Editing Biochemical Recurrence (section)

== 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)
*'''<span style="color:#ff0000">Detectable and rising PSA is usually the earliest evidence of tumor recurrence after radical prostatectomy</span>'''
** '''This rising PSA normally precedes clinically meaningful events in an extremely protracted and variable manner.''' (see Pound et al. below)

=== Definition ===
*'''<span style="color:#ff0000">Biochemical/PSA recurrence (BCR) after radical prostatectomy (AUA/ASTRO): PSA ≥ 0.2 ng/mL with a second confirmatory laboratory value[https://pubmed.ncbi.nlm.nih.gov/31042111/]</span>'''
**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 ===
* '''[https://www.mskcc.org/nomograms/prostate/post_op Nomogram] to predict the risk of BCR''' (and cancer-specific survival) '''after radical prostatectomy used (7):'''
*# '''PSA'''
*# '''Gleason score'''
*# '''Presence of extraprostatic extension'''
*# '''Seminal vesicle invasion'''
*# '''Lymph node involvement'''
*# '''Margin status'''
*# '''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):'''
***# '''Residual benign prostatic tissue''' (often used as the rationale for a detectable PSA level after radiation therapy)
***# '''Non-prostatic source:''' PSA is produced at very low levels by other cells such as the urethral glands and salivary glands
***# '''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'''
**'''<span style="color:#ff00ff">Pound et al. (Landmark study)</span>'''
*** '''<span style="color:#ff0000">Population: Cohort study of 1997 men who underwent radical prostatectomy</span>''' (mostly low risk based on clinical staging) without neo- or adjuvant treatment.
*** '''<span style="color:#ff0000">Results:</span>'''
**** 304 men '''developed biochemical recurrence'''
**** '''<span style="color:#ff0000">Median time from biochemical recurrence to metastasis: 8 years</span>'''
***** In a recent update, metastasis-free survival was 10 years
**** '''<span style="color:#ff0000">Median time from development of metastatic disease to death: 5 years</span>'''
**** '''Thus, the median time from biochemical recurrence to death is more than 13 years.'''
*** Pound, Charles R., et al. "[https://pubmed.ncbi.nlm.nih.gov/10235151/ 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.[https://pubmed.ncbi.nlm.nih.gov/30342843/]
**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[https://pubmed.ncbi.nlm.nih.gov/31248850/]
** 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 ===
* '''<span style="color:#ff0000">Need to define extent of disease local vs. distant) to guide management</span>'''
** '''<span style="color:#ff0000">If local failure: salvage radiation</span>'''
** '''<span style="color:#ff0000">If distant failure: treat as metastatic castrate-sensitive disease</span>''' (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.
** '''"<span style="color:#ff0000">Conventional" imaging: CT scan and bone scan</span>'''
*** '''<span style="color:#ff0000">Diagnostic yield is significantly influenced by the PSA level</span>'''
**** '''<span style="color:#ff0000">Limited if PSA < 10 ng/mL; very limited if PSA 0.2-1 ng/mL</span>'''
*** '''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'''
***'''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'''
***# '''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:'''
**# '''Persistent local disease'''
**# '''Recurrence of local disease'''
**# '''Persistence of metastasis'''
**# '''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.