Radiation Recurrent Prostate Cancer:
Give Your Patients A Curative Treatment Option
Dr. Timothy C. Goodson
Arkansas Urology, P.A.
Radiorecurrent PCa Patient Population
?
Secondary Treatment
70% | 58,000 patients
Radiorecurrent PCa Patients
60% | ~ 82,000 patients per year1
Androgen Deprivation Therapy
90% | 22,500 patients2,4
Received Secondary Treatment
30% | 25,000 patients3
Radiation Therapy
~ 137,170 patients per year1,4
Other Therapies
10% | 2,500 patients
A total of > 400,000 men or ~ 3% of Medicare’s male population
in the U.S. were prescribed ADT for PCa.5
1. Agarwal P.K., Sadetsky A. and Carroll P.R. et. al. Treatment Failure After Primary and Salvage Therapy for Prostate Cancer. Likelihood, Patterns of Care and
Outcomes. CANCER 2008;2: 307-314.
2. Grossfeld G.D., Li Y.P. and Carroll P.R. et.al. Predictors of Secondary Cancer Treatment in Patients Receiving Local Therapy for Prostate Cancer. Data from
Cancer of the Prostate Strategic Urologic Research Endeavour. J Uro 2002; 116:5226-34.
3. and 4. Jones J.S. Radiorecurrent Prostate Cancer: An Emerging and Largely Mismanaged Epidemic.
Eur Urol 2011, 411-412.
5. Gilbert, S., Kuo, Y., & Shahinian, V. Prevalent and Incident Use of Androgen Deprivation Therapy
Among Men with Prostate Cancer in the United States. Urol Oncol. 2011; 29: 647–53.
2
3
Radiorecurrent PCa Patient Population
 Currently, there is no consensus on when and how to detect and
cure local recurrence of prostate cancer after failed RT.
 Data from the CaPSURE database stated that:
 63% of prostate cancer patients who undergo radiation
therapy as first line treatment for their prostate cancer will
experience PSA recurrence within 10 years.
 Every year ~45,000 men with prostate cancer in the USA will
have a recurrence after definitive primary RT, manifested initially
as an asymptomatic, increasing serum PSA level.
Kimura M., Mouraviev V. and Polascik T.J. et. al. Current Salvage Methods for Recurrent Prostate
Cancer after Failure of Primary Radiotherapy. BJUI 2009. 191-201.
4
Treatment Options for Recurrence after Radiation
 Androgen Deprivation
 Additional Radiation (i.e. Brachytherapy)
 Surveillance
 Salvage Radical Prostatectomy
 Salvage High-Intensity Focused Ultrasound (HIFU)
 Salvage Cryotherapy
5
Use of ADT Among the Male Medicare Population
Analysis suggests more than 400,000 men
(about 3% of the male Medicare population)
in the U.S. were prescribed hormonal treatment for
prostate cancer.
Gilbert, S., Kuo, Y., & Shahinian, V. Prevalent and Incident Use of Androgen Deprivation Therapy
Among Men with Prostate Cancer in the United States. Urol Oncol. 2011; 29: 647–53.
6
NCCN 2011 Guidelines: Hormone therapy is not endorsed for
prostate biopsy-positive, non-metastatic local recurrences
NCCN 2011 Guidelines Version 1.2012 Prostate Cancer
7
 NCCN Guidelines 2011 on androgen deprivation therapy (ADT)
for clinically localized disease stated that1:
– Adjuvant ADT given after completion of primary treatment is
not a standard treatment at this time with the exception of
high-risk patients treated with radiation therapy.
– Low volume, high grade prostate cancer may warrant adjuvant
ADT for 4-6 month but 2-3 year may be considered.
– The side effects of continuous ADT increased with the
duration of treatment.
 The FDA (Food and Drug Administration) in 2010 issued a
warning about the link between hormonal therapy and heart
disease and diabetes in prostate cancer patients2.
1. NCCN 2011 Guidelines Version 1.2012 Prostate Cancer.
2. FDA Drug Safety Communication: Update to Ongoing Safety Review of GnRH Agonists and
Notification to Manufacturers of GnRH Agonists to Add New Safety Information to Labeling Regarding
Increased Risk of Diabetes and Certain Cardiovascular Diseases. October 20, 2010.
Radiorecurrent PCa Patient Population
?
Secondary Treatment
70% | 58,000 patients
Radiorecurrent PCa Patients
60% | ~ 82,000 patients per year1
Androgen Deprivation Therapy
90% | 22,500 patients2,4
Received Secondary Treatment
30% | 25,000 patients3
Radiation Therapy
~ 137,170 patients per year1,4
Other Therapies
10% | 2,500 patients
A total of > 400,000 men or ~ 3% of Medicare’s male population
in the U.S. were prescribed ADT for PCa.5
1. Agarwal P.K., Sadetsky A. and Carroll P.R. et. al. Treatment Failure After Primary and Salvage Therapy for Prostate Cancer. Likelihood, Patterns of Care and
Outcomes. CANCER 2008;2: 307-314.
2. Grossfeld G.D., Li Y.P. and Carroll P.R. et.al. Predictors of Secondary Cancer Treatment in Patients Receiving Local Therapy for Prostate Cancer. Data from
Cancer of the Prostate Strategic Urologic Research Endeavour. J Uro 2002; 116:5226-34.
3. and 4. Jones J.S. Radiorecurrent Prostate Cancer: An Emerging and Largely Mismanaged Epidemic.
Eur Urol 2011, 411-412.
5. Gilbert, S., Kuo, Y., & Shahinian, V. Prevalent and Incident Use of Androgen Deprivation Therapy
Among Men with Prostate Cancer in the United States. Urol Oncol. 2011; 29: 647–53.
8
Jones J.S. Radiorecurrent Prostate Cancer:
An Emerging and Largely Mismanaged Epidemic.
Eu Urol 2011; 60: 411-412.
 Radiorecurrent prostate cancer is the 4th most common genitourinary
cancer after primary PCa, Bladder Cancer and Kidney Cancer.
 More than 90% of patients undergoing secondary therapy following
radiation are treated with ADT in the CaPSURE database population
despite:
─ A total lack of evidence for efficacy for ADT
─ The growing understanding of its own morbidity
─ The complete inability of ADT to cure patients who often have local
recurrences that are amenable to curative local therapy
 Radiorecurrent prostate cancer is often veiled by ADT which suppresses
PSA level but has absolutely no chance of cure.
 Covering up radiorecurrent PCa by hormones is a disservice to the
growing number of men who have a potential for cure.
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10
Side Effects of Hormonal Therapy1
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Hot Flashes
Bone Loss- ↑risk osteoporosis, ↑risk of fracture
Weight gain
Loss of muscle mass
Sexual side effects: ↓ libido, erectile dysfunction
Breast enlargement
Cardiovascular side effects
Adverse effects on lipid profile (↑cholesterol , ↑ TG)
Effect on insulin/glucose regulation ↑fasting insulin levels
Anemia – androgens promote erythropoiesis
Cognitive impairment
1. Schwandt A. and Garcia J.A. Complications of Androgen Deprivation Therapy in Prostate Cancer.
Curr Opinion in Urol 2009; 19: 322–6.
2. FDA Drug Safety Communication: Update to Ongoing Safety Review of GnRH Agonists and Notification
to Manufacturers of GnRH Agonists to Add New Safety Information to Labeling Regarding Increased Risk of
Diabetes and Certain Cardiovascular Diseases. October 20, 2010.
11
Salvage Options with Curative Intent
 Radiation Therapy
 High-intensity Focused Ultrasound (HIFU)
 Radical Prostatectomy
 Cryotherapy
12
Salvage Brachytherapy
 Clinical Outcomes:
─ The 5 year bDFS after salvage BT is broadly 20-70%.1
─ Overall survival 54%-94%.2
─ Disease-specific survival 74%-100%. 2
 Complications1:
─ Grade 3-4 genitourinary toxicities 13% (range from 0-47%)
as a late complication.
─ Grade 3-4 gastrointestinal toxicities 5% (range 0-20%),
including rectal ulcers and colostomy for rectal bleeding.
─ Prostatic-rectal fistula 3.4% (range from 1-12%)
─ Incontinence rates 4% (range 0-29%)
1. Kimura M., Mouraviev M. and Polascik T.J. et al. Current Salvage Methods for Recurrent
Prostate Cancer after Failure of Primary Radiotherapy. BJUI 2010; 105(2): 191-201.
2. Ramney S.J. and Marshall D.T. Re-irradiation for Salvage of Prostate Cancer Failures after
Primary Radiotherapy. World J Urol 2012. (Ahead of print)
13
Salvage HIFU
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Only few studies have been conducted in salvage setting.
Largest published salvage HIFU series (Murat et al 2009)
167 patients
3 year progression-free survival 53%, 42%,25% for L,I,H
risk.
 Complications:
─
─
─
─
─
Rectourethral fistula: 3 - 16%
Urinary incontinence: 10 - 50%
Retention due to urethral stricture: 18%
Erectile dysfunction: 66 - 100%
HIFU has a higher incidence of complications than salvage
cryotherapy and brachytherapy.
Murat F.J., Poissonnier L. and Gelet A. et al. Mid-term Results Demonstrate salvage HIFU as
an Effective and Acceptably Morbid Salvage Treatment Option for Locally Radiorecurrent Prostate
Cancer. Eur Urol 2009; 55(3): 640- 7.
14
Salvage Radical Prostatectomy
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NCCN 2011 Guidelines stated that:
─ Salvage Radical prostatectomy (RP) is an option for highly selected patients with
local recurrence after EBRT, brachytherapy, or cryotherapy in the absence of
metastases, but the morbidity (incontinence, loss of erection, anastomotic stricture)
is high.1
─ Salvage RP is technically challenging. High volume surgeons in high volume
centers generally provide better outcomes.2
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Clinical Outcomes:
─ 10-year bDFS rate 30-43%.3
─ 10-year cancer-specific survival rates 70-77%.3
─ Biopsy-proven local recurrence is between 20% to 40%.4
─ Several salvage RP series reported 80% of patients have extraprostatic
extension.5
Only 25% of surveyed urologists and radiation oncologists would recommend
salvage RP to a patient between 45-65 years with definitive local recurrence after
RT. 3
1. and 2. NCCN 2011 Guidelines Version 1.2012 Prostate Cancer.
3. Kimura M., Mouraviev V. and Polascik T.J. et. al. Current Salvage Methods for Recurrent Prostate
Cancer after Failure of Primary Radiotherapy. BJUI 2009. 191-201.
4. Jones J.S. Radiorecurrent Prostate Cancer: An Emerging and Largely Mismanaged Epidemic.
Eur Urol 2011, 411-412.
5. Mouraviev V., Spiess P.E. and Jones S.J. Salvage Cryoablation for Locally Recurrent Prostate Cancer
Following Primary Radiotherapy. Eu Urology 2012; 61:1204-1211.
15
Better Understanding of Salvage Cryotherapy
 Well-defined patient selection criteria on salvage cryotherapy:
─ AUA 20081 and 2009 Best Practice Guidelines.2
─ NCCN 2011 Guidelines.
 More clinical data is now available on salvage cryotherapy:
─ Salvage cryotherapy is a potential cure compared to hormones.3
─ More data on lack of side-effects of cryoablation.
 Advances in cryoablation technology (3rd generation).
 Medicare approved salvage cryotherapy in 2001.
 More data on side-effects of hormones.4
1.
2.
3.
4.
Babaian R.J., Donnelly B. and Thrasher J.B. et. al. Best Practice Statement on Cryosurgery for the
Treatment of Localized Prostate Cancer. The Jour of Urol, 2008; 180: 1993-2004.
Prostate-Specific Antigen Best Practice Statement: 2009 Update.
Mouraviev V., Spiess P.E. and Jones S.J. Salvage Cryoablation for Locally Recurrent Prostate Cancer
Following Primary Radiotherapy. Eu Urology 2012; 61:1204-1211.
Schwandt A. and Garcia J.A. Complications of Androgen Deprivation Therapy in Prostate Cancer. Curr
Opinion in Urol 2009; 19: 322–6.
16
2008 AUA Best Practice Statement of Cryosurgery
Well-Defined Patient Selection Criteria1:
 PSA<10 ng/mL
 A PSA doubling-time >16 months or more
 At least a 10-year life expectancy
 Absence of seminal vesicle invasion
 A positive biopsy and a negative metastatic evaluation
1. Babaian R.J., Donnelly B. and Thrasher J.B. et. al. Best Practice Statement on Cryosurgery
for the Treatment of Localized Prostate Cancer. The Jour of Urol, 2008; 180: 1993-2004.
17
Patient Selection Criteria for Salvage Cryotherapy
Rising PSA after radiation therapy:
 How long ago was the primary
procedure?
 How high is the PSA?
 How fast is PSA increasing? (PSA
doubling time)
 Difficult to justify salvage
cryotherapy if PSA >10ng/ml
Biopsy proven recurrence:
 Unilateral or bilateral disease ?
 Often high grade. Number of cores
involved
 Biopsy proximal portion of each
seminal vesicle
 Is patient eligible for a focal salvage
procedure?
Work-Up:
 IPSS and IIEF scores
 Rectal examination
 Transrectal USS assessment
Staging investigations:
 Endorectal MRI (unless
brachytherapy was
performed)
 CT abdomen-pelvis / pelvic
lymphadenopathy
 Bone scan
18
Predictors of Salvage Success
 The best predictor identified so far is PSA1.
 PSA<10 ng/mL = most likely to be effective.
 Even better results if PSA< 5ng/mL2.
 Cryotherapy is cytocidal without regard to tumor differentiation2.
 Highly differentiated cancer may still be cured even if radiation was
not successful and if the persistent disease is localized to an area
suitable for cryo2.
The Key Issue
Early Intervention is Key. Salvage therapy must be administered
before cancer advances beyond where local treatment can reach.
1.
Wenske S., Quarrier S., Katz AE. Salvage Cryosurgery of the Prostate for Failure After Primary Radiotherapy or Cryosurgery: Long-term
Clinical, Functional, and Oncologic Outcomes in a Large Cohort at a Tertiary Referral Centre. Eu Urol. 2012. Ahead of Print.
2. Jones J.S. Radiorecurrent Prostate Cancer: An Emerging and Largely Mismanaged Epidemic. Eur Urol 2011, 411-412.
3. Williams AK and Chin JL. Disease-Free Survival Following Salvage Cryotherapy for Biopsy-Proven
Radio-Recurrent Prostate Cancer. E Urology 2011; 60: 405-410.
4. Mouraviev V., Spiess P.E. and Jones S.J. Salvage Cryoablation for Locally Recurrent Prostate Cancer
Following Primary Radiotherapy. Eu Urology 2012; 61:1204-1211.
19
Benefits of Salvage Cryotherapy
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Potentially curative without the side effect of hormones
Low side effect profile compared to salvage surgery
Usually single treatment. Repeatable if necessary
Regional anesthesia
No major blood loss
Salvage (nerve sparing) procedure is possible
Minimal postoperative discomfort
Very low risk of DVTs , PEs, urinary sepsis
Patients with co-morbidities tolerate procedure
No steep trendelenburg
Patients with LUTs who are not suitable for brachy
Can treat extracapsular disease
Caution re TURP + radiation + cryo patients
20
Growing Body of Data on Salvage Cryotherapy
 5-year bDFS survival 50%-70% (3rd generation technology).1
 Complications1:
─ Perineal pain: 4-14%
─ Mild-moderate incontinence: 6-13%
─ Severe incontinence: 2-4%
─ Urinary retention: 2-21%
─ Rectourethral fistula formation: 1-2%
─ Urinary incontinence: <1%
 Erectile function can be preserved using nerve sparing techniques.2
 Local control is high with only 17.6% positive post salvage biopsy.3
 The ability to freeze beyond the capsule into periprostatic tissues
(including proximal portions of the seminal vesicles) is a recognized
advantage of cryotherapy.4
1.
2.
3.
4.
Mouraviev V., Spiess P.E. and Jones S.J. Salvage Cryoablation for Locally Recurrent Prostate Cancer
Following Primary Radiotherapy. Eu Urology 2012; 61:1204-1211.
Wenske S., Quarrier S., Katz AE. Salvage Cryosurgery of the Prostate for Failure After Primary
Radiotherapy or Cryosurgery: Long-term Clinical, Functional, and Oncologic Outcomes in a Large
Cohort at a Tertiary Referral Centre. Eu Urol. 2012. Ahead of Print.
Williams AK and Chin JL. Disease-Free Survival Following Salvage Cryotherapy for Biopsy-Proven
Radio-Recurrent Prostate Cancer. E Urology 2011; 60: 405-410.
Jones J.S. Radiorecurrent Prostate Cancer: An Emerging and Largely Mismanaged Epidemic. Eur Urol
2011, 411-412.
21
Growing Body of Data on Salvage Cryotherapy
Salvage Cryotherapy on Radiorecurrent Patients (187)
Overall Survival
95%
87%
Overal bDFS
91%
83%
Metastatic-free Survival
Pre-radiation PSA, pre-salvage PSA, a pre-salvage Gleason
are factors correlated with recurrences.
Salvage Cryotherapy10-year DFS Rate
64%
87%
82%
6.7%
47%
39%
39%
Pre-Salvage < 5 ng/dl
Pre-Salvage > 5 ng/dl
Post-salvage PSA nadir are factors correlated with recurrences.
Salvage Cryotherapy Disease Free Rates
5-year
8-year
10-year
56%
5-year
8-year
46%
10-year
Williams AK and Chin JL. Disease-Free Survival Following Salvage Cryotherapy
for Biopsy-Proven Radio-Recurrent Prostate Cancer. E Urology 2011; 60:
405-410.
3%
0%
46%
0%
PSA nadir >1 ng / dl
PSA nadir <1 ng / dl
22
Advances in Cryotherapy Technology
 The incontinence rates decreased to <5% in recently
reported Salvage Cryoablation (SCA) series :
─ Because of the use of Multi-thermal sensors
(MTS) which allows precise thermal control of
the freezing process around the external
sphincter; and hence,
─ Optimizes the likelihood of preserving urinary
continence following treatment.
 Currently, SCA is a feasible option due to:
─ More precise prostate ice ball formation and
─ The flexibility to place additional cryoneedles
where needed to selectively target a site of
tumor recurrence.
Mouraviev V., Spiess P.E. and Jones S.J. Salvage Cryoablation for Locally Recurrent Prostate Cancer
Following Primary Radiotherapy. Eu Urology 2012; 61:1204-1211.
23
The Bottom Line
Salvage cryotherapy is supported for carefully selected men
whose cancer recurrence is identified, while localized to an
area that can potentially be cured.
Mouraviev V., Spiess P.E. and Jones S.J. Salvage Cryoablation for Locally Recurrent Prostate Cancer
Following Primary Radiotherapy. Eu Urology 2012; 61:1204-1211.