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14
Prostate Cancer
Ravi A. Madan and William L. Dahut
EPIDEMIOLOGY
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Prostate cancer (CaP) is the most common noncutaneous malignancy and the second most frequent
cause of cancer-related mortality in men in the United States; in 2013 there will be an estimated
238,590 men diagnosed with CaP and 29,720 deaths from the disease.
The frequency of clinically aggressive disease varies geographically, but the frequency of occult
tumors does not, suggesting the influence of environmental factors in the etiology of CaP. Studies of
Japanese immigrants to the United States show that the incidence of CaP increases after immigration.
RISK FACTORS
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Age: Risk increases progressively with age, with about 70% of cases in men over the age of 65.
Family history: Risk increases twofold with a first-degree relative diagnosed with CaP, fivefold with
two first-degree relatives.
Race: In the United States, incidence is highest among African Americans, followed by whites, then
Asians. African-American men are more likely to be diagnosed with advanced disease and have a
greater than twofold risk of death from the disease.
Geography: Risk is lowest in Asia, high in Scandinavia and the United States.
Diet: Consumption of red meat and animal fat has been associated with CaP, while eating cruciferous
vegetables, soy products, and lycopene-containing tomato products may be protective.
CHEMOPREVENTION TRIALS
5-𝛂 Reductase Inhibitors
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Two clinical trials have evaluated the ability of 5-α reductase inhibitors to prevent CaP in asymptomatic men older than 50 years.
In the Prostate Cancer Prevention trial, finasteride was compared to placebo in more than 9,000 men.
There was a reduction in the incidence of CaP from 24.8% in the placebo arm to 18.4% in the finasteride arm within 7 years (P < 0.001).
In the REDUCE trial, 8,321 men randomized to receive either dutasteride or placebo. Again, there
was a reduction in the incidence of CaP in the treatment arm by 22.8% over the 4-year study period
(P < 0.001).
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Both of these therapies are approved for benign prostatic hyperplasia-related symptoms but are not
approved for CaP prevention.
Both of these prevention studies found an increase in the percentage of aggressive tumors (Gleason
score 7 to 10) in patients treated with the respective 5-α reductase inhibitors compared to the placebo.
Subsequent pathology reviews of prostatectomy specimens did not confirm this increase, indicating
potential sampling bias in the biopsies, perhaps due to a preferential reduction in normal versus
tumor tissue caused by the effect of the 5-α reductase inhibitors. Without a definitive explanation for
these findings, enthusiasm to use these agents for prevention of CaP has been significantly diminished. Perhaps longer follow-up will provide additional data to better characterize these findings.
Selenium and Vitamin E Cancer Prevention Trial
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Retrospective data from two previous chemoprevention trials have suggested a preventive role
for selenium and vitamin E supplementation. Selenium and Vitamin E Cancer Prevention Trial
(SELECT) enrolled over 35,533 men at least 50 years old and found that selenium and vitamin E,
alone or in combination, did not prevent CaP.
SCREENING
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Screening for CaP involves testing for levels of PSA and/or DRE. Screening of asymptomatic men is controversial. Debate centers on whether biologically and clinically significant cancers are being detected
early enough to reduce mortality or, conversely, whether cancers detected by screening would cause
clinically significant disease if left undetected and untreated. Autopsy series have shown that more men
die with, rather than from, CaP, and the rate of occult CaP in men in their 80s is approximately 75%.
The Prostate, Lung, Colon, and Ovary (PLCO) screening trial and the European Study on Screening
for Prostate Cancer are evaluating clinical outcomes based on screening versus no screening. Preliminary data from the PLCO trial reveal that the rate of death from CaP was very low and did not differ
significantly between subjects assigned to screening or no screening, with 7 to 10 years of follow-up.
One caveat is that a high number of patients (about 50%) in the control arm obtained PSA screening
outside of the clinical trial.
Preliminary data from the European study suggest that PSA screening was associated with a reduction in rate of death from CaP by 20% after a median follow-up of 9 years. However, 1,410 men would
need to be screened and 48 additional cases of CaP would need to be treated to prevent one death
from CaP. Final results for these studies are expected in the coming years and may provide more
conclusive data.
Despite the controversy, PSA screening in the United States is widespread. Most advocates recommend annual screening beginning at age 50 for average-risk men and at age 40 for African-American
men and men with a family history of CaP.
• Most advocates of screening acknowledge the limited benefits in men who are over 75 years of
age or men with less than 10 years of projected survival due to other comorbidities. It is likely that
most men who fall in this category will not have their lifespan limited by CaP and thus screening
may be unnecessary.
Frank discussions with patients about the risks and potential benefits of screening should be standard
practice.
SIGNS AND SYMPTOMS
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With PSA screening now widely practiced in the United States, most men are asymptomatic at
diagnosis.
Patients with local or regional disease may be asymptomatic or have lower urinary tract symptoms similar to those of benign prostatic hypertrophy. Men with regional disease occasionally have
hematuria.
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Symptoms of metastatic disease include bone pain and weight loss; spinal cord compression is a rare
but serious complication of metastatic disease.
WORKUP AND STAGING
Biopsy
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Abnormal PSA and/or DRE is followed by transrectal ultrasound with core biopsy (generally 10 to
12 cores). Historically, a PSA of >4 ng/mL was the threshold for biopsy, but recent data suggest that
cancers can be seen with lower PSA levels. In recent years a greater emphasis has also been placed on
rate of PSA rise as a trigger for biopsy. A negative biopsy should prompt reassessment in 6 months
with repeat biopsy as needed.
Pathology
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Ninety-five percent of CaPs are adenocarcinomas. Adenocarcinoma arises in the peripheral zone of
the prostate in approximately 70% of patients.
Sarcoma, lymphoma, small cell carcinoma, and transitional carcinoma of the prostate are rare.
Although visceral or osteolytic bone metastases are found in a few patients with metastatic adenocarcinoma of the prostate, careful pathologic examination should be performed to rule out a nonadenocarcinoma variant, as treatment regimens differ.
Primary and secondary Gleason grades are determined by the histologic architecture of biopsy
tissue. The primary grade denotes the dominant histologic pattern; the secondary grade represents
the bulk of the nondominant pattern or a focal high-grade area. Primary and secondary grades
range from 1 (well differentiated) to 5 (poorly differentiated). The combined grades comprise the
GS (range 2 to 10). There is no role in re-evaluating GS once treatment has begun.
There is growing consensus that the highest GS is most predictive of clinical outcome. With current
grading practices, scores <6 are very rare. A GS of 8 to 10 represents poorly differentiated CaP that
is likely to be clinically aggressive.
Because of sampling bias, GS may change following radical prostatectomy (RP) (20% of scores are
upgraded and up to 10% are downgraded).
Prostatic intraepithelial neoplasia (PIN), and perhaps proliferative inflammatory atrophy (PIA), are
considered precursor lesions.
Baseline Evaluation
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In candidates for local treatment, a bone scan is indicated for patients with bone pain, T3 or T4, GS
>7, or PSA >10 ng/mL. There is no clinical evidence that a baseline bone scan improves survival in
patients with better prognostic factors.
In candidates for surgery, computed tomography (CT) or magnetic resonance imaging (MRI) of the
abdomen and pelvis is obtained for T3 and T4 lesions, PSA >20 ng/mL, or GS >7 to detect enlarged
lymph nodes. Endorectal MRI may help in determining the presence of extraprostatic extension.
CT scans aid in treatment planning for radiation therapy (RT).
Baseline laboratory tests include complete blood count, creatinine level, PSA (if not yet done), testosterone and alkaline phosphatase level.
PROGNOSTIC FACTORS
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Stage at diagnosis
Gleason grade/score
PSA level
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Number of cores and percentage of each core involved
Age at diagnosis
TREATMENT OF LOCALIZED DISEASE
Active Surveillance
For men aged 60 to 75 years with a >10-year life expectancy or low-grade (GS ≤ 6), T1c-T2a tumors,
active surveillance is a reasonable alternative to immediate local therapy (Fig. 14.1). In addition, men
aged 50 to 60 years with those same features and low-volume (<3 cores, <50% of any one core involved)
tumor may also be candidates for active surveillance. For patients with a <10-year life expectancy, CaPspecific mortality is very low and local definitive therapy may not be appropriate.
Surgery
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Radical Prostatectomy
Approaches include retropubic (RRP), perineal (RPP), or laparoscopic, with the latter often done with
robotic assistance (RALP). Typical hospital stays are 1 to 2 days, with 7 to 14 days of urethral catheterization. Surgeries are somewhat longer with RALP, but hospital stays are usually shorter.
Pelvic lymph node dissection may be performed at the time of RP in patients at high risk of developing positive lymph nodes, but may not be necessary in patients with T1c disease, PSA <10 ng/mL,
and GS <7.
Nerve-sparing RP may conserve potency in men with disease not adjacent to the neurovascular
bundles that travel posterior-lateral to the prostate. The bilateral nerve-sparing technique is associated with 60% to 90% of patients recovering spontaneous erections versus only 10% to 50% with the
unilateral technique. Both groups, however, may respond to oral therapy for erectile dysfunction.
There is no role for neoadjuvant androgen-deprivation therapy (ADT) prior to RP, although ongoing
studies in high-risk patients are evaluating ADT with modern antiandrogens to determine the potential to debulk tumor prior to RP.
Patients with microscopic lymph node metastasis diagnosed following RP may have a longer overall
survival (OS) if given ADT rather than at time of clinical recurrence.
Salvage RP following RT may be done in select cases where local disease is organ confined. However,
salvage RP is more technically demanding and is associated with higher morbidity.
Initial Diagnosis
of Prostate
Cancer
Low-Risk Features
Surveillance may be an
option for selected patients,
although some patients
may elect surgery or
radiation.
Intermediate-Risk Features
Surgery and radiation
therapy (possibly with shortcourse ADT) are both options.
Surveillance may also be an
option in selected patients.
High-Risk Features
Radiation therapy with 2 or 3
years of ADT is the common
recommendation, but surgery
may be an option in
selected patients.
FIGURE 14.1 Treatment options for patients diagnosed with localized prostate therapy. RT can include
EBRT or brachytherapy (generally reserved for select patients with intermediate- or low-risk disease), or
a combination of the two in some high-risk cases.
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Surgical Complications
Immediate morbidity or mortality: 2%.
Impotence: 35% to 60%.
Urinary incontinence: 10% with frank incontinence; up to 60% require protective garments.
Urinary structure.
Fecal incontinence: retropubic approach, approximately 5%; perineal approach, 18%.
The Prostate Cancer Outcomes Study found statistically significant differences in outcomes following
RP or RT. For patients with normal baseline function, RP was associated with inferior urinary function, better bowel function, and similar sexual dysfunction compared with RT.
Focal Therapy for Disease Confined to a Region of the Prostate
Focal therapy for newly diagnosed CaP confined to a limited area of the prostate remains investigational. This strategy is different from other therapies for localized disease in that only a focal region of
the prostate, as opposed to the entire glad, is targeted with hopes of limiting side effects. Cryosurgery
destroys CaP cells through probes that subject prostate tissue to freezing followed by thawing. This procedure is associated with high rates of erectile dysfunction due to freezing of the neurovascular bundle.
Additional focal therapy strategies include thermal ablation via laser or high-intensity focused ultrasound among other techniques. There are limited data on long-term outcomes for focal therapy. Thus, at
most centers prostate focal therapies are largely performed as salvage procedures.
Radiation Therapy
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External Beam RT
External beam RT (EBRT) targets the whole prostate, frequently including a margin of extraprostatic
tissue, seminal vesicles, and pelvic lymph nodes.
Higher doses (≥78 Gy) given over approximately 8 weeks are associated with higher PSA control
rates; however, survival data are not mature.
Three-dimensional (3D) conformal RT allows for maximal doses conforming to the treatment field,
while sparing normal tissue.
Intensity-modulated RT is a type of 3D conformal RT that is designed to conform even more precisely
to the target.
Unlike x-rays, which radiate beyond the target volume, proton beam irradiation focuses virtually all
its energy within a very small area, thus theoretically minimizing damage to normal tissue.
RT with Adjuvant ADT
At least three randomized controlled trials have shown that combining ADT with RT in patients at
high risk for recurrent disease (Table 14.1) improves OS. ADT is usually given during RT and for 2 to
3 years thereafter. It may also be used for 2 months prior to RT to help decrease tumor size and thus the
target volume of RT.
Table 14.1 Risk Categories for Posttherapy Prostate-Specific Antigen Failure
Stage
PSA
Gleason score
Qualifier
Low
Intermediate
High
T1c, T2a
<10
≤6
and
T2b
10–20
7
or
T2c
>20
≥8
or
Adapted from D’Amico AV, Whittington R, Malkowicz SB, et al. Optimizing patient selection for dose escalation techniques using the
prostate-specific antigen level, biopsy Gleason score, and clinical T-stage. Int J Radiat Oncol Biol Phys. 1999;45(5):1227-1233.
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Adjuvant RT
General indications for the use of adjuvant RT after RP include positive surgical margins, seminal
vesicle involvement, and evidence of extracapsular extension. Nonetheless, the potential for cure with
adjuvant RT will vary significantly from patient to patient and thus the risks and benefits of adjuvant
RT should be evaluated in each case individually.
Salvage RT
For select patients with rising PSA after RP and a high likelihood of organ-confined local recurrence
(e.g., PSA <1.5 and slowly rising), salvage RT may be considered. However, there are limited data on
which to make recommendations.
Brachytherapy
Interstitial brachytherapy with radioactive palladium or iodine seeds that delivers a much higher
dose of radiation to the prostate is used in CaP patients with low-risk tumors and some intermediaterisk patients. Better definitions of tumor volume and radiation dosimetry have made this outpatient
technique more accurate. CT and/or transrectal ultrasound are used to guide seed placement.
Combined EBRT and Brachytherapy
EBRT followed by brachytherapy boost is an increasingly used strategy. Preliminary clinical data
support the safety and efficacy of this approach in a selected population of patients. Long-term clinical
data including OS data from randomized trials are still pending. Nonetheless, some radiation oncologists are using this treatment combination in patients with high-risk disease.
Complications of RT
Acute
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Cystitis
Proctitis/enteritis
Fatigue
Long term
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Impotence
Incontinence (3%)
Frequent bowel movements (10% more than with RP)
Urethral stricture (RT delayed 4 weeks after transurethral resection of the prostate)
COMPARISON OF PRIMARY TREATMENT MODALITIES
Comparing treatment modalities in terms of overall and disease-free survival is difficult because of differences in study design, patient selection, and treatment techniques.
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While there have been no satisfactory randomized trials comparing RT with RP, these approaches
appear to have equivalent PSA-free survival (also called biochemical relapse-free survival) in appropriately matched patients at 5 years, but differ in type and frequency of side effects.
Brachytherapy appears promising, although most studies have been conducted only in patients with
early-stage, low-grade disease. One comparison of 3D conformational RT with 125I implants in comparable patients concluded that these modalities had equivalent efficacy, with higher urinary complications in the brachytherapy group.
FOLLOW-UP AFTER DEFINITIVE TREATMENT
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Patients treated with curative intent should have PSA levels checked at least every 6 months for
5 years, then annually. Annual DRE is appropriate for detecting recurrence.
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After RP, a detectable PSA suggests a relapse. PSA failure after RT is defined as 2 ng/mL over the nadir,
whether or not the patient had ADT with RT.
TREATMENT FOR MEN WITH RISING PSA AFTER
LOCAL THERAPY
Treatment for patients who have rising PSA (biochemical failure) after local therapy has not been
standardized and participation in clinical trials should be encouraged (Fig. 14.2). As previously
mentioned salvage RT, salvage RP, or salvage focal therapy may be offered to select patients with
local recurrence. ADT effectively lowers PSA and can be given intermittently to provide periods
of normal testosterone. Based on preliminary results from randomized studies, CaP-specific outcomes with intermittent and continuous ADT appear to be similar. However, there are no data
suggesting better survival with ADT than with no ADT. Recent data suggest that on average, men
live about 14 years after biochemical failure. Thus a more conservative approach (e.g., treating
Biochemical Recurrence
(Rising PSA after definitive
therapy with no evidence of
metastatic disease)
Salvage Radiation
May be considered in selected
patients who were initially treated
with surgery, depending on PSA
value, rate of rise, and time
from surgery.
Intermittent
ADT
Surveillance of PSA Values
Although there are limited data, it may
be reasonable to withhold ADT
until the PSA-doubling time is less
than 3–6 months. (Patients can be
evaluated every 2–3 months to
determine doubling time.)
Continuous
ADT
Continuous
ADT
FIGURE 14.2 Treatment options for biochemical recurrence/nonmetastatic castration-sensitive prostate
cancer. Continuous ADT employs repeated doses of GnRH agonists/antagonists to provide a constant
testosterone suppression. Orchiectomy would also be an option. Intermittent ADT employs two or three
doses of testosterone-lowering therapy, which are then discontinued if the PSA declines as expected. From
there, PSA slowly recovers, lagging behind testosterone recovery. In selected patients, this approach can be
used to alleviate some ADT toxicity. ADT is often reinstituted based on a PSA doubling time similar to the
“surveillance of PSA” approach described in the figure.
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when symptomatic) is a reasonable option for many men. Alternatively, using PSA-doubling time
(i.e., less than 3 to 6 months) as a trigger to initiate ADT or intermittent ADT is frequently done in
clinical practice; however, no randomized trials have prospectively evaluated this approach relative
to continuous or delayed ADT based on doubling time.
TREATMENT OF SYSTEMIC DISEASE
Response Criteria: Using PSA, a Historical Perspective
Only 40% of patients with castration-resistant prostate cancer (CRPC), or progressing disease despite
castrate levels of testosterone, have soft tissue disease. Therefore, PSA historically has been an important
tumor marker for preliminary assessment of efficacy in proof-of-principle trials. PSA response rates
(PRRs) are defined as percentage of patients with a PSA decline >50%, a traditionally used criterion.
Because of differences in patient selection, it is difficult to compare clinical trials by PRRs alone. Many
trials now include all PSA declines in a “waterfall plot.” It is important to note that some agents (particularly cytostatic agents) may upregulate or downregulate PSA expression independent of their effect
on cancer growth. Definitive studies historically have utilized skeletal-related events, palliation of symptoms, or OS for CRPC.
EVOLUTION OF RESPONSE CRITERIA IN
METASTATIC DISEASE
The Prostate Cancer Working Group 2 and the Implications for
Clinical Practice
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As the understanding of CaP has evolved in the last decade, in the context of new available therapies
and greater experience with older therapies, a general consensus was generated by Prostate Cancer
Working Group 2 (PSWG2) on determining response in clinical trials.
Perhaps most importantly, PSA should not be used as the sole criteria to discontinue a therapy.
Furthermore, the PSWG2 recommends that early changes in PSA and modest increases in pain,
which could represent a tumor flare phenomenon, should not result in the discontinuation of
therapy.
For patients with metastatic CaP, objective changes on imaging studies (CT and bone scan) should be
the primary criteria used to assess progression of disease in the absence of clear clinical progression
of symptoms.
In order to assess imaging, lymph nodes less than 2 cm in diameter are too small to be evaluated for
response or progression of disease.
Two new bone lesions on bone scan are required to document progressive disease, with one important exception. New lesions on the first bone scan should trigger another bone scan 6 or more weeks
later, as these new lesions may have been present on the first scan, but missed on initial imaging or
they may represent a the “tumor flare phenomenon.” If the second (and subsequent) bone scans show
less than two new lesions and the patient is otherwise clinically stable, he should be considered to
have stable disease.
For the treatment of patients outside of clinical trials the implications of the PCWG2 are as follows:
• Radiographic response criteria should be used to determine disease progression in metastatic CaP
as opposed to PSA alone.
• Initial changes on bone scan are not sufficient to remove patients from a treatment; patients could
continue therapy if subsequent bone scans show less than two new lesions.
• Changes in lymph nodes less than 2 cm in diameter should be interpreted with caution.
• PSA should still be followed but interpreted with caution and not be used as the sole criteria to
determine when to discontinue a therapy.
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ANDROGEN-DEPRIVATION THERAPY
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ADT is the mainstay of treatment for metastatic CaP (Table 14.2). However, as discussed previously,
it has also been used to treat localized disease and in neoadjuvant and adjuvant settings with RT. CaP
cells usually respond to hormonal manipulations that block the production of androgens, producing
durable remissions and significant palliation. Duration of response ranges from 12 to 18 months, with
20% of patients having a complete biochemical response at 5 years. However, ultimately, CRPC cells
emerge and lead to disease progression.
Table 14.2 Systemic Therapies for Prostate Cancer
Treatment
Dose
Most Common Side Effects
Bilateral orchiectomy
n/a
Impotence, loss of libido, gynecomastia,
hot flashes, and osteoporosis
GnRH Angonists (Most Common Formulations)
Goserelin acetate
(Zoladex)
3.6 mg SC every month or
10.8 mg SC every 3 mo
Leuprolide acetate
(Lupron)
7.5 mg SC every month or
22.5 mg i.m. every 3 mo, or
30 mg SC every 4 mo
Potential for tumor flare due to transient
initial increase in testosterone, loss of
libido, gynecomastia, hot flashes, and
osteoporosis
Potential for tumor flare due to transient
initial increase in testosterone, loss of
libido, gynecomastia, hot flashes, and
osteoporosis
GnRH Agonist
Degarelix (Firmagon)
240 mg SC initial dose followed
by 80 mg SC every 28 d
Hot flashes, weight gain, erectile
dysfunction, loss of libido, hypertension,
hepatotoxicity, gyecomastia, and
osteoporosis
Androgen Receptor Antagonists (ARAs)
Bicalutamide
(Casodex)
Flutamide (Eulexin)
50 mg PO daily
Nilutamide
(Nilandron)
150 mg PO daily
250 mg PO three times per day
Nausea, breast tenderness, hepatotoxicity,
hot flashes, loss of libido, and impotence
Diarrhea, nausea, breast tenderness,
hepatotoxicity, loss of libido, and
impotence
Visual field changes (night blindness or
abnormal adaptation to darkness),
hepatotoxicity, impotence, loss of libido,
hot flashes, nausea, disulfiram-like
reaction, and pulmonary fibrosis (rare)
Androgen Biosynthesis Inhibitors
Ketoconazole
(Nizoral)
200 or 400 mg PO 3 times a day
with hydrocortisone 20 mg
PO in the morning and 10 mg
in the evening. (Ketoconazole
is absorbed at an acidic pH;
therefore, the concomitant
use of H2 blockers, antacids,
or proton pump inhibitors
should be avoided.)
Adrenal insufficiency is limited with
physiologic dosing of hydrocortisone.
Other side effects include impotence,
pruritus, nail changes, adrenal
insufficiency, nausea, emesis, and
hepatotoxicity. (Ketoconazole is a
potent inhibitor of CYP3A4, and thus
multiple drug interactions are possible
so review of medications is important.)
(Continued )
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Table 14.2 (Continued)
Abiraterone (Zytiga)
1,000 mg PO daily (on an
empty stomach) Taken with
prednisone 5 mg PO twice
a day
Peripheral edema, hypertension, fatigue,
hypokalemia, hypernatremia, increased
triglycerides, hepatotoxicity, and
hot flashes. (Abiraterone is a potent
inhibitor of CYP3A4, and thus multiple
drug interactions are possible, so review
of medications is important.)
Androgen Receptor Inhibitor
Enzaluatmide
160 mg PO once daily
Hot flashes, diarrhea, peripheral edema,
fatigue, arthralgia, and musculoskeletal
pain. Limited risk of seizures (less than
1%) but care should be taken in patients
with seizure history or those who are
on medications that may lower the
seizure threshold
Immunotherapy
Infusion of ≥50 million
autologous CD54+ cells
after ex vivo cellular
processing given every 2 wk
for three total doses
Chemotherapy Regimens
Fatigue, fever, chills, headache, nausea,
emesis, myalgias, and infusion reaction
symptoms
Docetaxel
(Taxotere)
75 mg mg/m2 IV every 21 d
with prednisone 5 mg PO
twice daily
Cabazitaxel (Jevtana)
25 mg mg/m2 IV every 21 d
with prednisone 5 mg PO
twice daily
Mitoxantrone
(Novantrone)
12–14 mg mg/m2 IV every 21
d with prednisone 5 mg PO
twice daily
Docetaxel at 60 mg/m2 with
carboplatin AUC 4 every 21 d
with daily prednisone 5 mg PO
twice daily
Granulocytopenia, infection, anemia,
fatigue, anemia, neutropenia, fluid
retention, sensory neuropathy, nausea,
fatigue, myalgia, and alopecia
Myelosuppression, infection, fatigue/
weakness, fever, diarrhea, nausea, emesis,
peripheral neuropathy, arthralgias,
peripheral edema, alopecia, and dyspepsia
Edema, myelosuppresion, cardiac toxicity,
fever, fatigue, alopecia, nausea, diarrhea,
infection, and hepatotoxicity
Myelosuppression, infection, hyperglycemia,
hypoglycemia, pain, renal failure, and
thrombosis. (These were seen in limited
experience with 34 patients.)
Sipuleucel-T
(Provenge)
Docetaxel (Taxotere)
+ carboplatin
(Paraplatin)
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Bilateral surgical castration and depot injections of GnRH agonists (e.g., leuprolide, goserelin, and
buserelin) and a GnRH antagonist (degarelix) provide equally effective testosterone suppression.
Combined androgen blockade can be achieved by adding an oral androgen receptor antagonist (ARA;
e.g., nilutamide, flutamide, and bicalutamide). However, this is controversial and provides little if any
survival benefit.
GnRH agonists initially increase gonadotropin, causing a transient (∼14-day) increase in testosterone that can lead to tumor flare. A lower tumor volume reduces the risk of symptomatic tumor flare.
Tumor flare can be prevented by the use of an ARA, which binds to the androgen receptor (AR),
effectively stopping the ability of the AR to activate cell growth. An ARA is often given for 1 to 2 weeks
prior to GnRH agonist in patients at risk for complications (pain, obstruction, and cord compression) associated with tumor flare. For high-risk patients, bilateral orchiectomy or ketoconazole can
decrease testosterone more quickly.
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In patients initially treated with GnRH agonist or surgical castration alone, the addition of an ARA
may produce PSA declines or symptomatic improvement in up to 40% of patients.
• The use of the GnRH antagonist (degarelix) obviates the concern for tumor flare as it leads to more
rapid reduction in testosterone without an initial increase in serum testosterone levels. For this
reason, it may be preferred in the setting of initial treatment for men diagnosed with symptomatic
metastatic disease.
Continuing testosterone suppression after patients develop CRPC is also considered the standard of
care for both nonmetastatic and metastatic disease. Androgens still play a very important role in driving the growth of CRPC, as evidenced by the benefits seen with new antiandrogen therapy (enzalutamide and abiraterone) in metastatic CRPC (mCRPC). Levels of AR and intracellular androgens
within the tumor cells are significantly elevated in these patients and thus continuing ADT indefinitely in CRPC is recommended.
TREATMENT OF NONMETASTATIC CASTRATION-RESISTANT
PROSTATE CANCER AND THE USE OF SECOND-LINE ARAs
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Through the development of resistance mechanisms such as upregulation of the AR or intratumoral production of androgens, patients may develop progressive disease despite castration levels
of testosterone.
For patients with a rising PSA but no evidence of metastatic disease ARAs can be added to ADT in
order to provide a combined androgen blockade, which may delay disease progression or the development of metastasis, although clinical evidence supporting this is limited.
Upon progression of disease with ARA and ADT, it is important to note that that up to 20% of patients
treated with combined androgen blockade have a PSA decline of ≥50% upon discontinuation of oral
ARA (range, 15% to 33%), although these declines generally last only 3 to 5 months. This proportion
may be lower with shorter-term use ARA use. This ARA withdrawal response occurs within 4 to
6 weeks, depending on the ARA’s half-life.
Some patients with rising PSA (and still no evidence of metastasis) after ARA withdrawal may benefit
from switching to other ARAs or initiating treatment with ketoconazole. A proportion of patients
(35% to 50%) will have PSA declines with second-line and even third-line antiandrogen therapy.
Ketoconazole is a nonspecific inhibitor of secondary androgen production which may include
both adrenal production and production of androgens by the tumor itself, a well-described mechanism of CaP resistance to castrate levels of testosterone. Ketoconazole can be combined with
ADT to treat non-mCRPC, although ARAs are usually preferred because ARAs are better tolerated. When used, ketoconazole is combined with physiologic replacement of hydrocortisone to
compensate for its impact on steroidgenesis within the adrenal glands which could lead to adrenal
insufficiency.
TREATMENT FOR METASTATIC CASTRATION-RESISTANT
PROSTATE CANCER
Multiple treatment options are now available for the treatment of mCRPC as opposed to prior to 2010
when only docetaxel had demonstrated the ability to extend survival in this population. Given multiple
forms of therapy including immunotherapy, chemotherapy, radiopharmaceuticals, and modern antiandrogen therapy, symptoms and pace of disease will likely dictate which treatments are most appropriate
for each individual patient (Fig. 14.3).
Immunotherapy
■■
Sipuleucel-T (Provenge)—is an activated cellular therapy that is derived from a patient’s own immune
cells which are collected via leukapheresis. Once removed from circulation, the peripheral immune
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Assessment of
pain/symptoms, and
pace of disease
Minimal or no
pain/symptoms:
Sipuleucel-T,
Abiraterone,
Enzalutamide1
Progressive disease
with minimal or no
pain/symptoms:
Sipuleucel-T,
Abiraterone,
Enzalutamide1, 3
Progressive disease
with increasing pain/
symptoms/pace of
disease: Docetaxel
Moderate or
significant pain/
symptoms or rapidly
progressing disease:
Docetaxel2
Progressive
disease with
stable symptoms:
Abiraterone,
Enzalutamide3
Progressive disease
with increasing
pain/symptoms/pace
of disease:
Cabazitaxel4
FIGURE 14.3 Suggested treatment approach for patients with metastatic castration-resistant prostate
cancer. (1) Second-line antiandrogen therapies such as androgen receptor antagonists and ketoconazole
could also be used. (2) Abiraterone or enzalutamide may also be an option in asymptomatic patients with
rapid disease progression. (3) These agents may be given sequentially if there is disease progression after
the initial treatment. (4) Radiopharmaceuticals could also have a role in patients with symptomatic disease.
■■
■■
cells are sent to a central processing facility where there are exposed to a fusion peptide of PAPGMCSF for 48 hours. The goal is to activate immune cells via ex vivo processing so that when they are
reinfused into the patient, they generate an immune-mediated antitumor response.
Although sipuleucel-T has been shown to improve survival versus placebo (25.8 vs. 21.7 months;
hazard ratio 0.77; P = 0.02), it does not change short-term disease progression or cause decreases in
PSA in most patients. This is likely due to the characteristics of immune therapies that make them
distinct from more cytotoxic treatments. For this reason, sipuleucel-T should ideally be followed by
another therapy to provide short-term control and allow for the potential long-term effects which can
potentially improve survival. Patients whose disease on scans, PSA, and symptoms all remain stable
after sipuleucel-T could be followed up closely until one of those parameters dictates the initiation of
a subsequent therapy.
Sipuleucel-T is indicated in patients with minimal symptoms related to their CaP. Although sipuleucel-T can be given 3 months after chemotherapy, given its delayed effects, it would seem most
appropriate to give this treatment prior to chemotherapy.
Androgen Biosynthesis Inhibitor
■■
■■
■■
Abiraterone (Zytiga) is a selective and irreversible CYP17 inhibitor and significantly reduces secondary androgen production (including testosterone precursors dehydroepiandrosterone and androstenedione) from the adrenal glands and likely within CaP cells.
Abiraterone has demonstrated improved OS in mCRPC patients treated with chemotherapy relative to placebo (and has shown delayed progression in patient who have not been treated with
chemotherapy).
Abiraterone can be used in mCRPC patients who are chemotherapy-naïve and who have mild
pain from their metastatic disease. It has been shown to delay the need for narcotics in this
population.
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Abiraterone has been shown to improve pain and quality of life in patients who have already received
chemotherapy.
Androgen Receptor Inhibitor
■■
■■
Enzaluatmide (Xtandi) is a modern version of the ARAs previously discussed although this agent
has broader anti-AR properties beyond binding to the AR with greater binding affinity. It also significantly reduces AR translocation to the nucleus and limits DNA binding, and inhibits coactivator
recruitment and receptor-mediated DNA transcription. In addition, enzalutamide has not demonstrated any agonist properties unlike previous ARAs.
A phase 3 trial evaluated 1,199 mCRPC patients who had progressive disease on docetaxel, randomizing them 2:1 to enzalutamide 160 mg per day (n = 800) or placebo (n = 399). The OS-favored patients
randomized to the enzalutamide arm 18.4 to 13.6 months. This 4.8 months’ improvement in survival
represented a 37% risk reduction in death (hazard ratio 0.63; 95% CI 0.53 to 0.75; P < 0.001), the
largest relative and ­absolute improvement in OS in an appropriately powered phase 3 study in CaP.
Median TTP based on radiographic findings was 8.3 versus 2.9 months (HR 0.40; P < 0.001).
CHEMOTHERAPY FOR mCRPC
In spite of the advent of new antiandrogen therapies for mCRPC, chemotherapy is still important.
■■
■■
■■
■■
Docetaxel (Taxotere)
– Improved median OS from 16.5 months (mitoxantrone/prednisone) to 18.9 months (P = 0.0005)
and improved quality of life (functional assessment of cancer therapy-prostate, 22% vs. 13%;
P = 0.009). Although the absolute magnitude of the difference between the two arms was less than
3 months, it is important to note that the study did employ a cross-over meaning that patients not
randomized to docetaxel initially may have received docetaxel when they had progressive disease.
– Often used for patients with mCRPC who have intermediate or significant levels of symptoms.
– Docetaxel would also be a reasonable option for patients with rapidly progressing disease as determined by objective changes on imaging.
Cabazitaxel (Jevtana)
– This treatment became the second chemotherapy approved for CaP. A phase 3 study trial compared this taxane with mitoxantrone in patients who already received docetaxel. (Prednisone
5 mg twice daily was also given in both groups.) Cabazitaxel improved time to progression
2.8 ­versus 1.4 months (P < 0.0001) but also met the primary endpoint of the trial by extending
survival 15.1 versus 12.7 months (P < 0.0001).
– It is important to note that there was an 8% incidence of febrile neutropenia, and 2% of patients
died from neutropenia-related infections. Thus serious consideration should be given for the use
of growth factor support in appropriate patients.
– Although the true role for cabzitaxel remains elusive, it would be appropriate to consider this treatment in patients who remain symptomatic but also with a good performance status after progression on docetaxel.
Mitoxantrone (Novantrone) + prednisone
– Shown to improve quality of life, but not disease-free survival or OS, in two earlier randomized
controlled trials versus steroids alone.
– Mitoxantrone is stopped at a cumulative dose of 140 mg/m2. Prochlorperazine is used as an ­antiemetic.
– Mitoxantrone may be appropriate for symptomatic patients who have either progressed on or who
are not candidates for taxane-based chemotherapy regimens.
Docetaxel (Taxotere) + carboplatin
– A single-arm phase 2 trial of patients (n = 34) who progressed on docetaxel-based chemotherapy
evaluated this combination and showed a partial response rate of 14% with a median progressionfree survival of 3 months and an OS of 12.4 months.
– This combination may be most appropriate in patients who have a small cell variant of CaP
(­approximately 2% of patients).
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SUPPORTIVE MEASURES
■■
■■
■■
Hot flashes from hormonal therapy are most commonly treated with low-dose venlafaxine or gabapentin with variable success. The potential side effects of these medicines also have to be taken into
account when using them to treat hot flashes.
Painful gynecomastia, often seen when ARAs are used alone, can be prevented with EBRT to the
breasts (2 to 5 fractions) or may be treated with tamoxifen.
Testosterone-lowering therapy causes a decrease in estradiol, needed to maintain bone density, which
may lead to osteoporosis. Many specialists recommend that patients receiving ADT should be given
daily vitamin D and calcium supplements unless contraindicated. Obtain baseline bone mineral density before starting long-term ADT. Treatment with bisphosphonates should be considered in patients
with low bone mineral density.
MANAGEMENT OF BONE METASTASES
■■
■■
■■
■■
■■
While narcotics can be used to alleviate bone pain, the anti-inflammatory effects of NSAIDs should
not be overlooked in patients with bone metastasis.
RT directed to painful spinal cord metastases provides palliation in approximately 80% of patients.
Side effects generally are limited to fatigue and anemia that are usually reversible. Generally, the painful vertebral lesion and the two vertebrae superior to and inferior to the lesion are treated with 30 Gy.
The spinal cord can tolerate radiation up to approximately 50 Gy, so retreatment of some lesions may
be considered.
The radioisotope strontium-89 (Metastron), a calcium analog that preferentially localizes in the
tumor, can provide palliation for widespread metastases. Strontium relieves bone pain in up to 75%
of cases, typically after 1 to 3 weeks of treatment and for several months thereafter. Toxicities include
flare (15%), often associated with a later response, and a reversible thrombocytopenia (25%) that
usually resolves within 3 months. Strontium can often be readministered. Samarium-153 lexidronam (Quadramet) is a newer radioisotope with treatment indications similar to those of strontium,
but a shorter half-life and less marrow toxicity. Emerging data with α-particle emitting radium-223
(alpharadin) suggested minimal toxicity and a survival advantage in mCRPC. Its ultimate role in the
treatment of mCRPC remains undefined.
Bisphosphonates inhibit osteoclastic bone resorption and can decrease skeletal-related events in
patients with advanced CRPC. Zoledronic acid 4 mg IV every 3 to 4 weeks has been approved for this
indication. Side effects include infusion-related myalgias, renal dysfunction, and osteonecrosis of the
jaw. Dose should be adjusted for renal insufficiency.
Denosumab (Xgeva) is a fully humanized antibody that binds to RANK-ligand which is crucial in the
function of osteoclasts, which play a vital role in bone resorption. Studies show that denosumab can
also delay skeletal-related events in mCRPC. Furthermore, data have also indicated that denosumab
can delay the development of metastasis in patients with non-mCRPC, although its clinical utility in
delaying metastasis has not yet been established. Also, even though it is mechanistically different from
bisphosphonates, there is a similar incidence of osteonecrosis of the jaw.
SPINAL CORD COMPRESSION
■■
■■
Vertebral column metastases impinging on the spinal cord can cause spinal cord compression, an
oncologic emergency common in patients with CaP who have widespread bone metastases.
Pain is an early sign of spinal cord compression in more than 90% of patients. Muscle weakness or
neurologic abnormalities are other indicators of spinal cord compression, along with weakness and/
or sensory loss corresponding to the level of spinal cord compression, which often indicate irreversible damage. Genitourinary, gastrointestinal, and autonomic dysfunction are late signs; spinal cord
compression usually progresses rapidly at this point.
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Diagnosis requires a thorough history and physical, with special attention to musculoskeletal and
neurologic examinations. The standard for diagnosing and localizing spinal cord compression is MRI,
usually with gadolinium. A myelogram may be used in patients with contraindications to MRI such
as a pacemaker.
High-dose steroids should be started (e.g., dexamethasone >24 mg IV followed by 4 mg IV or PO
every 6 hours) as soon as history or neurologic examination suggests spinal cord compression. Neurologic or orthopedic surgeons and/or radiation oncologists should be consulted soon after diagnosis.
RT is the usual treatment modality, given as 3,000 cGy in 10 fractions to the involved vertebra and the
two superior and two inferior vertebrae.
Surgical resection of the vertebral body should be considered in the following instances:
–
–
–
–
The patient has had previous RT of the involved area or requires spinal stabilization.
The patient experiences progression despite treatment with steroids and RT.
RT facilities are not locally available.
The patient has a rapidly progressive neurologic deficit. A recent randomized trial showed that
patients subjected to decompressive surgical resection followed by RT retained the ability to walk
significantly longer than those treated with RT alone.
Review Questions
1. A 56-year-old male with a PSA of 7.8 ng/dL has Gleason 4+3 adenocarcinoma of the prostate
diagnosed on a biopsy. He elects to have a RP. After surgery, there are pathologic findings that
indicate that adjuvant radiotherapy may be of benefit. Which of the following findings would not
be an indication for adjuvant radiotherapy?
A. Extracapsular extension
B. Lymph node–positive disease
C. Seminal vesicle involvement
D. Positive surgical margins
2. A 72-year-old male with asymptomatic, nonmetastatic CaP has a rising PSA while on ADT. After
a discussion of treatment options, the patient agrees to add bicalutamide, an ARA. The patient
has a declining PSA for the following 12 months, but then his PSA starts to rise again. The PSA
rise is confirmed 1 month after the initial rising value was seen. The patient has no new symptoms since starting the bicalutamide. What is the appropriate next step for this patient?
A. Get an MRI to determine if the patient has metastatic disease.
B. Initiate chemotherapy for mCRPC.
C. Initiate abiraterone for non-mCRPC.
D. Evaluate for a bicalutamide withdrawal effect 6 weeks after discontinuing bicalutamide.
E. Consider switching from a GnRH agonist to a GnRH antagonist.
3. Which of the following patients would be an inappropriate patient for treatment with sipuleucel-T?
A. A chemotherapy-naïve, mCRPC patient who takes occasional NSAIDs for rare pain
­symptoms
B. A patient who completed docetaxel 6 months ago, but has slowly progressing disease and no
pain while on treatment with enzalutamide
C. A chemotherapy-naïve, mCRPC patient who has just completed treatment with abiraterone
and has minimal symptoms
D. A newly diagnosed, untreated patient with metastatic disease and minimal symptoms
4. Which of the following treatment strategies has been shown to delay the development of bone
metastasis in a phase 3 trial?
A. Zoledronic acid
B. Denosumab
(continued)
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THE BETHESDA HANDBOOK OF CLINIC AL Oncology
C. Calcium/vitamin D
D. Cabozantinib
E. Alendronate
5. Which of the following statements about the use of docetaxel in CaP is accurate?
A. Docetaxel is no longer indicated in CaP because of the advent of abiraterone, enzalutamide,
and sipuleucel-T.
B. Docetaxel with radiation in high-risk patients can enhance long-term outcomes.
C. Docetaxel is the most appropriate therapy for patients moderate to high levels of pain for
castration-resistant, metastatic CaP.
D. Docetaxel is the most appropriate therapy for patients all patients with castration-resistant,
metastatic CaP.
E. Docetaxel prior to surgery for high-risk CaP can improve survival.
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