Radiation Oncology/Prostate/Salvage RT


 * 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 &mdash; "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 &mdash; "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 &mdash; "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 &le;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 &mdash; 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 &mdash; "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 &mdash; "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 &mdash; "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 &mdash; "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 &mdash; "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."