Editing Management of Localized Prostate Cancer (section)

=== <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