Radiation Therapy for
Treatment of Prostate Cancer
Stephen Ko, M.D.
Mayo Clinic Florida
August 30, 2010
Overview
I. U.S. Epidemiology
II. Types of Radiation
III. Anatomy
IV. Technologic Advances
– 2-Dimensional Planning
– Intensity Modulated Radiotherapy
– Brachytherapy
V. Definition of Risk Categories
– Low Risk
– Intermediate Risk
– High Risk
Overview
VI. Dose-escalation Trials
–
–
–
–
MSKCC IMRT Dose Escalation
Proton Beam Dose Escalation
MDACC Randomized Trial (70 Gy vs. 78 Gy)
Harvard Randomized Trial (70.2 GyE vs. 79.2 GyE)
VII. Low Risk Disease Treatment
– IMRT alone
– Seeds alone
VIII. Intermediate Risk Disease Treatment
– IMRT alone
– 6 mo Hormone + EBRT
– Seeds + EBRT
Overview

IX. High Risk Disease Treatment
– Long-term Hormonal therapy Randomized Trials


RTOG randomized Trial
EORTC randomized Trial
– Seeds + EBRT

X. Comparing Modalities (Surgery vs.
Radiation)
 XI. Quality of Life Comparison
 XII. Conclusions
I. U.S. Epidemiology
2009
 New cases prostate cancer: 192,280
 Deaths from prostate cancer: 27,360


New cases prostate cancer in FL: 12,380 New
cases prostate cancer in GA: 5,210
Death from prostate cancer in FL: 2,470
 Death from prostate cancer in GA: 870
U.S. Epidemiology
2009
New Cases in U.S.
U.S. Epidemiology
.
2009
Deaths/year from cancer in U.S.
II. Types of Radiation
• External Beam: high energy
X-rays given with linear
accelerator
•
•
Primary therapy
Postoperative
• Brachytherapy: radioactive
seeds


Primary therapy
After external: boost dose
• Proton Beam: heavy particle
• Primary therapy
What is dose?





Dose is the amount of radiation used to treat
a patient
SI unit (joules/kg)
 Gray (Gy)
 Centigray (cGy)
 100 cGy = 1 Gy
Similar to milligrams for drugs
180 cGy or 200 cGy per day or 1.8 Gy or 2
Gy per day is usually given to treat prostate
1.8 Gy x 42 treatments = 75.6 Gy total
III. Anatomy
Seminal vesicles
Bladder
Rectum
Prostate
IV. Technological Advances
2-Dimensional
Planning
(Fluoroscopicbased)
3-Dimensional
Planning
(CT-based)
Intensity
Modulated
Radiotherapy or
IMRT
(CT-based)
2- Dimensional Vs. 3-Dimensional Planning
Rectum
Bladder
Prostate
Prostate
Rectum
External Beam Electronic Portal Imaging
Intraprostatic Marker Localization
CT Scan
Intended treatment
X-ray on the machine
Actual treatment
Gold
marker
Final position
Initial setup
Positional error
corrected
Intensity Modulated External Beam Radiotherapy
IMRT Prostate Dose Distribution
Dose
Prostate Brachytherapy

Disease contained within the
prostate gland (T1c - T2a)

Small - to - moderate prostate
size ( 60 cc)

Favorable pelvic anatomy

No or limited prior
transurethral prostatic resection

Minimal obstructive symptoms
(I-PSS  15, peak flow 10)
V.
Definition of Risk
Categories
-Low Risk
-Intermediate Risk
-High Risk
V. Prostate Cancer Risk Groups
Prostate Cancer Risk Groups
 Clinical
tumor stage, Gleason score and PSA
used to determine risk groups: (D`Amico)
 Low risk: Stage T1-2a, Gleason  6, and
PSA < 10 ng/mL
 Intermediate risk: Stage T2b or Gleason 7 or
PSA 10-20 ng/mL
 High risk: Stage > T2c or Gleason 8-10 or
PSA > 20 ng/mL
VI. Dose-escalation Trials
Retrospective Trials
– MSKCC IMRT Dose Escalation
– Proton Beam Dose Escalation
Prospective Randomized Trials
– MDACC Randomized Trial (70 Gy vs. 78 Gy)
– Harvard Randomized Trial (72 Gy vs. 79.2Gy)
Memorial Sloan Kettering Cancer Center
IMRT Dose Escalation

Began using IMRT in 1996 to facilitate dose
escalation
 high dose XRT using IMRT for localized prostate
cancer
 561pts. B/w April 1996 & Jan 2000
 Median age 68 (range 46-86)
Zelefsky MJ, Chan H, et. Al. Journal of Urology Vol. 176, 1415-1419, Oct 2006
Memorial Sloan Kettering Cancer Center
IMRT Dose Escalation

Escalated eventually to 81 Gy
 296 patients (53%) treated w/ short course (3-mo)
androgen deprivation therapy to decrease the size
of the prostate
 ADT discontinued at the completion of
radiotherapy
Zelefsky MJ, Chan H, et. Al. Journal of Urology Vol. 176, 1415-1419, Oct 2006
Memorial Sloan Kettering Cancer Center
IMRT Dose Escalation

Median f/u: 7 years (range 5 to 9)
 PSA relapse:
– ASTRO definition: 3 consecutive rises after
nadir
– Houston definition: nadir + 2
 None received post-irradiation androgen
deprivation or other anti-cancer therapy before
documentation of a PSA relapse
Zelefsky MJ, Chan H, et. Al. Journal of Urology Vol. 176, 1415-1419, Oct 2006
Memorial Sloan Kettering Cancer Center
IMRT Dose Escalation
Low Risk
T1-2, GS ≤6, PSA ≤10
Zelefsky MJ, Chan H, et. Al. Journal of Urology Vol. 176, 1415-1419, Oct 2006
Memorial Sloan Kettering Cancer Center
IMRT Dose Escalation
Intermediate Risk
T1-2, GS 6, PSA > 10
T1-2, GS >6, PSA  10
T3, GS  6, PSA  10
Zelefsky MJ, Chan H, et. Al. Journal of Urology Vol. 176, 1415-1419, Oct 2006
Memorial Sloan Kettering Cancer Center
IMRT Dose Escalation
High Risk
GS >6, PSA >10
Zelefsky MJ, Chan H, et. Al. Journal of Urology Vol. 176, 1415-1419, Oct 2006
Memorial Sloan Kettering Cancer Center
IMRT Dose Escalation
Biochemical Control
 Using the ASTRO definition, the 8-year actuarial PSA
relapse-free survival
– Favorable risk: 85%
– Intermediate risk: 76%
– Unfavorable risk: 72%
Zelefsky MJ, Chan H, et. Al. Journal of Urology Vol. 176, 1415-1419, Oct 2006
Memorial Sloan Kettering Cancer Center
IMRT Dose Escalation

Distant metastases
– developed in 17 (3%) pts


8-year actuarial likelihood of distant metastases
– Favorable 1%
– Intermediate 5%
– Unfavorable 4%,
– (favorable vs. intermediate risk p = 0.03; intermediate
vs.. unfavorable risk p = 0.86)
Cause specific survival outcomes
– Favorable 100%
– Intermediate 96%
– Unfavorable 84% (p = 0.17)
Zelefsky MJ, Chan H, et. Al. Journal of Urology Vol. 176, 1415-1419, Oct 2006
Memorial Sloan Kettering Cancer Center
IMRT Dose Escalation
Toxicity
 Rectal:
– Grade 2 rectal bleeding: 7 patients (1.5%)
– Grade 3 rectal toxicity: 3 patients (<1%)
– No grade 4 rectal complications
– 8-year actuarial likelihood of late grade > 2 rectal
toxicity: 1.6%
 Urinary:
– Late grade 2 chronic urethritis requiring medication for
symptom control: 9%
– Urethral stricture requiring dilation (gr3): 3%
– 8-year actuarial likelihood of late grade > 2 urinary
toxicities: 15%
Zelefsky MJ, Chan H, et. Al. Journal of Urology Vol. 176, 1415-1419, Oct 2006
Memorial Sloan Kettering Cancer Center
IMRT Dose Escalation
Toxicity
 Sexual:
– Before the initiation of therapy 403 (72%) patients
reported the ability to maintain an erection sufficient for
sexual intercourse
– In this group of pts ED developed in 49%
 Secondary Malignancy:
– None observed
Zelefsky MJ, Chan H, et. Al. Journal of Urology Vol. 176, 1415-1419, Oct 2006
Loma Linda Proton Beam Experience
Dose Escalation
.

B/w Oct 1991 & Dec 1997,
 1255 pts with Stages Ia-III prostate cancer
 No prior surgery, hormonal therapy, or distant
mets
 Treated with protons alone or in combination with
photon-beam XRT
Slater JD, Rossi CJ, et. Al. IJROBP Vol 59, No. 2, 348-352, 2004.
Loma Linda Proton Beam Experience
Dose Escalation
.

Freedom from biochemical evidence of disease
(bNED) used ASTRO consensus definition ( 3
consecutive PSA rises after reaching a nadir)
 Mean duration f/u: 63 months
 Median age: 69 years
Slater JD, Rossi CJ, et. Al. IJROBP Vol 59, No. 2, 348-352, 2004.
Loma Linda Proton Beam Experience
Dose Escalation

Overall 5-year & 8year actuarial
biochemical diseasefree survival rates:
75% & 73%
Slater JD, Rossi CJ, et. Al. IJROBP Vol 59, No. 2, 348-352, 2004.
Comparison of IMRT versus Proton Therapy
Median
Follow
up
Pts.
5yr
BDFS
8yr
BDFS
Multivariat
e
Analysis
Late
rectal
Late
Urinary
Sexual
Dysfunction
IMRT
7yrs
561
N/A
85% for
LR,
76% for
IR, 72%
for HR
Clinical
Stage & PreTreatment
PSA
significant
Gr 2 or
greater 1.6%,
Gr 3 <1%, no
Gr 4
Gr 2 or
greater
15%,
Gr 3 was
3%,
No Gr 4
49%
PBRT
62mo
1255
75%
73%
PreTreatment
PSA,
Gleason, &
PSA nadir
significant
Gr 3 <1%,
Gr 4 <1%
(1pt with
Gr 4)
Gr 3 or
greater
<1%, no
Gr 4
N/A
MDACC Randomized Dose Escalation Trial
Results Of A Randomized Dose-Escalation
Study Comparing 70 Gy To 78 Gy(isocenter)
For The Treatment Of Prostate Cancer
Pollack IJROBP 2002
MDACC Randomized Dose Escalation Trial
Freedom from Failure by PSA
PSA <=10 ng/ml
PSA >10 ng/ml
1.0
1.0
78 Gy
.9
78 Gy
.9
.8
Fraction free of failure
.8
.7
.6
.7
.6
70 Gy
.5
.4
.3
p = 0.46
.5
.4
.3
.2
.2
.1
.1
0.0
0.0
0
20
40
60
Months after radiotherapy
Pollack IJROBP 2002
80
100
p = 0.012
0
20
40
70 Gy
60
Months after radiotherapy
80
100
MDACC Randomized Dose Escalation Trial
Fraction Free of Distant Metastases, PSA > 10
1.0
78 Gy
.9
70 Gy
.8
.7
.6
p = 0.056
.5
0
20
40
60
80
Months after radiotherapy
Pollack IJROBP 2002
100
Harvard Randomized Dose Escalation Trial
Phase III trial comparing conventional dose with high dose
radiation in early stage prostate cancer:
results of PROG 95-09
Zietman A, et. al. JAMA, 2005, 294 (10): 1233
Harvard Randomized Dose Escalation Trial
Trial design
T1b-2b prostate cancer
PSA <15ng/ml
No hormonal therapy
randomization
ACR/RTOG
Proton boost
19.8 GyE
3-D conformal photons
50.4 Gy
Proton boost
28.8GyE
3-D conformal photons
50.4 Gy
Total prostate dose
Total prostate dose
70.2 GyE
79.2 GyE
Harvard Randomized Dose Escalation Trial
Freedom from Biochemical Failure (ASTRO definition)
1.0
*
Freedom from
Biochemical Failure Rate
0.9
79%
0.8
0.7
61%
0.6
*
0.5
0.4
0.3
70.2 GyE
79.2 GyE
0.2
P = <0.0001
0.1
* 95% confidence intervals
0.0
0
1
2
3
4
5
6
7
8
10
20
10
2
Years Since Randomization
# at
risk
197
195
196
194
171
184
139
163
118
148
76
99
31
46
Harvard Randomized Dose Escalation Trial
Freedom from Biochemical Failure (ASTRO definition)
Low
Intermediate/high
1.0
79%
0.9
79.2GyE
78% 79.2GyE
0.8
0.7
0.6
55%
0.5
61%
70.2GyE
70.2GyE
0.4
0.3
0.2
n = 162
p = 0.03
n = 230
p = <0.001
0.1
0.0
0
1
2
3
4
5
6
7
Years since randomization
8
0
1
2
3
4
5
6
7
Years since randomization
Zietman A, et. al. JAMA, 2005, 294 (10): 1233
8
VII. Low Risk Disease
Treatment
-IMRT alone
-Seeds alone
VII. Radiotherapy for Low Risk Prostate Cancer
Treatment Options for Low- Risk Group

Watchful waiting vs. active surveillance
 Radical prostatectomy
 IMRT
 Interstitial brachytherapy
Memorial Sloan Kettering Cancer Center
IMRT Dose Escalation
Low Risk
T1-2, GS ≤6, PSA ≤10
Zelefsky MJ, Chan H, et. Al. Journal of Urology Vol. 176, 1415-1419, Oct 2006
Brachytherapy for Low Risk Prostate Cancer
Study design

125 pts with T1-T2b treated with I-125
brachytherapy b/w 1988-1990
 Gleason < 6
 Median PSA 5.1
 Endpoint biochemical outcome
– Failure is 2 consecutive rises in PSA
Grimm P, et. al. IJROBP, 51 (1), 31-40, 2001.
Brachytherapy for Low Risk Prostate Cancer
Grimm P, et. al. IJROBP, 51 (1), 31-40, 2001.
VIII. Intermediate Risk
Disease Treatment
-IMRT alone
-6 mo Hormone + EBRT
-Seeds + EBRT
VIII. Radiotherapy for Intermediate Risk
Prostate Cancer
Memorial Sloan Kettering Cancer Center
IMRT Dose Escalation
Intermediate Risk
T1-2, GS 6, PSA > 10
T1-2, GS >6, PSA  10
T3, GS  6, PSA  10
Zelefsky MJ, Chan H, et. Al. Journal of Urology Vol. 176, 1415-1419, Oct 2006
6 mo Hormone + Radiotherapy for Intermediate Risk
Prostate Cancer
3DCRT Rx 67Gy normalized to
95% isodose
D` Amico A, et al. JAMA. 2004; 292(7): 821-826.
6 mo Hormone + Radiotherapy for Intermediate Risk
Prostate Cancer
Overall Survival
88%
78%
D` Amico A, et al. JAMA. 2004; 292(7): 821-826.
IX. High Risk Disease Treatment
-Long-term Hormonal therapy
Randomized Trials
-RTOG randomized Trial
-EORTC randomized Trial
-Seeds + EBRT
IX. Radiotherapy for High Risk
Prostate Cancer
Memorial Sloan Kettering Cancer Center
IMRT Dose Escalation
High Risk
GS >6, PSA >10
Zelefsky MJ, Chan H, et. Al. Journal of Urology Vol. 176, 1415-1419, Oct 2006
Randomized Trials Involving Hormone Therapy for Locally
Advanced Prostate Cancer
Trial
Eligibility
Arms
Overall Survival
p-value
RTOG
8531
T3 (15%) or T1-2, N+
or path T3 and
(+) margin or (+) SV
RT (HT @ failure)
RT + AHT indefinite
10-year
39% v 49%
p=.002
EORTC
22863
T3-4 (89%) or
T1-2 WHO 3
RT
RT+CAHT 3 years
5-year
62% v 78%
p=.0002
RTOG
8610
Bulky T2b, T3-4,
N+ allowed
RT v RT+NHT
(TAB) 3.7 mo
8-year
44% v 53%
p=.10
RTOG
9202
T2c-4 w/PSA <150,
N+ allowed
RT+NHT (TAB) 4 mo
RT+NHT+AHTx28mo
5-year
70% v 80% GS 8
p=.73
P < .004
GS8
RTOG
9413
T2c-4 w/Gleason>6, or
>15% risk of N+
WP+ 4mo NHT
WP+ 4mo AHT
PO+ 4mo NHT
PO+ 4mo AHT
4-year
84.7% v 84.3%
p=.94
DFCI
T1b-T2b, or mri-T3
PSA=10-40, GS≥7
3DRT
3DRT + 6mo (TAB)
5-year
78% v 88%
p=.04
TROG
9601
T2-4, any PSA, any GS
RT
RT + 3mo NHT
Not stated
p=ns
X. Comparing Modalities
X. Can we compare radiation modalities to
surgical therapy?

No modern clinical trials have successfully
compared these modalities
– Physicians and patients alike unwilling to
accept randomization

Different definitions of cancer control
 Patients are not comparable between
modalities, even at same institution
Comparison of Outcome by Modality
Kupelian, Potters et al, IJROBP 2004 (Cleveland Clinic & MSKCC Mercy Hospital)
Comparison of Outcome by Modality
Kupelian, Potters et al, IJROBP 2004 (Cleveland Clinic & MSKCC Mercy Hospital)
Comparison of Outcome by Modality
Multivariate analysis of factors predictive of
bRFS
Kupelian, Potters et al, IJROBP 2004 (Cleveland Clinic & MSKCC Mercy Hospital)
Surgery vs Radiotherapy for Prostate Cancer
Risk of Death
 7316
men treated at 44 U.S. medical institutions for
Stage II prostate cancer
 Risk of prostate cancer-related death was not
measurable affected by type of therapy
 Intermediate-risk patients with multiple risk factors
fared better with RT
Relative risk (RR) of death due to prostate cancer
D’Amico AV. J Clin Oncol 21:2163-72, 2003
Surgery vs Radiotherapy for Prostate Cancer
American Urological Association
 Prostate
Cancer Clinical Guidelines Panel convened
to analyze the literature regarding available treatment
methods
 MEDLINE search of 1453 journal articles
 Analysis confined to 165 “best” articles
 Articles did not permit valid comparisons of the
treatment methods
 Data from the medical literature do not provide clearcut superiority of any one treatment
Middleton RG. J Urol 154:2144-8, 1996.
XI. Quality of Life Comparison
XI. Quality of Life After Prostate Cancer Therapy
Urinary Bothersome
80
Brachytherapy (P < 0.0001)
External
60
Surgery
Controls
% 40
20
0
None
Very small
Small
Moderate
Big
Wei, JT: J Clin Oncol 20: 557-566, 2002
Quality of Life After Prostate Cancer Therapy
Bowel Bothersome
100
%
80
Brachytherapy (P < 0.0001)
(P < 0.0001)
External
60
Surgery
Controls
40
20
0
None
Very small
Small
Moderate
Big
Wei, JT: J Clin Oncol 20: 557-566, 2002
Quality of Life After Prostate Cancer Therapy
Sexual Function Bothersome
60
Brachytherapy (P < 0.0001)
50
40
External
(P < 0.0001)
Surgery
(P < 0.0001)
Controls
% 30
20
10
0
None
Very small
Small
Moderate
Big
Wei, JT: J Clin Oncol 20: 557-566, 2002
XII. Conclusions
Factors Influencing Management Approach




Patient expectations of medical care
Patient understanding of & engagement
in management of condition
Patient preference for type of treatment
Access of patient to each member of a
multispecialty team
Dr. Ko`s Treatment Recommendations

Low Risk Pts

Surgery or Radiation

Intermediate Risk Pts

Surgery or Radiation

Equivalent in terms of QOL and Outcomes
Equivalent in terms of QOL and Outcomes
High-Risk Pts

Radiation is the treatment of choice in terms
of cancer control