High Risk Localized Prostate Cancer Treatment Should Start with RT

Transcription

1 High Risk Localized Prostate Cancer Treatment Should Start with RT Jason A. Efstathiou, M.D., D.Phil. Assistant Professor of Radiation Oncology Massachusetts General Hospital Harvard Medical School 10 th Uro-Oncology Congress, Antalya Turkey October 27, 2011

2 Disclosures I have no conflicts of interest to disclose

3 Trends in practice patterns for primary localized prostate cancer: CaPSURE database (12,000 patients) AS 7%, RP 50%, EBRT 12%, Brachy 13%, Cryo 4%, PADT 14% Cooperberg et al JCO 2010

4 High-risk prostate cancer: The case for a radiation-based approach Principles: Contemporary radiation Effective local control Androgen deprivation Enhanced local control Reduction in distant metastases

5 Does EBRT Work? External radiation improves 10-year survival Scandinavian randomized trial SPCG-7 Widmark et al Lancet 2009

6 Scandinavian randomized trial SPCG-7 Widmark et al Lancet 2009 Locally advanced PCa 77% T3 23% T1-2 high-grade N=875 LHRH agonist External radiation Androgen antagonist Androgen antagonist Median FU 7.5 years

7 Scandinavian randomized trial SPCG-7 Widmark et al Lancet 2009 PSA recurrence

8 Scandinavian randomized trial SPCG-7 Widmark et al Lancet 2009 Cancer-specific survival Overall survival 12% gain at 10 years 10% gain at 10 years Hormones alone Hormones + EBRT Hormones alone Hormones + EBRT Clear and significant survival gains No QoL disadvantage

9 High-risk prostate cancer: The case for a radiation-based approach Would contemporary high-dose radiation be even better?

10 DOSE ESCALATION: Randomized phase III studies

11 High Dose Radiation in Prostate Cancer: Randomized phase III trials Trial stage n ADT Doses tested MDACC 2008 T vs 78Gy (3-D) PROG 2010 T vs 79Gy (3-D/P+) NKI 2008 T /+ 68 vs 78Gy (3-D) MRC 2007 T vs 74Gy (3-D) Hamilton 2005 T vs (HDR)

12 MDACC Patient Eligibility T1b-T3Nx-0 PSA stratified 10, 10-20, >20 ng/ml No ADT 70 Gy (n=150) vs 78 Gy (n=151) 4 field conventional technique followed by 3D conformal boost for the 78 Gy arm Follow-up: 8.7 years Kuban et al IJROBP 2008

13 MDACC: Updated Experience Significant Findings at 8 years 8 year FFPSAF Low Dose 59% High Dose 78% (p=0.004) PSA >10 FFPSAF (35%) Low Dose 39% High Dose 78% (p=0.001) Low Risk Patients (21%) Low Dose 63% High Dose 88% (p=0.042) High Risk Patients (34%) Low Dose 26% High Dose 63% (p=0.004) Local Control Low Dose 85% High Dose 93% (p=0.014) Distant Metastasis in High-Risk group Low Dose 17% High Dose 4% (p=0.035) CCS 95% vs 99% (p=0.063) OS 78% vs 79% (p=ns) Kuban et al IJROBP 2008

14 MDACC Improved cancer control through increased radiation dose Kuban et al IJROBP 2008

15 MDACC Improved DM-free survival with dose escalation in the high risk group Kuban et al IJROBP 2008

16 MRC n=843, T1-3, all received ADT 3-6mo 64 v 74 Gy Dearnaley et al Lancet Oncol 2007

17 PROG 9509 Latest analysis (Zietman et al JAMA 2005, JCO 2010) Median follow-up 8.9 years High dose 79.2Gy Conventional dose 70.2Gy

18 Dose Escalation: Summary Modest escalation in radiation dose improves freedom from biochemical, clinical and metastatic progression Level I evidence supports its use

19 Current Standard of Care Gy in Gy/fraction in fractions over 8-9 weeks Zietman et al. JCO 2010 Kuban et al. IJROBP 2008

20 What is the toxicity associated with dose escalation?

21 MDACC Significant Toxicity 10 year Grade 2 GI Low Dose 13% High Dose 26% (p=0.013) GU - Low Dose 8% - High Dose 13% 10 year Grade 3 Gl Low Dose 1% High Dose 7% (p=0.018) GU - Low Dose 5% - High Dose 4% Kuban et al IJROBP 2008

22 MDACC Randomized trial 301 men T1-3 tumors 70 vs 78Gy Median FU 8.7 years Higher chance for cure, higher risk of Gr 2+ rectal morbidity Kuban et al IJROBP 2008

23 PROG Zietman et al JAMA 2005, JCO 2010

24 PROG Zietman et al JAMA 2005, JCO 2010

25 PROG Cross-sectional quality of life study on long-term survivors Validated Prostate Cancer Symptom Index 83% questionnaire response Median follow-up 9.4 years Median age 76 years Talcott et al JAMA 2010

26 PROG 70Gy 79Gy Urinary obstr/irritn Bowel Sexual Symptom scales 0 = no symptoms 100 = maximal distress/dysfunction Talcott et al JAMA 2010

27 What are the QOL consequences of RT versus surgery?

28 Sanda et al NEJM 2008

29 Radical prostatectomies dark secrets Climacturia Penile shortening

30 Climacturia after Radical Prostatectomy all most rarely often occasionally Lee et al J Urol 2007

31 Penile Shortening after Radical Prostatectomy p = <0.01 p = <0.01 p = <0.01 ns Savoie et al J Urol 2003

32 Is hypofractionation possible in high risk disease (i.e. fewer, larger fractions)? Patient convenience Better resource utilization Lower treatment costs Potential for therapeutic gain

33 Recent Randomized Trial: Italian trial 2010 Phase III trial hypofractionated vs. conventional RT, single institution in Italy from High risk patients (GS 8-10, PSA >20, or 2 of the following: PSA 11-20, T2c or above, GS 7) All patients received 9-month course of ADT (combination of bicalutamide and LHRH agonist) Median follow-up 32 months Arcangeli et al. IJROBP 2010

34 Recent Randomized Trial: Italian trial Patients with Prostate Cancer Conventional RT 80 Gy in 40 fr 2.0 Gy / fr 3D-CRT Hypofractionated RT 62 Gy in 20 fr 3.1 Gy / fr 3D-CRT Arcangeli et al. IJROBP 2010

35 Recent Randomized Trial: Italian trial 2010 Freedom from Recurrence All patients 3 year FFBF 87% vs 79% (p=0.035) Freedom from Recurrence Very high risk patients Arcangeli et al. IJROBP 2010

36 Recent Randomized Trial: Italian trial 2010 Arcangeli et al. IJROBP 2010

37 Recent Randomized Trial: Italian trial 2010 Late Rectal Toxicity Grade 2 or Higher Late Urinary Toxicity Grade 2 or Higher 3 year incidence of G2 late complications: GI 17% vs 16% GU 14% vs 11% (p=ns) Arcangeli et al. IJROBP 2010

38 Extreme Hypofractionation How low can you go?

39 Widmark: Swedish Phase III Hypofractionation Trial Intermediate-High Risk Prostate Cancer 592 patients 78 Gy/ 2 Gy x Gy/ 6.1 Gy x7 Endpoint FFF

40 Radiation Offers New Cures, and Ways to Do Harm As Technology Surges, Radiation Safeguards Lag Radiation Therapy s Harmful Side A Pinpoint Beam Strays Invisibly, Harming Instead of Healing

41 Role of Androgen Deprivation In high-risk disease 3-6 months is better than 0 (RTOG 8610, TRUOG) 36 months is better than 0 (EORTC Bolla I) 24 months is better than 4 (RTOG 9202) 36 months is better than 6 (EORTC Bolla II) Hormones alone are inadequate without RT (Widmark) Duration of ADT in setting of dose escalation unknown

42 Does androgen deprivation allow radiation dose discounting? Randomized trial of 64 vs 74Gy in localized PCa Intermediate risk All received NADT Randomized by radiation dose Dearnaley et al Lancet 2007

43 Adverse Effects of GnRH agonists Loss of libido Vasomotor flushing Fatigue Anemia Osteoporosis Obesity Lipid alterations Insulin resistance Diabetes Cardiovascular disease

44 Concerns of Cardiac Mortality with ADT Study F/u (yrs) Events (n) Arms Crude rates of CV death p-value RTOG (Efstathiou JCO 2009) RT+ADT (indefinite) RT alone 11% 14% NS RTOG RT+ADT (4 mo) 14% NS (Roach JCO 2008) RT alone 11% RTOG RT+ADT (28 mo) 13.5% NS (Efstathiou Eur Urol 2008) RT+ADT (4 mo) 11% RTOG RT+ADT (4mo) 9.8% NS (Efstathiou ASTRO 2011) RT alone 10.7% EORTC ADT immediate 18% NS (Studer JCO 2006) ADT deferred 20% EORTC (Bolla NEJM 2009) RT + ADT (36 mo) RT + ADT (6 mo) 3% 4% NS Pooled-data RT+ADT (6mo) 7% NS (D Amico JCO 2007) RT alone 6%

45 RTOG 0521: Phase III Randomized Trial Localized High Risk Prostate Cancer 600 patients ADT + RT ADT + RT + Docetaxel x6 Primary endpoint Overall Survival

46 Closing Thoughts Mature prospectively collected and RCT data show that radiation therapy is effective treatment for high risk disease (lives are saved) with low rates of significant toxicity and good QOL Level I evidence supports dose escalation (>75Gy) to improve cancer control and hypofractionation is being investigated High risk disease mandates multi-modality therapy and we must look beyond technology to integrate new biology into RT