Biochemical Recurrence

Biochemical Recurrence After Radical Prostatectomy

Background

• After successful radical prostatectomy (complete removal of prostate and cancer), PSA is expected to become undetectable (after the appropriate number of half-lives for elimination; recall PSA half-life 2-3 days and fraction remaining is 1/(2exp(n)) where n is number of half-lives)
• Detectable and rising PSA is usually the earliest evidence of tumor recurrence after radical prostatectomy
  • This rising PSA normally precedes clinically meaningful events in an extremely protracted and variable manner. (see Pound et al. below)

Definition

• Biochemical/PSA recurrence (BCR) after radical prostatectomy (AUA/ASTRO): PSA ≥ 0.2 ng/mL with a second confirmatory laboratory value[1]
  • A period of undetectable PSA after radical prostatectomy is not required

Epidemiology

• Incidence: ≈25-41% develop PSA recurrence within 10 years of radical prostatectomy
  • In patients that have BCR after radical prostatectomy
    • ≈50% of recurrences appear within 3 years
    • ≈80% within 5 years
    • ≈99% within 10 years
    • Rarely, BCR can occur > 15 years after radical prostatectomy
    • Clinical implication: given low risk of recurrence after 10 years and protracted course of untreated biochemical recurrence (see Pound et al. below), likely low utility of PSA follow-up beyond 10 years, particularly in older patient (average life expectancy of US male in 2018: 78.5)

Risk factors

• Nomogram to predict the risk of BCR (and cancer-specific survival) after radical prostatectomy used (7):
  1. PSA
  2. Gleason score
  3. Presence of extraprostatic extension
  4. Seminal vesicle invasion
  5. Lymph node involvement
  6. Margin status
  7. Adjuvant radiation
  • Length of positive margin has also been associated with risk of BCR

Natural history

• Not all patients with detectable PSA level after radical prostatectomy will have clinical progression, defined as development of metastatic disease, need for second-line treatment, or death from prostate cancer.
  • Significant proportion will have a detectable PSA level that plateaus and does not progressively rise.
    • Potential explanations (3):
      1. Residual benign prostatic tissue (often used as the rationale for a detectable PSA level after radiation therapy)
      2. Non-prostatic source: PSA is produced at very low levels by other cells such as the urethral glands and salivary glands
      3. Residual low-grade prostate cancer destined to follow an indolent course
• In patients with untreated BCR after radical prostatectomy, the time to clinically meaningful events may be prolonged
  • Pound et al. (Landmark study)
    • Population: Cohort study of 1997 men who underwent radical prostatectomy (mostly low risk based on clinical staging) without neo- or adjuvant treatment.
    • Results:
      • 304 men developed biochemical recurrence
      • Median time from biochemical recurrence to metastasis: 8 years
        • In a recent update, metastasis-free survival was 10 years
      • Median time from development of metastatic disease to death: 5 years
      • Thus, the median time from biochemical recurrence to death is more than 13 years.
    • Pound, Charles R., et al. "Natural history of progression after PSA elevation following radical prostatectomy." Jama 281.17 (1999): 1591-1597.
• BCR has an impact on survival, but this effect appears to be limited to a subgroup of patients with specific clinical risk factors.[2]
  • If RP, short PSA-doubling time and a high final Gleason score after RP have a negative impact on survival.
  • If RP, short interval to biochemical failure after RT and a high biopsy Gleason score have a negative impact on survival.

Risk-stratification

• EAU defined risk groups[3]
  • Low-risk:
    • RP: PSA DT > 1 year and prostatectomy GS <8
    • RT: interval to BCR > 18 months and biopsy GS <8
  • High-risk:
    • RP: PSA-DT ≤1 yr or prostatectomy GS 8–10 (ISUP grade 4–5)
    • RT: interval to BCR ≤ 18 mo or biopsy GS 8–10 (ISUP grade 4–5)

Diagnosis and Evaluation

• Need to define extent of disease local vs. distant) to guide management
  • If local failure: salvage radiation
  • If distant failure: treat as metastatic castrate-sensitive disease (see AUA and CUA Guideline Notes)
  • PSA velocity, doubling time, interval from surgery to biochemical recurrence, and Gleason score usually help determine whether failure is local or distal, both of which are informative in deciding management.

Imaging

• Local failure
  • MRI
    • Useful even in low PSA values
    • Sensitivity, specificity, and accuracy of 98%, 94%, and 93%, respectively, in identifying local recurrence after RP when validated by PSA level decrease after external beam radiotherapy and had sensitivity, specificity, and accuracy of 100%, 97%, and 91% when validated by ultrasound-guided biopsy§
  • Novel PET-CT imaging
    • See below; also used to evaluate distant failure
• Distant failure
  • Median PSA at the time of a newly detected bone metastasis is 32 ng/mL in hormone therapy–naive men after radical prostatectomy,
    • ≈25% of those metastases occurred at PSA < 10 ng/mL.
  • "Conventional" imaging: CT scan and bone scan
    • Diagnostic yield is significantly influenced by the PSA level
      • Limited if PSA < 10 ng/mL; very limited if PSA 0.2-1 ng/mL
    • CT scan
      • Advantage
        • Good at detecting nodal and visceral metastases
      • Disadvantage
        • Bone metastases are difficult to detect
      • Meta-analysis (2004)
      • 25 studies evaluating prostate cancer staging
      • Results:
        • Detection of lymph node metastasis on CT scan based on PSA:
          • <20 ng/mL: 0%
          • >20 ng/mL: 1.1%
      • Abuzallouf, Sadeq, Ian Dayes, and Himu Lukka."Baseline staging of newly diagnosed prostate cancer: a summary of the literature." The Journal of urology 171.6 Part 1 (2004): 2122-2127.
    • Bone scan
      • Time consuming (3 - 4 hours)
      • Costs: 600-1000$ USD
      • Advantage
        • Good at detecting bone metastases
      • Disadvantage
        • Limited sensitivity at detecting bone metastases with low PSA
      • Meta-analysis (2004)
      • 23 studies evaluating prostate cancer staging
      • Results:
        • Detection of bone metastasis on bone scan based on PSA:
          • < 10 ng/mL: 2.3%
          • ≥10 - 20 ng/mL≤l: 5.3%
          • >20 - 49.9 ng/mL: 16.2%
      • Abuzallouf, Sadeq, Ian Dayes, and Himu Lukka."Baseline staging of newly diagnosed prostate cancer: a summary of the literature." The Journal of urology 171.6 Part 1 (2004): 2122-2127.
  • Novel PET-CT imaging§
    • See Prostate Cancer: Diagnosis and Evaluation Chapter Notes
    • Advantage over conventional imaging
      • Higher sensitivity for the detection of prostate cancer recurrence and metastases at low PSA values (<2.0ng/mL).
    • FDA approved after biochemical recurrence to evaluate for role of locoregional salvage treatment
    • 2021 CUA Best Practice Report: may be helpful after biochemical recurrence to evaluate for role of locoregional salvage treatment§
  • Newer generation prostate-specific membrane antigen (PSMA) antibodies are promising for both prostate cancer detection and potential therapy.

Local failure

• Salvage Radiation
  • See Management of Locally Advanced Prostate Cancer Chapter Notes
  • Radiation is considered ‘salvage’ in the context of persistent or rising PSA level after radical prostatectomy
    • Radiation is considered ‘adjuvant’ in the context of undetectable PSA level after radical prostatectomy
  • Improves biochemical recurrence-free survival, progression-free survival, cancer-specific survival, and overall survival
    • Of all salvage options, including ADT, radiation provides the best long-term progression-free survival.
  • Whole-pelvis vs. prostatic bed radiation therapy
    • No mature randomized controlled trial demonstrates the added benefit of whole-pelvis radiation compared to prostatic bed only radiation
    • RTOG 0534
      • RCT currently accruing patients with high-risk prostate cancer features on radical prostatectomy and with post-surgery PSA levels of 0.1 ng/mL or greater to < 2.0 ng/mL
      • Randomizing them to prostatic bed radiation alone, prostatic bed radiation + 6 months ADT, and prostatic bed radiation therapy plus pelvic lymph node radiation therapy + 6 months ADT
  • Timing
    • Outcomes improved when delivered at lower PSA values, some use ≤ 0.5 ng/mL
  • Dosage of salvage radiation
    • At least 64 Gy of salvage radiation should be administered to the prostatic bed. However, emerging evidence now demonstrates improvement with higher dosages.
      • Recall EBRT radiation dose for localized disease: 76-80 Gy
      • Recall brachytherapy radiation dose for localized disease: ≈145 Gy for iodine and 125 Gy for palladium
  • Concurrent Androgen Deprivation Therapy with Salvage Radiation
    • Theoretically, the use of systemic therapy with androgen deprivation may treat micrometastatic disease, shrink tumor burden making it more amenable to local salvage therapy, and potentially work in synergy with radiation therapy to treat remaining cancer cells.
    • Guidline Statement 9 from the 2017 AUA Adjuvant and Salvage Radiotherapy after Prostatectomy Guidelines: "Clinicians should offer hormone therapy to patients treated with salvage radiotherapy (postoperative PSA ≥0.2 ng/mL). Ongoing research may someday allow personalized selection of hormone or other therapies within patient subsets. (Standard; Evidence Strength: Grade A)"
    • GETUG-AFU 16
      • Population: 743 patients who underwent prostatectomy and whose prostate-specific antigen (PSA) increased from 0.1 ng/mL to between 0.2 ng/mL and 2.0 ng/mL
      • Randomized to radiotherapy +/- ADT (on first day of irridiation and 3 months later)
      • Primary outcome: progression-free survival
      • Results
        • Median follow-up: 112 months
        • Progression free-survival signficantly improved with addition of ADT (absolute benefit 15% at 10-years (65% radiation + ADT vs. 49% radiation alone)
      • Carrie, Christian, et al."Short-term androgen deprivation therapy combined with radiotherapy as salvage treatment after radical prostatectomy for prostate cancer (GETUG-AFU 16): a 112-month follow-up of a phase 3, randomised trial." The Lancet Oncology 20.12 (2019): 1740-1749.
    • RTOG 96-01
      • Population: 760 patients who underwent prostatectomy and were found to have pT3N0M0 or pT2 with positive margins and detectable PSA
      • Randomized to salvage radiation therapy +/- 2 years of bicalutamide
      • Results:
        • Median follow-up was 13 years
        • Bicalutamide had significantly improved OS, cancer-specific survival, and metastasis-free survival
        • Gynecomastia was significantly more common in the bicalutamide group
      • Shipley, William U., et al."Radiation with or without antiandrogen therapy in recurrent prostate cancer." New England Journal of Medicine 376.5 (2017): 417-428.
    • Observational study found that ADT most beneficial in patients with high-risk features§
    • Secondary analysis of RTOG 96-01 found that benefit of ADT was in those with PSA >0.60§
  • Prognosis
    • Patients most likely to have favorable responses to salvage radiotherapy are those with
      1. PSA recurrence long after surgery
      2. Slowly rising PSA
      3. Low-grade tumor
      4. No seminal vesicle invasion
      5. No lymph node metastases
    • Risk factors for biochemical relapse after salvage radiation include pathologic stage T3a or less versus T3b, pathologic Gleason score, and pre-salvage radiation PSA levels.
    • Patients with a PSA nadir > 0.05 ng/mL after salvage radiation therapy have an increased risk for distant metastatic disease and reduced prostate cancer–specific survival.
  • Failure after salvage radiation therapy can be due to:
    1. Persistent local disease
    2. Recurrence of local disease
    3. Persistence of metastasis
    4. Development of metastatic disease

Distant failure

• Treat as metastatic castrate-sensitive disease (see AUA and CUA Guideline Notes)

Androgen Deprivation Therapy for Biochemical Failure after Radical Prostatectomy

• ADT is non-curative for biochemical failure after radical prostatectomy (unlike salvage radiation which an be curative)
  • No data from prospective trials address a possible progression-free or overall survival benefit in the post prostatectomy setting
  • Despite the lack of survival benefit, ≈60% of patients with biochemical failure after radical prostatectomy will undergo ADT as second-line treatment
• 2020 AUA Advanced Prostate Cancer Guideliens: not recommended
  • ADT should not be routinely initiated for biochemical recurrence after radical prostatectomy
    • Two large observational studies found no difference in mortality in patients treated with immediate vs. deferred ADT for biochemical recurrence.
    • It is recognized that ADT is sometimes given to men with rapid PSA rises in the absence of radiographic metastases in an attempt to delay the appearance of metastases. There is no evidence to determine the best time to start ADT in the absence of radiographic metastases.
    • If ADT is initiated in the absence of metastatic disease, intermittent ADT may be offered in lieu of continuous ADT.
• Monotherapy with high-dose bicalutamide (150mg daily) administration has been reported to delay disease progression and yield overall survival results equivalent to those of treatment with orchiectomy among patients with PSA recurrence.
  • A possible advantage of this form of hormone therapy is that it is associated with less risk for sexual dysfunction and osteoporosis than other forms of ADT.
  • A disadvantage is a possible increased risk for cardiovascular complications and death associated with high-dose bicalutamide therapy.
  • Wirth, M., et al. "Bicalutamide (Casodex) 150 mg as immediate therapy in patients with localized or locally advanced prostate cancer significantly reduces the risk of disease progression." Urology 58.2 (2001): 146-150.

Biochemical Recurrence After Radiation Therapy

Definition

• 1996 ASTRO (American Society for Therapeutic Radiology and Oncology) definition: 3 consecutive PSA increases measured 6 months apart and backdating the time of cancer progression to halfway between the PSA nadir and the first rising PSA level
• 2005 Phoenix definition: PSA nadir + 2 ng/mL; failure is not backdated. Thus the time to recurrence is further prolonged after the PSA level begins to rise, and often it takes a considerably longer time for the PSA level to increase by 2 ng/mL
  • The Phoenix definition of definition of failure is associated with fewer false positives for failure than the ASTRO definition
• Given the differences in defining failure, it is not possible to make fair comparisons between radical prostatectomy and radiotherapy by use of these outcome measurements; other measurements such as metastasis-free survival or cancer-specific survival are more appropriate comparisons of treatment failure

• Post-radiation PSA bounce – See Section in Management of Localized Prostate Cancer Chapter Notes
• Biochemical failure determination and histologic failure are ideally identified at least 2 years after primary treatment to account for PSA bounce and ongoing histologic changes after radiation

Natural history

• PSA-only recurrence after definitive radiation therapy for prostate cancer leads to clinically relevant outcomes such as local and distant failure along with cancer-specific death.
• Men with PSA elevation after definitive radiotherapy are candidates for salvage therapy
• Factors associated with clinical progression after biochemical recurrence after radiation terapy (4):
  1. Time from radiation therapy to biochemical recurrence <3 years
  2. PSA doubling time <3 months
     1. PSA doubling time has consistently demonstrated the ability to predict for patients who are at highest risk for failure after radiotherapy and has been linked to freedom from biochemical recurrence, local relapse, distant metastasis, and overall survival.
  3. Pretreatment biopsy grade group ≥4
  4. Pretreatment clinical tumor stage ≥cT3b

Diagnosis and Evaluation

• Patients who experience biochemical recurrence after definitive radiotherapy are at risk for both local recurrence and distant failure. Differentiating local (by prostate biopsy) vs. distant failure (by imaging) is critical to guide management.

Imaging

• Primary
  • Imaging of the prostate after definitive radiotherapy remains challenging with traditional modalities because of fibrosis and shrinkage of the prostate.
  • MRI
    • The most promising technique for identifying recurrent tumors of the prostate in biochemical recurrence following radiotherapy.
  • PET/CT
    • Use in the setting of BCR after RT, while promising, has not been entirely defined and is under active study.
      • 11C-choline PET can assist with differentiating local recurrence from metastatic disease at a PSA value when salvage treatment can be considered. However, PET has poorer spatial resolution than MRI, limiting its ability to assist in biopsy guidance.
      • PSMA based imaging is a relatively new modality with potential use in the evaluation of BCR after RT.
• Distant
  • Bone scan
    • The lowest PSA value at which bone scans are reliably positive is not known, but PSADT is a reasonable indicator of bone scan reliability.
      • In patients with PSA <10 ng/ml the chance of detecting a lesion on bone scan is <1% in those with PSADT >6 months and 10% in those with PSADT <6 months.
  • Computerized tomography
    • Patients most likely to benefit from salvage therapy have a PSA <10 ng/ml
    • The probability that CT in asymptomatic men with PSA <10 ng/ml will yield actionable information (ie detection of metastatic disease) is low.
      • CT is reasonable if advanced imaging modalities are unavailable, although newer modalities (PSMA PET) are more sensitive for nodal disease detection.

Biopsy after radiotherapy

• Strongly recommended to document local recurrence before offering salvage treatments.
  • The goals of biopsy after definitive radiation are to identify the presence or absence of residual or recurrent disease and to identify the grade of remaining disease.
    • Diagnosis and grading may be problematic due to radiation induced histological changes and treatment effect, with a high false-positive rate the first year after RT. Nevertheless, histological grade serves as an important prognostic factor for salvage and systemic treatment responses.
  • The information from prostate biopsy will guide further treatment strategies and should be reserved for patients in whom salvage local therapy is considered.
• Multiparametric-MRI directed biopsy should be considered.
  • If there are no MRI detectable, ie PI-RADS (Prostate Imaging Reporting and Data System) score 1, or image enhanced lesions, standard systematic biopsy should be performed.
  • For a MRI detectable lesion, a standard 12-core systematic biopsy plus at least 1 MRI guided core obtained from each target of interest is recommended.
• Before widespread use of MRI targetting, biopsy of the seminal vesicles was recommended as prostate cancer invasion had been reported in up to 42% of cases

Management

• Based on pattern of failure: locoregional vs. systemic disease (presence of lymph node, bone or visceral metastases)
  • Aggressive local therapy is not recommended outside a clinical trial. Instead, treatment should focus on standard approaches for metastatic castrate sensitive disease

Local failures (no evidence of metastases)

Options (6)§:

1. Active surveillance/observation
2. Local salvage therapy
   1. Salvage radical prostatectomy
      • In highly selected cases by highly experience surgeons (see below)
   2. Salvage cryosurgery
   3. Salvage brachytherapy
   4. Salvage high intensity focused ultrasound
3. ADT (intermittent or continuous)

Active surveillance/observation

• A reasonable option, particularly for lower risk patients with:
  1. BCR >3 years from RT
  2. PSADT ≥16 months
  3. Pre-RT biopsy pathology grade group 1
  • These features indicate a low liklihood of prostate cancer-specific mortality over a 10-year period
• Minimizes morbidity and is well suited for older patients and those who do not wish to undergo further treatments.
• May be considered in men with a life expectancy <10 years.

Local salvage therapy

• May potentially increase metastasis-free survival, delay initiation of ADT and eradicate recurrent/ residual disease in appropriately selected patients
  • Unknown survival benefit
    • Studies comparing local salvage therapy vs. observation (and delayed intervention for metastasis) are lacking
• Biopsy-proven evidence of local recurrence should be obtained prior to local salvage therapy, given the potential for risk of complications with salvage therapy, particularly salvage radical prostatectomy
• Indications
  • Biochemical recurrence after radiation therapy with
    1. Clinically localized T1c-T2 disease
    2. PSA <10.0 ng/ml at biochemical recurrence
    3. No evidence of metastasis on prior evaluation
• Options (4):
  1. Salvage radical prostatectomy
  2. Salvage cryosurgery
  3. Salvage brachytherapy
  4. Salvage high intensity focused ultrasound

Salvage Radical Prostatectomy

• Historical
  • Feasability first published in 1980 in a series of 18 patients from the Mayo Clinic. Reasons for SRP included the discovery of an enlarging indurated prostatic mass after radiotherapy and compliance with a radiation-surgery protocol that was initiated for a time in 1969. There were 0 deaths, 1 pulmonary emobolus, 0 patients complained of total urinary incontinence, and no rectal injury reported.§
• Utilization
  • Not commonly used to treat biochemical recurrence after radical prostatectomy
  • Technically challenging operation with the potential for serious complications
    • Should only be performed by experienced surgeons.
      • No published report on learning curve with SRP
• Indications
  • NCCN§
    • Option for highly selected patients with local recurrence after EBRT, brachytherapy, or cryotherapy in the absence of metastases
  • EAU§
    • Should be considered only in patients with (6):
      1. Low co-morbidity
      2. Life expectancy > 10 years
      3. Initial clinical staging was T1 or T2
      4. Initial biopsy ISUP grade < 2/3
      5. Pre-salvage radical prostatectomy PSA < 10 ng/mL
      6. No LN involvement or evidence of distant metastatic disease pre-salvage radical prostatectomy
  • In summary, candidates for salvage surgery should be unrecognizable from the candidates we would choose for initial therapy with RRP and be highly motivated individuals who understand and accept the potentially higher morbidity associated with salvage surgery.
• Outcomes§§
  • Oncologic
    • Improved oncologic outcomes observed over time may be due to improved patient selection and stage migration
    • Systematic reviews
      • Positive surgical margin rate: ≈20%
      • Median follow-up ranges from 4.6 to 120 mo
        • Wide range of follow-up partly explains wide ranges of survival
          • Longer follow-up periods show a non-statistically significant trend toward adiminished BCR-free survival
      • Biochemical recurrence-free survival
        • 5 years: 47-82%
        • 10 years: 28-53%
      • Cancer-specific survival
        • 5 years: 89-100%
        • 10 years: 70-83%
      • Overall survival
        • 10 years: 54-90%
      • Prognostic factors§
        1. Pre-SRP PSA
        2. Considered the strongest prognostic factor; shown to significantly associated with PFS, CSS, and OS
        3. Gleason score on post irridation prostate biopsy
        4. Salvage RP Gleason score
        5. Salvage RP pathologic stage
        6. Salvage RP DNA ploidy
  • Complications
    • Significant high perioperative morbidity
      • Relatively poor postoperative urinary and sexual health related functional outcomes compared to primary radical prostatetomy
    • Urinary incontinence
      • Radiotherapy causes fibrosis of the bladder neck and external sphincteric tissues, resulting in delayed healing of the vesico-urethral anastomosis (prolonged urinary extravasation), an increased incidence of bladder neck contracture and worse post-operative continence rate.
        • High rate of urinary incontinence is likely the greatest factor discouraging physicians from considering patients with radio recurrent prostate cancer for salvage RP.
        • Bladder neck contracture rate: 0-55%
          • A method that involves closing the opening in the bladder neck in 2 layers after prostate removal and making a new 26Fr to 30Fr opening made anterior, away from the radiation field has been described§
    • Erectile dysfunction
      • Extremely high incidence of erectile dysfunction before SRP
      • Post-SRP erectile function dropped significantly
        • Erectile function sufficient for sexual intercourse: 0-20%
    • Rectal injury
      • Definitive radiotherapy obliterates the plane between the posterior surface of the prostate and the overlying rectal wall, resulting in the higher incidence of rectal injury observed during SRP
        • SRP after brachytherapy is associated with greater difficulty and surgical complexity because of increased adhesions
      • Rectal injury rate: 0–28%
      • Management of rectal injury§
        1. Two-layer closure (most commonly used)
        2. Oversewing with the remnants of the neurovascular bundles
        3. Use of omentoplasty
        4. Colostomy
        • Some use bowel preparation before SRP
    • Some complications improved over time, others have not
      • • Contemporary radiation approaches (EBRT and transperineal interstitial radiotherapy) associated with reduced pelvic fibrosis.
          • Early series reported complications in patients who had undergone pre-radiotherapy pelvic lymph node dissection (RT-PLND) and/or retropubic interstitial radiotherapy which frequently cause extensive pelvic fibrosis.
            • RT-PLND is now infrequently performed.
            • Retropubic interstitial radiotherapy has been abandoned.
        • Rate of rectal injury and anastomotic stricture has significantly reduced§
          • Rate of rectal injury before 2000: 0-28% vs. after 2000: 2-10%
          • Rate of anastomotic stricture before 2000: 7-28% vs. after 2000: 11-41%
        • Blood transfusion rates similar to the standard RP procedure
        • Urinary incontinence and ED remain problematic
• Nerve-sparing
  • Can be performed in select patients based on preoperative characteristics, ease of dissection and intraoperative findings.
• Pelvic lymph node dissection
  • SEER studies found that overall§ and cancer-specific§ survival were significantly improved in patients undergoing surgery + PLND after radiation compared to those undergoing surgery alone
    • Lymph node count independently predicted lower cancer-specific survival
      • After the 7th removed lymph node, the effect of cancer-specific survival became marginal
• Approach (open vs. robotic)
  • Multi-institutional study (n=18) of 395 SRP (186 open vs. 209 robotic)
  • Robotic surgery associated with significantly
    • Reduced blood loss and shorter hospital stay
    • Reduced anastomotic stricture rate (17% open vs. 8% robotic)
    • Improved urinary incontinence, defined as 3 or more pads per day (22% open vs. 32% robotic at 12 months)
    • Robotic approach independent predictor of continence preservation on multivariable analysis
  • No significant difference in
    • Overall complications (36% open vs. 34 robotic)
    • Major complications (12% open vs. 17% robotic)
    • Rectal injury (3% open vs. 0.5% robotic)
  • Gontero, Paolo, et al."Salvage radical prostatectomy for recurrent prostate cancer: morbidity and functional outcomes from a large multicenter series of open versus robotic approaches." The Journal of urology 202.4 (2019): 725-731.
• Concurrent ADT
  • Inadequate data to support use of concurrent ADT§
  • Data in salvage radiation after radical prostatectomy (GETUG-AFU 16 see above) suggests that short-term ADT improves progression-free survival

Salvage cryotherapy

• An alternative to salvage radical prostatectomy with durable progression-free and overall survival, low perioperative morbidity and relatively low risk of urinary incontinence.
• Less morbid than salvage radical prostatectomy and may be performed in the outpatient setting.
• Complications include erectile dysfunction (very common), urinary obstruction, urethrorectal fistula, urethral sloughing, urethral stricture, rectal pain, scrotal edema, and hematuria
  • Perioperative and postoperative complication frequencies have substantially declined with recent technical improvements in contemporary fourth generation devices, including enhanced urethral warmers and thermal controls to protect adjacent structures.

Salvage brachytherapy

• Evidence is lacking compared to salvage prostatectomy and salvage cryotherapy

Salvage High-Intensity Focused Ultrasound (HIFU)

• Although short- to intermediate-term follow-up has been demonstrated with HIFU, further studies are necessary to establish its place as a viable alternative in the radio-recurrent setting

ADT

• Most commonly used treatment for biochemical recurrence after RT
• Generally not curative in these patients
  • Patients with biopsy-proven local disease, no evidence of distant metastatic disease, and substantial life expectancy should be counseled about salvage local therapy such as prostatectomy, radiation approaches, and cryotherapy.
• The exact timing of ADT after failure is unknown.
  • The ideal management of PSA recurrence in patients at high risk for failure may be the initiation of intermittent ADT.
    • In a recent clinical trial, intermittent ADT was found to be noninferior compared to continuous therapy in patients with PSA levels greater than 3 ng/mL without evidence of metastatic disease. This came with the benefit of potential improvement in physical function, fatigue, urinary problems, hot flashes, libido, and erectile function (Crook et al, 2012).
    • See Hormonal Therapy Chapter Notes
• Considering the potential morbidity and cost of ADT, it is reasonable to start treatment in those patients at highest risk for distant failure
  • PSA doubling times < 12 months is associated with benefit from ADT after biochemical recurrence following radiation therapy to the prostate.

Management of Biochemical Recurrence after Definitive Cryotherapy in Prostate Cancer

• Definition of biochemical failure after definitive cryotherapy of the prostate for cancer is extremely varied in the literature
• Management strategies for cryotherapy failure are lacking; repeated cryotherapy, salvage radiation, and salvage prosatectomy have been described

Management of Biochemical Recurrence after Definitive High-Intensity Focused Ultrasound in Prostate Cancer

• PSA nadir + 1.2 ng/mL has been described as the most effective at predicting for clinical failure and has been proposed as the definition for biochemical failure after HIFU for prostate cancer.
• Salvage radiotherapy and salvage prostatectomy have been described as treatments for HIFU failure

EMBARK Trial

• Population: 1068 patients with high-risk biochemical recurrence (defined as a PSA doubling time of ≤9 months and a PSA level of ≥2 ng per milliliter above nadir after radiation therapy or ≥1 ng per milliliter after radical prostatectomy)
• Randomized to enzalutamide + leuprolide vs. enzalutamide only vs. leuprolide only
• Primary end point: metastasis-free survival in the combination group as compared with the leuprolide-alone group
• Results:
  • 5-year metastasis-free survival: absolute risk reduction: 16% (87% combination group vs. 71% leuprolide-alone group, significant); NNT: 6
  • 5-year overall survival: absolute risk reduction: 5% (92% combination group vs. 87% leuprolide-alone group, not significant)
  • Enzalutamide monotherapy better than leuprolide monotherapy for progression-free survival
    • First evidence that second-generation androgen deprivation therapy monotherapy better than first-generation monotherapy
• Freedland, Stephen J., et al. "Improved outcomes with enzalutamide in biochemically recurrent prostate cancer." New England Journal of Medicine 389.16 (2023): 1453-1465.

UrologySchool.com Summary

• Biochemical recurrence after RP for localized disease
  • Determine if localized or distant and consider disease aggressiveness (PSA, PSA doubling time, the interval from surgery to biochemical recurrence, and the Gleason score)
    • If localized and non-aggressive features
      • Salvage radiation + 2 years ADT (improved BFS, CSS, and OS)
    • If locoregional/metastatic disease
      • Consider treatment of metastatic castrate sensitive prostate cancer
• Biochemical recurrence after radiation for localized disease
  • Determine if localized (prostate biopsy) or If locoregional/metastatic disease
    • Local failure (biopsy positive), no evidence of metastatic disease, slow PSA doubling time
      • Salvage prostatectomy
      • Salvage cryotherapy
      • Salvage brachytherapy
      • Salvage HIFU
    • If locoregional/metastatic disease
      • Consider treatment of metastatic castrate sensitive prostate cancer

Questions

1. What is the definition of failure after radical prostatectomy?
2. Describe the Pound et al. study which illustrated the natural history of biochemical recurrence after radical prostatectomy
3. What is the median PSA in patients with newly detected bone metastasis?
4. What percentage of patients with biochemical recurrence after radical prostatectomy with PSA <10 ng/mL will have a positive bone scan?
5. What is the best study to determine local failure following radical prostatectomy or radiotherapy?
6. What is the minimum recommended dose of salvage radiation?

Answers

1. What is the definition of failure after radical prostatectomy?
   • PSA ≥ 0.2 ng/mL with a second confirmatory laboratory value
2. Describe the Pound et al. study which illustrated the natural history of biochemical recurrence after radical prostatectomy
   • Cohort study of 1997 men who underwent radical prostatectomy
   • 15% developed biochemical recurrence
   • The median time from biochemical recurrence to metastasis was 8 years
   • After development of metastatic disease, the median time to death was 5 years
3. What is the median PSA in patients with newly detected bone metastasis?
   • 32 ng/mL
4. What percentage of patients with biochemical recurrence after radical prostatectomy with PSA <10 ng/mL will have a positive bone scan?
   • 4%
5. What is the best study to determine local failure following radical prostatectomy or radiotherapy?
   • MRI
6. What is the minimum recommended dose of salvage radiation?
   • 64 Gy

References

• Wein AJ, Kavoussi LR, Partin AW, Peters CA (eds): CAMPBELL-WALSH UROLOGY, ed 11. Philadelphia, Elsevier, 2015, chap 119
• Bhargava, Peeyush, et al."Imaging biochemical recurrence after prostatectomy: where are we headed?." American Journal of Roentgenology 214.6 (2020): 1248-1258.