Michael A. Gorin, MD
Trinity J. Bivalacqua, MD, PhD
BASICS
DESCRIPTION
• The National Comprehensive Cancer Network (NCCN) (1) defines very−low-risk prostate cancer (PCa) with the following criteria: Clinical stage T1c, prostate-specific antigen (PSA) <10 ng/mL, PSA density <0.15 ng/mL/g, biopsy Gleason score ≤6, ≤2 positive biopsy cores, and ≤50% cancer in any 1 core.
– This definition is based on the work of Epstein et al. (2) which identified parameters associated with low-volume organ-confined (ie, insignificant) PCa at the time of radical prostatectomy.
• Active surveillance (AS) aims to spare men with insignificant tumors the side effects of treatment while maintaining the ability to intervene with curative intent upon the detection of disease progression.
– The goals of AS are accomplished by carefully following men with serial PSA measurements, digital rectal exams (DREs), and prostate biopsies.
• AS is most appropriate for men with very−low-risk PCa and a life expectancy of <20 yr, or for those with low-risk PCa (defined by the NCCN as clinical stage T1 to T2a, biopsy Gleason score ≤6, and PSA <10 ng/mL) and a life expectancy of <10 yr (1).
• The exact criteria for AS enrollment vary by institution.
– Triggers for intervention while on AS also vary by center, but typically include violation of the enrollment criteria or a rapid rise in PSA.
Dahabreh et al. (3) have reviewed the enrollment and progression criteria used at number of different institutions.
EPIDEMIOLOGY
Incidence
• ∼240,000 new cases of PCa are diagnosed annually in the United States.
• >90% of new cases will be clinically localized.
• Up to 40% cases would have remained clinically insignificant had they not been detected on routine screening.
Prevalence
An estimated 2.6 million men in the United States carry a diagnosis of PCa.
RISK FACTORS
• Age
• Family history/genetics
• African American race
• Possibly obesity and a Western diet
Genetics
Mutations in a number of genes have been linked to PCa including BRCA1, BRCA2, HOXB13, and HPC1.
PATHOPHYSIOLOGY
• A combination of genetic, hormonal, and environmental factors underlies the development of PCa.
• >95% of all tumors are adenocarcinoma.
– Other histologic types include transitional cell, small cell, and sarcoma.
NCCN risk categories and AS only pertain to adenocarcinoma.
• High-grade prostate intraepithelial neoplasia is felt to be a precursor to adenocarcinoma.
• Early-stage adenocarcinoma is androgen dependent. As PCa becomes more advanced, tumors dedifferentiate and lose this dependency.
• ∼70% of PCa arise from the peripheral zone of the prostate.
• Tumors are often multifocal.
ASSOCIATED CONDITIONS
• Many men with PCa also have benign prostatic hyperplasia (BPH)/lower urinary tract symptoms.
– BPH is not a precursor to PCa.
GENERAL PREVENTION
• The 5α-reductase inhibitors (5-ARIs) finasteride and dutasteride have been shown in 2 randomized clinical trials (PCPT and REDUCE) to decrease the incidence of PCa.
– These medications, however, failed to receive FDA approval for PCa prevention due to their suggested association with increased risk of high-grade tumors (controversial).
• The SELECT trial showed that daily selenium and/or vitamin in E do not prevent PCa and should not be recommended to patients.
DIAGNOSIS
HISTORY
• Uniformly asymptomatic.
– Typically detected on prostate biopsy performed for an elevated PSA and/or finding of a prostate nodule on DRE.
– Occasionally detected at the time of transurethral resection of the prostate for BPH.
PHYSICAL EXAM
Very−low-risk PCa has no findings on DRE (clinical stage T1c).
DIAGNOSTIC TESTS & INTERPRETATION
Lab
PSA <10 ng/mL and PSA density <0.15 ng/mL/g are required for the definition of very–low-risk PCa.
Imaging
• Transrectal ultrasound is used to guide template-based prostate biopsies.
• A bone scan and/or cross-sectional imaging are unnecessary due to the exceedingly low risk of metastatic disease.
• Magnetic resonance imaging (MRI) of the prostate is currently under investigation for its utility in evaluating tumor extent and the presence of high-grade disease.
Diagnostic Procedures/Surgery
• PCa is definitively diagnosed with prostate biopsy.
– Most commonly performed in the office setting using transrectal ultrasound.
A 10–12-core biopsy should be performed to ensure adequate sampling of the prostate.
Requires only local lidocaine for analgesia.
A hypoechoic lesion may represent an area of cancer but is not a sensitive finding.
– Transperineal biopsy is typically reserved for men with several negative biopsies in whom PCa is still suspected.
Allows for systematic saturation biopsies using a grid-based approach.
Requires general anesthesia.
– Image fusion biopsy combining ultrasound/MRI images are being explored.
Pathologic Findings
• Biopsy Gleason score ≤6 and ≤2 positive cores with ≤50% cancer in each core are required for the definition of very–low-risk PCa.
• Evolving use of genomic assays based on the prostate biopsy to determine risk of progression on AS (Oncotype DX and Prolaris).
DIFFERENTIAL DIAGNOSIS
• Localized PCa:
– BPH, prostatitis (granulomatous, acute, or chronic), recent instrumentation, nonadenocarcinoma prostate malignancy (sarcoma, urothelial carcinoma)
TREATMENT
GENERAL MEASURES
• Adequate patient evaluation and review of all treatment options is essential
• Identification of patients who may be an appropriate candidate for AS
MEDICATION
First Line
• No role for chemotherapy or androgen deprivation for men who are candidates for AS.
• 5-ARIs do not appear to prevent disease progression of men on AS.
Second Line
N/A
SURGERY/OTHER PROCEDURES
• Radical prostatectomy may be offered to men who desire treatment.
– A pelvic lymph node dissection may be omitted given the low risk of lymph node metastases in this population.
– Comparing open to robotic or laparoscopic surgery, outcomes appear to be equivalent between surgical approaches (4).
– Major side effects of surgery include urinary incontinence and erectile dysfunction.
ADDITIONAL TREATMENT
Radiation Therapy
• External beam radiation therapy or brachytherapy are acceptable alternatives to AS and surgery.
– Adjuvant hormonal therapy is not indicated with either approach in this group of men.
– When external beam radiation therapy is performed, treatment with either intensity-modulated or 3-dimensional conformal radiation therapy should be utilized to limit toxicity to surrounding organs.
– Brachytherapy should be avoided in men with symptoms of bladder outlet obstruction (high International Prostate Symptom Score) due to the risk of worsening lower urinary tract symptoms.
– Major side effects of radiation include urinary incontinence, irritative voiding symptoms, erectile dysfunction, radiation induced proctitis, hemorrhagic cystits and secondary malignancies most commonly of the bladder and rectum.
Additional Therapies
• Technologies for focal and hemi- ablation are currently in the early phases of investigation.
– Modalities include cryotherapy, high intensity focused ultrasound, interstitial laser and electroporation.
Complementary & Alternative Therapies
Low fat diet appropriate recommendation
ONGOING CARE
PROGNOSIS
• Up to 30% of men enrolled in AS will be reclassified and go onto require some form of treatment.
– It remains unknown if these men would have had a superior oncologic outcome had they undergone immediate treatment.
COMPLICATIONS
• AS spares men with insignificant tumors the side effects of unnecessary treatment.
• The major risk of AS is missing the opportunity to intervene when cure is still possible.
• A small percentage of men will experience an infectious or bleeding complication related to a prostate biopsy.
FOLLOW-UP
Patient Monitoring
• The optimal protocol for monitoring men on AS is unknown.
– Most advocate for biannual PSA measurements with DRE and annual 12–14-core prostate biopsy.
PSA kinetics do not appear to be helpful in predicting disease progression (5).
• Monitoring for disease progression is not indicated after age 75 of when life expectancy is <10 yr.
Patient Resources
• The NCCN Guidelines for Patients: Prostate Cancer. (http://www.nccn.org/patients/guidelines/prostate/)
• What You Need to Know About Prostate Cancer from the National Cancer Institute. (http://www.cancer.gov/cancertopics/wyntk/prostate/prostate.pdf).
REFERENCES
1. NCCN Practice Guidelines Version 1. 2014. http://www.nccn.org./ Accessed January 6, 2014.
2. Epstein JI, Walsh PC, Carmichael M, et al. Pathologic and clinical findings to predict tumor extent of nonpalpable (stage T1c) prostate cancer. JAMA. 1994;271:368–374.
3. Dahabreh IJ, Chung M, Balk EM, et al. Active surveillance in men with localized prostate cancer: A systematic review. Ann Intern Med. 2012;156:582–590.
4. Magheli A, Gonzalgo ML, Su LM, et al. Impact of surgical technique (open vs laparoscopic vs robotic-assisted) on pathological and biochemical outcomes following radical prostatectomy: An analysis using propensity score matching. BJU Int. 2011;107:1956–1962.
5. Ross AE, Loeb S, Landis P, et al. Prostate-specific antigen kinetics during follow-up are an unreliable trigger for intervention in a prostate cancer surveillance program. J Clin Oncol. 2010;28:2810–2816.
ADDITIONAL READING
• Heidenreicha A, Bellmunt J, Bolla M, et al. EAU guidelines on prostate cancer. Part 1: Screening, diagnosis, and treatment of clinically localised disease. Eur Urol. 2011;59:61–71.
• Thompson I, 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, General Considerations
• Prostate Cancer, Genomic Markers
• Prostate Cancer, Localized (T1, T2)
• PSA Elevation, General Considerations
CODES
ICD9
• 185 Malignant neoplasm of prostate
• 790.93 Elevated prostate specific antigen [PSA]
• V76.44 Screening for malignant neoplasms of prostate
ICD10
• C61 Malignant neoplasm of prostate
• R97.2 Elevated prostate specific antigen [PSA]
• Z12.5 Encounter for screening for malignant neoplasm of prostate
CLINICAL/SURGICAL PEARLS
• A large percentage of older men with screen-detected PCa will have insignificant tumors and, therefore, not benefit from intervention.
• To avoid the potential morbidity associated with treatment, AS should be offered to men with very−low-risk PCa and a life expectancy of <20 yr.
• The optimal follow-up protocol is not well defined but typically includes biannual PSA measurements with DRE and annual 12–14-core prostate biopsy.
• PSA kinetics are less useful than biopsy findings for accurately reclassifying men while on AS.
• It is unknown if men reclassified on AS would have been better served with immediate treatment; however, long-term data from a number of centers suggest good oncologic outcomes with this management strategy.