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Active Surveillance/Watchful Waiting

Active Surveillance

• Gleason 3: no proven metastatic potential compared to Gleason 4-5, any metastasis/death is caused by undiagnosed Gleason 4-5
• No unified active surveillance regimen
• Treatment upgrade: 30-73% patients undergo treatment by 10yrs, either due to upgrading or anxiety/fear
• Risk factors for upgrade:younger age, higher volume urologists, higher PSA< higher cancer volume at diagnosis (per Timilshina 2021)
• Endocrine dedifferentiation: cancer growth without PSA rise, occurs with undiagnosed hypogonadism, consider checking T level if concerned
• Watchful waiting: can transition off AS if life expectancy decreases to 5-10yrs

Active Surveillance Protocols

Guideline	PSA	DRE	MRI	Biopsy
AUA	q3-6mo	q12mo	Consider using	Repeat within 6-12mo Then q3-5yrs
ASCO			Not recommended
EAU	q6mo		Recommended if rising PSA
NCCN			Recommended
Cancer Care Ontario	q3-6mo		If disconnect between pathology and clinical findings
NICE	q3-4mo, adjust per kinetics		At enrollment

Watchful Waiting

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

Focal Therapies

Rationale for Focal Therapy as Treatment

• Minimizing harm: treat the GG2-5 with higher malignant potential while avoiding treatment of GG1 disease that can be safely observed
• Primary lesion theory: although prostate cancer can be multifocal, usually the highest grade found in index lesion, whereas satellite lesions are smaller and lower grade
• Monoclonal theory: metastatic disease tends to be of monoclonal origin, usually from index lesion
• Improved imaging modality: MRI can determine specific size/location of lesions requiring treatment and can watch other non-treated lesions

Therapy options

• Patient selection: at this time no specific criteria, no strong guideline recommendations for treatment, patients need to be adequately counseled that treatments are not yet considered "standard of care"
• Cryotherapy: cell kill via cold temperatures, prior TURP is relative contraindication (increases urethral sloughing risk), ED expected if whole gland therapy performed, tends to occur at apex, fistula occurs < 1% for primary and 10% for post-XRT salvage
• 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

Choosing 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
• Management: often requires multimodal therapy (RALP + XRT + ADT), acknowledge higher risk for recurrence and likely need for adjuvant therapies
• Obstruction management: channel TURP for urethral obstruction, stents/PCNs for ureteral obstruction
• Hematuria management: options include ADT, XRT, embolization, and TURP

Surgery

Considerations for counseling

• Goals: cure prostate cancer, maintain continence, maintain erectile function, if patient adamant regarding nerve sparing discuss that this may compromise cancer cure
• Effects of timing delay: no clear evidence that delaying treatment up to 12 months affects long-term outcomes, even for intermediate and high risk cancer (Nguyen 2021)
• Age: 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, prostatectomy should be completed even if concerning lymph nodes are found intraoperatively (survival benefit compared to aborting and giving ADT only), no benefit to removal of Cloquet node (per Plata Bello 2022)
• SPT placement: proven to cause less postop pain, patients do not enjoy having urethral catheter
• Hx outlet procedure: no difference in oncologic outcomes, but has been shown to have negative impact on continence and erectile function, per Leyh-Bannurah et al JU 2021
• Multifocal disease (per Matsumoto 2021): usually index lesion has both largest tumor and highest GG, but in settings with disconcordant size and GG, secondary lesion (highest GG) determines outcomes
• ADT: no proven benefit in surgical outcomes with neoadjuvant ADT

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

Post-Prostatectomy Incontinence

• Resolution: 90% dry within 6mo, 95% dry within 12mo - 1 PPD at 3mo is good predictor of long-term continence
• Age: younger patients show better continence recovery
• Bladder neck: attempting to preserve the bladder neck will not increase chances of final continence, but will improve rate at which continence is obtained
• Obesity: worsens incontinence
• Pre-surgery kegels: faster return of continence
• Non-surgical options: weight loss, kegels +/- pelvic floor PT (helps with relaxation and contraction)
• Sling: option for mild/moderate incontinence, contraindicated if XRT
• AUS: gold standard
• For more PPI info, see separate page

Post-Prostatectomy Erectile Dysfunction

• Assess preop erectile function (SHIM score) to frame post-op expectations
• Penile rehab: start within 2-6 weeks after surgery, strongest evidence for sildenafil 100mg daily (Motlagh 2021), other alternatives include tadalafil 5mg daily, tadalafil 20mg EOD, or sildenafil 100mg EOD, low evidence for pelvic floor PT
• Penile traction: per Toussi 2021, decreased postop loss of erections with RestoreX traction device
• If > 30% erection at 3mo, good predictor of regaining erectile function
• Rationale: loss of stimulation/blood flow immediately post-op leads to corporal fibrosis and loss of length/function
• For more ED info, see separate page

Postoperative findings

• Positive margin: 50% chance recurrence, higher overall mortality rate
• Postop XRT: give salvage XRT if postoperative PSA is detectable, but can consider observation if positive lymph nodes but undetectable PSA (30% will remain disease-free), multiple studies (RAVES, RADICALS, GETUG-AFU 17) show no clear benefit to adjuvant XRT over salvage XRT
• Benign prostate tissue at margin: not associated with biochemical recurrence or persistently elevated PSA (per Greenberg 2021)

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
• SpaceOAR: hydrogel injected between rectum and perineum, helps to decrease rectal toxicity, absorbed within 3 months, contraindicated in men without clear plane (concern for cancer invasion)
• PSA bounce: temporary PSA rise seen in 20-40%, usually within 1-3yr treatment, usually within 1mg/dL (but up to 16mg/dL)

Risk-Based Options

• Low: moderate/ultra hypofractionated EBRT or brachy
• Intermediate favorable: moderate/ultra hypofractionated EBRT or brachy without ADT
• Intermediate unfavorable: moderate/ultra hypofractionated EBRT or brachy with ADT x4-6mo
• High: moderate hypofractionated EBRT + ADT x18-36mo or EBRT + brachy

Risks, Side Effects, and Other Considerations

• Lymph node inclusion: only indicated for high risk, otherwise no proven benefit
• 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%)
• GU long-term symptoms: hemorrhagic cystitis seen (8%), urethral stricture (3%), incontinence (3%), self-limited hematuria can be seen in up to 33% patients (per Turchan 2022)
• Retention: more common with brachytherapy than EBRT
• Addition of ADT: increases systemic and sexual side effects, no specific timing before/during/after XRT, on stopping ADT 93% regain some testosterone with 72% completely regaining testosterone
• Brachytherapy contraindications: LUTS, prior TURP, or prostate > 60g
• EBRT contraindications: 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

• Ultrasensitive PSA: can consider checking, but confirm rising trend prior to recommending treatment
• If PSAdt < 10-12mo, 50% die within 10-13yrs
• Imaging: PSMA PET/CT is most sensitive, can consider F18 for poor PSA-producing cancers, can use MRI to assess prostate fossa for recurrence, bone scan only 4% positive if PSA < 10
• BPH: slow PSA rise can be due to residual BPH tissue even after RALP, can trend PSA in properly-selected patients
• Recurrence after focal therapy: treat with surgery or XRT

After RALP

• BCR Definition: PSA > 0.2ng/mL
• Risk factors: positive margins, SVI, EPE, higher GG - recurrence rates 60+% for high risk features after RP w/o ART
• PSMA PET/CT: can assist with XRT targeting (fossa vs whole pelvis), XRT still recommended even if PET/CT is negative for metastatic disease (may otherwise miss treatment window)
• XRT: greatest benefit if PSA < 1, long PSAdt, > 1-2yr since prostatectomy, and > 10yr life expectancy
• 5yr BCR based on PSA trigger for XRT: 27% if ≤ 0.2, 33% if 0.21-0.5, 38% if 0.51-1.0, 57% if 1.01-2.0 - therefore recommend XRT at PSA < 0.5, consider if PSA < 0.2 and risk factors (see above)
• aXRT vs sXRT: RAVES, RADICALS, and GETUG-AFU17 showed no difference in BCR, sXRT has less risk for toxicity and avoids overtreatment, aXRT recommended only for those patients with multiple risk factors for recurrence
• ADT: recommended with sXRT if PSA > 0.7, GG4-5, PSADT <6mo, persistently detectable post-operative PSA, seminal vesicle involvement, positive nodes - give for at least 4-6 and up to 18-24mo (if high risk features) - otherwise can offer XRT only
• TRUS bx: 45% positive if PSA < 0.5, 100% positive if PSA > 2, may not be informative if there is no palpable nodule to biopsy

After XRT

• BCR Definition (Phoenix criteria): rise of > 2ng/mL above nadir PSA
• Biopsy: perform prior to considering salvage therapy, not accurate if performed < 18mo after XRT, Gleason grading after XRT is not accurate, sample seminal vesicles for local invasion
• Options: RALP, HIFU, cryotherapy, further XRT, similar treatment efficacy at 2 and 5yr
• 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
• Salvage cryotherapy: may provide benefit in avoiding need for ADT (per Chin 2021)
• Nodal recurrence: if no XRT was given to nodes during initial treatment, can perform further XRT + ADT to pelvic nodes

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)
• 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
• For further management of metastatic disease and ADT use, see this page.

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