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Controversies in the management of PSA-only recurrent disease
Stephen J. Freedland, MDAssociate Professor of Urology and Pathology
Durham VA Medical CenterDuke Prostate CenterDuke Cancer Institute
Duke University School of Medicine
Treatment Options for PSA Failure
• Observation• Local therapy – post-surgery
◦ External beam radiation ◦ Brachytherapy (rare)
• Local therapy – post-radiation◦ Cryotherapy?◦ Repeat radiation?◦ Surgery?
• Systemic◦ Hormonal therapy◦ Role of chemotherapy?
Role of Imaging in PSA Failure
• Is the failure local or systemic?• Imaging
◦ Pelvic CT – limited role in low PSA◦ Bone scan – usually negative if PSA <10 ng/ml◦ ProstaScint® – low sensitive and specificity
• May be more helpful post radiation• Typically treat empirically
Risk of Prostate Cancer-Specific Mortality (PCSM) following PSA Recurrence after Radical Prostatectomy (RP)
• 5,096 men treated with radical prostatectomy (RP) from 1982–2000 at Johns Hopkins
• 979 (19%) recurrences• 379 with PSA doubling time (PSADT) data available• 66 (17%) prostate cancer deaths • Follow-up
◦ 10.3 y (range: 1–20 y) mean following surgery◦ 6.8 y (range: 1–16 y) following PSA failure
Freedland SJ et al. JAMA 2005;294(4):433-9.
Combined Risk Factors:15-year of Cause-Specific Survival
PSA-DT
Biochemical Recurrence >3 years after RP
Biochemical Recurrence ≤ 3 years after RP
Gleason score<8
Gleason score≥ 8
Gleason score<8
Gleason score≥ 8
≥ 15 mo 94% 87% 81% 62%
9.0 to 14.9 mo 86% 72% 59% 31%
3.0 to 8.9 mo 59% 30% 16% 1%
<3.0 mo 19% 2% <1% <1%
Natural History of Salvage XRT
• 1,540 men with PSA recurrence after RP all treated with salvage radiation therapy (XRT)
• Multicenter data• 7.5 year median follow-up after RP• Median pre-XRT PSA: 1.1 ng/ml• Median pre-XRT PSADT: 6.9 months
Stephenson AJ et al. J Clin Oncol 2007;25(15):2035-41.
PSA Response to Salvage XRT
Originally published by the American Society of Clinical Oncology. [Stephenson AJ et al: 25(15), 2007:2035-41]
PSA Response to Salvage XRT
PSA <0.5 ng/ml
PSA 0.51 – 1.00 ng/ml
PSA 1.01 – 1.50 ng/ml
PSA >1.5 ng/ml
Originally published by the American Society of Clinical Oncology. [Stephenson AJ et al: 25(15), 2007:2035-41]
Salvage XRT and PCSM
• 635 men treated with RP at Johns Hopkins from 1982 to 2004 who had PSA recurrence
• 397 no salvage XRT• 160 salvage XRT alone• 78 salvage XRT + androgen deprivation therapy
(ADT)• Median f/u 6 years after recurrence; 9 years after RP• 116 (18%) prostate cancer deaths
Trock BJ et al. JAMA 2008;299(23):2760-9.
Salvage XRT and PCSM
Prostate cancer-specific survival following salvage radiotherapy vs observation in men with biochemical recurrence after radical prostatectomy. June 18;299(23):2760-9. Copyright © (2008) American Medical Association. All rights reserved.
Predictors of PCSM after Salvage XRT
Trock BJ et al. JAMA 2008;299(23):2760-9.
VariableNo. deaths/No. patients
HR for PCSD p-value
Years from RP to recurrence 0.85 .001
Year of surgery 0.91 <0.001
Path Gleason 8 vs. ≤7 2.26 <0.001
PSA-DT <6 months No XRT XRT alone XRT + ADT
51/1034/293/34
1.0 (Reference)0.140.24
PSA-DT ≥6 months No XRT XRT alone XRT + ADT
38/29414/131
6/44
1.0 (Reference)0.850.66
Early vs. Delayed ADT: Retrospective Analysis
• 4,967 men treated with RP within CPDR from ’88 to ’02
• 1,352 had PSA recurrence• 355 had “early” ADT• 997 had delayed/no ADT• 103 metastasis• Median follow-up 5.2 years after RP• Patients who received salvage XRT were excluded
from this analysis
Moul JW et al. J Urol 2004;171(3)1141-7.
Early vs. Delayed ADT: Retrospective Analysis
• Regardless of whether hormonal therapy was early or late, no difference was found overall.
• However, recall that the majority of this group of men were not going to progress to metastases.
Moul JW et al. J Urol 2004;171(3)1141-7.
Early vs. Delayed ADT: Retrospective Analysis
• Evaluated group of high-risk men:- Gleason score ≥8 or- PSA doubling time <12 months
• Showed significant benefit to early hormonal therapy- Delayed progression time to metastatic disease
Moul JW et al. J Urol 2004;171(3)1141-7.
Treating PSA Recurrence – Post Radiation
• No clear standard• Most series are small
◦ Most use cryotherapy or surgery◦ Highly selected men
• Long-term PSA control unclear◦ Some series report reasonable PSA control,
though patients are highly selected
Treating PSA Recurrence – Post Radiation: Too Little Too Late?
• Surgery fewer metastases than radiation◦ Zelefsky MJ et al. J Clin Oncol 2010;28(9):1508-
13.◦ “These results may be confounded by differences
in the use and timing of salvage therapy”• Time to secondary treatment after PSA rise:
◦ Surgery: 13 months◦ Radiation: 69 months
• “Outcomes in high-risk cancers treated with EBRT could be further improved with the earlier administration of salvage therapy, local or systemic”
Clinical Trials for PSA Recurrence – Post Surgery
• RADICALS (next slide)• TAX 3503
◦ PSADT < 9 months◦ 1) ADT vs. 2) ADT + docetaxel◦ Progression free survival (includes PSA
progression)• RTOG 0534
◦ 1) Prostate bed XRT vs. 2) prostate bed XRT + ADT (4-6 months) vs. 3) whole-pelvis + prostate bed XRT + ADT (4-6 months)
◦ Primary outcome: Freedom from progression (includes PSA progression)
Clinical Trials for PSA Recurrence – Post Surgery: RADICALS
• Accrual on-going
• Primary outcome: Disease-specific survival
• ~4,000 men
• Results expected ~2020
Radical prostatectomyRadical prostatectomyRADICALS- overall designRADICALS- overall design
Assess need: Is immediatePost-operative RT required?Assess need: Is immediate
Post-operative RT required?
UncertainUncertain
RT timingRANDOMISATION
RT timingRANDOMISATION
ImmediateRT
ImmediateRT
ImmediateRT
ImmediateRT
YesYes NoNo
SalvageRT policySalvage
RT policySalvage
RT policySalvage
RT policy
Monitor on trialMonitor on trial Monitor off trialMonitor off trial
Rise in PSARise in PSANo rise in PSANo rise in PSA
Hormone durationRANDOMISATION
On trial
Off trial
Treatment
On trial
Off trial
TreatmentRT +2yr HT
Trial follow-upTrial follow-upTrial follow-upTrial follow-up
Outcomes measuresOutcomes measures
RT +6mo HT
RT +no HT
Outcomes measuresOutcomes measures
Hormone durationRANDOMISATION
RT +2yr HT
Trial follow-upTrial follow-up
Outcomes measuresOutcomes measures
RT +6mo HT
RT +no HT
KeyKey
http://www.ctu.mrc.ac.uk/plugins/StudyDisplay/protocols/RADICALS_Protocol_v2_2_December_2008.pdf
Clinical Trials for PSA Recurrence – Post Radiation
• None
Summary
• Determine risk of progression/death• If high-enough risk, treat local first
◦ XRT after surgery◦ Unknown after XRT
• If that fails, consider systemic therapy early for high-risk
• Low-risk can be safely watched for years• On-going clinical trials will hopefully address many of
these controversies