# Radiation Oncology/Prostate/Salvage RT

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    See also: Natural history of PSA after RP in Prostatectomy
    See also: Clinical and Pathologic Factors predicting recurrence in Adjuvant RT

## PSA Failure post-Radical Prostatectomy

* See PSA Failure
Probability of positive bone scan with rising PSA:
* MSKCC, 2005 - PMID 15774789 — "Pattern of prostate-specific antigen (PSA) failure dictates the probability of a positive bone scan in patients with an increasing PSA after radical prostatectomy." Dotan ZA et al. J Clin Oncol. 2005 Mar 20;23(9):1962-8.
** Article provides a handy nomogram.

## Workup

Bone scan: not recommended. Chance of positive bone scan is <5% until PSA reaches 30-40. (PMID 9751361)
Prostate re-biopsy is not necessary and The PSA level or threshold seemed to be 1.5 ng/mL.
* ASTRO consensus panel - PMID 10561174 — "Consensus statements on radiation therapy of prostate cancer: guidelines for prostate re-biopsy after radiation and for radiation therapy with rising prostate-specific antigen levels after radical prostatectomy. American Society for Therapeutic Radiology and Oncology Consensus Panel." Cox et al. J Clin Oncol 1999 17:1155-1163.
** The panel judged that prostate re-biopsy is not necessary as standard follow-up care and that the absence of a rising PSA level after radiation therapy is the most rigorous end point of total tumor eradication.
** The panel noted that most data indicate the PSA level at time of salvage radiation may make a prognostic difference in outcome. The PSA level or threshold, based on the data presented, seemed to be 1.5 ng/mL.
** Based on the data presented at this conference, the dose should be 64 Gy or slightly higher with standard fractionation (1.8 or 2.0 Gy per fraction).
** There is no standard role for androgen suppression therapy in patients with or without radiation therapy for rising PSA values after prostatectomy.
ProstaScint: (indium 111-capromab pendetide)
* ProstaScint study group (1987-95)
** PMID 11920467, 2002 — "Clinical utility of indium 111-capromab pendetide immunoscintigraphy in the detection of early, recurrent prostate carcinoma after radical prostatectomy." Raj GV et al. Cancer. 2002 Feb 15;94(4):987-96.
** 255 pts with rising PSA (but < 4 ng/mL) after prostatectomy, who had negative bone scans and negative nodes, underwent ProstaScint scan.
** Uptake in 72%; 31% in prostatic fossa only. Avg PSA 1.1 (all pts). Serum PSA did not correlate with pattern of positive scan.

## Outcome

Predictors of progression after salvage RT include Gleason Score 8-10, pre-RT PSA >2, negative surgical margins, PSA-DT <10 months and seminal vesicle invasion.
* Duke/Harvard; 2011 (1988-2008) PMID 21437885 -- "Salvage radiation in men after prostate-specific antigen failure and the risk of death." (Cotter SE, Cancer. 2011 Mar 22. doi: 10.1002/cncr.25993. [Epub ahead of print])
** Retrospective. 519 men treated with RP at Duke, with PSA failure. Median F/U 11.3 years
** Outcome: Salvage RT reduction in all-cause mortality (HR 0.5, SS)
** Conclusion: Salvage RT is associated with a decreased risk in mortality
* Johns Hopkins; 2008 (1982-2004) PMID 18560003 -- "Prostate cancer-specific survival following salvage radiotherapy vs observation in men with biochemical recurrence after radical prostatectomy." (Trock BJ, JAMA. 2008 Jun 18;299(23):2760-9.)
** Retrospective. Compared cohorts of pts who had biochemical failure after RP (n=635) from those who had 1) no salvage treatment (397 pts), 2) salvage RT alone (160), or 3) salvage RT + hormones (78).
** Median f/u 6 yrs after recurrence. Death from prostate cancer in 18% (116 pts). Risk of death with observation, 22% (89 deaths); following salvage RT, 11% (18 deaths); following RT + hormones, 12% (9 deaths). Salvage RT with 3-fold increase in PC-specific survival (HR=0.32) and OS. Addition of hormonal therapy not associated with additional increase in survival.
** Increase in survival with RT was limited to pts with PSA doubling time < 6 months. Salvage RT after 2 yrs provided no survival advantage. Men who did not achieve bNED after salvage RT did not experience an increase in survival.
* Multi-institutional
** 2004 PMID 15026399 -- Salvage radiotherapy for recurrent prostate cancer after radical prostatectomy. (2004 Stephenson AJ, JAMA)
** Retrospective review of 501 patients at 5 US academic tertiary centers who received salvage RT; median follow-up 45 months
** 4-year PFS was 45%
** No risk factors 4-year PFP was 77%
** Multivariate predictors of progression:
*** Gleason Score 8-10 (HR 2.6)
*** Pre-RT post-relapse PSA >2.0 (HR 2.3)
*** Negative surgical margins (HR 1.9)
*** PSA-DT <10 months (HR 1.7)
*** Seminal vesicle invasion (HR 1.4)
** Conclusion: "The Authors conducted a multicenter analysis of 501 patients undergoing salvage radiotherapy for an increasing PSA level after radical prostatectomy in order to reliably identify prognostic variables associated with a durable response.
*** In this cohort, a Gleason score of 8 to 10, preradiotherapy PSA level greater than 2.0 ng/mL, negative surgical margins, PSADT of 10 months or less, and seminal vesicle invasion were significant predictors of disease progression despite salvage radiotherapy.
*** In their multivariable analysis, only preradiotherapy PSA level greater than 2.0 ng/mL had a significant association with progression after salvage radiotherapy. However, patients receiving treatment at very low PSA levels (<0.6 ng/mL) had an improved outcome compared with patients with a preradiotherapy PSA level between 0.61 and 2.0 ng/mL. But the use of very low PSA thresholds risks overtreating patients whose PSA level is detectable due to residual benign prostatic tissue.
*** A patient with positive margins who relapses is more likely to benefit from salvage radiotherapy than a patient with negative margins, whose PSA level is more likely to represent distant disease.
**** patients with Gleason scores of 4 to 7 and a rapid PSADT, 67% will have a durable response to early salvage radiotherapy if they have positive surgical margins,
**** compared with 22% for those having negative margins.
*** Patients with a Gleason score of 4 to 7 and a slow PSADT (>10 months) had a 4-year PFP greater than 70% when radiation was delivered early, when the PSA level was lower.
** Gives flowchart to predict progression-free probability after salvage RT based on Gleason score, Pre-RT PSA, Surgical margins, and PSADT.
** 2007 Update PMID 17513807 -- "Predicting the outcome of salvage radiation therapy for recurrent prostate cancer after radical prostatectomy." (Stephenson AJ, J Clin Oncol. 2007 May 20;25(15):2035-41.)
*** Updates previous report with larger cohort and longer follow up; 1540 pts from 17 centers, median f/u 53 months.
*** Median pre-RT PSA 1.1, median doubling time 6.9 months. Median 64.8 Gy.
*** 6-yr PFP 32%. By pre-RT PSA: 6-yr PFP 48% for PSA <0.50, 40% 0.51-1.00, 28% 1.01-1.5, 18% >1.5.
*** PSA response: nadir of ≤0.10 achieved in 59% following RT
*** Nomogram and flowchart to predict PFP.
** 2016: New Contemporary Update PMID 27528718 -- "Contemporary Update of a Multi-Institutional Predictive Nomogram for Salvage Radiotherapy After Radical Prostatectomy." (Tendulkar RD, J Clin Oncol. 2016 Aug 15. [Epub ahead of print])
*** New cohort, including 2460 pts from 10 centers. Median f/u 5 yrs. Median pre-SRT PSA 0.5
*** Includes pts with lower pre-SRT PSA values <= 0.20 (18% of pts) who were excluded from the previous cohorts.
*** On multivariable analysis, pre-SRT PSA, GS, EPE, SVI, surgical margins, ADT use, and SRT dose were associated with FFBF. Pre-SRT PSA, GS, SVI, surgical margins, and ADT use were associated with DM, whereas EPE and SRT dose were not.
*** Conclusion: "Early SRT at low PSA levels after RP is associated with improved FFBF and DM rates. Contemporary nomograms can estimate individual patient outcomes after SRT in the modern era."
* PMID 7513108 - "Evaluation of serum prostate-specific antigen velocity after radical prostatectomy to distinguish local recurrence from distant metastases." Partin et al. Urology. 1994 May;43(5):649-59.
** Proposed criteria to distinguish local recurrence from distant metastases for patients with an increasing PSA level after radical prostatectomy. A Gleason score of 8 to 10, seminal vesicle invasion, positive lymph nodes, and a rapid PSA velocity were associated with distant metastases. Local recurrence was more frequently observed in patients with low-grade and organ-confined disease, a slow PSA velocity, and a disease free interval greater than 3 years, suggesting that isolated local recurrence has a low metastatic potential.
* Virginia Commonwealth University and University of Florida - PMID 15145145 — 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; p <0.0001) and had higher prostate-specific antigen (PSA) values before starting RT (4.5 vs. 0.86 ng/mL; p = 0.003). 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: Durable biochemical control is re-established in approximately 50% of patients who undergo salvage treatment, and 70–80% of patients in adjuvant series have disease control. 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.
* University of Heidelberg (Germany), 2007 (1991-2004)
** PMID 17275204 — "Long-term results and predictive factors of three-dimensional conformal salvage radiotherapy for biochemical relapse after prostatectomy." Neuhof D et al. Int J Radiat Oncol Biol Phys. 2007 Jan 31. [Epub ahead of print]
** 171 pts. Median f/u 39 mos.
** PSA decreased after RT in 82.5%. 5-yr bRFS 35.1%. On multivar. analysis, only Gleason score and pre-RT PSA level were predictive of PSA recurrence.
* Mayo, 2000 (1987-96)
** PMID 10687990 — "Radiotherapy for isolated serum prostate specific antigen elevation after prostatectomy for prostate cancer." Pisansky TM et al. J Urol. 2000 Mar;163(3):845-50.
** 166 pts. Median f/u 52 mos.
** 5-yr bRFS 46%. Predictors for relapse: SV invasion, tumor grade, pre-RT PSA.
Use of ProstaScint imaging:
* University of Chicago, 2008 (1988-2005)
** PMID 18234446 — "Salvage radiotherapy after postprostatectomy biochemical failure: does pretreatment radioimmunoscintigraphy help select patients with locally confined disease?" (Liawu SL, Int J Radiat Oncol Biol Phys. 2008 Aug 1;71(5):1316-21.)
** Retrospective, 82 pts. Compared outcomes for patients undergoing salvage RT with or without the use of pre-RT ProstaScint (RIS) scans. All pts had persistently elevated or increasing post-op PSA >0.1. Median pre-RT PSA 0.637. 3% had negative CT scan and/or bone scan. 47 pts had pre-RT ProstaScint scan. Pts were not included on the study if they had a RIS scan showing distant disease. RT was to median dose 66 Gy and included prostate bed (91% with RIS, 83% without) or pelvis + prostate bed (6% and 17%).
** Patients who had prostate bed-only uptake on RIS did not have improved outcomes, with biochemical control of 40% at 5 years. Positive margins were associated with improved control.
** Patients

## RT + Hormonal Therapy

Preliminary Trials:
* RTOG 96-01 (1998-2003) -- Post-op RT +/- Casodex 150 mg x 2 years for pT3 with PSA elevation.
** pT3N0 (or pT2N0 with positive surgical margin) with post-op PSA 0.2-4.0. Randomized to prostate bed RT 64.8 Gy +/- casodex beginning concurrent with RT.
* ASTRO 2010 Report with 7.1 years of follow up:
** Freedom from PSA progression at 7 yrs: 57% vs. 40% (p<0.01)
*** True across all Gleason scores
** Cumulative incidence of metastatic disease at 7 years: 7.4% vs. 12.6% (p<0.04)
** Not reporting survival yet given too few events
** Grade 3/4 Toxicity:
*** GI: 2.3% vs. 1.4%
*** Bladder: 5.9% vs 5.0%
*** Gynecomastia (predominantly grades 1/2): 89% vs. 15%

## Radiation Volume

Whole Pelvis vs Prostate Bed Only:
* Stanford, 2007 (1985-2005) PMID 17459606 -- "Radiotherapy after prostatectomy: improved biochemical relapse-free survival with whole pelvic compared with prostate bed only for high-risk patients." (Spiotto MT, Int J Radiat Oncol Biol Phys. 2007 Sep 1;69(1):54-61.)
** Retrospective. 160 pts, treated with adjuvant (21 pts) or salvage RT (139). Androgen suppression in 87. 114 pts considered 'high risk' for LN+ based on: GS >= 8, PSA > 20, SV+, prostate capsule involvement, or pN+. Of the high risk group, 72 treated with WPRT and 42 with RT to prostate bed only.
** Benefit of WPRT limited to high risk pts: 5-yr BRFS 47% (WPRT) vs 21% (PO). Benefit for androgen suppression when given concurrently with RT.
** Conclusion: WPRT confers superior bRFS compared with PBRT for high-risk patients receiving adjuvant or salvage RT after radical prostatectomy. This advantage was observed only with concurrent TAS.

## Timing of Salvage RT

Systematic Reviews:
* 2012: UCLA PMID 22795730 -- "The timing of salvage radiotherapy after radical prostatectomy: a systematic review." (King CR, Int J Radiat Oncol Biol Phys. 2012 Sep 1;84(1):104-11.)
** Review of 41 studies (published 1995-2012) including 5597 patients.
** PSA level before SRT and RT dose associated with RFS. Average 2.6% loss of RFS for each incremental 0.1 PSA at the time of SRT.
** Conclusion: "This study provides Level 2a evidence for initiating SRT at the lowest possible PSA. Dose escalation is also suggested by the data."

## High Dose Salvage RT

high dose in this context refers to a dose >= 66 Gy
* 2012: MSKCC (1988-2007) PMID 22300563 -- "Long-term outcomes after high-dose postprostatectomy salvage radiation treatment." (Goenka A, Int J Radiat Oncol Biol Phys. 2012 Sep 1;84(1):112-8.)
** 285 pts treated with salvage RT. Median PSA before SRT 0.4. 60 pts (21%) had MRI-detected local recurrence. 42 pts had pathologic confirmation of local recurrence.
** 95% were treated to a dose >= 66 Gy; 72% received >= 70 Gy. ADT used in 31%.
** Median f/u 60 mo. 7-yr bRFS 37%, DMFS 77%. Predictors of recurrence: vascular invasion, negative margins, presalvage PSA > 0.4, no use of ADT, Gleason >= 7, and +SV. RT dose >= 70 Gy was not associated with improved biochemical control. PSA-DT < 3 months was the only indep. predictor of DM. Trend toward benefit of dose >= 70 Gy in decreasing clinical local failure in pts who had radiographically visible local disease at the time of SRT.
** Conclusion: "Salvage RT provides effective long-term biochemical control and freedom from metastasis in selected patients presenting with detectable PSA after prostatectomy. Androgen-deprivation therapy was associated with improvement in biochemical progression-free survival. Clinical local failures were rare but occurred most commonly in patients with greater burden of disease at time of SRT as reflected by either radiographic imaging or a greater PSA level. Salvage radiation doses ≥70 Gy may ultimately be most beneficial in these patients, but this needs to be further studied."

## PSA measurements during RT

* PMID 12240547 — "The value of PSA measurements at 30 Gy, 50 Gy and 60 Gy for dose limitation in patients with radiotherapy for PSA increase after radical prostatectomy." Wiegel T et al. Strahlenther Onkol. 2002 Aug;178(8):422-5.
** 41 pts treated to 66.6 Gy. At 30 Gy, 26% of those who would eventually respond still had a rising PSA, but at 50 and 60 Gy, 93% had decreasing PSA. In those who would fail, 75% and 88% had rising PSA at 50 and 60 Gy.
* PMID 11483332 — "Serum PSA evaluations during salvage radiotherapy for post-prostatectomy biochemical failures as prognosticators for treatment outcomes." Do T et al. Int J Radiat Oncol Biol Phys. 2001 Aug 1;50(5):1220-5.
** 41 patients with biochemical failure after RP had PSA were treated to 59.4-66.6 Gy without hormone therapy. PSA checked at 30 Gy and 45 Gy.
** Rising PSA at 45 Gy significantly predicted for poor outcome. PSA at 30 Gy did not significantly predict for disease outcome.

## Toxicity

* Mayo, 2009 (1987-2003) PMID 19766337 -- "Late toxicity after postprostatectomy salvage radiation therapy." (Peterson JL, Radiother Oncol. 2009 Nov;93(2):203-6.)
** Retrospective. 308 pts treated at Mayo-Rochester or Mayo-Jacksonville. Median RT dose 64.8 Gy; no IMRT. Hormonal therapy in 19%.
** Late complication (any grade) in 14% by 5 yrs. Grade 3-4 complication: 4 pts (0.7%). GU toxicity: 3.9% gr 2 urethral strictures, 3 pts with gr 3 cystitis. GI: 1 pt with gr 4 rectal complication.

## Radiation Injury

* Toronto Sunnybrook PMID 15936551 -- Effect of androgen suppression on hemoglobin in prostate cancer patients undergoing salvage radiotherapy plus 2-year buserelin acetate for rising PSA after surgery. ( 2005 Chander S, Int J Radiat Oncol Biol Phys.)
** Conclusion: "Two-year AS resulted in a statistically significant drop in the mean Hb, but had no clinically apparent adverse effect. The pattern of Hb change was similar to that of testosterone change."