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Biochemical Recurrence: Difference between revisions

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**** '''Thus, the median time from biochemical recurrence to death is more than 13 years.'''
**** '''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.
*** 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.
*'''PSA velocity, doubling time, interval from surgery to biochemical recurrence, and Gleason score usually reflect how rapidly the tumor is likely to progress'''
*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 ===
=== Risk-stratification ===
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=== Definition ===
=== 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'''
* '''<span style="color:#ff0000">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</span>'''
* '''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
* '''<span style="color:#ff0000">2005 Phoenix definition: PSA nadir + 2 ng/mL; failure is not backdated</span>'''. 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'''
** '''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'''
* '''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'''
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=== Diagnosis and Evaluation ===
=== 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.'''
* '''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 ===
*** Imaging of the prostate after definitive radiotherapy remains challenging with traditional modalities because of fibrosis and shrinkage of the prostate.
* '''Primary'''
*** '''MRI'''
** Imaging of the prostate after definitive radiotherapy remains challenging with traditional modalities because of fibrosis and shrinkage of the prostate.
**** '''The most promising technique for identifying recurrent tumors of the prostate in biochemical recurrence following radiotherapy.'''
** '''MRI'''
*** '''PET/CT'''
*** '''The most promising technique for identifying recurrent tumors of the prostate in biochemical recurrence following radiotherapy.'''
**** '''Use in the setting of BCR after RT, while promising, has not been entirely defined and is under active study.'''
** '''PET/CT'''
***** 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.
*** '''Use in the setting of BCR after RT, while promising, has not been entirely defined and is under active study.'''
***** PSMA based imaging is a relatively new modality with potential use in the evaluation of BCR after RT.
**** 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.
** '''Distant'''
**** PSMA based imaging is a relatively new modality with potential use in the evaluation of BCR after RT.
*** Bone scan
* '''Distant'''
**** The lowest PSA value at which bone scans are reliably positive is not known, but PSADT is a reasonable indicator of bone scan reliability.
** Bone scan
***** 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.
*** The lowest PSA value at which bone scans are reliably positive is not known, but PSADT is a reasonable indicator of bone scan reliability.
*** Computerized tomography
**** 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.
**** Patients most likely to benefit from salvage therapy have a PSA <10 ng/ml
** Computerized tomography
**** The probability that CT in asymptomatic men with PSA <10 ng/ml will yield actionable information (ie detection of metastatic disease) is low.
*** Patients most likely to benefit from salvage therapy have a PSA <10 ng/ml
***** CT is reasonable if advanced imaging modalities are unavailable, although newer modalities (PSMA PET) are more sensitive for nodal disease detection.
*** The probability that CT in asymptomatic men with PSA <10 ng/ml will yield actionable information (ie detection of metastatic disease) is low.
* '''Biopsy after radiotherapy'''
**** CT is reasonable if advanced imaging modalities are unavailable, although newer modalities (PSMA PET) are more sensitive for nodal disease detection.
** '''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.
=== Biopsy after radiotherapy ===
**** 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.
* '''Strongly recommended to document local recurrence before offering salvage treatments.'''
*** '''The information from prostate biopsy will guide further treatment strategies and should be reserved for patients in whom salvage local therapy is considered.'''
** 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.
** Multiparametric-MRI directed biopsy should be considered.
*** 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.
*** 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.
** '''The information from prostate biopsy will guide further treatment strategies and should be reserved for patients in whom salvage local therapy is considered.'''
*** 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.
* Multiparametric-MRI directed biopsy should be considered.
** 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
** 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 ===
=== Management ===
* '''Based on pattern of failure: locoregional vs. systemic disease (presence of lymph node, bone or visceral metastases)'''
* '''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'''
** '''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)§:'''
=== Local failures (no evidence of metastases) ===
**# '''Active surveillance/observation'''
 
**# '''Local salvage therapy'''
==== Options (6)§: ====
**## '''Salvage radical prostatectomy'''
# '''Active surveillance/observation'''
**##* '''In highly selected cases by highly experience surgeons (see below)'''
# '''Local salvage therapy'''
**## '''Salvage cryosurgery'''
## '''Salvage radical prostatectomy'''
**## '''Salvage brachytherapy'''
##* '''In highly selected cases by highly experience surgeons (see below)'''
**## '''Salvage high intensity focused ultrasound'''
## '''Salvage cryosurgery'''
**# '''ADT (intermittent or continuous)'''
## '''Salvage brachytherapy'''
**#*
## '''Salvage high intensity focused ultrasound'''
**#* '''Active surveillance/observation'''
# '''ADT (intermittent or continuous)'''
**#** A reasonable option, particularly for lower risk patients with:
#*
**#**# BCR >3 years from RT
 
**#**# PSADT ≥16 months
===== Active surveillance/observation =====
**#**# Pre-RT biopsy pathology grade group 1
* A reasonable option, particularly for lower risk patients with:
**#*** These features indicate a low liklihood of prostate cancer-specific mortality over a 10-year period
*# BCR >3 years from RT
**#** Minimizes morbidity and is well suited for older patients and those who do not wish to undergo further treatments.
*# PSADT ≥16 months
**#** '''May be considered in men with a life expectancy <10 years.'''
*# Pre-RT biopsy pathology grade group 1
**#* '''Local salvage therapy'''
** These features indicate a low liklihood of prostate cancer-specific mortality over a 10-year period
**#** '''May potentially increase metastasis-free survival, delay initiation of ADT and eradicate recurrent/ residual disease in appropriately selected patients'''
* Minimizes morbidity and is well suited for older patients and those who do not wish to undergo further treatments.
**#*** '''Unknown survival benefit'''
* '''May be considered in men with a life expectancy <10 years.'''
**#**** '''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'''
===== Local salvage therapy =====
**#** '''Indications'''
* '''May potentially increase metastasis-free survival, delay initiation of ADT and eradicate recurrent/ residual disease in appropriately selected patients'''
**#*** '''Biochemical recurrence after radiation therapy with'''
** '''Unknown survival benefit'''
**#***# '''Clinically localized T1c-T2 disease'''
*** '''Studies comparing local salvage therapy vs. observation (and delayed intervention for metastasis) are lacking'''
**#***# '''PSA <10.0 ng/ml at biochemical recurrence'''
* '''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'''
**#***# '''No evidence of metastasis on prior evaluation'''
* '''Indications'''
**#** '''Options (4):'''
** '''Biochemical recurrence after radiation therapy with'''
**#**# '''Salvage radical prostatectomy'''
**# '''Clinically localized T1c-T2 disease'''
**#**# '''Salvage cryosurgery'''
**# '''PSA <10.0 ng/ml at biochemical recurrence'''
**#**# '''Salvage brachytherapy'''
**# '''No evidence of metastasis on prior evaluation'''
**#**# '''Salvage high intensity focused ultrasound'''
* '''Options (4):'''
**#*** '''Salvage Radical Prostatectomy'''
*# '''Salvage radical prostatectomy'''
**#**** '''Historical'''
*# '''Salvage cryosurgery'''
**#***** '''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.§'''
*# '''Salvage brachytherapy'''
**#**** '''Utilization'''
*# '''Salvage high intensity focused ultrasound'''
**#***** '''Not commonly used to treat biochemical recurrence after radical prostatectomy'''
 
**#***** '''Technically challenging operation with the potential for serious complications'''
====== Salvage Radical Prostatectomy ======
**#****** '''Should only be performed by experienced surgeons.'''
* '''Historical'''
**#******* '''No published report on learning curve with SRP'''
** '''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.§'''
**#**** '''Indications'''
* '''Utilization'''
**#***** '''NCCN§'''
** '''Not commonly used to treat biochemical recurrence after radical prostatectomy'''
**#****** '''Option for highly selected patients with local recurrence after EBRT, brachytherapy, or cryotherapy in the absence of metastases'''
** '''Technically challenging operation with the potential for serious complications'''
**#***** '''EAU§'''
*** '''Should only be performed by experienced surgeons.'''
**#****** '''Should be considered only in patients with (6):'''
**** '''No published report on learning curve with SRP'''
**#******# '''Low co-morbidity'''
* '''Indications'''
**#******# '''Life expectancy > 10 years'''
** '''NCCN§'''
**#******# '''Initial clinical staging was T1 or T2'''
*** '''Option for highly selected patients with local recurrence after EBRT, brachytherapy, or cryotherapy in the absence of metastases'''
**#******# '''Initial biopsy ISUP grade < 2/3'''
** '''EAU§'''
**#******# '''Pre-salvage radical prostatectomy PSA < 10 ng/mL'''
*** '''Should be considered only in patients with (6):'''
**#******# '''No LN involvement or evidence of distant metastatic disease pre-salvage radical prostatectomy'''
***# '''Low co-morbidity'''
**#***** '''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.'''
***# '''Life expectancy > 10 years'''
**#**** '''Outcomes§§'''
***# '''Initial clinical staging was T1 or T2'''
**#***** '''Oncologic'''
***# '''Initial biopsy ISUP grade < 2/3'''
**#****** '''Improved oncologic outcomes observed over time may be due to improved patient selection and stage migration'''
***# '''Pre-salvage radical prostatectomy PSA < 10 ng/mL'''
**#****** '''Systematic reviews'''
***# '''No LN involvement or evidence of distant metastatic disease pre-salvage radical prostatectomy'''
**#******* '''Positive surgical margin rate: ≈20%'''
** '''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.'''
**#******* '''Median follow-up ranges from 4.6 to 120 mo'''
* '''Outcomes§§'''
**#******** '''Wide range of follow-up partly explains wide ranges of survival'''
** '''Oncologic'''
**#********* '''Longer follow-up periods show a non-statistically significant trend toward adiminished BCR-free survival'''
*** '''Improved oncologic outcomes observed over time may be due to improved patient selection and stage migration'''
**#******* '''Biochemical recurrence-free survival'''
*** '''Systematic reviews'''
**#******** '''5 years: 47-82%'''
**** '''Positive surgical margin rate: ≈20%'''
**#******** '''10 years: 28-53%'''
**** '''Median follow-up ranges from 4.6 to 120 mo'''
**#******* '''Cancer-specific survival'''
***** '''Wide range of follow-up partly explains wide ranges of survival'''
**#******** '''5 years: 89-100%'''
****** '''Longer follow-up periods show a non-statistically significant trend toward adiminished BCR-free survival'''
**#******** '''10 years: 70-83%'''
**** '''Biochemical recurrence-free survival'''
**#******* '''Overall survival'''
***** '''5 years: 47-82%'''
**#******** '''10 years: 54-90%'''
***** '''10 years: 28-53%'''
**#******* '''Prognostic factors§'''
**** '''Cancer-specific survival'''
**#*******# '''Pre-SRP PSA'''
***** '''5 years: 89-100%'''
**#*******# '''Considered the strongest prognostic factor; shown to significantly associated with PFS, CSS, and OS'''
***** '''10 years: 70-83%'''
**#*******# '''Gleason score on post irridation prostate biopsy'''
**** '''Overall survival'''
**#*******# '''Salvage RP Gleason score'''
***** '''10 years: 54-90%'''
**#*******# '''Salvage RP pathologic stage'''
**** '''Prognostic factors§'''
**#*******# '''Salvage RP DNA ploidy'''
****# '''Pre-SRP PSA'''
**#***** '''Complications'''
****# '''Considered the strongest prognostic factor; shown to significantly associated with PFS, CSS, and OS'''
**#****** '''Significant high perioperative morbidity'''
****# '''Gleason score on post irridation prostate biopsy'''
**#******* '''Relatively poor postoperative urinary and sexual health related functional outcomes compared to primary radical prostatetomy'''
****# '''Salvage RP Gleason score'''
**#****** '''Urinary incontinence'''
****# '''Salvage RP pathologic stage'''
**#******* '''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.'''
****# '''Salvage RP DNA ploidy'''
**#******** '''High rate of urinary incontinence is likely the greatest factor discouraging physicians from considering patients with radio recurrent prostate cancer for salvage RP.'''
** '''Complications'''
**#******** '''Bladder neck contracture rate: 0-55%'''
*** '''Significant high perioperative morbidity'''
**#********* '''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§'''
**** '''Relatively poor postoperative urinary and sexual health related functional outcomes compared to primary radical prostatetomy'''
**#****** '''Erectile dysfunction'''
*** '''Urinary incontinence'''
**#******* '''Extremely high incidence of erectile dysfunction before SRP'''
**** '''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.'''
**#******* '''Post-SRP erectile function dropped significantly'''
***** '''High rate of urinary incontinence is likely the greatest factor discouraging physicians from considering patients with radio recurrent prostate cancer for salvage RP.'''
**#******** '''Erectile function sufficient for sexual intercourse: 0-20%'''
***** '''Bladder neck contracture rate: 0-55%'''
**#****** '''Rectal injury'''
****** '''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§'''
**#******* '''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'''
*** '''Erectile dysfunction'''
**#******** '''SRP after brachytherapy is associated with greater difficulty and surgical complexity because of increased adhesions'''
**** '''Extremely high incidence of erectile dysfunction before SRP'''
**#******* '''Rectal injury rate: 0–28%'''
**** '''Post-SRP erectile function dropped significantly'''
**#******* '''Management of rectal injury§'''
***** '''Erectile function sufficient for sexual intercourse: 0-20%'''
**#*******# '''Two-layer closure (most commonly used)'''
*** '''Rectal injury'''
**#*******# '''Oversewing with the remnants of the neurovascular bundles'''
**** '''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'''
**#*******# '''Use of omentoplasty'''
***** '''SRP after brachytherapy is associated with greater difficulty and surgical complexity because of increased adhesions'''
**#*******# '''Colostomy'''
**** '''Rectal injury rate: 0–28%'''
**#******** '''Some use bowel preparation before SRP'''
**** '''Management of rectal injury§'''
**#****** '''Some complications improved over time, others have not'''
****# '''Two-layer closure (most commonly used)'''
**#******** '''Contemporary radiation approaches (EBRT and transperineal interstitial radiotherapy) associated with reduced pelvic fibrosis.'''
****# '''Oversewing with the remnants of the neurovascular bundles'''
**#********* '''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.'''
****# '''Use of omentoplasty'''
**#********** '''RT-PLND is now infrequently performed.'''
****# '''Colostomy'''
**#********** '''Retropubic interstitial radiotherapy has been abandoned.'''
***** '''Some use bowel preparation before SRP'''
**#******** '''Rate of rectal injury and anastomotic stricture has significantly reduced§'''
*** '''Some complications improved over time, others have not'''
**#********* '''Rate of rectal injury before 2000: 0-28% vs. after 2000: 2-10%'''
***** '''Contemporary radiation approaches (EBRT and transperineal interstitial radiotherapy) associated with reduced pelvic fibrosis.'''
**#********* '''Rate of anastomotic stricture before 2000: 7-28% vs. after 2000: 11-41%'''
****** '''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.'''
**#******** '''Blood transfusion rates similar to the standard RP procedure'''
******* '''RT-PLND is now infrequently performed.'''
**#******** '''Urinary incontinence and ED remain problematic'''
******* '''Retropubic interstitial radiotherapy has been abandoned.'''
**#**** '''Nerve-sparing'''
***** '''Rate of rectal injury and anastomotic stricture has significantly reduced§'''
**#*****'''Can be performed in select patients based on preoperative characteristics, ease of dissection and intraoperative findings.'''
****** '''Rate of rectal injury before 2000: 0-28% vs. after 2000: 2-10%'''
**#**** Pelvic lymph node dissection
****** '''Rate of anastomotic stricture before 2000: 7-28% vs. after 2000: 11-41%'''
**#***** 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
***** '''Blood transfusion rates similar to the standard RP procedure'''
**#****** Lymph node count independently predicted lower cancer-specific survival
***** '''Urinary incontinence and ED remain problematic'''
**#******* After the 7th removed lymph node, the effect of cancer-specific survival became marginal
* '''Nerve-sparing'''
**#**** Approach (open vs. robotic)
**'''Can be performed in select patients based on preoperative characteristics, ease of dissection and intraoperative findings.'''
**#***** Multi-institutional study (n=18) of 395 SRP (186 open vs. 209 robotic)
* Pelvic lymph node dissection
**#***** Robotic surgery associated with significantly
** 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
**#****** Reduced blood loss and shorter hospital stay
*** Lymph node count independently predicted lower cancer-specific survival
**#****** Reduced anastomotic stricture rate (17% open vs. 8% robotic)
**** After the 7th removed lymph node, the effect of cancer-specific survival became marginal
**#****** Improved urinary incontinence, defined as 3 or more pads per day (22% open vs. 32% robotic at 12 months)
* Approach (open vs. robotic)
**#****** Robotic approach independent predictor of continence preservation on multivariable analysis
** Multi-institutional study (n=18) of 395 SRP (186 open vs. 209 robotic)
**#***** No significant difference in
** Robotic surgery associated with significantly
**#****** Overall complications (36% open vs. 34 robotic)
*** Reduced blood loss and shorter hospital stay
**#****** Major complications (12% open vs. 17% robotic)
*** Reduced anastomotic stricture rate (17% open vs. 8% robotic)
**#****** Rectal injury (3% open vs. 0.5% robotic)
*** Improved urinary incontinence, defined as 3 or more pads per day (22% open vs. 32% robotic at 12 months)
**#***** 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.
*** Robotic approach independent predictor of continence preservation on multivariable analysis
**#**** '''Concurrent ADT'''
** No significant difference in
**#***** '''Inadequate data to support use of concurrent ADT'''§
*** Overall complications (36% open vs. 34 robotic)
**#***** Data in salvage radiation after radical prostatectomy ('''GETUG-AFU 16''' see above) suggests that short-term ADT improves progression-free survival
*** Major complications (12% open vs. 17% robotic)
**#*** '''Salvage cryotherapy'''
*** Rectal injury (3% open vs. 0.5% robotic)
**#**** An alternative to salvage radical prostatectomy with durable progression-free and overall survival, low perioperative morbidity and relatively low risk of urinary incontinence.
** 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.
**#**** Less morbid than salvage radical prostatectomy and may be performed in the outpatient setting.
* '''Concurrent ADT'''
**#**** '''Complications include erectile dysfunction (very common),''' urinary obstruction, urethrorectal fistula, urethral sloughing, urethral stricture, rectal pain, scrotal edema, and hematuria
** '''Inadequate data to support use of concurrent ADT'''§
**#***** 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.
** Data in salvage radiation after radical prostatectomy ('''GETUG-AFU 16''' see above) suggests that short-term ADT improves progression-free survival
**#*** '''Salvage brachytherapy'''
 
**#**** Evidence is lacking compared to salvage prostatectomy and salvage cryotherapy
====== Salvage cryotherapy ======
**#*** '''Salvage High-Intensity Focused Ultrasound (HIFU)'''
* An alternative to salvage radical prostatectomy with durable progression-free and overall survival, low perioperative morbidity and relatively low risk of urinary incontinence.
**#**** 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
* Less morbid than salvage radical prostatectomy and may be performed in the outpatient setting.
**#** '''ADT'''
* '''Complications include erectile dysfunction (very common),''' urinary obstruction, urethrorectal fistula, urethral sloughing, urethral stricture, rectal pain, scrotal edema, and hematuria
**#*** '''Most commonly used treatment for biochemical recurrence after RT'''
** 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.
**#*** '''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.
====== Salvage brachytherapy ======
**#*** '''The exact timing of ADT after failure is unknown.'''
* Evidence is lacking compared to salvage prostatectomy and salvage cryotherapy
**#**** '''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).
====== Salvage High-Intensity Focused Ultrasound (HIFU) ======
**#***** See Hormonal Therapy Chapter Notes
* 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
**#*** 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.'''
===== 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 ==
== Management of Biochemical Recurrence after Definitive Cryotherapy in Prostate Cancer ==
Line 403: Line 416:
* '''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.'''
* '''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
* 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
* [https://pubmed.ncbi.nlm.nih.gov/37851874/ 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 ==
== UrologySchool.com Summary ==
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