martes, 24 de septiembre de 2019

Prostate Cancer Treatment (PDQ®) 3/8 –Health Professional Version - National Cancer Institute

Prostate Cancer Treatment (PDQ®)–Health Professional Version - National Cancer Institute

National Cancer Institute

Prostate Cancer Treatment (PDQ®)–Health Professional Version

Treatment Option Overview for Prostate Cancer

Local treatment modalities are associated with prolonged disease-free survival (DFS) 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.
Treatment options for each stage of prostate cancer are presented in Table 6.
Table 6. Treatment Options by Stage for Prostate Cancer
Stage (TNM Staging Criteria)Standard Treatment Options
EBRT = external-beam radiation therapy; LH-RH = luteinizing hormone-releasing hormone; TURP = transurethral resection of the prostate.
Stage I Prostate CancerWatchful waiting or active surveillance/active monitoring
Radical prostatectomy
External-beam radiation therapy (EBRT)
Interstitial implantation of radioisotopes
Stage II Prostate CancerWatchful waiting or active surveillance/active monitoring
Radical prostatectomy
EBRT with or without hormonal therapy
Interstitial implantation of radioisotopes
Stage III Prostate CancerEBRT with or without hormonal therapy
Hormonal manipulations with or without radiation therapy
Radical prostatectomy with or without EBRT
Watchful waiting or active surveillance/active monitoring
Stage IV Prostate CancerHormonal manipulations
Bisphosphonates
EBRT with or without hormonal therapy
Palliative radiation therapy
Palliative surgery with transurethral resection of the prostate (TURP)
Watchful waiting or active surveillance/active monitoring
Recurrent Prostate CancerHormone therapy
Chemotherapy for hormone-resistant prostate cancer
Immunotherapy
Radiopharmaceutical therapy/alpha emitter radiation
Side effects of each of the treatment approaches are covered in the relevant sections below. Patient-reported adverse effects differ substantially across the options for management of clinically localized disease, with few direct comparisons, and include watchful waiting/active surveillance/active monitoring, radical prostatectomy, and radiation therapy. The differences in adverse effects can play an important role in patient choice among treatment options. Detailed comparisons of these effects have been reported in population-based cohort studies, albeit with relatively short follow-up times of 2 to 3 years.[1,2]

Watchful Waiting or Active Surveillance/Active Monitoring

Asymptomatic patients of advanced age or with concomitant illness may warrant consideration of careful observation without immediate active treatment.[3,4] Watch and wait, observation, expectant management, and active surveillance/active monitoring are terms indicating a strategy that does not employ immediate therapy with curative intent.
Watchful waiting and active surveillance/active monitoring 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, transurethral resection of the prostate (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/active monitoring in men with early-stage disease (i.e., clinical stages T1b, T1c, or T2).[5] (Refer to the Radical Prostatectomy section in the Treatment Option Overview for Prostate Cancer section of this summary for more information.)
In contrast, the strategy behind active surveillance/active monitoring 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.[6-9] The intention 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/active monitoring often involves the following:
  • Regular patient visits.
  • Digital rectal examinations.
  • Prostate-specific antigen (PSA) testing.
  • Transrectal ultrasound (in some series).
  • Transrectal needle biopsies (in some series).
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. In the aggregate, men managed by watchful waiting or active surveillance/active monitoring (using various criteria, depending upon the study) have had very favorable prostate–cancer-specific mortalities ranging from about 1% to 10% (with the most favorable rates in more recent series).[10-18] Most men with screen-detected prostate cancer may, therefore, be candidates for active surveillance/active monitoring, with definitive therapy reserved for signs of tumor progression. This has been shown most clearly in the large Prostate Testing for Cancer Treatment (ProtecT [NCT02044172 and ISRCTN20141297]) randomized trial that compared active monitoring, radical prostatectomy, and radiation therapy.[19] (Refer to the Radical Prostatectomy section of this summary for information about comparisons of active surveillance and/or active monitoring with immediate therapies.)
(Refer to the Stage II Prostate Cancer Treatment section of this summary for more information.)

Radical Prostatectomy

A radical prostatectomy is usually reserved for patients who:[20-22]
  • Are in good health and elect surgical intervention.
  • Have tumor confined to the prostate gland (stage I and stage II).
Open 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.[23] Robot-assisted prostatectomy is an alternative to open prostatectomy and has become the most common technique in developed countries. In experienced hands, functional outcomes between open and robot-assisted prostatectomy appear to be very similar, at least in the short- to mid-term. In a randomized trial of 308 men suitable for prostatectomy, urinary, sexual, and bowel functional outcomes were similar between open retropubic and robotic surgeries at a median follow-up of 24 months.[24] The sample size and duration of follow-up were too small to detect meaningful differences in cancer outcomes.
For small, well-differentiated nodules, the incidence of positive pelvic nodes is less than 20%, and pelvic node dissection may be omitted.[25] With larger, less-differentiated tumors, a pelvic lymph node dissection is more important. In these cases, the value of open surgical or laparoscopic pelvic node dissection is not therapeutic, but it spares patients with positive nodes the morbidity of prostatectomy. Radical prostatectomy is usually not performed if a frozen-section evaluation of pelvic nodes reveals metastases; these 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.[26,27]
After 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.[10,28,29] 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).[10,28]
  • 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:[30]
  1. Radical prostatectomy.
  2. Definitive radiation therapy.
  3. Observation (watchful waiting or active surveillance/active monitoring).
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%).[31] 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.[32]
Radical prostatectomy has been compared with watchful waiting or active surveillance/active monitoring 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/active monitoring):
  1. 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.[33-35]
    • 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, 0.71; 95% CI, 0.59–0.86).[35][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).[35]
    • 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.
  2. The Prostate Intervention Versus Observation Trial (PIVOT-1 or VA-CSP-407) is a 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 or watchful waiting.[5,36,37][Levels of evidence: 1iiA, 1iiB]
    • About 50% of the men had nonpalpable, screen-detected disease.
    • After a median follow-up of 12.7 years (range up to about 19.5 years), the all-cause mortality was 61.3% in the prostatectomy arm versus 66.8% in the watchful-waiting study arm, with an absolute difference of 5.5 percentage points (95% CI, -1.5–12.4) that was not statistically significant (hazard ratio [HR], 0.84; 95% CI, 0.70–1.01). Prostate cancer-specific mortality was 7.4% versus 11.4%, and it also was not statistically significant (HR, 0.63; 95% CI, 0.3–1.02).
    • Although treatment for disease progression was given more frequently in the observation arm of the study, most of the treatment was for asymptomatic, local, or biochemical (PSA) progression.
    • As expected, urinary incontinence and erectile/sexual dysfunction was more common in the prostatectomy group during at least 10 years of follow-up. Absolute differences in patient-reported use of absorbent urinary pads was greater in the surgery group by more than 30 percentage points at all time points for at least 10 years. Disease- or treatment-related limitations in activities of daily living were worse with surgery than with observation through 2 years, but then were similar in both study arms.
  3. In the ProtecT trial (NCT02044172 and ISRCTN20141297), 82,429 men were screened with PSA testing, and 2,664 were diagnosed with clinically localized prostate cancer, of whom 1,643 (median age 62 years, range 50–69 years) consented to a randomly assigned comparison of active monitoring, radical prostatectomy (nerve-sparing when possible), or external-beam 3-dimensional (3D) conformal radiation therapy (74 Gy in 37 fractions). The primary endpoint was prostate cancer–specific mortality.[19]
    1. With a median follow-up of 10 years, there were 17 deaths from prostate cancer, with no statistically significant differences among the three study arms (P = .48). The 10-year prostate cancer–specific survival rates were 98.8% in the active monitoring arm, 99.0% in the radical prostatectomy arm, and 99.6% in the radiation therapy arm.[19][Level of evidence: 1iiA]
    2. Likewise, all-cause mortality was nearly identical in all three study arms: 10.9 deaths in the active monitoring arm, 10.1 in the radical prostatectomy arm, and 10.3 in the radiation therapy arm per 1,000 person-years (P = .87).[19][Level of evidence: 1iiB]
    3. There were statistically significant differences in progression to metastatic disease among the treatment arms (active monitoring, 33/545; radical prostatectomy, 13/553; radiation therapy, 16/545) that began to emerge after 4 years, but these differences had not translated into any difference in mortality at the 10-year follow-up. Over the course of 10 years, 52% of the patients required active intervention.
    4. As expected, there were substantial differences in patient-reported outcomes among the three management approaches.[38][Level of evidence: 1iiC] A substudy of patient-reported outcomes up to 6 years after randomization included the following:
      • Men in the radical prostatectomy study arm had substantial rates of urinary incontinence (e.g., using one or more absorbent pads qd was reported by 46% at 6 months and by 17% at year 6) with very little incontinence in the other two study arms.
      • Sexual function was also worse in the radical prostatectomy group (e.g., at 6 months, 12% of men reported erections firm enough for intercourse versus 22% in the radiation therapy arm and 52% in the active monitoring arm).
      • Bowel function, however, was worse in the radiation therapy arm (e.g., about 5% reported bloody stools at least half the time at 2 years and beyond vs. none in the radical prostatectomy and active-monitoring study arms).

Complications of radical prostatectomy

Complications of radical prostatectomy include the following:
Functional outcomes of radical prostatectomy with respect to sexual, urinary, bowel function, and health-related quality of life (QOL), appear to be similar whether the procedure is open retropubic, laparoscopic, or robot-assisted radical prostatectomy.[59]
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:[39]
  • 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.[39]
Prostatectomies done at hospitals where fewer of the procedures were performed than those done at hospitals where more were performed were associated with the following:[40,41]
  • 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).[41]
Urinary incontinence and impotence
Urinary incontinence and impotence are complications that can result from radical prostatectomy and have been studied in multiple studies.
Evidence (urinary incontinence and impotence after radical prostatectomy):
  1. A large case series of men undergoing the anatomic (nerve-sparing) technique of radical prostatectomy reported the following:[43]
    • 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.
  2. A national survey of Medicare patients who underwent radical prostatectomy in 1988 to 1990 reported more morbidity than in the case series reported above.[44]
    • 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.
    • About 28% of the patients reported follow-up treatment of cancer with radiation therapy and/or hormonal therapy within 4 years after their prostatectomy.
  3. 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:[45]
    • 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.
  4. 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.[46]
    • 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. This issue requires more study.
  5. 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.[47-49] 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.
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.
Penile shortening
Case series of men who have undergone radical prostatectomy have shown shortening of penile length (by an average of 1–2 cm).[50-52] The functional consequence of the shortening is not well studied, but it is noticeable to some men.
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.[60] 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.
Recovery of penile length to pre-operative measurements within 1 to 2 years has been reported in some, but not all, case series in which men were followed longitudinally.[61]
Inguinal hernia
Inguinal hernia has been reported as a complication of radical prostatectomy.
Evidence (inguinal hernia after radical prostatectomy):
  1. Retrospective cohort studies and case series have shown an increased incidence of inguinal hernia, ranging from 7% to 21%, in men undergoing radical prostatectomy, with rates peaking within 2 years of surgery.[53-57]
  2. 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;[53,54] or in men with prostate cancer who have undergone pelvic lymph node dissection alone or radiation therapy.[53,55,56]
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 because of frequent examinations or diagnostic imaging (i.e., detection bias). Men should be made aware of this potential complication of prostatectomy.
Fecal incontinence
Radical prostatectomy may cause fecal incontinence, and the incidence may vary with surgical method.[58]
Evidence (fecal incontinence after radical prostatectomy):
  1. 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 a 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.[58]

Radiation Therapy and Radiopharmaceutical Therapy

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.[62]
Long-term results with radiation therapy are dependent on stage and are associated with dosimetry of the radiation.
Evidence (EBRT):
  1. 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%).[63] An initial serum PSA level higher than 15 ng/mL is a predictor of probable failure with conventional radiation therapy.[64]
  2. 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).[65-69][Level of evidence: 1iiDiii] None of the studies demonstrated a cause-specific survival benefit to higher doses.
    • In the MRC-RT01 [NCT00003290] study that was powered to detect differences in both biochemical progression-free survival (PFS) and a 15% difference in overall survival (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.[68] 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.
    • Likewise, in the RTOG-0126 trial (NCT00033631), 1,532 men with stage cT1b to T2b (Gleason score 2 to 6 and PSA 10 to <20 ng/mL or Gleason score 7 and PSA <15 ng/mL) prostate cancer were randomly assigned to receive 79.2 Gy in 44 fractions compared with 70.2 Gy in 39 fractions (using 3D conformal or intensity-modulated radiation therapy [IMRT]).[69] With a median follow-up of 8.4 years (maximum, 13.0 years), 8-year OS rates were 76% and 75% (HR, 1.00; 95% CI, 0.83–1.20; P = .98). However, the high-dose radiation was associated with increased late-grade 2 or greater gastrointestinal and genitourinary toxicities (21% and 12% with 79.2 Gy and 15% and 7% with 70.2 Gy).
(Refer to the Radical prostatectomy compared with other treatment options section of this summary for direct comparisons of radiation therapy with active surveillance/active monitoring and radical prostatectomy.)
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.[70][Level of evidence: 1iiA]
Conventional versus hypofractionated EBRT
The more convenient schedules of hypofractionated radiation therapy (using fewer fractions at higher doses per fraction) appear to yield similar outcomes to conventional schedules of radiation, at least with respect to the intermediate outcomes of DFS and failure-free survival (low levels of evidence not known to translate into health outcomes), and early data on OS rates. However, hypofractionated radiation may incur more toxicity than standard doses, depending on the schedules used.[71]
Evidence (conventional vs. hypofractionated EBRT):
  1. In a small, randomized trial, primarily from one treatment center, conventional hypofractionation was not found to be superior to conventional fractionation.[72] In the trial, 303 assessable men were randomly assigned to receive 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, despite low mortality rates, and the trial was underpowered for mortality endpoints.[72][Level of evidence: 1iiDiii]
  2. In the much larger, multicenter Conventional or Hypofractionated High-Dose Intensity Modulated Radiotherapy in Prostate Cancer (CHHiP) trial [NCT00392535], 3,216 men with stages T1b–T3a, N0, M0 cancer and an estimated risk of seminal vesicle involvement of less than 30% were randomly assigned to receive either 74 Gy in 37 fractions (the conventional-fraction arm), 60 Gy in 20 fractions, or 57 Gy in 19 fractions (1:1:1 ratio).[73,74] The trial was designed as a noninferiority study.
    • The primary endpoint of biochemical or clinical treatment failure was reported after a median follow-up of 62.4 months. The 5-year failure-free survival rates were 88.3% (conventional, 74 Gy group), 90.6% (60 Gy group), and 85.9% (57 Gy group). The 60 Gy hypofractionated group fulfilled noninferiority criteria compared with conventional 74 Gy fractionation, but the 57 Gy group did not.[74][Level of evidence: 1iiD]
    • Overall mortality rates were very similar in the three groups: 9%, 7%, and 8%.[74][Level of evidence: 1iiA]
    • A QOL substudy was conducted with 2,100 participants and showed nearly identical patient-reported outcomes in each of the three arms at 2 years after study entry (median follow-up, 50 months).[73][Level of evidence: 1iiC]
    • The primary patient-reported outcome was bowel bother. Frequency of moderate bother was 5%, 6%, and 5% in the three study groups. Severe bother was reported in less than 1% of men in each study group.
    • Likewise, there were no differences in any of the secondary outcomes, which included overall QOL, overall urinary bother, or overall sexual bother.
  3. In another multicenter, randomized trial of Hypofractionated versus Conventionally Fractionated Radiotherapy for Patients with Prostate Cancer (HYPRO study [ISRCTN85138529]), conventional radiation therapy doses (78 Gy in 39 fractions over 8 weeks) were compared with hypofractionated radiation therapy doses (64.6 Gy in 19 fractions over 6.5 weeks) in a noninferiority design for hypofractionation in 820 men with intermediate- or high-risk prostate cancer (stages T1b–T4, NX–0, MX–0).[75,76] Median follow-up was 60 months.
    • The primary endpoint, 5-year relapse-free survival, was similar in the two study arms: 80.5% (95% CI, 75.7–84.4) with hypofractionation versus 77.1% (95% CI, 71.9–81.5), with conventional fractionation (HR, 0.86; 95% CI, 0.63–1.16; P = .36).[76][Level of evidence: 1iiD] The overall 5-year survival rate in the two arms was also similar: 86.2% (95% CI, 82.3–89.4) with hypofractionation versus 85.9% (95% CI, 81.8–89.2) with conventional fractionation (HR, 1.02; 95% CI, .71–1.46; P = .92).[76][Level of evidence: 1iiA]
    • With respect to toxicity (key endpoints of genitourinary [GU] or gastrointestinal [GI] grade 2+ toxicities at 3 years), noninferiority for hypofractionated radiation therapy could not be established after a median follow-up of 5 years: cumulative GU toxicity of 41.3% with hypofractionated radiation therapy versus 39% with conventional radiation therapy doses (HR, 1.16; 90% CI, 0.98–1.38); GI toxicity of 21.9% versus 17.7% (HR, 1.19; 90% CI, 0.93–1.52).
    • Cumulative GU grade 3+ toxicity was higher in the hypofractionation group: 19.0% versus 12.9% (P = .02).
    • Stool frequency (≥6 qd) was higher in the hypofractionation group: 7% versus 3% (P = .034).
    • In a substudy of 322 men who had a baseline assessment and at least one follow-up assessment, and either no or short-term androgen therapy, erectile dysfunction was similar between the two study arms during 3 years of follow-up.[77]
  4. The RTOG reported a noninferiority trial of 1,115 men with low-risk prostate cancer (T1b–T2c) who were randomly assigned to receive hypofractionated radiation therapy (70 Gy in 28 fractions over 5.6 weeks) versus conventional radiation therapy doses (73.8 Gy in 41 fractions over 8.2 weeks).[78]
    • After a median follow-up of 5.8 years, the hypofractionated radiation therapy arm met the prospective noninferiority criterion with respect to DFS: 86.3% with hypofractionated radiation therapy versus 85.3% with conventional radiation therapy doses (consistent with HR, <1.52; P < .001 for the hypothesis of noninferiority).[78][Level of evidence: 1iiDiii]
    • There were 49 deaths in the hypofractionated radiation therapy arm and 51 deaths in the conventional radiation therapy doses arm (HR for OS, 0.95; conventional radiation therapy doses vs. hypofractionated radiation therapy; 95% CI, 0.64–1.41).
    • However, late GI grade 2+ toxicity was worse in the hypofractionated radiation therapy arm: 22.4% versus 14.0% (P = .002); there was also a trend toward worse late GU grade 2+ toxicity: 29.7% versus 22.8% (P = .06).
  5. In a multicenter trial (NCT00304759), 1,206 men with intermediate-risk prostate cancer (T1–2a Gleason score ≤6, PSA 10.1–20 ng/mL; T2b–2c Gleason ≤6, PSA ≤20 ng/mL; or T1–2 Gleason = 7, PSA ≤20 ng/mL) were randomly assigned in a noninferiority trial design to receive conventional radiation therapy (78 Gy in 39 fractions) versus hypofractionated radiation therapy (60 Gy over 20 fractions).[79]
    • After a median follow-up of 6 years (maximum 10 years), the primary endpoint of biochemical clinical failure (87%, PSA failure) was nearly identical with each radiation therapy schedule (85% in both arms; [DFS, 95% CI, 82%–88%]; HR, 0.96; 90% CI, 0.77–1.20).[79][Level of evidence: 1iiDiii]
    • The trial was severely underpowered to detect any differences in overall or prostate-specific mortality. Only 12 deaths in the conventional radiation therapy arm and 10 deaths in the hypofractionated radiation therapy arm were from prostate cancer. Only 14% of all deaths were attributed to prostate cancer.
    • Short- and long-term genitourinary and gastrointestinal toxicities were similar in both study groups.

Brachytherapy

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 QOL and to determine the contribution of favorable patient selection to outcomes.[80][Level of evidence: 3iiiDiv]
Information about ongoing clinical trials is available from the NCI website.

Radiopharmaceutical therapy

Alpha emitter radiation
Radium Ra 223 (223Ra) 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. 223Ra improved OS in patients with prostate cancer metastatic to bone. In a double-blind, randomized, controlled trial, 921 men with symptomatic castration-resistant prostate cancer, two or more metastases, and no known visceral metastases were randomly assigned in a 2:1 ratio to 223Ra versus placebo. 223Ra statistically significantly improved OS (median 14.9 months vs. 11.3 months), rate of symptomatic skeletal events (33% vs. 38%), and spinal cord compression (4% vs. 7%).[81,82][Level of evidence: 1iA] 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

Definitive EBRT can result in acute cystitis, proctitis, and enteritis.[20,42,49,83-85] These conditions are generally reversible but may be chronic and rarely require surgical intervention.[85]
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.[46]
Radiation is also known to be carcinogenic.[86-88] 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.

Reducing complications

Potency, in most cases, is preserved with radiation therapy in the short term but appears to diminish over time.[85] Sildenafil citrate may be effective in the management of sexual dysfunction after radiation therapy in some men.
Evidence (reducing complications):
  1. 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).[89][Level of evidence: 1iC]
  2. A randomized trial (RTOG-0831 [NCT00931528]) of 121 men with intact erectile function compared daily preventive tadalafil (5 mg PO qd) with placebo for 24 weeks beginning at the start of either EBRT or brachytherapy.[90][Level of evidence: 1iC]
    • There were no statistically significant differences in spontaneous erectile function (the primary endpoint) or any other measures of sexual function.
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.[91,92]
Evidence (3D conformal vs. conventional radiation therapy):
  1. The side effects of similar doses of 3D conformal radiation therapy and conventional radiation therapy (total dose, 60–64 Gy) have been compared in a randomized nonblinded study.[92][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.[93-95] 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.[96]

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. Many side effects of definitive local therapy for prostate cancer persist well beyond a decade after therapy, and urinary problems in addition to sexual impotence may worsen with age.[97]
Evidence (complications of radical prostatectomy vs. radiation therapy):
  1. 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,[44] described above) has been reported, showing substantial differences in posttreatment morbidity profiles between surgery and radiation therapy.[98]
    • 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. >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.
  2. 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.[99]
    • 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:

Abiraterone acetate

Abiraterone acetate has been shown to improve OS when added to ADT in men with advanced prostate cancer who have castration-sensitive disease. Abiraterone acetate is generally well-tolerated; however, it is associated with an increase in the mineralocorticoid effects of grade 3 or 4 hypertension and hypokalemia compared with ADT alone.[100] It may also be associated with a small increase in respiratory disorders.[101]

Bilateral orchiectomy

Benefits of bilateral orchiectomy include the following:[42]
  • Ease of the procedure.
  • Compliance.
  • Immediacy in lowering testosterone levels.
  • Low cost relative to the other forms of ADT.
Disadvantages of bilateral orchiectomy include the following:[42,102]
  • Psychological effects.
  • Loss of libido.
  • Less reversible impotence.
  • Hot flashes.
  • Osteoporosis.[102]
Bilateral orchiectomy has also been associated with an elevated risk of coronary heart disease and myocardial infarction.[103-106]
(Refer to the PDQ summary on Hot Flashes and Night Sweats.)

Estrogen therapy

Estrogens at a dose of 3 mg qd 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.
There is some evidence that LH-RH agonists are associated with increased risk of cardiovascular morbidity or mortality, although the results are conflicting.[103-107]
Evidence (LH-RH agonists and cardiovascular disease):
  1. 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.[103-105]
  2. 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 to receive LH-RH agonists found no difference in cardiovascular death rates (11.0% vs. 11.2%; RRdeath, 0.93; 95% CI, 0.79–1.10; P = .41).[108] 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 therapy

Antiandrogen agents used in the treatment of prostate cancer include flutamide and bicalutamide. A systematic evidence review compared nonsteroidal antiandrogen monotherapy with surgical or medical castration from 11 randomized trials in 3,060 men with locally advanced, metastatic, or recurrent disease after local therapy.[109] Use of nonsteroidal antiandrogens as monotherapy decreased OS and increased the rate of clinical progression and treatment failure.[109][Level of evidence: 1iiA]
The pure antiandrogen, flutamide, may cause diarrhea, breast tenderness, and nausea. Case reports show fatal and nonfatal liver toxic effects.[110]
Bicalutamide may cause nausea, breast tenderness, hot flashes, loss of libido, and impotence.[111] (Refer to the PDQ summaries on Gastrointestinal Complications; Treatment-Related Nausea and Vomiting; and Hot Flashes and Night Sweats for more 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 QOL are required.[112]
ADT
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 QOL measures, including the following:[113][Level of evidence: 3iC]
  • Impact of cancer and treatment.
  • Concern regarding body image.
  • Mental health.
  • General health.
  • Activity.
  • Worries about cancer and dying.
  • Energy.
ADT 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.[114]
The use of ADT may be associated with complaints of penile shortening, although the data are very limited.[60] In a registry study of men with rising PSA after initial treatment of clinically localized prostate cancer treated with radiation therapy plus ADT, 6 of 225 men (2.7%) complained of reduced penile size. Of the 213 men treated with radiation therapy but no ADT, 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 ADT 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.[115]
The use of ADT has also been associated with an increased risk of colorectal cancer.
Evidence (increased risk of colorectal cancer):
  1. Using the Surveillance, Epidemiology, and End Results (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.[116]
    • 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 therapy

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

Treatment options under clinical evaluation for patients with prostate cancer include the following:
  1. Cryosurgery.
  2. Proton-beam therapy.
  3. Photodynamic therapy.
  4. Neoadjuvant hormonal therapy.
  5. Bicalutamide.

Cryosurgery

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.[117][Level of evidence: 3iiiC]; [Level of evidence: 3iii]; [118,119][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.[120]
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%.
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.[118,119] Other major complications include urethral sloughing, urinary fistula or stricture, and bladder neck obstruction.[120]

Proton-beam therapy

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.

Photodynamic therapy

Vascular-targeted photodynamic therapy using a photosensitizing agent has been tested in men with low-risk prostate cancer.[121]

Neoadjuvant hormonal therapy

The role of neoadjuvant hormonal therapy is not established.[26,27]

Bicalutamide

Bicalutamide has not been shown to improve OS in patients with localized or locally advanced prostate cancer.
Evidence (bicalutamide):
  1. The Early Prostate Cancer program is a large, randomized, placebo-controlled, international trial that compared bicalutamide (150 mg PO qd) 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.[122][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]).
Information about ongoing clinical trials is available from the NCI website.
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