Editing Biochemical Recurrence (section)

== Biochemical Recurrence After Radiation Therapy ==

=== Definition ===

* '''<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>'''
* '''<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'''
* '''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):'''
*# '''Time from radiation therapy to biochemical recurrence <3 years'''
*# '''PSA doubling time <3 months'''
*## '''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.
*# '''Pretreatment biopsy grade group ≥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)§: ====
# '''Active surveillance/observation'''
# '''Local salvage therapy'''
## '''Salvage radical prostatectomy'''
##* '''In highly selected cases by highly experience surgeons (see below)'''
## '''Salvage cryosurgery'''
## '''Salvage brachytherapy'''
## '''Salvage high intensity focused ultrasound'''
# '''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-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.'''