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Radiation Therapy for Treatment of Prostate Cancer

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Stephen Ko, M.D. Mayo Clinic Florida August 30, 2010 Radiation Therapy for Treatment of Prostate Cancer * * * * * * * * * * XI. Quality of Life Comparison XI. – PowerPoint PPT presentation

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Title: Radiation Therapy for Treatment of Prostate Cancer


1
Radiation Therapy forTreatment of Prostate
Cancer
Stephen Ko, M.D. Mayo Clinic Florida August 30,
2010
2
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

3
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

4
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

5
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

6
U.S. Epidemiology
2009
New Cases in U.S.
7
.
U.S. Epidemiology
Deaths/year from cancer in U.S.
2009
8
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

9
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

10
III. Anatomy
Seminal vesicles
Bladder
Rectum
Prostate
11
IV. Technological Advances
2-Dimensional Planning (Fluoroscopic-based)
Intensity Modulated Radiotherapy or
IMRT (CT-based)
3-Dimensional Planning (CT-based)
12
2- Dimensional Vs. 3-Dimensional Planning
Rectum
Bladder
Prostate
Prostate
Rectum
13
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
14
Intensity Modulated External Beam Radiotherapy
15
IMRT Prostate Dose Distribution
Dose
16
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)

17
Definition of Risk Categories-Low
Risk -Intermediate Risk -High Risk
18
V. Prostate Cancer Risk Groups
19
Prostate Cancer Risk Groups
  • Clinical tumor stage, Gleason score and PSA used
    to determine risk groups (DAmico)
  • Low risk Stage T1-2a, Gleason ? 6, and PSA lt 10
    ng/mL
  • Intermediate risk Stage T2b or Gleason 7 or PSA
    10-20 ng/mL
  • High risk Stage gt T2c or Gleason 8-10 or PSA gt
    20 ng/mL

20
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)

21
Memorial Sloan Kettering Cancer CenterIMRT 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
22
Memorial Sloan Kettering Cancer CenterIMRT 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
23
Memorial Sloan Kettering Cancer CenterIMRT 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
24
Memorial Sloan Kettering Cancer CenterIMRT 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
25
Memorial Sloan Kettering Cancer CenterIMRT Dose
Escalation
Intermediate Risk
T1-2, GS ?6, PSA gt 10 T1-2, GS gt6, PSA ? 10 T3,
GS ? 6, PSA ? 10
Zelefsky MJ, Chan H, et. Al. Journal of Urology
Vol. 176, 1415-1419, Oct 2006
26
Memorial Sloan Kettering Cancer CenterIMRT Dose
Escalation
High Risk
GS gt6, PSA gt10
Zelefsky MJ, Chan H, et. Al. Journal of Urology
Vol. 176, 1415-1419, Oct 2006
27
Memorial Sloan Kettering Cancer CenterIMRT 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
28
Memorial Sloan Kettering Cancer CenterIMRT 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
29
Memorial Sloan Kettering Cancer CenterIMRT Dose
Escalation
  • Toxicity
  • Rectal
  • Grade 2 rectal bleeding 7 patients (1.5)
  • Grade 3 rectal toxicity 3 patients (lt1)
  • No grade 4 rectal complications
  • 8-year actuarial likelihood of late grade gt 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 gt 2
    urinary toxicities 15

Zelefsky MJ, Chan H, et. Al. Journal of Urology
Vol. 176, 1415-1419, Oct 2006
30
Memorial Sloan Kettering Cancer CenterIMRT 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
31
Loma Linda Proton Beam ExperienceDose 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.
32
Loma Linda Proton Beam ExperienceDose 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.
33
Loma Linda Proton Beam ExperienceDose Escalation
  • Overall 5-year 8-year actuarial biochemical
    disease-free survival rates 75 73

Slater JD, Rossi CJ, et. Al. IJROBP Vol 59, No.
2, 348-352, 2004.
34
Comparison of IMRT versus Proton Therapy
Median Follow up Pts. 5yr BDFS 8yr BDFS Multivariate Analysis Late rectal Late Urinary Sexual Dysfunction
IMRT 7yrs 561 N/A 85 for LR, 76 for IR, 72 for HR Clinical Stage Pre-Treatment PSA significant Gr 2 or greater 1.6, Gr 3 lt1, no Gr 4 Gr 2 or greater 15, Gr 3 was 3, No Gr 4 49
PBRT 62mo 1255 75 73 Pre-Treatment PSA, Gleason, PSA nadir significant Gr 3 lt1, Gr 4 lt1 (1pt with Gr 4) Gr 3 or greater lt1, no Gr 4 N/A
35
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
36
Freedom from Failure by PSA
MDACC Randomized Dose Escalation Trial
PSA lt10 ng/ml
PSA gt10 ng/ml
78 Gy
78 Gy
70 Gy
70 Gy
p 0.46
p 0.012
Pollack IJROBP 2002
37
Fraction Free of Distant Metastases, PSA gt 10
MDACC Randomized Dose Escalation Trial
78 Gy
70 Gy
p 0.056
Pollack IJROBP 2002
38
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
39
Harvard Randomized Dose Escalation Trial
  • Trial design
  • No hormonal therapy

T1b-2b prostate cancer PSA lt15ng/ml
r a n d o m i z a t i o n ACR/RTOG
Proton boost 19.8 GyE
Proton boost 28.8GyE
3-D conformal photons 50.4 Gy
3-D conformal photons 50.4 Gy
Total prostate dose 79.2 GyE
Total prostate dose 70.2 GyE
40
Harvard Randomized Dose Escalation Trial
Freedom from Biochemical Failure (ASTRO
definition)
1.0

0.9
79
0.8
0.7
61
0.6

0.5
Freedom from Biochemical Failure Rate
0.4
0.3
70.2 GyE
P lt0.0001
0.2
79.2 GyE
0.1
95 confidence intervals
0.0
0
1
2
3
4
5
6
7
8
Years Since Randomization
at risk
197 196 171 139 118
76 31 10 10 195
194 184 163 148 99
46 20 2
41
Harvard Randomized Dose Escalation Trial
Freedom from Biochemical Failure (ASTRO
definition)
Low
Intermediate/high
1.0
79.2GyE
79
0.9
79.2GyE
78
0.8
0.7
0.6
61
70.2GyE
70.2GyE
55
0.5
0.4
0.3
n 162 p 0.03
n 230 p lt0.001
0.2
0.1
0.0
0
1
2
3
4
5
6
7
8
0
1
2
3
4
5
6
7
8
Years since randomization
Years since randomization
Zietman A, et. al. JAMA, 2005, 294 (10) 1233
42
VII. Low Risk Disease Treatment-IMRT
alone-Seeds alone
43
VII. Radiotherapy for Low Risk Prostate Cancer
44
Treatment Options for Low- Risk Group
  • Watchful waiting vs. active surveillance
  • Radical prostatectomy
  • IMRT
  • Interstitial brachytherapy

45
Memorial Sloan Kettering Cancer CenterIMRT 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
46
Study design
Brachytherapy for Low Risk Prostate Cancer
  • 125 pts with T1-T2b treated with I-125
    brachytherapy b/w 1988-1990
  • Gleason lt 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.
47
Brachytherapy for Low Risk Prostate Cancer
Grimm P, et. al. IJROBP, 51 (1), 31-40, 2001.
48
VIII. Intermediate Risk Disease Treatment-IMRT
alone-6 mo Hormone EBRT-Seeds EBRT
49
VIII. Radiotherapy for Intermediate Risk Prostate
Cancer
50
Memorial Sloan Kettering Cancer CenterIMRT Dose
Escalation
Intermediate Risk
T1-2, GS ?6, PSA gt 10 T1-2, GS gt6, PSA ? 10 T3,
GS ? 6, PSA ? 10
Zelefsky MJ, Chan H, et. Al. Journal of Urology
Vol. 176, 1415-1419, Oct 2006
51
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.
52
Overall Survival
6 mo Hormone Radiotherapy for Intermediate
Risk Prostate Cancer
88
78
D Amico A, et al. JAMA. 2004 292(7) 821-826.
53
Brachytherapy for Low, Interm, High Risk Grps
PSA Progression-Free Survival (N403)
94
Favorable
N279
N111
Intermediate
84
N13
CumulativeSurvival
54
Unfavorable
_at_risk
0.0
120
108
96
84
72
60
48
36
24
12
0
Months Postimplant
Seattle Prostate Institute.
Courtesy SPI and Medical Education Collaborative
54
IX. High Risk Disease Treatment-Long-term
Hormonal therapy Randomized Trials-RTOG
randomized Trial-EORTC randomized Trial-Seeds
EBRT
55
IX. Radiotherapy for High Risk Prostate Cancer
56
Memorial Sloan Kettering Cancer CenterIMRT Dose
Escalation
High Risk
GS gt6, PSA gt10
Zelefsky MJ, Chan H, et. Al. Journal of Urology
Vol. 176, 1415-1419, Oct 2006
57
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 _at_ failure) RT AHT indefinite 10-year 39 v 49 p.002
EORTC 22863 T3-4 (89) or T1-2 WHO 3 RT RTCAHT 3 years 5-year 62 v 78 p.0002
RTOG 8610 Bulky T2b, T3-4, N allowed RT v RTNHT (TAB) 3.7 mo 8-year 44 v 53 p.10
RTOG 9202 T2c-4 w/PSA lt150, N allowed RTNHT (TAB) 4 mo RTNHTAHTx28mo 5-year 70 v 80 GS 8 p.73 P lt .004 GS8
RTOG 9413 T2c-4 w/Gleasongt6, or gt15 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 PSA10-40, GS7 3DRT 3DRT 6mo (TAB) 5-year 78 v 88 p.04
TROG 9601 T2-4, any PSA, any GS RT RT 3mo NHT RT 6mo NHT Not stated pns
58
Brachytherapy for Low, Interm, High Risk Grps
PSA Progression-Free Survival (N403)
94
Favorable
N279
N111
Intermediate
84
N13
CumulativeSurvival
54
Unfavorable
_at_risk
0.0
120
108
96
84
72
60
48
36
24
12
0
Months Postimplant
Seattle Prostate Institute.
Courtesy SPI and Medical Education Collaborative
59
X. Comparing Modalities
60
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

61
Comparison of Outcome by Modality
Kupelian, Potters et al, IJROBP 2004 (Cleveland
Clinic MSKCC Mercy Hospital)
62
Comparison of Outcome by Modality
Kupelian, Potters et al, IJROBP 2004 (Cleveland
Clinic MSKCC Mercy Hospital)
63
Multivariate analysis of factors predictive of
bRFS
Comparison of Outcome by Modality
Kupelian, Potters et al, IJROBP 2004 (Cleveland
Clinic MSKCC Mercy Hospital)
64
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
DAmico AV. J Clin Oncol 212163-72, 2003
65
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
    clear-cut superiority of any one treatment

Middleton RG. J Urol 1542144-8, 1996.
66
XI. Quality of Life Comparison
67
XI. Quality of Life After Prostate Cancer Therapy
Urinary Bothersome
(P lt 0.0001)

Wei, JT J Clin Oncol 20 557-566, 2002
68
Quality of Life After Prostate Cancer Therapy
Bowel Bothersome
(P lt 0.0001)
(P lt 0.0001)

Wei, JT J Clin Oncol 20 557-566, 2002
69
Quality of Life After Prostate Cancer Therapy
Sexual Function Bothersome
(P lt 0.0001)
(P lt 0.0001)
(P lt 0.0001)

Wei, JT J Clin Oncol 20 557-566, 2002
70
XII. Conclusions
71
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

72
Dr. Kos Treatment Recommendations
  • Low Risk Pts
  • Surgery or Radiation-
  • Equivalent in terms of QOL and Outcomes
  • Intermediate Risk Pts
  • Surgery or Radiation-
  • Equivalent in terms of QOL and Outcomes
  • High-Risk Pts
  • Radiation is the treatment of choice in terms of
    cancer control
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