Prostate Carcinoma

The median age at diagnosis of carcinoma of the prostate is 66 years. Prostate cancer may be cured when localized, and it frequently responds to treatment when widespread. The rate of tumor growth varies from very slow to moderately rapid, and some patients may have prolonged survival even after the cancer has metastasized to distant sites, such as bone. The 5-year relative survival rate for men diagnosed in the United States from 2001 to 2007 with local or regional disease was 100%, and the rate for distant disease was 28.7%; a 99% survival rate was observed for all stages combined. The approach to treatment is influenced by age and coexisting medical problems. Side effects of various forms of treatment should be considered in selecting appropriate management.

Many patients—especially those with localized tumors—may die of other illnesses without ever having suffered disability from the cancer, even if managed conservatively without an attempt at curative therapy. In part, these favorable outcomes are likely the result of widespread screening with the prostate-specific antigen (PSA) test, which can identify patients with asymptomatic tumors that have little or no lethal potential. There is a large number of these clinically indolent tumors, estimated from autopsy series of men dying of causes unrelated to prostate cancer to be in the range of 30% to 70% of men older than 60 years.


Pathology   Staging   Treatment   Hormone Therapy and Systemic treatments (ASCO/ACS)   NCCN Guidelines  

Screening information for prostate cancer

Screening for prostate cancer is done to find evidence of cancer in otherwise healthy men. Two tests are commonly used to screen for prostate cancer:

Digital rectal examination (DRE). A DRE is a test in which the doctor inserts a gloved lubricated finger into a man’s rectum and feels the surface of the prostate for any irregularities.

PSA blood test. There is controversy about using the PSA test to look for prostate cancer in men with no symptoms of the disease. On one hand, the PSA test is useful for detecting early-stage prostate cancer, which helps many men get the treatment they need before the cancer spreads. On the other hand, PSA screening finds conditions that are not cancer, in addition to prostate cancers that would never threaten a man’s life. As a result, screening for prostate cancer may mean that some men have surgery and other treatments that may not be needed and may seriously affect a man’s quality of life.

ASCO recommends that men with no symptoms of prostate cancer be discouraged from PSA screening if they are expected to live less than 10 years. For men expected to live longer than 10 years, ASCO recommends that they talk with their doctors to find out if the test is appropriate for them.

Other organizations have different recommendations for screening:
• The U.S. Preventive Services Task Force has concluded that the potential risks of PSA screening in healthy men outweigh the potential benefits. This task force may revisit screening for prostate cancer because of the availability of newer and more sophisticated tests.
• Both the American Urological Association and the American Cancer Society recommend that men be told the risks and benefits of testing before PSA screening occurs.
• The National Comprehensive Cancer Network considers a patient’s age, PSA value, DRE results, and other factors in their recommendations.

It is not easy to predict which tumors will grow and spread quickly and which will grow slowly. Every man should discuss his situation and personal risk of prostate cancer with his doctor so they can work together to make a decision.

Screening

The issue of prostate cancer screening is controversial. In the United States, most prostate cancers are diagnosed as a result of screening, either with a PSA blood test or, less frequently, with a digital rectal examination. Randomized trials have yielded conflicting results. Systematic literature reviews and meta-analyses have reported no clear evidence that screening for prostate cancer decreases the risk of death from prostate cancer, or that the benefits outweigh the harms of screening.

(Refer to the PDQ summary on Prostate Cancer Screening for a detailed summary of evidence regarding the benefits and harms of screening for prostate cancer.)




Large clinical trials change experts’ minds on prostate cancer screening

For men 55 to 69, it should be an individual choice. For 70 and older, don’t bother.

Prostate cancer screening is now something to consider for men aged 55 to 69, according to the federal panel tasked with making recommendations for such preventative care options. In a finalized recommendation released Tuesday, the US Preventive Services Task Force (USPSTF) revealed that it has officially warmed to the screening—ever so slightly.

Back in 2012, the task force famously recommended against the then-common blood screening for elevated levels of PSA protein, which can indicate prostate cancer as well as other conditions. But, given new data from large, randomized clinical trials showing that routine screening can save a small number of lives, the USPSTF now says the scales have tipped in screening’s favor.

The task force still has the same recommendation for men aged 70 and over, which is against screening. The benefits still don’t outweigh the risks for this age group, the panel says. Read the entire article at arstechnica.com Large clinical trials change experts’ minds on prostate cancer screening   Copy

 

Pathology

More than 95% of primary prostate cancers are adenocarcinomas. Prostate adenocarcinomas are frequently multifocal and heterogeneous in patterns of differentiation. Prostatic intraepithelial neoplasia ([PIN] noninvasive atypical epithelial cells within benign appearing acini) is often present in association with prostatic adenocarcinoma. PIN is subdivided into low grade and high grade. The high-grade form may be a precursor for adenocarcinoma.

A number of rare tumors account for the remaining few percentages of cases. These include the following:
• Small-cell tumors.
• Intralobular acinar carcinomas.
• Ductal carcinomas.
• Clear cell carcinomas.
• Mucinous carcinomas.

Gleason score

The histologic grade of prostate adenocarcinomas is usually reported according to one of the variations of the Gleason scoring system, which provides a useful, albeit crude, adjunct to tumor staging in determining prognosis. The Gleason score is calculated based on the dominant histologic grades, from grade 1 (well differentiated) to grade 5 (very poorly differentiated). The classical score is derived by adding the two most prevalent pattern grades, yielding a score ranging from 2 to 10. Because there is some evidence that the least-differentiated component of the specimen may provide independent prognostic information, the score is often provided by its separate components (e.g., Gleason score 3 + 4 = 7; or 4 + 3 = 7).

There is evidence that, over time, pathologists have tended to award higher Gleason scores to the same histologic patterns, a phenomenon sometimes termed grade inflation. This phenomenon complicates comparisons of outcomes in current versus historical patient series. For example, prostate biopsies from a population-based cohort of 1,858 men diagnosed with prostate cancer from 1990 through 1992 were re-read in 2002 to 2004. The contemporary Gleason score readings were an average of 0.85 points higher (95% confidence interval, 0.79–0.91; P < .001) than the same slides read a decade earlier. As a result, Gleason-score standardized prostate cancer mortality rates for these men were artifactually improved from 2.08 to 1.50 deaths per 100 person years—a 28% decrease even though overall outcomes were unchanged.


Molecular markers

A number of tumor markers have been reported to be associated with the outcome of prostate cancer patients, including the following:
• Markers of apoptosis including Bcl-2, Bax.
• Markers of proliferation rate, such as Ki67.
• p53 mutation or expression.
• p27.
• E-cadherin.
• Microvessel density.
• DNA ploidy.
• p16.
• PTEN gene hypermethylation and allelic losses.

However, none of these has been prospectively validated, and they are not a part of the routine management of patients.

Gleason score for grading prostate cancer

Prostate cancer is also given a grade called a Gleason score. This score is based on how much the cancer looks like healthy tissue when viewed under a microscope. Less aggressive tumors generally look more like healthy tissue. Tumors that are more aggressive are likely to grow and spread to other parts of the body. They look less like healthy tissue.

The Gleason scoring system is the most common prostate cancer grading system used. The pathologist looks at how the cancer cells are arranged in the prostate and assigns a score on a scale of 1 to 5. Cancer cells that look similar to healthy cells receive a low score. Cancer cells that look less like healthy cells or look more aggressive receive a higher score. To assign the numbers, the doctor determines the main pattern of cell growth, which is the area where the cancer is most obvious; looks for any other less common pattern of growth; and gives each 1 a score. The scores are added together to come up with an overall score between 2 and 10.

The interpretation of the Gleason score by doctors has changed recently. Originally, doctors used a wide range of scores. Today, doctors no longer use Gleason scores of 5 or lower for cancer found with a biopsy. The lowest score used is 6, which is a low-grade cancer. A Gleason score of 7 is a medium-grade cancer, and a score of 8, 9, or 10 is a high-grade cancer. A lower-grade cancer grows more slowly and is less likely to spread than a high-grade cancer.

Doctors look at the Gleason score in addition to stage to help plan treatment. For example, active surveillance, described in the Treatment Options section, may be an option for a patient with a small tumor, low PSA level, and a Gleason score of 6. Patients with high Gleason score may need treatment that is more intensive, even if it does not appear that the cancer has spread.

Gleason X: The Gleason score cannot be determined.
Gleason 6 or lower: The cells are well differentiated, meaning they look similar to healthy cells.
Gleason 7: The cells are moderately differentiated, meaning they look somewhat similar to healthy cells.
Gleason 8, 9, or 10: The cells are poorly differentiated or undifferentiated, meaning they look very different from healthy cells.

Recently, pathologists have begun to adopt a new Gleason grouping system that arranges the scores into simplified groups that are translated as follows:
• Gleason Group I = Former Gleason 6
• Gleason Group II = Former Gleason 3 + 4 = 7
• Gleason Group III = Former Gleason 4 + 3 = 7
• Gleason Group IV = Former Gleason 8
• Gleason Group V = Former Gleason 9 or 10

 

Prognostic Factors

The survival of patients with prostate cancer is related to several factors, including the following:
•Extent of tumor.
•Histologic grade of tumor.
•Patient's age and health.
•Prostate-specific antigen (PSA) level.
(Refer to the Surveillance, Epidemiology, and End Results' 5-year and 10-year survival rates.)

Extent of tumor
When the cancer is confined to the prostate gland, long-term prognosis is excellent. Patients with locally advanced cancer are not usually curable, but 5-year survival is still very good. If prostate cancer has spread to distant organs, current therapy will not cure it. Median survival is usually 1 to 3 years, and most of these patients will die of prostate cancer. Even in this group of patients, indolent clinical courses lasting for many years may be observed.

Histologic grade of tumor
Poorly differentiated tumors are more likely to have metastasized before diagnosis and are associated with a poorer prognosis. The most commonly used method to report tumor differentiation is the Gleason score.
(Refer to the Pathology section of the General Information About Prostate Cancer section of this summary for more information.)

Patient's age and health
Any benefits of definitive local therapy with curative intent may take years to emerge. Therefore, therapy with curative intent is usually reserved for men with a sufficiently long life expectancy. For example, radical prostatectomy is often reserved for men with an estimated life expectancy of at least 10 years.

Prostate-specific antigen (PSA) level
PSA, an organ-specific marker, is often used as a tumor marker. The higher the level of PSA at baseline, the higher is the risk for metastatic disease or subsequent disease progression. However, it is an imprecise marker of risk.
For example, baseline PSA and rate of PSA change were associated with subsequent metastasis or prostate cancer death in a cohort of 267 men with clinically localized prostate cancer who were managed by watchful waiting or active surveillance in the control arm of a randomized trial comparing radical prostatectomy with watchful waiting or active surveillance. Nevertheless, the accuracy of classifying men into groups whose cancer remained indolent versus those whose cancer progressed was poor at all examined cut points of PSA or PSA rate of change.

Serum acid phosphatase levels
Elevations of serum acid phosphatase are associated with poor prognosis in both localized and disseminated disease. However, serum acid phosphatase levels are not incorporated into the American Joint Committee on Cancer's (AJCC) staging system for prostate cancer.

Use of nomograms as a prognostic tool
Several nomograms have been developed to predict outcomes either before radical prostatectomy or after radical prostatectomy with intent to cure.
Preoperative nomograms are based on clinical stage, PSA level, Gleason score, and the number of positive and negative prostate biopsy cores. One independently validated nomogram demonstrated increased accuracy in predicting biochemical recurrence-free survival by including preoperative plasma levels of transforming growth factor B1 and interleukin-6 soluble receptor.

Postoperative nomograms add pathologic findings, such as capsular invasion, surgical margins, seminal vesicle invasion, and lymph node involvement. The nomograms, however, were developed at academic centers and may not be as accurate when generalized to nonacademic hospitals, where the majority of patients are treated. In addition, the nomograms use nonhealth (intermediate) outcomes, such as PSA rise or pathologic surgical findings, and subjective endpoints, such as the physician's perceived need for additional therapy. In addition, the nomograms may be affected by changing methods of diagnosis or neoadjuvant therapy.

Prostate Cancer Risk Groups

In addition to stage, doctors use other prognostic factors to help plan the best treatment and predict how successful treatment will be. Two such risk assessment methods come from the National Comprehensive Cancer Network (NCCN) and the University of California, San Francisco (UCSF).

NCCN (National Comprehensive Cancer Network)
The NCCN developed 4 risk-group categories based on PSA level, prostate size, needle biopsy findings, and the stage of cancer. The lower your risk, the lower the chance that the prostate cancer will grow and spread.

Very low risk. The tumor cannot be felt during a DRE and is not seen during imaging tests but was found during a needle biopsy (T1c). PSA is less than 10 ng/mL. The Gleason score is 6 or less. Cancer was found in fewer than 3 samples taken during a core biopsy. The cancer was found in half or less of any core.

Low risk. The tumor is classified as T1a, T1b, T1c, or T2a (see above). PSA is less than 10 ng/mL. The Gleason score is 6 or less.

Intermediate risk. The tumor has 2 or more of these characteristics:
• Classified as T2b or T2c (see above)
• PSA is between 10 and 20 ng/mL
• Gleason score of 7

High risk. The tumor has 2 or more of these characteristics:
• Classified as T3a (see above)
• PSA level is higher than 20 ng/mL
• Gleason score is between 8 and 10

Very high risk. The tumor is classified as T3b or T4 (see above). The histologic grade is 5 for the main pattern of cell growth, or more than 4 biopsy cores have Gleason scores between 8 and 10.


UCSF Cancer of the Prostate Risk Assessment (UCSF-CAPRA) score
The UCSF-CAPRA score predicts a man’s chances of having the cancer spread and of dying. This score can be used to help make decisions about the treatment plan. Points are assigned according to a person’s age at diagnosis, PSA at diagnosis, Gleason score of the biopsy, T classification from the TNM system, and the percentage of biopsy cores involved with cancer. These categories are then used to assign a score between 0 and 10.

• CAPRA score 0 to 2 indicates low risk.
• CAPRA score 3 to 5 indicates intermediate risk.
• CAPRA score 6 to 10 indicates high risk.

Information about the cancer’s stage and other prognostic factors will help the doctor recommend a specific treatment plan.

 

Stage Information for NSCLC

Most men are diagnosed with prostate cancer at an early clinical stage and do not have detectable metastases. Therefore, they generally do not have to undergo staging tests, such as a bone scan, computed tomography (CT), or magnetic resonance imaging (MRI). However, staging studies are done if there is clinical suspicion of metastasis, such as bone pain; local tumor spread beyond the prostate capsule; or a substantial risk of metastasis (prostate-specific antigen [PSA] >20 ng/mL and Gleason score >7).

Tests used to determine stage include the following:

Radionuclide bone scans.
A radionuclide bone scan is the most widely used test for metastasis to the bone, which is the most common site of distant tumor spread.
Serum PSA level.
Serum PSA can predict the results of radionuclide bone scans in newly diagnosed patients.
In one series, only 2 of 852 patients (0.23%) with a PSA of less than 20 ng/mL had a positive bone scan in the absence of bone pain.
In another series of 265 prostate cancer patients, 0 of 23 patients with a PSA of less than 4 ng/mL had a positive bone scan, and 2 of 114 patients with a PSA of less than 10 ng/mLhad a positive bone scan.
MRI.
Although MRI has been used to detect extracapsular extension of prostate cancer, a positive-predictive value of about 70% and considerable interobserver variation are problems that make its routine use in staging uncertain. Ultrasound and MRI, however, can reduce clinical understaging and thereby improve patient selection for local therapy. MRI with an endorectal coil appears to be more accurate for identification of organ-confined and extracapsular disease, especially when combined with spectroscopy. MRI is a poor tool for evaluating nodal disease.
MRI is more sensitive than radionuclide bone scans in the detection of bone metastases, but it is impractical for evaluating the entire skeletal system.
Pelvic lymph node dissection (PLND).
PLND remains the most accurate method to assess metastasis to the pelvic nodes, and laparoscopic PLND has been shown to accurately assess pelvic nodes as effectively as an open procedure.
The determining factor in deciding whether any type of PLND is indicated is when definitive therapy may be altered. For example, radical prostatectomy is generally reserved for men without lymph node metastasis. Likewise, preoperative seminal vesicle biopsy may be useful in patients with palpable nodules who are being considered for radical prostatectomy (unless they have a low Gleason score) because seminal vesicle involvement could affect the choice of primary therapy and predicts for pelvic lymph node metastasis.
In patients with clinically localized (stage I or stage II) prostate cancer, Gleason pathologic grade and enzymatic serum prostatic acid phosphatase values (even within normal range) predict the likelihood of capsular penetration, seminal vesicle invasion, or regional lymph node involvement. Analysis of a series of 166 patients with clinical stage I or stage II prostate cancer undergoing radical prostatectomy revealed an association between Gleason biopsy score and the risk of lymph node metastasis found at surgery. The risks of nodal metastasis for patients grouped according to their Gleason biopsy score was 2%, 13%, and 23% for Gleason scores of 5, 6, and 8, respectively.
Whether to subject all patients to a PLND is debatable, but in patients undergoing a radical retropubic prostatectomy, nodal status is usually ascertained as a matter of course. In patients who are undergoing a radical perineal prostatectomy in whom the PSA value is less than 20 ng/mL and the Gleason sum is low, however, evidence is mounting that a PLND is probably unnecessary, especially in patients whose malignancy was not palpable but detected on ultrasound.
Transrectal or transperineal biopsy.
The most common means to establish a diagnosis and determine the Gleason score in cases of suspected prostate cancer is by needle biopsy. Most urologists now perform a transrectal biopsy using a bioptic gun with ultrasound guidance. Over the years, there has been a trend toward taking eight to ten or more biopsy samples at the same time. Less frequently, a transperineal, ultrasound-guided approach can be used for those patients who may be at increased risk of complications from a transrectal approach.
Transrectal ultrasound (TRUS).
TRUS may facilitate diagnosis by directing needle biopsy; however, ultrasound is operator dependent and does not assess lymph node size.
CT scans.
CT scans can detect grossly enlarged lymph nodes but poorly define intraprostatic features; therefore, it is not reliable for the staging of pelvic node disease when compared with surgical staging.


TNM staging system

Tumor (T)
TX: The primary tumor cannot be evaluated.
T0 (T plus zero): There is no evidence of a tumor in the prostate.

T1: The tumor cannot be felt during a DRE and is not seen during imaging tests. It may be found when surgery is done for another reason, usually for BPH or an abnormal growth of noncancerous prostate cells.
•T1a: The tumor is in 5% or less of the prostate tissue removed during surgery.
•T1b: The tumor is in more than 5% of the prostate tissue removed during surgery.
•T1c: The tumor is found during a needle biopsy, usually because the patient has an elevated PSA level.

T2: The tumor is found only in the prostate, not other parts of the body. It is large enough to be felt during a DRE.
•T2a: The tumor involves one-half of 1 lobe (part or side) of the prostate.
•T2b: The tumor involves more than one-half of 1 lobe of the prostate but not both lobes.
•T2c: The tumor has grown into both lobes of the prostate.

T3: The tumor has grown through the prostate capsule on 1 side and into the tissue just outside the prostate.
•T3a: The tumor has grown through the prostate capsule either on 1 side or on both sides of the prostate, or it has spread to the neck of the bladder. This is also known as an extraprostatic extension (EPE).
•T3b: The tumor has grown into the seminal vesicle(s), the tube(s) that carry semen.

T4: The tumor is fixed, or it is growing into nearby structures other than the seminal vesicles, such as the external sphincter, the part of the muscle layer that helps to control urination; the rectum; levator muscles; or the pelvic wall.

Node (N) NX: The regional lymph nodes cannot be evaluated.
N0 (N plus zero): The cancer has not spread to the regional lymph nodes.
N1: The cancer has spread to the regional (pelvic) lymph node(s).

Metastasis (M)
MX: Distant metastasis cannot be evaluated.
M0 (M plus zero): The disease has not metastasized.

M1: There is distant metastasis.
•M1a: The cancer has spread to nonregional, or distant, lymph node(s).
•M1b: The cancer has spread to the bones.
•M1c: The cancer has spread to another part of the body, with or without spread to the bone.

Stage Grouping Chart

I T1a, T1b, or T1c
T2a

Stage I: Cancer is found in the prostate only, usually during another medical procedure. It cannot be felt during the DRE or seen on imaging tests. A stage I cancer is usually made up of cells that look more like healthy cells and is usually slow growing.

N0 M0
II IIA:
T1a, T1b, or T1c
T2a or T2b

IIB:
T2c
This stage describes a tumor that is too small to be felt or seen on imaging tests. Or, it describes a slightly larger tumor that can be felt during a DRE. The cancer has not spread outside of the prostate gland, but the cells are usually more abnormal and may tend to grow more quickly. A stage II cancer has not spread to lymph nodes or distant organs. N0 M0
III T3a or T3b The cancer has spread beyond the outer layer of the prostate into nearby tissues. It may also have spread to the seminal vesicles. N0 M0
IV T4, N0, M0

Any T, N1, M0

Any T, Any N, M1
This stage describes any tumor that has spread to other parts of the body, such as the bladder, rectum, bone, liver, lungs, or lymph nodes.    

Note:
Stage I : Any T1 or T2a + G1 (Cancer cells that look more like healthy cells)
Stage IIA : Any T1 or T2a + G2-4
Stage IIA : T2b + Any G
Stage IIB : T2c + Any G



AJCC Stage Groupings

I - T1a, N0, M0, G1

IIA - T1a, N0, M0, G2–4
IIA - T1b, N0, M0, any G
IIA - T1c, N0, M0, any G

IIB - T1, N0, M0, any G
IIB - T2, N0, M0, any G

III - T3, N0, M0, any G

IV - T4, N0, M0, any G
IV - Any T, N1, M0, any G
IV - Any T, any N, M1, any G

 

 

Treatment Options for Prostate Cancer

Treatment Options for Prostate Cancer include active surveillance and watchful waiting, local treatments with Surgery and/or radiation, systemic treatments with Androgen deprivation therapy (ADT), Chemotherapy, immunotherapy and supportive treatments which inclde bone-modifying drugs.


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

Prostate ca Treatment Option Overview

EBRT = external-beam radiation therapy; LH-RH = luteinizing hormone-releasing hormone; TURP = transurethral resection of the prostate


Patient-reported adverse outcomes differ substantially across the options for management. The differences in adverse outcomes can play an important role in patient choice among treatment options. Detailed comparisons of these outcomes 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.
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). (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. 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). 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. (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:
• Are in good health and elect surgical intervention.
• Have tumor confined to the prostate gland (stage I and stage II).


Radical Prostatectomy

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.

The role of preoperative (neoadjuvant) hormonal therapy is not established.
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. 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).
• 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:
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%).
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/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.
      • 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).[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.

2. The Prostate Intervention Versus Observation Trial (PIVOT-1 or VA-CSP-407 [NCT00002606]) 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.[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-D conformal radiation therapy (74 Gy in 37 fractions). The primary endpoint was prostate cancer–specific mortality.
      a. 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.[Level of evidence: 1iiA]
      b. 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).[Level of evidence: 1iiB]
      c. 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.
      d. As expected, there were substantial differences in patient-reported outcomes among the three management approaches.[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

• Morbidity and mortality associated with general anesthesia and a major surgical procedure.
• Urinary incontinence and impotence.
• Penile shortening.
• Inguinal hernia.
• Fecal incontinence.

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.

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:
• 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.

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:
      • 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.
      • 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:
      • 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.
      • 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. 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.

Penile shortening
Case series of men who have undergone radical prostatectomy have shown shortening of penile length (by an average of 1–2 cm). 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. 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.

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, in the range of 7% to 21%, in men undergoing radical prostatectomy, with rates peaking within 2 years of surgery.
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; or in men with prostate cancer who have undergone pelvic lymph node dissection alone or radiation therapy.

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.

Fecal incontinence
Radical prostatectomy may cause fecal incontinence, and the incidence may vary with surgical method.

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.

 

 

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.

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%). An initial serum PSA level higher than 15 ng/mL is a predictor of probable failure with conventional radiation therapy.

2.S everal 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).[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 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. 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.

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]

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.

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. 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, despite low mortality rates, and the trial was underpowered for mortality endpoints.][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). 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.[Level of evidence: 1iiD]
      • Overall mortality rates were very similar in the three groups: 9%, 7%, and 8%.[Level of evidence: 1iiA]
      •A quality-of-life (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).[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). 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).[73][Level of evidence: 1iiD] Overall 5-year survival 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).[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).

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).
      • 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).[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).
      • 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).[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
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.Level of evidence: 3iiiDiv]

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%).[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. These conditions are generally reversible but may be chronic and rarely require surgical intervention.

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.

Radiation is also known to be carcinogenic. 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. 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).[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.[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.

Evidence (3-dimensional conformal vs. conventional radiation therapy):
1. 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.
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.
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.

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, 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. >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.
      • 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 (added to androgen deprivation therapy).
• Bilateral orchiectomy.
• Estrogen therapy.
• Luteinizing hormone-releasing hormone (LH-RH) agonist therapy.
• Antiandrogen therapy.
• ADT.
• Antiadrenal therapy.
      • Ketoconazole.
      • Aminoglutethimide.

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. It may also be associated with a small increase in respiratory disorders.

Bilateral orchiectomy
Benefits of bilateral orchiectomy include the following:
• 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:
• Psychological effects.
• Loss of libido.
• Less reversible impotence.
• Hot flashes.
• Osteoporosis.
Bilateral orchiectomy has also been associated with an elevated risk of coronary heart disease and myocardial infarction.

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.

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.

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). 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. Use of nonsteroidal antiandrogens as monotherapy decreased OS and increased the rate of clinical progression and treatment failure.[Level of evidence: 1iiA]

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.

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.

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:[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.

The use of ADT 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 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.

The use of ADT has also been associated with an increased risk of colorectal cancer.

Evidence (increased risk of colorectal cancer):
1. 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 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.

 

 

Treatment Options Under Clinical Evaluation


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.[Level of evidence: 3iiiC]; [Level of evidence: 3iii]; [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%.

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. Other major complications include urethral sloughing, urinary fistula or stricture, and bladder neck obstruction.

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.

Neoadjuvant hormonal therapy
The role of neoadjuvant hormonal therapy is not established.

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.[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]).

 

 

 

Stage I Prostate Cancer Treatment

Overview
Stage I prostate cancer is defined by the American Joint Committee on Cancer's TNM classification system:
• T1a–c, N0, M0, prostate-specific antigen (PSA) <10 ng/mL, Gleason ≤6.
• T2a, N0, M0, PSA <10 ng/mL, Gleason ≤6.
• T1–2a, N0, M0, PSA X, Gleason X.

The frequency of clinically silent, nonmetastatic prostate cancer that can be found at autopsy greatly increases with age and may be as high as 50% to 60% in men aged 90 years and older.
Undoubtedly, the incidental discovery of these occult cancers at prostatic surgery performed for other reasons accounts for the similar survival of men with stage I prostate cancer, compared with the normal male population, adjusted for age.

Many stage I cancers are well differentiated and only focally involve the gland (T1a, N0, M0); most require no treatment other than careful follow-up.

In younger patients (aged 50–60 years) whose expected survival is long, treatment should be considered.
Radical prostatectomy, external-beam radiation therapy (EBRT), interstitial implantation of radioisotopes, and watchful waiting and active surveillance/active monitoring yield apparently similar survival rates in noncontrolled, selected series. The decision to treat should be made in the context of the patient’s age, associated medical illnesses, and personal desires.

Standard Treatment Options for Stage I Prostate Cancer

1. Watchful waiting or active surveillance/active monitoring.

2. Radical prostatectomy.

3. External-beam radiation therapy (EBRT).

4. Interstitial implantation of radioisotopes.

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.
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.

Evidence (observation with delayed hormonal therapy):
1. In a retrospective pooled analysis, 828 men with clinically localized prostate cancer were managed by initial conservative therapy with subsequent hormonal therapy given at the time of symptomatic disease progression.
      • This study showed that the patients with grade 1 or grade 2 tumors experienced a disease-specific survival of 87% at 10 years and that their overall survival (OS) closely approximated the expected survival among men of similar ages in the general population.

 



Radical prostatectomy
Radical prostatectomy, usually with pelvic lymphadenectomy (with or without the nerve-sparing technique designed to preserve potency) is the most commonly applied therapy with curative intent. Radical prostatectomy may be difficult after a transurethral resection of the prostate (TURP).

Because about 40% to 50% of men with clinically organ-confined disease are found to have pathologic extension beyond the prostate capsule or surgical margins, the role of postprostatectomy adjuvant radiation therapy has been studied.

Consideration may also be given to postoperative radiation therapy (PORT) for patients who are found to have seminal vesicle invasion by tumor at the time of prostatectomy or who have a detectable level of PSA more than 3 weeks after surgery. Because duration of follow-up in available studies is still relatively short, the value of PORT is yet to be determined; however, PORT does reduce local recurrence. Careful treatment planning is necessary to avoid morbidity.

Evidence (radical prostatectomy followed by radiation therapy):
1. In a randomized trial of 425 men with pathologic T3, N0, and M0 disease, postsurgical EBRT (60–64 Gy to the prostatic fossa over 30–32 fractions) was compared with observation.[Level of evidence: 1iiA]
      • The primary endpoint, metastasis-free survival, could be affected by serial PSA monitoring and resulting metastatic work-up for PSA increase. This could have biased the primary endpoint in favor of radiation therapy, which was associated with a lower rate of PSA rise. Nevertheless, metastasis-free survival was not statistically different between the two study arms (P = .06). After a median follow-up of about 10.6 years, the overall median survival was 14.7 years in the radiation therapy group versus 13.8 years in the observation group (P = .16).
      • Although the OS rates were not statistically different, complication rates were substantially higher in the radiation therapy group: overall complications were 23.8% versus 11.9%, rectal complications were 3.3% versus 0%, and urethral stricture was 17.8% versus 9.5%.
      • After a median follow-up of about 12.5 years, however, OS was better in the radiation therapy arm; hazard ratio (HR)death, 0.72 (95% confidence interval [CI], 0.55–0.96; P = .023). The 10-year estimated survival rates were 74% in the radiation therapy arm and 66% in the control arm. The 10-year estimated metastasis-free survivals were 73% and 65% (P = .016).[Level of evidence: 1iiA]

2. Another randomized trial came to a different conclusion with respect to the effect of postoperative radiation therapy on OS.[Level of evidence: 1iiA] In the European Organization for Research and Treatment of Cancer (EORTC) trial (EORTC-22911 [NCT00002511]), 1,005 men aged 75 years and younger with clinical T0 to T3 prostate cancer were randomly assigned after prostatectomy to receive postoperative radiation (60 Gy) or observation, with subsequent therapy delayed until the occurrence of either biochemical or clinical relapse. The recommended treatment for local recurrence was radiation.
      • With a median follow-up of 10.6 years (up to 16.6 years), the biochemical progression-free survival (PFS) rates were higher in the observation study arm (60.6% vs. 41.1%; HR, 0.49; 95% CI, 0.41–0.59; P < .0001). Locoregional relapse rates were 8.4% versus 17.3% in favor of immediate radiation (HR, 0.45; 95% CI, 0.32–0.68; P < .0001).
      • However, the large differences in biochemical relapse-free survival and local recurrence did not translate into an advantage in either distant metastasis (11.0% vs. 11.3%; HR, 0.99; 95% CI, 0.67–1.44; P = .94) or in OS (76.9% with immediate radiation vs. 80.7% with observation; HR, 1.18; 95% CI, 0.91–1.53; P = .2). Nor was there a difference in prostate cancer-specific mortality (3.9% vs. 5.2%; HR, 0.78; 95% CI, 0.46–1.33; P = .34)
      • The 10-year cumulative risk of severe (grade 3) late toxicity in the immediate radiation study group was 5.3% versus 2.5% in the observation group (P = .052). Late adverse effects of any grade were also higher in the immediate radiation group (70.8% vs. 59.7%; P = .001).

Radical prostatectomy has been compared with watchful waiting or active surveillance/active monitoring. (Refer to the Radical prostatectomy compared with other treatment options section in the Treatment Option Overview for Prostate Cancer section of this summary for more information about radical prostatectomy compared with watchful waiting or active surveillance/active monitoring.)

Evidence (radical prostatectomy compared with watchful waiting):
1. The Prostate Intervention Versus Observation Trial (PIVOT-1 or VA-CSP-407 [NCT00002606]) 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 versus watchful waiting.[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% versus 66.8% in the prostatectomy and watchful-waiting study arms, respectively, an absolute difference of 5.5 percentage points (95% CI -1.5 to 12.4) that was not statistically significant (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 for 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.

External-beam radiation therapy (EBRT)
EBRT is another treatment option used with curative intent. Definitive radiation therapy should be delayed 4 to 6 weeks after TURP to reduce the incidence of stricture. Adjuvant hormonal therapy should be considered for patients with bulky T2b to T2c tumors.

Evidence (EBRT with or without adjuvant hormonal therapy):
1. Radiation Therapy Oncology Group's (RTOG) trial 7706 (RTOG-7706).[Level of evidence: 1iiA]
      • Prophylactic radiation therapy to clinically or pathologically uninvolved pelvic lymph nodes does not appear to improve OS or prostate cancer-specific survival.

2. RTOG-9413 (RTOG-9413 [NCT00769548]) trial. [Level of evidence: 1iiDiii]
      • Although RTOG-9413 showed increased PFS at 4 years for patients who had a 15% estimated risk of lymph node involvement and received whole-pelvic radiation therapy compared with prostate-only radiation therapy, OS and PSA failure rates were not significantly different.

3. In a randomized trial, 875 men with locally advanced nonmetastatic prostate cancer (T1b–T2 moderately or poorly differentiated tumors; T3 tumors of any grade) were randomly assigned to receive 3 months of a luteinizing hormone-releasing hormone agonist plus long-term flutamide (250 mg PO tid) with or without EBRT.[Level of evidence: 1iiA]
      • Nineteen percent of the men had tumor stage T2, and 78% of the men had T3. At 10 years, both overall mortality (29.6% vs. 39.4%; 95% CI for the difference, 0.8%–18.8%) and the prostate cancer-specific mortality (11.9% vs. 23.9%; 95% CI for the difference, 4.9%–19.1%) favored combined hormonal and radiation therapy.
      •Although flutamide might not be considered a standard hormonal monotherapy in the setting of T2 or T3 tumors, it is interesting to see that radiation therapy provided a disease-free survival or tumor-specific survival advantage even though this monotherapy was applied. This analysis rests on the assumption that flutamide does not shorten life expectancy and cancer-specific survival. Radiation therapy was not delivered by current standards of dose and technique.

Interstitial implantation of radioisotopes
Interstitial implantation of radioisotopes (i.e., iodine I 125 [125I], palladium, and iridium Ir 192) done through a transperineal technique with either ultrasound or computed-tomography guidance, is being used in patients with T1 or T2a tumors. Short-term results in these patients are similar to those for radical prostatectomy or EBRT. [Level of evidence: 3iiiDiv]

Factors for consideration in the use of interstitial implants include the following:
• The implant is performed as outpatient surgery.
• The rate of maintenance of sexual potency with interstitial implants has been reported to be 86% to 92%.[28,30] In contrast, rates of maintenance of sexual potency with radical prostatectomy were 10% to 40% and 40% to 60% with EBRT.
• Typical side effects from interstitial implants that subside with time include urinary tract frequency, urgency, and less commonly, urinary retention.
• Rectal ulceration may also be seen. In one series, a 10% 2-year actuarial genitourinary grade 2 complication rate and a 12% risk of rectal ulceration were seen. This risk decreased with increased operator experience and modification of the implant technique.

Long-term follow-up of these patients is necessary to assess treatment efficacy and side effects.

Retropubic freehand implantation with 125I has been associated with an increased local failure and complication rate and is now rarely done.

Treatment Options Under Clinical Evaluation for Stage I Prostate Cancer
1. High-intensity focused ultrasound therapy.

 

 

Stage II Prostate Cancer Treatment

Overview
Stage II prostate cancer is defined by the American Joint Committee on Cancer's TNM classification system:

Stage IIA
1.T1a–c, N0, M0, prostate-specific antigen (PSA) <20 ng/mL, Gleason 7.
2.T1a–c, N0, M0, PSA ≥10 <20 ng/mL, Gleason ≤6.
3.T2a, N0, M0, PSA ≥10 <20 ng/mL, Gleason ≤6.
4.T2a, N0, M0, PSA <20 ng/mL, Gleason 7.
5.T2b, N0, M0, PSA <20 ng/mL, Gleason ≤7.
6.T2b, N0, M0, PSA X, Gleason X.

Stage IIB
1.T2c, N0, M0, any PSA, any Gleason.
2.T1–2, N0, M0, PSA ≥20 ng/mL, any Gleason.
3.T1–2, N0, M0, any PSA, Gleason ≥8.


Radical prostatectomy, external-beam radiation therapy (EBRT), and interstitial implantation of radioisotopes are each employed in the treatment of stage II prostate cancer with apparently similar therapeutic effects.
Radical prostatectomy and radiation therapy yield apparently similar survival rates with as many as 10 years of follow-up.
For well-selected patients, radical prostatectomy is associated with a 15-year survival comparable with an age-matched population without prostate cancer. Unfortunately, randomized comparative trials of these treatment methods with prolonged follow-up are lacking.

Patients with a small, palpable cancer (T2a, N0, and M0) fare better than patients in whom the disease involves both sides of the gland (T2c, N0, and M0). Patients proven free of node metastases by pelvic lymphadenectomy fare better than patients in whom this staging procedure is not performed; however, this is the result of selection of patients who have a more favorable prognosis.

Side effects of the various forms of therapy—including impotence, incontinence, and bowel injury—should be considered in determining the type of treatment to employ.

Prostate-specific antigen (PSA) changes as markers of tumor progression
Often, changes in PSA are thought to be markers of tumor progression. Even though a tumor marker or characteristic may be consistently associated with a high risk of prostate cancer progression or death, it may be a very poor predictor of very limited utility in making therapeutic decisions.

Baseline PSA and rate of PSA change were associated with subsequent metastasis or prostate cancer death in a cohort of 267 men with clinically localized prostate cancer who were managed by watchful waiting or active surveillance in the control arm of a randomized trial comparing radical prostatectomy with watchful waiting. Nevertheless, the accuracy of classifying men into groups whose cancer remained indolent versus those whose cancer progressed was poor at all examined cut points of PSA or PSA rate of change.

Bisphosphonates and risk of bone metastases
Patients with locally advanced nonmetastatic disease (T2–T4, N0–N1, and M0) are at risk for developing bone metastases. Bisphosphonates are being studied as a strategy to decrease this risk.

Evidence (bisphosphonates and risk of bone metastases):
1. A placebo-controlled randomized trial (MRC-PR04) of a 5-year regimen of the first-generation bisphosphonate clodronate in high oral doses (2,080 mg qd) had no favorable impact on either time to symptomatic bone metastasis or survival.[Level of evidence: 1iA]


Standard Treatment Options for Stage II Prostate Cancer

1. Watchful waiting or active surveillance/active monitoring.

2. Radical prostatectomy.

3. External-beam radiation therapy (EBRT) with or without hormonal therapy.
      • 3-dimensional (3D) conformal radiation therapy.

4. Interstitial implantation of radioisotopes.

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. 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. (Refer to the Treatment Option Overview for Prostate Cancer section of this summary for more information).

Evidence (observation with delayed hormonal therapy):
1. In a retrospective pooled analysis, 828 men with clinically localized prostate cancer were managed by initial conservative therapy with subsequent hormonal therapy given at the time of symptomatic disease progression.
      • This study showed that the patients with well-differentiated tumors or moderately well-differentiated tumors experienced a disease-specific survival of 87% at 10 years and that their overall survival (OS) closely approximated the expected survival among men of similar ages in the general population.
      • The decision to treat should be made in the context of the patient’s age, associated medical illnesses, and personal desires.

 



Radical prostatectomy
Radical prostatectomy, usually with pelvic lymphadenectomy (with or without the nerve-sparing technique designed to preserve potency) is the most commonly applied therapy with curative intent. Radical prostatectomy may be difficult after a transurethral resection of the prostate (TURP).

Because about 40% to 50% of men with clinically organ-confined disease are found to have pathologic extension beyond the prostate capsule or surgical margins, the role of postprostatectomy adjuvant radiation therapy has been studied.

Consideration may also be given to postoperative radiation therapy (PORT) for patients who are found to have seminal vesicle invasion by tumor at the time of prostatectomy or who have a detectable level of PSA more than 3 weeks after surgery.
Because the duration of follow-up in available studies is relatively short, the value of PORT is yet to be determined; however, PORT does reduce local recurrence. Careful treatment planning is necessary to avoid morbidity.

Evidence (radical prostatectomy followed by radiation therapy):
1.In a randomized trial of 425 men with pathologic T3, N0, M0 disease, postsurgical EBRT (60–64 Gy to the prostatic fossa over 30–32 fractions) was compared with observation.[Level of evidence: 1iiA]
      • The primary endpoint, metastasis-free survival, could be affected by serial PSA monitoring and resulting metastatic work-up for PSA increase. This could have biased the primary endpoint in favor of radiation therapy, which was associated with a lower rate of PSA rise. Nevertheless, metastasis-free survival was not statistically different between the two study arms (P = .06). After a median follow-up of about 10.6 years, overall median survival was 14.7 years in the radiation therapy group versus 13.8 years in the observation group (P = .16).
      • Although the OS rates were not statistically different, complication rates were substantially higher in the radiation therapy group compared with the observation group: overall complications were 23.8% versus 11.9%, rectal complications were 3.3% versus 0%, and urethral stricture was 17.8% versus 9.5%, respectively.
      • After a median follow-up of about 12.5 years, however, OS was better in the radiation therapy arm; hazard ratio (HR)death, 0.72 (95% confidence interval [CI], 0.55–0.96; P = .023). The 10-year estimated survival rates were 74% in the radiation therapy arm and 66% in the control arm. The 10-year estimated metastasis-free survivals were 73% and 65% (P = .016).[Level of evidence: 1iiA]

Evidence (radical prostatectomy compared directly with watchful waiting/active surveillance/active monitoring and/or external-beam radiation therapy):
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.
      • 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% CI, 5.1–20.3 percentage points; relative risk [RR]death, 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.

2. The Prostate Intervention Versus Observation Trial (PIVOT-1 or VA-CSP-407 [NCT00002606]) 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 versus watchful waiting.[Levels of evidence: 1iiA, 1iiB]
      • About 50% of the men had palpable tumors.
      • After a median follow-up of 12.7 years (range up to about 19.5 years), the all-cause mortality was 61.3% versus 66.8% in the radical-prostatectomy and watchful-waiting study arms, respectively, an absolute difference of 5.5 percentage points (95% CI -1.5 to 12.4) that was not statistically significant (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 such treatment was for asymptomatic, local, or biochemical (PSA) progression.
      • As expected, urinary incontinence and erectile/sexual dysfunction was more common in the prostatectomy group for 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-D conformal radiation (74 Gy in 37 fractions). The primary endpoint was prostate cancer-specific mortality.
      a. With a median follow-up of 10 years, there were a total of 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% radiation therapy arms.[Level of evidence: 1iiA]
      b. 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).[Level of evidence: 1iiA]
      c. 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 by the 10-year follow-up. Over the course of 10 years, 52% of the patients required active intervention.
      d. As expected, there were substantial differences in patient-reported outcomes among the three management approaches.[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 versus none in the radical prostatectomy and active-monitoring study arms).

External-beam radiation therapy (EBRT) with or without hormonal therapy
EBRT is another treatment option often used with curative intent. Definitive radiation therapy should be delayed 4 to 6 weeks after TURP to reduce the incidence of stricture. Adjuvant hormonal therapy should be considered for patients with bulky T2b to T2c tumors.

The role of adjuvant hormonal therapy in patients with locally advanced disease has been analyzed by the Agency for Health Care Policy and Research (now the Agency for Healthcare Research and Quality). Most patients had more advanced disease, but patients with bulky T2b to T2c tumors were included in the studies that were re-evaluating the role of adjuvant hormonal therapy in patients with locally advanced disease.

Evidence (EBRT with or without adjuvant hormonal therapy):
1. The Radiation Therapy Oncology Group's (RTOG) trial 7706 (RTOG-7706).[Level of evidence: 1iiA]
      • Prophylactic radiation therapy to clinically or pathologically uninvolved pelvic lymph nodes does not appear to improve OS or prostate cancer-specific survival.

2. RTOG-9413 (RTOG-9413 [NCT00769548]) trial.[Level of evidence: 1iiDiii]
      • Although RTOG-9413 showed increased progression-free survival at 4 years for patients who had a 15% estimated risk of lymph node involvement and received whole-pelvic radiation therapy compared with prostate-only radiation therapy, OS and PSA failure rates were not significantly different.

3. In a randomized trial, 875 men with locally advanced nonmetastatic prostate cancer (T1b–T2 moderately or poorly differentiated tumors; T3 tumors of any grade) were randomly assigned to receive 3 months of a luteinizing hormone-releasing hormone (LH-RH) agonist plus long-term flutamide (250 mg PO tid) with or without EBRT.[Level of evidence 1iiA]
      • Nineteen percent of the men had tumor stage T2, and 78% of the men had tumor stage T3. At 10 years, both overall mortality (29.6% vs. 39.4%; 95% CI for the difference, 0.8%–18.8%) and prostate cancer-specific mortality (11.9% vs. 23.9%; 95% CI for the difference, 4.9%–19.1%) favored combined hormonal and radiation therapy.
      • Although flutamide might not be considered a standard hormonal monotherapy in the setting of T2 or T3 tumors, it is interesting to see that radiation therapy provided a disease-free survival or tumor-specific survival advantage even though this monotherapy was applied. This analysis rests on the assumption that flutamide does not shorten life expectancy and cancer-specific survival. Radiation therapy was not delivered by current standards of dose and technique.

4. Another trial compared androgen deprivation therapy (ADT: an LH-RH agonist or orchiectomy) with ADT plus radiation therapy (65–69 Gy to the prostate by 4-field box technique, including 45 Gy to the whole pelvis, seminal vesicles, and external/internal iliac nodes unless the lymph nodes were known to be histologically negative). This trial, NCIC CTG PR.3/MRC UKPRO7 [NCT00002633], from the National Cancer Institute of Canada randomly assigned 1,205 patients with high-risk (PSA >40 ng/mL or PSA >20 ng/mL and Gleason score ≥8), T2 (12%–13% of the patients), T3 (83% of the patients), and T4 (4%–5% of the patients) with clinical or pathologically staged N0, M0 disease.[Level of evidence; 1iiA]
      • At a median follow-up of 8 years (maximum = 13 years), OS was superior in the ADT-plus-radiation therapy group (HRdeath, 0.77; 95% CI, 0.57–0.85, P = .001). OS at 10 years was 55% for the ADT-plus-radiation therapy group versus 49% for the ADT-alone group.
      • Although radiation therapy had the expected bowel and urinary side effects, quality of life was the same in each study group by 24 months and beyond.

5. A meta-analysis of randomized clinical trial evidence comparing radiation therapy with radiation therapy plus prolonged androgen suppression has been published. The meta-analysis found a difference in 5-year OS in favor of radiation therapy plus continued androgen suppression (LH-RH agonist or orchiectomy) as compared with radiation therapy alone (HR, 0.631; 95% CI, 0.479–0.831).[Level of evidence: 1iiA]

6. A meta-analysis of seven randomized controlled trials comparing early hormonal treatment (adjuvant or neoadjuvant) to deferred hormonal treatment (LH-RH agonists an d/or antiandrogens) in patients with locally advanced prostate cancer, whether treated with prostatectomy, radiation therapy, or watchful waiting or active surveillance/active monitoring, showed improved overall mortality for patients receiving early treatment (RR, 0.86; 95% CI, 0.82–0.91).[Level of evidence: 1iiA]

7. Short-term neoadjuvant-androgen therapy administered before and during radiation therapy has shown benefit in at least some patients with clinically localized prostate cancer. In an open-label, randomized trial (RTOG-9408 [NCT00002597]), 1,979 men with nonmetastatic stage T1b–c, T2a, or T2b tumors and a PSA level of 20 ng/mL or less were randomly assigned to receive radiation therapy (66.6 Gy prostate dose in 1.8 Gy daily fractions ) with or without 4 months of ADT (flutamide 250 mg PO tid plus either monthly goserelin 3.6 mg subcutaneously (SQ) or leuprolide 7.5 mg intramuscularly), beginning 2 months before radiation therapy. Median follow-up was about 9 years.[Level of evidence: 1iiA]
      • The 10-year OS rate was 57% in the radiation-only group versus 62% in the combined-therapy group (HRdeath, 1.17; 95% CI, 1.01–1.35; P = .03).
      • In a post-hoc analysis, there was no statistically significant interaction between the treatment effect and baseline-risk category of the patients. However, there appeared to be little, if any, benefit associated with combined therapy in the lowest-risk category of patients (Gleason score ≤6; PSA ≤10 ng/mL; and clinical stage ≤T2a).
      • The OS benefit was most apparent in men with intermediate-risk tumors (Gleason score 7; or Gleason score ≤6 and PSA >10 ng/mL; or clinical stage T2b).

8. The duration of neoadjuvant hormonal therapy has been tested in a randomized trial (TROG 96.01 [ACTRN12607000237482]) involving 818 men with locally advanced (T2b, T2c, T3, and T4) nonmetastatic cancer treated with radiation therapy (i.e., 66 Gy in 2 Gy daily fractions to the prostate and seminal vesicles but not including regional lymph nodes). In an open-label design, patients were randomly assigned to radiation therapy alone, 3 months of neoadjuvant androgen deprivation therapy (NADT) (goserelin 3.6 mg SQ each month plus flutamide 250 mg PO tid) for 2 months before and during radiation, or 6 months of NADT for 5 months before and during radiation.[Level of evidence: 1iiA]
      • After a median follow-up of 10.6 years, there were no statistically significant differences between the radiation-alone group and the radiation-plus-3-months-of NADT group.
      • However, the 6-month NADT arm showed better prostate cancer-specific mortality and overall mortality than the radiation-alone group; 10-year all-cause mortality 29.2% versus 42.5% (HR, 0.63; 95% CI, 0.48–0.83, P = .0008).

9. The duration of neoadjuvant hormonal therapy was tested in another trial (RTOG 9910 [NCT00005044]) of 1,489 eligible men with intermediate-risk prostate cancer (T1b–4, Gleason score 2–6, and PSA >10 but ≤100 ng/mL; T1b–4, Gleason score 7, and PSA <20; or T1b–1c, Gleason score 8–10, and PSA <20) and no evidence of metastases. The men were randomly assigned to receive short-course neoadjuvant–androgen suppression (an LHRH agonist plus bicalutamide or flutamide for 8 weeks before and 8 weeks during radiation therapy) or long-course neoadjuvant–androgen suppression (28 weeks before and 8 weeks during radiation therapy). Both groups received 70.2 Gy radiation in 39 daily fractions to the prostate and 46.8 Gy to the iliac lymph nodes.[Levels of evidence: 1iiA and 1iiB]
      • After a median of 9.4 years, 10-year prostate-specific mortality, the primary endpoint, was low in both study arms: 5% versus 4% (HR, 0.81; 95% CI, 0.48–1.39).[Level of evidence: 1iiB]
      • No statistically significant differences in overall mortality or in locoregional disease progression were found.[Level of evidence: 1iiA]
      • There was also no apparent differential effect of androgen suppression duration among any of the risk-group subsets.

10. Addition of androgen suppression therapy to EBRT may benefit men who are at an elevated risk of disease recurrence and death from prostate cancer (RTOG-9202 [NCT00767286]).

3-dimensional (3D) conformal radiation therapy
EBRT designed to decrease exposure of normal tissues using methods such as CT-based 3-D conformal treatment planning is under clinical evaluation.

 



Interstitial implantation of radioisotopes
Interstitial implantation of radioisotopes (i.e., iodine I 125 [125I], palladium, and iridium), using a transperineal technique with either ultrasound or computed-tomography (CT) guidance, is being done in patients with T1 or T2a tumors. Short-term results in these patients are similar to those for radical prostatectomy or EBRT.[Level of evidence: 3iiiDiv]

Factors for consideration in the use of interstitial implants include the following:
• The implant is performed as outpatient surgery.
• The rate of maintenance of sexual potency with interstitial implants has been reported to be 86% to 92%. In contrast, rates of maintenance of sexual potency with radical prostatectomy were 10% to 40% and 40% to 60% with EBRT.
• Typical side effects from interstitial implants that are seen in most patients but subside with time include urinary tract frequency, urgency, and less commonly, urinary retention.
• Rectal ulceration may also be seen. In one series, a 10% 2-year actuarial genitourinary grade 2 complication rate and a 12% risk of rectal ulceration were seen. This risk decreased with increased operator experience and modification of the implant technique.

Long-term follow-up of these patients is necessary to assess treatment efficacy and side effects.

Retropubic freehand implantation with 125I has been associated with an increased local failure and complication rate and is now rarely done.

Treatment Options Under Clinical Evaluation for Stage II Prostate Cancer
1. Ultrasound-guided percutaneous cryosurgery.
2. High-intensity focused ultrasound.
3. Proton-beam radiation therapy.
4. Other clinical trials.

Ultrasound-guided percutaneous cryosurgery
Cryosurgery 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: 3iiiDiv]
Cryosurgery is less well established than standard prostatectomy, and long-term outcomes are not as well established as with prostatectomy or radiation therapy.
Serious toxic effects include:
• Bladder outlet injury.
• Urinary incontinence.
• Sexual impotence.
• Rectal injury.

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.

High-intensity focused ultrasound
High-intensity focused ultrasound has been reported in case series to produce good local disease control. However, it has not been directly compared with more standard therapies, and experience with it is more limited.

Proton-beam radiation therapy
There is growing interest in the use of proton-beam radiation therapy for the treatment of prostate cancer. Although the dose distribution of this form of charged-particle radiation has the potential to 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 that compare its efficacy and toxicity with those of other forms of radiation therapy.

Other clinical trials
Other clinical trials, including trials of neoadjuvant hormonal therapy followed by radical prostatectomy, are ongoing.

 

 

Stage III Prostate Cancer Treatment

Overview
Stage III prostate cancer is defined by the American Joint Committee on Cancer's TNM classification system:
• T3a–b, N0, M0, any prostate-specific antigen (PSA), any Gleason.
Extraprostatic extension with microscopic bladder neck invasion (T4) is included with T3a.

External-beam radiation therapy (EBRT), interstitial implantation of radioisotopes, and radical prostatectomy are used to treat stage III prostate cancer. Prognosis is greatly affected by whether regional lymph nodes are evaluated and proven not to be involved.

EBRT using a linear accelerator is the most common treatment for patients with stage III prostate cancer, and large series support its success in achieving local disease control and disease-free survival (DFS). The results of radical prostatectomy in stage III patients are greatly inferior compared with results in patients with stage II cancer. Interstitial implantation of radioisotopes is technically difficult in large tumors.

The patient’s symptoms related to cancer, age, and coexisting medical illnesses should be taken into account before deciding on a therapeutic plan. In a series of 372 patients treated with radiation therapy and followed for 20 years, 47% eventually died of prostate cancer, but 44% died of intercurrent illnesses without evidence of prostate cancer.

Standard Treatment Options for Stage III Prostate Cancer
1. External-beam radiation therapy (EBRT) with or without hormonal therapy.
2. Hormonal manipulations (with or without radiation therapy).
3. Radical prostatectomy with or without EBRT.
4. Watchful waiting or active surveillance/active monitoring.


External-beam radiation therapy (EBRT) with or without hormonal therapy
EBRT alone, luteinizing hormone-releasing hormone (LH-RH) agonist, or orchiectomy, in addition to EBRT, should be considered. Definitive radiation therapy should be delayed until 4 to 6 weeks after transurethral resection to reduce the incidence of stricture.
Hormonal therapy should be considered in conjunction with radiation therapy especially in men who do not have underlying moderate or severe comorbidities. Several studies have investigated its utility in patients with locally advanced disease.

Evidence (EBRT with or without hormonal therapy):
1. Although patients in the RTOG-9413 (NCT00769548) trial showed a 15% estimated risk of lymph node involvement and received whole-pelvic radiation therapy compared with prostate-only radiation therapy, overall survival (OS) and PSA failure rates were not significantly different.[Level of evidence: 1iiDiii]
2. In a randomized trial, 875 men with locally advanced nonmetastatic prostate cancer (T1b–T2 moderately or poorly differentiated tumors; T3 tumors of any grade) were randomly assigned to receive 3 months of an LH-RH agonist plus long-term flutamide (250 mg PO tid) with or without EBRT. Nineteen percent of the men had tumor stage T2, and 78% of the men had stage T3.[Level of evidence; 1iiA]
      • At 10 years, both overall mortality (29.6% vs. 39.4%; 95% confidence intervaI [CI] for the difference, 0.8%–8.8%) and the prostate cancer-specific mortality (11.9% vs. 23.9%; 95% CI for the difference, 4.9%–19.1%) favored combined hormonal and radiation therapy.
      • Although flutamide might not be considered a standard hormonal monotherapy in the setting of T2 or T3 tumors, it is interesting to see that radiation therapy provided a DFS or tumor-specific survival advantage even though this monotherapy was applied. This analysis rests on the assumption that flutamide does not shorten life expectancy and cancer-specific survival. Radiation therapy was not delivered by current standards of dose and technique.
3. Another trial compared androgen deprivation therapy (ADT: an LH-RH agonist or orchiectomy) to ADT plus radiation therapy (65–69 Gy to the prostate by 4-field box technique, including 45 Gy to the whole pelvis, seminal vesicles, and external/internal iliac nodes unless the lymph nodes were known to be histologically negative). This trial, NCIC (CTG PR.3/MRC UKPRO7 [NCT00002633]), from the National Cancer Institute of Canada, randomly assigned 1,205 patients with high-risk (PSA >40 ng/mL or PSA >20 ng/mL and Gleason score ≥8), T2 (12%–13% of the patients), T3 (83% of the patients), and T4 (4%–5% of the patients) with clinical or pathologically staged N0, M0 disease.[Level of evidence: 1iiA]
      • At a median follow-up of 8 years (maximum = 13 years), OS was superior in the ADT-plus-radiation therapy group (hazard ratio [HR]death 0.77; 95% CI, 0.57–0.85, P = .001). OS at 10 years was 55% for the ADT-plus-radiation therapy group versus 49% for the ADT-alone group.
      • Although radiation therapy had the expected bowel and urinary side effects, quality of life (QOL) was the same in each study group by 24 months and beyond.
4. The Radiation Therapy Oncology Group (RTOG) performed a prospective randomized trial (RTOG-8531) in patients with T3, N0, or any T, N1, M0 disease who received prostatic and pelvic radiation therapy and then were randomly assigned to receive immediate adjuvant goserelin or observation with administration of goserelin at time of relapse. In patients assigned to receive adjuvant goserelin, the drug was started during the last week of the radiation therapy course and was continued indefinitely or until signs of progression.[Level of evidence: 1iiA]
      • The actuarial 10-year OS rate for the entire population of 945 analyzable patients was 49% on the adjuvant arm versus 39% on the observation arm (P = .002). There was also an improved actuarial 10-year local failure rate (23% vs. 38%, P < .001).
5. A similar trial was performed by the European Organization for Research and Treatment of Cancer (EORTC). Patients with T1, T2 (World Health Organization grade 3), N0–NX or T3, T4, N0 disease were randomly assigned to receive either pelvic/prostate radiation therapy or identical radiation therapy and adjuvant goserelin (with cyproterone acetate for 1 month) starting with radiation therapy and continuing for 3 years. The 401 patients available for analysis were followed for a median of 9.1 years.[Levels of evidence: 1iiA, 1iiDii]
      • The Kaplan-Meier estimates of OS at 10 years were 58.1% in the adjuvant goserelin arm and 39.8% in the radiation alone arm (P = .0004). Similarly, 10-year DFS (47.7% vs. 22.7%, P < .0001) and local control (94.0% vs. 76.5%, P < .001) favored the adjuvant arm.
      • Two smaller studies, with 78 and 91 patients each, have shown similar results.
6. The role of adjuvant hormonal therapy in patients with locally advanced disease has been analyzed by the Agency for Health Care Policy and Research (AHCPR) (now the Agency for Healthcare Research and Quality). Randomized clinical trial evidence comparing radiation therapy with radiation therapy with prolonged androgen suppression (with an LH-RH agonist or orchiectomy) was evaluated in a meta-analysis. Most patients had more advanced disease, but patients with bulky T2b tumors were included in the study.[Level of evidence: 1iiA]
      • The meta-analysis found a difference in 5-year OS in favor of radiation therapy plus continued androgen suppression compared with radiation therapy alone (HR, 0.631; 95% CI, 0.479–0.831).
7. Additionally, the RTOG did a study (RTOG-8610) in patients with bulky local disease (T2b, T2c, T3, or T4), with or without nodal involvement below the common iliac chain: 456 men were randomly assigned to receive either radiation therapy alone or radiation therapy with androgen ablation, which was started 8 weeks before radiation therapy and continued for 16 weeks. This trial assessed only short-term hormonal therapy, not long-term therapy, as the studies analyzed by the AHCPR did.
      • At 10 years, OS was not statistically significantly different; however, disease-specific mortality (23% vs. 36%) and DFS (11% vs. 3%) favored the combined treatment arm.[Level of evidence: 1iiA]
8. A subset analysis of the RTOG-8610 trial and the RTOG-8531 trial that involved 575 patients with T3, N0, M0 disease indicated that long-term hormones compared with short-term hormones resulted in improved biochemical DFS and cause-specific survival.
9.This finding was confirmed by RTOG-9202 (NCT00767286), which reported that radiation therapy plus 28 months of androgen deprivation resulted in longer 10-year disease-specific survival (23% vs. 13%; P < .0001) but not OS (53.9% vs. 51.6%; P = .36).
      • An unplanned post-hoc–subgroup analysis found increased OS with longer androgen deprivation (28 months vs. 4 months) (45% vs. 32%; P = .0061) in men with high-grade cancers and Gleason scores of 8 through 10.
10. Likewise, a meta-analysis of seven randomized controlled trials comparing early hormonal treatment (adjuvant or neoadjuvant) with deferred hormonal treatment (LH-RH agonists and/or antiandrogens) in patients with locally advanced prostate cancer, whether treated by prostatectomy, radiation therapy, or watchful waiting or active surveillance/active monitoring, showed improved overall mortality for patients receiving early treatment (relative risk, 0.86; 95% CI, 0.82–0.91).[Level of evidence: 1iiA]
11. The duration of neoadjuvant hormonal therapy has been tested in a randomized trial (TROG 96.01 [ACTRN12607000237482]) involving 818 men with locally advanced (T2b, T2c, T3, and T4) nonmetastatic cancer treated with radiation therapy (i.e., 66 Gy in 2 Gy daily fractions to the prostate and seminal vesicles but not including regional lymph nodes). In an open-label design, patients were randomly assigned to radiation therapy alone, 3 months of neoadjuvant androgen deprivation therapy (NADT) (goserelin 3.6 mg SQ each month plus flutamide 250 mg PO tid) for 2 months before and during radiation, or 6 months of NADT for 5 months before and during radiation.[Level of evidence: 1iiA]
      • After a median follow-up of 10.6 years, there were no statistically significant differences between the radiation-alone group and the radiation plus 3 months of NADT group.
      • However, the 6-month NADT arm showed better prostate cancer-specific mortality and overall mortality than radiation alone; 10-year all-cause mortality 29.2% versus 42.5% (HR, 0.63; 95% CI, 0.48–0.83, P = .0008).
12. The duration of neoadjuvant hormonal therapy was tested in another trial (RTOG 9910 [NCT00005044]) of 1,489 eligible men with intermediate-risk prostate cancer (T1b–4, Gleason score 2–6, and PSA >10 but ≤100 ng/mL; T1b–4, Gleason score 7, and PSA <20; or T1b–1c, Gleason score 8–10, and PSA <20) and no evidence of metastases. The men were randomly assigned to receive short-course neoadjuvant–androgen suppression (an LH-RH agonist plus bicalutamide or flutamide for 8 weeks before and 8 weeks during radiation therapy) or long-course neoadjuvant–androgen suppression (28 weeks before and 8 weeks during radiation therapy). Both groups received 70.2 Gy radiation in 39 daily fractions to the prostate and 46.8 Gy to the iliac lymph nodes.[Levels of evidence: 1iiA and 1iiB]
      • After a median of 9.4 years, 10-year prostate-specific mortality, the primary endpoint, was low in both study arms: 5% versus 4% (HR, 0.81; 95% CI, 0.48–1.39).[Level of evidence: 1iiB]
      • No statistically significant differences in overall mortality or in locoregional disease progression were found.[Level of evidence: 1iiA]
      • There was also no apparent differential effect of androgen suppression duration among any of the risk-group subsets.

Hormonal manipulations (with or without radiation therapy)
Hormonal manipulations (orchiectomy or LH-RH agonists) may be used in the treatment of stage III prostate cancer.[Level of evidence: 1iiA]

Some data suggest that the efficacy of orchiectomy or LH-RH agonists may be enhanced by the addition of abiraterone acetate in men with locally advanced tumors.
In the randomized, open-label, STAMPEDE trial, 1,917 men (about 95% newly diagnosed; about 50% had metastatic disease and about 50% had locally advanced or node-positive disease) were treated with ADT alone or ADT plus abiraterone acetate (1,000 mg PO qd) and prednisolone (5 mg PO qd).
Local radiation therapy was mandated after 6 to 9 months for men with node-negative nonmetastatic disease and optional for those with node-positive nonmetastatic disease.
Hormone therapy was curtailed at 2 years or until progression. Radiation therapy was planned in about 40% of the study participants.

• With a median follow-up of 40 months, the 3-year OS was 83% in the abiraterone study group compared with 76% in the ADT-only study group (HRdeath, 0.63; 95% CI, 0.52–0.76; P <.001).[Level of evidence: 1iiA] Although there was no clear evidence of heterogeneity in relative treatment differences in metastatic disease versus nonmetastatic disease, absolute differences were much smaller in men with nonmetastatic disease and not statistically significant, perhaps because of the short follow-up (HRdeath, 0.75; 95% CI, 0.49–1.18).
• The main additional differences in toxicity associated with abiraterone compared with ADT alone were hypertension (5% vs. 1%), mild increase in blood aminotransferase levels (6% vs. <1%), and respiratory disorders (5% vs. 2%).

Antiandrogen monotherapy has also been evaluated in men with locally advanced prostate cancer as an alternative to castration.

Evidence (nonsteroidal antiandrogen monotherapy vs. surgical or medical castration):
1. 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. Use of nonsteroidal antiandrogens as monotherapy decreased OS and increased the rate of clinical progression and treatment failure.[Level of evidence: 1iiA]

Evidence (orchiectomy vs. LH-RH agonist):
1. In a randomized equivalence study involving 480 men with locally advanced (T3 and T4) disease, those who were treated with castration had a median OS of 70 months, whereas those treated with bicalutamide (150 mg qd) had a median OS of 63.5 months (HR,1.05; 95% CI, 0.81–1.36); these results failed to meet the prespecified criteria for equivalence.[Level of evidence: 1iiA]

Immediate versus deferred hormonal therapy
In patients who are not candidates for or who are unwilling to undergo radical prostatectomy or radiation therapy, immediate hormonal therapy has been compared with deferred treatment (i.e., watchful waiting or active surveillance/active monitoring with hormonal therapy at progression).

Evidence (immediate vs. deferred hormonal therapy):
1. A randomized trial looked at immediate hormonal treatment (orchiectomy or LH-RH agonist) versus deferred treatment in men with locally advanced or asymptomatic metastatic prostate cancer.[Level of evidence: 1iiA]
      • Initial results showed better OS and prostate cancer-specific survival with the immediate treatment. This subsequently lost statistical significance as was recorded in abstract form.
      • The incidence of pathologic fractures, spinal cord compression, and ureteric obstruction were also lower in the immediate treatment arm.

2. In another trial, 197 men with stage III or stage IV prostate cancer were randomly assigned to receive bilateral orchiectomy at diagnosis or at the time of symptomatic progression (or at the time of new metastases that were deemed likely to cause symptoms).[Level of evidence: 1iiA]
      • No statistically significant difference in OS was seen over a 12-year period of follow-up.

3. In the EORTC-30891 trial, 985 patients newly diagnosed with prostate cancer, stage T0–4, N0–2, M0, and a median age of 73 years were randomly assigned to receive androgen deprivation, either immediately or on symptomatic disease progression. The study was designed to demonstrate the noninferiority of deferred treatment as compared with immediate treatment in relation to OS.[Level of evidence: 1iiA]
      • At a median follow-up of 7.8 years, approximately 50% of the patients in the deferred treatment group had initiated androgen deprivation.
      • The median OS in the immediate treatment group was 7.4 years, and, in the deferred treatment group, it was 6.5 years, corresponding to a mortality HR of 1.25 (95% CI, 1.05–1.48), which failed to meet the criteria for noninferiority.

Continuous versus intermittent hormonal therapy
When used as the primary therapy for patients with stage III or stage IV prostate cancer, androgen suppression with hormonal therapy is usually given continuously until there is disease progression. Some investigators have proposed intermittent androgen suppression as a strategy to attain maximal tumor cytoreduction followed by a period without therapy to allow tumor repopulation by hormone-sensitive cells. Theoretically, this strategy might provide tumor hormone responsiveness for a longer period. An animal model suggested that intermittent androgen deprivation (IAD) could prolong the duration of androgen dependence of hormone-sensitive tumors.

Evidence (continuous vs. intermittent hormonal therapy):
1. A systematic review of 15 randomized trials that compared continuous versus IAD therapy for patients with advanced or recurrent prostate cancer found no significant difference in OS, which was reported in eight of the trials (HR, 1.02; 95% CI, 0.93–1.11); prostate cancer-specific survival, reported in five of the trials (HR,1.02; 95% CI, 0.87–1.19); or progression-free survival, reported in four of the trials (HR, 0.94; 95% CI, 0.84–1.05). The meta-analysis fulfilled prespecified criteria for noninferiority of OS (upper bound of 1.15 for the HRdeath, 1.15).[Level of evidence: 1iiA] However, of the 15 trials, all but one had an unclear or high risk of bias according to prespecified criteria.
      • There was minimal difference in patient-reported QOL, but most trials found better physical and sexual functioning in patients in the IAD arms.

 



Radical prostatectomy with or without EBRT
Radical prostatectomy may be used with or without EBRT (in highly selected patients). Because about 40% to 50% of men with clinically organ-confined disease are found to have pathologic extension beyond the prostate capsule or surgical margins, the role of postprostatectomy adjuvant radiation therapy has been studied.

Evidence (radical prostatectomy with or without EBRT):
1. In a randomized trial of 425 men with pathologic T3, N0, M0 disease, postsurgical EBRT (60–64 Gy to the prostatic fossa over 30–32 fractions) was compared with observation.
      • After a median follow-up of about 12.5 years, OS was better in the radiation therapy arm; HRdeath, 0.72 (95% CI, 0.55–0.96; P = .023). The 10-year estimated survival rates were 74% in the radiation therapy arm and 66% in the control arm.
      • The 10-year, estimated, metastasis-free survivals were 73% and 65% (P = .016).[Level of evidence: 1iiA]
      • Short-term complication rates were substantially higher in the radiation therapy group: overall complications were 23.8% versus 11.9%, rectal complications were 3.3% versus 0%, and urethral stricture was 17.8% versus 9.5%.
      • The role of preoperative (neoadjuvant) hormonal therapy is not established. Also, the morphologic changes induced by neoadjuvant androgen ablation may even complicate assessment of surgical margins and capsular involvement.

Watchful waiting or active surveillance/active monitoring
Careful observation without further immediate treatment may be used in the treatment of stage III prostate cancer.

Asymptomatic patients of advanced age or with concomitant illness may warrant consideration of careful observation without immediate active treatment. 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.

Treatment of Symptoms
Since many stage III patients have urinary symptoms, control of symptoms is an important consideration in treatment. The following modalities may be used to improve local control of disease and subsequent symptoms:
• Radiation therapy.
• Hormonal manipulation.
• Palliative surgery (transurethral resection of the prostate [TURP]).
• Interstitial implantation combined with EBRT.
• Alternative forms of radiation therapy (under clinical evaluation).
• Ultrasound-guided percutaneous cryosurgery (under clinical evaluation).

1. Radiation therapy. EBRT designed to decrease exposure of normal tissues using methods such as CT-based 3D-CRT treatment planning is under clinical evaluation.
2. Hormonal manipulations effectively used as initial therapy for prostate cancer include the following:
      • Orchiectomy.
      • Leuprolide or other LH-RH agonists (e.g., goserelin) in daily or depot preparations. These agents may be associated with tumor flare.
      • Estrogens (diethylstilbestrol [DES] is no longer available in the United States).
      • Nonsteroidal antiandrogens (e.g., flutamide, nilutamide, and bicalutamide) or steroidal antiandrogen (e.g., cyproterone acetate).

A meta-analysis of randomized trials comparing various hormonal monotherapies in men with stage III or stage IV prostate cancer (predominantly stage IV) came to the following conclusions:[Level of evidence: 1iiA]
      • OS at 2 years using any of the LH-RH agonists is similar to treatment with orchiectomy or 3 mg qd of DES (HR, 1.26; 95% CI, 0.92–1.39).
      • Survival rates at 2 years are similar or worse with nonsteroidal antiandrogens compared with orchiectomy (HR, 1.22; 95% CI, 0.99–1.50).
      • Treatment withdrawals, used as a surrogate for adverse effects, occurred less with LH-RH agonists (0%–4%) than with nonsteroidal antiandrogens (4%–10%).
3. Palliative surgery (TURP).
4. Interstitial implantation combined with EBRT is being used in selected T3 patients, but little information is available.
5. Alternative forms of radiation therapy are being employed in clinical trials. A randomized trial from the RTOG reported improved local control and survival with mixed-beam (neutron/photon) radiation therapy compared with standard photon radiation therapy. A subsequent randomized study from the same group compared fast-neutron radiation therapy with standard photon radiation therapy. Local-regional control was improved with neutron treatment, but no difference in OS was seen, although follow-up was shorter in this trial. Fewer complications were seen with the use of a multileaf collimator.[55] Proton-beam radiation therapy is also under investigation.
6. Ultrasound-guided percutaneous cryosurgery is under clinical evaluation. Cryosurgery is a surgical technique under development 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: 3iiiDiv] Cryosurgery is less well established than standard prostatectomy, and long-term outcomes are not as well established as with prostatectomy or radiation therapy. Serious toxic effects include bladder outlet injury, urinary incontinence, sexual impotence, and rectal injury. The technique of cryosurgery is under development. Impotence is common. 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.

 

 

Stage IV Prostate Cancer Treatment

Overview
Stage IV prostate cancer is defined by the American Joint Committee on Cancer's TNM classification system:
• T4, N0, M0, any prostate-specific antigen (PSA), any Gleason.
• Any T, N1, M0, any PSA, any Gleason.
• Any T, any N, M1, any PSA, any Gleason.
Extraprostatic extension with microscopic bladder neck invasion (T4) is included with T3a.

Treatment selection depends on the following factors:
• Age.
• Coexisting medical illnesses.
• Symptoms.
• The presence of distant metastases (most often bone) or regional lymph node involvement only.

The most common symptoms originate from the urinary tract or from bone metastases. Palliation of symptoms from the urinary tract with transurethral resection of the prostate (TURP) or radiation therapy and palliation of symptoms from bone metastases with radiation therapy or hormonal therapy are an important part of the management of these patients. Bisphosphonates may also be used for the management of bone metastases.

Standard Treatment Options for Stage IV Prostate Cancer
1. Hormonal manipulations.
2. Hormonal manipulations with chemotherapy.
3. Bisphosphonates.
4. External-beam radiation therapy (EBRT) with or without hormonal therapy.
5. Palliative radiation therapy.
6. Palliative surgery with TURP.
7. Watchful waiting or active surveillance/active monitoring.


Hormonal manipulations
Hormonal treatment is the mainstay of therapy for metastatic (Jewett stage D2) prostate cancer. Cure is rarely, if ever, possible, but striking subjective or objective responses to treatment occur in most patients. The most effective hormonal approach employs a combination of androgen deprivation therapy plus abiraterone acetate, an inhibitor of cytochrome P450c17, a critical enzyme in androgen biosynthesis.

1. In the randomized, double-blind LATITUDE (NCT01715285) trial, 1,199 men with high-risk metastatic castration-sensitive prostate cancer were given ADT plus either abiraterone acetate (1,000 mg PO qd) and prednisone (5 mg PO qd) or ADT plus abiraterone/prednisone placebos. High-risk disease was defined as having at least two of the following three factors: Gleason score of 8 or higher, three or more bone lesions, or measurable visceral metastases.
      • After a median follow-up of 30.4 months, the trial was stopped because of a clear overall survival (OS) benefit in the abiraterone study arm: median survival not reached versus 34.7 months OS (HR, 0.62; 95% CI, 0.51–0.76; P <.001).[Level of evidence: 1iA]
      • Abiraterone therapy was well tolerated, but there was an increase in the mineralocorticoid effects of grade 3 or 4 hypertension and hypokalemia compared with the placebo study arm.

2. In the randomized, open-label STAMPEDE trial, 1,917 men (about 95% newly diagnosed; about 50% had metastatic disease and about 50% had locally advanced or node-positive disease) were treated with ADT alone or ADT plus abiraterone acetate (1,000 mg PO qd) and prednisolone (5 mg PO qd). Local radiation therapy was mandated after 6 to 9 months for men with node-negative nonmetastatic disease and optional for those with node-positive nonmetastatic disease. Hormone therapy was curtailed at 2 years or until progression. Radiation therapy was planned in about 40% of study participants.
      • With a median follow-up of 40 months, the 3-year OS was 83% in the abiraterone study group compared with 76% in the ADT-only study group (HRdeath, 0.63; 95% CI, 0.52–0.76; P< .001).[Level of evidence: 1iA] Although there was no clear evidence of heterogeneity in relative treatment differences in metastatic disease versus nonmetastatic disease, absolute differences were much smaller in men with nonmetastatic disease and not statistically significant, perhaps because of the short follow-up (HRdeath, 0.75; 95% CI, 0.49–1.18).
      • The main additional differences in toxicity associated with abiraterone compared with ADT alone were hypertension (5% vs. 1%), mild increase in blood aminotransferase levels (6% vs. < 1%), and respiratory disorders (5% vs. 2%).

The addition of chemotherapy has been shown in randomized trials to improve OS compared with ADT alone, with efficacy that appears to be comparable with hormonal therapy that includes ADT plus abiraterone acetate. However, the two approaches have not been directly compared in a randomized study.

In the CHAARTED trial (NCT00309985), 790 patients with metastatic, hormone-sensitive disease were randomly assigned to receive androgen deprivation therapy (ADT) with or without docetaxel (75 mg/m2 IV every 3 weeks for six cycles). Previous adjuvant ADT was permissible if it lasted 12 months or less and progression had occurred within 12 months of completion. At a median follow-up of 28.9 months, median OS in the ADT plus docetaxel arm was 57.6 months and in the ADT-alone arm, it was 44.0 months (hazard ratio [HR]death, 0.61; 95% CI, 0.47–0.80; P < .001).[Level of evidence: 1iiA]

Hormonal manipulations effectively used as initial therapy for prostate cancer include the following:
      • Orchiectomy alone or with an androgen blocker as seen in the Southwest Oncology Group (SWOG-8894) trial.
      • Luteinizing hormone-releasing hormone (LH-RH) agonists, such as leuprolide in daily or depot preparations. These agents may be associated with tumor flare when used alone; therefore, the initial concomitant use of antiandrogens should be considered in the presence of liver pain, ureteral obstruction, or impending spinal cord compression.[Level of evidence: 1iiA]
      • Leuprolide plus flutamide; however, the addition of an antiandrogen to leuprolide has not been clearly shown in a meta-analysis to improve survival.
      • Estrogens (diethylstilboestrol [DES], chlorotrianisene, ethinyl estradiol, conjugated estrogens-USP and DES-diphosphate). DES is no longer commercially available in the United States.

In some series, pretreatment levels of PSA are inversely correlated with progression-free duration in patients with metastatic prostate cancer who receive hormonal therapy. After hormonal therapy is initiated, a PSA reduction to beneath a detectable level provides information regarding the duration of progression-free status; however, decreases in PSA of less than 80% may not be very predictive.

Orchiectomy and estrogens yield similar results, and selection of one or the other depends on patient preference and the morbidity of expected side effects. Estrogens are associated with the development or exacerbation of cardiovascular disease, especially in high doses. DES at a dose of 1 mg qd is not associated with cardiovascular complications as frequent as those found at higher doses; however, the use of DES has decreased because of cardiovascular toxic effects. DES is no longer commercially available in the United States.

The psychological implications of orchiectomy are objectionable to many patients, and many will choose an alternative therapy if effective. Combined orchiectomy and estrogens are not indicated to be superior to either treatment administered alone.

A large proportion of men experience hot flushes after bilateral orchiectomy or treatment with LH-RH agonists. These hot flashes can persist for years. Varying levels of success in the management of these symptoms have been reported with DES, clonidine, cyproterone acetate, or medroxyprogesterone acetate.

After tumor progression on one form of hormonal manipulation, an objective tumor response to any other form is uncommon. Some studies, however, suggest that withdrawal of flutamide (with or without aminoglutethimide administration) is associated with a decline in PSA and that one may need to monitor for this response before initiating new therapy. Low-dose prednisone may palliate symptoms in about 33% of cases. Newer hormonal approaches, such as inhibition of androgen receptors, have been shown to improve OS and quality of life (QOL) after tumor progression despite ADT.

Immediate versus deferred hormonal therapy
Some patients may be asymptomatic and careful observation without further immediate therapy may be appropriate.

Evidence (immediate vs. deferred hormonal therapy):
1. A meta-analysis of seven randomized controlled trials comparing early (adjuvant or neoadjuvant) with deferred hormonal treatment (LH-RH agonists and/or antiandrogens) in patients with locally advanced prostate cancer, whether treated with prostatectomy, radiation therapy, or watchful waiting or active surveillance/active monitoring, showed improved overall mortality with early treatment (relative risk, 0.86; 95% confidence interval (CI), 0.82–0.91).[Level of evidence: 1iiA]

2. In a small, randomized trial of 98 men who underwent radical prostatectomy plus pelvic lymphadenectomy and were found to have nodal metastases (stage T1–2, N1, M0), immediate continuous hormonal therapy with the LH-RH agonist goserelin or with orchiectomy was compared with deferred therapy until documentation of disease progression.[Level of evidence: 1iA];
      • After a median follow-up of 11.9 years, OS (P = .04) and prostate cancer-specific survival (P = .004) were superior in the immediate adjuvant therapy arm.
      • At 10 years, the survival rate in the immediate therapy arm was about 80% versus about 60% in the deferred therapy arm.

3. Another trial (RTOG-8531) with twice as many randomly assigned patients showed no difference in OS with early versus late hormonal manipulation.

4. Immediate hormonal therapy with goserelin or orchiectomy has also been compared with deferred hormonal therapy for clinical disease progression in a randomized trial (EORTC-30846) of men with regional lymph node involvement but no clinical evidence of metastases (any T, N+, M0). None of the 234 men had a prostatectomy or prostatic radiation therapy.[Level of evidence; 1iiA]
      • After a median follow-up of 8.7 years, the HR for OS in the deferred versus immediate hormonal therapy arms was 1.23 (95% CI, 0.88–1.71).
      • No statistically significant difference in OS between deferred and immediate hormonal therapy was found, but the trial was underpowered to detect small or modest differences.

5. Immediate hormonal treatment (e.g., orchiectomy or LH-RH agonist) versus deferred treatment (e.g., watchful waiting with hormonal therapy at progression) was examined in a randomized study in men with locally advanced or asymptomatic metastatic prostate cancer.[Level of evidence: 1iiA]
      • The initial results showed better OS and prostate cancer-specific survival with immediate treatment.
      • The incidence of pathologic fractures, spinal cord compression, and ureteric obstruction were also lower in the immediate treatment arm.

6. In another trial, 197 men with stage III or stage IV prostate cancer were randomly assigned to have a bilateral orchiectomy at diagnosis or at the time of symptomatic progression (or at the time of new metastases that were deemed likely to cause symptoms).[Level of evidence: 1iiA]
      • Over a 12-year period of follow-up, no statistically significant difference was observed in OS.

Luteinizing hormone-releasing hormone (LH-RH) agonists or antiandrogens
Approaches using LH-RH agonists or antiandrogens in patients with stage IV prostate cancer have produced response rates similar to other hormonal treatments.

Evidence (LH-RH agonists or antiandrogens):
1. In a randomized trial, the LH-RH agonist leuprolide (1 mg subcutaneously (SQ) qd) was found to be as effective as DES (3 mg PO qd) in any T, any N, M1 patients, but caused less gynecomastia, nausea and vomiting, and thromboembolisms.
2. In other randomized studies, the depot LH-RH agonist goserelin was found to be as effective as orchiectomy or DES at a dose of 3 mg qd. A depot preparation of leuprolide, which is therapeutically equivalent to daily leuprolide, is available as a monthly or 3-monthly depot.
3. 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. Use of nonsteroidal antiandrogens as monotherapy decreased OS and increased the rate of clinical progression and treatment failure.[Level of evidence: 1iiA]
4. A small randomized study comparing 1 mg DES PO tid with 250 mg of flutamide tid in patients with metastatic prostate cancer showed similar response rates with both regimens but superior survival with DES. More cardiovascular and/or thromboembolic toxic effects of borderline statistical significance were associated with DES treatment.[Level of evidence: 1iA] A variety of combinations of hormonal therapy have been tested.

Maximal androgen blockade (MAB)
On the basis that the adrenal glands continue to produce androgens after surgical or medical castration, case series studies were performed in which antiandrogen therapy was added to castration. Promising results from the case series led to widespread use of the strategy, known as MAB or total androgen blockade. Subsequent randomized controlled trials, however, cast doubt on the efficacy of adding an antiandrogen to castration.

Evidence (MAB):
1. In a large, randomized, controlled trial comparing treatment with bilateral orchiectomy plus either the antiandrogen flutamide or placebo, no difference in OS was reported.[Level of evidence: 1iA]
      • Although it has been suggested that MAB may improve the more subjective endpoint of response rate, prospectively assessed QOL was worse in the flutamide arm than in the placebo arm primarily because of more diarrhea and worse emotional function in the flutamide-treated group.[Level of evidence: 1iC]

2. A meta-analysis of 27 randomized trials of 8,275 patients comparing conventional surgical or medical castration with MAB—castration plus prolonged use of an antiandrogen such as flutamide, cyproterone acetate, or nilutamide—did not show a statistically significant improvement in survival associated with MAB.[Level of evidence: 1iA]
When trials of androgen suppression versus androgen suppression plus either nilutamide or flutamide were examined in a subset analysis, the absolute survival rate at 5 years was better for the combined-therapy group (2.9% better, 95% CI, 0.3–5.5); however, when trials of androgen suppression versus androgen suppression plus cyproterone acetate were examined, the absolute survival trend at 5 years was worse for the combined-therapy group (2.8% worse, 95% CI, -7.6 to +2.0).

3. The Agency for Health Care Policy and Research (AHCPR) (now AHRQ) has performed a systematic review of the available randomized, clinical trial evidence of single hormonal therapies and total androgen blockade performed by its Technology Evaluation Center, an evidence-based Practice Center of the Blue Cross and Blue Shield Association. A meta-analysis of randomized trials comparing various hormonal monotherapies in men with stage III or stage IV prostate cancer (predominantly stage IV) came to the following conclusions:[Level of evidence: 1iiA]
      • OS at 2 years using any of the LH-RH agonists is similar to treatment with orchiectomy or 3 mg every day of DES (HR, 1.26; 95% CI, 0.92–1.39).
      • Survival rates at 2 years are similar or worse with nonsteroidal antiandrogens compared with orchiectomy (HR, 1.22; 95% CI, 0.99–1.50).
      • Treatment withdrawals, used as a surrogate for adverse effects, occurred less with LH-RH agonists (0%–4%) than with nonsteroidal antiandrogens (4%–10%).

Total androgen blockade was of no greater benefit than single hormonal therapy and with less patient tolerance. Also, the evidence was judged insufficient to determine whether men newly diagnosed with asymptomatic metastatic disease should have immediate androgen suppression therapy or should have therapy deferred until they have clinical signs or symptoms of progression.

Continuous versus intermittent hormonal therapy
When used as the primary therapy for patients with stage III or stage IV prostate cancer, androgen suppression with hormonal therapy is often given continuously until there is disease progression. Another option is intermittent androgen suppression as a strategy to attain maximal tumor cytoreduction followed by a period without therapy to allow treatment-free periods. Theoretically, this strategy might provide tumor hormone responsiveness for a longer period. An animal model suggested that intermittent androgen deprivation (IAD) could prolong the duration of androgen dependence of hormone-sensitive tumors.

Evidence (continuous vs. intermittent hormonal therapy):
1. A systematic review of 15 randomized trials that compared continuous versus intermittent ADT for patients with advanced or recurrent prostate cancer found no significant difference in OS, which was reported in eight of the trials (HR, 1.02; 95% CI, 0.93–1.11); prostate cancer-specific survival, reported in five of the trials (HR,1.02; 95% CI, 0.87–1.19); or progression-free survival (PFS), reported in four of the trials (HR, 0.94; 95% CI, 0.84–1.05). The meta-analysis fulfilled prespecified criteria for noninferiority of OS (upper bound of 1.15 for the HRdeath, 1.15).[Level of evidence: 1iiA] However, of the 15 trials, all but one had an unclear or high risk of bias according to prespecified criteria.
      • There was minimal difference in patient-reported QOL, but most trials found better physical and sexual functioning in patients in the IAD arms.

Hormonal manipulations with chemotherapy
The addition of docetaxel has been tested in combination with long-term hormone therapy in the first-line management of metastatic prostate cancer and has been shown to improve results more than hormone therapy alone. A systematic evidence review and meta-analysis of randomized trials in hormone-sensitive metastatic prostate cancer summarizes these data.

Evidence (hormonal manipulations with chemotherapy):
1. In the analysis of three randomized trials (3,206 men), the HRdeath associated with the addition of docetaxel to standard of care was 0.77 (95% CI, 0.68–0.87; P < .0001), representing an absolute improvement of 9% in 4-year survival (95% CI, 5–14).[Level of evidence: 1iiA]

Bisphosphonates
In addition to hormonal therapy, adjuvant treatment with bisphosphonates has been tested.

Evidence (bisphosphonates):
1. In MRC-PR05, 311 men with bone metastases who were starting or responding to standard hormonal therapy were randomly assigned to oral sodium clodronate (2,080 mg qd) or a matching placebo for up to 3 years.[Level of evidence: 1iA]
      • At a median follow-up of 11.5 years, OS was better in the clodronate arm: HRdeath, 0.77 (95% CI, 0.60–0.98; P = .032).
      • Five- and 10-year survival rates were 30% and 17% in the clodronate arm versus 21% and 9% in the placebo arm.

2. A parallel study (MRC-PR04) in men with locally advanced but nonmetastatic disease showed no benefit associated with clodronate.

3. CALGB-90202 [NCT00079001] was a randomized controlled trial that compared zoledronic acid (4 mg IV every 4 weeks) with placebo in 645 men with androgen deprivation-sensitive prostate cancer that was metastatic to bone. Patients who progressed on hormone-therapy resistance received open-label, zoledronic acid.[Level of evidence: 1iDiii]
      • There was no difference between the two study arms in risk of the primary endpoint of time to skeletal-related events (defined as the need for palliative bone radiation, clinical fracture, spinal cord compression, bone surgery, or death from prostate cancer) after up to 7 years of follow-up.
      • There were also no differences in PFS or OS.

4. In another negative randomized trial, NCT00268476, 1,245 men with locally advanced (M0) or metastatic (M1) prostate cancer, who were initiating long-term hormonal therapy, were randomly assigned to one of three arms (ratio of 2:1:1): standard of care, celecoxib (400 mg bid for 1 year), and celecoxib plus zoledronic acid (4 mg IV for six 3-week cycles, then 4-week cycles for 2 years).
      • After a median follow-up of 69 months, there was no detectable improvement in survival associated with either celecoxib or celecoxib plus zoledronic acid.
      • Although survival was better in patients with M disease who received celecoxib plus zoledronic acid than in patients with M1 disease who received the standard of care (HRdeath, 0.78; 95% CI, 0.62–0.98), a formal test for interaction with metastasis status was not statistically significant; therefore, the unexpected finding can only be considered hypothesis-generating.
Bisphosphonates and decreasing risk of bone metastases
Patients with locally advanced nonmetastatic disease (T2–T4, N0–N1, and M0) are at risk for developing bone metastases, and bisphosphonates are being studied as a strategy to decrease this risk. However, a placebo-controlled randomized trial (MRC-PR04) of a 5-year regimen of the first-generation bisphosphonate clodronate in high oral doses (2,080 mg qd) had no favorable impact on either time to symptomatic bone metastasis or survival.[Level of evidence: 1iA]

External-beam radiation therapy (EBRT) with or without hormonal therapy
EBRT may be used for attempted cure in highly selected stage M0 patients. Definitive radiation therapy should be delayed 4 to 6 weeks after TURP to reduce incidence of stricture.

Hormonal therapy should be considered in addition to EBRT.

Evidence (radiation therapy with or without hormonal therapy):
1. The Blue Cross and Blue Shield Association Technology Evaluation Center, an evidence-based practice center of the Agency for Healthcare Research and Quality (AHRQ), performed a systematic review of the available randomized clinical trial evidence comparing radiation therapy with radiation therapy and prolonged androgen suppression.[Level of evidence: 1iiA] Some patients with bulky T2b tumors were included in the studied groups.
      • The meta-analysis found a difference in 5-year OS in favor of radiation therapy plus continued androgen suppression using an LH-RH agonist or orchiectomy compared with radiation therapy alone (HR, 0.63; 95% CI, 0.48–0.83).
      • This reduction in overall mortality indicates that adjuvant androgen suppression should be initiated at the time of radiation therapy and continued for several years.
      • The optimal duration of therapy and the issue of utility of neoadjuvant hormonal therapy have not been determined.

2. The duration of neoadjuvant hormonal therapy has been tested in a randomized trial (TROG 96.01 [ACTRN12607000237482]) of 818 men with locally advanced (T2b, T2c, T3, and T4), nonmetastatic cancer treated with radiation therapy (i.e., 66 Gy in 2 Gy daily fractions to the prostate and seminal vesicles but not including regional nodes). In an open-label design, patients were randomly assigned to radiation therapy alone, 3 months of neoadjuvant androgen deprivation therapy (NADT) (goserelin 3.6 mg SQ each month plus flutamide 250 mg PO tid) for 2 months before and during radiation, or 6 months of NADT for 5 months before and during radiation.[Level of evidence: 1iiA]
      • After a median follow-up of 10.6 years, there were no statistically significant differences between the radiation alone group and the radiation plus 3 months of NADT group.
      • However, the 6-month NADT arm showed better prostate cancer-specific mortality and overall mortality than radiation alone; 10-year all-cause mortality 29.2% versus 42.5%% (HR, 0.63; 95% CI, 0.48–0.83, P = .0008).

3. The duration of neoadjuvant hormonal therapy was tested in another trial (RTOG 9910 [NCT00005044]) of 1,489 eligible men with intermediate-risk prostate cancer (T1b–4, Gleason score 2–6, and PSA >10 but ≤100 ng/mL; T1b–4, Gleason score 7, and PSA <20; or T1b–1c, Gleason score 8–10, and PSA <20) and no evidence of metastases. The men were randomly assigned to receive short-course neoadjuvant–androgen suppression (an LHRH agonist plus bicalutamide or flutamide for 8 weeks before and 8 weeks during radiation therapy) or long-course neoadjuvant-androgen suppression (28 weeks before and 8 weeks during radiation therapy). Both groups received 70.2 Gy radiation in 39 daily fractions to the prostate and 46.8 Gy to the iliac lymph nodes.[Levels of evidence: 1iiA and 1iiB]
      • After a median of 9.4 years, 10-year prostate specific mortality, the primary endpoint, was low in both study arms: 5% versus 4% (HR, 0.81; 95% CI, 0.48–1.39).[Level of evidence: 1iiB]
      • No statistically significant differences in overall mortality or in locoregional disease progression were found.[Level of evidence: 1iiA]
      • There was also no apparent differential effect of androgen suppression duration among any of the risk-group subsets.

Palliative radiation therapy
A single fraction of 8 Gy has been shown to have similar benefits on bone pain relief and QOL as multiple fractions (3 Gy × 10) as was evidenced in the RTOG-9714 (NCT00003162) trial. [Level of evidence: 1iiC]

Palliative surgery with transurethral resection of the prostate (TURP)
Transurethral resection of the prostate may be useful in relieving urinary obstruction as part of palliative care in advanced prostate cancer.

Watchful waiting or active surveillance/active monitoring
Careful observation without further immediate treatment (in selected asymptomatic patients).

Treatment Options Under Clinical Evaluation for Stage IV Prostate Cancer
1. Radical prostatectomy with immediate orchiectomy.
      • An uncontrolled, retrospective review of a large series of patients with any T, N1–3, M0 disease treated at the Mayo Clinic with concurrent radical prostatectomy and orchiectomy was associated with intervals to local and distant progression; however, increase in OS has not been demonstrated.[54] Patient selection factors make such study designs difficult to interpret.

 

 

Recurrent Prostate Cancer Treatment

Overview
In recurrent prostate cancer, the selection of further treatment depends on many factors, including:
• Previous treatment.
• Site of recurrence.
• Coexistent illnesses.
• Individual patient considerations.


Local Recurrence
Definitive radiation therapy can be given to patients with disease that fails only locally after prostatectomy.
A randomized trial (RTOG 9601 [NCT00002874]) has shown improved overall survival (OS) and prostate cancer-specific survival with the addition of high-dose bicalutamide to radiation therapy compared with radiation therapy alone in men with locally recurrent prostate cancer after radical prostatectomy.

• In the trial, 760 men who were initially treated with radical prostatectomy for tumor stage T2 or T3, and who had a detectable PSA level of 0.2 to 4.0 ng/mL, but no evidence of metastases, were randomly assigned to receive radiation (64.8 Gy over 36 fractions) and either bicalutamide (150 mg PO qd) or placebo for 24 months. The median interval from surgery to PSA detectability was 1.4 years and from surgery to randomization was 2.1 years. Median follow-up was 13 years.
• Actuarial OS at 12 years was 76.3% in the bicalutamide group versus 71.3% in the placebo group (P = .04; hazard ratio [HR], 0.77; 95% confidence interval [CI], 0.59–0.99).[Level of evidence: 1iA]
• Prostate cancer-specific mortality at 12 years was 5.8% (bicalutamide) versus 13.4% (placebo), (HR, 0.49; 95% CI, 0.32–0.74; P < .001).[Level of evidence: 1iB]
• Most treatment-related toxicities were similar between the two groups, with the exception of gynecomastia, which occurred in 69.7% of the men on bicalutamide versus 10.9% of those on placebo. This side effect may be mitigated by prophylactic breast irradiation, which was not used in this study because of the double-blinded design.

Some patients with a local recurrence after definitive radiation therapy can be salvaged with prostatectomy; however, only about 10% of patients treated initially with radiation therapy will have local relapse only. In these patients, prolonged disease control is often possible with hormonal therapy, with median cancer-specific survival of 6 years after local failure.

Cryosurgical ablation of recurrence after radiation therapy is associated frequently with a high complication rate. This technique is still undergoing clinical evaluation.


Systemic Treatment Options for Recurrent Prostate Cancer
Hormone therapy.
Chemotherapy for hormone-resistant prostate cancer.
Immunotherapy.


Hormone therapy
Hormonal therapy is used to manage most relapsing patients with disseminated disease who initially received locoregional therapy with surgery or radiation therapy.

Immediate Versus Deferred Hormonal Therapy
Refer to the Treatment Option Overview for Prostate Cancer section for information on the use of immediate hormonal therapy (bicalutamide or LH-RH agonists) plus radiation in the setting of locally recurrent prostate cancer after radical prostatectomy.

Prostate-specific antigen (PSA) is often used to monitor patients after initial therapy with curative intent, and elevated or rising PSA is a common trigger for additional therapy even in asymptomatic men. Despite how common the situation is, it is not clear whether additional treatments given on the basis of rising PSA in asymptomatic men with prostate cancer increase OS. The quality of evidence is limited.

1. After radical prostatectomy, detectable PSA levels identify patients at elevated risk of local treatment failure or metastatic disease; however, a substantial proportion of patients with elevated or rising PSA levels after initial therapy with curative intent may remain clinically free of symptoms for extended periods. In a retrospective analysis of nearly 2,000 men who had undergone radical prostatectomy with curative intent and who were followed for a mean of 5.3 years, 315 men (15%) demonstrated an abnormal PSA of 0.2 ng/mLor higher, which is evidence of biochemical recurrence.
      • Of these 315 men, 103 men (34%) developed clinical evidence of recurrence.
      • The median time to development of clinical metastasis after biochemical recurrence was 8 years.
      • After the men developed metastatic disease, the median time to death was an additional 5 years.

2. After radiation therapy with curative intent, persistently elevated or rising PSA may be a prognostic factor for clinical disease recurrence. However, reported case series have used a variety of definitions of PSA failure. Criteria have been developed by the American Society for Therapeutic Radiology and Oncology Consensus Panel. The implication of the various definitions of PSA failure for OS is not known, and as in the surgical series, many biochemical relapses (rising PSA alone) may not be clinically manifested in patients treated with radiation therapy.

3. A randomized trial (PMCC-VCOG-PR-0103 [NCT00110162]) of androgen deprivation therapy (ADT) in men who received curative therapy but have a rising PSA, provides some evidence of improved OS associated with immediate versus delayed therapy. The study had important shortcomings.
      a. Two groups of men were randomly assigned to open-label, immediate-versus-delayed (at least 2-year delay) ADT:
            • Group 1 included men who had a PSA relapse after curative therapy (89% of the study population).
            • Group 2 included asymptomatic men who were considered unsuitable for curative treatment because of age, comorbidity, or locally advanced disease (11% of the study population).
Planned accrual was 750 patients, but because of slow accrual, the trial closed at 293 patients.
      b. In groups 1 and 2 combined, with a median follow-up of 5 years, the 5-year OS rate was 86.4% in the delayed ADT study arm versus 91.2% in the immediate ADT study arm (log rank, P = .047).[Level of evidence: 1iiA] After full adjustment for baseline characteristics, the HR for OS was 0.54 (95% CI, 0.27–1.06; P = .074).
      c. For group 1 only (those with PSA relapse after curative therapy, N = 261), the estimated 5-year survival rate was 78.2% versus 84.3% with delayed-versus-immediate ADT (log rank, P = .10; fully adjusted HR, = 0.59; 95% CI, 0.26–1.30, P = .19).       d. Toxicity was greater in the immediate ADT study arm compared with delayed therapy. Serious (grade 4) adverse events were reported in 42% of patients in the immediate ADT study arm versus 31% of patients in the delayed therapy arm. Quality of life (QOL) fell by 6.1% (considered a small but clinically important drop) with immediate ADT versus 3% with delayed ADT (considered a trivial drop); but this was not a statistically significant difference (P = .14). Sexual activity was lower and hormone-related symptoms (hot flashes and sore or enlarged nipples) were clinically and statistically significantly worse in the immediate ADT arm compared with the delayed therapy arm.

Hormonal Therapy for Recurring Disease
Nonsteroidal antiandrogen monotherapy versus surgical or medical castration
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. Use of nonsteroidal antiandrogens as monotherapy decreased OS and increased the rate of clinical progression and treatment failure.[Level of evidence: 1iiA]

Continuous versus intermittent hormonal therapy
The majority of men who are treated for recurrence after initial local therapy are asymptomatic, and the recurrence is detected by a rising PSA. It is possible that intermittent androgen deprivation (IAD) therapy can be used as an alternative to continuous androgen deprivation (CAD) therapy (ADT) in an attempt to improve QOL and decrease the amount of time during which the patient experiences the side effects of hormonal therapy, without decreasing the survival rate.
1. This important clinical question was addressed in a noninferiority-designed, randomized, controlled trial with 1,386 men who had rising PSA levels (>3 ng/mL, with serum testosterone >5 nmol/L) more than 1 year after primary or salvage radiation therapy for localized prostate cancer.[Levels of evidence: 1iiA, 1iiB, 1iiC]
      • The ADT arm consisted of 8-month treatment cycles with a luteinizing hormone-releasing hormone (LH-RH) agonist (combined with a nonsteroidal antiandrogen for at least the first 4 weeks) that was reinstituted if the PSA level exceeded 10 ng/mL. The study was powered to detect (with 95% confidence) an 8% lower OS rate in the IAD group compared with the CAD group at 7 years.
      • After a median follow-up of 6.9 years (maximum follow-up 11.2 years), OS in the two groups was nearly identical, and the study was stopped (median survival, 8.8 vs. 9.1 years; HRdeath, 1.02; 95% CI, 0.86–1.21). This fulfilled the prospective criterion of noninferiority.
      • In a retrospective analysis, prostate cancer-specific mortality was also similar in the two arms (HR, 1.18; 95% CI, 0.90–1.55; P = 0.24). In addition, IAD was statistically significantly better than CAD in several QOL domains, such as hot flashes, desire for sexual activity, and urinary symptoms. Patients on the IAD study arm received a median of 15.4 months of treatment versus 43.9 months on the CAD arm.
      • The study does not address the unanswered question about whether the initiation of any ADT for an elevated PSA after initial local therapy extends survival compared with delay until clinically symptomatic progression. Of note, 59% of all deaths were unrelated to prostate cancer, and only 14% of all patients died of prostate cancer.

2. A systematic review of 15 randomized trials that compared continuous versus IAD therapy for patients with advanced or recurrent prostate cancer found no significant difference in OS, which was reported in eight of the trials (HR, 1.02; 95% CI, 0.93–1.11); prostate cancer-specific survival, reported in five of the trials (HR, 1.02; 95% CI, 0.87–1.19); or progression-free survival (PFS), reported in four of the trials (HR, 0.94; 95% CI, 0.84–1.05). The meta-analysis fulfilled prespecified criteria for noninferiority of OS (upper bound of 1.15 for the HR of 1.15).[Level of evidence: 1iiA] However, of the 15 trials, all but one had an unclear or high risk of bias according to prespecified criteria.
      • There was minimal difference in patient-reported QOL, but most trials found better physical and sexual functioning in patients in the IAD arms.

 



Hormonal approaches
As noted above, studies have shown that chemotherapy with docetaxel or cabazitaxel and immunotherapy with sipuleucel-T can prolong OS in patients with hormone-resistant metastatic prostate cancer. Nevertheless, hormonal therapy has also been shown to improve survival even in men who have progressed after other forms of hormonal therapy as well as chemotherapy. Some forms of hormonal therapy are effective in the management of metastatic hormone–refractory prostate cancer.

Evidence (hormonal approaches):
1. Abiraterone acetate is an inhibitor of androgen biosynthesis that works by blocking cytochrome P450c17 (CYP17). Abiraterone has mineralocorticoid effects, producing an increased incidence of fluid retention and edema, hypokalemia, hypertension, and cardiac dysfunction. In addition, abiraterone is associated with hepatotoxicity. However, compared with other therapies, abiraterone toxicities are mild. In a double-blinded placebo-controlled trial, 1,088 men with progressing hormone refractory disease (serum testosterone <50 ng per deciliter on previous antiandrogen therapy), no previous chemotherapy, and Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 to 1 were given prednisone (5 mg PO bid) plus either abiraterone acetate (1,000 mg PO qd) or placebo.[Level of evidence: 1iA] The coprimary endpoints were radiologic PFS and OS. Four sequential analyses were planned.
      • At the second interim analysis, after a median follow-up of 22.2 months, the study was stopped and unblinded on the basis of aggregate efficacy and safety as assessed by the data monitoring committee. At that point, the radiologic PFS had reached the prespecified stopping boundary in favor of abiraterone (median PFS, 16.5 months vs. 8.3 months [HR, 0.53; 95% CI, 0.45–0.62; P < .001]).
      • At the fourth (and final) analysis with a median follow-up of 49.2 months (maximum 60 months), 65% had died in the abiraterone acetate study arm and 71% had died in the placebo study arm (HR, 0.81; 95% CI, 0.70–0.93: P = .033). Median OS was 34.7 versus 30.3 months.[Level of evidence: 1iA]
      •Median time to health-related QOL deterioration was long in the abiraterone study arm, as assessed by the Functional Assessment of Cancer Therapy-Prostate Version 4 (FACT-P) total score (12.7 months vs. 8.3 monhs; HR, 0.78; 95% CI, 0.66-0.92; P = .003) and by the prostate–cancer-specific subscale (11.1 months vs. 5.8 months; HR, 0.70; 95% CI, 0.60–0.83; P < .0001).[Level of evidence: 1iC]
      • In addition, patients in the abiraterone study group had statistically significant longer median times to opiate use for pain, initiation of cytotoxic chemotherapy, decline in PS, and PSA progression.[Levels of evidence: 1iC and 1iDiii]

2. Men with metastatic prostate cancer who had biochemical or clinical progression after treatment with docetaxel (N = 1,195) were randomly assigned in a 2:1 ratio to receive either abiraterone acetate (1,000 mg) (n = 797) or placebo (n = 398) PO qd (COU-AA-301 [NCT00638690]). Both groups received prednisone (5 mg PO bid).[Level of evidence; 1iA]
      • After a median follow-up of 12.8 months, the trial was stopped when an interim analysis showed an OS advantage in the abiraterone group. The final report of the trial was published after a median follow-up of 20.2 months.
      • Median OS was 15.8 months in the abiraterone group versus 11.2 months in the placebo group (HRdeath, 0.74; 95% CI, 0.64–0.86; P < .0001).
      • Compared with placebo, abiraterone was also associated with delay in median time to deterioration in the FACT-P QOL score (59.9 weeks vs. 36.1 weeks, P < .0001) and clinically important improvement in QOL in men with functional status impairment at baseline (48% vs. 32%, P < .0001).[Level of evidence: 1iC]

3. Enzalutamide, an androgen-receptor signaling inhibitor, has been shown to increase OS and QOL in men with metastatic prostate cancer that has progressed despite ADT. In the PREVAIL study, 1,717 asymptomatic or mildly symptomatic men with recurrent metastatic prostate cancer despite ADT were randomly assigned to receive enzalutamide (160 mg PO qd) versus placebo.[Levels of evidence: 1iA, 1iC]
      • After a median follow-up of 22 months, the study was stopped because of an OS benefit in the enzalutamide study arm (HR, 0.72; 95% CI, 0.6–0.84; P < .001). The proportion of men who had died was 28% versus 35%, and the median OS was 32.4 versus 30.2 months.
      • Median time until decline in global QOL, measured by the FACT-P score, was 11.3 months versus 5.6 months in the enzalutamide and placebo groups (P < .001), and delayed occurrence of first skeletal-related event requiring clinical intervention was also shown.[Levels of evidence: 1iC, 1iDi]
      • Grade 3 or worse adverse events were more common in the enzalutamide group (43% vs. 37%), primarily because of differences in hypertension, fatigue, and falls. Because patients receiving enzalutamide were on assigned therapy for an average of 1 year longer than those on placebo, the duration of response was longer in patients receiving enzalutamide, and this difference may have contributed to the increase in adverse events.

4.Enzalutamide has also been shown to increase survival in patients with progressive prostate cancer who previously received ADT as well as docetaxel. In a double-blind, placebo-controlled trial, 1,129 men were randomly assigned in a 2:1 ratio to receive enzalutamide (160 mg PO qd) versus placebo.[Levels of evidence: 1iA, 1iC]
      • After a median follow-up of 14.4 months, the study was stopped at the single-planned interim analysis because improved OS, the primary endpoint, was found in the enzalutamide study group (median OS, 18.4 months; 95% CI, 17.3 to not-yet-reached vs. 13.6 months; 95% CI, 11.3–15.8; HRdeath, 0.63; 95% CI, 0.53–0.75; P < .001). In addition, QOL, measured by the FACT-P questionnaire, was superior in the enzalutamide arm, as was time to first skeletal-related event.
      • A seizure was reported in five of the 800 men in the enzalutamide study group versus none in the placebo group; however, the relationship to enzalutamide is not clear. Of the reported seizures, two patients had brain metastases, one patient had just received intravenous lidocaine, and one seizure was not witnessed.

Because there are no head-to-head comparisons, there are no trials to help decide which of these agents should be used first or in what sequence.

Even among patients with metastatic hormone-refractory prostate cancer, some heterogeneity is found in prognosis and in retained hormone sensitivity. In such patients who have symptomatic bone disease, several factors are associated with worsened prognosis: poor performance status, elevated alkaline phosphatase, abnormal serum creatinine, and short (<1 year) previous response to hormonal therapy. The absolute level of PSA at the initiation of therapy in relapsed or hormone-refractory patients has not been shown to be of prognostic significance.

Some patients whose disease has progressed on combined androgen blockade can respond to a variety of second-line hormonal therapies. Aminoglutethimide, hydrocortisone, flutamide withdrawal, progesterone, ketoconazole, and combinations of these therapies have produced PSA responses in 14% to 60% of patients treated and have also produced clinical responses of 0% to 25% when assessed. The duration of these PSA responses has been in the range of 2 to 4 months. Survival rates are similar whether ketoconazole plus hydrocortisone is initiated at the same time as antiandrogen (e.g., flutamide, bicalutamide, or nilutamide) withdrawal or when PSA has risen after an initial trial of antiandrogen withdrawal as seen in the CLB-9583 trial, for example.[36][Level of evidence: 1iiA] Data on whether PSA changes while on chemotherapy are predictive of survival are conflicting.

Patients treated with either luteinizing-hormone agonists or estrogens as primary therapy are generally maintained with castrate levels of testosterone. One study from ECOG showed that a superior survival resulted when patients were maintained on primary androgen deprivation; however, another study from SWOG (formerly the Southwest Oncology Group) did not show an advantage to continued androgen blockade.

Prevention of bone metastases
Painful bone metastases can be a major problem for patients with prostate cancer. Many strategies have been studied for palliation, including:
• External-beam radiation therapy (EBRT).
• Bone-seeking radionuclides (strontium chloride Sr 89 [89Sr]).
• Denosumab (a monoclonal antibody that inhibits osteoclast function).
• Pain medication.
• Corticosteroids.
• Bisphosphonates.

Evidence (palliation for bone metastases using radiation therapy):
1. EBRT for palliation of bone pain can be very useful. A single fraction of 8 Gy has been shown to have similar benefits on bone pain relief and QOL as multiple fractions (3 Gy × 10) was seen in the RTOG-9714 trial, for example.[Level of evidence: 1iiC]

Evidence (palliation for bone metastases using strontium chloride):
The use of radioisotopes such as 89Sr has been shown to be effective as palliative treatment of some patients with osteoblastic metastases. As a single agent, 89Sr has been reported to decrease bone pain in 80% of patients treated.
1. A multicenter randomized trial of a single intravenous dose of 89Sr (150 MBq: 4 mCi) versus palliative EBRT was done in men with painful bone metastases from prostate cancer despite hormone treatment.[Level of evidence: 1iiA];
      • Similar subjective pain response rates were shown in both groups: 34.7% for 89Sr versus 33.3% for EBRT alone.
      • OS was better in the EBRT group than in the 89Sr group (P = .046; median survival, 11.0 months vs. 7.2 months).
      • No statistically significant differences in time to subjective progression or in PFS were seen.
      • When used as an adjunct to EBRT, 89Sr was shown to slow disease progression and to reduce analgesic requirements, compared with EBRT alone.

Evidence (palliation or prevention of bone metastases using denosumab):
1. A placebo-controlled randomized trial (NCT00321620) compared denosumab with zoledronic acid for the prevention of skeletal events (pathologic fractures, spinal cord compression, or the need for palliative bone radiation or surgery) in men with hormonal therapy-resistant prostate cancer with at least one bone metastasis.
      • The trial reported that denosumab was more effective than zoledronic acid; median time to first on-study skeletal event was 20.7 versus 17.1 months (HR, 0.82; 95% CI, 0.71–0.95).
      • Serious adverse events were reported in 63% of denosumab patients versus 60% in patients on zoledronic acid. The cumulative incidence of osteonecrosis of the jaw was low in both study arms (2% in the denosumab arm vs. 1% in the zoledronic acid arm). There was grade 3 to 4 toxicity. There was no difference in survival. The incidence of hypocalcemia was higher in the denosumab arm (13% vs. 6%).

2. A randomized placebo-controlled trial included 1,432 men with castration-resistant prostate cancer with no evidence of any metastases who were given denosumab (120 mg administered SQ every 4 weeks) to prevent the first evidence of bone metastasis (whether symptomatic or not).[Level of Evidence: 1iDiii]
      • After a median follow-up of 20 months, median bone metastasis-free survival was 29.5 versus 25.2 months in the denosumab versus placebo arms (HR, 0.85; 95% CI, 0.73–0.98; P = .028).
      • Symptomatic bone metastases were reported in 69 (10%) denosumab patients versus 96 (13%) placebo patients (HR, 0.67; 95% CI, 0.49–0.92; P = .01).
      • There were no differences in OS between the two groups.
      • Osteonecrosis occurred in 33 (5%) of men on the denosumab arm versus none on the placebo arm. Hypocalcemia occurred in 12 (2%) versus 2 (<1%) men, and urinary retention in 54 (8%) of men on denosumab versus 31 (4%) of men on placebo.

 



Chemotherapy for hormone-resistant prostate cancer
Evidence (chemotherapy for hormone-resistant prostate cancer):
1. A randomized trial showed improved pain control in patients with hormone-resistant prostate cancer treated with mitoxantrone plus prednisone compared with those treated with prednisone alone. Differences in OS or measured global QOL between the two treatments were not statistically significant.

2. Docetaxel has been shown to improve OS compared with mitoxantrone. In a randomized trial involving patients with hormone-refractory prostate cancer, docetaxel (75 mg/m2 every 3 weeks) and docetaxel (30 mg/m2 weekly for 5 out of every 6 weeks) were compared with mitoxantrone (12 mg/m2 every 3 weeks). All patients received oral prednisone (5 mg bid). Patients in the docetaxel arms also received high-dose dexamethasone pretreatment for each docetaxel administration (8 mg given at 12 hours, 3 hours, and 1 hour before the 3-week regimen; 8 mg given at 1 hour before the 5 out-of-every-6 weeks' regimen).
      • OS at 3 years was statistically significantly better in the 3-weekly docetaxel arm (18.6%) than in the mitoxantrone arm (13.5%, HRdeath, 0.79; 95% CI, 0.67–0.93).
      • However, the OS rate for the 5 out-of-every-6 weeks' docetaxel regimen was 16.8%, which was not statistically significantly better than mitoxantrone.
      • QOL was also superior in the docetaxel arms compared with mitoxantrone (P = .009).[Levels of evidence: 1iiA, 1iiC]

3. In another randomized trial involving patients with hormone-refractory prostate cancer, a 3-week regimen of estramustine (280 mg PO tid for days 1 to 5, plus daily warfarin and 325 mg aspirin to prevent vascular thrombosis), and docetaxel (60 mg/m2 intravenously [IV] on day 2, preceded by dexamethasone [20 mg × 3 starting the night before]) was compared with mitoxantrone (12 mg/m2 IV every 3 weeks) plus prednisone (5 mg qd).][Level of evidence: 1iiA]
      • After a median follow-up of 32 months, median OS was 17.5 months in the estramustine/docetaxel arm versus 15.6 months in the mitoxantrone arm (HRdeath, 0.80; 95% CI, 0.67–0.97; P = .02).
      • Global QOL and pain palliation measures were similar in the two treatment arms.[Level of evidence: 1iiC]

4. A 2-weekly regimen of docetaxel has been compared with a 3-weekly regimen. OS appeared to be better in the 2-week regimen, and hematologic toxicity was less.[Level of evidence: 1iiA]
      • In the trial, 361 men with metastatic hormone-resistant prostate cancer were randomly assigned to receive docetaxel either in a 2-weekly regimen (50 mg/m2 IV) or a 3-weekly regimen (75 mg/m2 IV) until progression. All patients were also to receive prednisolone (10 mg PO qd) and dexamethasone (7.5–8.0 mg qd), starting the day before and continuing for 1 to 2 days after each docetaxel dose. Fifteen randomly assigned patients (4.2%) were thought to be ineligible in retrospect or withdrew consent, and they were dropped from the analysis.
      • With a median follow-up of 18 months, there was a small difference in time to treatment failure, the primary endpoint of the study (5.6 months [95% CI, 5.0–6.2] vs. 4.9 months [95% CI, 4.5–5.4]; P = .014). However, there was a larger difference in median OS, a secondary endpoint, in favor of the 2-week regimen (19.5 months [95% CI, 15.9–23.1] vs. 17.0 months [95% CI, 15.0 –19.1]; P = .02).
      • There was a lower rate of grade 3 to 4 neutropenia with the 2-week regimen (36% vs. 53%; P < .0001) and a lower rate of febrile neutropenia (4% vs. 14%; P = .001).

5. In patients with metastatic hormone/castrate-refractory prostate cancer (mCRPC) and no prior chemotherapy, cabazitaxel and docetaxel appeared to provide similar results with respect to OS.
      • In the FIRSTANA trial (NCT01308567), 1,168 men with mCRPC were randomly assigned (1:1:1 ratio) to receive cabazitaxel 20 mg/m2, cabazitaxel 25 mg/m2, or docetaxel 75 mg/m2 IV every 3 weeks (plus prednisone 10 mg PO qd) until disease progression. Median OS was similar across all three study arms and not statistically significantly different (24.5 vs. 25.2 vs. 24.3 months, respectively), with virtually overlapping survival curves.[Level of evidence; 1iiA]
      • However, toxicities varied across the study arms, with adverse event rates of 41.2%, 60.1%, and 46.0%, respectively, which required urgent treatment.

6. In patients with mCRPC whose disease progressed during or after treatment with docetaxel, cabazitaxel was shown to improve survival compared with mitoxantrone in a randomized trial (NCT00417079). In this trial, 755 such men were treated with prednisone (10 mg PO qd) and randomly assigned to receive either cabazitaxel (25 mg/m2 IV) or mitoxantrone (12 mg/m2 IV) every 3 weeks.[Level of evidence; 1iiA]
      • Median OS was 15.1 months in the cabazitaxel arm and 12.7 months in the mitoxantrone study arm (HRdeath, 0.70; 95% CI, 0.59–0.83; P < .0001).

7. In a noninferiority-design randomized trial comparing cabazitaxel (20 mg/m2 IV every 3 weeks) with cabazitaxel (25 mg/m2 IV every 3 weeks) in a similar population of 1,200 men with mCRPC who had received prior docetaxel, the lower dose of cabazitaxel fulfilled noninferiority criteria with respect to OS (HRdeath, 1.024; CI, upper bound at 1.184), but with less toxicity.[Level of evidence; 1iiA]

Other chemotherapy regimens reported to produce subjective improvement in symptoms and reduction in PSA level include the following:[Level of evidence: 3iiiDiii];

      • Paclitaxel.
      • Estramustine/etoposide.
      • Estramustine/vinblastine.
      • Estramustine/paclitaxel.

A study suggests that patients whose tumors exhibit neuroendocrine differentiation are more responsive to chemotherapy.

Immunotherapy
Sipuleucel-T, an active cellular immunotherapy, has been shown to increase OS in patients with hormone-refractory metastatic prostate cancer. Sipuleucel-T consists of autologous peripheral blood mononuclear cells that have been exposed ex vivo to a recombinant fusion protein (PA2024) composed of prostatic acid phosphatase fused to granulocyte-macrophage colony-stimulating factor.

Side effects are generally consistent with cytokine release and include chills, fever, headache, myalgia, sweating, and influenza-like symptoms, usually within the first 24 hours of infusion. No increase in autoimmune disorders or secondary malignancies has been noted.

Evidence (immunotherapy):
1. In the largest trial (Immunotherapy for Prostate Adenocarcinoma Treatment: IMPACT trial [NCT00065442]), 512 patients with hormone-refractory metastatic disease were randomly assigned in a 2:1 ratio to receive sipuleucel-T (n = 341) versus placebo (n = 171) by IV in a 60-minute infusion every 2 weeks for a total of 3 doses. Patients with visceral metastases, pathologic bone fractures, or Eastern Cooperative Oncology Group (ECOG) performance status worse than 0–1 were excluded from the study. At documented disease progression, patients in the placebo group could receive, at the physician’s discretion, infusions manufactured with the same specifications as sipuleucel-T but using cells that had been cryopreserved at the time that the placebo was prepared (63.7% of the placebo patients received these transfusions). Time to disease progression and time to development of disease-related pain were the initial primary endpoints, but the primary endpoint was changed before unblinding based upon survival differences in two previous trials of similar design (described below).[Level of evidence: 1iA]
      • After a median follow-up of 34.1 months, the overall mortality was 61.6% in the sipuleucel-T group versus 70.8% in the placebo group (HRdeath, 0.78; 95% CI, 0.61–0.98; P = .03). However, the improved survival was not accompanied by measurable antitumor effects.
      • There was no difference between the study groups in rate of disease progression. In 2011, the estimated price of sipuleucel-T was $93,000 for a 1-month course of therapy. This translates into an estimated cost of about $276,000 per year-of-life saved.

2. The same investigators previously performed two smaller trials (NCT00005947) of nearly identical design to the IMPACT trial.
      • The combined results of the two smaller trials, involving a total of 225 patients randomly assigned in a 2:1 ratio of sipuleucel-T to placebo were similar to those in the IMPACT trial. The HRdeath was 0.67 (95% CI, 0.49–0.91), but the time to progression rates were not statistically significantly different.

Low-dose prednisone may palliate symptoms in some patients.

Evidence (low-dose prednisone for palliation):
1. A randomized comparison of prednisone (5 mg qid) with flutamide (250 mg tid) was conducted in patients with disease progression after androgen ablative therapy (castration or LH-RH agonist).
      • Prednisone and flutamide produced similar OS, symptomatic response, PSA response, and time to progression; however, there were statistically significant differences in pain, nausea and vomiting, and diarrhea in patients who received prednisone.

Ongoing clinical trials continue to explore the value of chemotherapy for these patients.

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 by IV and selectively taken up by newly formed bone stroma. The high-energy alpha particles have a short range of <100 mcM. 223Ra improved OS in patients with prostate cancer metastatic to the bone.

Evidence (alpha emitter radiation):
1. In a placebo-controlled trial, 921 men with symptomatic castration-resistant prostate cancer, two or more bone metastases, and no known visceral metastases, were randomly assigned in a 2:1 ratio to receive 223Ra at a dose of 50kBq per kg body weight every 4 weeks for six injections versus placebo. All study participants had already received docetaxel, were not healthy enough to receive it, or declined it.
      • Median OS was 14.9 months in the 223Ra study group versus 11.3 months in the placebo groups (HRmortality, 0.70; 95% CI, 0.58–0.83; P < .001).[Level of evidence: 1iA]
      • The rates of symptomatic skeletal events (33% vs. 38%) and spinal cord compression (4% vs. 7%) were also statistically significantly improved.
      • Prospectively measured, QOL was also better in the 223Ra study group (25% vs. 16% had a ≥10 point improvement on a scale of 0 to 156; P = .02).[Level of evidence: 1iC]
      • With administration of 223Ra at a dose of 50kBq per kg of body weight every 4 weeks for six injections, the side effects were similar to those of a placebo.

 

 

 

Hormone Therapy and Systemic treatments

Androgen deprivation therapy (ADT)

Because prostate cancer growth is driven by male sex hormones called androgens, lowering levels of these hormones can help slow the growth of the cancer. The most common androgen is testosterone. Testosterone levels in the body can be lowered either by surgically removing the testicles, known as surgical castration, or by taking drugs that turn off the function of the testicles, called medical castration. Which ADT method is used is less important than the main goal: that testosterone levels are lowered.

ADT is used to treat prostate cancer in different situations, including locally advanced, recurrent prostate cancer, and metastatic prostate cancer. Metastatic prostate cancer is cancer that has spread to another part of the body. Some of the situations in which ADT may be used include:
• Men with NCCN-based intermediate-risk and high-risk prostate cancer who are having definitive therapy with radiation therapy are candidates for ADT. Definitive therapy is a treatment given with the intent to cure the cancer. Men with intermediate-risk prostate cancer should receive ADT for at least 6 months. Those with high-risk prostate cancer should receive ADT for 24 to 36 months.
• ADT may also be given to men who have had surgery and microscopic cancer cells were found in the removed lymph nodes. ADT is done to eliminate any remaining cancer cells and reduce the chance the cancer will return. This is known as adjuvant therapy. Although the use of adjuvant ADT is controversial, some specific patients appear to benefit from this approach.
• ADT should also be considered as adjuvant therapy if prostate cancer has been found in the lymph nodes after a radical prostatectomy.

Specific types of ADT
• Bilateral orchiectomy. Bilateral orchiectomy is the surgical removal of both testicles and was the first treatment used for metastatic prostate cancer more than 70 years ago. Even though this is an operation, it is considered an ADT because it removes the main source of testosterone production, the testicles. The effects of this surgery are permanent and cannot be reversed.

• LHRH agonists. LHRH stands for luteinizing hormone-releasing hormone. Medications known as LHRH agonists prevent the testicles from receiving messages sent by the body to make testosterone. By blocking these signals, LHRH agonists reduce a man’s testosterone level just as well as removing his testicles. Unlike surgical castration, the effects of LHRH agonists are often reversible, so testosterone production usually begins again once a patient stops treatment. However, testosterone recovery can take any time from 6 months to 24 months, and for a small proportion of patients testosterone recovery does not happen.
LHRH agonists are injected or placed as small implants under the skin. Depending on the drug used, they may be given once a month or once a year. When LHRH agonists are first given, testosterone levels briefly increase before falling to very low levels. This effect is known as a “flare.” Flares occur because the testicles temporarily release more testosterone in response to the way LHRH agonists work in the body. This flare may increase the activity of prostate cancer cells and cause symptoms and side effects, such as bone pain in men with cancer that has spread to the bone.

• LHRH antagonist. This class of drugs, also called a gonadotropin-releasing hormone (GnRH) antagonist, stops the testicles from producing testosterone like LHRH agonists, but they reduce testosterone levels more quickly and do not cause a flare. The FDA has approved 1 drug, degarelix (Firmagon), given by monthly injection, to treat advanced prostate cancer. One side effect of this drug is that it may cause a severe allergic reaction.

• Anti-androgens. While LHRH agonists and antagonists lower testosterone levels in the blood, anti-androgens block testosterone from binding to so-called “androgen receptors,” which are chemical structures in cancer cells that allow testosterone and other male hormones to enter the cells. These drugs include bicalutamide (Casodex), flutamide (Eulexin), and nilutamide (Nilandron) and are taken as pills. Anti-androgens are usually given to men who have “hormone-sensitive” prostate cancer, which means that the prostate cancer still responds to testosterone suppression therapy. Anti-androgens are not usually used by themselves in prostate cancer treatment.

• Combined androgen blockade. Sometimes anti-androgens are combined with bilateral orchiectomy or LHRH agonist treatment to maximize the blockade of male hormones. This is because even after the testicles are no longer producing hormones, the adrenal glands still make small amounts of androgens. Many doctors also feel that this combined approach is the safest way to start ADT, as it prevents the possible flare that sometimes happens in response to LHRH agonist treatment. Some, but not all, research has shown that combined androgen blockade can help patients live longer than treatment with just ADT, surgery, or LHRD agonists or antagonists. Therefore, some doctors prefer to give combined drug treatment, while others may only give the combination early in the treatment to prevent the flare.

Side effects of ADT
Traditionally, ADT was given for the patient’s lifetime or until it stopped controlling the cancer. Then the cancer was called castration-resistant, meaning that ADT has stopped working, and other treatment options were considered. During the past 2 decades, researchers have studied the use of intermittent ADT, which is ADT that is given for specific times and then stopped temporarily according to a schedule. Using ADT in this way may lower the side effects and improve a patient’s quality of life. Only patients without evidence of metastases are candidates for this approach. Intermittent ADT has not been shown to be equivalent or superior to lifelong ADT in men with metastatic disease.

ADT will cause side effects that will generally go away after treatment has finished, except in men who have had an orchiectomy. General side effects of ADT include:
• Erectile dysfunction
• Loss of sexual desire
• Hot flashes with sweating
• Gynecomastia, which is growth of breast tissue that sometimes can lead to discomfort
• Depression
• Cognitive dysfunction and memory loss
• Weight gain
• Loss of muscle mass
• Osteopenia or osteoporosis, which is thinning of bones


Although testosterone levels may recover after stopping ADT, some men who have had medical castration with LHRH agonists for many years may continue to have hormonal effects, even if they are no longer taking these drugs.

Another serious side effect of ADT is the risk of developing metabolic syndrome. Metabolic syndrome is a set of conditions, such as obesity, high levels of blood cholesterol, and high blood pressure that increases a person’s risk of heart disease, stroke, and diabetes. Currently, it is not certain how often this happens or exactly why it happens, but it is quite clear that patients who receive a surgical or medical castration with ADT have an increased risk of developing metabolic syndrome. The risk is increased even if the medical castration is temporary. Find out more about the symptoms of hormone deprivation and how to manage them.

The risks and benefits of castration should be carefully discussed with your doctor. For men with metastatic prostate cancer, especially if it is advanced and causing symptoms, most doctors believe that the benefits of castration far outweigh the risks of side effects. Aggressive management of side effects is very important for patients receiving ADT. These include getting regular exercise, quitting smoking, following a healthy diet, supplementing vitamin D and calcium intake, and receiving aggressive, preventive cardiovascular follow-up care.



Androgen deprivation therapy (ADT)

■ Bilateral orchiectomy ± Artificial testicles

■ LHRH agonists
Leuprolide (Lupron, Eligard), Goserelin (Zoladex), Triptorelin (Trelstar), Histrelin (Vantas)

Leuprolide (Lupron, Eligard)
Lupron 22.5 mg intramuscularly every 3 months, 30 mg intramuscularly every 4 months, or 45 mg intramuscularly every 6 month
Eligard: 7.5 mg subcutaneous (depot injection) once monthly, 22.5 mg subcutaneous (depot injection) every 3 months, 30 mg subcutaneous (depot injection) every 4 months, or 45 mg subcutaneous (depot injection) every 6 months.

Injectable Administration
Leuprolide is administered subcutaneously or intramuscularly depending upon the formulation.
Injection sites should be rotated periodically.
SUPPLIED
Eligard Subcutaneous Inj Susp: 7.5mg, 22.5mg, 30mg, 45mg
Leuprolide Acetate/Lupron Subcutaneous Inj Sol: 0.2mL, 1mg
Lupron Depot/Lupron Depot-Ped Intramuscular Inj Pwd F/Susp: 3.75mg, 7.5mg, 11.25mg, 15mg, 22.5mg, 30mg, 45mg

Hepatic or Renal Impairment
Specific guidelines for dosage adjustments are not available; it appears that no dosage adjustments are needed.

WARNCNGS
Initially, Leuprolide acetate, like other LH-RH agonists, causes increases in serum levels of testosterone. Transient worsening of symptoms, or the occurrence of additional signs and symptoms of prostate cancer, may occasionally develop during the first few weeks of Leuprolide acetate treatment.
A small number of patients may experience a temporary increase in bone pain, which can be managed symptomatically.
As with other LH-RH agonists, isolated cases of ureteral obstruction and spinal cord compression have been observed, which may contribute to paralysis with or without fatal complications.
Hyperglycemia and an increased risk of developing diabetes have been reported in men receiving GnRH agonists. Hyperglycemia may represent development of diabetes mellitus or worsening of glycemic control in patients with diabetes. Monitor blood glucose and/or glycosylated hemoglobin (HbA1c) periodically in patients receiving a GnRH agonist and manage with current practice for treatment of hyperglycemia or diabetes.
Effect on QT/QTc Interval
Androgen deprivation therapy may prolong the QT/QTc interval. Providers should consider whether the benefits of androgen deprivation therapy outweigh the potential risks in patients with congenital long QT syndrome, congestive heart failure, frequent electrolyte abnormalities, and in patients taking drugs known to prolong the QT interval. Electrolyte abnormalities should be corrected. Consider periodic monitoring of electrocardiograms and electrolytes.
CONTRAINDICATIONS / PRECAUTIONS
Renal impairment, spinal cord compression, urinary tract obstruction
Leuprolide may cause a sudden onset or worsening of prostate cancer or breast cancer symptoms (flare) due to transient increases in testosterone or estrogen levels, respectively, such as bone pain, neuropathy, hematuria, or urethral or bladder outlet obstruction. Patients with urinary tract obstruction or metastatic vertebral lesions should be monitored carefully for signs of renal impairment or spinal cord compression, respectively, during initial leuprolide treatment.
Pituitary insufficiency
Since leuprolide suppresses the pituitary-gonadal axis, diagnostic tests for pituitary insufficiency or other pituitary-gonadal function conducted during treatment and after cessation of therapy may be misleading.

■ LHRH antagonist
Degarelix (Firmagon) is an LHRH antagonist. It works like the LHRH agonists, but it lowers testosterone levels more quickly and doesn’t cause tumor flare like the LHRH agonists do. Treatment with this drug can also be considered a form of medical castration.
This drug is used to treat advanced prostate cancer. It is given as a monthly injection under the skin. The most common side effects are problems at the injection site (pain, redness, and swelling) and increased levels of liver enzymes on lab tests. Other side effects are discussed elsewhere.

■ Anti-androgens
Androgens have to bind to a protein in the prostate cell called an androgen receptor to work. Anti-androgens are drugs that bind to these receptors so the androgens can’t.
Anti-androgens are not often used by themselves in the United States. An anti-androgen may be added to treatment if orchiectomy or an LHRH agonist or antagonist is no longer working by itself. An anti-androgen is also sometimes given for a few weeks when an LHRH agonist is first started to prevent a tumor flare.
An anti-androgen can also be combined with orchiectomy or an LHRH agonist as first-line hormone therapy. This is called combined androgen blockade (CAB). There is still some debate as to whether CAB is more effective in this setting than using orchiectomy or an LHRH agonist alone. If there is a benefit, it appears to be small.
In some men, if an anti-androgen is no longer working, simply stopping the anti-androgen can cause the cancer to stop growing for a short time. Doctors call this the anti-androgen withdrawal effect, although they are not sure why it happens.

Anti-androgens. While LHRH agonists and antagonists lower testosterone levels in the blood, anti-androgens block testosterone from binding to so-called “androgen receptors,” which are chemical structures in cancer cells that allow testosterone and other male hormones to enter the cells. These drugs include bicalutamide (Casodex), flutamide (Eulexin), and nilutamide (Nilandron) and are taken as pills. Anti-androgens are usually given to men who have “hormone-sensitive” prostate cancer, which means that the prostate cancer still responds to testosterone suppression therapy. Anti-androgens are not usually used by themselves in prostate cancer treatment.

Drugs of this type include: Flutamide (Eulexin) Bicalutamide (Casodex) Nilutamide (Nilandron)
They are taken daily as pills.

Casodex (bicalutamide)
50mg po daily
Oral nonsteroidal antiandrogen structurally related to flutamide; used in the treatment of metastatic prostatic carcinoma; unlike flutamide, bicalutamide can be dosed once-daily; also, bicalutamide is more selective for the peripheral androgen receptor and has less activity at the central (HPA) androgen receptor.
SUPPLIED: Bicalutamide/Casodex Oral Tab: 50mg

• Combined androgen blockade. Sometimes anti-androgens are combined with bilateral orchiectomy or LHRH agonist treatment to maximize the blockade of male hormones. This is because even after the testicles are no longer producing hormones, the adrenal glands still make small amounts of androgens. Many doctors also feel that this combined approach is the safest way to start ADT, as it prevents the possible flare that sometimes happens in response to LHRH agonist treatment. Some, but not all, research has shown that combined androgen blockade can help patients live longer than treatment with just ADT, surgery, or LHRD agonists or antagonists. Therefore, some doctors prefer to give combined drug treatment, while others may only give the combination early in the treatment to prevent the flare.


Castrate-resistant prostate cancer,

■ CYP17 inhibitor
LHRH agonists and antagonists can stop the testicles from making androgens, but other cells in the body, including prostate cancer cells themselves, can still make small amounts, which can fuel cancer growth.
Abiraterone (Zytiga) blocks an enzyme called CYP17, which helps stop these cells from making androgens.
Abiraterone can be used in men with advanced prostate cancer that is either:
High risk (cancer with a high Gleason score, spread to several spots in the bones, or spread to other organs)
Castrate-resistant (cancer that is still growing despite low testosterone levels from an LHRH agonist, LHRH antagonist, or orchiectomy)

This drug is taken as pills every day. It doesn’t stop the testicles from making testosterone, so men who haven’t had an orchiectomy need to continue treatment with an LHRH agonist or antagonist. Because abiraterone also lowers the level of some other hormones in the body, prednisone (a corticosteroid drug) needs to be taken during treatment as well to avoid certain side effects.

Abiraterone acetate is an inhibitor of androgen biosynthesis that works by blocking cytochrome P450c17 (CYP17). Abiraterone has mineralocorticoid effects, producing an increased incidence of fluid retention and edema, hypokalemia, hypertension, and cardiac dysfunction. In addition, abiraterone is associated with hepatotoxicity. However, compared with other therapies, abiraterone toxicities are mild.

Abiraterone (Zytiga)
SUPPLIED Oral Tab: 125mg, 250mg, 500mg
• For the treatment of metastatic castration-resistant prostate cancer, in combination with prednisone.
1,000 mg PO once daily in combination with prednisone 5 mg PO twice daily and androgen deprivation therapy (ADT) (e.g., concurrent gonadotropin-releasing hormone (GnRH) analog or bilateral orchiectomy), until disease progression or unacceptable toxicity. Do not substitute Yonsa for or with Zytiga.
• For the treatment of metastatic high risk hormone-sensitive prostate cancer, in combination with prednisone and androgen-deprivation therapy.
1,000 mg PO once daily in combination with prednisone 5 mg PO once daily and androgen deprivation therapy (ADT) (e.g., concurrent gonadotropin-releasing hormone (GnRH) analog or bilateral orchiectomy), until disease progression or unacceptable toxicity. Do not substitute Yonsa for or with Zytiga.

■ Newer types of anti-androgens
Enzalutamide (Xtandi) and apalutamide (Erleada) are newer types of anti-androgens. Normally when androgens bind to their receptor, the receptor sends a signal to the cell’s control center, telling it to grow and divide. These drugs block this signal. They are taken as pills each day.
These drugs can often be helpful in men whose cancer is no longer responding to other forms of hormone therapy (known as castrate-resistant prostate cancer). Enzalutamide is typically used for metastatic cancer (cancer that has spread to other parts of the body), while apalutamide is typically used for non-metastatic cancer.

enzalutamide (Xtandi)
Androgen receptor inhibitor. Used for the treatment of castration-resistant prostate cancer
Seizures have been reported
SUPPLIED XTANDI Oral Cap: 40mg
160 mg PO once daily. Patients should concurrently receive treatment with a gonadotropin-releasing hormone (GnRH) analog or have had a bilateral orchiectomy.

apalutamide (ERLEADA)
Androgen receptor inhibitor. Used for nonmetastatic castration-resistant prostate cancer
Evaluate for fall and fracture risk; treat with bone-targeted agents if appropriate
SUPPLIED, ERLEADA Oral Tab: 60mg
240 mg by mouth once daily until disease progression or unacceptable toxicity. Patients should concurrently receive treatment with a gonadotropin-releasing hormone (GnRH) analog or have had a bilateral orchiectomy.

■ Prevention of bone metastases
A randomized placebo-controlled trial included 1,432 men with castration-resistant prostate cancer with no evidence of any metastases who were given denosumab (120 mg administered SQ every 4 weeks) to prevent the first evidence of bone metastasis (whether symptomatic or not).[Level of Evidence: 1iDiii]

Hormone Therapy for Prostate Cancer

Hormone therapy is also called androgen deprivation therapy (ADT) or androgen suppression therapy. The goal is to reduce levels of male hormones, called androgens, in the body, or to stop them from affecting prostate cancer cells.
Androgens stimulate prostate cancer cells to grow. The main androgens in the body are testosterone and dihydrotestosterone (DHT). Most of the androgens are made by the testicles, but the adrenal glands (glands that sit above your kidneys) also make a small amount. Lowering androgen levels or stopping them from getting into prostate cancer cells often makes prostate cancers shrink or grow more slowly for a time. But hormone therapy alone does not cure prostate cancer.

When is hormone therapy used?
Hormone therapy may be used:
If the cancer has spread too far to be cured by surgery or radiation, or if you can’t have these treatments for some other reason
If the cancer remains or comes back after treatment with surgery or radiation therapy
Along with radiation therapy as initial treatment if you are at higher risk of the cancer coming back after treatment (based on a high Gleason score, high PSA level, and/or growth of the cancer outside the prostate)
Before radiation to try to shrink the cancer to make treatment more effective

Types of hormone therapy
Several types of hormone therapy can be used to treat prostate cancer.

(1) Treatments to lower androgen levels
Orchiectomy (surgical castration)
Even though this is a type of surgery, its main effect is as a form of hormone therapy. In this operation, the surgeon removes the testicles, where most of the androgens (testosterone and DHT) are made. This causes most prostate cancers to stop growing or shrink for a time.
This is done as an outpatient procedure. It is probably the least expensive and simplest form of hormone therapy. But unlike some of the other treatments, it is permanent, and many men have trouble accepting the removal of their testicles.
Some men having this surgery are concerned about how it will look afterward. If wanted, artificial testicles that look much like normal ones can be inserted into the scrotum.

LHRH agonists
Luteinizing hormone-releasing hormone (LHRH) agonists (also called LHRH analogs or GnRH agonists) are drugs that lower the amount of testosterone made by the testicles. Treatment with these drugs is sometimes called chemical castration or medical castration because they lower androgen levels just as well as orchiectomy.
Even though LHRH agonists cost more than orchiectomy and require more frequent doctor visits, most men choose this method. With these drugs, the testicles remain in place, but they will shrink over time, and they may even become too small to feel.

LHRH agonists are injected or placed as small implants under the skin. Depending on the drug used, they are given anywhere from once a month up to once a year. The LHRH agonists available in the United States include:

Leuprolide (Lupron, Eligard)
Goserelin (Zoladex)
Triptorelin (Trelstar)
Histrelin (Vantas)

When LHRH agonists are first given, testosterone levels go up briefly before falling to very low levels. This effect is called flare and results from the complex way in which these drugs work. Men whose cancer has spread to the bones may have bone pain. If the cancer has spread to the spine, even a short-term increase in tumor growth as a result of the flare could press on the spinal cord and cause pain or paralysis. Flare can be avoided by giving drugs called anti-androgens (discussed below) for a few weeks when starting treatment with LHRH agonists.

LHRH antagonist
Degarelix (Firmagon) is an LHRH antagonist. It works like the LHRH agonists, but it lowers testosterone levels more quickly and doesn’t cause tumor flare like the LHRH agonists do. Treatment with this drug can also be considered a form of medical castration.
This drug is used to treat advanced prostate cancer. It is given as a monthly injection under the skin. The most common side effects are problems at the injection site (pain, redness, and swelling) and increased levels of liver enzymes on lab tests. Other side effects are discussed in detail below.

CYP17 inhibitor
LHRH agonists and antagonists can stop the testicles from making androgens, but other cells in the body, including prostate cancer cells themselves, can still make small amounts, which can fuel cancer growth.
Abiraterone (Zytiga) blocks an enzyme called CYP17, which helps stop these cells from making androgens.
Abiraterone can be used in men with advanced prostate cancer that is either:
High risk (cancer with a high Gleason score, spread to several spots in the bones, or spread to other organs)
Castrate-resistant (cancer that is still growing despite low testosterone levels from an LHRH agonist, LHRH antagonist, or orchiectomy)

This drug is taken as pills every day. It doesn’t stop the testicles from making testosterone, so men who haven’t had an orchiectomy need to continue treatment with an LHRH agonist or antagonist. Because abiraterone also lowers the level of some other hormones in the body, prednisone (a corticosteroid drug) needs to be taken during treatment as well to avoid certain side effects.

(2) Drugs that stop androgens from working
Anti-androgens
Androgens have to bind to a protein in the prostate cell called an androgen receptor to work. Anti-androgens are drugs that bind to these receptors so the androgens can’t.

Drugs of this type include:
Flutamide (Eulexin)
Bicalutamide (Casodex)
Nilutamide (Nilandron)

They are taken daily as pills.

Anti-androgens are not often used by themselves in the United States. An anti-androgen may be added to treatment if orchiectomy or an LHRH agonist or antagonist is no longer working by itself. An anti-androgen is also sometimes given for a few weeks when an LHRH agonist is first started to prevent a tumor flare.

An anti-androgen can also be combined with orchiectomy or an LHRH agonist as first-line hormone therapy. This is called combined androgen blockade (CAB). There is still some debate as to whether CAB is more effective in this setting than using orchiectomy or an LHRH agonist alone. If there is a benefit, it appears to be small.

In some men, if an anti-androgen is no longer working, simply stopping the anti-androgen can cause the cancer to stop growing for a short time. Doctors call this the anti-androgen withdrawal effect, although they are not sure why it happens.

Enzalutamide (Xtandi) and apalutamide (Erleada) are newer types of anti-androgens. Normally when androgens bind to their receptor, the receptor sends a signal to the cell’s control center, telling it to grow and divide. These drugs block this signal. They are taken as pills each day.

These drugs can often be helpful in men whose cancer is no longer responding to other forms of hormone therapy (known as castrate-resistant prostate cancer, described below). Enzalutamide is typically used for metastatic cancer (cancer that has spread to other parts of the body), while apalutamide is typically used for non-metastatic cancer.

(3) Other androgen-suppressing drugs
Estrogens (female hormones) were once the main alternative to orchiectomy for men with advanced prostate cancer. Because of their possible side effects (including blood clots and breast enlargement), estrogens have been replaced by other types of hormone therapy. Still, estrogens may be tried if other hormone treatments are no longer working.

Ketoconazole (Nizoral), first used for treating fungal infections, blocks production of certain hormones, including androgens, much like abiraterone. It's most often used to treat men just diagnosed with advanced prostate cancer who have a lot of cancer in the body, as it offers a quick way to lower testosterone levels. It can also be tried if other forms of hormone therapy are no longer working.

Ketoconazole also can block the production of cortisol, an important steroid hormone in the body, so men treated with this drug often need to take a corticosteroid (such as prednisone or hydrocortisone).

Possible side effects of hormone therapy

Orchiectomy and LHRH agonists and antagonists can all cause similar side effects from lower levels of hormones such as testosterone. These side effects can include:
Reduced or absent sexual desire
Erectile dysfunction (impotence)
Shrinkage of testicles and penis
Hot flashes, which may get better or go away with time
Breast tenderness and growth of breast tissue
Osteoporosis (bone thinning), which can lead to broken bones
Anemia (low red blood cell counts)
Decreased mental sharpness
Loss of muscle mass
Weight gain
Fatigue
Increased cholesterol levels
Depression

Some research has suggested that the risk of high blood pressure, diabetes, strokes, heart attacks, and even death from heart disease is higher in men treated with hormone therapy, although not all studies have found this.

Anti-androgens have similar side effects. The major difference from LHRH agonists and antagonists and orchiectomy is that anti-androgens may have fewer sexual side effects. When these drugs are used alone, sexual desire and erections can often be maintained. When these drugs are given to men already being treated with LHRH agonists, diarrhea is the major side effect. Nausea, liver problems, and tiredness can also occur.

Enzalutamide and apalutamide can cause diarrhea, fatigue, and worsening of hot flashes. These drugs can also cause some nervous system side effects, including dizziness and, rarely, seizures. Men taking one of these drugs are more likely to fall, which may lead to injuries.

Abiraterone can cause joint or muscle pain, high blood pressure, fluid buildup in the body, hot flashes, upset stomach, and diarrhea.

Many side effects of hormone therapy can be prevented or treated. For example:
Hot flashes can often be helped by treatment with certain antidepressants or other drugs.
Brief radiation treatment to the breasts can help prevent their enlargement, but this is not effective once breast enlargement has occurred.
Several drugs can help prevent and treat osteoporosis.
Depression can be treated with antidepressants and/or counseling.
Exercise can help reduce many side effects, including fatigue, weight gain, and the loss of bone and muscle mass.
There is growing concern that hormone therapy for prostate cancer may lead to problems thinking, concentrating, and/or with memory, but this has not been studied thoroughly. Still, hormone therapy does seem to lead to memory problems in some men. These problems are rarely severe, and most often affect only some types of memory. More studies are being done to look at this issue.

Current issues in hormone therapy

There are many issues around hormone therapy that not all doctors agree on, such as the best time to start and stop it and the best way to give it. Studies are now looking at these issues. A few of them are discussed here.

Treating early-stage cancer: Some doctors have used hormone therapy instead of watchful waiting or active surveillance in men with early stage prostate cancer who do not want surgery or radiation. Studies have not found that these men live any longer than those who don’t get any treatment until the cancer progresses or symptoms develop. Because of this, hormone treatment is not usually advised for early-stage prostate cancer.

Early versus delayed treatment: For men who need (or will eventually need) hormone therapy, such as men whose PSA levels are rising after surgery or radiation or men with advanced prostate cancer who don’t yet have symptoms, it’s not always clear when it is best to start hormone treatment. Some doctors think that hormone therapy works better if it’s started as soon as possible, even if a man feels well and is not having any symptoms. Some studies have shown that hormone treatment may slow the disease down and perhaps even help men live longer.

But not all doctors agree with this approach. Some are waiting for more evidence of benefit. They feel that because of the side effects of hormone therapy and the chance that the cancer could become resistant to therapy sooner, treatment shouldn’t be started until a man has symptoms from the cancer. This issue is being studied.

Intermittent versus continuous hormone therapy: Most prostate cancers treated with hormone therapy become resistant to this treatment over a period of months or years. Some doctors believe that constant androgen suppression might not be needed, so they advise intermittent (on-again, off-again) treatment. The hope is that giving men a break from androgen suppression will also give them a break from side effects like decreased energy, sexual problems, and hot flashes.

In one form of intermittent hormone therapy, treatment is stopped once the PSA drops to a very low level. If the PSA level begins to rise, the drugs are started again. Another form of intermittent therapy uses hormone therapy for fixed periods of time – for example, 6 months on followed by 6 months off.

At this time, it isn’t clear how this approach compares to continuous hormone therapy Some studies have found that continuous therapy might help men live longer, but other studies have not found such a difference.

Combined androgen blockade (CAB): Some doctors treat patients with both androgen deprivation (orchiectomy or an LHRH agonist or antagonist) plus an anti-androgen. Some studies have suggested this may be more helpful than androgen deprivation alone, but others have not. Most doctors are not convinced there’s enough evidence that this combined therapy is better than starting with one drug alone when treating prostate cancer that has spread to other parts of the body.

Triple androgen blockade (TAB): Some doctors have suggested taking combined therapy one step further, by adding a drug called a 5-alpha reductase inhibitor – either finasteride (Proscar) or dutasteride (Avodart) – to the combined androgen blockade. There is very little evidence to support the use of this triple androgen blockade at this time.

Castrate-resistant versus hormone-refractory prostate cancer: Both these terms are sometimes used to describe prostate cancers that are no longer responding to hormones, although there is a difference between the two.

• Castrate-resistant means the cancer is still growing even when the testosterone levels are as low as what would be expected if the testicles were removed (called castrate levels). Levels this low could be from an orchiectomy, an LHRH agonist, or an LHRH antagonist. Some men might be uncomfortable with this term, but it’s specifically meant to refer to these cancers, some of which might still be helped by other forms of hormone therapy, such as the drugs abiraterone, enzalutamide, and apalutamide. Cancers that still respond to some type of hormone therapy are not completely hormone-refractory.
• Hormone-refractory refers to prostate cancer that is no longer helped by any type of hormone therapy, including the newer medicines.

 



Chemotherapy

Systemic chemotherapy gets into the bloodstream to reach cancer cells throughout the body. Chemotherapy for prostate cancer is given through an intravenous (IV) tube placed into a vein using a needle. It may help patients with advanced or castration-resistant prostate cancer. A chemotherapy regimen usually consists of a specific number of cycles given over a set period of time.

There are several standard drugs used for prostate cancer. In general, standard chemotherapy begins with docetaxel (Taxotere) combined with a steroid called prednisone (multiple brand names). This chemotherapy has been shown to help men with metastatic castration-resistant prostate cancer live longer when compared with another chemotherapy drug, mitoxantrone (Novantrone). Mitoxantrone was one of the first chemotherapies approved for metastatic castration-resistant prostate cancer, but it is not commonly used. Mitoxantrone is most useful for controlling pain from the cancer and is sometimes considered in specific situations.

The FDA has also approved another drug, cabazitaxel (Jevtana), based on research that showed it improved survival when compared with mitoxantrone for patients whose disease progressed after having docetaxel. In clinical trials, cabazitaxel was compared with docetaxel in patients who had not received chemotherapy. In these patients, treatment with cabazitaxel was not better than treatment with standard docetaxel. Another study compared the standard dose with a lower dose of cabazitaxel in people whose tumors grew after treatment with docetaxel. This study did not find that the lower dose helped patients live longer; however, they did have fewer side effects.

Recent research shows that adding chemotherapy after the completion of 2 years of ADT for men with high-risk prostate cancer who are having definitive radiation therapy is an effective approach to reduce recurrence and improve survival. Although these results are interesting, longer follow-up is required to see if this treatment helps people with prostate cancer.

In general, the side effects of chemotherapy depend on the individual, the type of chemotherapy received, the dose used, and the length of treatment, but they can include fatigue, sores in the mouth and throat, diarrhea, nausea and vomiting, constipation, blood disorders, nervous system effects, changes in thinking and memory, sexual and reproductive issues, appetite loss, pain, and hair loss. The side effects of chemotherapy usually go away once treatment has finished. However, some side effects may continue, come back, or develop later.

Chemotherapy and ADT
New research shows a role for chemotherapy and ADT in the treatment of metastatic prostate cancer. For example, 2 recent clinical trials showed that men with metastatic, hormone-sensitive prostate cancer who received docetaxel with ADT survived longer than men who received only ADT. All patients should have a thorough discussion with their doctor about the potential benefits and risks of receiving chemotherapy.

Immunotherapy
Sipuleucel-T (Provenge) is an immunotherapy. Immunotherapy is designed to boost the body’s natural defenses to fight the cancer. It uses materials made either by the body or in a laboratory to improve, target, or restore immune system function.

Sipuleucel-T is adapted for each patient. Before treatment, blood is removed from the patient in a process called leukapheresis. Special immune cells are separated from the patient’s blood, modified in the laboratory, and then put back into the patient. At this point, the patient’s immune system may recognize and destroy prostate cancer cells. When this treatment is used, it is difficult to know if the treatment is working to treat the cancer because treatment with Sipuleucel-T does not lead to PSA reductions, shrinking of the tumor, or keeping the cancer from getting worse. However, results from clinical trials have shown that treatment with sipuleucel-T can increase survival in men with castration-resistant metastatic prostate cancer with few or no symptoms.

 

 

 

INITIAL PROSTATE CANCER DIAGNOSIS

INITIAL PROSTATE CANCER DIAGNOSIS

Initial Prostate Cancer Diagnosis
Initial suspicion of prostate cancer is based on an abnormal DRE or an elevated PSA level.
Definitive diagnosis requires biopsies of the prostate, usually performed by a urologist using a needle under TRUS guidance. A pathologist assigns a Gleason primary and secondary grade to the biopsy specimen.
Clinical staging is based on the TNM classification from the AJCC Staging Manual, 8th edition.

NCCN treatment recommendatio are based on risk stratification that includes TNM staging rather than on AJCC prognostic grouping.
Pathology synoptic reports (protocols) are useful for reporting results from examinations of surgical specimens; these reports assist pathologists in providing clinically useful and relevant information.
The NCCN Guidelines Panel favors pathology synoptic reports from the College of American Pathologists (CAP) that comply with the Commission on Cancer requirements.

RISK STRATIFICATION AND STAGING WORKUP

RISK STRATIFICATION AND STAGING WORKUP

Very low risk AND asymptomatic:
    ● Men with a life expectancy of less than 10 years → Observation, no furthwe work-up or treatment until symptomatic.
    ● Men with a life expectancy of 10 to 20 years should undergo active surveillance.
    ● Men with a life expectancy of 20 years or above, the NCCN Panel agreed that active surveillance, EBRT or brachytherapy, or radical prostatectomy are all viable options and should be discussed thoroughly.

Low risk AND asymptomatic:
    ● Men with a life expectancy of less than 10 years → Observation, no furthwe work-up or treatment until symptomatic.
    ● If the patient’s life expectancy is 10 years or more, initial treatment options include: 1) active surveillance; 2) EBRT or brachytherapy; or 3) radical prostatectomy with or without a PLND if the predicted probability of pelvic lymph node involvement is ≥ 2%.
Molecular tumor testing can be considered for these men for prognostic information.

Favorable Intermediate risk:
    ● Life expectancy of less than 5 years AND asymptomatic → Observation, no furthwe work-up or treatment until symptomatic.
    ● Options for patients with a life expectancy <10 years include: 1) observation; 2) EBRT; and 3) brachytherapy.
    ● Men with a life expectancy ≥10 years can consider molecular tumor testing for additional prognostic information independent of their NCCN risk group. Initial treatment options for these patients include: 1) radical prostatectomy, with PLND if the predicted probability of lymph node metastasis is ≥2%; 2) EBRT; 3) brachytherapy; and 4) active surveillance.

Unfavorable Intermediate risk:
    ● Life expectancy of less than 5 years AND asymptomatic → Observation, no furthwe work-up or treatment until symptomatic.
    ● Options for patients with a life expectancy <10 years include: 1) observation; 2) EBRT; and 3) brachytherapy.
    ● Men with a life expectancy ≥10 years can consider molecular tumor testing for additional prognostic information independent of their NCCN risk group. Initial treatment options for these patients include: 1) radical prostatectomy, with PLND if the predicted probability of lymph node metastasis is ≥2%; 2) EBRT; 3) brachytherapy; and 4) active surveillance.

High and Very High Risk:
Treatment options are the same for these 2 risk groups.
    ● If life expectancy is >5 years, treatment options include EBRT in conjunction with 2 to 3 years of neoadjuvant/concurrent/adjuvant ADT (category 1); ADT alone is insufficient. In particular, patients with low-volume, high-grade tumor warrant aggressive local radiation combined with 2 or 3 years of neoadjuvant/concurrent/adjuvant ADT.
    ● Fit men can consider 6 cycles of docetaxel with concurrent steroid after EBRT is completed and while continuing ADT.
    ● The combination of EBRT and brachytherapy, with 1 to 3 years of neoadjuvant/concurrent/adjuvant ADT, is another primary treatment option (category 1).
    ● Finally, radical prostatectomy with PLND remains an option. In particular, younger and healthier men may benefit from operation.



ADT as a primary treatment for localized prostate cancer (in low-risk groups) does not improve survival and is not recommended by the NCCN Guidelines Panel.

Cryotherapy or other local therapies are not recommended as routine primary therapy for localized prostate cancer due to lack of long-term data comparing these treatments to radiation or radical prostatectomy.

Low or Intermediate risk AND symptomatic OR High risk AND asymptomatic:
    Life expectancy > 5 years → Work-up →
    ● M0 Disease: Observation or ADT or EBRT
    ● M1 Disease: ADT+docetaxel (Category 1), ADT+abiraterone with prenisone (Category 1), or ADT, or ADT+abiraterone with methylprenisolone (Category 2B)

    Life expectancy < 5 years → Work-up →
    ● M0 Disease: Observation or ADT
    ● M1 Disease: ADT+docetaxel for high-volume disease; ADT and/or local radiation for low-volume disease.

NCCN Recommendations

Very Low Risk
Men with all of the following tumor characteristics are categorized in the very-low-risk group:
clinical stage T1c (The tumor is found during a needle biopsy, usually because the patient has an elevated PSA level),
biopsy Gleason score ≤6/Grade Group 1,
PSA <10 ng/mL,
presence of disease in fewer than 3 biopsy cores, ≤50% prostate cancer involvement in any core, and
PSA density <0.15 ng/mL/g.

The use of targeted biopsy increases the chancethat patients will have a higher number of positive cores or >50% involvement in some cores. Men with targeted biopsies who otherwise qualify for very-low-risk prostate cancer should still be considered as very low risk regardless of percent core involvement or number of positive cores in the targeted biopsies.

Given the potential side effects of definitive therapy, men in this group who have an estimated life expectancy of less than 10 years should undergo observation (monitoring no more often than every 6 months).
Unlike active surveillance, observation schedules do not involve biopsies. Men with very low risk and a life expectancy of 10 to 20 years should undergo active surveillance.
For patients who meet the very-low-risk criteria but who have a life expectancy of 20 years or above, the NCCN Panel agreed that active surveillance, EBRT or brachytherapy, or radical prostatectomy are all viable options and should be discussed thoroughly.

Low Risk
The NCCN Guidelines definethe low-risk group as patients with
clinical stage T1 to T2a,
Gleason score 6/Grade Group 1, and
serum PSA level <10 ng/mL.

Observation is recommended for men with low-risk prostate cancer and a life expectancy of less than 10 years. If the patient’s life expectancy is 10 years or more, initial treatment options include: 1) active surveillance; 2) EBRT or brachytherapy; or 3) radical prostatectomy with or without a PLND if the predicted probability of pelvic lymph node involvement is ≥ 2%.
Molecular tumor testing can be considered for these men for prognostic information independent of NCCN risk groups.

ADT as a primary treatment for localized prostate cancer does not improve survival and is not recommended by the NCCN Guidelines Panel. Cryotherapy or other local therapies are not recommended as routine primary therapy for localized prostate cancer due to lack of long-term data comparing these treatments to radiation or radical prostatectomy.

Favorable Intermediate Risk
The NCCN Guidelines define the favorable intermediate-risk group as patients with clinical stage T2b to T2c, Gleason score 3+4=7/Grade Group 2, or PSA 10 ng/mL to 20 ng/mL. Patients with multiple of these adverse factors should be shifted to the unfavorable intermediate-risk group. In addition, to qualify for favorable intermediate risk, a patient must have <50% of biopsy cores positive for cancer.

Options for patients with a life expectancy <10 years include: 1) observation; 2) EBRT; and 3) brachytherapy.

Men in this group with a life expectancy ≥10 years can consider molecular tumor testing for additional prognostic information independent of their NCCN risk group (see Molecular Testing).
Initial treatment options for these patients include: 1) radical prostatectomy, with PLND if the predicted probability of lymph node metastasis is ≥2%; 2) EBRT; 3) brachytherapy; and 4) active surveillance.

The literature on outcomes of active surveillance in men with intermediate-risk prostate cancer is limited.
In the PIVOT trial, men with clinically localized prostate cancer and a life expectancy ≥10 years were randomized to radical prostatectomy or observation.
Of the 120 participants with intermediate-risk disease who were randomized to observation, only 13 died from prostate cancer, a non-significant difference compared with 6 prostate cancer deaths in 129 participants with intermediate-risk disease in the radical prostatectomy arm (HR, 0.50; 95% CI, 0.21–1.21; P=.12). After longer follow-up (median 12.7 years), a small difference was seen in all -cause mortality in those with intermediate risk disease (absolute difference, 14.5 percentage points; 95% CI, 2.8–25.6), but not in those with low-risk disease (absolute difference, 0.7 percentage points; 95% CI, -10.5–11.8). Urinary incontinence and erectile and sexual dysfunction, however, were worse through 10 years in the radical prostatectomy group. These results and the less-than-average health of men in the PIVOT study suggest that men with competing risks may safely be offered active surveillance. Other prospective studies of active surveillance that included men with intermediate-risk prostate cancer resulted in prostate cancer-specific survival rates of 94% to 100% for the full cohorts.

The panel interpreted these data to show that a subset of men with intermediate-risk prostate cancer may be considered for active surveillance, although longer-term follow-up is needed in these and others studies to increase confidence about the risks and benefits of active surveillance in this population. Men must understand that a significant proportion of men clinically staged as favorable intermediate-risk prostate cancer may have higher risk disease.

The panel believes that active surveillance may be considered for men with favorable intermediate-risk prostate cancer, but should be approached with caution, include informed decision-making, and use close monitoring for progression.

Unfavorable Intermediate Risk
NCCN defines unfavorable intermediate risk as T2b-T2c, Gleason score 7/Grade Group 2-3, and/or PSA 10 to 20 ng/mL. Patients with only one of these risk factors and fewer than 50% of biopsy cores positive for cancer fall into the favorable intermediate risk group.

Options for treatment for men with unfavorable intermediate risk include 1) EBRT with 4 to 6 months of ADT; and 2) EBRT + brachytherapy with or without 4 to 6 months of ADT regardless of life expectancy. Additionally, for men with a life expectancy ≥10 years, radical prostatectomy, with PLND if the predicted probability of lymph node metastasis is ≥ 2%, can be performed. Finally, observation is an option for men with life expectancy <10 years.
Active surveillance is not recommended for patients with unfavorable intermediate risk prostate cancer (category 1).

High and Very High Risk
Men with prostate cancer that is clinical stage T3a, Gleason score 8 to 4+5=9/Grade Group 4–5, or PSA level greater than 20 ng/mL are categorized by the panel as high risk.
Patients at very high risk (locally advanced) are defined by the NCCN Guidelines as men with clinical stage T3b to T4, primary Gleason pattern 5, or more than 4 biopsy cores with Gleason score 8 to 10/Grade Group 4–5.
Men in these risk groups can be considered for germline testing for mutations in homologous recombination genes (see Family History and DNA Repair Mutations, above). Treatment options are the same for these 2 risk groups. If life expectancy is >5 years, treatment options include EBRT in conjunction with 2 to 3 years of neoadjuvant/concurrent/adjuvant ADT (category 1); ADT alone is insufficient. In particular, patients with low-volume, high-grade tumor warrant aggressive local radiation combined with 2 or 3 years of neoadjuvant/concurrent/adjuvant ADT. Fit men can consider 6 cycles of docetaxel with concurrent steroid after EBRT is completed and while continuing ADT. The combination of EBRT and brachytherapy, with 1 to 3 years of neoadjuvant/concurrent/adjuvant ADT, is another primary treatment option (category 1).
Finally, radical prostatectomy with PLND remains an option. In particular, younger and healthier men may benefit from operation.

 

SYSTEMIC THERAPY FOR CASTRATION-NAIVE DISEASE

SYSTEMIC THERAPY FOR CASTRATION-NAIVE DISEASE


Observation involves monitoring the course of disease with the expectation to deliver palliative therapy for the development of symptoms or a change in exam or PSA that suggests symptoms are imminent. See Principles of Active Surveillance and Observation.

Workup for progression should include chest x-ray or chest CT, bone imaging, and abdominal/pelvic CT or MRI with and without contrast. Consider C-11 choline PET/CT or PET/MRI or F-18 fluciclovine PET/CT or PET/MRI for further soft tissue evaluation or F-18 sodium fluoride PET/CT for further bone evaluation.

The term "castration-naive" is used to define patients who are not on ADT at the time of progression. The NCCN Prostate Cancer Panel uses the term "castration-naive" even when patients have had neoadjuvant, concurrent, or adjuvant ADT as part of radiation therapy provided they have recovered testicular function.

Intermittent ADT can be considered for men with M0 or M1 disease to reduce toxicity. See Principles of Androgen Deprivation Therapy

High-volume disease is differentiated from low-volume disease by visceral metastases and/or 4 or more bone metastases, with at least one metastasis beyond the pelvis vertebral column. Patients with low-volume disease have less certain benefit from early treatment with docetaxel combined with ADT.

NCCN Recommendations for Castration-Naïve mCaP
• By disease-related symptoms:
  – Asymptomatic
• Intermittent ADT
• Discuss possible decrease in OS
• Trade off fori mproved QoL during off cycle
  – Symptomatic
• Consider continuous ADT
• If PSA falls to <4 and certainly < 0.2, intermittent ADT reasonable
• By age and comorbidities:
  − Younger and healthier, docetaxel or abiraterone + ADT
  − Older and/or unhealthier, ADT

Effect on OS of Adding Docetaxel to Standard of Care for Castration-Naïve CaP
• Systematic review identified 5 RCTs in M1 and 11 RCTs in M0
• Meta-analysis of 3206 M1 patients from 3 RCTs and 3978 M0 patients from3RCTs

Effect on OS of Adding Docetaxel to Standard of Care for Castration-Naïve CaP

LATITUDE Phase III Trial: ADT ± Abiraterone/Prednisone for Castration-Naïve mCaP
• 1199 men at 235sites in 34 countries
• Planned interim analysis at median follow-up 30 mo/406 deaths
• Grade 3 hypertension and hypokalemia greater in tx arm
• Median OS was not reached in the tx arm vs 35 mo in the placebo group; medians for radiographic PFS (rPFS) were 33 mo vs 15 mo

LATITUDE Phase III Trial: ADT ± Abiraterone/Prednisone for Castration-Naïve mCaP

 

Systemic therapy for Castration-resistant prostate cancer (CRPC)


M0 Disease (No distant metastasis)


Systemic therapy for Castration-resistant prostate cancer (CRPC), M0 Disease

1. Continue ADT to maintain testosterone level < 50 ng/dL
  * If PSA doubling time > 10 months → Observation
  * If PSA doubling time < 10 months :
    ● Apalutamide (Category 1)
    ● Enzalutamide (Category 1)
    ● Other secondary hormone therapy
2. Monitor PSA level
  * If PSA level stable → Maintain current treatment and continue monitor PSA level
  * If PSA level increasing → Imaging
    ● If metastasis → See systemic therapy for M1 CRPC
    ● No meatstasis → Change or maintain current treatment

Note:
Observation involves monitoring the course of disease with the expectation to deliver palliative therapy for the development of symptoms or a change in exam or PSA that suggests symptoms are imminent.
Workup for progression (Image) should include chest x-ray or chest CT, bone imaging, and abdominal/pelvic CT or MRI with and without contrast. Consider C-11 choline PET/ CT or PET/MRI or F-18 fluciclovine PET/CT or PET/MRI for further soft tissue evaluation or F-18 sodium fluoride PET/CT for further bone evaluation.
Castration-resistant prostate cancer (CRPC) is prostate cancer that progresses clinically, radiographically, or biochemically despite castrate levels of serum testosterone (<50 ng/dL)


SPARTAN: Apalutamide for M0 CRPC

• Non-steroidal anti-androgen (apalutamide)
• 332 sites in 26 countries
• 1207 men with non-metastatic CRPC and PSADT ≤10 mo
• Technitium-99 bone scans and whole body CT
• N0 or N1 < 2 cm and within pelvis
• Randomized 2:1 to apalutamide 240 mg/day or placebo
• Primary endpoint: Time to distant metastasis or death
• Adverse events requiring discontinuation of trial regimen 10.6% in apalutamide group 7.0% in placebo group
• Adverse events more frequent in apalutamide group Rash (23.8% vs 5.5%) Hypothyroidism (8.1% vs 2.0%) Fracture (11.7% vs 6.5%)

SPARTAN: Apalutamide for M0 CRPC
SPARTAN: Apalutamide for M0 CRPC

 

■ M1 Disease (with distant metastasis)

Systemic therapy for Castration-resistant prostate cancer (CRPC), M1 Disease

    * Consider Tumor testing for MSI-H or dMMR
    * Consider testing for these genes (germline or somatic): BRCA1, BRCA2, ATM, PALB2, FANCA; refer to genetic counseling if positive. At present, this information may be used for early use of platinum chemotherapy or eligible for clinical trials (e.g., PARP inhibitors).

1. Continue ADT to maintain testosterone level < 50 ng/dL
2. Additional treatment options:
    ● Bone anti-resorptive therapy if bone metastases present: denosumab or zoledronic acic (both category 1)
    ● Immunotherapy with sipuleucel-T (category 1)
    ● Palliative RT for painful bone metastases
    ● Best supportive care

Visceral metastases?
    * Yes →
        ● See systemic therapy for M1 CRPC: Visceral metastases

    * No →
        ● Abiraterone with prenisone (Category 1)
        ● Docetaxel (Category 1)
        ● Enzalutamide (Category 1)
        ● Radium-223 for symtomatic bone metastases (Category 1)
        ● Abiraterone with methylprenisolone
        ● Clinical trials
        ● Other secondary hormone therapy
    * At progression → Re-stage and
         See Subsequent Therapy for M1 CRPC: No Visceral Metastases OR
         See Systemic Therapy for M1 CRPC: Visceral Metastases

Note:
Visceral metastases refers to liver, lung, adrenal, peritoneal, and brain metastases. Soft tissue/lymph node sites are not considered visceral metastases. Sipuleucel-T has not been studied in patients with visceral metastases.

DNA analysis for MSI and IHC for MMR are different assays measuring the same biological effect. If MSI-H or dMMR is found, refer to genetic counseling to assess for the possibility of Lynch syndrome. MSI-H or dMMR indicate eligibility for pembrolizumab in later lines of treatment for CRPC.

Consider testing for mutation in these genes (germline and somatic): BRCA1, BRCA2, ATM, PALB2, FANCA; refer to genetic counseling if positive. At present, this information may be used for genetic counseling, early use of platinum chemotherapy, or eligibility for clinical trials (e.g., PARP inhibitors).

Workup for progression should include chest x-ray or chest CT, bone imaging, and abdominal/pelvic CT or MRI with and without contrast. Consider C-11 choline PET/CT or PET/MRI or F-18 fluciclovine PET/CT or PET/MRI for further soft tissue evaluation or F-18 sodium fluoride PET/CT for further bone evaluation

Although most patients without symptoms are not treated with chemotherapy, the survival benefit reported for docetaxel applies to those with or without symptoms. Docetaxel may be considered for patients with signs of rapid progression or visceral metastases despite lack of symptoms.

Radium-223 is not approved for use in combination with docetaxel or any other chemotherapy.

 

SUBSEQUENT SYSTEMIC THERAPY FOR M1 CRPC

No visceral metastases SUBSEQUENT SYSTEMIC THERAPY FOR M1 CRPC, No visceral metastases

Note:
Workup for progression should include chest x-ray or chest CT, bone imaging, and abdominal/pelvic CT or MRI with and without contrast. Consider C-11 choline PET/CT or PET/MRI or F-18 fluciclovine PET/CT or PET/MRI for further soft tissue evaluation or F-18 sodium fluoride PET/CT for further bone evaluation.

Sipuleucel-T has not been studied in patients with visceral metastases

SYSTEMIC THERAPY FOR M1 CRPC Visceral Metastases

Visceral metastases SUBSEQUENT SYSTEMIC THERAPY FOR M1 CRPC, With visceral metastases

Note:
Radium-223 is not approved for use in combination with docetaxel or any other chemotherapy.

Patients can continue through all treatment options listed. Best supportive care is always an appropriate option.
Limited data suggest a possible role for AR-V7 testing to help guide selection of therapy
Patients who received docetaxel with ADT in the metastatic castration-naive setting can be considered for docetaxel rechallenge in the CRPC setting.

Mitoxantrone with prednisone is for palliation in symptomatic patients who cannot tolerate other therapies.

 

 

 

Additional Useful Information

Why are Prostate Cancer (CaP) Guidelines Needed?
• Overdetection leads to overtreatment
• Patients (and physicians) believe “if it’s new, it’s better”
• MDs, hospitals, insurers, and government are rewarded when “more stuff is done to more patients”
• New CRPC agents are expensive and sequence of use remains uncertain

Costs of new agents for CRPC

Life Expectancy Estimation   (http://www.cdc.gov/nchs/hus/contents2016.htm#015)
• 2007 NCCN Guidelines, for the first time, included “Principles of Life Expectancy Estimation”
• Life expectancy can be estimated using the Minnesota Metropolitan Life Insurance Tables, Social Security Administration Life Expectancy Tables, or US Department of Health Trend Tables
• Life expectancy can be adjusted for individual patients by adding or subtracting 50% based upon whether one believes the patient is in the healthiest quartile or the unhealthiest quartile, respectively
  − Life expectancy for 65-year-old African-American man = 16 yrs
  − If upper quartile of health, life expectancy = 24 yrs
  − If lower quartile of health, life expectancy = 8 yrs

Calculate PSA doubling time (PSADT)
• Assume symptoms at PSA 100-200
• Add 5 yrs for ADT-induced remission
• Example
  − Average PSADT for clinically detected CaP = 4yrs
  − Diagnosed at PSA=6
  − PSA >100 after 4 doublings or 16 yrs
  − Death after 21 yrs

Real World Example
• Average PSADT for clinically detected CaP = 4 yrs
  − Diagnosed at PSA = 6
  − PSA > 100 after 4 doublings or 16 yrs
  − Death after 21 yrs
• 65-year-old African-American man
  − If upper quartile of health, Life Exp = 24 yrs
• AS risky, probably treat (RP or EBRT)
  − If, middle 2 quartiles of health, Life Exp = 16 yrs
• All options (AS, RP, EBRT)
  − If lower quartile of health, Life Exp = 8 yrs
• Operation wrong
• Observation or radiatio
SEveral Studies Show No Harm from Treatment Delay.

Strong Family History
• Brother or fatherm or multiple family members diagnosed with prostate cancer at <60 years of age
• Known germline DNA repair gene abnormalities, especially BRCA2 mutation or Lynch syndrome (germline mutations in MLH1, MSH2, MSH6, or PMS2)
• > 1 relative with breast, ovarian, or pancreatic cancer (suggests possibility of BRCA2 mutation) or colorectal, endometrial, gastric, ovarian, pancreatic, small bowel, urothelial, kidney, or bile duct cancer (suggests possibility of Lynch syndrome)

Tumor-Based Molecular Assays for Clinically Localized CaP
• Men with low or favorable intermediate risk CaP may consider the use of Decipher, Oncotype DX Prostate, Prolaris, ProMark
• Retrospective studies have shown that molecular assays performed on prostate biopsy or radical prostatectomy specimens provide prognostic information independent of NCCN risk groups.
  – likelihood of death with conservative management
  – likelihood of biochemical progression after radical prostatectomy or external beam therapy
  – likelihood of developing metastasis after radical prostatectomy or salvage radio therapy

Molecular Assays for Advanced CaP
• Consider testing for germline and/or somatic testing for mutations in inherited homologous recombination genes in all men with high risk, very high risk, regional, or metastatic CaP
• Prevalence
  – 6.0% in clinically localized high risk CaP
  – 11.8% in metastatic CaP
• BRCA1, BRCA2, ATM, PALB2, FANCA
• Refer to genetic counseling if positive
• Early use of platinum chemotherapy
• Eligibility for clinical trials (e.g., PARP inhibitors)

Molecular Assays for Metastatic CRPC
• DNA analysis for microsatellite instability (MSI) and IHC for mismatch repair deficiency (dMMR; MLH1, MLH2, MSH6, PMS2)
are different assays measuring the same biological effect.
• If MSI or dMMR is found, refer to genetic counseling to assess for the possibility of Lynch syndrome.
• MSI or dMMR indicate eligibility for pembrolizumab in later lines of treatment for CRPC.

Use of IMRT:
The ability to deliver many “beamlets” of varying radiation intensity, within one treatment field

PET for CaP
• F-18 fluorodeoxyglucose (FDG) PET has little if any role for staging CaP.
• PET/CT or PET/MRI imaging using tracers other than F-18 FDG for staging of small volume recurrent or metastatic CaP is a rapidly developing field.

Combined Androgen Blockade
• 1995-2016: Numerous RCTs and meta-analyses demonstrate little if any benefit to CAB, which increases costs and side effects of ADT

Toxicities Associated with ADT
• Fatigue
• Hot flashes/hot flushes
• Loss of libido
• Osteoporosis
• Metabolic syndrome
− Stroke
− Myocardial infarction
− Diabetes

Intermittent ADT
• Meta-analysis of 6 RCTs from 26 eligible (2996 men)
• Mortality similar for intermittent vs continuous ADT
• QoL better for intermittent vs continuous ADT (example, erectile dysfunction)

Can intermittent ADT Be Personalized Using End-of-Induction PSA?
No response: PSA>10; survival 13 mo
Excellent response: PSA 0.2 - <4.0; survival 4 yrs
Outstanding response: PSA<0.2; survival 6 yrs

 

Conclusion: Management for Prostatic Cancer

Conclusion: Management for Prostatic Cancer