Divya Ajay, MD
Judd W. Moul, MD, FACS
BASICS
DESCRIPTION
• Pathologic T3/T4 (pT3/T4) is prostate cancer that extends beyond the confines of the prostatic gland without evidence of lymph node or distant metastases after radical prostatectomy (RP) based on pathology
• Pathologic stage is determined by histologic analysis of the prostate, SVs, and lymph nodes
• Per the TNM system, this is considered locally advanced prostate cancer defined by the categories T3a, T3b, T4, if combined with an absence of regional lymph node metastasis (N0) and distant metastasis (M0). Where:
– T3a: Extracapsular extension
– T3b: Tumor invades seminal vesicle(s)
– T4: Tumor is fixed or invades adjacent structures other than seminal vesicles (bladder neck, external sphincter, rectum, levator muscles, or pelvic wall)
• Tumor volume, grade, pelvic lymph node involvement, extracapsular and SV extension, and surgical margin status predict biochemical recurrence-free survival and cancer-specific survival
EPIDEMIOLOGY
Incidence
PSA screening has led to downward pathologic stage migration. Since 2001, rates of extracapsular extension had remained stable at 25%. In 2012 and 2013, USPSTF and AUA revised guidelines against PSA screening; this may increase rates of T3–T4 disease.
RISK FACTORS
• Poor health literacy, use of multivitamins more than 7 times a week, obesity, and lack of screening increase the risk of locally advanced disease at presentation
• Partin tables use DRE-based primary T stage, serum PSA, and Gleason grade to predict cancer extent and long-term outcomes
• D’Amico has also suggested a risk stratification into low, intermediate, and high risk based on DRE, PSA, and Gleason grade
• While these predictive models are helpful in counseling patients, studies show that status post prostatectomy up to 3% of men were down-T-staged and 35% of men were up-T-staged (1)
Genetics
• Abnormal p53 expression, low levels of p16 and deregulation of the RB pathway and aneuploidy of Chr 9 have been associated with locally advanced prostate cancer
• In 2013, 2 commercial genetic biomarker assays (Prolaris, Oncotype Dx-prostate) became available. Based on RNA expression profiles, these assays may help to predict more advanced stage/grade
PATHOPHYSIOLOGY
• Peripheral zone tumors tend to invade the capsule more often than transition zone tumors
• Tumor spread:
– T3a (extracapsular invasion) occurs posteriorly and posterolaterally by vascular invasion and increases risk of recurrence after RP
• Tumor volume:
– Extraprostatic invasion is more common in tumors >0.5 cm3 and seminal vesicle invasion is more common in tumors >4 cm3
– Tumor volume does not independently predict postsurgical progression once grade, pathologic stage, and margins are accounted for
ASSOCIATED CONDITIONS
Locally invasive prostate cancer can present with resulting symptoms such as hematuria, obstructive voiding symptoms, and changes in bowel habits
GENERAL PREVENTION
• 5-Alpha Reductase Inhibitors (5-ARIs): Finasteride and dutasteride; discuss with patient risks/benefits of 5-ARI use for CaP prevention; not FDA approved
• 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
DIAGNOSIS
HISTORY
• Family history of CaP; race
• Voiding symptoms: Obstructive/irritative, hematuria
• Any bone/back/hip pain or 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
– Laboratory variability: 20–25%
• PSA density: Serum PSA/Prostate volume
– >0.15 is associated with CaP, >0.35 is associated with 66% risk extra-prostatic 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
Imaging
• Preoperative imaging for locally advanced cancer:
– Pelvic CT or MRI is indicated for locally advanced disease (PSA >20 ng/mL, Gleason score 8 or greater, or a T3/T4 tumor) to evaluate for pelvic lymph node involvement
– Distal metastasis may be ruled out using Technetium 99 bone scan, axial MRI, PET, and immunoscintigraphy
– Multiparametric prostate MRI using a 3T magnet and/or an endorectal coil is being touted to improve accuracy
– Repeat or 1st time staging with bone scan and/or CT may be needed in selected patients who are significantly upstaged and/or upgraded after RP
Diagnostic Procedures/Surgery
Prostate biopsy rarely indicates the presence of pathologic T3 disease; seminal vesical biopsy may confirm T3
Pathologic Findings
• Clinically localized disease is upstaged if pathologic tissue from a prostatectomy indicate T3 or T4 disease
• The risk of cancer recurrence after prostatectomy is based on extracapsular extension, seminal vesicle involvement, lymph node involvement, and corresponds most strongly with a positive surgical margin
• A gross PSMs carry worse 5-r progression survivals vs. microscopic margins 65% vs. 40%
• PSM at the bladder neck, vas deferens, and posterolateral surface of the prostate have been shown to have a particularly poor progression-free outcomes in comparison to PSM at the apex, posterior, anterior, or lateral prostate
• With respect to the nerve-sparing technique, when patients are selected appropriately, no statistical difference has been shown in PSM in comparison to the nonnerve sparing technique
TREATMENT
GENERAL MEASURES
• The American Society of Therapeutic Radiation Oncology (ASTRO) and the American Urologic Association (AUA) have a joint guideline on the use of adjuvant and salvage radiotherapy after prostatectomy
– They note clinical benefit of adjuvant radiotherapy in reducing clinical progression in high-risk patients (seminal vesicle involvement, positive surgical margins, extra prostatic extension) while the impact on future development of metastasis and survival remains less clear
– It also emphasizes the value of early intervention with a threshold PSA ≥ 0.2 ng/mL with a 2nd confirmatory after surgery to confirm relapse (2)
• Therapy is considered adjuvant if the postoperative PSA level is undetectable (<0.2 ng/mL)
• Therapy is considered salvage if there is a biochemical/PSA recurrence
• Lymph node metastasis is an indication for ADT, pelvic RT, or observation
MEDICATION
First Line
• Androgen deprivation therapy (ADT) using an LHRH agonist or GNRH antagonist with or without an oral antiandrogen is sometimes added to adjuvant or salvage EBRT although there is not yet level I evidence from RCTs in the adjuvant/salvage setting for pathologic T3/T4 disease
• Potential benefits of ADT must be balanced against the side-effect profile
Second Line
Newer generation oral hormonal therapies (abiraterone acetate, enzalutamide) may have future role in adjuvant and salvage therapy
SURGERY/OTHER PROCEDURES
• In the setting of clinical T3/T4 disease, extended lymph node dissection is gaining support in these patients (obturator, external iliac, internal iliac, and presacral nodes)
• Neoadjuvant ADT with leuprolide and flutamide for 3 mo prior to RP has shown to reduce positive margins, but has no impact on lymph node metastasis or 5-yr biochemical recurrence rate. It may be used in selected cases for technical downsizing
• Chemo hormonal downstaging trials are ongoing before RP for clinical T3/T4 disease
ADDITIONAL TREATMENT
Radiation Therapy
• 3 randomized trials have been completed demons-trating a benefit to early adjuvant radiation therapy
• Treatment is optimally offered after continence is restored, to allow healing to take place after surgery
• With a median follow-up of 12 yr, (Southwest Oncology Group [SWOG] 8794), confirmed a significant improvement in the risk of metastasis (43% vs. 54%) and overall survival (41% vs. 52%) among patients randomized to adjuvant radiation (3)
• The largest trial included 1,000 patients with T3 disease randomly assigned to 60 Gy of radiation vs. observation. At 5-yr, progression-free survival was significantly improved (74% vs. 53%), with no demonstration of an overall survival benefit (4)
– A subsequent update suggested that the benefit might be limited to patients with positive surgical margins
• A German trial of 395 patients demonstrated a biochemical progression-free survival benefit (72% vs. 54%) to early radiation therapy in this pT3 group. The benefit of therapy was observed with or without positive margins (5)
• Genomic assays may allow more rationale decision making for post operative radiation following radical prostatectomy (7)
Additional Therapies
Proton beam external radiotherapy is offered at selected major US centers. However, there is no Level I evidence that it is superior to photon-based radiotherapy using an intensity modulated method.
Complementary & Alternative Therapies
No level I evidence of benefit
ONGOING CARE
PROGNOSIS
• With salvage EBRT and persistent or increasing PSA levels after surgery 45% of patients were free of disease at 4 yr after salvage EBRT
– Patients with no adverse risk features achieved a 4-yr progression-free probability of 77%. A nomogram based on established risk factors to more accurately identify patient-specific risks to assist in clinical decision-making is available (6)
COMPLICATIONS
• Morbidity from pelvic RT include radiation proctitis, cystitis, incontinence, ED, lymphedema, and stricture disease
• Morbidity from hormone therapy include hot flushes, breast tenderness, osteoporosis, diabetes mellitus, depression, and cardiac disease
FOLLOW-UP
Patient Monitoring
For pT3/T4 after RP; patients are generally followed every 3 mo for the 1st yr, every 6 mo for the next 2–5 yr and yearly thereafter depending on risk.
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. Cooke EW, Shrieve DC, Tward JD, et al. Clinical versus pathologic staging for prostate adenocarcinoma: How do they correlate? Am J Clin Oncol. 2012;35(4):364–368.
2. Thompson IM, Valicenti RK, Albertsen P, et al. Adjuvant and salvage radiotherapy after prostatectomy: AUA/ASTRO guideline. J Urol. 2013;190(2):144–149.
3. Thompson IM, Tangen CM, Paradelo J, et al. Adjuvant radiotherapy for pathological T3N0M0 prostate cancer significantly reduces risk of metastases and improves survival: Long-term follow-up of a randomized clinical trial. J Urol. 2009;181:956–962.
4. Bolla M, Collette L, Blank L, et al. Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): A phase III randomized trial. Lancet. 2002;360:103–106.
5. Wiegel T, Bottke D, Steiner U, et al. Phase III postoperative adjuvant radiotherapy after radical prostatectomy compared with radical prostatectomy alone in pT3 prostate cancer with postoperative undetectable prostate-specific antigen: ARO96-02/AUO AP 09/95. J Clin Onc. 2009;27(28):2924–2930.
6. Stephenson AJ, Shariat SF, Zelefsky MJ, et al. Salvage radiotherapy for recurrent prostate cancer after radical prostatectomy. JAMA. 2004;291:1325–1332.
7. Den RB, Feng FY, Showalter TN, et al. Genomic prostate cancer classifier predicts biochemical failure and metastases in patients after postoperative radiation therapy. Int J Radiat Oncol Biol Phys.2014;89(5):1038–1046.
ADDITIONAL READING
NCCN Prostate Cancer Guidelines: http://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf (Accessed May 21, 2014)
See Also (Topic, Algorithm, Media)
• Prostate Cancer, General
• Prostate Cancer, Locally Advanced (Clinical T3, T4)
• Prostate Cancer, Locally Advanced (Pathlogic T3, T4) Images 
• PSA Elevation, General Considerations
– PSA, General Considerations
• Reference Tables: TNM: Prostate Cancer
• Prostate Cancer, Positive Margin Following RP
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
• Pathologic T3/T4 prostate cancer includes extracapsular cancer than extends beyond the gland, without distant metastasis.
• High clinical stage, PSA levels, and Gleason score (from biopsy cores) predict more advanced pathologic staging.
• Level I evidence from 3 RCTs support adjuvant EBRT for high-risk pT3/T4 prostate cancer after RP.
• For patients who do not receive adjuvant EBRT, close follow-up with early salvage EBRT is very commonly practiced.
• There is no level I evidence for adding ADT to EBRT as part of adjuvant or salvage EBRT, but selected high-risk patients may benefit.