Erin M. Burns, MD
James S. Rosoff, MD
BASICS
DESCRIPTION
• Clinical stage T3 prostate cancer (CaP) refers to disease that is thought to extend outside the prostate and may be palpable or seen on imaging
• Pathologic stage T3 CaP refers to extracapsular extension (T3a), or tumor invading seminal vesicles (SVs) (T3b) based on final surgical pathology
• Clinical stage T4 CaP refers to palpable tumor that is fixed and/or invading adjacent structures
• Pathologic stage T4 CaP refers to tumor that is invading the bladder neck, external sphincter, rectum, or levator muscle, and/or is fixed to the pelvic sidewall based on final surgical pathology
• Transrectal ultrasound (TRUS) of the prostate, magnetic resonance imaging (MRI), and computed tomography (CT) can supplement physical exam findings to assist with diagnosing clinical stage T3 and T4 disease
EPIDEMIOLOGY
Incidence
Declining incidence of locally advanced CaP: 10–15% in 1989–1990, 1–5% in 2001–2003 (1,2)
Prevalence
N/A
RISK FACTORS
• Higher Gleason score, elevated prostate-specific antigen (PSA), and increased tumor volume on biopsy predict increased likelihood of locally advanced disease
• Older males (≥75) are more likely to present with high-risk prostate cancer (3)
• African Americans and men with diabetes tend to have more aggressive disease and higher stage at presentation (4)
Genetics
Research is ongoing to determine genetic markers that differentiate organ confined from locally advanced CaP
PATHOPHYSIOLOGY
• Extension beyond prostatic capsule occurs when tumor develops biologic ability to degrade physical barriers to cancer cell movement, such as the prostatic capsule and/or fascial investments of the prostate and SVs
– Intermediate-grade (Gleason 7) and high-grade (Gleason 8–10) CaPs more commonly extend outside the prostate than low-grade (Gleason 6) CaP.
ASSOCIATED CONDITIONS
Locally invasive prostate cancer can present with resulting symptoms such as hematuria, obstructive voiding symptoms and changes in bowel habits
GENERAL PREVENTION
• 5α-Reductase inhibitors (5-ARIs): Finasteride and dutasteride
– Discuss with patient risks/benefits of 5-ARI use for CaP prevention (5)[A]
• Vitamin E, selenium, vitamin C:
– No beneficial effect; should not be used
• Statins, green tea, lycopene
– Insufficient evidence to advocate these supplements for CaP prevention (6)
DIAGNOSIS
HISTORY
• Family history of CaP
• Voiding symptoms: Obstructive/irritative, hematuria
PHYSICAL EXAM
Digital rectal exam (DRE): Note palpable abnormalities, unilateral vs. bilateral, whether prostate is fixed, any extension of mass into adjacent structures
DIAGNOSTIC TESTS & INTERPRETATION
Lab
• PSA
– Positive predictive value (PPV): 12–32% for PSA levels 4–10, 60–80% for PSA levels >10, higher PSA increases risk for capsular penetration and SV invasion
– Value is decreased by 5-ARIs, elevated with instrumentation, infection, larger prostate volume
– Lab variability: 20–25% (7)[A]
• PSA density: Serum PSA/prostate volume
– >0.15 is associated with CaP, >0.35 is associated with 66% risk of extraprostatic extension
• PSA velocity
– Rate of rise of >0.75/yr is a specific marker for CaP
– Should be calculated over 18 mo with 3 PSA measurements
• Free PSA (fPSA)
– Lower fPSA is found in CaP; <10% free correlates with 56% probability of CaP
PSA velocity, density, and fPSA do not correlate with Gleason score or CaP stage
• PCA3
– RNA overexpressed in CaP, higher values indicate higher risk of CaP
– Collected via post-DRE urine sample
– Sensitivity 48%, specificity 79%, not currently used for routine screening
– May correlate with Gleason score (8)
Imaging
• TRUS
– Low sensitivity (23–66%), specificity (46–86%), and PPV (50–62%) for predicting extracapsular extension (9)[A]
– Useful in guiding widespread sampling of prostate tissue during biopsy
• MRI
– May delineate T2 from T3 disease
– Specificity for T3 disease is 95% when PSA >10, abnormal DRE and >3 cores positive on TRUS biopsy (10)[A]
• CT
– Consider for staging when PSA >20 or Gleason score ≥8
• Bone scan
– Indicated when PSA ≥20 to evaluate for skelet al metastases
• ProstaScint
– May be useful in ruling out metastatic disease in patients with locally advanced CaP
Diagnostic Procedures/Surgery
• TRUS-guided prostate biopsy
– Should be performed for abnormal DRE or PSA elevation
Pathologic Findings
TRUS biopsy can confirm T3 disease with biopsy of the capsule or SVs
DIFFERENTIAL DIAGNOSIS
• PSA can be elevated in the setting of prostatic and/or urethral instrumentation, infection, or benign prostatic hypertrophy (BPH)
• Lesions of the prostate seen on imaging can be areas of infarct, prostatitis, or tumor
• No single diagnostic modality can accurately predict pathologic stage of CaP; incorporating multiple clinical parameters helps to best determine disease extent
TREATMENT
GENERAL MEASURES
• Currently no consensus regarding optimal management of locally advanced CaP
• Compared to clinically localized, low-grade CaP, locally advanced CaP has a higher risk of recurrence after any single treatment modality (up to 30%), and should be treated unless life expectancy is ≤5 yr
MEDICATION
First Line
• Androgen deprivation therapy (ADT): Option for patients unable or unwilling to undergo surgery or radiation therapy (RT)
– Orchiectomy, luteinizing hormone-releasing hormone (LHRH) agonist or antagonist
– Can be administered continuously or intermittently; optimal timing of administration with respect to quality of life and survival benefit is debated
– More effective when combined in neoadjuvant or adjuvant fashion with RT
Second Line
Antiandrogen monotherapy is less effective and not usually recommended; however, side effects are more tolerable overall
SURGERY/OTHER PROCEDURES
• Radical prostatectomy (RP) with pelvic lymph node dissection (PLND)
– Select patients can benefit from local control
– Complete excision/cure is possible
– Clinical overstaging of T3 disease can occur in up to 7–27% of patients, thus exclusion from surgery on the basis of clinical staging may be inappropriate
• Neoadjuvant ADT does not confer cancer specific or overall survival (OS) benefit
• Adjuvant RT 55–70 Gy improves local control and reduces the risk of biochemical recurrence for T3 disease; it may also confer OS benefit (11)[A]
– Indications include T3 disease, positive surgical margins, Gleason score of 8–10
– Should be administered within 1 yr of surgery and after operative side effects (eg, urinary continence) have improved/stabilized
ADDITIONAL TREATMENT
Radiation Therapy
• 75–80 Gy to prostate, SVs, and pelvic lymph nodes, or 40–50 Gy and brachytherapy for cT3/T4 disease
– NCCN guidelines recommend 2–3 yr neoadjuvant/concomitant/adjuvant ADT for higher disease free and OS in men with T3 and T4 disease (12)[A]
• Advances in 3D conformal, intensity-modulated and image-guided RT are designed to deliver higher doses directly to prostate, avoiding adjacent structures and thus limiting side effects
Additional Therapies
• Cryoablation of the prostate
– Higher rates of biochemical failure than RT (87% vs. 53%) for T2c–T3 CaP (13)[A]
• High-intensity focused ultrasound (HIFU)
– Currently investigational, may prove to be an option in combination with ADT for intermediate- and high-risk CaP
Complementary & Alternative Therapies
Clinical trials should be considered
ONGOING CARE
PROGNOSIS
• Significant risk of progression and disease-specific death if locally advanced prostate cancer is left untreated
– OS without intervention ranges from 10 to 92% at 5 yr and 14–78% at 10 yr for high-grade/stage CaP
• RP for T3 CaP: OS 64–96% at 5 yr, 13–72% at 10 yr
– Cancer-specific survival (CSS): 85–92% at 5 yr, 79–82% at 10 yr
• RT monotherapy: OS 60–70% at 5 yr and <50% at 10 yr
– RT with ADT: OS 72–87% at 5 yr
COMPLICATIONS
• Therapy complications are similar to those for localized CaP
• Untreated T3–T4 CaP may lead to hematuria, obstruction at the level of the prostate requiring indwelling catheter or transurethral resection of the prostate, or ureterovesical junction obstruction requiring ureteral stents or percutaneous nephrostomy
FOLLOW-UP
Patient Monitoring
• Periodic PSA measurements, initially at 3-mo intervals posttherapy and then gradually increasing to annually
• Failure of PSA to nadir or consecutive rises in PSA should prompt further evaluation with bone scan and/or CT
– Risk of biochemical recurrence increased in: Gleason score 8–10, PSA doubling time <10 mo (14)
– ProstaScint scan may be helpful in identifying local recurrence if bone scan and CT scan are negative
– Consider additional treatment options such as ADT, adjuvant RT, and/or chemotherapy and participation in clinical trials
Patient Resources
• AUA Prostate Cancer Guide: http://www.auanet.org/content/media/pc08.pdf
• NCCN Patient Guidelines for Prostate Cancer: http://www.nccn.org/patients/patient_guidelines/prostate/index.html
REFERENCES
1. Greene KL, Cowan JE, Cooperberg MR, et al. ; Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) Investigators. Who is the average patient presenting with prostate cancer? Urology. 2005;66(5 suppl):76–82.
2. Cooperberg MR, Lubeck DP, Mehta SS, et al. Time trends in clinical risk stratification for prostate cancer: Implications for outcomes (data from CaPSURE). J Urol. 2003;170(6):21–27.
3. Bechis SK, Carroll PR, Cooperberg MR. Impact of age at diagnosis on prostate cancer treatment and survival. J Clin Oncol. 2011;29(2):235–241.
4. Mitin T, Chen MH, Zhang Y, et al. Diabetes mellitus, race, and odds of high grade prostate cancer in men treated with radiation therapy. J Urol. 2011;186(6):2233–2237.
5. Kramer BS, Hagerty KL, Justman S, et al. Use of 5-α-reductase inhibitors for prostate cancer chemoprevention: American Society of Clinical Oncology/American Urological Association 2008 Clinical Practice Guideline. J Clin Oncol. 2009;27(9):1502–1516.
6. Stephenson AJ, Abouassaly R, Klein EA. Chemoprevention of prostate cancer. Urol Clin North Am. 2010;37(1):11–21.
7. AUA PSA Best Practice Statement. Available at http://www.auanet.org/content/media/psa09.pdf. (Accessed May 21, 2014)
8. Artibani W. Landmarks in prostate cancer diagnosis: The biomarkers. BJU Int. 2012;110:8–13.
9. Hsu CY, Joniau S, Oyen R, et al. Detection of clinical unilateral T3a prostate cancer-by digital rectal exam or transrectal ultrasonography. BJU Int. 2006;98(5):982–985.
10. Cornud F, Flam T, Chauveinc L, et al. Extraprostatic spread of clinically localized prostate cancer: Factors predictive of pT3 tumor and of positive endorectal MR imaging examination results. Radiology. 2002;224(1):203–210.
11. Thompson IM, Tangen CM, Paradelo J, et al. Adjuvant radiotherapy for pathologic T3N0M0 prostate cancer significantly reduces risk of metastases and improves survival: Long-term followup of a randomized clinical trial. J Urol. 2009;181:956–962.
12. NCCN Prostate Cancer Guidelines. Available at http://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf (Accessed May 21, 2014)
13. Chin JL, Ng CK, Touma NJ, et al. Randomized trial comparing cryoablation and external beam radiotherapy for T2c-T3b prostate cancer. Prostate Cancer Prostatic Dis. 2008;11:40–45.
14. Stephenson AJ, Shariat SF, Zelefsky MJ, et al. Salvage radiotherapy for recurrent prostate cancer after radical prostatectomy. JAMA. 2004;291:1325–1332.
ADDITIONAL READING
Thompson IM, Valicenti RK, Albertsen P, et al. Adjuvant and salvage radiotherapy after prostatectomy: AUA/ASTRO Guideline. J Urol. 2013;190(2):441–449.
See Also (Topic, Algorithm, Media)
• Prostate Cancer, General
• Prostate Cancer, Locally Advanced (Clinical T3, T4) Images 
• Prostate Cancer, Locally Advanced (Pathologic T3, T4)
• Prostate Cancer, Positive Margin Following Radical Prostatectomy
• PSA Elevation, General Considerations
• Reference Tables: TNM: Prostate Cancer
CODES
ICD9
• 185 Malignant neoplasm of prostate
• 198.1 Secondary malignant neoplasm of other urinary organs
• 198.82 Secondary malignant neoplasm of genital organs
ICD10
• C61 Malignant neoplasm of prostate
• C79.11 Secondary malignant neoplasm of bladder
• C79.82 Secondary malignant neoplasm of genital organs
CLINICAL/SURGICAL PEARLS
• Risk assessment requires incorporating serum PSA, clinical stage, Gleason score, tumor volume, and patient age and comorbidities to best provide counseling and treatment recommendations.
• RP should include PLND for locally advanced CaP, and adjuvant RT should be offered for T3–T4 disease, particularly if surgical pathology demonstrates positive margins.
• RT should be administered in conjunction with ADT for locally advanced CaP to maximize survival benefit with support from randomized clinical trials.