Treatment Option Overview for Prostate Cancer
Local treatment modalities are associated with prolonged disease-free survival for many patients with localized prostate cancer but are rarely curative in patients with locally extensive tumors. Because of clinical understaging using current diagnostic techniques, even when the cancer appears clinically localized to the prostate gland, some patients develop disseminated tumors after local therapy with surgery or radiation. Metastatic prostate cancer is currently not curable.
Treatment options for each stage of prostate cancer are presented in Table 9.
Watchful Waiting or Active Surveillance
Asymptomatic patients of advanced age or with concomitant illness may warrant consideration of careful observation without immediate active treatment.[1,2] Watch and wait, observation, expectant management, and active surveillance are terms indicating a strategy that does not employ immediate therapy with curative intent.
Watchful waiting and active surveillance are the most commonly used terms, and the literature does not always clearly distinguish them, making the interpretation of results difficult. The general concept of watchful waiting is patient follow-up with the application of palliative care as needed to alleviate symptoms of tumor progression. There is no planned attempt at curative therapy at any point in follow-up. For example, TURP or hormonal therapy may be used to alleviate tumor-related urethral obstruction should there be local tumor growth; hormonal therapy or bone radiation might be used to alleviate pain from metastases. Radical prostatectomy has been compared with watchful waiting or active surveillance in men with early-stage disease (i.e., clinical stages T1b, T1c, or T2). (Refer to the Radical Prostatectomy section in the Treatment Option Overview for Prostate Cancer section of this summary.)
In contrast, the strategy behind active surveillance is to defer therapy for clinically localized disease but regularly follow the patient and initiate local therapy with curative intent if there are any signs of local tumor progression.[4-6] The idea is to avoid the morbidity of therapy in men who have indolent or nonprogressive disease but preserve the ability to cure them should the tumor progress. Active surveillance usually involves:
- Regular patient visits.
- Digital rectal examinations.
- Prostate-specific antigen (PSA) testing.
- Transrectal ultrasound.
- Transrectal needle biopsies.
Patient selection, testing intervals, and specific tests, as well as criteria for intervention, are arbitrary and not established in controlled trials.
In the United States, as in other settings with widespread PSA screening, the results of conservative management of localized prostate cancer are particularly favorable. Many men with screen-detected prostate cancer are candidates for active surveillance, with definitive therapy reserved for signs of tumor progression.
Evidence (watchful waiting or active surveillance):
- A population-based study with 15 years of follow-up (mean observation time of 12.5 years) has shown excellent survival without any treatment in patients with well-differentiated tumors or moderately well-differentiated tumors clinically confined to the prostate, irrespective of age.
- Tumor was not detected in any of these men 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. 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 had very similar results at 4 to 9 years of follow-up.
- In a selected series of 50 Jewett stage C patients, 48 of whom had well-differentiated tumors or moderately well-differentiated tumors, the prostate cancer-specific survival rate at 5 years was 88% and, at 9 years, the rate was 70%.
- In a population-based Surveillance, Epidemiology and End Results (SEER) Medicare-linked database, 14,516 men with localized prostate cancer (T1 or T2 cancer) diagnosed from 1992 to 2002 were followed on conservative management (no surgery or radiation for at least 6 months) for a median of 8.3 years. The median age at diagnosis was 78 years.[Levels of evidence: 3iA, 3iB]
- At 10 years, the prostate cancer-specific mortality rates were 8.3% for men with well-differentiated tumors, 9.1% for men with moderately well-differentiated tumors, and 25.6% for men with poorly differentiated tumors.
- Corresponding risks of dying of other causes were 59.8%, 57.2%, and 56.6%, respectively.
- 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. A nationwide Swedish cohort of 6,849 men aged 70 years 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).[Levels of evidence: 3iA, 3iB]
- 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% in the prostatectomy group and 3.3% in the radiation therapy group).
- The 10-year risk of dying from causes other than prostate cancer was 19.2% in the surveillance group versus 10.2% in the curative intent group, showing evidence of selection of patients who were not as healthy for surveillance on average.
- Tumor pathologic 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 with those who underwent immediate prostatectomy. 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 group 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 the assignment of higher tumor grades.
- A retrospective analysis of outcomes of men with prostate cancer 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; this is similar to a previous study using the SEER database with survival rates of 93% and 77%, respectively.
- In a retrospective analysis from the European Randomized Study of Screening for Prostate Cancer (ERSPC), 616 men (mean age of 66.3 years) diagnosed with prostate cancer in the screening arm met criteria for active surveillance that included PSA (≤10 ng/ml). PSA density (<0.2 ng/ml), tumor stage T1c/T2, Gleason score (≤3 + 3 = 6), or two or more positive biopsy cores.[Level of evidence: 3iiB]
- 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 (but 55.8% of these men received treatment despite continued favorable PSA and PSA-doubling time). The overall survival (OS) rate at 10 years was 77%.
(Refer to the Stage II Prostate Cancer Treatment section of this summary for more information.)
- Are in good health and elect surgical intervention.
- Have tumor 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. For small, well-differentiated nodules, the incidence of positive pelvic nodes is less than 20%, and pelvic node dissection may be omitted. 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) in these cases 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.
Following radical prostatectomy, pathologic evaluation stratifies tumor extent into the following classes:
- Margin-positive disease—The incidence of disease recurrence increases when the tumor margins are positive.[7,10,24] Results of the outcome of patients with positive surgical margins have not been systematically reported.
- Specimen-confined disease—The incidence of disease recurrence increases when the tumor is not specimen-confined (extracapsular).[7,10]
- Organ-confined disease—Patients with extraprostatic disease (not organ-confined) are suitable candidates for clinical trials of which the Radiation Therapy Oncology Group's (RTOG) RTOG-9601 (NCT00002874) trial, was an example. These trials have included evaluation of postoperative radiation delivery, cytotoxic agents, and hormonal treatment using luteinizing hormone-releasing hormone (LH-RH) agonists and/or antiandrogens.
Radical prostatectomy compared with other treatment options
In 1993, a structured literature review of 144 papers was done in an attempt to compare the three primary treatment strategies for clinically localized prostate cancer:
- Radical prostatectomy.
- Definitive radiation therapy.
- Observation (watchful waiting or active surveillance).
The authors concluded that poor reporting and selection factors within all series precluded a valid comparison of efficacy for the three management strategies.
In a literature review of 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%). 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.
Radical prostatectomy has been compared with watchful waiting or active surveillance in men with early-stage disease (i.e., clinical stages T1b, T1c, or T2) in randomized trials, with conflicting results. The difference in results may be the result of differences in how the men were diagnosed with prostate cancer.
Evidence (radical prostatectomy vs. watchful waiting or active surveillance):
- In a randomized clinical trial performed in Sweden in the pre-PSA screening era, 695 men with prostate cancer were randomly assigned to radical prostatectomy versus watchful waiting. Only about 5% of the men in the trial had been diagnosed by PSA screening. Therefore, the men had more extensive local disease than is typically the case in men diagnosed with prostate cancer in the United States.[28-30]
- The cumulative overall mortality at 18 years was 56.1% in the radical prostatectomy arm and 68.9% in the watchful waiting study arm (absolute difference, 12.7%; 95% confidence interval [CI], 5.1–20.3 percentage points; relative risk [RR]death of 0.71; 95% CI, 0.59–0.86).[Level of evidence: 1iiA]
- The cumulative incidence of prostate cancer deaths at 18 years was 17.7% versus 28.7% (absolute difference, 11.0%; 95% CI, 4.5–17.5 percentage points; RRdeath from prostate cancer, 0.56; 95% CI, 0.41–0.77).
- In a post-hoc–subset analysis, the improvement in overall and prostate cancer-specific mortality associated with radical prostatectomy was restricted to men younger than 65 years.
- The Prostate Intervention Versus Observation Trial (PIVOT-1 or VA-CSP-407
[NCT00002606]) is the only published randomized trial conducted in the PSA screening era that directly compared radical prostatectomy with watchful waiting. From November 1994 through January 2002, 731 men aged 75 years or younger with localized prostate cancer (stage T1–2, NX, M0, with a blood PSA <50 ng/ml) and a life expectancy of at least 10 years were randomly assigned to radical prostatectomy versus watchful waiting.[31,32][Levels of evidence 1iiA, 1iiB]
- About 50% of the men had nonpalpable, screen-detected disease.
- After a median follow-up of 10 years (range up to about 15 years), the all-cause mortality was 47.0% versus 49.9% in the prostatectomy and watchful-waiting study arms, respectively, a difference that was not statistically significant (hazard ratio [HR], 0.88; 95% CI, 0.71–1.08; P = .22). Prostate cancer-specific mortality was 5.8% versus 8.4%, and it also was not statistically significant (HR, 0.63; 95% CI, 0.36–1.09; P = .09].
- Subgroup analyses showed a statistically significant reduction in overall mortality in the group of men with a baseline PSA greater than 10 ng/ml (61 of 126 men vs. 77 of 125 men; HR, 0.67) but no difference in men with a PSA of 10 ng/ml or less (110 of 238 men vs. 101 of 241 men; HR, 1.03; P value for interaction = .04). Because the test for interaction was not adjusted for the numerous subgroup comparisons, it should be interpreted with caution.
- Although there was a trend favoring prostatectomy, for prostate cancer-specific mortality, in men with a PSA greater than 10 ng/ml, the numbers were very small (7 of 126 men vs. 16 of 125 men for a PSA >10 ng/ml; 14 of 238 men vs. 15 of 241 men with lower PSA levels), and the interaction with the PSA level was not statistically significant (P = .11). There were no statistically significant differences in efficacy associated with prostatectomy by age (<65 years vs. ≥65 years), Gleason score, Charlson comorbidity status, race, or performance score.
Complications of radical prostatectomy
Complications of radical prostatectomy include the following:
Morbidity and mortality associated with radical prostatectomy
An analysis of Medicare records on 101,604 radical prostatectomies performed from 1991 to 1994 showed the following:
- A 30-day operative mortality rate of 0.5%.
- A rehospitalization rate of 4.5%.
- A major complication rate of 28.6%.
Over the study period, these rates decreased by 30%, 8%, and 12%, respectively.
- Higher rates of 30-day postoperative mortality.
- Major acute surgical complications.
- Longer hospital stays.
- Higher rates of rehospitalization.
Operative morbidity and mortality rates increase with age. 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%. Thirty-day surgical complication rates also depended more on comorbidity than age (i.e., about 5% vs. 40% for men with 0 vs. ≥4 underlying comorbid conditions, respectively).
Urinary incontinence and impotence
Urinary incontinence and impotence are complications that can result from radical prostatectomy and have been studied in multiple studies.
(Refer to the PDQ summary on Sexuality and Reproductive Issues for more information on impotence and erectile and urinary dysfunction.)
Evidence (urinary incontinence and impotence following radical prostatectomy):
- A large case series of men undergoing the anatomic (nerve-sparing) technique of radical prostatectomy reported the following:
- 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. 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.
- A national survey of Medicare patients who underwent radical prostatectomy in 1988 to 1990 reported more morbidity than in the case series reported above.
- 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. (Refer to the PDQ summary on Sexuality and Reproductive Issues for more information on erectile dysfunction.)
- About 28% of the patients reported follow-up treatment of cancer with radiation therapy and/or hormonal therapy within 4 years after their prostatectomy.
- 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 reported the following:
- 15.4% of the men had either frequent urinary incontinence or no urinary control at 5 years after surgery.
- 20.4% of those studied wore pads to stay dry.
- 79.3% of men reported an inability to have an erection sufficient for intercourse.
- A cross-sectional survey of prostate cancer patients who were treated with radical prostatectomy, radiation therapy, or watchful waiting and active surveillance in a managed care setting showed substantial sexual and urinary dysfunction in the prostatectomy group.
- Results reported by the patients were consistent with those from the national Medicare survey.
- In addition, although 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. (Refer to the PDQ summary on Sexuality and Reproductive Issues for more information on sexual and urinary dysfunction.) This issue requires more study.
- 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, although the men in these case series were on average younger than those in the Medicare survey.[41-43] One of the case series used the same questionnaire as that used in the Medicare survey. The urinary incontinence rate in that series was also similar to that in the Medicare survey.
Differences are often reported between population-based surveys and case series from individual centers. Reasons could include the following:
- Age differences among the populations.
- Surgical expertise at the major reporting centers.
- Patient selection factors.
- Publication bias of favorable series.
- Different methods of collecting information from patients.
Case series of men who have undergone radical prostatectomy have shown shortening of penile length (by an average of 1–2 cm).[44-46] The functional consequence of the shortening is not well studied, but it is noticeable to some men. (Refer to the PDQ summary on Sexuality and Reproductive Issues for more information.)
In a registry of men with rising PSA after initial treatment of clinically localized prostate cancer, 19 of 510 men (3.7%) who had undergone radical prostatectomy complained of reduced penile size. However, the data were based upon physician reporting of patients' complaints rather than direct patient questioning or before-and-after measurement of penile length. Also, the study sample was restricted to patients with known or suspected tumor recurrence, making generalization difficult.
Inguinal hernia has been reported as a complication of radical prostatectomy.
Evidence (inguinal hernia following radical prostatectomy):
- 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.[47-51]
- 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;[47,48] or in men with prostate cancer who have undergone pelvic lymph node dissection alone or radiation therapy.[47,49,50]
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 cause fecal incontinence, and the incidence may vary with surgical method.
Evidence (fecal incontinence following radical prostatectomy):
- 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 of the respondents reported moderate amounts of fecal leakage, and 4% of the respondents reported large amounts of fecal leakage. Fewer than 15% of men with fecal incontinence had reported it to a physician or health care provider.
External-beam radiation therapy (EBRT)
Candidates for definitive radiation therapy must have a confirmed pathologic diagnosis of cancer that is clinically confined to the prostate and/or surrounding tissues (stage I, stage II, and stage III). Staging laparotomy and lymph node dissection are not required.
Radiation therapy may be a good option for patients who are considered poor medical candidates for radical prostatectomy. These patients can be treated with an acceptably low complication rate if care is given to the delivery technique.
Long-term results with radiation therapy are dependent on stage and are associated with dosimetry of the radiation.
- A retrospective review of 999 patients treated with megavoltage radiation therapy showed that cause-specific survival rates at 10 years varied substantially by T stage: T1 (79%), T2 (66%), T3 (55%), and T4 (22%). An initial serum PSA level higher than 15 ng/ml is a predictor of probable failure with conventional radiation therapy.
- Several randomized studies have demonstrated an improvement in freedom from biochemical (PSA based) recurrence with higher doses of radiation therapy (74–79 Gy) as compared with lower doses (64–70 Gy).[57-60][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. For example, in the MRC-RT01 [NCT00003290] study that was powered to detect differences in both biochemical progression-free survival (PFS) and a 15% difference in OS, 843 men with stage T1b through T3a, N0, M0 prostate cancer were randomly assigned to receive 64 Gy in 32 fractions versus 74 Gy in 37 fractions by conformal delivery. Men in both study groups received neoadjuvant LH-RH agonist injections every 4 weeks for 3 to 6 months before the start of radiation therapy and throughout the radiation course.
- After a median follow-up of 10 years, despite a statistically significant improvement in biochemical PFS with the higher dose of radiation, the 10-year OS was the same in both groups: 71% (HR, 0.99; 95% CI, 0.77–1.28; P = .96). Likewise, there were no differences in prostate cancer-specific survival.
- Another ongoing study through the RTOG (RTOG-0126 [NCT00033631]) has been powered for OS.
- In a small randomized trial, primarily from one treatment center, conventional hypofractionation was not found to be superior to conventional fractionation. In the trial, 303 assessable men were randomly assigned to receive intensity-modulated radiation therapy (IMRT) for a total of 76 Gy in 38 fractions at 2.0 Gy per fraction (conventional IMRT [CIMRT]) versus IMRT for a total of 70.2 Gy in 26 fractions at 2.7 per fraction (hypofractionated IMRT [HIMRT]).
- The primary endpoint was biochemical or clinical disease failure (BCDF). The 5-year BCDF rates in the two arms were 21.4% for the CIMRT arm (95% CI, 14.8%–28.7%) and 23.3% for the HIMRT arm (95% CI, 16.4%–31.0%), P = .75.
- Likewise, there were no statistically significant differences in the secondary endpoints of overall mortality, prostate cancer–specific mortality, prostate local failure, or distant failure, though the mortality rates were low, and the trial was underpowered for mortality endpoints.[Level of evidence: 1iiDiii]
Prophylactic radiation therapy to clinically or pathologically uninvolved pelvic lymph nodes does not appear to improve OS or prostate cancer-specific survival as was seen in the RTOG-7706 trial, for example.[Level of evidence: 1iiA]
Patients undergoing brachytherapy are often selected for favorable characteristics that include the following:
- Low Gleason score.
- Low PSA level.
- Stage T1 to T2 tumors.
More 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.[Level of evidence: 3iiiDiv]
Information about ongoing clinical trials is available from the NCI Web site.
Alpha emitter radiation
Radium-223 emits alpha particles (i.e., two protons and two neutrons bound together, identical to a helium nucleus) with a half-life of 11.4 days. It is administered intravenously and selectively taken up by newly formed bone stroma. The high-energy alpha particles have a short range of less than 100 mcM. Radium-223 has been shown to improve OS in patients with prostate cancer metastatic to bone. With administration at a dose of 50kBq per kg body weight every 4 weeks for six injections, the side effects were similar to those of a placebo.
Complications of radiation therapy
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 and active surveillance showed substantial sexual and urinary dysfunction in the radiation therapy group. (Refer to the PDQ summary on Sexuality and Reproductive Issues for more information.)
Radiation is also known to be carcinogenic.[68-70] EBRT for prostate cancer is associated with an increased risk of bladder and gastrointestinal cancer. Brachytherapy is associated with an increased risk of bladder cancer.
Potency, in most cases, is preserved with radiation therapy in the short term but appears to diminish over time. Sildenafil citrate may be effective in the management of sexual dysfunction after radiation therapy in some men.
- In a completed, randomized, placebo-controlled, crossover design study (RTOG-0215 [NCT00057759]) 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).[Level of evidence: 1iC]
- A randomized trial (RTOG-0831 [NCT00931528]) of 121 men with intact erectile function compared daily preventive tadalafil (5 mg orally per day) with placebo for 24 weeks beginning at the start of either EBRT or brachytherapy.[Level of evidence: 1iC]
- There were no statistically significant differences in spontaneous erectile function (the primary endpoint) or any other measures of sexual function.
Evidence (3-dimensional conformal vs. conventional radiation therapy):
- The side effects of similar doses of 3-D conformal radiation therapy and conventional radiation
therapy (total dose = 60–64 Gy) have been compared in a
randomized nonblinded study.[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 radiation arm than in the standard therapy arm (37% vs. 56%; P = .004). Urinary symptoms were similar in the two treatment groups, as were local tumor control and OS rates at 5 years of 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 area that contained the dissected pelvic nodes. Previous TURP is associated with an increased 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 is lower.[75-77] Pretreatment TURP to relieve obstructive symptoms has been associated with tumor dissemination; however, multivariable analysis in pathologically staged cases indicates that this may be due to a worse underlying prognosis of the cases that require TURP rather than the result of the procedure itself.
Comparison of complications from radiation therapy and from radical prostatectomy
In general, radical prostatectomy is associated with a higher rate of urinary incontinence and early sexual impotence but a lower rate of stool incontinence and rectal injury. However, over time, the differences in sexual impotence diminish because the risk rises with time since radiation.
Evidence (complications of radical prostatectomy vs. radiation therapy):
- A population-based survey of Medicare recipients who had received radiation
therapy as primary treatment for prostate cancer (similar in design to the
survey of Medicare patients who underwent radical prostatectomy, described above) has been reported, showing substantial differences in posttreatment
morbidity profiles between surgery and radiation therapy.
- 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 patients who received radiation reported additional subsequent treatment for known or suspected cancer persistence or recurrence within 3 years of primary therapy.
- A prospective, community-based cohort study of men aged 55 to 74 years treated with
radical prostatectomy (n = 1,156) or EBRT (n = 435)
attempted to compare the acute and chronic complications of the two treatment
strategies after adjusting for baseline differences in patient characteristics
and underlying health.
- 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.
Hormonal Therapy and Its Complications
Several different hormonal approaches are used in the management of various stages of prostate cancer.
These approaches include the following:
Benefits of bilateral orchiectomy include the following:
- Ease of the procedure.
- Immediacy in lowering testosterone levels.
- Low cost relative to the other forms of androgen deprivation therapy.
- Psychological effects.
- Loss of libido.
- Less reversible impotence.
- Hot flashes.
Estrogens at a dose of 3 mg per day of diethylstilbestrol (DES) will achieve castrate levels of testosterone. Like orchiectomy, estrogens may cause loss of libido and impotence. Estrogens also cause gynecomastia, and prophylactic low-dose radiation therapy to the breasts is given to prevent this complication.
DES is no longer manufactured or marketed in the United States and is seldom used today because of the risk of serious side effects, including myocardial infarction, cerebrovascular accidents, and pulmonary embolism.
Luteinizing hormone-releasing hormone (LH-RH) agonist therapy
LH-RH agonists, such as leuprolide, goserelin, and buserelin lower testosterone to castrate levels. Like orchiectomy and estrogens, LH-RH agonists cause impotence, hot flashes, and loss of libido. Tumor flare reactions may occur transiently but can be prevented by antiandrogens or short-term estrogens at a low dose for several weeks.
Evidence (LH-RH agonists and cardiovascular disease):
- In a population-based study within the Department of Veterans Affairs' system, LH-RH agonists were associated with an increased risk of diabetes as well as cardiovascular disease, including coronary heart disease, myocardial infarction, sudden death, and stroke.[82-84]
- A systematic evidence review and meta-analysis of eight trials (4,141 patients) of men with nonmetastatic prostate cancer who were randomly assigned to receive or not receive LH-RH agonists found no difference in cardiovascular death rates (11.0% vs. 11.2%; RRdeath of 0.93; 95% CI, 0.79–1.10; P = .41). Median follow-up in those studies was 7.6 to 13.2 years. No excess risk of LH-RH agonists was found regardless of treatment duration or patient age (median age of <70 years or ≥70 years).
Antiandrogen agents used in the treatment of prostate cancer include flutamide and bicalutamide. The pure antiandrogen, flutamide, may cause diarrhea, breast tenderness, and nausea. Case reports show fatal and nonfatal liver toxic effects.
Bicalutamide may cause nausea, breast tenderness, hot flashes, loss of libido, and impotence. (Refer to the PDQ summaries on Gastrointestinal Complications; Nausea and Vomiting; Hot Flashes and Night Sweats; and Sexuality and Reproductive Issues for information.)
The steroidal antiandrogen, megestrol acetate, suppresses androgen production incompletely and is generally not used as initial therapy.
Additional studies that evaluate the effects of various hormone therapies on quality of life are required.
Androgen deprivation therapy
A national Medicare survey of men who had undergone radical prostatectomy for prostate cancer and either had or had not undergone androgen depletion (either medically or surgically induced) showed a decrease with androgen depletion in all seven health-related, quality-of-life measures, including:[Level of evidence: 3iC]
- Impact of cancer and treatment.
- Concern regarding body image.
- Mental health.
- General health.
- Worries about cancer and dying.
Androgen deprivation therapy 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 with 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.
The use of androgen deprivation therapy may be associated with complaints of penile shortening, although the data are very limited. In a registry study of men with rising PSA after initial treatment of clinically localized prostate cancer treated with radiation therapy plus androgen deprivation therapy, 6 of 225 men (2.7%) complained of reduced penile size. Of the 213 men treated with radiation therapy but no androgen deprivation therapy, none complained of changes in penile size. However, the data were based upon physician reporting of patients' complaints rather than direct patient questioning or before-and-after measurement of penile length. Also, the study sample was restricted to patients with known or suspected tumor recurrence, making generalization difficult.
Placebo-controlled, randomized trials have shown that treatment of bone loss with bisphosphonates decreases the risk of bone fracture in men receiving androgen deprivation therapy for prostate cancer (RR, 0.80 in a meta-analysis of 15 trials; 95% CI, 0.69–0.94). In the meta-analysis, zoledronate appeared to have the largest effect.
The use of androgen deprivation therapy has also been associated with an increased risk of colorectal cancer.
Evidence (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.
- 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).
Antiadrenal agents used in the treatment of prostate cancer include ketoconazole and aminoglutethimide. 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.
Treatment Options Under Clinical Evaluation
Cryosurgery, or cryotherapy, is under evaluation for the treatment of localized prostate cancer. It is a surgical technique that involves destruction of prostate cancer cells by intermittent freezing of the prostate with cryoprobes, followed by thawing.[Level of evidence: 3iiiC]; [Level of evidence: 3iii][95,96][Level of evidence: 3iiiDiv] There is limited evidence regarding its efficacy and safety compared with standard prostatectomy and radiation therapy, and the technique is evolving in an attempt to reduce local toxicity and normal tissue damage. 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.
Serious toxic effects associated with cryosurgery include bladder outlet injury, urinary incontinence, sexual impotence, and rectal injury. Impotence is common, ranging from about 47% to 100%. (Refer to the PDQ summary on Sexuality and Reproductive Issues for more information on impotence.)
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.[95,96] Other major complications include urethral sloughing, urinary fistula or stricture, and bladder neck obstruction.
There is interest in the use of proton-beam therapy for the treatment of prostate cancer. Although the dose distribution of this form of charged-particle radiation 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 reported that compare its efficacy and toxicity with those of other forms of radiation therapy.
Neoadjuvant hormonal therapy
Bicalutamide has not been shown to improve OS in patients with localized or locally advanced prostate cancer.
- The Early Prostate Cancer program is a large, randomized, placebo-controlled, international trial that compared bicalutamide (150 mg orally per day) plus standard care (radical prostatectomy, radiation therapy, or watchful waiting, depending on local custom) with standard care alone for men with nonmetastatic localized or locally advanced prostate cancer (T1–2, N0, and NX; T3–4, any N; or any T, N+). Less than 2% of the 8,113 men had known nodal disease.[Level of evidence: 1iA]
- At a median follow-up of 7.4 years, there was no difference in OS between the bicalutamide and placebo groups (about 76% in both arms [HR, 0.99; CI, 95%, 0.91–1.09; P = .89]).
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with prostate cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
- Chodak GW, Thisted RA, Gerber GS, et al.: Results of conservative management of clinically localized prostate cancer. N Engl J Med 330 (4): 242-8, 1994. [PUBMED Abstract]
- Whitmore WF Jr: Expectant management of clinically localized prostatic cancer. Semin Oncol 21 (5): 560-8, 1994. [PUBMED Abstract]
- Wilt TJ, Brawer MK, Jones KM, et al.: Radical prostatectomy versus observation for localized prostate cancer. N Engl J Med 367 (3): 203-13, 2012. [PUBMED Abstract]
- Shappley WV 3rd, Kenfield SA, Kasperzyk JL, et al.: Prospective study of determinants and outcomes of deferred treatment or watchful waiting among men with prostate cancer in a nationwide cohort. J Clin Oncol 27 (30): 4980-5, 2009. [PUBMED Abstract]
- Klotz L: Active surveillance with selective delayed intervention: using natural history to guide treatment in good risk prostate cancer. J Urol 172 (5 Pt 2): S48-50; discussion S50-1, 2004. [PUBMED Abstract]
- Carter HB, Walsh PC, Landis P, et al.: Expectant management of nonpalpable prostate cancer with curative intent: preliminary results. J Urol 167 (3): 1231-4, 2002. [PUBMED Abstract]
- Johansson JE, Holmberg L, Johansson S, et al.: Fifteen-year survival in prostate cancer. A prospective, population-based study in Sweden. JAMA 277 (6): 467-71, 1997. [PUBMED Abstract]
- Johansson JE, Andrén O, Andersson SO, et al.: Natural history of early, localized prostate cancer. JAMA 291 (22): 2713-9, 2004. [PUBMED Abstract]
- Waaler G, Stenwig AE: Prognosis of localised prostatic cancer managed by "watch and wait" policy. Br J Urol 72 (2): 214-9, 1993. [PUBMED Abstract]
- Adolfsson J, Rönström L, Löwhagen T, et al.: Deferred treatment of clinically localized low grade prostate cancer: the experience from a prospective series at the Karolinska Hospital. J Urol 152 (5 Pt 2): 1757-60, 1994. [PUBMED Abstract]
- Lu-Yao GL, Albertsen PC, Moore DF, et al.: Outcomes of localized prostate cancer following conservative management. JAMA 302 (11): 1202-9, 2009. [PUBMED Abstract]
- Stattin P, Holmberg E, Johansson JE, et al.: Outcomes in localized prostate cancer: National Prostate Cancer Register of Sweden follow-up study. J Natl Cancer Inst 102 (13): 950-8, 2010. [PUBMED Abstract]
- Holmström B, Holmberg E, Egevad L, et al.: Outcome of primary versus deferred radical prostatectomy in the National Prostate Cancer Register of Sweden Follow-Up Study. J Urol 184 (4): 1322-7, 2010. [PUBMED Abstract]
- Barry MJ, Albertsen PC, Bagshaw MA, et al.: Outcomes for men with clinically nonmetastatic prostate carcinoma managed with radical prostactectomy, external beam radiotherapy, or expectant management: a retrospective analysis. Cancer 91 (12): 2302-14, 2001. [PUBMED Abstract]
- Lu-Yao GL, Yao SL: Population-based study of long-term survival in patients with clinically localised prostate cancer. Lancet 349 (9056): 906-10, 1997. [PUBMED Abstract]
- van den Bergh RC, Roemeling S, Roobol MJ, et al.: Outcomes of men with screen-detected prostate cancer eligible for active surveillance who were managed expectantly. Eur Urol 55 (1): 1-8, 2009. [PUBMED Abstract]
- Catalona WJ, Bigg SW: Nerve-sparing radical prostatectomy: evaluation of results after 250 patients. J Urol 143 (3): 538-43; discussion 544, 1990. [PUBMED Abstract]
- Corral DA, Bahnson RR: Survival of men with clinically localized prostate cancer detected in the eighth decade of life. J Urol 151 (5): 1326-9, 1994. [PUBMED Abstract]
- Zincke H, Bergstralh EJ, Blute ML, et al.: Radical prostatectomy for clinically localized prostate cancer: long-term results of 1,143 patients from a single institution. J Clin Oncol 12 (11): 2254-63, 1994. [PUBMED Abstract]
- Schuessler WW, Vancaillie TG, Reich H, et al.: Transperitoneal endosurgical lymphadenectomy in patients with localized prostate cancer. J Urol 145 (5): 988-91, 1991. [PUBMED Abstract]
- Fournier GR Jr, Narayan P: Re-evaluation of the need for pelvic lymphadenectomy in low grade prostate cancer. Br J Urol 72 (4): 484-8, 1993. [PUBMED Abstract]
- Witjes WP, Schulman CC, Debruyne FM: Preliminary results of a prospective randomized study comparing radical prostatectomy versus radical prostatectomy associated with neoadjuvant hormonal combination therapy in T2-3 N0 M0 prostatic carcinoma. The European Study Group on Neoadjuvant Treatment of Prostate Cancer. Urology 49 (3A Suppl): 65-9, 1997. [PUBMED Abstract]
- Fair WR, Cookson MS, Stroumbakis N, et al.: The indications, rationale, and results of neoadjuvant androgen deprivation in the treatment of prostatic cancer: Memorial Sloan-Kettering Cancer Center results. Urology 49 (3A Suppl): 46-55, 1997. [PUBMED Abstract]
- Grossfeld GD, Chang JJ, Broering JM, et al.: Impact of positive surgical margins on prostate cancer recurrence and the use of secondary cancer treatment: data from the CaPSURE database. J Urol 163 (4): 1171-7; quiz 1295, 2000. [PUBMED Abstract]
- Wasson JH, Cushman CC, Bruskewitz RC, et al.: A structured literature review of treatment for localized prostate cancer. Prostate Disease Patient Outcome Research Team. Arch Fam Med 2 (5): 487-93, 1993. [PUBMED Abstract]
- Adolfsson J, Steineck G, Whitmore WF Jr: Recent results of management of palpable clinically localized prostate cancer. Cancer 72 (2): 310-22, 1993. [PUBMED Abstract]
- Austenfeld MS, Thompson IM Jr, Middleton RG: Meta-analysis of the literature: guideline development for prostate cancer treatment. American Urological Association Prostate Cancer Guideline Panel. J Urol 152 (5 Pt 2): 1866-9, 1994. [PUBMED Abstract]
- Holmberg L, Bill-Axelson A, Helgesen F, et al.: A randomized trial comparing radical prostatectomy with watchful waiting in early prostate cancer. N Engl J Med 347 (11): 781-9, 2002. [PUBMED Abstract]
- Bill-Axelson A, Holmberg L, Ruutu M, et al.: Radical prostatectomy versus watchful waiting in early prostate cancer. N Engl J Med 352 (19): 1977-84, 2005. [PUBMED Abstract]
- Bill-Axelson A, Holmberg L, Garmo H, et al.: Radical prostatectomy or watchful waiting in early prostate cancer. N Engl J Med 370 (10): 932-42, 2014. [PUBMED Abstract]
- Wilt TJ, Brawer MK, Jones KM, et al.: Radical prostatectomy versus observation for localized prostate cancer. N Engl J Med 367 (3): 203-13, 2012.
- Wilt TJ: The Prostate Cancer Intervention Versus Observation Trial: VA/NCI/AHRQ Cooperative Studies Program #407 (PIVOT): design and baseline results of a randomized controlled trial comparing radical prostatectomy with watchful waiting for men with clinically localized prostate cancer. J Natl Cancer Inst Monogr 2012 (45): 184-90, 2012. [PUBMED Abstract]
- Yao SL, Lu-Yao G: Population-based study of relationships between hospital volume of prostatectomies, patient outcomes, and length of hospital stay. J Natl Cancer Inst 91 (22): 1950-6, 1999. [PUBMED Abstract]
- Lu-Yao GL, McLerran D, Wasson J, et al.: An assessment of radical prostatectomy. Time trends, geographic variation, and outcomes. The Prostate Patient Outcomes Research Team. JAMA 269 (20): 2633-6, 1993. [PUBMED Abstract]
- Alibhai SM, Leach M, Tomlinson G, et al.: 30-day mortality and major complications after radical prostatectomy: influence of age and comorbidity. J Natl Cancer Inst 97 (20): 1525-32, 2005. [PUBMED Abstract]
- Sanda MG, Dunn RL, Michalski J, et al.: Quality of life and satisfaction with outcome among prostate-cancer survivors. N Engl J Med 358 (12): 1250-61, 2008. [PUBMED Abstract]
- Catalona WJ, Basler JW: Return of erections and urinary continence following nerve sparing radical retropubic prostatectomy. J Urol 150 (3): 905-7, 1993. [PUBMED Abstract]
- Fowler FJ Jr, Barry MJ, Lu-Yao G, et al.: Patient-reported complications and follow-up treatment after radical prostatectomy. The National Medicare Experience: 1988-1990 (updated June 1993). Urology 42 (6): 622-9, 1993. [PUBMED Abstract]
- Potosky AL, Davis WW, Hoffman RM, et al.: Five-year outcomes after prostatectomy or radiotherapy for prostate cancer: the prostate cancer outcomes study. J Natl Cancer Inst 96 (18): 1358-67, 2004. [PUBMED Abstract]
- Litwin MS, Hays RD, Fink A, et al.: Quality-of-life outcomes in men treated for localized prostate cancer. JAMA 273 (2): 129-35, 1995. [PUBMED Abstract]
- Jønler M, Messing EM, Rhodes PR, et al.: Sequelae of radical prostatectomy. Br J Urol 74 (3): 352-8, 1994. [PUBMED Abstract]
- Geary ES, Dendinger TE, Freiha FS, et al.: Nerve sparing radical prostatectomy: a different view. J Urol 154 (1): 145-9, 1995. [PUBMED Abstract]
- Lim AJ, Brandon AH, Fiedler J, et al.: Quality of life: radical prostatectomy versus radiation therapy for prostate cancer. J Urol 154 (4): 1420-5, 1995. [PUBMED Abstract]
- Savoie M, Kim SS, Soloway MS: A prospective study measuring penile length in men treated with radical prostatectomy for prostate cancer. J Urol 169 (4): 1462-4, 2003. [PUBMED Abstract]
- Gontero P, Galzerano M, Bartoletti R, et al.: New insights into the pathogenesis of penile shortening after radical prostatectomy and the role of postoperative sexual function. J Urol 178 (2): 602-7, 2007. [PUBMED Abstract]
- McCullough A: Penile change following radical prostatectomy: size, smooth muscle atrophy, and curve. Curr Urol Rep 9 (6): 492-9, 2008. [PUBMED Abstract]
- Sun M, Lughezzani G, Alasker A, et al.: Comparative study of inguinal hernia repair after radical prostatectomy, prostate biopsy, transurethral resection of the prostate or pelvic lymph node dissection. J Urol 183 (3): 970-5, 2010. [PUBMED Abstract]
- Sekita N, Suzuki H, Kamijima S, et al.: Incidence of inguinal hernia after prostate surgery: open radical retropubic prostatectomy versus open simple prostatectomy versus transurethral resection of the prostate. Int J Urol 16 (1): 110-3, 2009. [PUBMED Abstract]
- Lughezzani G, Sun M, Perrotte P, et al.: Comparative study of inguinal hernia repair rates after radical prostatectomy or external beam radiotherapy. Int J Radiat Oncol Biol Phys 78 (5): 1307-13, 2010. [PUBMED Abstract]
- Lodding P, Bergdahl C, Nyberg M, et al.: Inguinal hernia after radical retropubic prostatectomy for prostate cancer: a study of incidence and risk factors in comparison to no operation and lymphadenectomy. J Urol 166 (3): 964-7, 2001. [PUBMED Abstract]
- Lepor H, Robbins D: Inguinal hernias in men undergoing open radical retropubic prostatectomy. Urology 70 (5): 961-4, 2007. [PUBMED Abstract]
- Bishoff JT, Motley G, Optenberg SA, et al.: Incidence of fecal and urinary incontinence following radical perineal and retropubic prostatectomy in a national population. J Urol 160 (2): 454-8, 1998. [PUBMED Abstract]
- Parekh A, Chen MH, Hoffman KE, et al.: Reduced penile size and treatment regret in men with recurrent prostate cancer after surgery, radiotherapy plus androgen deprivation, or radiotherapy alone. Urology 81 (1): 130-4, 2013. [PUBMED Abstract]
- Forman JD, Order SE, Zinreich ES, et al.: Carcinoma of the prostate in the elderly: the therapeutic ratio of definitive radiotherapy. J Urol 136 (6): 1238-41, 1986. [PUBMED Abstract]
- Duncan W, Warde P, Catton CN, et al.: Carcinoma of the prostate: results of radical radiotherapy (1970-1985) Int J Radiat Oncol Biol Phys 26 (2): 203-10, 1993. [PUBMED Abstract]
- Zietman AL, Coen JJ, Shipley WU, et al.: Radical radiation therapy in the management of prostatic adenocarcinoma: the initial prostate specific antigen value as a predictor of treatment outcome. J Urol 151 (3): 640-5, 1994. [PUBMED Abstract]
- Peeters ST, Heemsbergen WD, Koper PC, et al.: Dose-response in radiotherapy for localized prostate cancer: results of the Dutch multicenter randomized phase III trial comparing 68 Gy of radiotherapy with 78 Gy. J Clin Oncol 24 (13): 1990-6, 2006. [PUBMED Abstract]
- Zietman AL, DeSilvio ML, Slater JD, et al.: Comparison of conventional-dose vs high-dose conformal radiation therapy in clinically localized adenocarcinoma of the prostate: a randomized controlled trial. JAMA 294 (10): 1233-9, 2005. [PUBMED Abstract]
- Pollack A, Zagars GK, Starkschall G, et al.: Prostate cancer radiation dose response: results of the M. D. Anderson phase III randomized trial. Int J Radiat Oncol Biol Phys 53 (5): 1097-105, 2002. [PUBMED Abstract]
- Dearnaley DP, Jovic G, Syndikus I, et al.: Escalated-dose versus control-dose conformal radiotherapy for prostate cancer: long-term results from the MRC RT01 randomised controlled trial. Lancet Oncol 15 (4): 464-73, 2014. [PUBMED Abstract]
- Pollack A, Walker G, Horwitz EM, et al.: Randomized trial of hypofractionated external-beam radiotherapy for prostate cancer. J Clin Oncol 31 (31): 3860-8, 2013. [PUBMED Abstract]
- Asbell SO, Martz KL, Shin KH, et al.: Impact of surgical staging in evaluating the radiotherapeutic outcome in RTOG #77-06, a phase III study for T1BN0M0 (A2) and T2N0M0 (B) prostate carcinoma. Int J Radiat Oncol Biol Phys 40 (4): 769-82, 1998. [PUBMED Abstract]
- Ragde H, Blasko JC, Grimm PD, et al.: Interstitial iodine-125 radiation without adjuvant therapy in the treatment of clinically localized prostate carcinoma. Cancer 80 (3): 442-53, 1997. [PUBMED Abstract]
- Parker C, Nilsson S, Heinrich D, et al.: Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med 369 (3): 213-23, 2013. [PUBMED Abstract]
- Schellhammer PF, Jordan GH, el-Mahdi AM: Pelvic complications after interstitial and external beam irradiation of urologic and gynecologic malignancy. World J Surg 10 (2): 259-68, 1986. [PUBMED Abstract]
- Hanlon AL, Schultheiss TE, Hunt MA, et al.: Chronic rectal bleeding after high-dose conformal treatment of prostate cancer warrants modification of existing morbidity scales. Int J Radiat Oncol Biol Phys 38 (1): 59-63, 1997. [PUBMED Abstract]
- Hamilton AS, Stanford JL, Gilliland FD, et al.: Health outcomes after external-beam radiation therapy for clinically localized prostate cancer: results from the Prostate Cancer Outcomes Study. J Clin Oncol 19 (9): 2517-26, 2001. [PUBMED Abstract]
- Nieder AM, Porter MP, Soloway MS: Radiation therapy for prostate cancer increases subsequent risk of bladder and rectal cancer: a population based cohort study. J Urol 180 (5): 2005-9; discussion 2009-10, 2008. [PUBMED Abstract]
- Abdel-Wahab M, Reis IM, Wu J, et al.: Second primary cancer risk of radiation therapy after radical prostatectomy for prostate cancer: an analysis of SEER data. Urology 74 (4): 866-71, 2009. [PUBMED Abstract]
- Nam RK, Cheung P, Herschorn S, et al.: Incidence of complications other than urinary incontinence or erectile dysfunction after radical prostatectomy or radiotherapy for prostate cancer: a population-based cohort study. Lancet Oncol 15 (2): 223-31, 2014. [PUBMED Abstract]
- Incrocci L, Koper PC, Hop WC, et al.: Sildenafil citrate (Viagra) and erectile dysfunction following external beam radiotherapy for prostate cancer: a randomized, double-blind, placebo-controlled, cross-over study. Int J Radiat Oncol Biol Phys 51 (5): 1190-5, 2001. [PUBMED Abstract]
- Pisansky TM, Pugh SL, Greenberg RE, et al.: Tadalafil for prevention of erectile dysfunction after radiotherapy for prostate cancer: the Radiation Therapy Oncology Group  randomized clinical trial. JAMA 311 (13): 1300-7, 2014. [PUBMED Abstract]
- Hanks GE, Hanlon AL, Schultheiss TE, et al.: Dose escalation with 3D conformal treatment: five year outcomes, treatment optimization, and future directions. Int J Radiat Oncol Biol Phys 41 (3): 501-10, 1998. [PUBMED Abstract]
- Dearnaley DP, Khoo VS, Norman AR, et al.: Comparison of radiation side-effects of conformal and conventional radiotherapy in prostate cancer: a randomised trial. Lancet 353 (9149): 267-72, 1999. [PUBMED Abstract]
- Greskovich FJ, Zagars GK, Sherman NE, et al.: Complications following external beam radiation therapy for prostate cancer: an analysis of patients treated with and without staging pelvic lymphadenectomy. J Urol 146 (3): 798-802, 1991. [PUBMED Abstract]
- Seymore CH, el-Mahdi AM, Schellhammer PF: The effect of prior transurethral resection of the prostate on post radiation urethral strictures and bladder neck contractures. Int J Radiat Oncol Biol Phys 12 (9): 1597-600, 1986. [PUBMED Abstract]
- Green N, Treible D, Wallack H, et al.: Prostate cancer--the impact of irradiation on urinary outlet obstruction. Br J Urol 70 (3): 310-3, 1992. [PUBMED Abstract]
- Zelefsky MJ, Whitmore WF Jr, Leibel SA, et al.: Impact of transurethral resection on the long-term outcome of patients with prostatic carcinoma. J Urol 150 (6): 1860-4, 1993. [PUBMED Abstract]
- Fowler FJ Jr, Barry MJ, Lu-Yao G, et al.: Outcomes of external-beam radiation therapy for prostate cancer: a study of Medicare beneficiaries in three surveillance, epidemiology, and end results areas. J Clin Oncol 14 (8): 2258-65, 1996. [PUBMED Abstract]
- Potosky AL, Legler J, Albertsen PC, et al.: Health outcomes after prostatectomy or radiotherapy for prostate cancer: results from the Prostate Cancer Outcomes Study. J Natl Cancer Inst 92 (19): 1582-92, 2000. [PUBMED Abstract]
- Daniell HW: Osteoporosis after orchiectomy for prostate cancer. J Urol 157 (2): 439-44, 1997. [PUBMED Abstract]
- Keating NL, O'Malley AJ, Freedland SJ, et al.: Diabetes and cardiovascular disease during androgen deprivation therapy: observational study of veterans with prostate cancer. J Natl Cancer Inst 102 (1): 39-46, 2010. [PUBMED Abstract]
- Keating NL, O'Malley AJ, Smith MR: Diabetes and cardiovascular disease during androgen deprivation therapy for prostate cancer. J Clin Oncol 24 (27): 4448-56, 2006. [PUBMED Abstract]
- D'Amico AV, Denham JW, Crook J, et al.: Influence of androgen suppression therapy for prostate cancer on the frequency and timing of fatal myocardial infarctions. J Clin Oncol 25 (17): 2420-5, 2007. [PUBMED Abstract]
- 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 (3): 194-201, 2010 May-Jun. [PUBMED Abstract]
- Nguyen PL, Je Y, Schutz FA, et al.: Association of androgen deprivation therapy with cardiovascular death in patients with prostate cancer: a meta-analysis of randomized trials. JAMA 306 (21): 2359-66, 2011. [PUBMED Abstract]
- Wysowski DK, Freiman JP, Tourtelot JB, et al.: Fatal and nonfatal hepatotoxicity associated with flutamide. Ann Intern Med 118 (11): 860-4, 1993. [PUBMED Abstract]
- Soloway MS, Schellhammer PF, Smith JA, et al.: Bicalutamide in the treatment of advanced prostatic carcinoma: a phase II multicenter trial. Urology 47 (1A Suppl): 33-7; discussion 48-53, 1996. [PUBMED Abstract]
- Kirschenbaum A: Management of hormonal treatment effects. Cancer 75 (7 Suppl): 1983-86, 1995.
- Fowler FJ Jr, McNaughton Collins M, Walker Corkery E, et al.: The impact of androgen deprivation on quality of life after radical prostatectomy for prostate carcinoma. Cancer 95 (2): 287-95, 2002. [PUBMED Abstract]
- Shahinian VB, Kuo YF, Freeman JL, et al.: Risk of fracture after androgen deprivation for prostate cancer. N Engl J Med 352 (2): 154-64, 2005. [PUBMED Abstract]
- Serpa Neto A, Tobias-Machado M, Esteves MA, et al.: Bisphosphonate therapy in patients under androgen deprivation therapy for prostate cancer: a systematic review and meta-analysis. Prostate Cancer Prostatic Dis 15 (1): 36-44, 2012. [PUBMED Abstract]
- Gillessen S, Templeton A, Marra G, et al.: Risk of colorectal cancer in men on long-term androgen deprivation therapy for prostate cancer. J Natl Cancer Inst 102 (23): 1760-70, 2010. [PUBMED Abstract]
- Robinson JW, Saliken JC, Donnelly BJ, et al.: Quality-of-life outcomes for men treated with cryosurgery for localized prostate carcinoma. Cancer 86 (9): 1793-801, 1999. [PUBMED Abstract]
- Donnelly BJ, Saliken JC, Ernst DS, et al.: Prospective trial of cryosurgical ablation of the prostate: five-year results. Urology 60 (4): 645-9, 2002. [PUBMED Abstract]
- Aus G, Pileblad E, Hugosson J: Cryosurgical ablation of the prostate: 5-year follow-up of a prospective study. Eur Urol 42 (2): 133-8, 2002. [PUBMED Abstract]
- Shelley M, Wilt TJ, Coles B, et al.: Cryotherapy for localised prostate cancer. Cochrane Database Syst Rev (3): CD005010, 2007. [PUBMED Abstract]
- McLeod DG, Iversen P, See WA, et al.: Bicalutamide 150 mg plus standard care vs standard care alone for early prostate cancer. BJU Int 97 (2): 247-54, 2006. [PUBMED Abstract]