# Radiation Oncology/Prostate/Adjuvant RT

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## Clinical and Pathologic Factors predicting recurrence

    See also: Natural history after RP section at Prostatectomy
The prognostic factors that most consistently predict for disease recurrence and overall survival are:
* 1 penetration through the prostatic capsule (pT3a),
* 2 the presence of tumor at the inked surgical margins,
* 3 high preoperative PSA, and
* 4 unfavorable surgical Gleason score.
* 5 invasion of the seminal vesicles
* 6 Nodal involvement
* 7 PSADT <=10 mo
* 8 PSA velocity (Annual PSA velocity of more than 2.0 ng per milliliter and PSADT <= 3 mo)
* PMID 15247353, 2004 — D'amico AV et al: "Preoperative PSA velocity and the risk of death from prostate cancer after radical prostatectomy N Engl J Med." 2004 Jul 8;351(2):125-35.
** RESULTS: As compared with an annual PSA velocity of 2.0 ng per milliliter or less, an annual PSA velocity of more than 2.0 ng per milliliter was associated with a significantly shorter time to death from prostate cancer (P<0.001) and death from any cause (P=0.01). An increasing PSA level at diagnosis (P=0.01), a Gleason score of 8, 9, or 10 (P=0.02), and a clinical tumor stage of T2 (P<0.001) also predicted the time to death from prostate cancer. For men with an annual PSA velocity of more than 2.0 ng per milliliter, estimates of the risk of death from prostate cancer and death from any cause seven years after radical prostatectomy were also influenced by the PSA level, tumor stage, and Gleason score at diagnosis.
** CONCLUSIONS: Men whose PSA level increases by more than 2.0 ng per milliliter during the year before the diagnosis of prostate cancer may have a relatively high risk of death from prostate cancer despite undergoing radical prostatectomy.
* PMID 15535442, 2004 — D'Amico AV et al.: "Prostate specific antigen doubling time as a surrogate end point for prostate cancer specific mortality following radical prostatectomy or radiation therapy J Urol." 2004 Nov;172(5 Pt 2):S42-6
** PURPOSE: A short posttreatment prostate specific antigen (PSA)-doubling time (DT) following radical prostatectomy or radiation therapy was evaluated as a surrogate end point for prostate cancer specific mortality (PCSM).
** CONCLUSIONS: Posttreatment PSA-DT appears to be a surrogate end point for PCSM following surgery or radiation therapy. We recommend that consideration should be given to enrollment onto a clinical trial and/or initiating androgen suppression therapy at the time of PSA defined recurrence when PSA-DT is less than 3 months to delay the imminent sequelae of metastatic bone disease.
* Indiana University, 2001 (1988-2001)
** PMID 11696735 — "Accuracy of predicting long-term prostate specific antigen outcome based on early prostate specific antigen recurrence results after radical prostatectomy." Soergel TM et al. J Urol. 2001 Dec;166(6):2198-201.
** 60 pts. Analyzed how PSA doubling time (DT) changes over time -- eventual DT vs early DT.
** DT did not accelerate. Distant mets developed in 60% of pts with eventual DT < 6 m. For DT of 6-12 mo, DM in 20%.
* PMID 10737489, 2000 — Grossfeld GD, Chang JJ, Broering JM, et al: Impact of positive surgical margins on prostate cancer recurrence and the use of secondary cancer treatment: Data from the CaPSURE database. J Urol 163:1171-1177, 2000
** Results and Conclusions: surgical margin status was an important independent predictor of PSA recurrence and secondary treatment (p = 0.06 and 0.0011, respectively). The number of positive margins and positive margin location had little impact on the outcomes measured.
* PMID 9817331, 1998 — D’Amico AV, Whittington R, Malkowicz SB, et al: The combination of preoperative prostate specific antigen and postoperative pathological findings to predict prostate specific antigen outcome in clinically localized prostate cancer. J. Urol 160:2096-2101, 1998.
** RESULTS: Preoperative PSA, pathological stage, margin status and prostatectomy Gleason score were independent predictors of time to postoperative PSA failure.
** CONCLUSIONS: Pts who are high risk for early PSA failure can be identified and can be selected for adjuvant therapy trials. Unfortunately, the use of this endpoint does not allow one to identify the source of recurrence with a high degree of accuracy.
* PMID 9302141, 1997 — Lowe BA, Lieberman SF: Disease recurrence and progression in untreated pathologic stage T3 prostate cancer: Selecting the patient for adjuvant therapy. J Urol 158:1452-1456, 1997.
** Prospectively followed untreated pT3 pts.
** Poor prognostic factors were number of surgical margins involved by tumor, pathologic Gleason score and pre-prostatectomy PSA level. PSA recurrence in 20.8% of pts with 1 surgical margin involved, 40.9% with 2 margins, and 50% with 3 or more margins; in 20.3% with Gleason score < 7, 33.9% with Gleason score 7, and 74.2% with > 7; in 17.3% with PSA < 10, 45.4% with PSA > 10.
** High risk (Gleason 7-10, PSA > 10, 2 or more positive margins) or low risk (the others). Risk of recurrence 8.5% for low risk and 44.8% for high risk.

## Radical Prostatectomy +/- Adjuvant RT

Meta-Analysis
* Loyola Meta-Analysis; 2017 PMID 28225445 -- "Adjuvant Radiotherapy Versus Wait-and-See Strategy for Pathologic T3 or Margin-Positive Prostate Cancer: A Meta-Analysis." (Shaikh MP, Alite F, Wu MJ, Solanki AA, Harkenrider MM, Am J Clin Oncol. 2017 Feb 20. doi: 10.1097/COC.0000000000000358. [Epub ahead of print])
** Meta-analysis. 3 RCTs pooled, 1737 patients with pT3 or margin-positive prostate cancer
** Outcome:
*** ART resulted in improved biochemical PFS (BPFS, HR=0.48, SS) including benefit in all subsets: SM+, ECE, SV invasion, pre-op PSA<=10, pre-op PSA>10, post-op PSA<=0.2, post-op PSA>0.2, GS<=6 as well as in GS>6.
*** Greater clinical PFS (CPFS, HR=0.73, SS) including benefit in subsets with SM+ or SV invasion.
*** Greater hormone-free survival (HFS, HR=0.64, SS).
*** Improved 10-year metastasis-free survival with ART (10-yr MFS, OR=0.77, SS).
*** There was no OS benefit (HR=0.97, NS).
** Toxicity: Statistically significant but small absolute increase in moderate/severe toxicity with ART: Grade 2+ GU toxicity (17.1% vs. 10.3%), Grade 2+ GI toxicity (2.5% vs. 1.1%), urinary stricture rates (11.1% vs. 5.7%) and, urinary incontinence (6.9% vs. 2.7%).
** Conclusion: 10-yr MFS, BPFS, CPFS, and HFS were improved with ART. Small absolute increase in Grade 2+ GI & GU toxicities, urinary strictures and urinary incontinence with ART. Therefore, ART should be offered to patients with these high-risk features.
* Ontario; 2008 PMID 18501455 -- "Adjuvant radiotherapy following radical prostatectomy for pathologic T3 or margin-positive prostate cancer: A systematic review and meta-analysis." (Morgan SC, Radiother Oncol. 2008 May 21. [Epub ahead of print])
** Meta-analysis. 3 randomized trials, 1743 patients with pT3 or R1
** Outcome: No benefit for OS. Significant benefit for bPFS (HR 0.47, SS)
** Toxicity: No significant different in Grade 3+ GI or GU toxicity at 5 years
** Conclusion: No OS benefit over active surveillance, but significant improvement in bPFS without excess severe late toxicity
* German ARO 96-02 / AUO AP 09/95 (1997-2004) -- Adjuvant RT vs. observation
** Randomized. 388 men randomized, radical prostatectomy (open RP and PLND, nerve sparing allowed) pT3-4 pN0, age <76 years. Randomization was prior to determination of post-op PSA. If undetectable PSA was not achieved, pts were removed from protocol and scored as having progressive disease. Pts with undetectable post-op PSA (<0.1) assigned treatment(n=80%). Arm 1) observation vs. Arm 2) RT 60/30 Gy. RT 3D plan prostatic fossa + SV + 1cm. Start 6-12 weeks after RP. Primary endpoint PSA control (PSA relapse defined as undetectable to detectable, followed by another increase). Patients not reaching undetectable PSA (20%) treated with 66.6 Gy. LR not investigated because DRE often false positive
** Randomization:
*** Eligible (n=385): 192 arm 1(observation), 193 arm 2(RT).
*** 78 pts excluded (20%) -- arm 1:33, arm 2:45 -- for persistent PSA
*** Treatment (n=307): 159 assigned arm 1. 148 assigned arm 2.
*** Per protocol (n=268): Given wait and see: 154. Given RT per protocol: 114.
** 2005 ASCO Abstract - "Phase III results of adjuvant radiotherapy (RT) versus wait and see (WS) in patients with pT3 prostate cancer following radical prostatectomy (RP)(ARO 96-02 / AUO AP 09/95)." (Wiegel T, Proc ASCO 2005; 4513.) Median F/U 3.1 years
*** Outcome: Patients treated per protocol bNED 81% vs. 60% (SS). Greatest benefit SM+, PSA >10, GS <7
*** Late toxicity: GU grade 3 2%, GI no grade 3
*** Conclusion: Adjuvant RT significantly improves risk of PSA progression after RP
** 2009 PMID 19433689 Full text -- "Phase III Postoperative Adjuvant Radiotherapy After Radical Prostatectomy Compared With Radical Prostatectomy Alone in pT3 Prostate Cancer With Postoperative Undetectable Prostate-Specific Antigen: ARO 96-02/AUO AP 09/95." (Wiegel T, J Clin Oncol. 2009 May 26.) Median F/U 4.5 years
*** Outcome: 5-year bPFS observation 54% vs. RT 72% (HR 0.53, SS). DM 3% vs. 2%. Negative predictors preop PSA >10, stage pT3c
*** Toxicity: No Grade 4, 1 patient with Grade 3 bladder, Grade 2 in 3%
*** Conclusion: Patients with pT3 PCA who achieve undetectable PSA after surgery benefit from adjuvant RT
** 2013 ASCO Abstract (Genitourinary Cancers Symposium) -- "Phase III results of adjuvant radiotherapy (RT) versus wait-and-see (WS) in patients with pT3 prostate cancer following radical prostatectomy (RP)(ARO 96-02/AUO AP 09/95): Ten years follow-up." (Wiegel T, J Clin Oncol 31, 2013 (suppl 6; abstr 4))
*** Median f/u 111 months (9.2 yr).
*** Outcome: bNED at 10-yrs: 35% (no RT) vs 56% (RT); HR=0.51 (SS). No sig difference in DMFS or OS.
*** Toxicity: 2 pts with Grade 2 late rectal toxicity, 4 pts with Grade 2+ bladder toxicity. No grade 4 events.
*** Conclusion: "With only one grade 3 case of late toxicity, ART was safe in pT3 prostate cancer. At 10 years median follow up, it reduced the risk of bNED by 49%. The study was not powered to detect differences in OS."
** 2014 PMID 24680359 -- "Adjuvant Radiotherapy Versus Wait-and-See After Radical Prostatectomy: 10-year Follow-up of the ARO 96-02/AUO AP 09/95 Trial."
** 2015 PMID 25445556 "Prostate-Specific Antigen Persistence After Radical Prostatectomy as a Predictive Factor of Clinical Relapse-Free Survival and Overall Survival: 10-Year Data of the ARO 96-02 Trial" (Wiegel et al. Int J Radiat Oncol Biol Phys. 2015 Feb 1;91(2):288-94.)
*** Persistent PSA post-prostatectomy poor prognostic indicator with 10 yr metastasis-free survival of 67% vs. 83% (in pT3-4 pts with undetectable PSA) and OS of 68% vs. 84% p=SS
*** Gleason score >= 8, pT >= 3c and ECE >= 2 mm unfavorable risk factors
* EORTC 22911 (1992-2001) Protocol -- Adjuvant RT vs. observation
** Randomized. 1005 patients. Radical prostatectomy pT2-3N0, ilio-obturator LND, with extracapsular disease (ECE, SV+, SM+). Arm 1) observation vs. Arm 2) RT 60/30, start within 16 weeks of RP. RT technique conventional (non-3D), 50/25 + 10/5 boost with smaller margins. Borders surgical limits SV to apex. No Gleason scoring (used WHO grade). Biochemical failure increase of 0.2 from postop nadir measured on 3 occasions at least 2 weeks apart and is dated from first day of rise. After biochemical or clinical failure, could get salvage RT. By risk: 43% had one RF only, 43% had two RFs, 12% had all three RFs. Primary endpoint clinical PFS, amended to bNED in 2003
** QA; 2002 PMID 12208577 - Quality assurance of the EORTC trial 22911. A phase III study of post-operative external radiotherapy in pathological stage T3N0 prostatic carcinoma: the dummy run. Davis JB, Reiner B, Dusserre A, Giraud JY, Bolla M; EORTC.Radiother Oncol. 2002 Jul;64(1):65-73.
** 5-years; 2005 PMID 16099293, 2005 — "Postoperative radiotherapy after radical prostatectomy: a randomised controlled trial (EORTC trial 22911)." (Bolla M, Lancet. 2005 Aug 13-19;366(9485):572-8.) Median F/U 5 years
*** Outcome: 5-year bNED RT 74% vs observation 53% (SS), regardless of risk factors. Most failures loco-regional. Clinical PFS 85% vs. 78% (SS). OS 91-92% (NS).
*** Late toxicity: Grade 3 RT 4% vs. observation 3% (p=0.07)
*** Conclusion: Post-operative radiotherapy results in improved biochemical and clinical PFS, but its benefit should be weighed against the risk of increased toxicity.
** Subset analysis; 2007 PMID 17878474 -- "Identification of patients with prostate cancer who benefit from immediate postoperative radiotherapy: EORTC 22911." (Van der Kwast TH, J Clin Oncol. 2007 Sep 20;25(27):4178-86.)
*** Pathology data review. 552 patients
*** Surgical margin impact: if SM+, RT prevents 291 events/1000 patients (SS); need to treat 3 patients to prevent 1 recurrence. If SM-, RT prevents 88 events/1000 patients (NS).
*** Conclusion: After careful central path review, RT beneficial only for patients with positive margins (this effect was not seen when using the local pathology data), no benefit if negative margins
** 10-years; 2012 PMID: 23084481, 2012 - "Postoperative radiotherapy after radical prostatectomy for high-risk prostate cancer: long-term results of a randomised controlled trial (EORTC trial 22911)." (Bolla M, Lancet 2012 Dec 8;380(9858):2018-27.) Median F/U 10.6 years
*** Outcome: Post-op RT improved 10 yr bPFS 61% vs. 41% (SS). 10 yr LRR 7.3% (RT) vs 16.6% (obs) (SS). No difference in DM, OS or CSS.
*** Conclusion: Postop RT improves bPFS and local control vs. observation, consistent with 5-yr results. However, improvements in clinical PFS were not maintained.
* SWOG-8794 / RTOG 90-19 / INT-0086 (1988-95) -- Adjuvant RT vs. observation
** Randomized. 473 patients, radical prostatectomy with extraprostatic disease (ECE, SV+, or SM+). Pelvic LND required until 1995, when very low risk patients (T1a or T2a GS2-6 PSA <10, T1b-c GS2-5 PSA <10, T2b GS2-6 PSA <6, T2c GS2-6 PSA <4) were exempt. Randomized (within 16 weeks of RP) to Arm 1) Prostatic fossa RT 60-64 Gy vs Arm 2) observation. No concurrent hormones . RT field non-3D, 4-field, 9x9 or 10x10 cm. Primary endpoint mets-free survival
** 2005 ASTRO Abstract Plenary #1 Webcast - "Phase III Randomized Study of Adjuvant Radiation Therapy versus Observation in Patients with Pathologic T3 Prostate Cancer (SWOG 8794)" Swanson GP et al. IJROBP Volume 63, Supplement 1 , 1 October 2005, Page S1.
*** Median f/u 9.7 yrs. RT improved bDFS 10-yr 47% vs 23%, metastasis free survival 83% vs 61%, OS 74% v 63%.
** 10-years; 2006 PMID 17105795 — "Adjuvant radiotherapy for pathologically advanced prostate cancer: a randomized clinical trial." (Thompson IM Jr, JAMA. 2006 Nov 15;296(19):2329-35.) Median F/U 10.6 years
*** Outcome: Mets-free survival RT 65% vs. observation 57% (p=0.06), median 14.7 years vs. 13.2 years. However, 33% of observation group received salvage RT for disease relapse instead of observation alone. Biochemical progression (defined as PSA >=0.4) RT 35% vs. 64% (SS), median TTF 10.3 yrs vs observation 3.1 yrs (SS). Recurrence free survival 61% vs. 47% (SS). Hormones initiated in 10% vs 21%(SS). No difference in OS.
*** Rectal complications 3% vs 0%, urethral strictures 18% vs 9%, total urinary incontinence 6% vs 3%.
*** Conclusion: Adjuvant RT decreases PSA and clinical recurrence by ~50%. However, while ~ 70% of pts have biochemical relapse, after censoring for death without mets, mets free survival ~ 78% at 13.2 years (rate of events was lower than anticipated).
** Failure analysis; 2007 PMID 17538167 -- "Predominant treatment failure in postprostatectomy patients is local: analysis of patterns of treatment failure in SWOG 8794." (Swanson GP, J Clin Oncol. 2007 Jun 1;25(16):2225-9.)
*** Biochemical progression defined as PSA >= 0.4
*** 10-year PSA failure:
**** Postsurgical PSA <0.2: Biochemical Progression: Obs 72% vs. RT 42%; local failure 20% vs. 7%; DM 12% vs. 4%
**** Postsurgical PSA 0.2-1.0: Biochemical Progression: Obs 80% vs. RT 72%; local failure 25% vs. 9%; DM 16% vs. 12%
**** Postsurgical PSA >1.0: Biochemical Progression: Obs 100% vs. RT 94%; local failure 28% vs. 9%; DM 44% vs. 18%
*** Conclusion: Failure in high risk patients predominately local; adjuvant RT reduces risk of failure
** QOL; 2008 PMID 18165645 -- "Health-related quality of life results in pathologic stage C prostate cancer from a Southwest Oncology Group trial comparing radical prostatectomy alone with radical prostatectomy plus radiation therapy." (Moinpour CM, J Clin Oncol. 2008 Jan 1;26(1):112-20.)
*** 217 patients registered on HRQL study. Questionnaire for GI/GU symptoms, and physical/emotional function
*** Outcome: Global QOL initially worse for RP+RT, but improved over time and eventually exceeded RP alone (SS). RP+RT worse bowel function through 2 years, and worse GU function. No difference on ED
*** Conclusion: Adding RT to surgery resulted in more frequent urination, and early bowel dysfunction, but long-term QoL better
** SVI; 2008 PMID 18930488 -- "The Prognostic Impact of Seminal Vesicle Involvement Found at Prostatectomy and the Effects of Adjuvant Radiation: Data From Southwest Oncology Group 8794." (Swanson GP, J Urol. 2008 Oct 17. [Epub ahead of print])
*** Subset analysis. 139 patients with SVI, regardless of ECE or SM. Compared with SVI-, SVI+ had worse 10-year bFFS (22% vs 33%, SS), mets-free survival (56% vs. 70%, SS), and overall survival (61% vs. 74%, SS)
*** Outcome: Adjuvant RT improved 10-year bFFS (12% to 36%, SS), with trend for mets-free survival (47% to 66%, NS), and overall survival (51% to 71%, p=0.08)
*** Conclusion: SVI involvement is a negative prognostic factor, but long term control possible with adjuvant RT
** 2008 ASTRO "Update of SWOG 8794: Adjuvant Radiotherapy for pT3 Prostate Cancer Improves Metastasis Free Survival" Swanson GP et al. IJROBP Volume 72, Issue 1, Supplement 1, 1 September 2008, Page S31. Confirmed 15 year metastasis-free survival advantage (46% vs. 38%, p=0.036) and suggested an overall survival advantage (47% vs. 37%, p=0.053) favoring adjuvant RT.
** 15 year update; 2009 PMID 19167731 Full text -- "Adjuvant radiotherapy for pathological T3N0M0 prostate cancer significantly reduces risk of metastases and improves survival: long-term followup of a randomized clinical trial." (Thompson, J Urol 2009)
*** RT improved metastasis free survival (HR 0.71, 93/214 vs. 114/211)
*** RT improved overall survival: HR 0.72, 59% vs 48%, p=0.023. # of Deaths 88/214 vs 110/211.
*** Median f/u of ~12.5y in both arms
*** 70 of 211 pts on observation arm ultimately received RT.

## Adjuvant RT Retrospective studies

* PMID 15708249, 2005 — Improved biochemical outcome with adjuvant radiotherapy (EBRT)after radical prostatectomy (RP) for prostate cancer with poor pathologic features. Vargas C, Kestin LL, Weed DW, Krauss D, Vicini FA, Martinez AA. Int J Radiat Oncol Biol Phys. 2005 Mar 1;61(3):714-24
** 617 pts, retrospective. Clinical stage T1-T2N0. 34 pts with undetectable post-op PSA and poor pathologic features underwent post-op RT. Median dose 59.4 Gy (range: 50.4-66.6 Gy).
** Adjuvant RT: Median f/u 8.2 yrs. Despite worse pathologic features for the RT group, 5-year biochemical control rate was 57% for RT group vs 47% for RP alone group (N.S.). For extracapsular extension, 52% vs 30%; for seminal vesicle invasion, 60% vs 18%; for positive margins, 64% vs 27% (All S.S.).
** Salvage RT: 99 pts (17% of 585 RP alone pts) required RT salvage for palpable or biochemical recurrence. Median dose 59.4 Gy, median interval 1.3 years, median PSA before salvage 0.8. 5-yr and 8-yr BC rate (PSA <0.1), 41% and 35%. 8-yr LR rate after salvage RT was 4%.
** Conclusion: Adjuvant RT is efficacious for those with poor pathologic factors.
* Italian - PMID 15183470, 2004 (1986-98) — "Role of postoperative radiotherapy after pelvic lymphadenectomy and radical retropubic prostatectomy: a single institute experience of 415 patients." Cozzarini C et al. Int J Radiat Oncol Biol Phys. 2004 Jul 1;59(3):674-83.
** 415 pts. Retrospective. pT2b-pT4, pN0-pN1. Of the 415 pts, 237 pts underwent early adjuvant RT (within 6 months) and 178 had either no RT or salvage RT.
** Median f/u 62 months. 8-yr freedom from biochemical failure was 69% vs 31%, freedom from local failure 93% vs 63%, f.f. systemic failure 88% vs 75%, and cause-specific survival 93% vs. 80%. All were S.S. Subgroup analysis showed improvement in CSS for those with positive margins, extracapsular extension, Gleason 7 or above, and positive lymph nodes.
* Virginia Commonwealth University / University of Florida - PMID 15145145, 2004 — "Comparison Of Adjuvant Versus Salvage Radiotherapy Policies For Postprostatectomy Radiotherapy." Hagan et al. Int. J. Radiation Oncology Biol. Phys., Vol. 59, No. 2, pp. 329–340, 2004.
** The Authors compared the long-term results of postprostatectomy radiotherapy (RT) from two institutions, one adapting a prospective policy of adjuvant RT (69 patients) and the other salvage RT (88 patients). The salvage group underwent RT after longer postoperative intervals (median, 40.3 vs. 2.9 months; S.S.) and had higher prostate-specific antigen (PSA) values before starting RT (4.5 vs. 0.86 ng/mL; S.S.). Both groups were routinely treated to a minimal total dose of 60 Gy.
** Results: Of the 69 patients referred for adjuvant RT, 22 (32%) had nonzero PSA values before RT. Multivariable modeling of BRFS found only the PSA value before RT to be statistically significant (p <0.0001). RT after prostatectomy was equally effective in either setting when the pre-RT PSA level was <1 ng/mL. When the PSA value before RT was >1 ng/mL, the 5-year BRFS for each group was inferior.
** Conclusion: Although the adjuvant treatment policy was associated with significantly improved BRFS, this was attributable to low pre-RT PSA values. When the treatment groups were stratified for pre-RT PSA level, the differences in BRFS were not statistically significant. Patients with a rising PSA level after prostatectomy, regardless of their initial risk, should receive prompt referral for RT.
* PMID 10737490, 2000 — Leibovich BC, Engen DE, Patterson DE, et al: Benefit of adjuvant radiation therapy for localized prostate cancer with a positive surgical margin. J Urol 163:1178-1182, 2000.
** PURPOSE: The Authors' study was limited to men with organ confined cancer and a single positive margin.
** MATERIALS AND METHODS: They retrospectively evaluated the records of a nested matched cohort of 76 patients with pathological stage T2N0 prostate cancer and a single positive margin who underwent adjuvant radiation therapy within 3 months of radical prostatectomy. There was a positive margin at the prostatic apex in 35 cases, prostatic base in 18, posterior prostate in 11, urethra in 7, and prostatic apex and urethra in 5. These patients were matched 1:1 with 76 controls who did not receive adjuvant radiation therapy. Neither group received androgen deprivation therapy. Patients and controls were matched exactly for the margin positive site, age at surgery, preoperative serum prostate specific antigen, Gleason score and DNA ploidy. Biochemical relapse was defined as posttreatment PSA greater than 0.2 ng./ml
** RESULTS: Overall there was significant estimated improvement plus or minus standard error in 5-year clinical and biochemical progression-free survival in 88% vs 59% (S.S.) of patients treated with adjuvant radiation therapy versus no radiation therapy. No patient who received radiation therapy had local or distant recurrence, while 16% of controls had recurrence (S.S.).
** CONCLUSIONS: Patients with localized prostate cancer and a single positive surgical margin appear to have a lower rate of biochemical relapse at 5 years when adjuvant radiation therapy is administered. Definitive evidence of the beneficial effect of adjuvant radiation therapy for patients with involved surgical margins awaits conclusion of randomized clinical trials.
* PMID 10477006, 1999 — Valicenti RK, Gomella LG, Ismail M, et al: The efficacy of early adjuvant radiation therapy for pT3N0 prostate cancer: a matched-pair analysis. Int J Radiat Oncol Biol Phys 45:53-58, 1999.
** 149 patients undergoing radical prostatectomy were found to have pT3N0 prostate cancer, had an undetectable postoperative prostate-specific antigen (PSA) level, and had no immediate hormonal therapy. Fifty-two patients received adjuvant RT within 3 to 6 months of surgery. Ninety-seven underwent radical prostatectomy alone and were observed until PSA failure. From these two cohorts, we matched patients 1:1 according to preoperative PSA (<10 ng/ml vs. >10 ng/ml), Gleason score (<7 vs. > or =7), seminal vesicle invasion, and surgical margin status. Seventy-two patients (36 pairs) were included in the analysis. Median follow-up time was 41 months. We calculated a matched-pairs risk ratio for cumulative risk of PSA relapse (a rise above 0.2 ng/ml).
** RESULTS: After controlling for the prognostic factors by matching, there was an 88% reduction (95% confidence interval [CI]: 78-93%) in the risk of PSA relapse associated with adjuvant RT. The 5-year freedom from PSA relapse rate was 89% (95% CI: 76-100%) for patients receiving adjuvant RT as compared to 55% (95% CI: 34-79%) for those undergoing radical prostatectomy alone.
** CONCLUSIONS: These data suggest that adjuvant RT for pT3N0 prostate cancer may significantly reduce the risk of PSA failure as compared to radical prostatectomy alone. Its effect on clinical outcome awaits further follow-up.
* PMID 9587124, 1998 (1989-95) — Valicenti RK, Gomella LG, Ismail M, et al: Pathologic seminal vesicle invasion after radical prostatectomy for patients with prostate carcinoma: Effect of early adjuvant radiation therapy on biochemical control. Cancer 82:1909-1914, 1998
** 53 pts. RT for pathologic seminal vesicle invasion and negative pelvic lymph node dissection (pT3cN0).
** 18 men had an elevated PSA immediately after surgery and received salvage RT. For this group, 3-yr bNED rate was 38%. The other 35 men had undetectable PSA at 3 months. 15 received RT and 20 were observed. 3-yr bNED was 86% for immediate adjuvant RT vs 48% for observation group.
** Conclusion: adjuvant RT reduces risk of biochemical failure for men with pT3b disease and undetectable PSA after surgery.
* PMID 7543893, 1995 — Anscher MS, Robertson CN, Prosnitz LR: Adjuvant radiotherapy for pathologic stage T3/4 adenocarcinoma of the prostate: Ten-year update. Int J Radiat Oncol Biol Phys 33:37-43, 1995.
** Between 1970 and 1983, 159 patients underwent RP for newly diagnosed adenocarcinoma of the prostate and were found to have pathologic Stage T3/4. Forty-six received adjuvant RT and 113 did not. Radiotherapy usually consisted of 45-50 Gy to the whole pelvis followed by a boost to the prostate bed of 10-15 Gy, to a total dose of 55-65 Gy.
** RESULTS:
*** The actuarial survival at 10 and 15 years was 62% and 62% for the RT group compared to 52% and 37%, respectively, for the RP group (N.S.).
*** The disease-free survival for the RT group was 55% and 48% at 10 and 15 years, respectively, compared to 37% and 33% for the RP group (N.S.).
*** Similarly, there was no difference in the rate of distant metastases between the two groups.
*** In contrast, the local relapse rate was significantly reduced by the addition of postoperative radiotherapy. The actuarial local control rate at 10 and 15 years was 92% and 82%, respectively, for the RT group vs 60% and 53% for the RP group (S.S.).
** CONCLUSIONS: While postoperative pelvic RT significantly improves local control compared to RP alone for pathologic Stage T3/4 prostate cancer, it has no impact on distant metastases and consequently does not improve survival. These data are consistent with the conclusion that many patients with pathologic Stage T3/4 prostate cancer have occult metastases at presentation and will not be cured by local therapies alone. The optimal treatment for this patient population remains to be established.

## Timing of RT

* MRC/NCIC "RADICALS" Protocol (ongoing)
** Randomized. 2x3 design evaluating timing of RT and duration of ADT. First randomization: Arm 1) Early adjuvant RT vs. Arm 2) Salvage RT with PSA rise. Second randomization: Arm 1) No ADT vs. Arm 2) Short-term (4 months) ADT vs. Arm 3) Long-term (2 years) ADT

## RT + Hormones

* Analysis of RTOG 85-31 (1987-92)
** PMID 10475361, 1999 — "Does androgen suppression enhance the efficacy of postoperative irradiation? A secondary analysis of RTOG 85-31." Corn BW et al. Urology. 1999 Sep;54(3):495-502.
** Of the pts treated on 85-31, 139 were s/p prostatectomy, 71 with RT + immediate androgen suppression and 68 with RT alone (and hormones reserved for relapse).
** At a median f/u of 5 yrs, PFS (failure defined at PSA of > 0.5) was 65% vs 42%; for different endpoints, 71% vs 46% (PSA of 1-3.9) or 76% vs 55% (PSA > 4). No differences in distant failure or overall survival.
** Conclusion: pts with indications for post-op RT should be considered for RT + hormones. No overall survival difference.

## Node Positive

See also: Radiation Oncology/Prostate/Node Positive
Above studies:
* PMID 15183470, Cozzarini C

## Technical Considerations
### CTV

* Princess Margaret; 2007 PMID 17967303 -- "Anatomic boundaries of the clinical target volume (prostate bed) after radical prostatectomy." (Wiltshire KL, Int J Radiat Oncol Biol Phys. 2007 Nov 15;69(4):1090-9.)
** Anatomic boundaries described for CTV (prostate bed)
** Inferior border: penile bulb or 8mm below vesico-urethral anastomosis (whichever is more superior)
** Anterior border: posterior edge of symphysis pubis, up to top of symphysis pubis. Then 1.5cm anteriorly to posterior bladder wall (to account for bladder deformation)
** Posterior border: anterior rectal wall and levator ani; superiorly mesorectal fascia
** Lateral border: medial border of levator ani and obturator internus; superiorly the sacrorectogenitopubic fascia
** Superior border: surgical clips (excluding high lymphadenectomy clips) or 5mm above inferior edge of vas deferens. Include retained SVs when pathologically involved
** Borders extended 1 cm beyond gross recurrent disease

### Organ motion

See also: Radiation Oncology/Prostate/External Beam RT#Prostate Localization
* Italy, 2005 - PMID 15734207 — "Rectal and bladder motion during conformal radiotherapy after radical prostatectomy." Fiorino C et al. Radiother Oncol. 2005 Feb;74(2):187-95.
** Conclusion: "Rectal motion (and consequent shifts of CTV) was large at the half cranial portion of the rectum while it was very small below the flexure."

### Dose

* Milan, Italy; 2009 PMID 19619960 -- "Need for High Radiation Dose (>/=70 Gy) in Early Postoperative Irradiation After Radical Prostatectomy: A Single-Institution Analysis of 334 High-Risk, Node-Negative Patients." (Cozzarini C, Int J Radiat Oncol Biol Phys. 2009 Jul 18. [Epub ahead of print])
** Retrospective. 334 high risk patients (pT3-T4 and/or SM+, N0), s/p RP and adjuvant RT. Dose <70.2 Gy (median 66.6 Gy, n=153) vs >=70.2 Gy (median 70.2 Gy, n=181). Median F/U 10 and 7 years
** Outcome: Median TTF 36 vs 38 months (NS), but 5-year bPFS <70.2 Gy 71% vs. 70.2 Gy 83% (SS), 5-year DFS 88% vs 94% (SS)
** Conclusion: Strong support for adjuvant EBRT dose >= 70.2 Gy after RP
* Stanford (1984-2004)
** Dose Modeling; 2008 PMID 18234451 -- "Radiotherapy After Prostatectomy: Is The Evidence for Dose Escalation Out There?" (King CR, Int J Radiat Oncol Biol Phys. 2008 Jan 28 [Epub ahead of print])
*** Salvage RT: TCP consistent with radical RT TCP, suggesting macroscopic disease. Radical RT TD50 65.9 Gy, slope 2.6%/Gy; salvage RT TD50 66.8 Gy, slope 3.8%/Gy
*** Adjuvant RT: TD50 60 Gy
*** Conclusion: Both adjuvant and RT salvage doses still on steep part of dose-response curve.
** Salvage dose; 2008 PMID 18207668 -- "Improved outcomes with higher doses for salvage radiotherapy after prostatectomy." (King CR, Int J Radiat Oncol Biol Phys. 2008 May 1;71(1):23-7. Epub 2008 Jan 22.)
*** Retrospective. 122 patients, pN0, salvage RT. Median prostate bed 60 Gy (n=38) or 70 Gy (n=84). Median F/U >5 years
*** Outcome: 5-year bNED 60 Gy 25% vs. 70 Gy 58% (SS). Prognostic factors: dose 70 Gy, post RP PSA <=1 ng/ml, no SV+
*** Conclusion: Significant dose response; recommend salvage dose 70 Gy to prostate bed

## Hypofractionation

* Milan; 2008 (Italy)(2005-2006) PMID 18455253 -- "Hypofractionated adjuvant radiotherapy with helical Tomotherapy after radical prostatectomy: Planning data and toxicity results of a Phase I-II study." (Cozzarini C, Radiother Oncol. 2008 Apr 30. [Epub ahead of print])
** Phase I-II. 50 patients, after RP and PLND with pT2R1/pT3a-bN0. RT 58/20 @ 2.9 Gy/fx. Median F/U 2.1 years
** Toxicity: Late GI G2+ 0%, GU G2+ 12%
** Conclusion: Acute toxicity and early late toxicity post-RP excellent