Prostate Neoplasms

Prostate cancer
Incidence and Epidemiology

 Approximately 30,000 men die of the disease annually—more than any

other tumor type except lung cancer.

 The number of prostate cancer deaths annually is far outweighed by the

number of diagnoses, and most men diagnosed ultimately die of other
causes, most often cardiovascular disease.

 Of all cancers, the prevalence of prostate cancer increases the most

rapidly with age.
 increasing age heightens the risk for prostate cancer. The probability of CaP diagnosis in a man
younger than 40 years is 1 in 10,000; for men 40–59 years old, it is 1 in 103; and for men 60–79 years
old, it is 1 in 8.

 African Americans are at a higher risk of developing and mortality.

 A positive family history of CaP also increases the relative risk for CaP.

 Total fat intake, animal fat intake, and red meat intake are associated with an increased risk of
prostate cancer, whereas intake of fish is associated with a decreased risk.

 Some studies suggest that obesity is associated with an increased risk of more advanced disease
and a higher recurrence rate after treatment. In addition, lycopene, selenium, omega-3 fatty acids
(fish), and vitamin E intake have been shown to be protective, whereas vitamin D and calcium
increase risk.
 men with a family history of breast and/ or ovarian cancer may be offered a predictive genetic
test to determine whether or not they carry the family specific BRCA1/2 mutations as they are at
increased risk of breast and prostate cancers.
Risk factors

 The most important risk factor for the development of prostate cancer is
increasing age.
 risk of prostate cancer is higher in African Americans compared with other
ethnic groups.
 Genetic factors, especially germline mutations in DNA repair genes (such
as BRCA2)
 Other factors, such as diet, hormone levels, and obesity, have been studied
with the goal of developing strategies to reduce the risk of prostate cancer.
Pathology

 95% of the prostate cancers are adenocarcinomas.

 5% of prostate cancer is heterogeneous, arising from stromal, epithelial, or

ectopic cells.

 Nonadenocarcinoma variants can be categorized into two groups based

on the cellular origin: epithelial and nonepithelial.

 The cytologic characteristics of CaP include hyperchromatic, enlarged

nuclei with prominent nucleoli. Cytoplasm is often abundant and slightly
blue tinged or basophilic.
 The basal cell layer is absent in CaP

 highmolecular- weight keratin immunohistochemical staining is useful, as it

preferentially stains basal cells.

 Prostatic intraepithelial neoplasia (PIN) and atypical small acinar proliferation

(ASAP) are thought to be precursor lesions.

 High-grade PIN (HGPIN) is characterized by cellular proliferations within

preexisting ducts and glands, with nuclear and nucleolar enlargement similar to
prostate cancer. However, unlike cancer, HGPIN retains a basal cell layer
identifiable by immunohistochemistry.
Location and invasion

 Approximately 60–70% of cases of CaP originate in the peripheral zone, 10–

20% originate in the transition zone, and 5–10% in the central zone.

 Penetration of the prostatic capsule by cancer is a common event and

often occurs along perineural spaces. Seminal vesicle invasion is associated
with a high likelihood or regional or distant disease. Locally advanced CaP
may invade the bladder trigone, resulting in ureteral obstruction. Rectal
involvement is rare.

 Lymphaticmetastases are most often identified in the obturator, external

iliac, and internal lymph node chains. Other sites of nodal involvement
include the common iliac, presacral, and periaortic lymph nodes.
Metastases

 The axial skeleton is the most usual site of distant metastases, with the lumbar spine being most
frequently implicated.
 The next most common sites in decreasing order are proximal femur, pelvis, thoracic spine, ribs,
sternum, skull, and humerus.
 Bone lesions of metastatic CaP are typically osteoblastic.
 Involvement of long bones can lead to pathologic fractures.
 Vertebral body involvement with significant tumor masses extending into the epidural space can
result in cord compression.
 Visceral metastases most commonly involve the lung, liver, and adrenal gland.
 Central nervous system involvement is usually a result of direct extension from skull metastasis.
 imaging for distant metastases is not routinely recommended for very low- and low-risk disease
according to the clinical staging system described above, while it is recommended for more
advanced disease. Bone imaging and pelvic imaging, with or without abdominal imaging, are
recommended for those with intermediate- and high-risk disease.
Symptoms

 majority of patients with early-stage CaP are asymptomatic.

 presence of symptoms often suggests locally advanced or metastatic disease.

 At the time of diagnosis, 78 percent of patients have localized cancer, regional
lymph node involvement is present in 12 percent, and 6 percent have distant
metastases. This is mostly due to creening methods
 Obstructive or irritative voiding complaints can result from local growth of the
tumor into the urethra or bladder neck or from its direct extension into the
trigone of the bladder.

 Metastatic disease to the bones may cause bone pain. Also, paresthesias
andweakness of the lower extremities and urinary or fecal incontinence can be
noticed.
Signs

 Induration or nodularity on DRE, if detected, must alert the physician.

 weakness or spasticity of the lower extremities and a hyperreflexic

bulbocavernosus reflex( with cord compression)

 lymphedema of the lower extremities (with local LN involvement).

General Laboratory Findings

 Azotemia can result from bilateral ureteral obstruction

 Anemia may be present in metastatic disease.

 Alkaline phosphatase may be elevated in the presence of bone

metastases.
 Prostate-Specific Antigen and
Other Tumor Markers
 PSA is a serine protease in the human kallikrein (hK) family.

 BPH and prostatitis—as well as urethral instrumentation and perineal insults such as
prolonged bike ride—can elevate the PSA, producing false-positive results.

 A “normal” PSA has traditionally been defined as ≤4 ng/mL. For levels in excess of 10 ng/mL,
the positive predictive value increases from 42% to 71.4%.

 Use of medications such as 5α-reductase inhibitors (including the 1 mg finasteride

formulation must be ascertained, as these medications can artificially lower the PSA by
approximately 50%.

 Attempts at refining PSA have included PSA velocity (PSAV) (change of PSA over time), PSA
kinetics (standardizing levels in relation to the size of the prostate), and PSA isoforms (free vs
protein bound molecular forms of PSA).
 1. PSA kinetics—PSAV refers to the rate of change of serum PSA; its inverse, PSA
doubling time (PSADT) indicates the amount of time required for the PSA to double.

 Patients whose serum PSA increases by 0.75 ng/mL per year appear to be at an
increased risk of harboring cancer. However, Very rapid PSA increases may be
indicative of prostatitis.

 2. PSA density—The ratio of PSA to gland volume is termed the PSA density. Some
investigators advocate prostate biopsy only if the PSA density exceeds 0.1 or 0.15,
while others have not found PSA density to be useful.

 Problems with this approach include the facts that (1) epithelial–stromal ratios vary
from gland to gland and only the epithelium produces PSA and (2) errors in
calculating prostatic volume based on TRUS may approach 25%.
 Molecular forms of PSA—Various molecular isoforms of PSA have been identified
and studied. Approximately 90% of the serum PSA is bound to α1-antichymotrypsin
(ACT), and lesser amounts are free or are bound to α2-macroglobulins.

 Early studies suggest that prostate cancer patients demonstrate a lower

percentage of free PSA than do patients with benign disease.
 free to total PSA (f/t PSA):An f/t PSA <10 to 15 percent is highly suspect for prostate
cancer, whereas an f/t PSA >25 percent is highly likely to be due to BPH. F/t PSA
ratios are of most value when deciding whether a repeat biopsy is necessary in an
older patient who has a prior negative biopsy, but a PSA level that is still suspicious.
 A truncated form of PSA designated −2proPSA has also shown promise in this setting
and is likewise undergoing validation studies.
 PCA3—Prostate cancer antigen 3 may be particularly useful in the evaluation of
men with a negative prior biopsy and a rising PSA.
Diagnosis and Evaluation

 Decision to biopsy — Results of PSA testing, DRE, and any adjunctive PSA tests and imaging
performed are used to inform the clinical likelihood for harboring significant disease and
thus guide the decision about whether a biopsy is needed to obtain tissue for histologic
diagnosis. (See "Prostate biopsy".)
 After shared decision-making with the patient, we usually proceed to biopsy if:
 ●Life expectancy is at least 10 years (some contributors biopsy if life expectancy is >5
years)
 AND
 ●PSA is elevated above the range for the patient's age cohort, or PSA has increased more
than 0.75 ng/mL over one year, or there is a palpable concerning abnormality on DRE
 Not pursuing prostate biopsy, even if PSA is elevated or increased, may be appropriate in
older patients or patients who have significant comorbidities that limit their life expectancy
when the patient’s goals are aligned with less aggressive diagnostics and interventions.
Diagnosis and Evaluation

 A. Prostate Biopsy:
1. Prostate biopsy should be considered in men with an elevated serum PSA,
abnormal DRE, or a combination of the two.
2. Biopsies are taken throughout the peripheral zone of the prostate, with optional
additional sampling of any abnormal areas on DRE and/or TRUS.
3. Taking more than 10 and performing more laterally directed biopsies of the
peripheral zone will increase detection rates 14–20%.
4. Some practitioners do add biopsies of the anterior commissure, a relatively
frequent site of initially missed cancers found on second or subsequent biopsy.
 Prostate biopsy is usually performed using local anesthesia and preprocedure
antibiotic prophylaxis (usually a fluoroquinolone). Hematospermia,
hematochezia, and hematuria are common occurring in approximately 40–50%
of patients.
 B. Grading and Staging
 The Gleason system is the most commonly employed grading system.
 The system relies on the low-power appearance of the glandular architecture under the microscope. In
assigning a grade to a given tumor, pathologists assign a primary grade to the pattern of cancer that is
most commonly observed and a secondary grade to the second most commonly observed pattern in
the specimen. Grades range from 1 to 5.
 In contemporary pathology practice, Gleason patterns 1 and 2 are rarely assigned, so Gleason pattern 3
corresponds with low-grade disease (variable-sized glands that percolate through normal stroma and
between normal glands),
 Gleason pattern 4 corresponds with intermediate grade disease (incompletely formed glands with
variable amounts of fusion and more infiltrative growth pattern).
 Gleason pattern 5 corresponds with high-grade disease (single infiltrating cells with no gland formation).
 A Gleason score 6 (3 + 3) tumor is uniformly low grade.
 In Gleason score 7 tumors, those assigned 4 + 3 are more aggressive than those read as 3 + 4.
 TNM staging system uses results of the DRE and TRUS, but not the results of the biopsy.

 Clinical versus pathologic staging — For patients who undergo radical prostatectomy, additional
information about the extent of disease is obtained from the surgical specimen, and this forms the basis
for pathologic staging (figure 1). When this reveals poor prognostic features (Gleason grade higher than
the original biopsy, extraprostatic extension, seminal vesicle involvement, or lymph node involvement),
additional therapy may be recommended following prostatectomy.
Imaging

 1. TRUS:
 useful in helping guide prostatic biopsies and other prostate-directed
interventions.
 TRUS also provides useful local staging information.
 CaP tends to appear as a hypoechoic lesion in the peripheral zone and/or
hypervascularity seen on power Doppler examination.

2. Endorectal magnetic resonance imaging (MRI):

 Use of magnetic resonance spectroscopy (MRS) in conjunction with MRI
mayimprove the accuracy of imaging.
 Prostate cancer is associated with proportionately lower levels of citrate and
higher levels of choline and creatine compared with BPH or normal prostate
tissue.
Imaging

 3. Axial imaging (CT, MRI):

 performed to exclude lymph node metastases.
 imaging is costly and its sensitivity is limited (30–40%). Various criteria can be used to
identify patients for axial imaging, including negative bone scans and either T3 cancers or
a PSA >20 ng/mL and primary Gleason grade 4 or 5 cancers.
 4. Bone scan:
 When prostate cancer metastasizes, it most commonly does so to the bone.
 Several investigators have shown that bone scans can be omitted in patients with newly
diagnosed, untreated prostate cancer who are asymptomatic, have T1 and T2 disease,
and have serum PSA concentrations <20 ng/mL.
 5. Antibody imaging
 new antibodies, which recognize the extracellular domain of PSMA, appear to allow for
recognition of both bone and soft tissue metastases and could be used as agents for
therapy, not only improved imaging.
Multivariable Risk Assessment

 risk stratification intended to help identify the best timing and intensity of treatment for a
given patient.

 1. Risk groups:
 Low risk: PSA ≤10, Gleason ≤6, and clinical stage T1 or T2a.
 Intermediate risk: PSA 10–20, Gleason 7, or clinical stage T2b.
 High risk: PSA >20, Gleason 8–10, or clinical stage T2c or T3a.

 The major advantage to this system is its simplicity, and it is used very commonly.
 it has significant drawbacks. First, it overweights T stage which is not an accurate measure
of tumor extent within the T2 category. Second, it does not distinguish between Gleason 3
+ 4 and 4 + 3 tumors, which behave very differently within the Gleason 7 category.
Multivariable Risk Assessment

 2. Lookup tables and nomograms:

 a patient is assigned a number of points for each risk factor; these are then
summed to yield a prediction for the outcome.
 3. CAPRA score:
 points are assigned based primarily on the PSA and Gleason score, with
lesser weights given to T stage, percent of biopsy cores positive, and
patient age.
 CAPRA scores in the 0–2 range indicate relatively low-risk disease, CAPRA
3–5 tumors are intermediate risk, and CAPRA 6–10 tumors are high risk.
 it has been shown to predict metastasis and mortality as well as
biochemical outcomes—after surgery, radiation therapy, and hormonal
therapy.
Prostate Cancer Screening

 The case for CaP screening is supported by the following:

 the disease is burdensome in this country
 PSA improves detection of clinically important tumors without significantly
increasing the detection of unimportant tumors
 most PSA-detected tumors are curable
 prostate cancer mortality is declining in regions where screening occurs
 Curative treatments are available.
 If screening is undertaken, it appears that the use of both DRE and serum
PSA is preferable to either one used alone.
Prostate Cancer Screening

 Although most guidelines recommend that screening be undertaken at age 50,

some have advocated for earlier screening starting at age 40, based on
 (1) less confounding of PSA assessment by BPH at earlier ages and
 (2) the fact that a small but significant number of men already have high-risk or
advanced prostate cancer by the age of 50.
 There is broader consensus that screening should start earlier for men with risk
factors such as family history and/or African American ethnicity.
 Although annual screening is most often recommend in the United States, some
feel that men with very low serum PSA level (eg, ≤1 ng/mL) may be able to be
screened at less frequent intervals (every 2 or 3 years).
 if the PSA level remains <1 ng/mL by the age of 60, then the likelihood of death
from prostate cancer by the age of 85 falls to <1%.
 A PSA of ≥4.0 ng/mL has been the most widely accepted standard to
balance tradeoffs between sensitivity and specificity. However, there is no
single PSA value that avoids missing important cancers at a curable stage,
avoids false-positives and detection of clinically insignificant disease, and
avoids subjecting men to unnecessary prostate biopsies. A PSA cutoff of 4.0
ng/mL had a sensitivity of 21 percent with specificity of 91 percent for
detection of any prostate cancer; for detection of a high-grade cancer,
sensitivity was 51 percent.The low sensitivity means that some men with PSA
levels <4 ng/mL will have prostate cancer
Chemoprevention

 The high incidence of prostate cancer, its associated morbidity and mortality,
and its hormone dependency all have made prostate cancer an important
target for chemopreventive strategies. (See 'Rationale' above.)
 ●In randomized trials, 5-alpha-reductase (5-AR) inhibitors have been shown to
significantly decrease the incidence of prostate cancer. However, no trials have
demonstrated an impact on prostate cancer mortality.
 For most men, we suggest not using chemopreventive therapy with a 5-AR
inhibitor. However, chemopreventive therapy with a 5-AR inhibitor in
conjunction with monitoring serum prostate-specific antigen may be
appropriate for those who consider preventing cancer more important than the
side effects associated with such therapy(gynecomastia, decreased libido,
erectile dysfunction).
 There are no data that support the use of vitamin E, selenium, or other agents
for routine use, and such agents remain experimental.
Treatment

 Localized Disease
 Currently, treatment decisions are based on the grade and stage of the
tumor, the life expectancy of the patient, the ability of each therapy to
ensure disease-free survival, its associated morbidity, and patient and
physician preferences.

 A well-conducted randomized trial of RP versus surveillance in men with

early stage prostate cancer generally diagnosed before the PSA era was
conducted in Scandinavia. With 13 years follow-up, men who underwent
RP were less likely to die of prostate cancer (relative risk, 0.62). The
advantage to surgery was most apparent in younger patients.
Treatment

 A more modern concept of watchful waiting is better termed “active

surveillance.” In surveillance, men with very well-characterized, early-stage, and
low- to intermediate grade cancer are followed very carefully with serial DRE
and PSA assessments, and follow-up TRUS-guided biopsies to ensure stability of
the tumor.

 Radical prostatectomy:
 Lymph node dissection, once done routinely, may be performed only in those
at significant risk of lymph node metastases. Such men can be identified with
use of probability tables and nomograms as described earlier.
 Previously, only limited node dissections were performed harvesting lymph
nodes from the obturator fossa. However, results from extended dissections
showed that more than half of lymph node metastases are found outside this
region. Therefore, a more extended and meticulous dissection is advised.
Treatment

 robot-assisted or unassisted laparoscopic surgery.

 PSA should fall to undetectable levels within 6 weeks of surgery in most
cases.
 Patients with organ-confined cancer have 10-year diseasefree survival
ranging from 70% to 85% in several series. Those with focal extracapsular
extension demonstrate 85% and 75% disease-free survival at 5 and 10 years,
respectively. Patients with more extensive extracapsular extension
demonstrate 70% and 40% disease-free survival at 5 and 10 years,
respectively.
 Disease-free survival at 10 years for patients with Gleason sum 2–6 tumors is
in excess of 70%; for Gleason sum 7, 50%; and for Gleason sum >8, 15%.
Treatment

 Neoadjuvant androgen deprivation, studied by several investigators, reduces the risk of positive
surgical margins, but it does not appear to impact long-term biochemical relapse-free survival.

 What is unknown is whether there is a benefit to true adjuvant radiation—that is, radiation given
to a man with adverse pathology but an undetectable PSA— compared with early salvage—
that is, deferring treatment among those with undetectable PSAs but administering radiation at
the first sign of a rising PSA identified with an ultrasensitive assay (ie, with a PSA >0.01 but <0.1
ng/mL). Relatively good evidence supports earlier rather than later salvage radiation—that is,
treating at as low a detectable PSA level as possible.

 Morbidity associated with RP can be significant and is in part related to the experience of the
surgeon. Immediate intraoperative complications include blood loss, rectal injury, and ureteral
injury.

 laparoscopic approaches decrease such bleeding. Rectal injury is rare with the retropubic
approach and more common with the perineal approach but usually can be immediately
repaired without long-term sequelae. Ureteral injury is rare with any technique.
treatment

 Perioperative complications include deep venous thrombosis, pulmonary

embolism, lymphocele formation, and wound infection. Late complications
include urinary incontinence and impotence.

 Preservation of potency varies as a function of age, preoperative sexual

function, and preservation of one or both neurovascular bundles. However, the
nerve-sparing procedure should be used selectively, for extracapsular extension
may be a common finding in patients with presumed localized CaP. If
extracapsular extension is present, preservation of the neurovascular bundle
may increase the likelihood that the tumor will recur.

 Potency can be improved with early use of PDE-5 inhibitors and other, more
aggressive approaches to “penile rehabilitation.”
 Radiation therapy—external beam therapy:

 Improved imaging and use of novel treatment planning (three-dimensional, conformal

radiation therapy [3DCRT] and intensity-modulated radiation therapy [IMRT]) allow for
better targeting, conforming, or shaping radiation volume more closely around the
prostate, and the use of higher doses without exceeding tolerance of surrounding normal
tissues.

 Day-today variations in patient/prostate position can be accounted for by the use of daily
online CT scanning, transabdominal ultrasound imaging, and insertion of an endorectal
balloon or imaging of radiopaque fiducial markers placed before treatment.

 several investigators have shown that the results of radiation therapy may be improved
with the use of neoadjuvant, concurrent, and adjuvant androgen deprivation especially in
those with intermediate- or high-risk disease.
 men who undergo radiation are more likely to suffer obstructive or irritative
voiding or bowel symptoms (urgency, frequency, diarrhea, hematuria,
rectal bleeding,and tenesmus). Although the impact of surgery on sexual
function occurs early and may improve with time, the impact of radiation
on sexual function may not be seen for 18–24 months. Sexual side effects
may be exacerbated with the concurrent use of androgen deprivation.

 Long-term risks, such as urethral stricture, rectourinary fistula, and radiation

cystitis, are uncommon but can be quite challenging to manage.
 Radiation therapy—brachytherapy:
 A resurgence in the interest in brachytherapy has occurred because of the technologic
developments making it possible to place radioactive seeds under TRUS guidance.

 As opposed to external beam radiation, androgen deprivation does not appear to

improve the outcomes of men with intermediate disease who are treated with
brachytherapy.
 Cryosurgery:
 Freezing of the prostate is carried out by using a multiprobe cryosurgical device. Multiple
hollow-core probes are placed percutaneously under TRUS guidance.
 The temperature at the edge of the iceball is 0°C to −2°C, while actual cell destruction
requires −25°C to −50°C. Therefore, actual tissue destruction occurs a few millimeters inside
the iceball edge and cannot be monitored precisely by ultrasound imaging.
Recurrent Disease

 A substantial number of men who are treated with either surgery or radiation for
presumed clinically localized prostate cancer will relapse based on evidence of
a detectable or rising serum PSA after treatment, respectively.
 Defining failure as a rise of at least 2 ng/mL greater than the nadir level.
 Following radical prostatectomy :Cancer recurrence is more common in those
with positive surgical margins, established extracapsular extension, seminal
vesicle invasion, and high-grade disease.
 Patients at low risk (eg,long interval to recurrence, slow PSA kinetics) and/or
thosewith limited life expectancy may be observed.
 those with suspected local recurrence (particularly in the setting of positive
margins) may benefit from salvage radiation therapy
 those with probable or documented distant disease should receive systemic
therapy with androgen deprivation.
Recurrent Disease

 Following radiation therapy:

 Up to one-third of patients will experience a “PSA bounce” following
radiation (especially brachytherapy), which is defined by a rise in serum
PSA followed by a decline. Such patients are not at an increased risk of
cancer recurrence and repeat prostate biopsy should be deferred in such
patients.
 Most patients who fail radiation therapy, irrespective of the site of
recurrence, currently are managed with androgen deprivation.
TREATMENT

 In published guidelines, including those of the NCCN, active surveillance is usually

recommended for men with very low-risk disease and a life expectancy >10 years.
However, this approach is associated with a need for close follow-up and may create
significant anxiety, causing many patients to subsequently choose definitive intervention.
 Clinically localized, NCCN low risk:Active surveillance, with serial monitoring and the
initiation of definitive treatment if there is evidence of progression, is a preferred care
option for most men. Clinicians may offer definitive therapy (radical prostatectomy or RT)
to patients who may have a high probability of progression on active surveillance. If
chosen, RT may be delivered by either an external beam source or brachytherapy.
 Clinically localized, NCCN intermediate risk : RT, which may be delivered by an external
beam source and/or brachytherapy. Because of the increased risk of recurrence or
disseminated disease, androgen deprivation therapy (ADT) is recommended as a
component of a combined modality approach. Radical prostatectomy with pelvic lymph
node dissection, which may be carried out with either an open or minimally invasive
approach. For patients managed with radical prostatectomy, the presence of adverse
pathologic features in the surgical staging specimen may be an indication for adjuvant
(postoperative) RT.
 Clinically localized, NCCN high risk : same as before.

 Clinically locally advanced or NCCN very high risk:they should all undergo imaging of the pelvis
(computed tomography [CT] or magnetic resonance imaging [MRI]) prior to treatment. External
beam RT with long-term ADT. In some cases, the external beam RT may be combined with
brachytherapy to increase the radiation dose to the primary tumor. Radical prostatectomy
combined with extended pelvic lymph node dissection may also be an option for very high-risk
patients, especially for younger individuals. In this setting, serum PSA provides important
information on whether or not all disease has been resected and whether further therapy is
indicated.
 •For patients in whom serum PSA is undetectable following definitive surgery, careful monitoring is
indicated, including digital rectal examination and serum PSA every three to six months.
 •If the PSA fails to fall to undetectable levels or if the PSA subsequently rises, patients are
presumed to have residual or recurrent disease. Such patients should be evaluated for evidence
of metastatic disease, and subsequent therapy is dictated by the results of that evaluation.
 We tend to prefer external beam RT plus brachytherapy and long-term ADT for these patients,
although prostatectomy may be preferred for younger individuals.
 High-grade, low-PSA prostate cancer – High-grade (Gleason score 8 to 10)
prostate cancer with a low PSA appears to comprise a distinct but
uncommon subset that includes the small cell and large cell prostatic
neuroendocrine carcinomas.
 •For patients with localized disease, treatment is similar to that for other
patients with high-risk or very high-risk disease.
 •For patients with metastatic disease, there may be an increased role for
chemotherapy using regimens similar to those used for small cell carcinoma
of the lung.
Metastatic Disease

 It is well known that most prostatic carcinomas are hormone dependent and
that the large majority of men with metastatic CaP respond initially to various
forms of androgen deprivation.
 Androgen deprivation may be induced at several levels along the pituitary–
gonadal axis using a variety of methods or agents.
 Use of a class of drugs (LHRH agonists) has allowed induction of androgen
deprivation without orchiectomy or administration of diethylstilbestrol. There are
four LHRH agonists currently approved by the FDA for the treatment of prostate
cancer: goserelin acetate, triptorelin pamoate, histrelin acetate, and leuprolide
acetate.
 LHRH antagonist (degarelix) was recently released. LHRH antagonists avoid the
“flare” phenomenon associated with LHRH agonists, in which serum testosterone
concentrations increase before falling.
 Like LHRH agonists, estrogens achieve castration by feedback inhibition of the hypothalamic–pituitary
axis and, perhaps, by a direct cytotoxic effect. Although effective, their use is limited due to an
increased risk of negative cardiovascular effects.
 Because of its rapid onset of action, ketoconazole should be considered in patients with advanced
prostate cancer who present with spinal cord compression or disseminated intravascular coagulation.
Ketoconazole and the novel agent abiraterone inhibit androgen biosynthesis throughout the body—in
the testes and adrenals and within the tumor cells.

 Complete androgen blockade can be achieved by combining an androgen receptor antagonist

(flutamide, bicalutamide, or nilutamide) with the use of an LHRH agonist or orchiectomy. A meta-analysis
of monotherapy and complete androgen blockade for the treatment of men with advanced prostate
carcinoma suggested that there might be a small survival advantage to complete androgen blockade.

 ADT plus abiraterone — Loss of efficacy of ADT in controlling prostate cancer may be mediated by the
intracellular conversion of steroid precursors to androgenic steroids within prostate cancer cells. The
rationale for combining ADT with abiraterone is based upon the ability of abiraterone to block this
conversion.
 in those with metastatic disease, castration is associated with better survival, and
antiandrogen monotherapy is not commonly used in the United States.
 Androgen deprivation is not without side effects including hot flashes, anemia, loss of libido
and sexual function, loss of bone mineral density, increased weight and body fat, and
cognitive changes. In addition, increases in total cholesterol, low- and high-density
lipoproteins, and serum triglycerides have been reported.
 Combining ADT with either abiraterone or docetaxel increases overall survival compared
with ADT alone in patients with high-risk and/or de novo presentation with metastases.
 Serial evaluation of serum prostate-specific antigen (PSA) is the mainstay of testing.
Consensus-based guidelines from the National Comprehensive Cancer Network (NCCN)
recommend testing PSA every three to six months during treatment for advanced prostate
cancer. Most clinicians make decisions about the need for radiographic evaluation based
on changes in PSA values and/or the development of new symptoms.
 Ultimately, most prostate cancers will adapt to survive without androgens, at which point
they are denoted “hormone refractory” or “castrate resistant.”
 Metastatic disease – In the setting of patients with overt metastatic disease,
several randomized trials and a meta-analysis found that immediate
compared with delayed ADT was associated with a statistically significant
decrease in prostate cancer-related death, although there was no overall
survival benefit.
 ●Rising serum PSA – The optimal timing for the initiation of ADT for patients
with a rising serum PSA is controversial. Proponents of early treatment argue
that this approach can delay disease progression and may prolong
survival. Others contend that treatment is best deferred until clinical
metastases or symptoms develop since there is no consistent evidence for
a significant survival benefit with ADT in this setting.
 Briefly, interventions now available include the following:
 • Cessation of antiandrogen therapy if the patient has been on combined
androgen blockade.
 • Secondary hormonal therapy aimed at the androgen biosynthesis
pathway (ketoconazole, abiraterone).
 • Immunotherapy via administration of autologous dendritic cells primed
for recognition of prostatic acid phosphatase (sipuleucel-T).
 • Receptor activator of NFκB (RANK) ligand antibody therapy to slow
development and progression of bone metastases (denosumab).
 • Taxane-based chemotherapy (docetaxel, cabazitaxel).
Prognosis

 Multiple molecular prognostic tests are emerging, specifically with an aim

to better risk stratify both untreated and treated men with localized
prostate cancer.
 ●Studies involving retrospective analysis of tissue from cohorts with clinical
outcomes exist for some of these tests, including Ki-67
immunohistochemistry (IHC), phosphatase and tensin homolog (PTEN) IHC,
and RNA-based tests, such as the cell cycle progression score (Prolaris), the
genomic prostate score (Oncotype DX Prostate), and the genomic
classifier (Decipher).