1. Radiation Therapy for Treatment of Prostate Cancer Stephen Ko, M.D. Mayo Clinic Florida August 30, 2010

2. I. U.S. Epidemiology II. Types of Radiation III. Anatomy IV. Technologic Advances – 2-Dimensional Planning – Intensity Modulated Radiotherapy – Brachytherapy V. Definition of Risk Categories – Low Risk – Intermediate Risk – High Risk OverviewOverview

3. VI. Dose-escalation Trials – MSKCC IMRT Dose Escalation – Proton Beam Dose Escalation – MDACC Randomized Trial (70 Gy vs. 78 Gy) – Harvard Randomized Trial (70.2 GyE vs. 79.2 GyE) VII. Low Risk Disease Treatment – IMRT alone – Seeds alone VIII. Intermediate Risk Disease Treatment – IMRT alone – 6 mo Hormone + EBRT – Seeds + EBRT OverviewOverview

4. IX. High Risk Disease Treatment – Long-term Hormonal therapy Randomized Trials RTOG randomized Trial EORTC randomized Trial – Seeds + EBRT X. Comparing Modalities (Surgery vs. Radiation) XI. Quality of Life Comparison XII. Conclusions OverviewOverview

5. 2009 New cases prostate cancer: 192,280 Deaths from prostate cancer: 27,360 New cases prostate cancer in FL: 12,380 New cases prostate cancer in GA: 5,210 Death from prostate cancer in FL: 2,470 Death from prostate cancer in GA: 870 I. U.S. Epidemiology

6. 2009 U.S. Epidemiology New Cases in U.S.

7. . 2009 U.S. Epidemiology Deaths/year from cancer in U.S.

8. II. Types of Radiation External Beam: high energy X-rays given with linear accelerator Primary therapy Postoperative Brachytherapy: radioactive seeds Primary therapy After external: boost dose Proton Beam: heavy particle Primary therapy

9. l Dose is the amount of radiation used to treat a patient l SI unit (joules/kg) l Gray (Gy) l Centigray (cGy) l 100 cGy = 1 Gy l Similar to milligrams for drugs l 180 cGy or 200 cGy per day or 1.8 Gy or 2 Gy per day is usually given to treat prostate l 1.8 Gy x 42 treatments = 75.6 Gy total What is dose?

10. Bladder Prostate Rectum Seminal vesicles III. Anatomy

11. IV. Technological Advances 2-Dimensional Planning (Fluoroscopic- based) 3-Dimensional Planning (CT-based) Intensity Modulated Radiotherapy or IMRT (CT-based)

12. 2- Dimensional Vs. 3-Dimensional Planning Prostate Rectum Bladder Rectum Prostate

13. External Beam Electronic Portal Imaging Intraprostatic Marker Localization External Beam Electronic Portal Imaging Intraprostatic Marker Localization CT Scan Intended treatment X-ray on the machine Actual treatment Positional error corrected Initial setup Final position Goldmarker

14. Intensity Modulated External Beam Radiotherapy

15. IMRT Prostate Dose Distribution Dose

16. l Disease contained within the prostate gland (T1c - T2a) l Small - to - moderate prostate size (  60 cc) l Favorable pelvic anatomy l No or limited prior transurethral prostatic resection l Minimal obstructive symptoms (I-PSS  15, peak flow  10) Prostate Brachytherapy

17. V.Definition of Risk Categories -Low Risk -Intermediate Risk -High Risk

18. V. Prostate Cancer Risk Groups

19. Clinical tumor stage, Gleason score and PSA used to determine risk groups: (D`Amico)  Low risk: Stage T1-2a, Gleason  6, and PSA < 10 ng/mL  Intermediate risk: Stage T2b or Gleason 7 or PSA 10-20 ng/mL  High risk: Stage > T2c or Gleason 8-10 or PSA > 20 ng/mL Prostate Cancer Risk Groups

20. Retrospective Trials – MSKCC IMRT Dose Escalation – Proton Beam Dose Escalation Prospective Randomized Trials – MDACC Randomized Trial (70 Gy vs. 78 Gy) – Harvard Randomized Trial (72 Gy vs. 79.2Gy) VI. Dose-escalation Trials

21. Began using IMRT in 1996 to facilitate dose escalation high dose XRT using IMRT for localized prostate cancer 561pts. B/w April 1996 & Jan 2000 Median age 68 (range 46-86) Memorial Sloan Kettering Cancer Center IMRT Dose Escalation Zelefsky MJ, Chan H, et. Al. Journal of Urology Vol. 176, 1415-1419, Oct 2006

22. Escalated eventually to 81 Gy 296 patients (53%) treated w/ short course (3-mo) androgen deprivation therapy to decrease the size of the prostate ADT discontinued at the completion of radiotherapy Memorial Sloan Kettering Cancer Center IMRT Dose Escalation Zelefsky MJ, Chan H, et. Al. Journal of Urology Vol. 176, 1415-1419, Oct 2006

23. Median f/u: 7 years (range 5 to 9) PSA relapse: – ASTRO definition: 3 consecutive rises after nadir – Houston definition: nadir + 2 None received post-irradiation androgen deprivation or other anti-cancer therapy before documentation of a PSA relapse Memorial Sloan Kettering Cancer Center IMRT Dose Escalation Zelefsky MJ, Chan H, et. Al. Journal of Urology Vol. 176, 1415-1419, Oct 2006

24. Low Risk T1-2, GS ≤6, PSA ≤10 Memorial Sloan Kettering Cancer Center IMRT Dose Escalation Zelefsky MJ, Chan H, et. Al. Journal of Urology Vol. 176, 1415-1419, Oct 2006

25. Intermediate Risk Memorial Sloan Kettering Cancer Center IMRT Dose Escalation Zelefsky MJ, Chan H, et. Al. Journal of Urology Vol. 176, 1415-1419, Oct 2006 T1-2, GS  6, PSA > 10 T1-2, GS >6, PSA  10 T3, GS  6, PSA  10

26. High Risk GS >6, PSA >10 Memorial Sloan Kettering Cancer Center IMRT Dose Escalation Zelefsky MJ, Chan H, et. Al. Journal of Urology Vol. 176, 1415-1419, Oct 2006

27. Biochemical Control Using the ASTRO definition, the 8-year actuarial PSA relapse-free survival – Favorable risk: 85% – Intermediate risk: 76% – Unfavorable risk: 72% Memorial Sloan Kettering Cancer Center IMRT Dose Escalation Zelefsky MJ, Chan H, et. Al. Journal of Urology Vol. 176, 1415-1419, Oct 2006

28. Distant metastases – developed in 17 (3%) pts 8-year actuarial likelihood of distant metastases – Favorable 1% – Intermediate 5% – Unfavorable 4%, – (favorable vs. intermediate risk p = 0.03; intermediate vs.. unfavorable risk p = 0.86) Cause specific survival outcomes – Favorable 100% – Intermediate 96% – Unfavorable 84% (p = 0.17) Memorial Sloan Kettering Cancer Center IMRT Dose Escalation Zelefsky MJ, Chan H, et. Al. Journal of Urology Vol. 176, 1415-1419, Oct 2006

29. Toxicity Rectal: – Grade 2 rectal bleeding: 7 patients (1.5%) – Grade 3 rectal toxicity: 3 patients (<1%) – No grade 4 rectal complications – 8-year actuarial likelihood of late grade > 2 rectal toxicity: 1.6% Urinary: – Late grade 2 chronic urethritis requiring medication for symptom control: 9% – Urethral stricture requiring dilation (gr3): 3% – 8-year actuarial likelihood of late grade > 2 urinary toxicities: 15% Memorial Sloan Kettering Cancer Center IMRT Dose Escalation Zelefsky MJ, Chan H, et. Al. Journal of Urology Vol. 176, 1415-1419, Oct 2006

30. Toxicity Sexual: – Before the initiation of therapy 403 (72%) patients reported the ability to maintain an erection sufficient for sexual intercourse – In this group of pts ED developed in 49% Secondary Malignancy: – None observed Memorial Sloan Kettering Cancer Center IMRT Dose Escalation

31. . B/w Oct 1991 & Dec 1997, 1255 pts with Stages Ia-III prostate cancer No prior surgery, hormonal therapy, or distant mets Treated with protons alone or in combination with photon-beam XRT Loma Linda Proton Beam Experience Dose Escalation Slater JD, Rossi CJ, et. Al. IJROBP Vol 59, No. 2, 348-352, 2004.

32. . Freedom from biochemical evidence of disease (bNED) used ASTRO consensus definition ( 3 consecutive PSA rises after reaching a nadir) Mean duration f/u: 63 months Median age: 69 years Loma Linda Proton Beam Experience Dose Escalation Slater JD, Rossi CJ, et. Al. IJROBP Vol 59, No. 2, 348-352, 2004.

33. Overall 5-year & 8- year actuarial biochemical disease- free survival rates: 75% & 73% Loma Linda Proton Beam Experience Dose Escalation Slater JD, Rossi CJ, et. Al. IJROBP Vol 59, No. 2, 348-352, 2004.

34. Median Follow up Pts.5yr BDFS 8yr BDFS Multivariat e Analysis Late rectal Late Urinary Sexual Dysfunction IMRT7yrs561N/A85% for LR, 76% for IR, 72% for HR Clinical Stage & Pre- Treatment PSA significant Gr 2 or greater 1.6%, Gr 3 <1%, no Gr 4 Gr 2 or greater 15%, Gr 3 was 3%, No Gr 4 49% PBRT62mo125575%73%Pre- Treatment PSA, Gleason, & PSA nadir significant Gr 3 <1%, Gr 4 <1% (1pt with Gr 4) Gr 3 or greater <1%, no Gr 4 N/A Comparison of IMRT versus Proton Therapy

35. Results Of A Randomized Dose-Escalation Study Comparing 70 Gy To 78 Gy(isocenter) For The Treatment Of Prostate Cancer MDACC Randomized Dose Escalation Trial Pollack IJROBP 2002

36. p = 0.46 78 Gy 70 Gy p = 0.012 78 Gy 70 Gy PSA <=10 ng/ml PSA >10 ng/ml Freedom from Failure by PSA Pollack IJROBP 2002 MDACC Randomized Dose Escalation Trial

37. p = 0.056 78 Gy 70 Gy Fraction Free of Distant Metastases, PSA > 10 Pollack IJROBP 2002 MDACC Randomized Dose Escalation Trial

38. Phase III trial comparing conventional dose with high dose radiation in early stage prostate cancer: results of PROG 95-09 Zietman A, et. al. JAMA, 2005, 294 (10): 1233 Harvard Randomized Dose Escalation Trial

39. Trial design No hormonal therapy T1b-2b prostate cancer PSA <15ng/ml Proton boost 19.8 GyE Proton boost 28.8GyE 3-D conformal photons 50.4 Gy 3-D conformal photons 50.4 Gy Total prostate dose 70.2 GyE Total prostate dose 79.2 GyE r a n d o m i z a t i o n ACR/RTOG Harvard Randomized Dose Escalation Trial

40. 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 012345678 Years Since Randomization Freedom from Biochemical Failure Rate 70.2 GyE 79.2 GyE # at risk 197 196 171 139 118 76 31 10 10 195 194 184 163 148 99 46 20 2 Freedom from Biochemical Failure (ASTRO definition) * * 95% confidence intervals * P = <0.0001 61% 79% Harvard Randomized Dose Escalation Trial

41. 012345678 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 01234567 8 Freedom from Biochemical Failure (ASTRO definition) Low Intermediate/high 70.2GyE 79.2GyE Years since randomization n = 230 p = <0.001 n = 162 p = 0.03 55% 79% 61% 78% Harvard Randomized Dose Escalation Trial Zietman A, et. al. JAMA, 2005, 294 (10): 1233

42. VII. Low Risk Disease Treatment -IMRT alone -Seeds alone

43. VII. Radiotherapy for Low Risk Prostate Cancer

44. Watchful waiting vs. active surveillance Radical prostatectomy IMRT Interstitial brachytherapy Treatment Options for Low- Risk Group

45. Low Risk T1-2, GS ≤6, PSA ≤10 Memorial Sloan Kettering Cancer Center IMRT Dose Escalation Zelefsky MJ, Chan H, et. Al. Journal of Urology Vol. 176, 1415-1419, Oct 2006

46. Study design 125 pts with T1-T2b treated with I-125 brachytherapy b/w 1988-1990 Gleason < 6 Median PSA 5.1 Endpoint biochemical outcome – Failure is 2 consecutive rises in PSA Brachytherapy for Low Risk Prostate Cancer Grimm P, et. al. IJROBP, 51 (1), 31-40, 2001.

47. Brachytherapy for Low Risk Prostate Cancer Grimm P, et. al. IJROBP, 51 (1), 31-40, 2001.

48. VIII. Intermediate Risk Disease Treatment -IMRT alone -6 mo Hormone + EBRT -Seeds + EBRT

49. VIII. Radiotherapy for Intermediate Risk Prostate Cancer VIII. Radiotherapy for Intermediate Risk Prostate Cancer

50. Intermediate Risk Memorial Sloan Kettering Cancer Center IMRT Dose Escalation Zelefsky MJ, Chan H, et. Al. Journal of Urology Vol. 176, 1415-1419, Oct 2006 T1-2, GS  6, PSA > 10 T1-2, GS >6, PSA  10 T3, GS  6, PSA  10

51. 3DCRT Rx 67Gy normalized to 95% isodose D` Amico A, et al. JAMA. 2004; 292(7): 821-826. 6 mo Hormone + Radiotherapy for Intermediate Risk Prostate Cancer 6 mo Hormone + Radiotherapy for Intermediate Risk Prostate Cancer

52. Overall Survival D` Amico A, et al. JAMA. 2004; 292(7): 821-826. 6 mo Hormone + Radiotherapy for Intermediate Risk Prostate Cancer 6 mo Hormone + Radiotherapy for Intermediate Risk Prostate Cancer 88% 78%

53. 9915436554394300220223 Months Postimplant 12010896847260483624120 1.0.9.8.7.6.5.4.3.2.1 0.0 Cumulative Survival @risk Favorable Intermediate Unfavorable N=111 N=279 N=13 PSA Progression-Free Survival (N=403) 94% 84% 54% Seattle Prostate Institute. Courtesy SPI and Medical Education Collaborative Brachytherapy for Low, Interm, & High Risk Grps

54. IX. High Risk Disease Treatment -Long-term Hormonal therapy Randomized Trials -RTOG randomized Trial -EORTC randomized Trial -Seeds + EBRT

55. IX. Radiotherapy for High Risk Prostate Cancer IX. Radiotherapy for High Risk Prostate Cancer

56. High Risk GS >6, PSA >10 Memorial Sloan Kettering Cancer Center IMRT Dose Escalation Zelefsky MJ, Chan H, et. Al. Journal of Urology Vol. 176, 1415-1419, Oct 2006

57. TrialEligibilityArmsOverall Survivalp-value RTOG 8531 T3 (15%) or T1-2, N+ or path T3 and (+) margin or (+) SV RT (HT @ failure) RT + AHT indefinite 10-year 39% v 49% p=.002 EORTC 22863 T3-4 (89%) or T1-2 WHO 3 RT RT+CAHT 3 years 5-year 62% v 78% p=.0002 RTOG 8610 Bulky T2b, T3-4, N+ allowed RT v RT+NHT (TAB) 3.7 mo 8-year 44% v 53% p=.10 RTOG 9202 T2c-4 w/PSA <150, N+ allowed RT+NHT (TAB) 4 mo RT+NHT+AHTx28mo 5-year 70% v 80% GS 8 p=.73 P <.004 GS8 RTOG 9413 T2c-4 w/Gleason>6, or >15% risk of N+ WP+ 4mo NHT WP+ 4mo AHT PO+ 4mo NHT PO+ 4mo AHT 4-year 84.7% v 84.3% p=.94 DFCIT1b-T2b, or mri-T3 PSA=10-40, GS≥7 3DRT 3DRT + 6mo (TAB) 5-year 78% v 88% p=.04 TROG 9601 T2-4, any PSA, any GSRT RT + 3mo NHT RT + 6mo NHT Not statedp=ns Randomized Trials Involving Hormone Therapy for Locally Advanced Prostate Cancer Randomized Trials Involving Hormone Therapy for Locally Advanced Prostate Cancer

58. 9915436554394300220223 Months Postimplant 12010896847260483624120 1.0.9.8.7.6.5.4.3.2.1 0.0 Cumulative Survival @risk Favorable Intermediate Unfavorable N=111 N=279 N=13 PSA Progression-Free Survival (N=403) 94% 84% 54% Seattle Prostate Institute. Courtesy SPI and Medical Education Collaborative Brachytherapy for Low, Interm, & High Risk Grps

59. X. Comparing Modalities

60. No modern clinical trials have successfully compared these modalities – Physicians and patients alike unwilling to accept randomization Different definitions of cancer control Patients are not comparable between modalities, even at same institution X. Can we compare radiation modalities to surgical therapy? X. Can we compare radiation modalities to surgical therapy?

61. Kupelian, Potters et al, IJROBP 2004 (Cleveland Clinic & MSKCC Mercy Hospital) Comparison of Outcome by Modality

62. Kupelian, Potters et al, IJROBP 2004 (Cleveland Clinic & MSKCC Mercy Hospital) Comparison of Outcome by Modality

63. Multivariate analysis of factors predictive of bRFS Kupelian, Potters et al, IJROBP 2004 (Cleveland Clinic & MSKCC Mercy Hospital) Comparison of Outcome by Modality

64. 7316 men treated at 44 U.S. medical institutions for Stage II prostate cancer Risk of prostate cancer-related death was not measurable affected by type of therapy Intermediate-risk patients with multiple risk factors fared better with RT Surgery vs Radiotherapy for Prostate Cancer Risk of Death Surgery vs Radiotherapy for Prostate Cancer Risk of Death D’Amico AV. J Clin Oncol 21:2163-72, 2003 Relative risk (RR) of death due to prostate cancer

65. Prostate Cancer Clinical Guidelines Panel convened to analyze the literature regarding available treatment methods MEDLINE search of 1453 journal articles Analysis confined to 165 “best” articles Articles did not permit valid comparisons of the treatment methods Data from the medical literature do not provide clear- cut superiority of any one treatment Surgery vs Radiotherapy for Prostate Cancer American Urological Association Surgery vs Radiotherapy for Prostate Cancer American Urological Association Middleton RG. J Urol 154:2144-8, 1996.

66. XI. Quality of Life Comparison

67. XI. Quality of Life After Prostate Cancer Therapy Wei, JT: J Clin Oncol 20: 557-566, 2002 % Urinary Bothersome (P < 0.0001)

68. Quality of Life After Prostate Cancer Therapy % Bowel Bothersome (P < 0.0001) Wei, JT: J Clin Oncol 20: 557-566, 2002

69. Quality of Life After Prostate Cancer Therapy % Sexual Function Bothersome (P < 0.0001) Wei, JT: J Clin Oncol 20: 557-566, 2002

70. XII. Conclusions XII. Conclusions

71. l Patient expectations of medical care l Patient understanding of & engagement in management of condition l Patient preference for type of treatment l Access of patient to each member of a multispecialty team Factors Influencing Management Approach

72. l Low Risk Pts l Surgery or Radiation- l Equivalent in terms of QOL and Outcomes l Intermediate Risk Pts l Surgery or Radiation- l Equivalent in terms of QOL and Outcomes l High-Risk Pts l Radiation is the treatment of choice in terms of cancer control Dr. Ko`s Treatment Recommendations