Permanent Seed Brachytherapy for Prostate Cancer Long Term Results. BCCRC Peter Grimm, DO Seattle Prostate Institute. Outline

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1 Permanent Seed Brachytherapy for Prostate Cancer Long Term Results BCCRC Peter Grimm, DO Seattle Prostate Institute Outline Brachytherapy Origins Outcomes/Comparisons Low Risk Intermediate risk High Risk Complications 1

2 1895: Rontgen s New Kind of Rays Transperineal Prostatectomy

3 Between 1904 and 1926, Young performed only 26 radical prostatectomies How did he treat his other prostate cancer patients? 1917 Young s First J Urology Article 3

4 Intraurethral & Intrarectal Radium Application Young s Radium Map 4

5 Young s Prostate Cancer Experience: 26 Radical prostatectomy's prostate brachytherapy patients Benjamin Barringer

6 6

7 Barringer Innovations Transperineal & Suprapubic implantation Transperineal biopsy Combined implant & ebrt Combined implant & castration Screening for prostate cancer Barringer Medal Outstanding Achievements in Urology 7

8 Detail of Reverse of Barringer Medal Cancer Death Rates*, for Men, Rate Per 100,000 Lung & bronchus Stomach Prostate Colon & rectum BC Prostate X Pancreas Leukemia Liver *Age-adjusted to the 2000 US standard population. Source: US Mortality Public Use Data Tapes , US Mortality Volumes , National Center for Health Statistics, Centers for Disease Control and Prevention,

9 Five-year Relative Survival (%)* during Three Time Periods By Cancer Site Site Prostate Rectum Urinary bladder *5-year relative survival rates based on follow up of patients through Recent changes in classification of ovarian cancer have affected survival rates. Source: SEER Surveillance, Epidemiology, and End Results Program, NCS , Division of Cancer Control and Population Sciences, National Cancer Institute, British Columbia Stats Prostate Cancer 3200 men diagnosed 550 Deaths (17%) Second lowest PCA death rate in Canada *In BC elevated mortality for business owners and managers, farmers and farm managers and school teachers* Occupational Risk Factors for Prostate Cancer Mortality in British Columbia, CanadaJane A. Buxton, MBBS 2, Richard P Gallagher, MA 1 2 *, Nhu D. Le, PhD 1 3, Pierre R. Band, MD, FRCP(C) 4, Joel L. Bert, PhD 51Cancer Control Research Program, BC Cancer Agency, Vancouver, BC Canada 9

10 Challenges in Comparing RP, EBRT and Brachytherapy No randomized studies No central pathology review Surgical studies drop + LN and + margin patients Different definitions of BRFS No PSA data for Robot RP LOW RISK Zelefsky PSA < 10 GS < 6 T1-T2b or D Amico Stage T1c, T2a and PSA level 10 ng/ml and Gleason score < 6 10

11 Overall Survival Typical 70 y/o SPI 37% Years Since Implant Seattle Prostate Institute 10/2007 Overall Survival Low Risk & T1-2 Group Average 70 Y/O 11 9*** **** ** * 1 + +* *2 Well Dif ** Mod Diff 5, *** Low Risk, **** Int Risk Age 60 at dx, GS 5-7; Age < 60 at dx, GS

12 10 yr Death rate due to PCA P = NS Tward et al. ( U Utah) Cancer 107 p P S A P R O G R E S S I O N F R E E Seeds Seattle Prostate Institute Surgery Johns Hopkins LOW RISK YEARS 15 Years 86% JHU (RP), Hernandez, et. al, JUROL 2007 Seattle Prostate Institute, Sylvester, Grimm, Blasko et. al, IJROBP

13 % Progression Free Low Risk Comparison PSA Progression Free 14** * P *** 9 Years +wd c CRYO + No TX HIFU P Protons *Hypofractionated ** HDR *** D 90 > 130 Gy wd= well Diff Grimm 11/07 % Progression Free Low Risk Comparison PSA Progression Free 25 14** * *** wd 18 Brachy Surgery 3 CRYO + No TX HIFU Years *Hypofractionated ** HDR *** D 90 > 130 Gy wd= well Diff 13

14 % Progression Free Low Risk* D Amico Robotic PSA RFS P Years wd Brachy Robotic Surgery NO PSA Data! 3 c CRYO + No TX HIFU P Protons *Hypofractionated ** HDR *** D 90 > 130 Gy wd= well Diff Grimm 11/07 % Progression Free Low Risk* D Amico PSA RFS P Years wd Brachy Surgery EBRT 3 c CRYO + No TX HIFU P Protons *Hypofractionated ** HDR *** D 90 > 130 Gy wd= well Diff Grimm 1/01/08 14

15 15 Year I 125 Monotherapy Seattle Prostate Institute Results 215 Patients treated I 125 implant 144 Gy (TG 43) Median follow up = 15.4 years 18 Year I 125 Monotherapy Patient Characteristics 215 Patients treated from T1 = 24% T2a = 61.6% Majority LOW RISK T2b = 13.6% T2c = 0.8% GS %, GS 6 42% Likely under-graded 15

16 Overall bpfs by PSA Control Definition POST 5 yr Rise PSA 92% Nadir % + SPI 2 Rises 85% Seattle Prostate Institute 2007 Is Current Technique Better? Merrick et al 10 Year 100 Progression-Free Survival (%) PSA % Low Risk 96.8% Median Follow-up 6.4 yrs Median PSA < Years Since Implant 16

17 Seattle Early Technique Pre Planned Pre Planned Loose Seeds Crude stabilization No Saggital Imaging No CT Dosimetry No Standard QA Connected Seeds Elegant Stabilization Saggital Imaging CT Dosimetry Standard QA Is Brachy Better than High Dose IMRT for Low Risk? Zelefsky ( MSKCC) ASTRO 2007 #1074 # Patients Dose 7 Yr brfs Sig Brachy Gy 98% <0.001 IMRT Gy median 88% <

18 Path Stage Positive Margin Rates Robot Prostatectomy Robotic Prostatectomy ct1c? pt2a 4 15% 1,2,3,4 pt2 b/c 11-19% 1,2, pt3a 29-37% 1,2,3,4 % Progression Free Low Risk Comparison PSA Progression Free 25 14** * *** wd 18 Brachy Surgery 3 CRYO + No TX HIFU Years *Hypofractionated ** HDR *** D 90 > 130 Gy wd= well Diff 18

19 Capsule Chao, et al. Clinicopathologic Analysis of Extracapsular Extension (ECE) in Prostate IJROBP; 65(4): , (William Beaumont) 19

20 Disease Outside Prostate? Disease Outside Implant/Surgery Volume? Implant /surgery Margin EPE Davis BJ, et al. Cancer. 1999;85:

21 External Beam Prostate SEEDS Treatment Margins Seattle Prostate Institute 2006 V100 V150 V 200 Prostate R 21

22 Focal Therapy Treatment of part of the Prostate - usually done only with Cryotherapy The Risk of PCa in another sextant, when found in one sextant is up to 80%* No Proof that focal therapy ( e.g. focal Cryotherapy) Works Bottom Line: Focal Therapy Unproven and should be only offered as a trial Problem with Cryotherapy 17% CaP abut the urethra* 84% of cases, urethra to CaP 5mm* Cryotherapy urethra warmer spares approximately 5 mm of tissue around urethra The five-year rate for non-rising postoperative PSA levels for low and medium risk patients ranged between 60 and 76 percent ** 22

23 P S A P R O G R E S S I O N F R E E Seeds Seattle Prostate Institute 80% Surgery Johns Hopkins 60% Intermediate Risk YEARS 15 Years JHU (RP), Hernandez, et. al, JUROL 2007 Seattle Prostate Institute, Sylvester, Grimm, Blasko et. al, IJROBP 2007 Progression Free Survival Intermediate Comparison % Progression Free Ď P % Brachy Surgery 25 EBRT & ADT EBRT & Seeds P Protons Years Grimm 11/07 23

24 P S A P R O G R E S S I O N F R E E EBRT & Seeds Seattle Prostate Institute 68% 15 Years High Risk Surgery Johns Hopkins 40% JHU (RP), Hernandez, et. al, JUROL 2007 Seattle Prostate Institute, Sylvester, Grimm, Blasko et. al, IJROBP 2007 Should I have Protons? Is it Superior Treatment to Brachytherapy? 24

25 Brachytherapy vs High Dose Proton Boost CASE Matched bned ASTRO w/o backdating Low risk 89% Intermediate risk 94% 94% 84% P=0.34 P = 0.85 Years 5yr Years 5yr Zietman et al MGH Seattle Mtg 2006 Is There any Proven Complication Advantage to Protons? NO Late GU Complications Trial Dose MDAH 78.0 Gy 3D RTOG 79.2 Gy 3D MSKCC 81.0 Gy IMRT PROG 79.2 Gy Protons Gy safely delivered with 3D photons, IMRT, or protons Zietman et al MGH Seattle Mtg

26 High Risk Comparison PSA Progression Free % Progression Free Surgery 13 EBRT Brachy EBRT & ADT EBRT Seeds Years Grimm 11/07 EBRT Seeds + ADT Is Local Failure a Problem for Surgery or EBRT in High Risk prostate cancer patients? Yes Modality Local failure rate Lerner radical prostatectomy 29% (J Urol 1995:154:1447) Van den Ouden radical prostatectomy 44% (J Urol 1998: 160: 1392) Laverdiere EBRT 65% (IJROBP 1997: 37: 247) Zelefsky EBRT 37% (J Urol 2001: 166: 871) 26

27 Radical Prostatectomy and High Risk **MSKKC Gleason 8-10 on Biopsy 10 yr brfs 39% T1c 58% were downgraded to GS 7 or less *Johns Hopkins Gleason 8-10 on Biopsy Overall 10 yr brfs 27% Favorable (-margins,organ confined- 50% Bottom Line: Surgery Alone should not be recommended for High Risk Patients *Cancer 2006, Aug 9 **J Urol 2006 sep; 176(3) FREEDOM FROM PSA FAILURE: HIGH RISK PATIENTS 83% HT & EBRT & SEEDS Note: 78% fail within 3 years Stock Stone

28 Brachytherapy Exercises 28

29 Seattleprostate.com ProQura.com Predicting Disease Outside Margin with Partin Tables Gleason < 6 =LN + SV + (EPE X 0.25) Gleason >7 =LN + SV + (EPE X 0.50) *Epstein J, et al J Urol Vol ,

30 Low Risk Patients ERA of Treatment Freedom from PSA Failure Late Era Early Era P< Years High Risk Prostate Cancer Stock and Stone patient High risk definition 2 or more of the following intermediate risk features: PSA 10 20, stg t2b, Gleason score 7 1 or more high risk feature: PSA > 20, stage t2c t3, Gleason score 8-10, positive seminal vesicle biopsy All patients treated with combined modality therapy: 9 mos of hormonal therapy Partial PD-103 or I-125 implant EBRT: 45 Gy 30

31 High Risk Prostate Cancer Stock and Stone patients All patients treated with combined modality therapy: 9 mos of hormonal therapy Partial PD-103 or I-125 implant EBRT: 45 Gy Secondary Bladder Ca Tx AGE 5 yr 10 Yr Critz EBRT & Seeds 0.7% 1.5% Seer No RT 60 y/o 0.94% No RT % Seattle Seeds 69 y/o avg EBRT & Seeds 69 y/o avg 1.6% 3.6% 31

32 Is Current Technique Better? Mt Sinai Stock, Stone % Low Risk 85% 77% Freedom from PSA Failure P< Years % Progression Free Is Brachy Better Than IMRT? Low Risk 25 14** * *** wd 18 Brachy EBRT 3 CRYO + No TX HIFU Years *Hypofractionated ** HDR *** D 90 > 130 Gy wd= well Diff 32

33 UCSF Results EBRT vs Seeds Roach unpublished presented 3/4/07 Seattle Seeds EBRT PSA < % 50% ASTRO 5 Yr 93% 76% No PCA on Spec MRI 93% 40% Is Brachy Better than High Dose IMRT for Low Risk? Zelefsky ( MSKCC) ASTRO 2007 #1074 # Patients Dose 7 Yr brfs Sig Brachy Gy 98% <0.001 IMRT Gy median 88% <

34 Capsule Chao, et al. Clinicopathologic Analysis of Extracapsular Extension (ECE) in Prostate IJROBP; 65(4): , (William Beaumont) 34

35 Robot vs Standard Prostatectomy Study RP/LRP/ RALP Pos Margin PSA Outcome U Texas 1 169/111/0 No Diff No Diff Detroit 2 100/50/565 No Diff Better UC Irvine 3 60/0/60 No Diff No Diff INTERMEDIATE RISK Zelefsky 1 Risk Factor or D Amico Stage T2b or Gleason score of 7 or PSA level >10 and 20 ng/ml 35

36 Progression Free Survival Intermediate Comparison % Progression Free 15 Ď P % Brachy Surgery 25 EBRT & ADT EBRT & Seeds P Protons Years Grimm 11/07 Intermediate Comparison PSA Progression Free % Progression Free Brachy EBRT Surgery EBRT & Seeds Years 36

37 HIGH RISK Zelefsky 2 Risk Factors PSA > 10,GS > 7, > T2c D Amico Stage T2c or PSA level >20 or Gleason 8-10 High Risk Comparison PSA Progression Free % Progression Free Surgery 13 EBRT Brachy EBRT & ADT EBRT Seeds Years Grimm 11/07 EBRT Seeds + ADT 37

38 HIGH RISK % 62% 52% 42% 25% * Seattle Prostate Institute High Risk of Local Failure Surgery or EBRT Modality Local failure Lerner radical prostatectomy 29% (J Urol 1995:154:1447) Van den Ouden radical prostatectomy 44% (J Urol 1998: 160: 1392) Laverdiere EBRT 65% (IJROBP 1997: 37: 247) Zelefsky EBRT 37% (J Urol 2001: 166: 871) 38

39 High Risk Comparison PSA Progression Free % Progression Free * ** SURGERY Years 6 29 EBRT Seeds +ADT EBRT & ADT EBRT Seeds EBRT Seeds + ADT Conclusions Low Risk Long Term Brachytherapy PSA control is Better than Surgery and IMRT Robotic Prostatectomy likely not to be better Low Intermediate Patients Seed implantation Better than Surgery, IMRT EBRT Other Intermediate External beam and Seeds Better than EBRT and Surgery High Risk PSA Combination EBRT seeds and HT may be best approach for Long term PSA control 39

40 Brachytherapy QA Side Effects Complications QUALITY OF LIFE Side Effects 40

41 IPSS Rate of IPSS resolution pts who normalized IPSS Year 60% of all pts normalized IPSS Keyes et al BCCA ESTRO 2006, Leipzig CARO 2006, Calgary 41

42 Change in IPSS symptoms Rise above baseline Months IPSS 16% (# 117) 84% (# 607) Keyes et al BCCA ESTRO 2006, Leipzig CARO 2006, Calgary P=<

43 Effect of hormonal manipulation on I-PSS normalization Merrick et al Prophylactic vs. Therapeutic Alpha Blockers: Differences in I-PSS values over times Merrick et al 43

44 Incontinence Incontinence Validated Questionnaire Unbiased Author Surgery Seeds Talcott et al JCO Nov

45 TURP Post Brachytherapy and Urinary Incontinence Ref. No. Pts % Retention % Incontinence TURP No TURP Stone et al Blasko et al Wallner et al Dattoli et al Kaye et al Sexual Dysfunction Erectile Dysfunction Dependent on pre implant function Rehabilitation? Ejaculation fluid Almost all patients experience a decrease in fluid Climaxability Almost all patients can climax Fertility Seeds not a Contraceptive! 45

46 Sexual Dysfunction Validated Questionnaire Unbiased Author Talcott et al JCO Nov Brachy Potency Preservation 46

47 Potency Preservation: With and Without Sildenafil Support Potency Preservation: Full vs Partial Preimplant Potency 47

48 Potency Preservation: Monotherapy vs XRT plus implant Potency Preservation: Age 48

49 Strictures Strictures Tx F/u Comment Crook Seeds 4 yr 1.3% Matthews Seeds NS 4.5% Keyes Seeds NS 1.0% Merrick Seeds NS 5.0% Related to Urethra dose 49

50 Obstruction/Irritation Validated Questionnaire Unbiased Author Talcott et al JCO Nov Retention Requiring Temporary Catheter 50

51 TURP or Retention Requiring Temporary Catheter Tx F/u Catheter TURP Crook Seeds 4 yr 3.4% 0.4% Seattle Seeds 5yr 4% <1.0% Keyes Seeds 4.8 yr - <2.0% Merrick Seeds 3.0% Matthews Seeds 5yr 7.5% <1.0% Mean dysuria frequency score 51

52 Bowel Problems Validated Questionnaire Unbiased Author Talcott et al JCO Nov Prospective Validated Questionnaire Rectal bleeding Highly dependent on rectal dose Onset peaks at 8-24 months Usually self-limited Incidence 5-12% Usually resolves spontaneously 52

53 Rectal Bleeding/ Ulceration after Brachytherapy Alone Shah % Waterman 98 10% Han 111 1% Gelblum % Kang 58* 1.5% Wallner % Merrick % ** Rectal Ulcer/Bleeding Only 2 pts had bleeding requiring pads 58 implant alone 76 combined * *represents the difference between pre and post implant bleeding Rectal Bleeding/ Ulceration after EBRT and Brachytherapy Han 36 14% Gelblum % Kang 76* 1.5% Wallner % Lee % Merrick 95 14% ** Rectal Bleed/ Ulcer Only 2 pts had bleeding requiring pads 58 implant alone /76 combined * *represents the difference between pre and post implant bleeding 53

54 Rectal Fistulas after Implant Alone Patients Rectal Fistulas Howard/Wallner % Gelblum 825 0% SPI > % Kang 58 0% Wallner % Waterman 98 0% Rectal Fistulas after EBRT and Seeds Patients Rectal Fistulas Howard/Wallner % Gelblum 825 0% Kang 76 0% SPI > % Lee % 54

55 Rectal Injury Surgery Patients Lu-Yao-Medicare 93, % Lepor % Hisasue et al % Gillitzer % Gaylis % Lerner ( Mayo) % Serious Rectal Injury Secondary Cancers 55

56 Rectal Ca and EBRT Studies SEER 9 Regs Release 4/2004 #1 (Neugut) study 1997 No Association #2 Movsas 1998 No Association #3 Keinerman No Association #4 Grady 2005 (Seer) Increased Risk #5 Baxter 2005 Increased Risk over surgery Kendal (Seer) 2006 No Association Age most important factor Incidence of Rectal Cancer Proportion cancer free Surgery EBRT RP XRT Years from initial treatment Baxter, et al Gastro

57 Secondary Rectal Cancers Baxter RP 16% 10 Year Gutman Brachy 15% Seattle Seeds +/- EBRT 0.6% Critz Seer Data Seer Data Secondary Bladder Ca Tx AGE 5 yr 10 Yr EBRT & Seeds 0.7% 1.5% No RT <60 y/o 0.94% No RT y/o 2.42% Seattle Seeds 69 y/o avg 1.6% Seattle EBRT & Seeds 69 y/o avg 3.6% 57

58 Lap Radical Prostatectomy City of Hope Experience Intra-operative Complications Ureteral injury 3 (0.1%) Rectotomy 4 (0.2%) Enterotomy 1 (0.1%) Conversion 3 (0.1%) Kawachi Presented in Seattle 04/07 Lap Radical Prostatectomy City of Hope Experience Post-Operative Complications Rectal-Urethral fistula 2 (0.1%) Prolonged anastamotic leak 21 (1.3%) Enterocutaneous fistula 1 (0.3%) Bladder neck contracture 11 (0.6%) Transfusion 14 (0.9%) Kawachi Presented in Seattle 04/07 58

59 Bottom Line: No Matter What You do, Sometimes Things go Wrong 59

60 Conclusions The Largest Impact We have on Prostate Cancer is Finding it Early Screening will save more lives than better treatment Brachytherapy Failures 60

61 Proportional Hazards Model Definitely irradiated Potentially irradiated Nonirradiated HR p-value HR p-value HR p-value Age at diagnosis < < < < <0.001 Baxter, et al Gastro 2005 Local Failure after Brachytherapy Rare % in Low risk patients If PSA failure 35% will have + biopsy 46% if brachy alone, 0% if EBRT, Brachy and ADT If PSA failure and implant Satisfactory 22% Positive biopsy rate Stock, Stone, Int J Rad Onc Biol 64, ,

62 Selection for Salvage Therapy Negative or No biopsy Distant disease Gleason 7-10 PSA > 10 ng/ml Life Expectancy <5yrs Disease free < 2 years PSA DT < 6 months Positive biopsy Negative metastatic w/u Gleason 2 6 PSA < 10 ng/ml Life expectancy >10 yrs Disease free > 2 years PSA DT > 9 months Brachy Salvage for EBRT/Brachy Failures Suh MGH ASTRO 2007 # pts LR after EBRT 12 after Brachy MPD 137 gy Med F/u 47 mo PSA control 705 at 4 years 30% G 3-4 GU/Gi toxicity 13% fistula rate Conclusion: Feasible but not with out risk 62

63 RP Salvage for EBRT Failures Gaston et al ( MDA ) AUA 2007 # pts LR after EBRT No intra operative complications 10% major post op Blood loss avg 1250 cc No deaths 57% incontinent 76% brfs Conclusion: Open RP successful but sig risk of incontinence LapRP Salvage for EBRT/Brachy Failures Viterbo et al ( City of Hope ) AUA 2007 # pts LR after EBRT 10/20 robot Operating time med 228 minutes Blood loss avg 200 cc No deaths No conversions to open Positive margins 2/20 PSA control <0.1 15/20 Conclusion: Feasible with good initial results Incontinence rate? 63

64 Accurate Stratification of Colorectal Cancer Risk Elucidation of implicated factors Genetic Family history of polyps and cancers Environmental High BMI High fat diet Prostate Cancer may share the same influences 64

65 Prostate and Rectal Cancers 10 Year cumulative incidence of Prostate Cancer 10.7% with colorectal cancer 3.8% without colorectal cancer Ozden, et al Int J Gastroint Cancer 2003 Prostate and Rectal Cancers 44% of patients with second primary malignancies after CaP had colorectal cancer. Mydlo, et al Urol

66 Radiation-induced Solid Malignancies Latency period of 5-15 years Linear increase in cancer risk with doses up to 4 Gy followed by plateau or decrease Hall and Wuu, IJROBP 2003 Increased Risk of Rectal Cancer after Prostate Radiation SEER registry data Mean follow-up 9.3 years Minimum follow-up 5 years 85,815 patients 55,263 RP 30,552 XRT Baxter, et al Gastro

67 Colorectal Cancer Sites RP-only XRT # cases (%) # cases (%) irradiated (rectum) 143 (0.26) 124 (0.40) potentially irradiated (rectosigmoid, sigmoid, cecum) 437 (0.79) 249 (0.81) non-irradiated (remainder of colon) 324 (0.59) 160 (0.52) total 904 (1.64) 533 (1.74) Baxter, et al Gastro 2005 Patient Characteristics Age at diagnosis (years) RP-only (%) XRT p-value mean <0.001 < % 9.0% % 40.0% % 51.0% Baxter, et al Gastro

68 Proportional Hazards Model Definitely irradiated Potentially irradiated Nonirradiated HR p-value HR p-value HR p-value Treatment RP-only XRT 1.70 < Baxter, et al Gastro 2005 SEER Registry Data Shortcomings: Absolute RR for rectal cancer more closely related to patient age than treatment approach Absence of information regarding Target volume Radiation does Fractionation scheme Radiation source 68

69 Temporal Relationship Between Prostate Brachytherapy and the Diagnosis of Colorectal Cancer Brachytherapy Study Population 1351 consecutive patients Mean age at brachytherapy 66 years Median follow-up 4.8 years Median Gleason Score 7 Median pre-treatment PSA 6.7 ng/ml (mean 8.3ng/ml) Supplemental therapies XRT 699 (51.7%) ADT 531 (39.3%) Gutman, et al

70 Routine GI Surveillance All patients with post-brachytherapy rectal bleeding undergo colonoscopy Since 2001, all patients undergo colonoscopy within 18 months of brachytherapy if colonoscopy had not been performed within 4 years of brachytherapy Colorectal Cancer Status # cases No colorectal cancer Pre-treatment colorectal cancer Post-treatment colorectal cancer Gutman, et al

71 Colorectal Cancer Status No difference in clinical, treatment, or dosimetric parameters between the 3 cohorts except colorectal cancer patients presented with higher clinical stage ( T2c, p=0.001) Gutman, et al 2006 Distribution of Colorectal Cancer Location Count Pre-treatment Colorectal Cancer (n = 23 ) Clinical Stage (mean) Post-Treatment Colorectal Cancer (n = 25 ) Count Clinical Stage (mean) Rectum 3 T2 4 T2 Sigmoid 4 T2 6 T2 Colon 16 T2 15 T2 Gutman, et al

72 Incidence of Rectal Cancers Baxter, et al (Gastro 2005) 16% in RP-only cohort Ikeda, et al (Am J Gastro 1998) 31% in non-cap patients Gutman, et al (2006) 15% in brachytherapy patients Number of Patients Developing Colorectal Cancer Over Time 6.00 Number of cases sigmoid cancer colon cancer rectal cancer Time from implant (years) Gutman, et al

73 Relationship Between Colorectal Cancer and Supplemental XRT Colorectal Cancer # Cases # Supplemental XRT Pre-brachytherapy Post-brachytherapy Gutman, et al 2006 Significant Predictors for Post- Brachytherapy Colorectal Cancer by Cox Regression Analysis Parameter Multivariate RR 95% C.I. Prostate D /1.053 Gutman, et al

74 Post-Brachytherapy Colorectal Polyps Distribution of Post-Brachytherapy Colorectal Polyps Location Post-Treatment Colorectal Polyps (n = 192 ) (%) Rectum 27 (14.1) Sigmoid Colon 62 (32.3) Colon 103 (53.6) Gutman, et al

75 Post-Brachytherapy Rectal Polyps Total # 27 5 limited to rectum 22 associated with sigmoid and/or colon polyps Gutman, et al 2006 Distribution of Colorectal Polyps McCashland, et al Gutman, et al (Am J Gastro 2001) (2006) Site Incidence (%) Incidence (%) Rectum Sigmoid Colon

76 Number of Patients Developing Post- Implant Colorectal Polyps Over Time 60 Rectum polyp Recto-sigmoid polyp Colon polyp Number of cases Time from implant (years) Gutman, et al 2006 Significant Predictors for Post- Brachytherapy Rectal Polyps by Cox Regression Analysis Parameters Multivariate RR 95% C.I. Age at implant /0.986 % positive biopsies < /1.037 hypertension /5.101 Gutman, et al

77 Significant Predictors for Post- Brachytherapy Sigmoid and Colon Polyps by Cox Regression Analysis Parameters Multivariate RR 95% C.I. Age at implant /0.985 Planning volume /1.034 XRT /2.393 Gutman, et al 2006 Conclusions In brachytherapy patients Colorectal cancer was diagnosed with equal frequency prior to and following treatment with comparable stage and geographic distributions. Peak incidence of colorectal cancer and polyps one year following brachytherapy was a result of intense post-prostate cancer surveillance. Studies without intensive post-treatment surveillance for rectal cancer are likely to falsely attribute some of the malignancies to radiation. 77

78 Secondary Rectal Cancers after Radiation Factors that influence risk of radiation induced malignancies Hall et al IJROBP Vol.56,No.1pp83-88,2003 Dose rate effect- fractionated and low dose rate radiation result in a lower risk of carcinogenesis (A-bomb survivors vs radiologists) Animal and human data show a linear increase in risk of cancer with doses up to 4 Gy, after that the risk either plateaus, decreases rapidly or slowly 78

79 Criteria to Establish Causality 1. Strong Association in order to reduce confounding influences 2. Consistently evident between observers SEER Secondary Rectal Ca > 5yrs Kendal Int J Rad Onc Bio Phys Vol 65 p AGE Surgery EBRT Neither < NS NS NS NS NS 79

80 Secondary Cancers Baxter RP 16% 10 Year Gutman Brachy 15% Seattle Seeds +/- EBRT 0.6% Summary Secondary Rectal Cancers Causality has not been not been established between RT and Rectall Ca Age is the most important predictor of risk The older the greater the risk There is no statistical difference between RT and Surgery patients 80

81 Radiation Induced Malignancies John Sylvester M.D. Seattle Prostate Institute at Swedish Medical Center Radiation Carcinogenesis: Observations Hall et al IJROBP Vol.56,No.1pp83-88,2003 Data from A-bomb survivors and medically exposed individuals Increase incidence of carcinoma of GI tract, Thyroid, Breast and Bladder is linear with dose up to ~ 2.5 Gy Radiation therapy is associated with an increased risk of carcinomas (often at sites distal to xrt fields) and of sarcomas in-field in high dose areas 81

82 Radiation therapy induced cancers Carcinomas in and out side of xrt fields Sarcomas in-field in high dose areas (not seen in A-bomb survivors Variation in risk (young 15x higher risk than middle age patients) Radiation Therapy induced cancers XRT pts increased risk for 2 nd cancer due to genetics and lifestyle (Tobacco, obesity, old age) Large studies show a Statistically significant, but very small increase risk (in long term survivors) in radiotherapy versus surgical patients Data on Prostate and Cervix cancer patients apply 82

83 Second Malignancies in prostate cancer patients after radiotherapy compared to surgery Brenner et al Cancer 2000;88: Used SEER data and compared risk of second cancers in surgical and radiotherapy patients (EBRT) Relative risk of 2 nd cancer was 6% greater with ebrt vs surgery at any time Maximum increased RR was 34% at 10 years Bladder a 77% increase at > 10 years Rectum a 105% increase at > 10 years Sarcoma a 145% increase at > 5 years Bladder cancer risk after radiotherapy In radiotherapy data (prostate and cervix) all of the bladder received a significant dose RR of bladder cancer at 10 years is 1.8 after prostate ebrt (48-67 Gy to bladder) RR of bladder cancer at 10 years is 5 after cervix ebrt/brachy (30-80 Gy to bladder) RR stable between 2-80 Gy 83

84 How you MIGHT decrease risk Treat smaller volume Fractionate or use low dose rate radiation Use combination ebrt + seeds only when seeds alone not a good option Think twice about IMRT Think twice about IMRT Welsh et al Technol Cancer Res Treat Apr;4(2) Hall et al IJROBP Vol.56,No.1pp83-88,2003 Increased number of fields: increases the volume of normal tissue exposed to low dose (carcinogenic) radiation (RR ~ 0.5%) Increased leak and scatter due to increase in monitor units (RR ~ 0.25%) Thus, about a doubling of second cancers predicted with switch to IMRT 84

85 What does this mean? Bladder Carcinoma and Other second Malignancies after Radiotherapy for Prostate Carcinoma Neugut et al Cancer April 15, 1997 Vol. 79 No. 8 SEER data (Surveillance, Epidemiology and End Results Program) 34,889 prostate cancer pts had xrt 106,872 prostate cancer pts did not RR of bladder cancer 1.5 at 8 years in pts receiving xrt RR 1.0 in the others No increased risk of rectal cancer, leukemia's 85

86 Why increased risk cancers? Radiation induced cancers Radiation patients are older Radiation patients more unhealthy smokers Radiation caused hematuria so some incidental cancers found due to cystoscopy for xrt cystitis RR versus actual risk to patient Actuarial risk is 0.19% per person-year (no RT) Actuarial risk is 0.26% per person-year (with RT) So radiotherapies increased risk (>0.07% per person year = 0.7% risk at 10 years) is statistically significant, but perhaps not clinically significant (to most pts) RP has ~ 3% risk of PE, and a < 0.2% risk of death 86

87 Radical Cystectomy for Bladder Cancer after Definitive Prostate Cancer Treatment Schuster et al. Urology 61 (2),2003: University of Michigan patients received radical cystectomy 12 had prior radical prostatectomy for CaP 17 had prior radiotherapy for CaP 5 (17%) had an orthotopic neobladder diversion 2 had RT and 3 had RP Fibrotic scarring and desmoplastic reaction was seen in both the RT and RP patients. RT patients: more obliteration of tissue planes RP patients had a more difficult urethrovesical dissection Second malignancies following prostate brachytherapy 7,148 men treated with brachytherapy followed by EBRT (by Critz since 1984) 29 developed bladder cancer s/p treatment 0.7% risk at 5 years 1.5% risk at 10 years Median follow = 3 years 4 invasive (2 died), 25 superficial treated with intra vesicle therapy none progressed to invasive 87

88 Does the Risk of Secondary Malignancies Exclude Young Men from Brachy? Seattle Series Secondary Cancers Total of 345 patients, Med f/u = 9.4 & 11 yrs patients treated with ebrt + seeds patients treated with I 125 monotherapy Follow-up involved SEER data base, chart reviews and telephone calls in 2005 Second Bladder or Rectal cancer considered radiation induced if 88

89 Seattle Second Malignancies 12/345 Patients developed secondary cancers 2/122 I 125 monotherapy patients (1.6%) 10/223 EBRT + I 125 /Pd 103 patients (4.48%) 2/122 I 125 monotherapy (1.6%) bladder cancer 8/223 EBRT + I 125 /Pd 103 (3.6%) bladder cancer SEER Data Incidence of TCCA/100,000 men years old = years old = years old = years old = years old =

90 Risk of Bladder Cancer: SEER vs Seattle Brachytherapy Data SEER: probability of Bladder Ca: 0.94% at 10 years for a 60 year old Seer: 2.42% risk of men age year old developing bladder cancer Seattle brachytherapy patients average age 69 at treatment. Median follow-up 10 years -2.9% developed bladder cancer -1.6% on I 125 monotherapy patients -3.6% of EBRT + I 125 /Pd 103 patients Treatment of second cancers 10 Bladder - 2 unknown - 1 cystoprostatectomy - 7 TURBT +/- BCG or IVC 2 Rectal - 1 pre-op chemo/xrt-lar: did well - 1 cancer in rectal fistula - APR 90

91 Summary SEER and institutional reports indicate that radiotherapy increases the risk of secondary malignancies (especially bladder) 8+ years after treatment Volume treated to > 2-4 Gy related to risk The increase is statistically significant The main risk is bladder cancer For the individual patient the risk is ~ 0.07% per year higher than RP patients risk When a secondary Bladder cancer occurs it can usually be treated with TURBT Salvage Brachytherapy for Prostate Cancer David C. Beyer, M.D., F.A.C.R. Arizona Oncology Services Phoenix, Arizona 91

92 The Four Questions Can we identify patients most likely to require treatment? Can we identify patients most likely to respond? What is expected morbidity? What other options should be considered? Cryo Salvage for EBRT Failure? Abelhady et al ( London) ASTRO #

93 Magnitude of the Problem 190,000 new prostate cancer cases in US 80% of prostate cancer localized at diagnosis 30% of patients receive XRT Two-fold increase in radiation for young men 10%-50% recurrence (based on risk groups) 13,500 US patients annually with recurrence following XRT Jemal et al, CA: Cancer J Clin 52:23-47, 2002 Age Health Who needs treatment? Risk of competing mortality Risk of distant disease 93

94 Recurrence post RT Diminish 5 year survival from 89% to 66% after clinical recurrence Kuban, et al Cancer 63: , year OS 65% and CSS 76% after PSA failure Documented local recurrence 26% Distant metastases 47% Lee et al J. Clin. Onc. 15: , 1997 PSA Failure Following XRT Median age ~ 73 years Half of deaths unrelated to prostate cancer 10 year cause specific survival 92% low risk 72% intermediate risk 44% high risk D'Amico et al, J Urol 169: ,

95 CSS from PSA Failure: Benefit to Early Hormone Therapy Kestin, Vicini, Martinez; IJROBP, 2004, 60(2): Cause Specific Survival From Failure PROBABILITY Favorable Intermediate and Unfavorable P= YEARS 95

96 Recurrence post Surgery After PSA failure Median time to metastasis 8 years Median time to death (after metastasis) 5 years Highly selected population Age Stage, grade, etc. Pound et al, JAMA 281: , 1999 PSA Kinetics Indicates Distant Disease? Failure after Radical Prostatectomy Interval from surgery <24 months (Pound) Doubling time <5, <6, <9 months Various series (Partin, Pollack, Hanks) 96

97 Effect of PSA dt from Failure: 544 Patients Kim-Sing, Pickles, IJROBP 2004, 60(1): Impact on CSS Univariate Multivariate PSA dt < Time of Interventio n < Early Adverse!! Gleason < PSA Neoadjuvant Kim-Sing, Pickles, IJROBP 2004, 60(1):

98 Significance of Absolute PSA Value? PSA value >1.1, >1.0, >2.5 Various series (Schild, Vicini, Raymond, Wu) When is Salvage Treatment Given? Time to salvage treatment Surgery 4.9 months Radiation 15.6 months Mean PSA at salvage Surgery 1.1 ng/ml Radiation 9.1 ng/ml Tefilli et al, Urology 52: ,

99 PSA at Salvage Brachytherapy Very limited data PSA > 10 PSA <10 25% 5 year NED 67% 5 year NED Beyer, Urology 54: , 1999 Who Needs Treatment? Documented local failure No documented distant disease Life expectancy >5-10 years Disease free interval > 2 years PSA < 10 PSA doubling time > 6 months 99

100 Who Will Respond to Treatment? Very little data Who Will Respond to Treatment? Salvage after retropubic implant (prepsa) 170 Gy MPD 51% freedom from second local failure 10 of 13 with distant metastasis 59% 5 year overall survival Wallner, J Urol 144: ,

101 198 Au Salvage Locally advanced disease 40% negative biopsy 67% 5 year survival Loening and Turner, Prostate 23: , 1993 PSA Era Salvage 46 patients failed: XRT to 66 Gy Implant (3) RP (3) Hormone refractory (11) 160 Gy 125 I or 120 Gy 103 Pd Grado et al, Urology 53:2-10,

102 High Risk Patients bned 48% at 3 years 34% at 5 years 56% at 5 years (47% PSA < 0.5) 15% at 5 years (for PSA> 0.5) Grado et al, Urology 53:2-10, 1999 Arizona Oncology Results 17 patients 160 Gy 125 I or 120 Gy 103 Pd 53% BDFS 93% CSS 83% BDFS in low risk population Beyer, Urology 54: ,

103 30 patients Arizona Oncology Additional Follow-up Median 46 months (125 maximum) Beyer, Seminars Rad Onc 13(2): , 2003 Significance of Gleason Sum Beyer, Seminars Rad Onc 13(2): ,

104 Significance of PSA Beyer, Seminars Rad Onc 13(2): , 2003 Overall Survival Beyer, Seminars Rad Onc 13(2): ,

105 Cause Specific Survival 60% Beyer Seminars Rad Onc 13(2): , 2003 Significance of Gleason on Survival 105

106 AOS 2005 Update Salvage Brachytherapy 35 patients 18 high grade (Gleason 7-10) 6 with PSA >10 Follow-up months Mean 63.1 months BNED from Salvage Brachytherapy 106

107 Cause Specific Survival From Salvage Brachytherapy Probability Years Cause Specific Survival From Salvage Brachytherapy: Impact of High Gleason Gleason 2-6 Gleason

108 Cause Specific Survival From Salvage Brachytherapy: Impact of PSA PSA > 10 PSA > 10 Overall Survival From Salvage Brachytherapy 108

109 BNED from Salvage Brachytherapy PHM ALL BNED from Salvage Brachytherapy: By Gleason Gleason 2-6 Gleason

110 BNED from Salvage Brachytherapy Impact of PSA>10 PSA > 10 PSA > 10 So Expectation from Salvage Treatment? With Gy 125 I or Gy 103 Pd Overall ~ 50% bned Better case selection: PSA < 10 Gleason < 7 110

111 Expected Morbidity No data on acute symptoms or case selection Similar to primary treatments No quality of life reports Physician reported Late Morbidity Range Hematuria 0-4% Pelvic / penile pain 0-6% Urinary incontinence 0-24% Proctitis 0 4% Rectal necrosis / colostomy 0 5% 111

112 Observation Androgen Blockade Other Options Radical Prostatectomy Other experimental techniques Cryotherapy Thermal Ablation Author Very Short Follow-up: Cryosurgical Ablation Number of Patients De la Taille Perotte Greene Pisters Chin Lee Miller Follow-up Mean months 112

113 Five Year Retrospective Multi-institutional Pooled Analysis of Cancer Related Outcomes After Cryosurgical Ablation of the Prostate Complications Impotence 93% Incontinence 7.5% Fistula 0.5% TURP 13% Median Follow-up 24 months Long et al, Urology, 57: , 2001 Is This Really How You Want Prostate Cancer Treated???? 113

114 Salvage Brachytherapy for Prostate Cancer David C. Beyer, M.D., F.A.C.R. Arizona Oncology Services Phoenix, Arizona Conclusions Sexual function Short Term slightly better with Seeds Incontinence much better with seeds Bowel Function better with surgery Efficiency Brachytherapy is superior to surgery or EBRT Convenient for Patients 114

115 Positive Margins Robotic Surgery Kawachi City of Hope 04/07 Path Stage COH Montsouris N = 860 N = 1000 pt2a 8.9% 6.9% pt2b/c 15.9% 18.6% pt3a 28.6% 30% pt3b 33.8% 34% Gleason Score GS 5,6 13.8% 15% GS % 21% GS 8,9,10 30% 30% Prostate and Rectal Cancers May share the same genetic and environmental influences 115

116 Thermal Ablation Intraprostatic Temperatures >60 C 116

117 19 Patients PSA Results - ThermoRod* C Thermal Implants & One Hour of ThermoTherapy 01-WS 02-JD 03-GT 04-AS 05-JF 06-JR 07-WP 08-PE 09-PM 10-DW PSA (ng/ml) Retreated 9/12/ Time Since Treatment (Months) *CAUTION: Investigational Device. Limited by U.S. law to investigational use only. Can we identify patients most likely to require treatment? Can we identify patients most likely to respond? What is expected morbidity? What other options should be considered? 117

118 Incidence of Cecum and Rectosigmoid Cancer RP XRT Proportion cancer free Years from initial treatment Baxter, et al Gastro

119 Gregory S. Merrick, M.D. Schiffler Cancer Center and Wheeling Jesuit University Wheeling, WV Temporal Relationship Between Prostate Cancer and the Diagnosis of Colorectal Cancer Late and Acute Urinary toxicity Post Implant Keyes ( BC Cancer Agency) I Seattle pre plan technique Med V100 92% 724 pts follow up > 3 years 84% returned to within 2 IPSS pts of norm 16% never normalized IPSS 90% of the 84% normalize IPSS by 2 years but the rest may take up to 5 years 119

120 Potency Robotic Prostatectomy If normal prior to surgery 20-40% lose ability Kawachi City of Hope 11/05 Presented St Mary s Michigan Secondary Cancers After Brachytherapy or Surgery 120

121 Incidence of Rectal Cancer At 10 years = XRT 1.0% = RP 0.5 % p= Baxter, et al Gastro 2005 Incidence of Colon Cancer Proportion cancer free RP XRT Years from initial treatment Baxter, et al Gastro

122 No Relationship between Prostate XRT and Rectal Cancer Movsas, et al IJROBP ,135 Connecticut Tumor Registry patients and 543 XRT patients Second Malignancies 84% outside XRT portals 97% within 3 years of XRT 1/543 patients (0.18%) developed an infield malignancy >5 years after XRT Rectal Bleeding Tx F/u Comments Crook Seeds 4 yr 1.3% 1.5% Matthews Seeds 5% Transient No Surg Seattle Seeds 10 yr 3% Transient No Surg Seattle EBRT and Seed 6% 1 pt fistula 122

123 Rectal Bleeding/ Fistula EBRT 2, 3 4 Vargas (Wm Beaumont) 1 244/75-78Gy1.8Gy Chism (Fox 132/82/2Gy/3DCRT 9 0 Chase)2 Fiorino3 160/76Gy 12 0 Heemsbergen 278/70-78/2 Gy Kuban (MDA) 163/74-78/2Gy Michalski (RTOG 9406) Patients/dose/Fractions % Grade 256/77/1.8-2Gy Late Rectal Bleeding after EBRT Dose Volume Effect - Higher dose & Higher volume = increase risk 1,2,4,5,6 Telagiectasia are not necessarily permanent 3 EBRT- NHT (RTOG) does not confer increased risk 7 123

124 PSA Bounce Seattle Prostate Institute Bounce = Transient rise in PSA 534 patients 35% of implants patients had a PSA Bounce 7% of the bounce patients failed Seattle Prostate Institute 2003 Overall Survival Low Risk & T1-2 Group Average 70 Y/O 11 9*** **** ** * 1 + +* *2 Well Dif ** Mod Diff 5, *** Low Risk, **** Int Risk Age 60 at dx, GS 5-7; Age < 60 at dx, GS

125 % Progression Free Low Risk* D Amico PSA RFS P Years wd Brachy Surgery EBRT 3 c CRYO + No TX HIFU P Protons *Hypofractionated ** HDR *** D 90 > 130 Gy wd= well Diff Grimm 11/07 % Progression Free Low Risk* D Amico Robotic PSA RFS P Years wd Brachy Robotic Surgery NO Data! 3 c CRYO + No TX HIFU P Protons *Hypofractionated ** HDR *** D 90 > 130 Gy wd= well Diff Grimm 11/07 125

126 Long Term Brachy Seattle PSA RFS % Progression Free P wd Brachy 3 c CRYO + No TX HIFU P Protons Years *Hypofractionated ** HDR *** D 90 > 130 Gy wd= well Diff Grimm 11/07 Overall Survival P = NS Tward et al. ( U Utah) Cancer 107 p

127 10 yr PCa Caused Death P = NS Tward et al. ( U Utah) Cancer 107 p T2a 8.9% T2b 16% T3a 28% Robotic Prostatectomy Positive Margins GS 5,6 14% GS 7 25% GS % Kawachi City of Hope 11/05 Presented St Mary s Michigan 127

128 PSA Bounce 534 SPI patients 44% had PSA Rise 80% of these pts with PSA Rise were PSA Bounce Therefore 35% of patients will have a PSA Bounce 7% of bounce patients fail Seattle Prostate Institute % of Patients Only 7% will progress 128

129 The Dawn of Prostate Brachytherapy Jesse N. Aronowitz, M.D. University of Massachusetts Levine Cancer Center Worcester, MA (Per author s request, following 13 slides have been omitted from the handout) 129