no comorbidities had a predicted 30-day mortality of 0.74%.[43] Thirty-day surgical complication rates also depended more on comorbidity than age (i.e., about 5% vs. 40% for 0 vs. 4 or more underlying comorbid conditions).

In one large case series of men undergoing the anatomic (nerve-sparing) technique of radical prostatectomy, approximately 6% of the men required the use of pads for urinary incontinence, but an unknown additional proportion of men had occasional urinary dribbling. About 40% to 65% of the men who were sexually potent before surgery retained potency adequate for vaginal penetration and sexual intercourse.[44] Preservation of potency with this technique is dependent on tumor stage and patient age, but the operation probably induces at least a partial deficit in nearly all patients.[44]

A national survey of Medicare patients who underwent radical prostatectomy in 1988 to 1990 reported more morbidity than in the case series.[45] In that survey, more than 30% of the men reported the need for pads or clamps for urinary wetness, and 63% of all patients reported a current problem with wetness. About 60% of the men reported having no erections since surgery; about 90% of the men had no erections sufficient for intercourse during the month before the survey. (For more information on erectile dysfunction, refer to the Sexuality and Reproductive Issues summary.) About 28% of the patients reported follow-up treatment of cancer with radiation therapy and/or hormonal therapy within 4 years after their prostatectomy.

In a population-based longitudinal cohort (Prostate Cancer Outcomes Study) of 901 men aged 55 to 74 years who had recently undergone radical prostatectomy for prostate cancer, 15.4% of the men had either frequent urinary incontinence or no urinary control at 5 years after surgery, and 20.4% of those studied wore pads to stay dry.[46] Inability to have an erection sufficient for intercourse was reported by 79.3% of men. Reasons for the difference in outcomes between the population-based surveys and previous case series could include the following:

  • Age difference among the populations.
  • Surgical expertise at the major reporting centers.
  • Selection factors.
  • Publication bias of favorable series.
  • Different methods of collecting information from patients.

Case series of 93, 459, and 89 men who had undergone radical prostatectomy by experienced surgeons showed rates of impotence as high as those in the national Medicare survey when men were carefully questioned about sexual potency, though the men in the case series were on average younger than those in the Medicare survey.[47,48,49] One of the case series used the same questionnaire as that used in the Medicare survey.[47] The urinary incontinence rate in that series was also similar to that in the Medicare survey.

A cross-sectional survey of prostate cancer patients who were treated in a managed care setting by radical prostatectomy, radiation therapy, or watchful waiting showed substantial sexual and urinary dysfunction in the prostatectomy group.[50] Results reported by the patients were consistent with those from the national Medicare survey. In addition, though statistical power was limited, differences in sexual and urinary dysfunction between men who had undergone either nerve-sparing or standard radical prostatectomy were not statistically significant. (For information on sexual and urinary dysfunction, refer to the Sexuality and Reproductive Issues summary.) This issue requires more study.

Case series in men who have undergone radical prostatectomy have shown shortening of penile length (by an average of 1–2 cm).[51,52,53] The functional consequence of the shortening is not well studied, but it is noticeable to some men.

Retrospective cohort studies and case series have shown an increased incidence of inguinal hernia, in the range of 7% to 21%, in men undergoing radical prostatectomy, with rates peaking within 2 years of surgery.[54,55,56,57,58] Observational studies suggest that the rates are higher than in comparable men who have undergone prostate biopsy alone, transurethral resections, and simple open prostatectomy for benign disease;[54,55] or in men with prostate cancer who have undergone pelvic lymph node dissection alone or radiation therapy.[54,56,57] Although the observations of increased rates of inguinal hernia after radical prostatectomy are consistent, it is conceivable that men with prostate cancer who are being followed carefully by urologists could have higher detection rates of hernia as a result of frequent examinations or diagnostic imaging (i.e., "detection bias"). Men should be made aware of this potential complication of prostatectomy.

Radical prostatectomy may also cause fecal incontinence, and the incidence may vary with surgical method.[59] In a national survey sample of 907 men who had undergone radical prostatectomy at least 1 year before the survey, 32% of the men who had undergone perineal (nerve-sparing) radical prostatectomy and 17% of the men who had undergone retropubic radical prostatectomy reported accidents of fecal leakage. Ten percent and 4% of the respondents reported moderate and large amounts of fecal leakage, respectively. Fewer than 15% of men with fecal incontinence had reported it to a physician or health care provider.

Radiation Therapy Complications

Definitive external-beam radiation therapy (EBRT) can result in acute cystitis, proctitis, and sometimes enteritis.[1,41,49,60,61,62] These conditions are generally reversible but may be chronic and rarely require surgical intervention. Potency, in the short term, is preserved with radiation therapy in most cases but may diminish over time.[62] A cross-sectional survey of prostate cancer patients who had been treated in a managed care setting by radical prostatectomy, radiation therapy, or watchful waiting showed substantial sexual and urinary dysfunction in the radiation therapy group.[50] (Refer to the PDQ summary on Sexuality and Reproductive Issues for more information.)

Morbidity may be reduced with the employment of sophisticated radiation therapy techniques—such as the use of linear accelerators—and careful simulation and treatment planning.[63] Radiation side effects of three-dimensional conformal versus conventional radiation therapy using similar doses (total dose of 60–64 Gy) have been compared in a randomized nonblinded study.[64][Level of evidence: 1iiC] No differences were observed in acute morbidity, and late side effects serious enough to require hospitalization were infrequent with both techniques; however, the cumulative incidence of mild or greater proctitis was lower in the conformal arm than in the standard therapy arm (37% vs. 56%; P = .004). Urinary symptoms were similar in the two groups as were local tumor control and OS rates at 5 years' follow-up.

Radiation therapy can be delivered after an extraperitoneal lymph node dissection without an increase in complications if careful attention is paid to radiation technique. The treatment field should not include the dissected pelvic nodes. Previous transurethral resection of the prostate (TURP) increases the risk of stricture above that seen with radiation therapy alone, but if radiation therapy is delayed 4 to 6 weeks after the TURP, the risk of stricture can be minimized.[65,66,67] Pretreatment TURP to relieve obstructive symptoms has been associated with tumor dissemination; however, multivariate analysis in pathologically staged cases indicates that this is the result of a worse underlying prognosis of the cases that require TURP rather than the result of the procedure itself.[68]

A population-based survey of Medicare recipients who had received radiation therapy as primary treatment of prostate cancer (similar in design to the survey of Medicare patients who underwent radical prostatectomy,[45] described above) has been reported, showing substantial differences in posttreatment morbidity profiles between surgery and radiation therapy.[69] Although the men who had undergone radiation therapy were older at the time of initial therapy, they were less likely to report the need for pads or clamps to control urinary wetness (7% vs. more than 30%). A larger proportion of patients treated with radiation therapy before surgery reported the ability to have an erection sufficient for intercourse in the month before the survey (men <70 years, 33% who received radiation therapy vs. 11% who underwent surgery alone; men =70 years, 27% who received radiation therapy vs. 12% who underwent surgery alone). Men receiving radiation therapy, however, were more likely to report problems with bowel function, especially frequent bowel movements (10% vs. 3%). As in the results of the surgical patient survey, about 24% of radiation patients reported additional subsequent treatment of known or suspected cancer persistence or recurrence within 3 years of primary therapy.

Sildenafil citrate may be effective in the management of sexual dysfunction after radiation therapy in some men. In a randomized placebo-controlled, crossover design study (RTOG-0215) of 60 men who had undergone radiation therapy for clinically localized prostate cancer, and who reported erectile dysfunction that began after their radiation therapy, 55% reported successful intercourse after sildenafil versus 18% after placebo (P <.001).[70][Level of evidence: 1iC]

A prospective community-based cohort of men aged 55 to 74 years treated with radical prostatectomy (N = 1156) or EBRT (N = 435) attempted to compare acute and chronic complications of the two treatment strategies after adjusting for baseline differences in patient characteristics and underlying health.[71] Regarding acute treatment-related morbidity, radical prostatectomy was associated with higher rates of cardiopulmonary complications (5.5% vs. 1.9%) and the need for treatment of urinary strictures (17.4% vs. 7.2%). Radiation therapy was associated with more acute rectal proctitis (18.7% vs. 1.6%). With regard to chronic treatment-related morbidity, radical prostatectomy was associated with more urinary incontinence (9.6% vs. 3.5%) and impotence (80% vs. 62%). Radiation therapy was associated with slightly greater declines in bowel function.

Radiation is also known to be carcinogenic.[72,73] EBRT for prostate cancer is associated with an increased risk of both bladder and rectal cancer. Brachytherapy is associated with bladder cancer.

Cryotherapy Complications

Impotence is common in the reported case series, ranging from about 47% to 100%. Other major complications include incontinence, urethral sloughing, urinary fistula or stricture, and bladder neck obstruction.[40]

Hormone Therapy Complications

Several different hormonal approaches can benefit men in various stages of prostate cancer. These approaches include bilateral orchiectomy, estrogen therapy, LHRH agonists, antiandrogens, ketoconazole, and aminoglutethimide.

Benefits of bilateral orchiectomy include ease of the procedure, compliance, its immediacy in lowering testosterone levels, and low cost. Disadvantages include psychologic effects, loss of libido, impotence, hot flashes, and osteoporosis.[41,74] (For information on loss of libido and impotence, refer to the Sexuality and Reproductive Issues summary; refer to the PDQ summary on Fever, Sweats, and Hot Flashes.)

Estrogens at a dose of 3 mg per day of diethylstilbestrol will achieve castrate levels of testosterone. Like orchiectomy, estrogens may cause loss of libido and impotence. Gynecomastia may be prevented by low-dose radiation therapy to the breasts. Estrogen is seldom used today because of the risk of serious side effects, including myocardial infarction, cerebrovascular accident, and pulmonary embolism.

In a population-based study within the Veterans Administration system, LHRH agonists were associated with an increased risk of diabetes as well as cardiovascular disease, including coronary heart disease, myocardial infarction, sudden death, and stroke. Bilateral orchiectomy was also associated with an elevated risk of coronary heart disease and myocardial infarction.[75,76,77]

LHRH agonists such as leuprolide, goserelin, and buserelin will lower testosterone to castrate levels. Like orchiectomy and estrogens, LHRH agonists cause impotence, hot flashes, and loss of libido. Tumor flare reactions may occur transiently but can be prevented by antiandrogens or by short-term estrogens at low dose for several weeks. There is conflicting evidence regarding whether LHRH agonists are associated with increased risk of cardiovascular morbidity or mortality.[78]

The pure antiandrogen flutamide may cause diarrhea, breast tenderness, and nausea. Case reports show fatal and nonfatal liver toxic effects.[79] Bicalutamide may cause nausea, breast tenderness, hot flashes, loss of libido, and impotence.[80] (For information on diarrhea, refer to the Gastrointestinal Complications summary; refer to the Nausea and Vomiting and the Fever, Sweats, and Hot Flashes summaries; and for information on loss of libido and impotence, refer to the Sexuality and Reproductive Issues summary.) The steroidal antiandrogen megestrol acetate suppresses androgen production incompletely and is generally not used as initial therapy.

Long-term use of ketoconazole can result in impotence, pruritus, nail changes, and adrenal insufficiency. (Refer to the PDQ summary on Pruritus for more information.) Aminoglutethimide commonly causes sedation and skin rashes. A national Medicare survey of men who had undergone radical prostatectomy for prostate cancer showed a decrease in all seven health-related quality-of-life measures (impact of cancer and treatment, concern regarding body image, mental health, general health, activity, worries about cancer and dying, and energy) in men who had received androgen-depletion therapy (either medically or surgically induced) versus those who had not.[81][Level of evidence: 3iC] Additional studies that evaluate the effects of various hormone therapies on quality of life are required.[82]

Androgen-deprivation therapy also can cause osteoporosis and bone fractures. In a population-based sample of 50,613 Medicare patients aged 66 years or older followed for a median of 5.1 years, men who had been treated with either a gonadotropin-releasing hormone (GnRH) or orchiectomy had a 19.4% bone fracture rate compared to 12.6% in men who had not received hormone-deprivation therapy. The effect was similar in men whether or not they had metastatic bone disease.[83] A small nonblinded study with short follow-up suggests that the bisphosphonate pamidronate can prevent bone loss in men receiving a GnRH agonist for prostate cancer.[84] Forty-seven prostate cancer patients (41 evaluable) with locally advanced prostate cancer, but with no known bone metastases, were randomly assigned to receive 3-monthly depot leuprolide with or without pamidronate (60 mg intravenously). No bone fractures were reported in either group. The use of surrogate endpoints and unblinded assessment of endpoints makes it difficult to know with certainty whether pamidronate use would prevent fractures.[84][Level of evidence: 1iiDiii]

The use of androgen deprivation therapy has also been associated with an increased risk of colorectal cancer. Using the SEER Medicare database, investigators assessed the risk of subsequent colorectal cancer in 107,859 men aged 67 years and older after an initial diagnosis of prostate cancer.[85] The rates of colorectal cancer per 1,000 person-years were 6.3 (95% CI, 5.3–7.5) in men who had orchiectomy, 4.4 (95% CI, 4.0–4.9) in men treated with GnRH agonists, and 3.7 (95% CI, 3.5–3.9) in men who had no androgen deprivation. In men treated with GnRH agonists, the risk increased with increasing duration of treatment (P for trend = .01).

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