1. No category

5/2/2010
Why Discuss this topic?
1. ~15 to 75% of CaP pts recur after definitive RT
a) >100K men with recurrent Dz post PPI?
2. Heterogeneous group of patients including:
“Salvage” Radiation
Mack Roach III, MD
Professor and
Urology,
Chair Radiation
Oncology UCSF
for Local & Regional
a) Those with slow failures
b) Those with rapid failures
3. Recurrences – local? +/- regional? +/- distant?
a) Suitable for local salvage therapies?
Recurrences:
b) Suitable for regional salvage therapies?
c) Suitable for following carefully?
PPI, HDR & IMRT
d) Not suitable for more radiotherapy
Treatment Failure After Primary and Salvage
Therapy for Prostate Cancer.
Treatment Failure After Primary and Salvage
Therapy for Prostate Cancer.
Agarwal et al. Cancer 2008; 112:307-14
Agarwal et al. Cancer 2008; 112:307-14
BACKGROUND: … authors report the
likelihood of treatment failure and the
outcomes after salvage therapy among
men with prostate cancer who initially
either received EBRT …
RESULTS.: Recurrent Dz developed in 63%
in the EBRT group, (mean 38 mo.)
METHODS: Using a national disease
registry, the CaPSURE) database, …
received EBRT (n=935).
319 men in the EBRT group (74%) failed
salvage tx at mean of 43.8 mos.
Pts w recurrent disease … death (19% vs
3%) & bone mets (15% vs 1%).
Data after salvage tx available for 430
They had a greater death rate than … pts
not failing salvage tx (24.8% vs 6.9%)
1
5/2/2010
Types of Salvage Therapy after EBRT
CaPASURE (n=430)
Androgen Deprivation Therapy
93.5%
Cryotherapy
3.0%
EBRT
1.9%
Radical Prostatectomy
0.9%
Unknown
0.5%
Brachytherapy
0.2%
Agarwal et al. Cancer 2008; 112:307-14
Widmark et al Lancet 2009
Local
Cryo
Hi-Fu
PPI/HDR
Other?
++
++
+
++
?
Marginal
Failure (“T3”)
+
++
+
-/++
?
“Cold spot”
(small vs large)
+/+
?
++/+
?
Focal e.g. due
to Inadequate
Dose (“T1c”)
Diffuse
Failure
+/-/++
?
Regional
Focal e.g. due
to Inadequate
Dose (“T1c”)
Salvage RP
EXAMPLES OF TYPES OF PSA LOCAL FAILURES
Local
EXAMPLES OF TYPES OF PSA LOCAL FAILURES
Marginal
Failure (“T3”)
“Cold spot”
(small vs large)
Diffuse
Failure
Lymph Nodes: How defined?:
Internal iliac
External iliac
Peri-rectal
Presacral
Para-aortic
MRI/CT (poor)
PET/CT (FDG vs Choline non-FDA)
Prostascint (poor?)
Nanoparticles (non-FDA)
Other? (Trofex, Hyperpolar Carbon)
2
5/2/2010
Locally Recurrent Prostate Cancer After Initial
Radiation Therapy: A Comparison of Salvage
Radical Prostatectomy Versus Cryotherapy.
Locally Recurrent Prostate Cancer After Initial
Radiation Therapy: A Comparison of Salvage
Radical Prostatectomy Versus Cryotherapy.
Pisters et al. J of Urology 182:517-527, 2009
Pisters et al. J of Urology 182:517-527, 2009
PURPOSE: … compared … outcomes of salvage
prostatectomy and cryotherapy for pts with
locally recurrent prostate cancer after initial RT.
M & M: … retrospectively reviewed … pts who
underwent salvage RP at the Mayo 1990-99, & …
salvage cryo at MDA 1992-95.
Eligibility criteria: PSA<10 ng/ml, post-RT
biopsy <GS 8 & prior RT without salvage ADT
RESULTS: Mean fu 7.8 & 5.5 yrs for RP & cryo.
DFS (>0.4 ng/ml): Cryo 21% vs RP 61% at 5 yrs,
p <0.001; or 42% vs 66% at 5 years, p = 0.002) &
OS (at 5 yrs cryo 85% vs RP 95%, p = 0.001)…
After adjusting for … GS & PSA on multivariate
salvage RP remained superior to salvage cryo.
... Biochemical failure assessed using: 1) PSA>
0.4 ng/ml & 2) 2 increases above the nadir.
CONCLUSIONS: Young, healthy pts with
recurrent prostate cancer after should consider
salvage RP ...
Locally Recurrent Prostate Cancer After Initial
Radiation Therapy: A Comparison of Salvage
Radical Prostatectomy Versus Cryotherapy.
Locally Recurrent Prostate Cancer After Initial
Radiation Therapy: A Comparison of Salvage
Radical Prostatectomy Versus Cryotherapy.
Pisters et al. J of Urology 182:517-527, 2009
Pisters et al. J of Urology 182:517-527, 2009
3
5/2/2010
Current salvage methods for recurrent prostate
cancer after failure of primary radiotherapy.
Current salvage methods for recurrent prostate
cancer after failure of primary radiotherapy.
Kimura et al. BJUI 105:191-201, 2009
Kimura et al. BJUI 105:191-201, 2009
… reviewed … salvage methods for pts with
local recurrent prostate ca. after primary RT
… search of relevant Medline/PubMed articles
published from 1982 to 2008, … search terms:
'radiorecurrent prostate ca,, salvage treatment,
salvage radical prostatectomy (RP), salvage
cryoablation, salvage brachytherapy, salvage
high-intensity focused ultrasound (HIFU)’….
Conclusions:
RP has the longest fu with acceptable … results, but
… challenging … with a high complication rate.
Cryo feasible … using 3rd-generation tech, avg DFS
rate is 50-70% … fewer … severe complications.
Salvage brachytherapy, with short-term cancer
control, is comparable to other salvage methods …
HIFU is a relatively recent option ...
Salvage Brachytherapy
Permanent Brachytherapy as Salvage
Treatment for Recurrent Prostate Cancer
Beyer Urol 54: 880-883, 1999
Salvage Brachytherapy
Salvage Brachytherapy for Localized Prostate Cancer
After Radiotherapy Failure.
Grado et al. J Urol 53: 2-10, 1999
• 17 pts 1989-94: I125 120 Gy, /Pd-103 90 Gy
• 49 pts : I125 /Pd-103 median fu 64.1 mo.
• DFS = 67% PSA < or = 10 vs 25%
• 5 Year DFS = 34%, DSS = 79%
• DFS = 83% if low grade vs 30% high grade
• 4% rectal ulcers, 6% incont. & persistent pain
• Incontinence 24%
• 2% colostomy
4
5/2/2010
Magnetic resonance image-guided salvage
brachytherapy after radiation in select men
who initially presented with favorable-risk
prostate cancer: a prospective phase 2 study
Magnetic resonance image-guided salvage
brachytherapy after radiation in select men
who initially presented with favorable-risk
prostate cancer: a prospective phase 2 study
Nguyen et al. Cancer 110:1485-92, 2007
Nguyen et al. Cancer 110:1485-92, 2007
• BACKGROUND: The authors prospectively
evaluated the late gastrointestinal (GI) and
genitourinary (GU) toxicity and PSA control
of
MRI-guided
brachytherapy
used
as
salvage for radiation therapy failure.
• METHODS: October 2000-05, 25 men with a rising
PSA and +Bx, at least 2 years post:
– EBRT (n=13) or brachytherapy (n=12)
– GS < or =7, PSA < 10 ng/mL, negative pelvic and
bone imaging studies),
• Received MRI-guided salvage brachytherapy to
a MPD of 137 gray on a phase 1/2 protocol!
Magnetic resonance image-guided salvage
brachytherapy after radiation in select men
who initially presented with favorable-risk
prostate cancer: a prospective phase 2 study
Patient-reported quality of life after salvage
brachytherapy for radio-recurrent prostate
cancer: a prospective phase II study
Nguyen et al. Cancer 110:1485-92, 2007
Nguyen et al. Brachytherapy 8:345-352, 2009
RESULTS:
• Med fu 47 mos. the 4-yr est. of grade 3 or 4 GI
or GU toxicity was 30%
• 13% of patients required a colostomy and/or
urostomy to repair a fistula.
• Interval of < 4.5 yrs between RT courses
associated with HR ~ 12 (p= 0.02) for grade 3-4
tox & 25 (p= 0.04) for colostomy &/or urostomy.
… 25 men who … received MRI-guided salvage
brachy as … a prospective Phase II study & … a
validated patient-reported QOL questionnaire …
3, 15, & 27 mo. … to determine the degree of
sexual, bowel, & urinary dysfunction (max
dysfunction score=100).
5
5/2/2010
Patient-reported quality of life after salvage
brachytherapy for radio-recurrent prostate
cancer: a prospective phase II study
Patient-reported quality of life after salvage
brachytherapy for radio-recurrent prostate
cancer: a prospective phase II study
Nguyen et al. Brachytherapy 8:345-352, 2009
Nguyen et al. Brachytherapy 8:345-352, 2009
RESULTS:
On average, sex function continued to decline
… at 27 mos than baseline (p=0.01)
… GI & GU symptoms worse at 3 or 15 mos …
no sign. diff between baseline & 27-mo. scores.
… interval to re-irradiation <4.5 yrs & prior
brachy … associated … with largest
decrements in bowel function (p=0.035).
Patient-reported quality of life after salvage
brachytherapy for radio-recurrent prostate
cancer: a prospective phase II study
Patient-reported quality of life after salvage
brachytherapy for radio-recurrent prostate
cancer: a prospective phase II study
Nguyen et al. Brachytherapy 8:345-352, 2009
Nguyen et al. Brachytherapy 8:345-352, 2009
6
5/2/2010
Methods
Methods
Salvage Permanent Perineal Radioactive Seed
Implantation For The Treatment of Localized
Prostate Adenocarcinoma Recurrence After
External Beam Radiation
Salvage Permanent Perineal Radioactive Seed
Implantation For The Treatment of Localized
Prostate Adenocarcinoma Recurrence After
External Beam Radiation
David S. Aaronson, Ichiro Yamasaki, Alexander Gottschalk, Joycelyn
Speight, I-Chow Hsu, Barby Pickett, Mack Roach III, Katsuto Shinohara
David S. Aaronson, Ichiro Yamasaki, Alexander Gottschalk, Joycelyn
Speight, I-Chow Hsu, Barby Pickett, Mack Roach III, Katsuto Shinohara
• Retrospective single institution cross-sectional design.
• Inclusion/Exclusion:
• Secondary outcomes:
– IPSS
– Treated with primary EBRT for biopsy proven local
recurrence 2 yrs after initial Tx
– IIEF
– Negative metastat w/u.
– Complications: Common Terminology Criteria for
Adverse Events (version 3).
• Primary outcomes: biochemical relapse free survival
(Phoenix definition).
• Pre-planned I-125 or Pd-103 radioactive seeds
transperineally placed using ultrasound guidance.
Aaronson et al. BJU Int 104:600-604, 2009
Aaronson et al. BJU Int 104:600-604, 2009
Results
Patient Characteristics
Table 1. Clinical Characteristics of the Study Cohort
Prior to Salvage Therapy (N = 24)
Characteristics
Results: PSA control & Survival
No. of patients (%)
Median age at salvage therapy [range], 66 (54-88)
Median initial PSA [range], ng/mL 9.9 [3.2-69]
0 to < 4
4 to < 10
>10
Unknown
Initial Gleason score
3+3 = 6
3+4 = 7
4+3 = 7
4+4 = 8
4+5 = 9
Unknown
Initial clinical tumor (T) classification
T1c
T2
Unknown
Initial RT received
EBRT (66-70.2 Gy)
EBRT+Ir192 LDR
Median interval between EBRT [range],
4.4years [2.2-9.1]
<2
2 to < 5
>5
Median PSA at salvage [range], ng/mL
3.41 [0.3-10]
0 to < 4
4 to < 10
>10
2
11
10
1
(8)
(46)
(42)
(4)
9 (38)
2 (8)
6 (25)
2 (8)
1 (4)
4 (16)
11 (46)
11(46)
2 (8)
23 (96)
1 (4)
0 (0)
15 (62)
9 (38)
17 (71)
6 (25)
1 (4)
Table 2: Cancer specific survival and biochemical
relapse free survival.
Cancer specific death:
*Biochemical failure:
1(4%)
3(12%)
*Definition: PSA nadir + 2.0 ng/ml
Biochemical relapse free survival
1 year (n=17):
95.5%
2 years (n=10):
89.5%
3 years (n=6):
89.5%
*PSA indicates prostate specific antigen; EBRT, external beam radiation therapy;
Gy, grays
Aaronson et al. BJU Int 104:600-604, 2009
Aaronson et al. BJU Int 104:600-604, 2009
7
5/2/2010
Results
Results: Survival
Results
Results: Last PSA at follow-up
Frequency
60%
50%
50%
40%
21%
30%
20%
17%
13%
10%
<0.1
0.1-0.5
>0.5
on hormones
PSA range
Aaronson et al. BJU Int 104:600-604, 2009
Results-Complications
Complication Rates, Common Terminology
Criteria for Adverse Events (version 3)
Aaronson et al. BJU Int 104:600-604, 2009
Case
• 56 yo man s/p Pd-103 implant followed
by 45 Gy of XRT and neo-adjuvant
Complication
Hematochezia
Grade
Grade 1: 2, after 17 mos
Grade 3: 1, after 17 mos
Hematuria
Grade 2: 5, after 9 mos (med)
Urethral Stricture Grade 2: 1, after 15 mos
Urinary Incontin Grade 2: 1
hormone therapy in 1998
• PSA 5.6, Gleason 3+3 apex involvement
• PSA gradually rose upto 1.6
• Biopsy Gleason 4+3, 7 mm at L apex
Aaronson et al. BJU Int 104:600-604, 2009
8
5/2/2010
MRSI Imaging after Brachytherapy
Example of poorly covered apex
MRSI Imaging after Brachytherapy
Example of poorly covered apex
9
5/2/2010
Pre-Salvage MRSI Imaging
& CT Post Brachytherapy
SALVAGE BRACHYTHERAPY
After primary brachytherapy
PRE IMPLANT
POST IMPLANT
Pd seeds
Actual apex
I-125 seeds
Example of poorly covered apex
Methods
Feasibility of high-dose-rate brachytherapy salvage
for local prostate cancer recurrence after
radiotherapy: The University of California-San
Francisco experience
Brian Lee, Katsuto Shinohara, Vivian Weinberg, Alexander
Gottschalk, Jean Pouliot, Mack Roach III,
and I-Chow Hsu,
• Retrospectively evaluate salvage HDR for locally
recurrent prostate ca after EBRT.
• Treated post primary EBRT for biopsy proven local
recurrence and Negative mets w/u.
• All patients were treated with 36 Gy in 6 fractions using
2 HDR prostate implants, separated by 1 week.
• Eleven pts received NHT immediately pre-salvage.
• Primary outcomes: ASTRO definition.
IJROBP 67:1106-1112 2007
Methods
Feasibility of high-dose-rate brachytherapy salvage
for local prostate cancer recurrence after
radiotherapy: The University of California-San
Francisco experience
Brian Lee, Katsuto Shinohara, Vivian Weinberg, Alexander
Gottschalk, Jean Pouliot, Mack Roach III, I-Chow Hsu,
Results:
• 89% 2 yr BNED 13 pts (>50%) achieved a PSA nadir
</=0.1 ng/ml, but others still declining.
• 2 PSA failures, (both PSA nadirs >/=1), and have
subsequently been found to have distant metastases.
• 18 patients reported Grade 1 to 2 genitourinary
symptoms by 3 months post salvage.
• 3 pts developed Grade 3 GU toxicity.
• Max observed GI tox was Grade 2; all cases
spontaneously resolved.
• Conclusions: Salvage HDR prostate brachytherapy
appears to be feasible and effective.
IJROBP 67:1106-1112 2007
10
5/2/2010
Salvage Radiotherapy to Nodal Mets
Conclusions about the
UCF Experience:
1. With very careful pt selection & planning
salvage radiotherapy has a high early control
rate and acceptable toxicity
2. >100 patients have received Salvage RT post
RT failure to date
3. Only centers with a lot of experience
sophisticated imaging & planning expertise
should consider this option?
4. Randomized Trials are required to determine
the relative merits of various options
Acknowledgements
Katsuto Shinohara M.D
Alexander Gottschalk M.D.
Joycelyn Speight M.D.
I-Chow Hsu M.D.
Barby Pickett
David S. Aaronson M.D.
Ichiro Yamasaki M.D.
Brian Lee M.D., PhD
Vivian Weinberg PhD
John Kurhanewicz PhD
Jelle Barentsz
11