Biochemical Recurrence

Biochemical recurrence after radical prostatectomy

Definition (AUA/ASTRO) of biochemical/PSA recurrence (BCR) after radical prostatectomy: PSA ≥ 0.2 ng/mL with a second confirmatory laboratory value§
- 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.)
  - Ultrasensitive Prostate-Specific Antigen
    - Introduced In the early 1990s to detect very low levels of PSA
    - Limited utility in deciding on secondary therapy.
- After radical prostatectomy, ≈25-41% develop PSA recurrence within 10 years
  - 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.), 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 for BCR after prostatectomy
    - Nomogram to predict the risk of BCR and cancer-specific survival after radical prostatectomy used variables
      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 also has been associated with risk of BCR
Natural history of BCR after Radical Prostatectomy
- 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
- Pound et al.
  - 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.
Risk-stratification
- EAU defined risk groups§
  - 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 reflect how rapidly the tumor is likely to progress and can help determine whether failure is local or distal, both of which are informative in deciding managment.
- 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§
  - 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.
Management
- 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
    - 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
        PSA recurrence long after surgery
        
        Slowly rising PSA
        
        Low-grade tumor
        
        No seminal vesicle invasion
        
        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

Background
- Definitions of treatment failure – See Section in Management of Localized Prostate Cancer Chapter Notes
- 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 of PSA recurrence after definitive radiation
- 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:
        BCR >3 years from RT
        
        PSADT ≥16 months
        
        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
        Clinically localized T1c-T2 disease
        
        PSA <10.0 ng/ml at biochemical recurrence
        
        No evidence of metastasis on prior evaluation
        
        Options (4):
        Salvage radical prostatectomy
        
        Salvage cryosurgery
        
        Salvage brachytherapy
        
        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):
        Low co-morbidity
        
        Life expectancy > 10 years
        
        Initial clinical staging was T1 or T2
        
        Initial biopsy ISUP grade < 2/3
        
        Pre-salvage radical prostatectomy PSA < 10 ng/mL
        
        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§
        Pre-SRP PSA
        
        Considered the strongest prognostic factor; shown to significantly associated with PFS, CSS, and OS
        
        Gleason score on post irridation prostate biopsy
        
        Salvage RP Gleason score
        
        Salvage RP pathologic stage
        
        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§
        Two-layer closure (most commonly used)
        
        Oversewing with the remnants of the neurovascular bundles
        
        Use of omentoplasty
        
        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-sp