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17/12/2014
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The Royal Marsden
PACE Study
Dr Nicholas van As
London: 1 December 2014
The Royal Marsden
Outline of today’s talk
• Background rationale for PACE?
• A bit about technology….
• What is PACE?
• How can I get involved?
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The Royal Marsden The Royal Marsden
Hypofractionation
The Royal Marsden
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Traditional Model of Fractionation
Fraction size (Gy)
0
50
100
150
200
250
0 1 2 3 4 5 6 7 82 4
Late adverse effects
Tumour control
Response α/β<10Gy
α/β≥10Gy
Courtesy of Prof.John Yarnold
The Royal Marsden 5
New Model of Tumour Fractionation
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Fraction size (Gy) 2 4
0
50
100
150
200
250
0 1 2 3 4 5 6 7 8
Other tumours
Response α/β<10Gy
α/β≥10Gy
Breast and prostate cancer
Courtesy of Prof.John Yarnold
The Royal Marsden
What’s the fraction sensitivity of prostate cancer ?
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BED if
α/β ratio
= 5
BED if
α/β ratio
= 4
BED if
α/β ratio
= 3
BED if
α/β ratio
= 2.7
BED if
α/β ratio
= 1.5
78 Gy in
39
fractions
109 Gy 117 Gy 130 Gy 135 Gy 182 Gy
36.25 Gy
in 5
fractions
88 Gy 101 Gy 123Gy 134 Gy 211 Gy
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Is using hypofrctionation, dose escalation by “stealth”?
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prostate cancer
(usuallyT1b – T4N0M0)
Dose 2
radiotherapy
randomize
radiotherapy
Dose 1
Radiation dose – response trials
no. patients
Prostate cancer dose escalation trials
The Royal Marsden
Prostate cancer dose escalation trials
Institute no pts dose comparisonLHRHa
MD Anderson US 305 70 vs 78Gy
ICR/RMH UK 126 64 vs 74 Gy ±
MRC RT01 UK 850 64 vs 74 Gy ±
Netherlands NL 669 68 vs 78Gy ±
FNC LCC F 300 70 vs 78Gy
Mass/Loma Linda US 393 70 vs 78Gy
RTOG US 1520 72 vs 78Gy
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Prostate cancer dose escalation trials
Netherlands - Photons
Peeters et al 2006
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Netherlands - Photons
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St. Thomas Hospital; 1991 (UK)(1964-1984)
– Radical external beam radiotherapy for localised carcinoma of the prostate using a hypofractionation technique
– Retrospective 232 patients, clinically localized PCA.
– RT 36/6
– Conclusion: Comparable results to other series, early and late morbidity acceptable
– Collins CD, Clin Oncol (R Coll Radiol). 1991 May;3(3):127-32.
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Christie Hospital, UK; 2009 (1995-1998)
– Hypofractionated conformal radiotherapy in carcinoma of the prostate: five-year outcome analysis
– Retrospective. 705 men with T1-T4N0 PCA, 4F conformal RT
– dose 50/16 @ 3.13 Gy/fx.
– Conclusion: Similar tumor control and toxicity to standard 65-70 Gy
Livsey JE, Int J Radiat Oncol Biol Phys. 2003 Dec 1;57(5):1254-9.
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Randomised evidence
A Prospective Phase III Randomized Trial of Hypofractionation Versus Conventional Fractionation in Patients with High-Risk Prostate Cancer
80/40 (2 Gy/fx) vs 62/20 (3.1 Gy/fx)
3-year bPFS conventional 79% vs hypofx 87%
Conclusion: Hypofractionated schedule superior for biochemical control, comparable for late toxicity
Arcangeli G, Int J Radiat Oncol Biol Phys. 2010 Jan 2. [Epub ahead of print]
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CHHiP : Phase III Trial of Conventional or
Hypofractionated High Dose intensity Modulated
Radiotherapy in Prostate Cancer
– Conventional 74Gy 37F 7.4w
– Hypofractionated 60Gy 20F 4w
– Hypofractionated 57Gy 19F 3.8w
– Part 1 Pilot randomised ‘phase I’ : 2 centres (n=150)
– Part 2 Preliminary phase III study : 6 centres (n=450)
– Part 3 Full Phase III trial : ≥ 20 centres (n=3000)
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Evidence for profound hypofractionation
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Randomised trials
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Phase III study of HYPOfractionated RadioTherapy
of intermediate risk localised Prostate Cancer
– Fractionation schedule and treatment durations: Conventional arm:
– 39 fractions of 2.0 Gy, = 78.0 Gy.
– Hypofractionated arm: radiotherapy is given working-days with 7 fractions of 6.1 Gy, = 42.7 Gy.
– Prof Anders Widmark
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Non randomised data
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Stereotactic Body Radiotherapy for
Intermediate-risk Organ-confined Prostate Cancer:
Interim Toxicity and Quality of Life Outcomes from a Multi-Institutional
Study
Robert Meier, MD
Swedish Cancer Institute, Seattle WA
I. Kaplan2, A. Beckman3, G. Henning4, S. Woodhouse5, S. Williamson6, N. Mohideen7, D. Herold8, C. Cotrutz1, M. Sanda2
2Beth Israel Deaconess Medical Center, Boston, MA 3Central Baptist Hospital, Lexington, KY 4St. Joseph Mercy Hospital System, Ypsilanti, MI 5Community Cancer Center, Normal, IL 6Capital Health System, Trenton, NJ 7Northwest Community Hospital, Arlington Heights, IL 8Jupiter Medical Center, Jupiter, FL
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Patient Characteristics
Age (yrs) Mean 69
Range 48 – 88
Clinical
Stage
T1a 0
T1b 2 (2%)
T1c 100 (76%)
T2a 19 (15%)
T2b 8 (6%)
Initial PSA
(ng/ml)
Mean 6.49
Range 1.10 – 17.90
Gleason
Score
≤ 6 34 (26%)
3 + 4 69 (54%)
4 + 3 26 (20%)
Prostate
Vol (cc)
Mean 42
Range 12 -105
– 129 patients enrolled December 2007 through April 2010
– 21 centers
– Follow up 2 – 4½ yrs Median 36 months
– Central pathology review
Data courtesy of Bob Meier
The Royal Marsden
Data courtesy of Bob Meier
The Royal Marsden
Data courtesy of Bob Meier
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The Royal Marsden PSA Response
5.93
0.8 0.4 0.2 0.13
0
1
2
3
4
5
6
7
0 12 24 36 48
Me
dia
n P
SA
(n
g/m
l)
Months after Treatment (# pts)
# Pts (129) (122) (114) (72) (17)
Data courtesy of Bob Meier
The Royal Marsden
SBRT for Localized Prostate Cancer: 5 year outcomes
Debra Freeman and Christopher King
The Royal Marsden
Results
– 43 pts.with minimum 5 yr. follow up
– 5 yr. biochemical progression-free survival of 92.7%
– Mean post-treatment PSA = 0.35
– 3 biochemical failures (33 mos, 37 mos, 42 mos); all biopsy-confirmed
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Toxicity
– No grade 3 rectal toxicity
– One grade 3 urinary toxicity (dysuria), following repeated instrumentation
– No incontinence reported
– ED rate 18-48%
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Results
– King, et al, have reported pooled data from a consortium of institutions treating with the Cyberknife system
– 1100 patients with a median follow up of 36 months
– Biochemical relapse free survival (bRFS) at 5 years was 95%, 84%, and 81% for low, intermediate, and high risk disease, respectively
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Prostate SBRT
– Good outcomes – PSA and toxicity
But without randomisation, where is the
evidence that this is equivalent to
conventionally fractionated IMRT?
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Technology
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Arc therapy
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RapidArc VMAT
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CyberKnife
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PACE
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Question 1:
Is SBRT equivalent to surgery for men with localised prostate cancer?
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Question 2
Is SBRT as good, or better, than current standard radiotherapy regimens?
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PACE Study Overview Study Scheme
Randomize
SBRT
36.25Gy/5#
Conventional
IGRT (78Gy/39#)
Randomize
Laparoscopic
prostatectomy SBRT
36.25Gy/5#
Yes No
Surgical Consideration
Early Stage Prostate Cancer
n=858 n=858
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Study treatments
Prostatectomy:
Laparoscopic or robot-assisted laparoscopic
Conventional radiotherapy:
Image-guided (fiducials) IMRT – 78Gy/39# daily
No androgen deprivation therapy
SBRT:
Robotic or gantry-based – 36.25Gy/5# daily or alternate daily
No androgen deprivation therapy
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Pace Study Objectives
– Primary objectives:
• To determine whether prostate SBRT is non-inferior to laparoscopic prostatectomy.
• To determine whether prostate SBRT is non-inferior to conventional radiotherapy (image-guided IMRT).
• Primary end-point: biochemical progression-free survival at 5 years.
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Pace Study Objectives
– Secondary objective:
• To determine the relative benefits of prostatectomy, conventional radiotherapy and SBRT, with respect to:
• local failure
• distant failure
• disease-free survival
• disease-specific survival
• overall survival
• toxicity
• quality of life (generic and organ specific domains)
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Pace Study Inclusion Criteria
–Low and intermediate risk organ confined prostate cancer
• Clinical and MRI stage T1c –T2c, N0-X, M0-X
• Gleason score ≤ 3+4
• PSA ≤ 20 ng/ml (completed within 60 days of registration)
• Histological confirmation of prostate adenocarcinoma, min 10 biopsy core
• WHO performance status 0 – 2
• Prostate volume ≤ 90 cc
• Ability of the research subject to understand and the willingness to sign a written informed consent document
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Pace Study Exclusion Criteria
• Clinical stage T3 or greater • Gleason score ≥ 4+3
• Prior pelvic radiotherapy • Prior androgen deprivation therapy
• Prior treatment for prostate cancer (active surveillance ok)
• Life expectancy < 5 years
• Previous malignancy in last five years except BCC or SCC skin
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Recruitment
• Currently 160 patients have been recruited by two UK centres.
• Experience has been that patients are keen to participate in this study and accept randomisation.
• Recruitment is lower than anticipated at this point due to delays in sponsorship transfer from Accuray inc. to Royal Marsden.
• Sponsorship is now resolved, and recuitment is expected to complete in early 2017; at least 20 centres in the UK and internationally are keen to participate.
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Adverse Events and Quality of Life Assessment
• Adverse Events Grading – CTCAEv4 and RTOG scales
• International Prostate Symptom Score (IPSS)
• International Index of Erectile Function (IIEF)
• Vaizey – patient questionnaire to assess bowel function
• EPIC – patient questionnaire to assess urinary, bowel, sexual function
• EORTC PR-25 (optional) – patient questionnaire to assess urinary, bowel, sexual function
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Pace Study Quality Assurance
Surgery QA
• minimum number of procedures per year >20 • data on surgical margin positivity and postoperative complications
SBRT and RT
• Calibration, daily and intermittent QA performed as per local guidelines • Approved by the Physics Chair
Planning QA • Benchmark Study • first patient for each treatment allocation pre-treatment • one patient per year post-treatment
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Data management and results
– Trial now sponsored by The Royal Marsden Hospital NHS Foundation Trust
– Unrestricted grant provided by Accuray inc.
– All the data will be analysed by the Clinical Trials Unit of the Institute for
– Cancer Research, UK
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Data management and results
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–IDMC (independent data monitoring committee)
– Prof Søren Bentzen
– Prof Joe O’Sulivan
– Dr Raj Persad
TSC (Trial steering committee)
– Prof Anthony Zietman
– Prof Mark Emberton
– Dr Ann Henry
– Prof Gert De Meerler
– Dr John Norrie
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Contacts
– Chief Investigator: Dr Nicholas van As
– Research fellow: Dr Daniel Henderson
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Thank you
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