Robert B. Den, MD
Mark Hurwitz, MD
BASICS
DESCRIPTION
Prostate cancer (CaP) usually refers to adenocarcinoma as other types are rare
EPIDEMIOLOGY
Incidence/Prevalence
• Most common solid tumor in US males
• 2014: 233,000 new cases; 29,480 deaths
• Advent of PSA blood test led to a sharp increase of CaP incidence from 1989 to 1992
• Highest worldwide incidence is in African Americans, with a relative incidence of ∼2 compared to US whites
• Lowest worldwide incidence is in Asian men (1.9/100,000/yr in China); however, Asians who immigrate to US increase risk to that of US men
• Mortality rate decreased sharply since 1991; now lower than before PSA era
• 5-yr relative survival rates ∼100%
• Lifetime CaP risk is 16.15%
RISK FACTORS
• Genetic and environmental factors are important in CaP development
• Family history: Risk is increased by number of affected family members, degree of relation, and age at diagnosis.
• Infection/inflammation: Prostatitis and STD
• Oxidant stress: Several genetic determinant of CaP code for proteins that repair oxidant stress
• Western diet (high levels of meat, dairy, and saturated fat); folate supplements
• Androgens: Essential for development and maturation of prostate gland
– Lack of androgen associated with decreased risk of CaP, although no dose-dependent relationship has been established
– Shortened CAG repeat length in the AR gene associated with increased risk
– Estrogen: Mixed effects on CaP
– IGF-1
– Vitamin D may protect against CaP
Genetics
• HPC-1 gene on chromosome 1 associated with familial CaP; HPC-1 mutation leads to defective RNase L, accumulation of genetic defects, and eventually cancer
• CaP susceptibility genes: P53 tumor suppressor, ELAC2/HPC2, SR-A/MSR1, CHEK2, BRCA2, PON1, OGG1, and MIC1.
– Multifocal and heterogeneous nature of CaP makes clinical genetic studies difficult
• Familial CaP tends to follow a similar clinical course to sporadic CaP
PATHOPHYSIOLOGY
• Normal adult prostate 20–25 g; secretes fluid comprising about 30% of ejaculate
• Most CaP arise in peripheral zone of gland
• High-grade prostatic intraepithelial neoplasia (HGPIN) may be a premalignant lesion:
– Risk of CaP on subsequent biopsy 16–44%; repeat biopsy within a year not necessary unless other signs of cancer
• Atypical small acinar proliferation (ASAP) considered premalignant; 42–49% risk of cancer, biopsy should be repeated
ASSOCIATED CONDITIONS
ED and urinary incontinence are associated with all local CaP therapies.
GENERAL PREVENTION
• Randomized trials have been conducted
– Prostate Cancer Prevention Trial (PCPT) finasteride vs. placebo; REDUCE (dutasteride vs. placebo); while there was 23–25% reduction in CaP risk, concern over slight increase in diagnosis of high-grade cancers prevented these from being FDA-approved agents
– SELECT: Examined antioxidants Vit E and selenium terminated in 2008 due to lack of benefit; increased risk of CaP and diabetes
DIAGNOSIS
HISTORY
• Rarely presents with symptoms; most cases are detected by PSA screening and/or DRE
• Occasionally local tumor symptoms: Urinary obstruction, irritative voiding symptoms, rarely impotence, hematuria, hematospermia
• Metastatic symptoms: Bone pain, weight loss, malaise; spinal cord compression with paralysis
PHYSICAL EXAM
DRE may reveal induration, nodularity, or asymmetry in the gland (uncommon in most men)
DIAGNOSTIC TESTS & INTERPRETATION
Lab
• PSA, is typically elevated in serum of patients with CaP (See Section I: PSA Elevation, General)
• PSA is the most widely used and controversial screening test (sensitivity/specificity suboptimal)
• Recent guidelines have called PSA screening into question
• PSA velocity of >2.0 ng/mL/yr: Poorer prognosis after prostatectomy or radiation therapy
• Free PSA: Lower % free PSA indicates higher risk of CaP
• Prostatic acid phosphatase: Limited utility
• Alkaline phosphatase: Elevated in bone mets
Imaging
• Transrectal ultrasound (TRUS) primarily used to guide biopsy; CaP classically a hypoechoic nodule on TRUS, but can be iso- and hyperechoic
• Multiparametric MRI w/ or w/o endorectal coil may identify some cancers, used to assess local extent of disease; utility of multiparametric MRI growing
• Bone scan: Usually ordered in intermediate- and high-risk patients; blastic bone lesions w/mets
• CT abdomen/pelvis: Used to assess for visceral or lymph node metastasis; indicated for intermediate- and high-risk patients
• ProstaScint: Nuclear scan using a PSMA monoclonal antibody to detect occult metastases. FDA-approved post prostatectomy; limited use
Diagnostic Procedures/Surgery
• TRUS-guided needle biopsy extended template now standard (10–12 cores)
• Effort should be made to sample all hypoechoic lesions and palpable nodules
• Transperineal w/ or w/o MRI image fusion increasing
Pathologic Findings
• >95% CaP adenocarcinoma, with <5% transitional cell (next most common), small cell carcinoma, and sarcoma
• Gleason Grade (1–5) determined by architectural features observed at low magnification. The 2 most prominent grades are added together for Gleason score (2–10):
– Main criterion of CaP: Loss of basal cell layer
– Small, crowded acini with irregular contours, nuclear, and nucleolar enlargement
– Hormonal Rx artifactual grade increase
– Score <6 rare today; 6, 7, 8–10 are low-, intermediate-, and high-grade disease, respectively
• Staging:
– TNM staging, see Section VII
– 75% of newly diagnosed cases are T1c
– PSA >10, Gleason score ≥7, or T2b or higher should undergo imaging (CT/bone scan)
– CaP spreads from the prostate directly to adjacent tissues, usually via the perineural and lymphovascular spaces
– Can also directly invade the seminal vesicle
– Early metastasis to the pelvic lymph nodes
– Distant metastasis: To bone, less common lung, and in advanced stages, the liver and CNS
DIFFERENTIAL DIAGNOSIS
• Localized: BPH, prostatitis (granulomatous, acute, chronic), recent instrumentation, nonadenocarcinoma prostate malignancy (sarcoma, urothelial carcinoma)
• Metastatic: Paget disease, other causes of pelvic/retroperitoneal lymphadenopathy (lymphoma, TB, etc.)
TREATMENT
GENERAL MEASURES
• Localized disease, best treatment controversial and must be individualized; includes active surveillance, radical prostatectomy, radiation therapy, cryotherapy
• Consider age, overall health, life expectancy, patient and physician preferences
• Metastatic disease less controversial and relies primarily on reduction of testosterone
• Risk groups (localized disease, per NCCN)
– Low risk: T1-2a/Gleason 2–6/PSA <10 ng/mL
– Intermediate: T2b–T2c/Gleason 7/PSA 10–20 ng/mL
– High:T3a or greater or Gleason score 8–10 or PSA >20 ng/mL
MEDICATION
First Line
• Metastatic disease: Androgen deprivation
– LHRH agonists: Leuprolide, goserelin, triptorelin; histrelin; transient flare then suppression of pituitary LH and FSH
– LHRH antagonists: Degarelix; suppress LH and FSH release by the pituitary
– Antiandrogens: Flutamide, bicalutamide, nilutamide, directly block the activity of androgens on the androgen receptor
– LHRH agonists can be used alone or in combination with oral antiandrogens
– LHRH agonist 1st dose, a release of testosterone is induced (androgen flare) that may exacerbate symptoms from metastatic lesions. In particular, patients with spinal metastasis may be in jeopardy of cord compression. Minimize flare by antiandrogen therapy 2 wk prior to 1st LHRH agonist injection
Second Line
• Metastatic castrate–resistant CaP: W/rising PSA and “castrate” testosterone (<50 ng/dL)
– Secondary hormonal manipulations
Ketoconazole: Inhibits adrenal and gonadal androgen synthesis; castration hormone levels in <8 hr, historically used w/ spinal compression
Add/stop nonsteroidal antiandrogens
– Sipuleucel-T: Autologous immunotherapy; minimally symptomatic or asymptomatic disease
– Abiraterone: Androgen biosynthesis inhibitor; approved in men with metastatic castrate–resistant prostate cancer previously treated with docetaxel and pre-docetaxel
– Enzalutamide: 2nd gen oral antiandrogen, previously treated with docetaxel and pre-docetaxel
– Radium 223 chloride; systemic α-emitter for symptomatic bone mets, no visceral disease
– Cabazitaxel and prednisone: Systemic microtubule inhibitor failing docetaxel
– Docetaxel and prednisone: Systemic microtubule inhibitor
SURGERY/OTHER PROCEDURES
• For low-risk (T1 and T2a) cancer, 5-yr biochemical disease-free rates are equivalent for prostatectomy, radiation therapy, and brachytherapy. Thus, therapy should be driven by the preferences of the well-informed patient
• Radical prostatectomy:
– Resection of prostate and seminal vesicles and reanastomosis of bladder to urethra
– Nerve-sparing technique if possible
– Open (retropubic, perineal), laparoscopic, or robot-assisted laparoscopic; Laparoscopic approaches may offer quicker discharge, lower blood loss; equivalent functional/oncologic results between techniques; robot higher cost
• Bilateral orchiectomy provides permanent androgen ablation in men with advanced disease
• Cryotherapy uses multiple probes to ablate prostate tissue by freezing and thawing, using TRUS to monitor the extent of the ice ball
ADDITIONAL TREATMENT
Radiation Therapy
• External beam RT:
– IMRT with IGRT: Provides high doses of radiation to prostate, minimal dose to surrounding tissues
– Wide-field pelvic XRT with neoadjuvant androgen deprivation may be considered in men at high risk for nodal metastases
– Proton beam gaining support
– Hypofractionation approaches in clinical trials
• Brachytherapy:
– RT is delivered locally by permanent radioactive (low dose rate I125 or Pd103) seeds or temporary (high dose rate with Ir192) placed percutaneously through the perineum:
– Low-dose monotherapy appropriate for low-risk disease and gland <60 g
– Gleason ≥7, PSA ≥10, and ≥T2b use EBRT in lieu of or in addition to brachytherapy
• Neoadjuvant/concurrent androgen deprivation for 6 mo–3 yr with XRT increases survival vs. XRT alone or hormonal therapy alone (select intermediate and all high-risk patients)
Additional Therapies
• Active surveillance: Option for many patients due to the slow progression of CaP, especially in men >70 who may be likely to die of other causes
– Ideal patient: PSA <10 ng/mL, T1c, Gleason ≤6; <3 biopsy cores positive (<50% cancer in any core); PSA density <0.15 ng/mL/g
• HIFU: Investigational focal ablative therapy in use outside of US
Complementary & Alternative Therapies
Consider dietary changes: Reduced meat and saturated fat; increased vitamin D (see “Risk Factors”); increased lycopenes (cooked tomato products, red fruits; increased fiber and exercise
ONGOING CARE
PROGNOSIS
• Determining prognosis is multimodal
• Increased recurrence risk with:
– High PSA (≥10), high Gleason score (≥7), advanced clinical stage (≥T3)
– Pathologic features: Positive surgical margins, seminal vesicle invasion, capsular penetration, lymph node involvement
– New genomic markers available for prognosis (See Section II: “Prostate Cancer, Genomic markers.”)
COMPLICATIONS
• Disease related:
– Bladder outlet obstruction, bone pain, pathologic fractures, spinal cord compression, ureteral obstruction usually due to metastasis
• Treatment related:
– Local therapy (surgery, radiation): Impotence, incontinence, rectal injury
– Androgen deprivation: Hot flashes, loss of libido, impotence, fatigue, osteoporosis
– Chemotherapy: Neutropenia, sepsis
FOLLOW-UP
Patient Monitoring
• PSA every 6–12 mo × 5 yr; yearly after:
– Should be undetectable (<0.1 ng/mL) after prostatectomy
– Should drop to <0.5 ng/mL after radiation for best prognosis
• DRE every other year
• CT of abdomen/pelvis and/or bone scan if patient has new bone pain, rapid PSA rise, short doubling time
Patient Resources
American Cancer Society. http://www.cancer.org/cancer/prostatecancer/index?sitearea=%26dt=10
REFERENCES
1. NCCN Practice Guidelines Version 1.2014 http://www.nccn.org./ Accessed January 6, 2014
2. Thompson IM, Goodman PJ, Tangen CM, et al. The influence of finasteride on the development of prostate cancer. N Engl J Med. 2003;349:215–224.
3. D’Amico AV, Chen MH, Roehl KA, et al. Preoperative PSA velocity and the risk of death from prostate cancer after radical prostatectomy. N Engl J Med. 2004;351:125–135.
4. Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004;351:1502–1512.
5. Pilepich MV, Winter K, John MJ, et al. Phase III Radiation Therapy Oncology Group (RTOG) trial 86–10 of androgen deprivation adjuvant to definitive radiotherapy in locally advanced carcinoma of the prostate. Int J Radiat Oncol Biol Phys. 2001;50:1243–1252.
ADDITIONAL READING
Thompson IM, Thrasher JB, Aus G, et al. Guideline for the management of clinically localized prostate cancer: 2007 update. J Urol. 2007;177:2106–2131.
See Also (Topic, Algorithm, Media)
• Prostate Cancer, Castration Resistant
• Prostate Cancer, General Images 
• Prostate Cancer, Genomic Markers
• Prostate Cancer, Localized (T1, T2)
• Prostate Cancer, Locally Advanced (T3, T4)
• Prostate Cancer, Metastatic (N+, M+)
• Prostate Cancer, Very Low Risk and Active Surveillance
• PSA Elevation, General
• PSA, General Considerations
• Reference Tables: TNM: Prostate Cancer
CODES
ICD9
• 185 Malignant neoplasm of prostate
• 601.9 Prostatitis, unspecified
• V16.42 Family history of malignant neoplasm of prostate
ICD10
• C61 Malignant neoplasm of prostate
• N41.9 Inflammatory disease of prostate, unspecified
• Z80.42 Family history of malignant neoplasm of prostate
CLINICAL/SURGICAL PEARLS
Prostate cancer requires informed decision making and a risk based approach; consider active surveillance if low risk and <10-yr life expectancy.