Editing Management of Localized Prostate Cancer (section)

==== 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.'''