Management of Low and Intermediate Risk Prostate Cancer Michael J Zelefsky M.D. Professor of Radiation Oncology Chief, Brachytherapy Service Memorial Sloan Kettering Cancer Center Weill Cornell Medical College, Cornell University, Division of Radiation Oncology
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Management of Low and Intermediate Risk Prostate Cancer
Michael J Zelefsky M.D. Professor of Radiation Oncology
Chief, Brachytherapy Service Memorial Sloan Kettering Cancer Center
Weill Cornell Medical College, Cornell University, Division of Radiation Oncology
Early Stage Disease: Low and Intermediate Risk Disease
` Role of Active Surveillance for Low Risk Disease • Role of dose escalation for Low risk disease
• Comparison of tumor control outcomes and toxicity profiles between IMRT
and BRT. • Enhanced technologies or treatment delivery for EBRT: IGRT, Protons,
SBRT • Management of Intermediate risk disease
– Role of androgen deprivation therapy – Use of combined modality therapy (BRT+EBRT)
• Selection criteria for optimal radiotherapeutic management of low and
intermediate risk disease
NCCN- Very Low Risk Group
• Criteria
•T1c, Gleason score ≤6, PSA < 10
•fewer than 3 cores positive, ≤50% involved
•in each core, PSA density <0.15 ng/mL/g <20 years
Radical Prostatectomy Vs Observation for Localized Disease
(Wilt et al NEJM 2012)
• PIVOT trial enrolled 731 patients from 1994-2002 • Median age: 67 years • Median Follow-up: 10 yrs • Primary Outcome: All cause-mortality • Secondary Outcome: PC mortality • Initial design of the trial to accrue 2000 patients with
a median follow up of 15 years • Trial redesigned for a randomization goal of 740 and
with an expectation of a 25% reduction in mortality
Radical Prostatectomy Vs Observation for Localized Disease (Wilt et al NEJM 2012)
• Findings: – No significant difference in all-cause or PC
specific mortality in patients with low risk disease – Fewer deaths from PC or any cause among high
risk patients treated with surgery – Surgery arm had more complications including
urinary incontinence and ED – Bone metastases noted more often for the
observation group
Survival Outcomes-PIVOT
Improving Staging for Low and Intermediate Risk
The Role of Imaging
Benefit of MRI for Tumor Detection
• MRI sensitivity for disease detection ranges from 40-90%
• MRI sensitivity for disease > 1cm is noted to be 85%
• Accuracy for smaller tumors less clear • Repeat biopsy in low volume disease shows
upgrading or greater volume in 20% which was highly correlated with MRI findings with sensitivity of 90% (Vargas J Urol 2012)
2T Weighted MRI Identification of a Dominant Lesion
Added Value of Multi-parametric MRI in Tumor Staging
78-year-old: PSA= 6.3 ng/Ml, Stage T1C, Initial Biopsy Gleason 6 in 1 of 12 cores
Final pathology showed prostate cancer with Gleason score of 8 (4+4)
Tumor Detection in Prostate Cancer: Multi-Parametric Functional Imaging
• T2 Weighted imaging combined with DWI and DCE-MRI associated with 85% and 83% sensitivity and specificity for low risk disease.
• MRI can better detect anterior PC which comprise 21% of PC which are hard to detect on TRUS biopsy
• TZ directed needle biopsy does not detect a dominant anterior lesion in 80% of cases ( Harrer et al J Urol 2009)
Decision-Related Variable for Consideration of Therapy vs. Observation
• Pathology Variable – Presence of grade 4/5 – > 2 cores involved with >50% core involvement
• Imaging Variables – Evidence of capsular invasion or encroachment – Multi-focality, dominant lesion, larger volume
disease • PSA Kinetics • Patient age • Presence of co-morbidities
Randomized Trials of Dose Escalation with EBRT Series # Randomization PRFS Advantage
MDACC (2002, 2008)
301 78 Gy vs 70 Gy 73% vs 50% (10-yr)
Intermediate Risk ( PSA>10)
MGH/LLMC (2006, 2010)
393 79.2 vs 70.2 Gy (protons)
83% vs 68% (10-yr)
Low and Int Risk
Peeters (2006)
669 78 Gy vs 68 Gy 64% vs 54%
Intermediate Risk
Dearnelay (2007)
843 74 Gy vs 64 Gy (with ADT)
71% vs 60%
All risk groups
GETUG (2011)
306 80 Gy vs 70 Gy
72% vs 61%
Dose Escalation Advantage for Favorable Risk Disease Zietman et al JCO 2010
Favorable Risk
Intermediate Risk
Improved Targeting of Radiotherapy
( Zelefsky et al J Urol 2006)
• IMRT has radi
13%
2% P< 0.001
Risk Group 5-year (%) 10-year (%) Low risk* 97.70 93.40
Intermediate risk 89.10 75.50 High risk 76.10 65.80
Outcome of 1002 Patients Treated with 86.4 Gy IMRT
(Spratt et al IJROBP 2012)
Dose Constraints Used for 86.4 Gy
Structures Constraint To
Rectal Wall 53% of total volume V47 30% of total volume V75.6 97% - 99% Max Point Dose
Bladder Wall 53% of total volume V47
105% - 107% Max Point Dose Large Bowel 60Gy Max Point Dose Small Bowel 50Gy Max Point Dose
IGRT @MSKCC for Prostate Cancer • In 2008 gold fiducials routinely placed for all
definitive prostate cancer IMRT. • During this time our PTV margins were
maintained as 1 cm except at the prostate-rectal interface where a 6 mm margin used.
• In late 2010 PTV margins reduced to 6mm circumferentially
• Further margin reductions to 5 mm around the PTV and 3 mm posteriorly used for hypo-fractionated IGRT such as SRS and supplemental IMRT after brachytherapy
Comparison of Toxicity Outcomes Between IGRT and IMRT
(Zelefsky et al IJROBP- 2012)
Characteristics Non-IGRT (N=190) 2006-2008
IGRT (N=186) 2008-2010
Radiation Dose 86.4 Gy 86.4 Gy
CTV-PTV Margins 1 cm except at prostate rectal interface where 6 mm margin used
1 cm except at prostate rectal interface where 6 mm margin used
Use of Androgen Deprivation Therapy
54% 42%
Median IPSS Score 9 9
Actuarial Late Grade 2 or Higher Urinary Toxicity
( Zelefsky et al Int J Radiat Oncol Biol Phys- 2012)
P=0.024
Multivariable Analysis for Predictors of Late Urinary Toxicity
Variable Coefficient %95 Confidence (+/-)
Standard Error
P value Hazard Exponent
Use of Hormones
0.064 0.562 0.287 0.822 1.067
Non-IGRT vs IGRT
0.700 0.603 0.308 0.023 2.015
Age>65 0.138 0.636 0.325 0.670 1.148
Baseline IPSS >15
0.642 0.609 0.311 0.04 1.901
External Beam Radiotherapy 2014 for Low and Intermediate Risk
• High dose IMRT (>=78 Gy) recommended even for low risk disease.
• Target volume should include prostate (+ seminal vesicles) and not pelvis.
• Routine use of IGRT with fiducial marker
placement where margins can be tighter ( at MSKCC a 6 mm circumferential margin is used).
• Increasing interest in hypo-fractionated regimens
Prostate Cancer Brachytherapy 2014 • Careful selection of patients to reduce the morbidity
of therapy. – Prostate size of 50 grams or less – IPSS < 18 – Post-void residual of 100 cc or less – No evidence of ECE on imaging
• Improved accuracy of seed delivery with
enhancements in image guidance and sophisticated intraoperative planning systems has resulted in excellent long-term outcomes.
• Use of combined treatment of brachytherapy with external beam radiotherapy to provide dose escalation for intermediate and high risk patients.
Brachytherapy for Low Risk Disease
• 10 year biochemical tumor control outcomes of > 90%.
• Results achieved with permanent interstitial I-125 or Pd-103 or HDR monotherapy.
• Optimal tumor control outcomes seen with proper application of dose – D90 > 140 Gy (for I-125) to the prostate associated
with improved long-term tumor control outcomes
Contemporary Series Reporting Proctitis Rates after Prostate Brachytherapy
Series # pts Median F/U
Grade 2 Grade 3
Phan 2008
263 5.5 yrs 3.7% 0.4%
Zelefsky 2010
448 6.5 yrs 5.1% 1.1%
Shiraishi 2011
458 4 yrs 9.7% NS
Keyes 2012
1006 5 yrs 7.3% 0.9%
Late Urinary Toxicity after Prostate Brachytherapy
Series # pts Median F/U
% G-2 % G-3 % G-4
Anderson (2009)
351 5.7 yrs 6.5% 1.7% 0.5%
Keyes (2009)
712 5 yrs 24% 6% 0.1%
Zelefsky (2010)
448 6.5 yrs 15.6% 2.2% 0%
Zilli (2011)
250 3 yrs 22% 1% -----
Sexual Function after Radiotherapy
• Approximately 30-50% of patients develop ED after RT.
• Almost all patients will develop significant reduction in the ejaculate
• Based on prospective QOL studies , patients who receive BRT may achieve better erectile preservation but this may be related to selection bias
• Sildenafil citrate associated with a 60-70% improvement in EF function.
• Results of randomized trial comparing prophylactic sildenafil versus placebo given to reduce ED after RT indicate especially after 1-2 years improvements of function noted ( Zelefsky et al J Urol in press)
Comparison of Outcomes Between Brachytherapy and
IMRT
Limitations of Comparisons • Lack of prospective randomized data leaves
us with retrospective data subject to selection bias.
• The use of hormone and patient age and co-morbidity differences make the comparison not as straightforward.
• Moving Target Phenomenon: Significant enhancements in treatment delivery over time confound comparisons of therapeutic interventions.
Patient Characteristics Between Treatment Groups
Characteristic Brachytherapy (n=448)
IMRT @ 81 Gy P Value
Age >65
58%
70%
P=0.002
Pre-Treatment PSA <4 >4
21% 79%
15% 85%
P=0.08
T Stage T1c
81%
70%
P=0.001
Use of Neoadjuvant Hormones
31% 32% P=0.81
PSA-Relapse Free Survival Favorable Risk Patients
( Zelefsky et al Urology 2011)
BRT vs EBRT: 95% versus 89% at 7 years Median PSA Nadir (ng/ml): 0.1 BRT; 0.6 EBRT
BRT
EBRT
Cox Regression Analysis for PSA-RFS
Factor UVA MVA HR P-value HR P-value
Mode (Brachy vs. EBRT) 0.30 <0.00001 0.517 0.0004
Age (continuous) 1.0 0.85
Age (>69 vs <=69) 0.993 0.96
HT (1 vs 0) 1.63 0.0003 0.82 0.18
Dose level (8640 vs 8100cGy)
1.03 0.86
Combined Brachytherapy and IMRT as an Effective Means of Dose Escalation
Comparison of LDR Brachytherapy vs IMRT @ 81 Gy
for Low Risk Patients Toxicity Brachytherapy IMRT P Value
GI Late Toxicity Grade 2 Grade 3
5.1% 1.1%
1.4% 0
0.01 0.19
GU Late Toxicity Grade 2 Grade 3
15.6% 2.2%
4.3% 1.4%
<0.001 0.62
Prostate Cancer Results Study Group
( Grimm BJU Int 2012)
• Meta-analysis of over 18000 identifying cohorts who were risk-stratified with 5 year follow-up
• Conclusions similar – Low risk: BRT provides superior biochemical
control – Intermediate Risk: combined EBRT+BRT
provide similar biochemical outcomes compared to selected patients undergoing BRT alone
3/10/2014 BJU Int, 2012, Vol. 109(Supp
43
7
60
70
80
90
100
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Seeds Surgery EBRT
5
22
← Years from Treatment →
CRYO
• Prostate Cancer Results Study Group • Numbers within symbols refer to references
1 12
24
14 8
2
23
HIFU
% P
SA P
rogr
essi
on F
ree
11
15
Protons
21
4
18
9
10
EBRT & Seeds
25
Robot RP 26
Prostate Cancer Center of Seattle
27
HDR
28 29
30
31 32 33
34
19 36
37
38
LOW RISK RESULTS Weighted >40 months follow-up or less than 100 patients
Trea
tmen
t Suc
cess
3 39
35
40
41
100
101
13
65
49
76
80
56
59 63
41
75
51
71 72
90
73
74
70
42
57
85 84
66
43 64
44 EBRT & ADT
53
82 81 62
54
79
86
87
88
45
58
69
78
77
46
48
91
+ Seeds & ADT
93
92
89
50
67
68
95 94
55 52 83 47
61
Brachy EBRT
Surgery
Hypo EBRT
96
103
102
97
98
60 6
16
104
105
106
99
107 108
17
Comparing Radiotherapeutic Interventions for
Intermediate Risk Disease
Comparing Outcomes for Intermediate Risk Disease
Sathya et al, JCO 2005
EBRT 66 Gy/33 fx to isocenter
LDR 35 Gy + EBRT of 40 Gy
vs.
EBRT 55 Gy/20 fx to isocenter (EQD2 65.3 Gy)
HDR 17 Gy /2 fx + EBRT of 35.75 Gy
vs.
Hoskin et al, Radiotherapy and Oncology, 2012
Two phase III RCT demonstrated biochemical control benefit of EBRT + brachy boost (combo-RT) over non-dose escalated EBRT alone
Combo
EBRT
41
33
37
21
26
16
11
4
Phase III Randomized Trial of HDR and EBRT vs EBRT alone for Localized Prostate Cancer
( Hoskin et al Radioth Oncol 2012)
Comparison of HDR+IMRT versus IMRT Alone
• 2 modalities of radiation dose escalation: – Ultra-high dose prostate IMRT to 86.4 Gy
• 470 patients, 53 months median followup (Zelefsky, IJROBP 2008)
• Prostate Cancer Results Study Group • Numbers within symbols refer to references
15 4
36
Prostate Cancer Center of Seattle
37
38
+
Seeds Alone
Seeds + ADT 40
Robot RP
41
42
44
43
45
46
INTERMEDIATE RISK RESULTS weighted >40 months follow-up or less than 100 patients
7
11
14
20
35
34
39
23 24
16
6
26
33
82
66
88
67
70
97 63
65 102 103
101
86
87 85
58 68
71 81 50
EBRT + ADT
94
93
92
77
91 51
69
Hypo EBRT 99
75
90
89
56 55
54
80
57
83
60
73 72
98
53
52
79
95 64
100
84
78
59
62 74
96
76
EBRT
Brachy
Surgery
EBRT & Seeds
EBRT, Seeds + ADT
Trea
tmen
t Suc
cess
104
105 30
27 47
48
49
150
151
106 107 31
109
108
Ultra-hypofractionated SBRT for Prostate Cancer
Ongoing Phase I Dose Escalation Study at
MSKCC • Ultra-hypofractionated IGRT Phase I dose escalation
study – 650 cGy x5- accrual completed – 700 cGy x 5- accrual completed – 750 cGy x 5- accrual completed – 800 cGy x 5- accrual initiated – 850 cGy x 5
• Primary endpoint is toxicity • Secondary endpoints included PSA tumor control and 2-
year biopsy outcomes • Eligibility includes IPSS< 17, Favorable/Intermediate
Risk, no prior ADT
Planning constraints – Converted from 8640 planning
protocols. RW max 3832 cGy D53 Rw 2400 cGy RW NTCP 12.5 ( Average NTCP of 8640cGy patient) Urethra max 4011 cGy Bladder wall 4100 cGy D53 BW 2400 cGy BOWEL S/L 2516 / 2899 cGy
1. Margins 3 mm at prostate rectal interface and 5 mm circumferentially 2. Patient simulated with catheter so urethra can be well delineated 3. Real time Tracking employed for each of the 5 fractions
PTV D95 = 3700
Color Wash of SHARP Dose Distribution
Ultra-Hypofractionated RT Tumor Control Outcomes
Study # Dose/Fx Fx Total Dose
Median F/u (mo)
PSA Control
Virginia Mason (2010)
40 6.7 5 33.5 Gy 41 90%
Stanford (2009)
41 7.25 5 36.25 Gy
33 100%
Naples (2009)
112 7-7.25 5 35-36 Gy
24 99%
Winthrop (2010)
304 7-7.25 5 35-36 Gy
30 99%
Boike (2011)
45 9-10 Gy 5 45-50 Gy
30 100%
Georgetown (2013)
100 7-7.25 5 35-36 Gy
27 99%
Ultra-Hypofractionated RT- Toxicity Outcomes
Study Dose/ Median F/u (mo)
Late GI Toxicity
Late GU Toxicity
King et al 2009
36.25Gy 33 48% G1-G2
65% G1-G2; 5% G3
Katz et al 2010
35 Gy 30 9% G1/G2 9% G1/G2 0.5%- G3
Bolzicco et al 2010
35 Gy 20 2.2% G-2 9% G1/G2 2.2%- G3
Freeman et al (2010)
36.25 Gy 60 15.5% G1-G2
32% G1/G2 2.5%- G3
King et al 2012
36.25 Gy 32 16% G1-G2
28% G1/G2 3.5%- G3
Adapted from Seisen et al 2013
Ultra-hypofractionated SBRT for Prostate Cancer
• So far excellent results reported albeit with shorter follow-up.
• Recent meta-analysis by King et al notes >90% PSA control rates in over 1000 patients treated (36.25 /4-5 fractions). PSA outcome for low, intermediate and high risk was 95%, 84% and 81%.
• Preliminary results also indicate excellent tolerance especially when using tight margins and intra-fraction motion tracking.
Protons for Early Stage Disease
Protons and Prostate Cancer • Between 2006-2009 there has been a doubling
of prostate cancer patients treated with proton therapy
• Increase in usage speculated to be related to the allure of new technology and high reimbursement per course of treatment
• No evidence in the literature of superior tumor control outcomes with protons compared to photons for treatment of prostate cancer
• University of Penn and MGH and other conducting randomized trial of IMRT vs proton for clinically localized disease
Comparison of Outcomes and Toxicity Between Proton Therapy and IMRT
( Sheets et al JAMA 2012) • Population=based study using SEER-
Medicare Linked data of treatments from 2000-2009
• Salient Findings: – IMRT patients had lower rates of GI toxicity
(absolute risk: 12.2 vs 17.8 per 100 person-years; RR-0.66)
– No significant differences in rates of other morbidities
– Comparable tumor control outcomes as reflected by need to receive additional cancer therapies
Comparison of Need for Additional Cancer Therapies Between Patients Treated Initially with Proton Therapy Vs IMRT
The Physics Facts And Uncertainties About Protons ( Lawrence and Feng 2013)
• Bragg peak serves as advantage to reduced exit dose potentially leading to reduced normal tissue exposure and theoretically lower risk of secondary cancers
• Bragg peak of a single energy is too to treat a tumor so different energies must be used to broaden the peak increasing the entrance dose
• Uncertainty as to how far protons will travel, so the high dose region is typically extended several mm beyond the target
– EBRT alone (79.2Gy/44fx to PTV) – Combination EBRT + brachy (either LDR or HDR)
• EBRT: 45Gy/25fx to prostate/SV • LDR: I-125 (110Gy) or Pd-103 (100Gy) • HDR: 21Gy/2fx
Conclusions-1 • Very Low Risk patients should be considered for AS;
MP MR imaging could provide valuable information re: volume of disease.
• Outcomes with EBRT has been improved with conformal therapies and dose escalation appears to be necessary for both low and intermediate risk disease.
• Outcomes with Brachytherapy for low and intermediate risk disease based on 2 randomized and retrospective comparisons appear to demonstrate superior biochemical tumor control outcomes and DMFS for BRT vs EBRT.
• Stereotactic hypofractionated radiotherapy demonstrates promise with excellent PSA-RFS for low and intermediate risk disease with excellent tolerance profiles; follow-up still short
• Proton therapy provide excellent dose distributions yet no clear data demonstrating any superiority over dose escalated photon therapy; toxicity not shown to be lower at this time.
• There is no role for ADT in low risk patients yet for intermediate risk patients short course ADT associated with improved survival outcomes when combined with EBRT.
• The role of ADT for intermediate risk patients treated with brachytherapy is unclear
• RTOG 0815 will address these issues as well as the role of ADT in intermediate risk patients when treated with dose escalation