Prostate Cancer
Prostate cancer is usually adenocarcinoma.
Symptoms are typically absent until tumor growth causes hematuria and/or
obstruction with pain. Diagnosis is suggested by digital rectal examination or
prostate-specific antigen (PSA) measurement and confirmed by transrectal
ultrasound biopsy.
Screening is controversial and should
involve shared decision-making. Prognosis for most patients with prostate
cancer, especially when it is localized or regional (usually before symptoms
develop), is very good; more men die with prostate cancer than of it. Treatment
is with prostatectomy, radiation therapy, palliative measures (eg, hormonal
therapy, radiation therapy, chemotherapy), or, for many older patients and even
carefully selected younger patients, active surveillance.
Prostate cancer usually progresses slowly
and rarely causes symptoms until advanced. In advanced disease, hematuria and
symptoms of bladder outlet obstruction (eg, straining, hesitancy, weak or
intermittent urine stream, a sense of incomplete emptying, terminal dribbling)
or ureteral obstruction (eg, renal colic, flank pain, renal dysfunction) may
appear. Bone pain, pathologic fractures, or spinal cord compression may result
from osteoblastic metastases to bone (commonly pelvis, ribs, vertebral bodies).
Diagnosis of Prostate Cancer
Screening by digital rectal examination
(DRE) and prostate-specific antigen (PSA)
Diagnosis by needle biopsy of the prostate
(most common) or biopsy of metastatic lesion
Grading by histology
Staging by CT/MRI and bone scanning,
possibly prostate-specific membrane antigen (PSMA)–based PET CT
Sometimes stony-hard induration or nodules
are palpable during DRE, but the examination is often normal; induration and
nodularity suggest cancer but must be differentiated from granulomatous
prostatitis, prostate calculi, and other prostate disorders. Extension of
induration to the seminal vesicles and lateral fixation of the gland suggest
locally advanced prostate cancer. Prostate cancers detected by DRE tend to be
large, and > 50% extend through the capsule.
Diagnosis of prostate cancer requires
histologic confirmation, most commonly by transrectal or transperineal
ultrasound–guided needle biopsy, which can be done in an office with use of
local anesthesia or in an operating room under sedation. Hypoechoic areas are
more likely to represent cancer. Occasionally, prostate cancer is diagnosed
incidentally in tissue removed during surgery for benign prostatic hyperplasia
(BPH). Multiparametric MRI can risk-stratify patients for the need for a biopsy
and identify suspect areas that should be targeted. It is now used before
initial biopsy in men with a prior negative biopsy or in men who are on active
surveillance.
Screening
Most cancers today are found by screening
with serum PSA levels (and sometimes DRE). Screening is commonly done annually
in men > 50 years old but is sometimes begun earlier for men at high risk
(eg, those with a family history of prostate cancer and Black men). Screening
is not usually recommended for men with a life expectancy < 10 to 15 years.
Abnormal findings are further investigated with transrectal ultrasound
(TRUS)-guided needle biopsy or transperineal ultrasound-guided needle biopsy.
It is still not certain whether screening
decreases morbidity or mortality or whether any gains resulting from screening
outweigh the decreases in quality of life resulting from treatment of
asymptomatic cancers. Screening is recommended by some professional
organizations and discouraged by others
A level of ≥ 3 ng/mL (3 micrograms [mcg]/L)
is often considered an indication for biopsy in men > 50 years old. Although
very high levels are significant (suggesting extracapsular extension of the
tumor or metastases) and likelihood of cancer increases with increasing PSA
levels, there is no cut-off below which there is no risk.
In asymptomatic patients, positive
predictive value for cancer is 67% for PSA > 10 ng/mL (10 mcg/L) and 25% for
PSA 4 to 10 ng/mL (4 to 10 mcg/L); recent evidence indicates a 15% prevalence
of cancer in men ≥ 55 years old with PSA < 4 ng/mL (4 mcg/L) and a 10%
incidence with PSA between 0.6 and 1.0 ng/mL (0.6 and 1.0 mcg/L). However,
cancer present in men with lower levels (often < 1 mL) tends to be smaller
and of lower grade, although high-grade cancer (Gleason score 7 to 10) can be
present at any level of PSA; perhaps 15% of cancers manifesting with PSA < 4
ng/mL (4 mcg/L) are high grade. Although it appears that a cut-off of 4 ng/mL
(4 mcg/L) will miss some potentially serious cancers, the cost and morbidity
resulting from the increased number of biopsies necessary to find them are
unclear.
The decision whether to biopsy may be
helped by other PSA-related factors, even in the absence of a family history of
prostate cancer. For example, the rate of change in PSA (PSA velocity) should
be < 0.75 ng/mL/yr (0.75 mcg/L/yr; lower in younger patients). Biopsy is
usually recommended for PSA velocities > 0.75 ng/mL/yr (0.75 mcg/L/yr).
Similarly, PSA density (PSA relative to prostate volume) can help guide need
for biopsy; biopsy should be considered if values are ≥ 0.15 (or sometimes ≥
0.10) ng/mL/cc).
Assays that determine the free-to-total PSA
ratio and complex PSA are more tumor specific than standard total PSA
measurements and may reduce the frequency of biopsies in patients without cancer.
Prostate cancer is associated with less free PSA; no standard cut-off has been
established, but generally, levels < 10 to 20% warrant biopsy. Other
isoforms of PSA and new markers for prostate cancer are being studied. None of
these other uses of PSA answers all of the concerns about possibly triggering
too many biopsies. Many new tests (eg, urinary prostate cancer antigen 3
[PCA-3], Prostate Health Index, 4Kscore, urinary SelectMDX, and others) are
available commercially and may be useful aids in screening decisions.
Clinicians should discuss the risks and
benefits of PSA testing with patients. Some patients prefer to eradicate cancer
at all costs—no matter how low the potential for progression and possible
metastasis—and may prefer annual PSA testing. Others may value quality of life
highly and can accept some uncertainty; they may prefer less frequent (or no)
PSA testing.
Men with newly diagnosed prostate cancer
should be offered germline testing and genetic counseling if they have
intraductal histology, metastatic or high-grade localized prostate cancer, a
strong family history of prostate cancer, or a known family history of BRCA1/2
mutations/Lynch syndrome/hereditary breast and ovarian cancer.
Grading and staging
Grading, based on the resemblance of tumor
architecture to normal glandular structure, helps define the aggressiveness of
the tumor. Grading takes into account histologic heterogeneity in the tumor.
The Gleason score is commonly used. The most prevalent pattern and the next
most prevalent pattern are each assigned a grade of 1 to 5, and the two grades
are added to produce a total score. Most experts consider a score ≤ 6 to be
well differentiated, 7 moderately differentiated, and 8 to 10 poorly
differentiated. The lower the score, the less aggressive and invasive is the
tumor and the better is the prognosis. For localized tumors, the Gleason score
helps predict the likelihood of capsular penetration, seminal vesicle invasion,
and spread to lymph nodes. Gleason grades 1 and 2 have now been eliminated; as
a result, the lowest score possible (3 + 3) is 6. However, a Gleason score of 6
does not sound low on a scale previously ranging from 2 to 10.
The grade group is a newer score to help
communicate this to patients, and also to simplify pathologic grading. This new
scoring system was accepted by the World Health Organization (WHO) in 2016:
Grade group 1 = Gleason 3+3
Grade group 2 = Gleason 3+4
Grade group 3 = Gleason 4+3
Grade group 4 = Gleason 8
Grade group 5 = Gleason 9 and 10
Gleason grade group, clinical stage, and
PSA level together (using tables or nomograms) predict pathologic stage and
prognosis better than any of them alone.
Prostate cancer is staged to define extent
of the tumor . Transrectal ultrasonography (TRUS) or MRI of the prostate may
provide information for staging, particularly about capsular penetration and
seminal vesicle invasion. Patients with clinical stage T1c to T2a tumors, low
Gleason score (≤ 7), and PSA < 10 ng/mL (10 mcg/L) usually get no additional
staging tests before proceeding to treatment. Radionuclide bone scans are
rarely helpful for finding bone metastases (they are frequently abnormal
because of the trauma of arthritic changes) until the PSA is > 20 ng/mL (20
mcg/L) or unless the Gleason score is high (ie, ≥ 8 or [4 +3]). CT (or MRI) of
the abdomen and pelvis is commonly done to assess pelvic and retroperitoneal
lymph nodes if the Gleason score is 8 to 10 and the PSA is > 10 ng/mL (10
mcg/L), or if the PSA is > 20 ng/mL (20 mcg/L) with any Gleason score.
Suspect lymph nodes can be further evaluated by using needle biopsy. An MRI may
also help define the local extent of the tumor in patients with locally
advanced prostate cancer (stage T3). The role of PSMA (prostate-specific
membrane antigen) and fluciclovine F18 PET scanning for staging is evolving but
is certainly not needed for early, localized disease.
Elevated serum acid phosphatase—especially
the enzymatic assay—correlates well with the presence of metastases,
particularly in lymph nodes. However, this enzyme may also be elevated in
benign prostatic hyperplasia (BPH)—and is slightly elevated after vigorous
prostatic massage— multiple myeloma, Gaucher disease, and hemolytic anemia. It
is rarely used today to guide treatment or to follow patients after treatment,
especially because its value when done as a radioimmune assay (the way it is
usually done) has not been established. Reverse transcriptase–polymerase chain
reaction assays for circulating prostate cancer cells are being studied as
staging and prognostic tools.
Risk of cancer spread is considered low if
Stage is ≤ T2a
Gleason score is ≤ 6
PSA level is ≤ 10 ng/mL (10 mcg/L)
T2b-c tumor, Gleason score 7, or PSA >
10 ng/mL (10 mcg/L) are considered intermediate risk by most experts. T3 tumor,
Gleason score ≥ 8, or PSA > 20 ng/mL (20 mcg/L; or 2 intermediate risk
factors) are generally high risk.
Risk of cancer spread can be estimated by
tumor stage, Gleason score, and PSA level:
Low risk: Stage ≤ T2a, Gleason score ≤ 6,
and PSA level ≤ 10 ng/mL (10 mcg/L)
Intermediate risk: Stage T2b-c, Gleason
score = 7, or PSA level ≥ 10 (10 mcg/L) and ≤ 20 ng/mL (20 mcg/L)
High risk: Stage ≥ T3, Gleason score ≥ 8,
or PSA ≥ 20 ng/mL (20 mcg/L)
Both acid phosphatase and PSA levels
decrease after treatment and increase with recurrence, but PSA is the most
sensitive marker for monitoring cancer progression and response to treatment
and has virtually replaced acid phosphatase for this purpose.
Prognosis for Prostate Cancer
Prognosis for most patients with prostate
cancer, especially when it is localized or regional, is very good. Life
expectancy for older men with prostate cancer may differ little from
age-matched men without prostate cancer, depending on their age and comorbidities.
For many patients, long-term local control, or even cure, is possible.
Potential for cure, even when cancer is clinically localized, depends on the
tumor’s grade and stage. Without early treatment, patients with high-grade,
poorly differentiated cancer have a poor prognosis. Undifferentiated prostate
cancer, squamous cell carcinoma, and ductal transitional carcinoma respond
poorly to conventional therapies. Metastatic cancer has no cure. Median life
expectancy with metastatic disease is 1 to 3 years, although some patients live
for many years.
Treatment of Prostate Cancer
For localized cancer within the prostate,
surgery, radiation therapy, or active surveillance
For cancer outside of the prostate,
palliation with hormonal therapy, radiation therapy, or chemotherapy
For some men who have low-risk cancers,
active surveillance without treatment
Treatment is guided by prostate-specific
antigen (PSA) level, grade and stage of tumor, patient age, coexisting
disorders, life expectancy, and patient preferences. The goal of therapy can be
Active surveillance
Local (aimed at cure)
Systemic (aimed at decreasing or limiting
tumor extent) and extending quantity and quality of life
Many patients, regardless of age, prefer
definitive therapy if cancer is life-threatening and potentially curable.
However, therapy is palliative rather than definitive if cancer has spread
outside the prostate because cure is unlikely. Watchful waiting can be used for
men unlikely to benefit from definitive therapy (eg, because of older age or
comorbidity); these patients are treated with palliative measures if symptoms
develop.
Active surveillance
Active surveillance is appropriate for many
asymptomatic patients with low-risk, or possibly even intermediate-risk,
localized prostate cancer or if life-limiting disorders coexist; in these
patients, risk of death due to other causes is greater than that due to
prostate cancer. This approach requires periodic digital rectal examination
(DRE), PSA measurement, and monitoring of symptoms. In healthy younger men with
low-risk cancer, active surveillance also requires periodic repeat biopsies.
The optimal interval between biopsies has not been established, but most
experts agree that it should be ≥ 1 year, possibly less frequently if biopsies
have been repeatedly negative. If the cancer progresses, treatment is required.
About 30% of patients undergoing active surveillance eventually require
therapy. In older men, active surveillance results in the same overall survival
rate as prostatectomy; however, patients who had surgery have a significantly
lower risk of distant metastases and disease-specific mortality.
Local therapies
Local therapy is aimed at curing prostate
cancer and may thus also be called definitive therapy. Radical prostatectomy, some
forms of radiation therapy, and cryotherapy are the primary options. Careful
counseling concerning the risks and benefits of these treatments and
considerations of patient-specific characteristics (age, health, tumor
characteristics) are critical in decision making.
Radical prostatectomy (removal of prostate
with seminal vesicles and regional lymph nodes) is probably best for patients
< 75 years old with a tumor confined to the prostate. Prostatectomy is
appropriate for some older men, based on life expectancy, coexisting disorders,
and ability to tolerate surgery and anesthesia. Prostatectomy is done through
an incision in the lower abdomen. More recently, a robot-assisted laparoscopic
approach has been developed that minimizes blood loss and hospital stay but has
not been shown to alter morbidity or mortality. Complications include urinary
incontinence (in about 5 to 10%), bladder neck contracture or urethral
stricture (in about 7 to 20%), erectile dysfunction (in about 30 to
100%—heavily dependent on age and current function), and rectal injury (in 1 to
2%). Nerve-sparing radical prostatectomy reduces the likelihood of erectile
dysfunction but cannot always be done, depending on tumor stage and location.
Cryotherapy (destruction of prostate cancer
cells by freezing with cryoprobes, followed by thawing) is less well
established; long-term outcomes are unknown. Adverse effects include bladder
outlet obstruction, urinary incontinence, erectile dysfunction, and rectal pain
or injury. Cryotherapy is not commonly the therapy of choice in the US but may
be used if radiation therapy is unsuccessful.
Standard external beam radiation therapy
usually delivers 70 grays (Gy) in 7 weeks, but this technique has been
supplanted by conformal 3-dimensional radiation therapy and by
intensity-modulated radiation therapy (IMRT), which safely deliver doses
approaching 80 Gy to the prostate; data indicate that the rate of local control
is higher, especially for high-risk patients. Some decrease in erectile
function occurs in at least 40%. Other adverse effects include radiation
proctitis, cystitis, diarrhea, fatigue, and possibly urethral strictures,
particularly in patients with a prior history of transurethral resection of the
prostate. Results with external-beam radiation therapy, radical prostatectomy,
and active monitoring were shown to be comparable at a median of 10 years after
treatment for localized prostate cancer, as demonstrated in the ProtecT trial (
1). Newer forms of external radiation therapy such as proton therapy are more
costly, and the benefits in men with prostate cancer are not clearly
established. External beam radiation therapy also has a role if cancer is left
after radical prostatectomy or if the PSA level begins to rise after surgery
and no metastasis can be found. Recent evidence also supports the use of
radiation to the prostate in men with low-volume metastatic disease, often
called oligometastatic disease. Recent advances in prostate cancer radiation
therapy include the use of fiducial markers placed around the prostate to
improve targeting. Hydrogel spacers can be placed by transrectal needle
placement to help reduce rectal toxicity. The hydrogel spacers resorb with
time. Hypofractionation is an evolving concept in radiation treatment, in which
the total dose of radiation is divided into large doses and treatments are
given once a day or less often. Hypofractionated radiation therapy is given
over a shorter period of time (fewer days or weeks) than standard radiation
therapy.
Brachytherapy involves the implantation of
radioactive seeds into the prostate through the perineum. These seeds emit a
burst of radiation over a finite period (usually 3 to 6 months) and are then
inert. Research protocols are examining whether high-quality implants used as
monotherapy or implants plus external beam radiation therapy are superior for
intermediate-risk patients. Brachytherapy also decreases erectile function,
although onset may be delayed and patients may be more responsive to
phosphodiesterase type 5 inhibitors than patients whose neurovascular bundles
are resected or injured during surgery. Urinary frequency, urgency, and, less
often, retention are common but usually subside over time. Other adverse
effects include increased bowel movements; rectal urgency, bleeding, or
ulceration; and prostatorectal fistulas.
HIFU (high-intensity focused ultrasound)
uses intense ultrasound energy administered transrectally to ablate prostate
tissue. It has been used for many years in Europe and Canada and has recently
become available in the US. The role of this technology in the management of
prostate cancer is evolving; presently, it appears to be best suited for
radiation-recurrent prostate cancer.
If cancer localized to the prostate is high
risk, various therapies may need to be combined (eg, for high-risk prostate
cancer treated with external beam radiation, addition of hormonal therapy for
periods varying from 6 months to 2 to 3 years.).
Systemic therapies
If cancer has spread beyond the prostate
gland, cure is unlikely; systemic treatment aimed at decreasing or limiting
tumor extent is usually given.
Patients with a locally advanced tumor or
metastases may benefit from androgen deprivation therapy (ADT) by castration,
either surgically with bilateral orchiectomy or medically with luteinizing
hormone-releasing hormone (LHRH) agonists, such as leuprolide, goserelin,
triptorelin, histrelin, and buserelin, with or without radiation therapy. LHRH
antagonists (eg, degarelix, relugolix) can also lower the testosterone level,
usually more rapidly than LHRH agonists. LHRH agonists and LHRH antagonists
usually reduce serum testosterone almost as much as bilateral orchiectomy.
Androgen-receptor targeted therapies (abiraterone acetate with prednisone,
enzalutamide, or apalutamide) or chemotherapy (with docetaxel) can be given in
combination with ADT; choice of therapy is determined by volume of metastatic
disease and patient comorbidities.
All androgen-deprivation treatments cause
loss of libido and erectile dysfunction and may cause hot flushes. LHRH
agonists may cause PSA levels to increase temporarily. Some patients benefit
from adding antiandrogens (eg, flutamide, bicalutamide, nilutamide, cyproterone
acetate [not available in US]) for total androgen blockade. Combined androgen
blockade usually refers to LHRH agonists plus antiandrogens, but its benefits
appear minimally better than those of an LHRH agonist (or LHRH antagonist or
orchiectomy) alone. Another approach is intermittent androgen blockade, which
purports to delay emergence of androgen-independent prostate cancer and helps
to limit some adverse effects of androgen deprivation. Total androgen ablation
is given until PSA levels are reduced (usually to undetectable levels), then
stopped. Treatment is started again when PSA levels rise above a certain
threshold, although the ideal threshold is not yet defined. The optimal
schedules for treatment and time-off treatment have not been determined and
vary widely among practitioners.
Androgen deprivation may impair quality of
life significantly (eg, self-image, attitude toward the cancer and its
treatment, energy levels) and cause osteoporosis, anemia, and loss of muscle
mass with long-term treatment. Exogenous estrogens are rarely used because they
have a risk of cardiovascular and thromboembolic complications.
Hormonal therapy is effective in metastatic
prostate cancer for a limited amount of time. Cancer that progresses (indicated
by an increasing PSA level) despite a testosterone level consistent with castration
(< 50 ng/dL [1.74 nmol/L]) is classified as castrate-resistant prostate
cancer. Castrate-resistant prostate cancer (CRPC) can be further classified as
M0 (nonmetastatic) CRPC or M1 (metastatic) prostate cancer. An increasing PSA
despite low testosterone and absence of lesions on CT or bone scan is
nonmetastatic prostate cancer. Risk of metastases is high. Apalutamide,
darolutamide and enzalutamide are now available and can slow progression from
M0 to M1 CRPC. Treatments that prolong survival in metastatic CRPC (many
identified since 2010) include
Docetaxel (a taxane chemotherapy drug)
Sipuleucel-T (a patient-derived vaccine
designed to induce immunity against prostate cancer cells)
Abiraterone (which blocks androgen
synthesis in the tumor as well as in the testes and adrenal glands)
Enzalutamide, darolutamide, apalutamide
(which blocks binding of androgens to their receptors)
Cabazitaxel (a taxane chemotherapy drug
that may have activity in tumors that have become resistant to docetaxel)
Radium-233 (which emits alpha radiation,
recently found to prolong survival as well as prevent complications due to bone
metastases in men with CRPC)
PARP (poly [ADP-ribose]) inhibitors
(olaparib, rucaparib) appear active in mCRPC patients with BRCA1/2 mutations
Some data suggest that sipuleucel-T should
be used at the earliest sign of CRPC. In general, treatments for
castrate-resistant prostate cancer are being tried earlier during the course of
prostate cancer and are now showing benefit in hormone-sensitive metastatic prostate
cancer. However, choice of treatment may involve many factors, and few data may
be available to help predict results; thus patient education and shared
decision-making are recommended.
To help treat and prevent complications due
to bone metastases (eg, pathologic fractures, pain, spinal cord compression),
an osteoclast inhibitor (eg, denosumab, zoledronic acid) can be used.
Traditional external beam radiation therapy has been used to treat individual
bone metastases.
Key Points
Prostate cancer develops very commonly with
aging but is not always clinically important.
Symptoms develop only after the cancer has
enlarged enough to be more difficult to cure.
Complications due to bone metastases are
common and consequential.
Diagnose prostate cancer by transrectal
ultrasound-guided needle biopsy.
Discuss advantages and disadvantages of
screening in men > age 50 with life expectancy > 10 or 15 years.
For localized prostate cancer, consider
local, curative treatment (eg, prostatectomy, radiation therapy) and active
surveillance.
For cancer that has spread beyond the
prostate, consider systemic treatments (eg, various hormonal therapies,
sipuleucel-T, taxane chemotherapy).
For bone metastases, consider radium-233
and osteoclast inhibitors.