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Screening

Screening considerations

• Prostate cancer is slow growing and patients should only be screened if they have a life expectancy >10-15yrs (calculator here) to see the benefits of cancer diagnosis and treatment, otherwise do not screen.
• Overall lifetime risk of prostate cancer mortality is 3%
• There is no PSA threshold at any age that definitively rules out prostate cancer
• DRE: PPV 4-11% if PSA 0-2.9, 33-85% if PSA 3+

Age-specific recommendations

• Age < 40: do not screen - risk of cancer < 0.1%
• Age 40-55: only screen if family history or AA race
• Age 55-70: screen after discussing risks/benefits, consider screening q1-2yrs (q4yrs if PSA < 1)
• Age > 70: do not screen except in rare circumstances, stop screening if PSA < 3, consider biopsy only if PSA > 10
• If 1st degree relative with prostate cancer, screen 10yrs earlier than diagnosis

Elevated PSA differential

• Specific for the prostate, but non-specific for prostate disease - elevation can be cancer, BPH, or prostatitis
• Intercourse/ejaculation: 10% risk of causing PSA rise, if concerned then repeat after abstaining from ejaculation for 48hrs
• Bike riding:
• DRE: elevated PSA slightly, rarely causes false positive results
• 5ARi: obtain baseline PSA prior to treatment, variable reduction in PSA, multiply by 2.3 after 2yrs and 2.5 after 7yrs, no difference between 1mg and 5mg finasteride dose

PSA density

• Prostate cancer is more dense than BPH
• PSAd > 0.15 increases likelihood of cancer diagnosis
• PSAd < 0.08 has low chance of cancer diagnosis
• Elevated density has sensitivity/specificity of 75%/44% for predicting cancer on repeat biopsy

Prostate Biopsy

Recommendations

• Measure volume: W x L x H x 0.5 - 20-25g if < 50yo, 45-50g if 60-70yo
• 12 biopsies provides greatest benefit with least risk
• Obtain targeted biopsies if palpable nodule or lesion on MRI
• Anesthesia: inject lateral to prostate along neurovascular bundle, or at junction of SVs and prostatic base
• Make sure needle passing proximal to dentate line to minimize pain
• Risk of finding high grade cancer on prostate biopsy
• Post-treatment changes: 30% decreased size after ADT, 21% decreased side after 5ARi, edema with brachytherapy, smooth tapering of bladder neck to urethra after prostatectomy
• Antibiotics: fluoroquinolones, cephalosporins, and aminoglycosides are all options
• Anticoagulation: do not neede to discontinue ASA 81, but all other anticoagulants need to be stopped or bridged
• Enema: improves imaging but does not affect infection rates
• Transperineal biopsy: improved anterior and apicla tumor detection rates

Risks of biopsy

• Contraindications: coagulopathy, immunosuppression, acute prostatitis, anal stenosis
• Pain: temporary, treat w/ OTC meds, use ice pack behind scrotum
• Bleeding: expected hematospermia in 10-70%, hematuria in 14-50%, ~1% require hospitalization/transfusion, severe bleeding raree but may require sclerotherapy, epinephrine, angiography, and sutures
• Infection: overall rates 0.1-7%, sepsis rates 0.3-3.1%, hospitalization rate 0.6-4.1%
• Vasovagal response: seen in 1-5%, place in trendelenburg and give IV hydration if able
• Urinary retention: seen in 0.2-0.4%, may require temporary catheter

Prostate MRI

• PIRADS score: compares T2, DWI, DCE, ADC phases (requires contrast)
• Optional to obtain before biopsy, not yet a recommendation
• False negative: 10-16% chance of missing clinically significant cancer (negative MRI may still need biopsy)
• Inadequate results if obtained within 6-8 weeks of biopsy (inflammation/bleeding)
• Clinically significant cancer: PPV 17-23%, 34-49%, 67-77% for PIRADS 3, 4, 5
• PROMIS trial (Ahmed 2017): all men underwent standard and saturation biopsy + mpMRI, mpMRI (vs standard TRUS bx) showed increased sensitivity (93% vs 48%) and NPV (89% vs 74%) but decreased specificity (41% vs 96%) and PPV (51% vs 90%)
• PRECISION trial (Kasivisvanathan 2018): either had standard or MRI targeted biopsy, targeted biopsy had higher detection rate of clinically significant disease and lower detection of insignificant disease

Biopsy findings besides cancer

• HGPIN: seen 4-5%, 20-30% cancer risk on subsequent biopsy within 1yr (same as negative biopsy), repeat biopsy only recommended for multifocal HGPIN
• ASAP: increased cancer risk, consider repeat biopsy

Prostate Cancer AUA Risk Classifications

Risk Group	Grade Group	Clinical Stage	PSA	# Cores Positive	% Core Involvement	PSA Density	Further Workup	Treatment Recommendations	Metastatic risk on surveillance
Very Low	GG1	cT1-T2a	< 10	< 1/3	< 50%	< 0.15	none	Active Surveillance	< 1% @ 10-15yrs
Low				-				Active Surveillance (unless high risk for progression)	~3% @ 10-15yrs
Intermediate Favorable	GG1 GG2	cT2b-c	10-20 <10				*	RALP +/- PLND XRT +/- ADT	> 10-20% @ 15yrs
Intermediate Unfavorable	GG2 GG3	cT2b-c	10-20 < 20				*	RALP + PLND XRT w/o ADT
High	GG4-5	cT3-T4	> 20				CT +/- MR bone scan Consider genetic testing	RALP + PLND XRT + ADT ADT only (palliative option)

*Indications/Notes for Further Staging after Diagnosis

• AUA: stage w/ MR/CT if 2/3 are present - palpable nodule on DRE, GG2-3, PSA > 10
• NCCN: stage if life expectancy > 5yrs, get bone scan if cT2 + PSA > 10, get CT if T2 and nomogram predicts > 10% nodal involvement
• Bone scan: if PSA < 10, NPV 99.5% do not order bone scan, if PSA < 20 then < 1% will have positive bone scan findings

Active Surveillance/Watchful Waiting

Active Surveillance

• Gleason 3 has no metastatic potential compared to Gleason 4-5
• Any metastasis/death is caused by undiagnosed Gleason 4-5
• No unified active surveillance regimen
• 50-73% patients undergo treatment by 10yrs, either due to upgrading or anxiety/fear
• Endocrine dedifferentiation: cancer growth without PSA rise, occurs with undiagnosed hypogonadism, consider checking T level if concerned

Active Surveillance Protocols

Guideline	PSA	DRE	MRI	Biopsy
AUA	q3-6mo	q12mo	Unclear role	Repeat within 6-12mo Then q3-5yrs
ASCO
Cancer Care Ontario			If disconnect between pathology and clinical findings
NICE	q3-4mo, adjust per kinetics		At enrollment

Watchful Waiting

• Watchful waiting: PSA and clinical monitoring only, no biopsy or MRI
• Consider if life expectancy < 5yrs regardless of risk category
• Consider ADT for symptom management in absence of other treatments, no improvement in survival but may improve QoL

Focal Therapies

Basis for Focal Therapy as Treatment

• Treat GG2-5 with higher malignant potential, while avoiding treatment of GG1 disease that can be observed
• Although prostate cancer can be multifocal, usually the highest grade found in index lesion, whereas satellite lesions are smaller and lower grade
• Metastatic disease tends to be of monoclonal origin, usually from index lesion
• MRI can determine specific size/location of lesions requiring treatment and can watch other non-treated lesions

Therapy options

• Cryotherapy: cell kill via cold temperatures, prior TURP is relative contraindication (increases urethral sloughing risk), ED expected if whole gland therapy performed
• HIFU: transrectally applied US heats tissue to at least 55degrees
• Laser: transperineal/transrectal applied laser, requires safety margin otherwise angiogenesis occurs
• Irreversible Electroporation (IRE): direct current electricity applied, causes holes in cell membrane
• Vascular-Targeted Photodyanmic Therapy (VTP): near-infrared laser destroys tissues that are pre-sensitized with an intravascular agent preferentially taken up by cancer cells
• Brachytherapy: can be applied locally with rapid falloff of radiation exposure as distance from tumor increases
• HIDU/TULSA: transurethrally applied US similar to HIFU

Surgery (RALP) vs Radiation (XRT)

Considerations

• Equivalent chance for cure
• Deciding factors include age, comorbidities, and personal preferences
• Patients usually decided prior to physician discussion

	Surgery	XRT
Benefits	Removes all cancerous tissue Confirms diagnosis for upstaging Salvage XRT "easier" than salvage surgery	No incisions/surgery, no recovery needed No anesthetic risk
Risks	Immediate incontinence, 5-10% persistence at 1yr Immediate erectile dysfunction (with improvement over time) Usual surgical risks	Salvage RALP has high complication rate Worsens baseline LUTS Hematuria Acute/delayed GI toxicity Secondary malignancy

Locally advanced disease (T3-T4)

• Individualized management, no generalizable recommendations
• Manage with RALP/XRT, acknowledge high risk for recurrence and likely need for adjuvant therapies

Surgery

Surgical considerations

• Goals (in this order): cure prostate cancer, maintain continence, maintain erectile function
• If patient adamant regarding nerve sparing, discuss that this may compromise cancer cure
• Younger/healthier patients see greater long-term benefit with surgery - more likely to regain continence and erectile function
• No proven difference in open/robotic approach, depends on surgeon experience
• Pelvic lymphadenectomy recommended for patients with unfavorable intermediate or high risk disease

MSK nomograms

• Recurrence risk based on pre-surgical factors
• Recurrence risk based on post-surgical factors
• Mortality risk if biochemical recurrence after RALP
• Treatment success rate after salvage XRT

Specific surgical risks for counseling

• Post-op pain
• Bleeding - need for transfusion rare
• Infection - check preop UCx
• Bowel/intraabdominal organ injury - rare
• Cancer recurrence - depends on path results
• Incontinence - most (~90-95%) regain function by 1yr, pre-op Kegels shown to help
• Erectile dysfunction - best case scenario will be at pre-surgical baseline, can take up to 2yrs to return, 50-95% regain some function with nerve-sparing approach
• Anastomotic leak
• Lymphocele - occur in up to 60% after PLND (usually asymptomatic), may require intervention in 0-16% w/ sclerosis, unroofing
• Anejaculation - expected side effect of surgery, unrelated to orgasm potential
• Climacturia - occurs in 30%

Radiation (XRT)

General XRT options and terms

• External beam (EBRT): group of treatments with externalized administration of XRT
• Intensity Modulated (IMRT): type of EBRT, multiple beams with the goal of sparing adjacent tissues
• Stereotactic Body (SBRT): type of EBRT, photon based, hypofractionated (5 or less)
• Low dose brachytherapy: permanently implanted seeds
• High dose brachytherapy: temporarily placed seeds on the end of small catheters

Risk-Based Options

• Low: EBRT or brachy
• Intermediate favorable: EBRT or brachy without ADT
• Intermediate unfavorable: EBRT or brachy with ADT x2yrs
• High: EBRT + ADT x2yrs or EBRT + brachy

Risks, Side Effects, and Other Considerations

• Acute effects (< 90 days): mild GI/GU effects are common, but serious effects occur in < 5%
• Chronic effects (> 90 days): up to 28% report GU effects (dysuria, hematuria)
• Erectile dysfunction: 37-60% after EBRT, 30-51% after brachytherapy
• GI symptoms (proctitis) more common than after surgery (< 10%)
• Brachytherapy has higher risk for retention than EBRT
• Addition of ADT increases systemic and sexual side effects
• On stopping ADT, 93% regain some testosterone with 72% completely regaining testosterone
• Brachytherapy contraindicated if LUTS, prior TURP, or prostate > 60g
• EBRT contraindicated if ataxia telangiectasia (absolute), prior XRT (relative), history of IBD (relative)
• Secondary malignancy: rectal cancer rates at 10yrs - 0.03% (EBRT), 0.006% (brachy)

Biochemical Recurrence

Considerations

• Risk factors: positive margins, SVI, EPE, higher GG - recurrence rates 60+% for high risk features after RP w/o ART
• Post-prostatectomy: PSA > 0.2ng/mL
• Post-XRT (Phoenix criteria): rise of > 2ng/mL above nadir PSA
• PSA bounce: elevation of 0.1-0.15 over prebounce PSA with subsequent decrease, secondary to post-treatment prostatitis or delayed cell death
• If PSAdt < 10-12mo, 50% die within 10-13yrs
• Imaging: consider CT, MR, PET, although low utility if PSA < 5-10

After RALP

• XRT: greatest benefit if PSAdt < 6mo (any PSA), PSA < 2, PSAdt > 6mo (if Gleason 8-10 or positive margin)
• Bone scan: only 4% positive for metastasis if PSA < 10
• TRUS bx: 45% positive if PSA < 0.5, 100% positive if PSA > 2
• TRUS bx may not be informative if there is no palpable nodule to biopsy
• There is no proven difference between adjuvant and salvage radiation therapy

After XRT

• Gleason grading after XRT is not accurate
• Salvage RALP criteria: bx-proven cancer, 10+yrs life expectancy, no metastasis on imaging, and PSA < 10
• Salvage RALP side effects: 6-15% rectal injury, 20-28% BNC, 40-60% incontinence

PSA rise after RALP + XRT (no further local treatment options)

• Assess PSA doubling time, cutoff 12mo used to assess low vs high risk
• Consider CT, MR, bone scan, PET, although likely negative if PSA low (< 5-10)
• If metastatic disease, see recommendations below
• If no metastatic disease, discuss observation vs ADT, influenced by PSA doubling time
• Can consider intermittent ADT, cutoff PSA 4-10, no impact on overall mortality as long as PSAdt > 9mo
• No evidence/recommendation for best time to start ADT in absence of radiographic metastases

Androgen Deprivation Therapies (ADT)

Treatment Class	Specific Treatment	Uses	Side Effects
Surgical Treatment	Orchiectomy	Castration within 6hrs	Cosmetic perception Less side effects than drugs
Androgen Receptor Antagonist	First Generation: Bicalutamide (50mg daily) Flutamide	Prevent T surge with initiation of GnRH agonists	Inadequate as monotherapy T converted to E, gynecomastia Impotency (80%) Hepatitis (monitor LFTs) Withdrawal can decrease PSA due to mutation causing drug to act as an agonist
	Second Generation Enzalutamide (160mg daily) Apalutamide (240mg daily)	mCRPC	Both: rash, fatigue, diarrhea Enzalutamide: seizures (< 1%) Apalutamide: falls/fractures (12%), hypothyroid (8%)
GnRH Inhibition	Agonists: leuprolide, goserelin Antagonists: degarelix, cetorelix	Monotherapy or combination with other medications	T surge: occurs within 10-20 days, can cause symptom exacerbation if bone mets
Androgen Synthesis Inhibitors	Abiraterone (1000mg daily)	CYP17 inhibitor	Treat with prednisone (5mg QD-BID) to prevent hypocortisolism
	Ketoconazole (400mg TID)	Blocks 17,20 desmolase castration within 4hrs	Treat with hydrocortisone (5-20mg BID) Gynecomastia, hepatitis
Non-ADT Treatments	Docetaxel	Microtubule assembly inhibitor	Febrile neutropenia (15%) Systemic symptoms (7%) GI symptoms (8%)
	Cabazitaxel	Used for mCRPC after docetaxel	Neutropenia
	Sipuleucel-T	Immunotherapy	Improves survival without clinical/serologic/radiographic response
	Radium-223	a-emitting particle causing dsDNA breaks Bone metastases without visceral metastases	Neutropenia (2%) Thrombocytopenia (6%) Do not give with abiraterone PSA monitoring is not accurate
	Olaparib	PARP inhibitor	Anemia, nausea
	Pembrolizumab	anti-PD1 monoclonal antibody	Immunosuppresion side effects

When to Use Immediate ADT

Situation	Immediate ADT?
Low risk, localized disease	No benefit
Locally advanced	Improves cancer-specific survival No benefit in overall survival
Asymptomatic metastatic disease
Node-positive prior to primary therapy	May provide benefit
Node-positive after surgery	Improves overall survival
After biochemical recurrence, asymptomatic	Not required, okay for intermittent ADT (set threshold)

General complications of ADT

• Osteoporosis: risk of fracture 19% (vs 13%) at 5yrs and 40% (vs 19%) at 15yrs, recommend Ca 1000-1200 mg/d and Vitamin D 400-1000 IU/d, can consider bisphosphonates, calculate 10yr risk with FRAX calculator
• Hot flashes: seen in 50-80%, treat with megestrol 20mg BID, cyproterone acetate 50-300mg/d, venlafaxine 12.5mg BID
• Sexual dysfunction: 10-17% maintain erectile function, 5% maintain libido, PDE5i are not effective
• Cognitive function: questionable decline
• Weight gain: 2-4% at 1yr and loss of muscle mass
• Diabetes: increased insulin resistance
• Heart disease: 20% increased risk of CV morbidity at 1yr, 5.5% vs 2% at 5yrs
• Gynecomastia: 3-16% with leuprolide, can treat with prophylactic XRT (10-15Gy single fraction) but has no benefit after development of symptoms
• Anemia: common, 10+%

Metastatic Prostate Cancer

Defining Metastatic Disease

• High Volume (CHAARTED definition): visceral metastases and/or greater than 4 bone metastases, with at least one outside the vertebral column and pelvis
• Low Volume: does not meet high-volume criteria
• High risk (LATITUDE definition): 2/3 features - Gleason ≥8, ≥ 3 bone lesions, or visceral metastases

Treatment Recommendations for Metastatic and/or Castrate Resistant Prostate Cancer

Metastatic?	Castrate Resistant?	Workup	Treatments	Monitoring
No	No	PSAdt CT/MR Bone scan Consider PET	Observation iADT (PSA cutoff 4-10) Clinical trials	PSA q3-6mo Consider repeat imaging q6-12mo
Yes	No	CT/MR Bone scan PET (57% positive if PSA > 1) Consider genetic testing	ADT XRT + ADT (if low volume) Abiraterone + ADT Apalutamide/Enzalutamide + ADT Docetaxel + ADT
No	Yes	Calculate PSAdt (cutoff ≤ 10mo) CT/MR Bone scan	ADT (if PSAdt > 10mo) Apalutamide/Enzalutamide/Darolutamide + ADT (if PSAdt ≤ 10mo)
Yes	Yes	PSA, T, LDH, Hgb, AlkPhos CT/MR Bone scan Consider genetic testing	ADT + Abiraterone ADT + Docetaxel ADT + Enzalutamide Sipuleucel-T (if asymptomatic or minimally symptomatic) Radium-223 (if bony metastases only) Cabazitaxel (if prior docetaxel) Olaparib/Rucaparib (if germline mutation) Carboplatin (if no germline mutation) Pembrolizumab (if MMR mutations)	Annual imaging

Initial management of metastatic disease

• Obtain bone scan and CT A/P to assess degree of presumed metastatic prostate cancer
• Confirm diagnosis with tissue biopsy (prostate, bone)
• Risk of LH/T surge highest with spinal metastases and weight-bearing bones
• Consider bicalutamide 50mg daily x1mo prior to starting long-term ADT
• In acute setting, consider ketoconazole 400mg TID x3 days, then switch to bicalutamide

Follow Up

Post-RALP

• Year 1: PSA at 1mo, 4mo, 8mo, 12mo postop
• year 2-10+: annual PSA
• Assess continence and erectile function at each visit

Post-XRT

• No clear guidelines
• Usually PSA q3-6mo for 2yrs, then space out afterwards if PSA stable

Post-ADT

• Shorter time from ADT initiation to undetectable PSA correlates with improved cancer-specific mortality
• If undetectable PSA not achieved, progression to castrate-resistant disease is 15x higher
• Median survival: 75mo if PSA < 0.2, 44mo if PSA 0.2-4, 13mo if PSA > 4

Metastatic disease

• Check PSA q3-6mo depending on treatment intervals

References:

• AUA Core Curriculum
• Antonarakis, E., and M. Carducci. "Treatment of Castration-Resistant Prostate Cancer." Campbell-Walsh Urology 12 (2020).
• Bolla, Michel, et al. "Postoperative radiotherapy after radical prostatectomy for high-risk prostate cancer: long-term results of a randomised controlled trial (EORTC trial 22911)." The Lancet 380.9858 (2012): 2018-2027.
• Carter, H. Ballentine, et al. "Early detection of prostate cancer: AUA Guideline." The Journal of urology 190.2 (2013): 419-426.
• Eggener, S. "Hormonal Therapy for Prostate Cancer." Campbell-Walsh Urology 12 (2020).
• Klotz, L. "Active Surveillance of Prostate Cancer." Campbell-Walsh Urology 12 (2020).
• Lee, E., and J. Thrasher. "Management Strategies for Biochemical Recurrence of Prostate Cancer." Campbell-Walsh Urology 12 (2020).
• Loeb, S. and J. Eastham. "Diagnosis and Staging of Prostate Cancer." Campbell-Walsh Urology 12 (2020).
• Lowrance, William, et al. "Adavanced prostate cancer: AUA/ASTRO/SUO guideline." AUA https://www. auanet. org/guidelines/advanced-prostate-cancer (2020).
• Phillips, R., S. Hazell, and D. Song. "Radiation Therapy for Prostate Cancer." Campbell-Walsh Urology 12 (2020).
• Pound, Charles R., et al. "Natural history of progression after PSA elevation following radical prostatectomy." Jama 281.17 (1999): 1591-1597.
• Sanda, Martin G., et al. "Clinically localized prostate cancer: AUA/ASTRO/SUO guideline. Part I: risk stratification, shared decision making, and care options." The Journal of urology 199.3 (2018): 683-690.
• Sanda, Martin G., et al. "Clinically localized prostate cancer: AUA/ASTRO/SUO guideline. Part I: risk stratification, shared decision making, and care options." The Journal of urology 199.3 (2018): 683-690.
• Stephenson, A., R. Abouassaly, and E. Klein. "Epidemiology, Etiology, and Prevention of Prostate Cancer." Campbell-Walsh Urology 12 (2020).
• Tay, KJ. and T. Polascik. "Focal Therapy for Prostate Cancer." Campbell-Walsh Urology 12 (2020).
• Thompson, Ian M., et al. "Adjuvant radiotherapy for pathological T3N0M0 prostate cancer significantly reduces risk of metastases and improves survival: long-term followup of a randomized clinical trial." The Journal of urology 181.3 (2009): 956-962.
• Thompson, Ian M., et al. "Adjuvant and salvage radiotherapy after prostatectomy: AUA/ASTRO Guideline." The Journal of urology 190.2 (2013): 441-449.
• Trabulsi, E., E. Halpern, and L. Gomella. "Prostate Biopsy: Techniques and Imaging." Campbell-Walsh Urology 12 (2020).