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Radiation Therapy for Treatment of Prostate Cancer

Radiation Therapy for Treatment of Prostate Cancer. Stephen Ko, M.D. Mayo Clinic Florida August 30, 2010. Overview. I. U.S. Epidemiology II. Types of Radiation III. Anatomy IV. Technologic Advances 2-Dimensional Planning Intensity Modulated Radiotherapy Brachytherapy

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Radiation Therapy for Treatment of Prostate Cancer

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

  2. Overview 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

  3. Overview 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

  4. Overview • 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

  5. I. U.S. Epidemiology 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

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

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

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

  10. III. Anatomy Seminal vesicles Bladder Rectum Prostate

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

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

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

  14. Intensity Modulated External Beam Radiotherapy

  15. IMRT Prostate Dose Distribution Dose

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

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

  18. V. Prostate Cancer Risk Groups

  19. Prostate Cancer Risk Groups • 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

  20. VI. Dose-escalation Trials 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)

  21. Memorial Sloan Kettering Cancer CenterIMRT Dose Escalation • 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) Zelefsky MJ, Chan H, et. Al.Journal of UrologyVol. 176, 1415-1419, Oct 2006

  22. Memorial Sloan Kettering Cancer CenterIMRT Dose Escalation • 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 Zelefsky MJ, Chan H, et. Al.Journal of UrologyVol. 176, 1415-1419, Oct 2006

  23. Memorial Sloan Kettering Cancer CenterIMRT Dose Escalation • 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 Zelefsky MJ, Chan H, et. Al.Journal of UrologyVol. 176, 1415-1419, Oct 2006

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

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

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

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

  28. Memorial Sloan Kettering Cancer CenterIMRT Dose Escalation • 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) Zelefsky MJ, Chan H, et. Al.Journal of UrologyVol. 176, 1415-1419, Oct 2006

  29. Memorial Sloan Kettering Cancer CenterIMRT Dose Escalation 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% Zelefsky MJ, Chan H, et. Al.Journal of UrologyVol. 176, 1415-1419, Oct 2006

  30. Memorial Sloan Kettering Cancer CenterIMRT Dose Escalation 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 Zelefsky MJ, Chan H, et. Al.Journal of UrologyVol. 176, 1415-1419, Oct 2006

  31. Loma Linda Proton Beam ExperienceDose Escalation . • 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 Slater JD, Rossi CJ, et. Al. IJROBP Vol 59, No. 2, 348-352, 2004.

  32. Loma Linda Proton Beam ExperienceDose Escalation . • 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 Slater JD, Rossi CJ, et. Al. IJROBP Vol 59, No. 2, 348-352, 2004.

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

  34. Comparison of IMRT versus Proton Therapy

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

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

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

  38. Harvard Randomized Dose Escalation Trial 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

  39. Harvard Randomized Dose Escalation Trial Trial design No hormonal therapy T1b-2b prostate cancer PSA <15ng/ml r a n d o m i z a t i o n ACR/RTOG 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 79.2 GyE Total prostate dose 70.2 GyE

  40. Harvard Randomized Dose Escalation Trial Freedom from Biochemical Failure (ASTRO definition) 1.0 * 0.9 79% 0.8 0.7 61% 0.6 * Freedom from Biochemical Failure Rate 0.5 0.4 0.3 70.2 GyE P = <0.0001 0.2 79.2 GyE 0.1 * 95% confidence intervals 0.0 0 1 2 3 4 5 6 7 8 Years Since Randomization # at risk 197 196 171 139 118 76 31 10 10 195 194 184 163 148 99 46 20 2

  41. Harvard Randomized Dose Escalation Trial Freedom from Biochemical Failure (ASTRO definition) Low Intermediate/high 1.0 79% 79.2GyE 0.9 78% 79.2GyE 0.8 0.7 0.6 61% 70.2GyE 70.2GyE 55% 0.5 0.4 0.3 n = 162 p = 0.03 n = 230 p = <0.001 0.2 0.1 0.0 0 1 2 3 4 5 6 7 8 8 0 1 2 3 4 5 6 7 Years since randomization Years since randomization 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. Treatment Options for Low- Risk Group • Watchful waiting vs. active surveillance • Radical prostatectomy • IMRT • Interstitial brachytherapy

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

  46. Brachytherapy for Low Risk Prostate Cancer 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 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

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

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