NY Prostate Cancer Conference - D. Dearnaley - Session 4: Predicting clinical and biochemical endpoints before external radiotherapy combined with hormonal therapy
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NY Prostate Cancer Conference - D. Dearnaley - Session 4: Predicting clinical and biochemical endpoints before external radiotherapy combined with hormonal therapy
1. Predicting clinical and biochemical
endpoints before external radiotherapy
combined with hormonal treatment
Professor David Dearnaley
Institute of Cancer Research/Royal Marsden Hospital
2. Increasing use of gonadotropin-releasing hormone agonists for the
treatment of localized prostate carcinoma Shahinian,Cancer 2005 103
1615
% of patients treated with LHRHa or orchidectomy within the first 6
months of diagnosis over the time period 1991-1999.
3. No. 517 1988-98 median FU 44months
NAD median 5.5months
RT dose 64GY
PSA median 20ng/ml, T3/4 disease in 56%
PSA failure 233 men
Multivariate analysis
PSA, Histological grade , T stage, Age
4.
5.
6.
7. Problems
• PSA progression not a good endpoint as testosterone
suppression delays failure
• Derived from datasets in academic centres
• Do not include data from randomised phase III trials of
neo/adjuvant hormone therapy
• Perform less well in ‘community’ - overestimate
likelihood of control
• Only apply to population similar to index population
8.
9. Metaanalysis of homones and RT
Bria Cancer 2009 115 3446
• 7 trials - 4387 patients - 3 long /4 short course
• HR 0.76 for PSA failure HR 0.81 for CPFS
16. • RT +/- 6months AD
• No. 206 Int/high risk FU 7.6yrs
• Overall Deaths 44 vs 30
HR 1.8 p = 0.01
• 8yr survival 74% vs 61%
Absolute advantage 13%
• Prostate cancer specific mortality
14 vs 4 deaths HR 4.1 p=0.01
• NNT treat is 10.4 to prevent 1 CaP death
at 8 yrs
• NNT treat is 7.7 to prevent 1 death from
any cause at 8 yrs
17. Lancet Oncol 2010 11 1066
EORTC 22863
• No.415 FU 9 yrs
• RT Pr (70Gy)/Pelvis (50Gy) +/-3yr adj AD
• High Grade T1/2 or T3/4
• iPSA >20 in 55%
21. 2009, 3560, 2516-27
• 6m vs 36m AD (triptorelin 1 or 3m depot :
MAB for initial 6m)
• No. 977 ; 6.4yr FU
• 78% T3/4 ; PSA 19 (1-160) ;18%≥ GL 8
• 5 yr overall mortality
19% vs 15% HR 1.42 NNT 26
• 5yr prostate specific mortality
4.7% vs 3.2% HR 1.71 NNT 67
22. RTOG 92-02:Radiotherapy and duration of
androgen suppression
No. 1554 Follow up 56m
5 year results 4m AD 28m AD
Local failure 13% 6% p=.0001
PSA control 21% 46% p=.0001
Disease specific survival 87% 92% p=.07
Overall survival 78% 79% NS
BUT
DSS Gl 8-10 (22% of cases) 78% 90% p=.007
OS Gl 8-10 69% 80% p=.02
Hanks JCO 2003 21 3972
23. Is biochemical response more important than duration
of neoadjuvant therapy hormone before RT :
analysis of the 3 vs 8 month trial
Alexander IJROBP 2010 76 23-30
• Canadian RCT; no.378; RT 66Gy and 3 vs 8m CAB;
No difference by randomised group
• PSA pre RT ≤0.1(n=125) vs >0.1(n=210)
• bDFS 55% vs 49% (p=0.04 ), 57% vs 29% (p=0.02)
for high risk group
• MV analysis GL,T stage ,iPSA and pre RT PSA
related to outcome
24. Recovery of serum testosterone after neoadjuvant
androgen deprivation therapy and radical radiotherapy
in localized prostate cancer. Murthy BJU Int 97 476
1 month LHRHA depot (4-6)
25. Time to recovery of testosterone levels
after adjuvant androgen suppression
using an LHRHa
Single 3 month depot 9-13.6 months (median time to normal range)
Oefelein J.Urol 1998,
Dearnaley J.Urol 1999
2x3 month depot 15 months (median recovery time to baseline)
D’Amico Cancer 2007 Age related
2x3 month depot 7.5-9 months (recovery to normal range)
Gulley J.Urol 2005
3-6 x 1 month depot 13 week (median) (recovery to normal range)
Shahidi Clin Oncol 2001, 18 week 85%
Murthy BJU Int 2006/7 No fall over next 5 years
3-28 months. 1-3m depots 26% normal 6 month, 71% normal 12 month
Padula IJROBP 2002 Related to duration of therapy
26. Test set Validating set
MSK 1988-98 No. 1042 Cleveland 1986-98 No. 912
NAD 37% NAD 23%
Dose med 75.6Gy (65-86) Dose med 70Gy (65-78)
PSA 11.0 PSA 9.9
T3 23% T3 11%
28. No. 3264 median FU 51 Months
Low risk 21% Int Risk 51% High Risk 28%
30% androgen deprivation
Positive biopsy cores median 50% (29-67%)
End point biochemical failure
MV analysis independent parameters :
Age, PSA, GL,Stage, AD duration,RT dose (all p< 0.001)
%+ve biopsy cores p=0.01
inclusion increased c-index from 0.72 to 0.73
29. NB differences in relative importance of age,stage,GL,AD duration cf PSA
30. • 4 centres (PMCC,FCCC,WB,BCCA)
• 3666 patients 1198 PSA failures
• LR14%,IR 53%,HR 33%
• AD from 0-36 months (type not specified)
31. 66% risk reduction with 3ys vs no AD
56% of benefit
86% of benefit
99% of benefit
32. Magnitude of Effect of AD
Effect of AD duration independent of
duration dependant on dose
risk group except for T3 disease
33.
34. Questions for use of adjuvant
androgen suppression
• How long?
• Where is “dividing line” between
long and short course treatment?
• Are anti-androgens as effective?
• Predictive markers ??
• Can additional agents improve on
LHRHa alone? Abiraterone ??
35. J Clin Oncol 2009;27:3177-3184
• High MDM2 and Ki-67
expression levels
independently related to
distant metastases and
cause specific survival
• Previous studies suggest eg
Protein Kinase A,p53 and
Cox 2 expression related to
benefit of long term AD
42. A predictive marker for benefit of Dose
Escalation ? Osteopontin Expression
Morgan NCIC Conf 2009
MRC RT01 Patients treated at RMH in phase 3
trials of dose escalation
64Gy
74Gy
74Gy
64Gy
HR 1.41 (0.53-3.76) HR 0.42 (0.26-0.7)
P = 0.49 p = 0.001
43. • Aim to produce a marker panel to
individualise treatment
• ≥2150 samples for TMA
• Assessment of aprox 20 biomarkers for
prediction of dose and fraction size
sensitivity (and prognosis)
• Radiation response - cell proliferation,
hypoxia, DNA repair, DNA checkpoint
response , apoptosis – other prognostic
markers in CaP
44. CHHiP : Phase III Trial of Conventional or
Hypofractionated High Dose intensity Modulated
Radiotherapy in Prostate Cancer
Hypothesis: alpha/beta ratio in ca prostate may be low
Conventional 74Gy 37F 7.4w
Hypofractionated 60Gy 20F 4w
Hypofractionated 57Gy 19F 3.8w
NAD 3-6 months in intermediate/high risk patients
• 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 : ≥ 40 centres (n=3160)
45. CHHiP Trial
Centres and
Recruitment
Recruitment March’11
3110 out of 3160
115 pts/month-peak
42 Centres
48. Predictive Biomarker
Biomarker Positive Biomarker Negative
1.00 1.00
0.80 0.80
Progression Free
Progression Free
0.60 0.60
0.40 Shedule 2 vs Schedule 1 0.40 Shedule 2 vs Schedule 1
Hazard Ratio 0.5 Hazard Ratio 1.0
0.20 0.20
0.00 0.00
0 1 2 3 4 5 0 1 2 3 4 5
Years since Randomisation Years since Randomisation
• Biomarker Positive patients show a better
response to Schedule 2 than Biomarker Negative
patients
• Interaction RHR 0.5/1.0 = 0.5
49. How strong is the evidence of an
Interaction?
Z > 1.0 or Z < -1.0 P<0.32
Increasing evidence
Interaction RHR
Use Z = ______________
Z > 1.96 or Z < -1.96 P<0.05
SE
Z > 2.58 or Z < -2.58 P<0.01
Z > 3.3 or Z < -3.3 P<0.001
SCREENING STAGE
Evaluate Biomarkers in first half of samples
Only study biomarker in enriched stage if Z > 1.2 or Z < -1.2
ENRICHED STAGE
Evaluate qualifying Biomarkers in second half of samples
Of value if Z > 2.58 or Z < -2.58
50. Interaction RHR Z-values
RHR=0.5
80% chance of
significant
significance
Expected result
if RHR=0.5
Non -significant
RHR=1
75% chance of
hitting screening
boundary
Screening boundary
51. Additional Points
• Biomarkers may be either single factors or
composed of multiple factors
e.g. in breast cancer ER versus Oncotype Dx
• Statistical methods may be adjusted to allow
incorporation of results from similar studies
e.g. allow a biomarker through screening stage if
other studies suggest it is important.
53. Toward the optimal use of androgen suppression therapy in
the radiotherapeutic management of prostate cancer.
D’Amico JCO 2007 1 8
“Evidence is needed to determine
the minimum duration of AST that
provides the maximal prolongation in
overall survival while minimizing the
impact on HRQOL in an individual
man planning to undergo RT for
high-risk localized or locally
advanced prostate cancer”.