Editing Management of Localized Prostate Cancer (section)

== Radiation therapy ==

* '''See Radiation Therapy in Prostate Cancer Chapter Notes'''
* '''Pre-RT prognostic factors in localized disease:'''
*# Pre-treatment PSA level and velocity
*# Biopsy grade group
*# Percentage of positive prostate biopsy scores
*# Clinical T stage
*# MRI findings

=== <span style="color:#ff0000">Contraindications</span> ===

*'''<span style="color:#0000ff">ST-LIAR</span> (<span style="color:#0000ff">S</span><span style="color:#ff0000">ize, </span><span style="color:#0000ff">T</span><span style="color:#ff0000">URP, </span><span style="color:#0000ff">L</span><span style="color:#ff0000">UTS, </span><span style="color:#0000ff">I</span><span style="color:#ff0000">BD, </span><span style="color:#0000ff">A</span><span style="color:#ff0000">taxia telangiectaisia, </span><span style="color:#0000ff">R</span><span style="color:#ff0000">adiation)[https://www.auanet.org/guidelines/archived-documents/prostate-cancer-clinically-localized-guideline]</span>'''
** '''<span style="color:#ff0000">Absolute (2)</span>'''
**# '''<span style="color:#ff0000">Prior </span><span style="color:#0000ff">T<span style="color:#ff0000">URP for brachytherapy if the TUR defect precludes adequate placement of seeds</span>''' (also associated with increased risk of stricture)
**#* Note that Campbell's considers prior TURP a relative contraindication for both brachytherapy and EBRT but the 2017 AUA Localized Prostate Cancer Guidelines describe the above contraindication)
**# '''<span style="color:#0000ff">A</span><span style="color:#ff0000">taxia telangiectasia</span>''' (severe response to ionizing radiation)
** '''<span style="color:#ff0000">Relative (4)</span>'''
**# '''<span style="color:#ff0000">Significant baseline <span style="color:#0000ff">L</span><span style="color:#ff0000">ower urinary tract voiding symptoms</span>''' (can cause acute urinary retention and worsen storage and voiding symptoms, '''risk increased with brachytherapy;''' on the other hand, radiotherapy can gradually relieve obstructive urinary symptoms in men with urinary outflow obstructive symptoms)
**# '''<span style="color:#ff0000">Large (>60 cc) prostate </span><span style="color:#0000ff">S</span><span style="color:#ff0000">ize for brachytherapy''' (increased risk of urinary side effects)
**# '''<span style="color:#0000ff">I</span><span style="color:#ff0000">nflammatory bowel disease</span>''' (increased risk for treatment-related morbidity)
**# '''<span style="color:#ff0000">History of prior pelvic </span><span style="color:#0000ff">R</span><span style="color:#ff0000">adiotherapy</span>''' (increased risk for treatment-related morbidity)

=== <span style="color:#ff0000">Modalities</span> ===

==== External beam radiotherapy (EBRT) ====
*'''<span style="color:#ff0000">Most commonly involves the use of gamma radiation, usually photons, directed at the prostate and surrounding tissues</span>'''
*'''Advances in Radiation Technology'''
**In the era before CT [pre-1990s], RT technique was sometimes referred to as '''conventional radiation'''
**3D tumor visualization and treatment planning using CT scans began in the 1990s. The result is described as '''3DCRT''' (because the radiation beams conform to the shape of the treatment target
**A major advance in the delivery of radiation came with the advent of '''intensity-modulated radiation therapy (IMRT).''' IMRT is a sophisticated way of treatment delivery in which the intensity of radiation can be varied from each beam angle.
*** IMRT requires the use of advanced software, specialized personnel, and hardware adaptations to linear accelerators
***'''IMRT results in reduced radiation doses to the rectum, bladder, femoral heads, and small bowel compared to 3DCRT'''
**'''Image-guided radiation therapy (IGRT) is a method in which imaging techniques are used to guide IMRT to the target area.''' Image guidance was development based on a realization that the
**#Daily location of the prostate within the pelvis throughout the course of RT is not identical (interfraction motion)
**#Prostate is mobile even during a single session of RT (intrafraction motion).*** With image guidance, the location of the prostate can be verified daily before delivering radiation
**'''Stereotactic body radiotherapy (SBRT, CyberKnife)''' defines an external-beam RT that delivers a high dose each treatment using precisely targeted and highly conformal radiation in a small number of fractions (hypofractionation).
***'''Limited results have been published in a small number of patients with low-risk disease'''
*'''<span style="color:#ff0000">Radiation dose and field of treatment</span>'''
** '''<span style="color:#ff0000">Currently, doses of 76-80 Gy or more have been shown to improve cancer control</span>'''
*** Low-risk patients are now frequently treated with 70-72 Gy, intermediate-risk patients with 75-76 Gy, and high-risk patients with ≥80 Gy
*** Randomized trials consistently show that higher dose radiation improved disease control have led to the '''<span style="color:#ff0000">dose-escalated RT, the current standard of care</span>'''
* '''<span style="color:#ff0000">Combining EBRT and ADT for localized PCa</span>'''
** '''<span style="color:#ff0000">Intermediate-risk</span>'''
*** '''<span style="color:#ff0000">2022 AUA Guidelines: short-term (6-month) concurrent ADT with EBRT is recommended in patients with intermediate-risk, localized disease</span>'''
**** '''2 randomized trials (RTOG 94-08 and D’Amico JAMA 2015) support the addition of ADT to EBRT for intermediate-risk prostate cancer. 4-6 months of ADT were used in these trials. A caveat to these trials was the use of lower radiation doses no longer considered standard today. Therefore, the benefit of adding ADT to modern higher doses of radiation is the subject of continued investigation.'''
***** In a randomized trial, D’Amico and colleagues confirmed that 6 months of ADT improved outcomes, mostly in the intermediate-risk patients; However, all of the benefit was observed in patients with no or minimal comorbidities. Men with comorbidities did worse with ADT. ADT was associated with an earlier onset of fatal myocardial infarcts in this study.
** '''<span style="color:#ff0000">High-risk</span>'''
*** '''<span style="color:#ff0000">2022 AUA Guidelines: long-term (18-36 months) ADT is recommended</span>'''
**** '''No randomized trial has exclusively studied the additional benefit of ADT in the high-risk patients receiving radiotherapy for localized prostate cancer. However, on the basis of the trials involving locally advanced disease, concurrent ADT is recommended'''
**** '''<span style="color:#ff00ff">EORTC 22863 (Bolla et al. NEJM 1997)</span>'''
***** '''Population: 415 men with (cT1-T2 and grade 3, cT3-T4 and any grade) disease'''
***** '''Randomized''' '''to EBRT +/- 3 years ADT (goserelin)'''
***** Primary outcome: disease-free survival (time to clinical progression or death)
***** Secondary outcomes: overall survival, distant metastasis
***** '''Results:'''
****** Median follow-up: 9.1 years in 2010 publication (5.5 in original)
****** '''Significantly improved DFS (absolute difference 25%,''' 10-year DFS 48% ADT group vs. 23% in the RT-alone) '''with concurrent''' '''ADT'''
****** '''Significantly improved OS (absolute difference 18.4%,''' OS 58% vs. 40%) '''with concurrent''' '''ADT'''
****** Distant metastases, locoregional failure, biochemical failure significantly favour ADT + rads
***** [https://www.ncbi.nlm.nih.gov/pubmed/20933466 Bolla, Michel, et al.] "External irradiation with or without long-term androgen suppression for prostate cancer with high metastatic risk: 10-year results of an EORTC randomised study." The lancet oncology 11.11 (2010): 1066-1073. (original publication 1997)
**** '''<span style="color:#ff00ff">RTOG 86-10</span>'''
***** Population: 471 men with bulky tumors (T2–T4) with or without pelvic lymph node involvement and without evidence of distant metastases
***** Randomized to EBRT +/- 4 months ADT
***** Results:
****** Significant improvement in local control, distant metastases, disease-free survival, and cancer-specific mortality with ADT, but no benefit in OS (but OS benefit in patients with Gleason score 2-6)(median follow-up 6.7 years)
***** [https://www.ncbi.nlm.nih.gov/pubmed/11483335 Pilepich, Miljenko V., et al.] "Phase III radiation therapy oncology group (RTOG) trial 86-10 of androgen deprivation adjuvant to definitive radiotherapy in locally advanced carcinoma of the prostate." International Journal of Radiation Oncology* Biology* Physics 50.5 (2001): 1243-1252.
**** '''<span style="color:#ff0000">Duration of ADT</span>'''
***** '''<span style="color:#ff00ff">RTOG 92-02</span>'''
****** Population: patients with locally advanced prostate cancer (PC; T2c-4) and with prostate-specific antigen level < 150 ng/mL
****** Randomized to radiation + 4 months of ADT before and during radiation therapy vs. radiation + 28 months of ADT before, during, and after radiation therapy
****** Results:
******* Significant improvement in all clinical end points except for overall survival with 28 months of ADT. However, an overall survival benefit of a longer course of hormone therapy was observed in patients with Gleason grade 8 to 10 disease.
***** '''<span style="color:#ff00ff">EORTC 22961</span>'''
****** Population: 970 men with histologically confirmed prostate adenocarcinoma T1c to T2a–b, pathological nodal stage N1 or N2, and no clinical evidence of metastatic spread (M0) OR with clinical tumor stages T2c to T4, clinical nodal stages N0 to N2, and no clinical evidence of metastatic spread
****** Randomized to radiation + 6 months ADT vs. radiation + 3 years ADT
****** Results:
******* Radiotherapy plus 6 months of ADT provided inferior survival compared with radiotherapy plus 3 years of ADT.
*** '''The trials above have evaluated the benefit of adding ADT to radiation. It has been questioned whether the benefits of radiation plus ADT are superior to ADT alone for locally advanced disease.'''
**** '''<span style="color:#ff00ff">PR3/PR07 trial</span>'''
***** Population: 1,2015 men with with T3-4, N0/Nx, M0 prostate cancer or T1-2 disease with either prostate-specific antigen (PSA) of more than 40 μg/L or PSA of 20 to 40 μg/L plus Gleason score of 8 to 10
***** Randomized to lifelong ADT +/- radiation
****** Compared to the previous study, in this study, patients had more advanced disease, ADT was accomplished by either continuous LHRH agonist or orchiectomy, and pelvic nodes were treated with RT.
***** Results:
****** Improved OS and DFS with addition of RT to ADT (8 years follow-up in 2015 publication)
***** [https://www.ncbi.nlm.nih.gov/pubmed/25691677 Mason, Malcolm D., et al.] "Final report of the intergroup randomized study of combined androgen-deprivation therapy plus radiotherapy versus androgen-deprivation therapy alone in locally advanced prostate cancer." Journal of Clinical Oncology 33.19 (2015): 2143.(original publication 2011)
**** '''<span style="color:#ff00ff">SPCG-7/SFUO-3</span>'''
***** A Scandinavian trial comparing ADT alone with ADT plus radiation in patients with locally advanced prostate cancer revealed that ADT plus radiotherapy halved the 10-year prostate cancer–specific mortality and substantially decreased overall mortality with fully acceptable risk of side effects compared with ADT alone (Widmark et al, 2009)
** '''Of note, radiation doses used in the modern era for prostate cancer are much higher than those used in these trials and should be even more effective.'''

==== Brachytherapy ====
* '''Brachytherapy (“short” therapy) is the placement of radioactive sources into or near tumors for therapeutic purposes'''
* The goal of prostate brachytherapy is to deliver a homogeneous dose to the prostate while minimizing dose to nearby sensitive normal structures such as the rectum and urethra; seeds should be distributed evenly throughout the gland with periurethral sparing. Radioactive sources (seeds or needles) are implanted directly into the prostate gland, sometimes into the surrounding tissues
* There is no preferred isotope for brachytherapy.
** The most commonly used permanent implants are iodine-125 (125I), palladium-103 (103Pd), or cesium-131 (131Cs) seeds.
* '''Assessment of permanent implant quality'''
** '''Post-implant dosimetry in these dose-limiting regions is important to assess implant quality.'''
*** '''Post-implantation CT''' with or without MRI '''is performed to determine seed localization and reference the dose to the prostate and other structures of importance. A significant source of error in these calculations is prostatic edema, which is invariably observed after implantation'''
** Dosimetry can be adversely affected by poor implantation or migration of the seeds after implantation
* '''<span style="color:#ff0000">Brachytherapy radiation dose and fields</span>'''
** '''<span style="color:#ff0000">The doses delivered to the prostate substantially higher than those for EBRT:</span> ≈145 Gy for iodine and 125 Gy for palladium'''
*** '''Although the prostate itself can tolerate high doses of radiation, the rectal toxicity limits the dose that can be given in brachytherapy'''
* '''Brachytherapy Combined with ADT'''
** '''ADT should not be added to brachytherapy except to reduce the size of the prostate to allow the dosimetry to be optimized'''
*** In patients who have an enlarged prostate gland, it can be technically challenging to implant the entire prostate volume, especially anteriorly. Accordingly, patients are often treated with ADT to shrink the prostate before brachytherapy is performed.
*** There are no randomized trials demonstrating a survival benefit from adding ADT to low-dose rate or high-dose rate brachytherapy monotherapy
* '''Brachytherapy Combined with External Irradiation'''
** '''Although outcomes in patients with low-risk prostate cancer using brachytherapy are excellent, biochemical control can be improved for intermediate-risk and the higher risk subset of intermediate-risk patients by combining brachytherapy with EBRT;''' the role of EBRT + brachytherapy versus brachytherapy alone for selected intermediate-risk men is being investigated in a randomized clinical trial by RTOG 0232
** '''The brachytherapy is usually given first''', so that the EBRT can be discontinued if the patient begins to experience toxicity
* '''High-dose-rate (HDR) Brachytherapy'''
** Permanent seed implantation delivers a dose over a number of weeks to months depending on the isotope chosen, hence the term low dose rate. An alternative method of brachytherapy, which delivers short but high doses of radiation using temporary catheters, is HDR brachytherapy.
** HDR has been used primarily as a boost in combination with EBRT for patients with intermediate-risk or high-risk features, although it is becoming more common as monotherapy in patients with low-risk disease.
** '''HDR brachytherapy as a monotherapy has been reported to achieve results similar to EBRT in intermediate-risk prostate cancer'''

=== <span style="color:#ff0000">Adverse events</span> ===
* '''<span style="color:#ff0000">Adverse effects are primarily related to injury to the microvasculature</span>''' of the bladder, rectum, striated sphincter muscle, cavernous nerves, corpora cavernosa, and urethra.
* '''≈1/3 of patients experience <span style="color:#ff0000">acute proctitis</span> or <span style="color:#ff0000">cystitis</span> during the course of radiotherapy.'''
** '''<span style="color:#ff0000">Symptoms usually subside after the completion of therapy, however, ≈5-10% have permanent symptoms, such as irritable bowel syndrome, intermittent rectal bleeding, bladder irritability and intermittent gross hematuria</span>[https://www.ncbi.nlm.nih.gov/pubmed/24440474]'''.
** '''In some patients, chronic symptoms develop years after treatment.'''
** '''Some patients require laser cauterization or argon plasma coagulation of radiation-induced telangiectasia for bleeding from the bladder or the rectum.'''
* '''<span style="color:#ff0000">GU toxicity</span>'''
** '''<span style="color:#ff0000">Less common with EBRT than brachytherapy,</span>''' especially in patients with prostatic hyperplasia.
** To avoid these problems, α-adrenergic blockers and ADT are usually administered before treatment and '''may decrease the severity and duration of urinary symptoms'''
** '''<span style="color:#ff0000">EBRT</span>'''
*** '''Acute urinary symptoms recover over time'''
*** '''Urinary incontinence is uncommon after RT'''
** '''<span style="color:#ff0000">Brachytherapy</span>'''
*** The IPSS tends to increase significantly immediately after implantation and then decrease, at a rate depending on the half-life of the isotope used
*** '''Significant post-brachytherapy voiding symptoms refractory to medical management occur in ≈2-3% of patients'''
*** '''Brachytherapy after TURP is associated with increased risk for urinary incontinence'''
*** '''Acute urinary retention'''
**** Occurs between 12-35% of patients undergoing brachytherapy
**** Risk factors[https://pubmed.ncbi.nlm.nih.gov/11849794/]
***** Prostate volume of > 35 grams
***** Post-treatment volume of > 55 grams
***** Number of needle punctures > 33
***** AUA Symptom Score of > 12.
**** '''Management'''
***** '''Usually initially treated with an indwelling urethral catheter and medical management with alpha-blocker and/or 5-alpha-reductase inhibitor.'''
***** '''After a 1-2 weeks with the catheter, a voiding trial is usually attempted, but patients often fail this and go on CIC'''
***** Patients with retention following seed implant may resolve retention following 6-12 months of CIC.
***** '''If patients remain in retention after an adequate trial of CIC, TURP may be required.'''
****** '''The timing of this second procedure should be delayed for as long as possible and should not be attempted until at least one year after seed implantation.'''
****** Iodine-125 (125I) has a half-life of 60 days and TURP has been suggested to be contraindicated in the first 9 months after treatment because of the risk of radioactive exposure to the surgeon, operating room personnel, and pathologists.
* '''<span style="color:#ff0000">GI toxicity</span>'''
** '''<span style="color:#ff0000">5-10% persistent irritable bowel symptoms and 10-15% intermittent rectal bleeding</span>'''
**Fecal leakage by 12 years: 12% radiotherapy vs. 6% active monitoring vs. 6% prostatectomy[https://evidence.nejm.org/doi/full/10.1056/EVIDoa2300018]
** '''<span style="color:#ff0000">More common with EBRT than brachytherapy</span>'''
** '''<span style="color:#ff0000">EBRT</span>'''
*** '''Acute bowel symptoms including urgency and frequency''', partially recover with time
*** '''Compared to 3DCRT, IMRT is associated with lower rates of acute and late GI toxicity, but not GU toxicity,''' despite being used to give higher doses to the prostate; advances in radiation technology have simultaneously allowed a higher radiation dose to be given while resulting in lower toxicity.
** '''<span style="color:#ff0000">Brachytherapy</span>'''
*** '''Acute minor rectal symptoms secondary to brachytherapy are usually self-limiting.'''
*** '''Late rectal toxicity—specifically, rectal bleeding secondary to radiation proctitis'''—can be a minor, self-limiting side effect of radiation or a major toxicity requiring surgical intervention such as argon plasma coagulation or, in the worst cases, diverting colostomy
*** Dose delivered to the rectum is directly related to the likelihood and degree of late morbidity from brachytherapy
* '''<span style="color:#ff0000">Erectile dysfunction</span>'''
** Studies suggest that erectile dysfunction after radiation is caused predominantly by vascular damage
** '''<span style="color:#ff00ff">Prostate Cancer Outcome Study</span>'''
*** Population: 1655 males who had undergone either surgery or radiotherapy for localized prostate cancer
*** Functional status was assessed at baseline and at 2, 5, and 15 years after diagnosis
*** Results
**** 78.8% of post-prostatectomy patients not having erections firm enough for intercourse two years after surgery compared to 60.8% of men having ED two years following prostate radiotherapy.
**** After 15 years from the time of treatment, the prevalence of ED increases further to 87% post-prostatectomy and 94% post-radiotherapy
*** [https://pubmed.ncbi.nlm.nih.gov/23363497/ Resnick, Matthew J., et al.] "Long-term functional outcomes after treatment for localized prostate cancer." ''N Engl J Med'' 368 (2013): 436-445.
** '''≈50% of patients develop erectile dysfunction after radiotherapy for prostate cancer'''
*** '''<span style="color:#ff0000">More common with EBRT than brachytherapy</span>'''
**** In a prospective QoL study, poor erections at 60 months increased by 44% after radical prostatectomy, 23% after EBRT, and 21% after brachytherapy from baseline
**** Another study found that the predicted probability of maintaining erectile function after brachytherapy was 0.76, after brachytherapy plus EBRT 0.60, after EBRT 0.55, after nerve-sparing radical prostatectomy 0.34, after standard radical prostatectomy 0.25, and after cryotherapy 0.13.[https://www.ncbi.nlm.nih.gov/pubmed/12419432]
**** 2017 AUA Guidelines on Localized Prostate Cancer suggest similar ED rates
** '''<span style="color:#ff0000">Usually begins about 1 year after the completion of treatment</span>'''
*** '''Decline worse in patients receiving combination with ADT'''
** Younger patients with good baseline erectile function are more likely to retain adequate erections
* '''<span style="color:#ff0000">Secondary radiation-induced malignancies</span>'''
** '''Incidence of new primary prostate cancers and highly aggressive second malignancies ≈1/70 patients living > 10 years after treatment with radiotherapy for prostate cancer,''' especially radiation-induced cancers of the bladder and rectum; however, the true magnitude of risk is difficult to quantify
* '''<span style="color:#ff0000">Constitutional symptoms: fatigue</span>'''
*'''<span style="color:#ff0000">Other complications associated with brachytherapy include seed migration and rectourethral fistula</span>'''

=== <span style="color:#ff0000">End points for treatment success or failure</span> ===
* '''Cancer cells are not killed immediately after exposure to ionizing radiation'''. Rather, they sustain lethal DNA damage, but do not die until their next attempt to enter into cell division.
* '''<span style="color:#ff0000">The PSA level gradually decreases for up to 2-3 years after the completion of radiotherapy; the PSA level is usually monitored at 6-month intervals until it reaches a nadir</span>'''
* '''<span style="color:#ff0000">Nadir PSA</span>'''
** '''<span style="color:#ff0000">Sources of PSA that potentially contribute to the nadir (3):</span>'''
**# '''<span style="color:#ff0000">Residual benign prostatic epithelium</span>'''
**#* Unlike the situation after radical prostatectomy, residual benign glands may be responsible for a low level of PSA production following RT; however, '''an “acceptable” PSA level after successful RT is markedly lower than the normal range for an age-matched population because of marked atrophy of non-malignant acini'''
**# '''<span style="color:#ff0000">Residual local prostate cancer cells</span>'''
**# '''<span style="color:#ff0000">Subclinical micrometastases</span>'''
** '''<span style="color:#ff0000">Prognostic significance</span>'''
*** '''<span style="color:#ff0000">The use of PSA nadir of 0.2 ng/mL for patients treated with combined external beam therapy (EBRT) and brachytherapy has been recommended. Failure to achieve this nadir by 60 months almost always is associated with persistent disease.</span>'''
**** No absolute nadir threshold can or should be used to define cure
**** '''Post-treatment PSA levels are usually higher in patients treated with EBRT only,''' and thus these patients might not easily achieve a nadir of 0.2 ng/mL.
***** '''With EBRT, the prostate gland is not completely ablated (more organ sparing than brachytherapy)''' and the remaining prostate epithelium continues to produce PSA.
*** '''<span style="color:#ff0000">Nadir PSA is a significant predictor of distant metastases, cancer-specific survival, and reflects the pattern of failure</span>'''
**** '''<span style="color:#ff0000">A nadir > 2 ng/mL is associated with distant failure</span>'''
**** '''<span style="color:#ff0000">The time to PSA nadir is also associated with distant metastases and cancer-specific survival</span>'''
**** '''<span style="color:#ff0000">The longer the time to nadir and the lower the absolute nadir, the more likely it is that only benign prostatic epithelium remains.</span>'''
***** A higher radiation dose achieves a more complete ablation of normal epithelium and thus a lower nadir.
***** '''Residual local prostate cancer cells: for patients in whom radiotherapy fails to eradicate all the local tumor, the PSA declines progressively until the rate of growth of the surviving prostate cancer cells is greater than the death rate of those fatally damaged by the radiation, at which point the PSA begins to rise, generally relatively slowly.'''
***** '''Subclinical micrometastases''' continue to grow unchecked despite successful treatment of the primary tumor. This growth rate outstrips the rate of decline in the local tumor population relatively early after treatment, leading to a '''higher and earlier nadir and a more rapid doubling time.'''
*** '''The post-nadir PSA doubling time also reflects the pattern of failure'''
**** '''Distant failures: shorter PSA doubling times of 3-6 months'''
**** '''Local failures: PSA doubling time > 12 months'''
*** '''An interval to biochemical failure of < 2 years and a PSA doubling time of < 12 months are associated with worse cancer-specific survival'''
**** '''PSA doubling time is the most predictive factor of prostate cancer-specific mortality in patients who have a recurrence after definitive local treatment.'''
* '''<span style="color:#ff0000">Definitions of treatment failure</span>'''
** '''<span style="color:#ff0000">1996 American Society for Therapeutic Radiology and Oncology (ASTRO) definition of biochemical failure: 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 of biochemical failure: PSA nadir + 2 ng/mL;</span> 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">The Phoenix definition of definition of failure is associated with fewer false positives for failure than the ASTRO definition</span>'''
** '''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'''
* '''<span style="color:#ff0000">Post-radiation PSA “bounce”[https://auau.auanet.org/content/course-305]</span>'''
** '''<span style="color:#ff0000">Defined as a rise in PSA (variable threshold from 0.1-0.5 ng/mL[https://auau.auanet.org/content/course-305];</span>''' Campbell's Chapter 116 says 0.2 ng/mL) '''<span style="color:#ff0000">over the pre-bounce PSA level, with a subsequent rapid decrease in the PSA level to the nadir</span>'''
*** '''In the presence of residual benign epithelium or before the full effect of RT has been expressed, PSA may fluctuate or show several consecutive increases,''' possibly due to:
***# Post-treatment prostatitis
***# Delivery of a sublethal dosage of radiation with associated delayed cellular death
** '''Occurs in ≈20% of patients''', '''<span style="color:#ff0000">usually within the first 2 years after treatment</span> (within 12 months of completing EBRT[https://auau.auanet.org/content/course-305])'''; rarely, a PSA bounce can occur up to 3 years after therapy
*** '''<span style="color:#ff0000">More common with brachytherapy than EBRT</span>'''
**** ≈35% of men will experience a PSA bounce of ≥0.2 ng/mL after LDR brachytherapy
** '''<span style="color:#ff0000">Currently, there is no reliable way to discern whether a rising PSA in the first 3 years after radiation (brachytherapy or EBRT[https://auau.auanet.org/content/course-305]) represents treatment failure; it is recommended that a rising PSA within 30 months of brachytherapy be monitored</span>'''
*** '''In patients with a continuously rising PSA, especially those who are candidates for salvage therapy, evaluation for locally recurrent vs metastatic disease should be considered before attainment of the Phoenix BCR threshold.[https://auau.auanet.org/content/course-305]'''
*** '''<span style="color:#ff0000">If the rise approaches 10 ng/mL, systemic staging is warranted</span>'''
*** '''<span style="color:#ff0000">If the bounce persists > 30 months, a prostate biopsy is warranted</span>'''
** When neoadjuvant androgen deprivation is used before radiotherapy, patients often start radiotherapy with an already undetectable PSA. If the PSA remains undetectable, it is impossible to determine a true nadir or time to nadir. A substantial proportion of patients treated with EBRT and ADT experience a PSA increase when the testosterone recovers. Subsequently, as the effect of the radiotherapy is expressed, the PSA declines once again.
* '''<span style="color:#ff0000">Evaluating treatment failure</span>'''
** '''Serum PSA is the most useful marker to assess relapse.'''
** '''Although serum PSA nadir has been widely adopted as a surrogate end point to determine RT efficacy, it cannot distinguish between local and systemic failure'''
** '''<span style="color:#ff0000">Post-RT biopsy</span>'''
*** Can be used to assess the efficacy of local therapies to control cancer; however, major issues involve timing of the biopsies with respect to completion of RT, interpretation of indeterminate biopsies that show marked radiation effect, and the uncertainty imposed by sampling error.
**** '''<span style="color:#ff0000">The optimal time to biopsy is 30 to 36 months after radiotherapy</span>'''
**** '''<span style="color:#ff0000">Gleason scoring of irradiated prostate cancer should be performed only if the histologic evidence of radiation effect is absent or minimal.</span>'''
***** '''Inappropriate application of the Gleason scoring system to disintegrating malignant glands showing a marked RT effect results in a false-positive biopsy often misinterpreted as high grade and may lead to unnecessary salvage therapy'''
**** '''Scoring systems for the degree of radiation effect have been proposed based on cytoplasmic and nuclear changes and can be helpful in interpreting the biopsy'''. Their importance is to emphasize the need to differentiate between biopsies showing no or minimal radiation effect and those showing marked treatment effect
** '''<span style="color:#ff0000">Imaging</span>'''
*** '''<span style="color:#ff0000">MRI is preferred as it offers vastly improved soft tissue definition over either CT or US</span>'''
*** TRUS alone is of limited diagnostic use after radiotherapy because the increase in fibrosis alters the echogenic characteristics of the irradiated prostate

=== Pre-operative radiotherapy for high-risk disease ===
* Pre'''-'''operative radiotherapy may have advantages over post-operative treatment.
* A phase I study for high-risk prostate cancer demonstrated no dose-limiting toxicity with 54 Gy given preoperatively