3/22/2014. Goals of this Presentation: in 15 min & 5 min Q & A. Radiotherapy for. Localized Prostate Cancer: What is New in 2014?

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1 3/22/ Goals of this Presentation: in 15 min & 5 min Q & A 1. Potency Preservation. a. Dosimetric considerations Radiotherapy for b. Drugs 2. Update on duration of short term ADT Mack III, MD Professor and Urology, Chair Radiation Oncology UCSF Localized Prostate Cancer: What is New in? March 22 nd 3:55-4:15 3. RP vs RT? 4. Salvage PPI: Who, how, results? 5. SBRT vs IMRT? Radiation Dose-Volume Effects and the Penile Bulb. et al. IJROBP 76: S , 2010 S132 I. J. Radiation Oncology d Biology d Physics 1

2 3/22/ Reliability Score: Potent sample 4: 100% 3: % 2: 50-75% 1: <50% 0: Not specified Potency evaluation 3: EPIC/SHIM 2: Other validated questionaire 1: Non-validate questionaire 0: Questionaire not specified Reliability Score (contd.): Dose ranges to PTV 4:Multiple contours & large range of doses 3:Single contourer & large range of doses 2:Multiple contourers but narrow range 1:Single contourer & narrow range 0:Prescribed dose range not specified Threshold effect with dose (e.g. > 50Gy) 1:Yes 0:No Penile Bulb Definition 2:Single observer or by consensus 1:Corpus spongiosum contoured by > 1 observer 0: Not specified Erectile dysfunction after radiotherapy for prostate cancer: A model assessing the conflicting literature on dose-volume effects del Campo, Thomas, Weinberg and Results of both reviewers, expressed in terms of the reliability score (max=14) (a) total from each study; (b) avg. score Duration of Short-Course Androgen Suppression Therapy and the Risk of Death As a Result of Prostate Cancer. D Amico et al. JCO 29: , 2011 PURPOSE: evaluated whether the duration of AST had an impact on the risk of PCSM in men with unfavorable-risk PC PATIENTS AND METHODS 761 men with unfavorable-risk PC were treated in Australia, New Zealand, Ireland, or the USA in a randomized trial with RT and 3, 4, or 6 months of AST... RESULTS: 6 vs 3 or 4 mos of AST was associated with a reduced risk of PCSM CONCLUSION: AST durations of no less than 6 mos should be considered when treating GS 7 PC with conventional dose RT. 2

3 3/22/ Cause Specific Survival Jones* vs D Amico** 8 Year Outcomes and Hazard Ratios PCS Survival RT+4 mo. vs RT RT+ 6 mo. vs 3/4 mo. Low Risk 98% 99% - - Intermediate Risk High Risk 98% 92% 92% 88% 95-97% 93-83% 85% 73% *RTOG 9408 NEJM vs **JCO 29: My Conclusions Are: 1. 4 mo. improves OS vs 0 for Int Risk (RTOG 9408, 8610?) 2. 3 a little worse (p=ns) than 6 or 8 mo. (TROG, Crook) 3. 4 ~ 8 or 28 (Armstrong, RTOG 9202) (why worse than 6?) 4. Therefore no evidence > 4 mo. required for Inter Risk Pts Radical Prostatectomy vs Radiation: you can t fool all the people all of the time The report by Sooriakumaran et al. joins a number of studies that conclude survival is better after prostatectomy (RP) than radiation (EBRT) [1 2]. These studies have several common features. They assume a cause and effect relationship between survival and treatment. They claim they corrected for confounders. They acknowledge suboptimal EBRT (e.g. dose and use of androgen deprivation therapy (ADT) [3]. They acknowledge limitations including potential unaccounted for differences between the groups. Then, they imply their findings are fact! Some ignore PSA data and level I evidence concerning the use of ADT and EBRT [3]. This brings to mind a saying: You can fool all the people some of the time, and some of the people all of the time, but you can t fool all the people all the time (Abraham Lincoln). You can fool all the people some of the time, Propensity scores can t correct for large effects due to unknown factors, when the populations are fundamentally different. Such adjustments can make things worse by allowing us to fool ourselves. If it takes 34,000 patients to show statistically significant differences, they may not be clinically significant. When baseline variables show large differences, it is very likely that there are other uncorrected differences, and some such as differences of the percentage people of + biopsies all of or the Gleason time, 4+3 vs 3+4 tumors. Patients chosen for surgery are very different as is shown by their baseline characteristics. The profound impact of these differences has been well documented [4 5]. Men treated with RP have a better survival than men without cancer and a lower risk of all causes of death. I wish they would stop trying to prove what only but a phase you III trial can t (which adjust fool for unknown all variables the people by randomization) all can the prove, time because, you can not fool all of the people all of the time and I am tired of writing this kind letter [2]. Mack III MD, FACR Professor Radiation Oncology and Urology Chair Department of Radiation Oncology UCSF Helen Diller Family Comprehensive Cancer Center 1600 Divisadero Street, Suite H 1031 San Francisco, Ca ; fax mroach@radonc.ucsf.edu (Abraham Lincoln) Sooriakuman et al. BMJ

4 3/22/ Conclusions about the BMJ study: Notion that propensity adjustment is 90 adequate is preposterous Non-randomized treatment & salvage 3. Misclassification and co-morbidities Baseline characteristics of pts too different 60 a. Can t adjust for % + biopsies 50 b. PNI 40 c. 4+3 vs Treatment not relevant 20 a. ADT with RT? b. No brachytherapy 10 c. No IGRT 0 Sooriakuman et al. BMJ 2004 Limits of Observational Data in Determining Outcomes From Cancer Therapy. Giordano et al. Cancer 112: (2008) Observation Non-Cancer Radiation Radical Prostatectomy Causes of Death After Prostatectomy at a Large Tertiary Center. Eifler et al. J of Urol 188: , 2012 Causes of Death After Prostatectomy at a Large Tertiary Center. Eifler et al. J of Urol 188: ,

5 3/22/ Results Salvage brachytherapy for recurrent prostate ca. Vargas et al. Brachytherapy 13:53-58, PURPOSE: s-brachy for recurrent CaP after EBRT. M&M: 69 pts Rx salvage brachy Bx+ > 2 yrs post RT Pd-103 was used with a prescribed pd90 of 100 Gy. 90% of pts ADT as part of their salvage therapy. Pts with PSA>5.0 ng/ml on ADT were considered CRPC. Pts on ADT >6mo pre s-brachy delayed therapy Pts retreated < 5 yrs after RT considered early failures RESULTS: med fu 5.0 yrs PSA control for low-risk pts ~ 86%, intermed-risk pts 75%, & high-risk pts 66%. 5-yr NED 74% non-crpc vs 22% for CRPC cases (<0.05). Gu Grade 3 toxicity of 8.7% CONCLUSIONS: A subset of failures after RT local in nature, and excellent control is possible with s-brachy. Results: bned Survival Aaronson et al. BJU Int 104: , 2009 Feasibility of MR Imaging /MR Spectroscopy-Planned Focal Partial Salvage Salvage Permanent Prostate Implant (PPI) for Localized Recurrence After Initial PPI for Prostate Cancer. Hsu, Hsu, Pickett IJROBP 2012 Salvage brachytherapy for recurrent prostate cancer. Vargas et al. Brachytherapy 13:53-58, 1. Phoenix definition too generous 2. Full dose Pd-103 why entire gland? 3. 90% ADT with PPI? 4. 6 mo. delayed? 5. < or = 5 years early 6. Excellent results? 5

6 3/22/ Proton versus intensity-modulated radiotherapy for prostate cancer: patterns of care and early toxicity. Yu et al. JNCI 105:25-32, k men; 553 (2%) PRT & 27,094 (98%) IMRT. PRT pts younger, healthier, & more affluent... Med: reimbursement $32 vs $18.5k for PRT & IMRT PRT associated with a reduction in GU toxicity at 6 mo. compared with IMRT (but not) at 12 mo. Conclusions: PRT is substantially more costly than IMRT, no difference in toxicity in a comprehensive cohort with prostate cancer at 12 months post-treatment. The truth is rarely pure and never simple Oscar Wilde, The Importance of Being Earnest, 1895, Act I Irish dramatist, novelist, & poet ( ) D Amico et al. JAMA 280: ,

7 3/22/ Take-home messages from review of Radiotherapy for CaP Spare the bulb and use drugs early! 4 mo (not 6 mo.) of ADT for Int. risk CaP RP vs RT don t be hoodwinked If you don t treat for Cure, you won t cure those you treat Salvage PPI is real but be very careful about who, how & expectations! Is SBRT really worse than IMRT? The devil is in the details 7