Predicting clinical and biochemicalendpoints before external radiotherapy  combined with hormonal treatment         Profes...
Increasing use of gonadotropin-releasing hormone agonists for thetreatment of localized prostate carcinoma Shahinian,Cance...
No. 517 1988-98 median FU 44monthsNAD median 5.5monthsRT dose 64GYPSA median 20ng/ml, T3/4 disease in 56%PSA failure 233 m...
Problems• PSA progression not a good endpoint as testosterone  suppression delays failure• Derived from datasets in academ...
Metaanalysis of homones and RT                Bria Cancer 2009 115 3446• 7 trials - 4387 patients - 3 long /4 short course...
Metaanalysis of hormones and RT Bria Cancer 2009 115 3446HR 0.76 for CSS and HR 0.86 for OS
RR 1.46
Combined modality treatment using androgen              suppression and radiotherapyPotential mechanisms 1) additive/syner...
Lancet epub
802 men median follow-up of 10·6 years3 months of NADTPSA progression HR 0·72 p=0·003          Distant prog        HR 0·89...
Local prog              CSS              OSMetastases
• 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%  A...
Lancet Oncol 2010 11 1066    EORTC 22863•   No.415 FU 9 yrs•   RT Pr (70Gy)/Pelvis (50Gy) +/-3yr adj AD•   High Grade T1/2...
Lancet Oncol 2010 11 1066                            NNT (10yrs) 4.0
Lancet Oncol 2010 11 1066                            NNT (10yrs) 7.0
Lancet Oncol 2010 11 1066                            NNT (10yrs) 4.0
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 ...
RTOG 92-02:Radiotherapy and duration of             androgen suppression                  No. 1554             Follow up 5...
Is biochemical response more important than duration      of neoadjuvant therapy hormone before RT :            analysis o...
Recovery of serum testosterone after neoadjuvantandrogen deprivation therapy and radical radiotherapy in localized prostat...
Time to recovery of testosterone levels        after adjuvant androgen suppression                   using an LHRHaSingle ...
Test set                  Validating setMSK 1988-98   No. 1042    Cleveland 1986-98   No. 912NAD 37%                   NAD...
Note overridingimportance of PSA                              Note all ≥T2b closeNote all GL ≥7 close                     ...
No. 3264 median FU 51 MonthsLow risk 21% Int Risk 51% High Risk 28%30% androgen deprivationPositive biopsy cores median 50...
NB differences in relative importance of age,stage,GL,AD duration cf PSA
•   4 centres (PMCC,FCCC,WB,BCCA)•   3666 patients 1198 PSA failures•   LR14%,IR 53%,HR 33%•   AD from 0-36 months (type n...
66% risk reduction with 3ys vs no AD56% of benefit       86% of benefit                     99% of benefit
Magnitude of Effect of AD                             Effect of AD duration independent ofduration dependant on dose      ...
Questions for use of adjuvant   androgen suppression• How long?• Where is “dividing line” between  long and short course t...
J Clin Oncol 2009;27:3177-3184                                 •   High MDM2 and Ki-67                                    ...
Biomarkers tested in RTOG radiotherapy trialsBiomarker    Study   No.     Prognostic       Predictive      Type  Ki67     ...
McCarthy J Clin Pathol. 2009 62 694–698
A predictive marker for benefit of DoseEscalation ? Osteopontin Expression                                 Morgan NCIC Con...
• Aim to produce a marker panel to  individualise treatment• ≥2150 samples for TMA• Assessment of aprox 20 biomarkers for ...
CHHiP : Phase III Trial of Conventional orHypofractionated High Dose intensity Modulated       Radiotherapy in Prostate Ca...
CHHiP Trial Centres and RecruitmentRecruitment March’113110 out of 3160115 pts/month-peak42 Centres
TransCHHiPStatistical Consideration Slides          CR UK CTSU
Expected TransCHHiP MaterialPatients in Trial                  3163Samples retrievable 80%            2530Evaluable Biomar...
Predictive Biomarker                                  Biomarker Positive                                                  ...
How strong is the evidence of an              Interaction?                                  Z > 1.0 or Z < -1.0          P...
Interaction RHR Z-values                                                                   RHR=0.5                        ...
Additional Points• Biomarkers may be either single factors or  composed of multiple factors  e.g. in breast cancer ER vers...
JCO 2003 21 3573-79
Toward the optimal use of androgen suppression therapy in  the radiotherapeutic management of prostate cancer.            ...
NY Prostate Cancer Conference - D. Dearnaley - Session 4: Predicting clinical and biochemical endpoints before external ra...
NY Prostate Cancer Conference - D. Dearnaley - Session 4: Predicting clinical and biochemical endpoints before external ra...
NY Prostate Cancer Conference - D. Dearnaley - Session 4: Predicting clinical and biochemical endpoints before external ra...
NY Prostate Cancer Conference - D. Dearnaley - Session 4: Predicting clinical and biochemical endpoints before external ra...
NY Prostate Cancer Conference - D. Dearnaley - Session 4: Predicting clinical and biochemical endpoints before external ra...
NY Prostate Cancer Conference - D. Dearnaley - Session 4: Predicting clinical and biochemical endpoints before external ra...
NY Prostate Cancer Conference - D. Dearnaley - Session 4: Predicting clinical and biochemical endpoints before external ra...
NY Prostate Cancer Conference - D. Dearnaley - Session 4: Predicting clinical and biochemical endpoints before external ra...
NY Prostate Cancer Conference - D. Dearnaley - Session 4: Predicting clinical and biochemical endpoints before external ra...
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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. 1. Predicting clinical and biochemicalendpoints before external radiotherapy combined with hormonal treatment Professor David Dearnaley Institute of Cancer Research/Royal Marsden Hospital
  2. 2. Increasing use of gonadotropin-releasing hormone agonists for thetreatment of localized prostate carcinoma Shahinian,Cancer 2005 1031615% of patients treated with LHRHa or orchidectomy within the first 6months of diagnosis over the time period 1991-1999.
  3. 3. No. 517 1988-98 median FU 44monthsNAD median 5.5monthsRT dose 64GYPSA median 20ng/ml, T3/4 disease in 56%PSA failure 233 menMultivariate analysisPSA, Histological grade , T stage, Age
  4. 4. 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
  5. 5. 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
  6. 6. Metaanalysis of hormones and RT Bria Cancer 2009 115 3446HR 0.76 for CSS and HR 0.86 for OS
  7. 7. RR 1.46
  8. 8. Combined modality treatment using androgen suppression and radiotherapyPotential mechanisms 1) additive/synergistic local effect 2) spatial co-operation Initial (neoadjuvant) Reduction in prostate volume androgen suppression Increased cell kill Normal tissue sparing with irradiation (rectum/bladder) Improved local control increased dose (conformal RT) Adjuvant androgen suppression Reduction in metastases Reduced RT complications Improved survival
  9. 9. Lancet epub
  10. 10. 802 men median follow-up of 10·6 years3 months of NADTPSA progression HR 0·72 p=0·003 Distant prog HR 0·89 p=0·55local progression HR 0·49 p=0·0005 CSM HR 0·86 p=0·40Event-free survival HR 0·63 p<0·0001 all-cause mortality HR 0·8 p=0·18 6 months of NADTPSA progression HR 0·57 p<0·0001 Distant prog HR 0·49 p=0·001local progression HR 0·45 p=0·0001 CSM HR 0·49 p=0·0008Event-free survival HR 0·51 p<0·0001 all-cause mortality HR 0·63 p=0·0008
  11. 11. Local prog CSS OSMetastases
  12. 12. • 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
  13. 13. 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%
  14. 14. Lancet Oncol 2010 11 1066 NNT (10yrs) 4.0
  15. 15. Lancet Oncol 2010 11 1066 NNT (10yrs) 7.0
  16. 16. Lancet Oncol 2010 11 1066 NNT (10yrs) 4.0
  17. 17. 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
  18. 18. RTOG 92-02:Radiotherapy and duration of androgen suppression No. 1554 Follow up 56m5 year results 4m AD 28m ADLocal failure 13% 6% p=.0001PSA control 21% 46% p=.0001Disease specific survival 87% 92% p=.07Overall survival 78% 79% NS BUTDSS Gl 8-10 (22% of cases) 78% 90% p=.007OS Gl 8-10 69% 80% p=.02 Hanks JCO 2003 21 3972
  19. 19. 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
  20. 20. Recovery of serum testosterone after neoadjuvantandrogen deprivation therapy and radical radiotherapy in localized prostate cancer. Murthy BJU Int 97 476 1 month LHRHA depot (4-6)
  21. 21. Time to recovery of testosterone levels after adjuvant androgen suppression using an LHRHaSingle 3 month depot 9-13.6 months (median time to normal range)Oefelein J.Urol 1998,Dearnaley J.Urol 19992x3 month depot 15 months (median recovery time to baseline)D’Amico Cancer 2007 Age related2x3 month depot 7.5-9 months (recovery to normal range)Gulley J.Urol 20053-6 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 years3-28 months. 1-3m depots 26% normal 6 month, 71% normal 12 monthPadula IJROBP 2002 Related to duration of therapy
  22. 22. Test set Validating setMSK 1988-98 No. 1042 Cleveland 1986-98 No. 912NAD 37% NAD 23%Dose med 75.6Gy (65-86) Dose med 70Gy (65-78)PSA 11.0 PSA 9.9T3 23% T3 11%
  23. 23. Note overridingimportance of PSA Note all ≥T2b closeNote all GL ≥7 close Small hormonal treatment effect
  24. 24. No. 3264 median FU 51 MonthsLow risk 21% Int Risk 51% High Risk 28%30% androgen deprivationPositive biopsy cores median 50% (29-67%)End point biochemical failureMV analysis independent parameters :Age, PSA, GL,Stage, AD duration,RT dose (all p< 0.001)%+ve biopsy cores p=0.01inclusion increased c-index from 0.72 to 0.73
  25. 25. NB differences in relative importance of age,stage,GL,AD duration cf PSA
  26. 26. • 4 centres (PMCC,FCCC,WB,BCCA)• 3666 patients 1198 PSA failures• LR14%,IR 53%,HR 33%• AD from 0-36 months (type not specified)
  27. 27. 66% risk reduction with 3ys vs no AD56% of benefit 86% of benefit 99% of benefit
  28. 28. Magnitude of Effect of AD Effect of AD duration independent ofduration dependant on dose risk group except for T3 disease
  29. 29. 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 ??
  30. 30. 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
  31. 31. Biomarkers tested in RTOG radiotherapy trialsBiomarker Study No. Prognostic Predictive Type Ki67 92-02 537 LF, DM, CSD LTAD Proliferative Mib-1 86-10 456 BF, LF, DM, CSM - ProliferativePKA type 1 86-10 108 DM, DSS - Proliferative BCL2 92-02 502 - LTAD Apoptosis BAX 92-02 502 BF (BC22+BAX-) Apoptosis P53 92-02 777 CSM, DM LTAD Cell repair P16 92-02 500 DM LTAD Cell repair Cox-2 92-02 586 BF, LF, DM LTAD ? STAT3 86-10 62 DM - Transcription
  32. 32. McCarthy J Clin Pathol. 2009 62 694–698
  33. 33. A predictive marker for benefit of DoseEscalation ? Osteopontin Expression Morgan NCIC Conf 2009MRC 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
  34. 34. • 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
  35. 35. CHHiP : Phase III Trial of Conventional orHypofractionated High Dose intensity Modulated Radiotherapy in Prostate CancerHypothesis: alpha/beta ratio in ca prostate may be lowConventional 74Gy 37F 7.4wHypofractionated 60Gy 20F 4wHypofractionated 57Gy 19F 3.8wNAD 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)
  36. 36. CHHiP Trial Centres and RecruitmentRecruitment March’113110 out of 3160115 pts/month-peak42 Centres
  37. 37. TransCHHiPStatistical Consideration Slides CR UK CTSU
  38. 38. Expected TransCHHiP MaterialPatients in Trial 3163Samples retrievable 80% 2530Evaluable Biomarkers 85% 2150Expected progressive disease 30% 645
  39. 39. Predictive Biomarker Biomarker Positive Biomarker Negative 1.00 1.00 0.80 0.80Progression 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
  40. 40. How strong is the evidence of an Interaction? Z > 1.0 or Z < -1.0 P<0.32 Increasing evidence  Interaction RHRUse 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<0.001SCREENING STAGE Evaluate Biomarkers in first half of samples Only study biomarker in enriched stage if Z > 1.2 or Z < -1.2ENRICHED STAGE Evaluate qualifying Biomarkers in second half of samples Of value if Z > 2.58 or Z < -2.58
  41. 41. 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 boundaryScreening boundary
  42. 42. 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.
  43. 43. JCO 2003 21 3573-79
  44. 44. 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”.

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