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