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  1. Highlights in the Management of Urogenital Cancer Rome May 9-10, 2008 Radiation Therapy is the best treatment approach for localized prostate cancer Giorgio Arcangeli

  2. CARCINOMA OF THE PROSTATE High probability of cure in localized tumors risk to treat scarcely aggressive indolent tumors multiple therapeutic options

  3. CRITERIA FOR TREATMENT CHOICE • TUMOR RELATED (Stage - G.S. - PSA) • PATIENT RELATED (age - P.S.) • TREATMENT RELATED (Acute and late side effects, QOL)

  4. Clinical Staging of prostate cancer

  5. Clinical Staging of prostate cancer

  6. Clinical Staging of prostate cancer

  7. Clinical Staging of prostate cancer

  8. SISTEMA DI GLEASON (1974) SISTEMA DI GLEASON MODIFICATO (ISUP 2005)

  9. CARCINOMA OF THE PROSTATADefinitive treatment options in localized tumors HIGH DOSE RADIOTHERAPY± ANDROGEN DEPRIV. RADICAL PROSTATECTOMY

  10. CARCINOMA OF THE PROSTATE AGE < 70 years YEARS OF DIAGNOSIS (Harlan: J Clin Oncol, 1995)

  11. CARCINOMA OF THE PROSTATE AGE > 70 anni YEARS OF DIAGNOSI (Harlan: J Clin Oncol, 1995)

  12. A Multi-institutional* Pooled Analysis of Radiation Therapy For Clinically Localized Prostate Cancer (Shipley, JAMA 281:1598, 1999) * Fox Chase; Mass General; Michigan University; Washington University; EVMS; Stanford

  13. ACR Patterns of Care Study : Risk of Grade 3-4 Complications by Radiation Dose in Carcinoma of the Prostate Dose # Patients % Complications <70 Gy 428 3.5% >70 Gy 174 6.9% p = 0.03 Modified from Leibel SA, Hanks GE, Kramer S. IJROBP, 10, 401, 1984

  14. 100 80 60 40 20 0 20 40 60 80 100 120 Shifting The Organ Toxicity Curve by Decreasing the Irradiated Volume Tumor Control Organ Toxicity Probability (%) Prescription Dose

  15. Multileaf Collimator for Conformal or Intensity Modulater Radiation Therapy

  16. Dynamic Multileaf ( “Sliding window”) • le lamelle si muovono in modo continuo ed unidirezionale durante l’erogazione, sempre da sinistra verso destra, fino ad una velocità di 2.5 cm/s; • ogni lamella si sposta a velocità diversa dalle altre, ricongiungendosi alla lamella opposta nella posizione finale; • l’erogazione è continua durante il movimento delle lamelle. Fluence Matrix

  17. Why IMRT ??? • Creation of concave or convex isodose surfaces with sharp dose gradients • Higher dose to target volume • Specific sparing of sensitive volumes (organs at risk) within complex treatment geometries 3-field IMRT 3-field RT Beam Profile #1 1 Prescribed Dose (typical distribution) Dose Intensity RO RO PTV PTV Beam Profile # 2 Beam Profile #3 With IMRT dose distribution can be shaped to the target to spare Organs at Risk

  18. 20-30% 40-50% 60-70% 80-90% 90-100% >100% 20-30% 40-50% 60-70% 80-90% 90-100% >100% bladdder 6 fields-3DCRT 5 fields-IMRT PTV rectum Isodose comparison betwen CRT or IMRT 6 FIELDS-3DCRT 5 FIELDS-IMRT Dose prescription: 80 Gy to isocentre, 2 Gy per fractions, 5 fr/week

  19. 7560 cGy (446) 8100 cGy (61) 7020 cGy (268) 20 15 Percent Grade 2 Rectal Bleeding 10 5 6480 cGy (96) 0 0 12 24 36 48 60 72 84 96 108 Zelefsky 1999 Time (months)

  20. 20 81 Gy Conventional 3D-CRT (61) 15 Percent ≥ Grade 2 GI Toxicity 10 p< 0.001 5 81 Gy IMRT (171) 0 12 24 36 48 60 72 84 96 Months 0 Zelefsky 2001

  21. Dose escalation with External Beam Radiation Therapy

  22. Zietman AL, JAMA 2005 Biochemical Failure-Free 70.2 Gy vs 79.2 Gy Low risk All Pts. Intermediate to high risk

  23. Peeters STH et al. JCO 2006

  24. Conventional vs. High dose 3D-CRT in pts with prostate cancer receiving 3-6 mos NCADT Randomized phase III study (MRC RT01) 74 Gy 64 Gy HR=0.67(0.53-0.85) P=0.0007 Dearnaley, Lancet Oncol 2007

  25. External Beam Radiation Therapy Vs Radical Prostatectomy

  26. bNed for surgically and radiation-managed patients stratified into risk groups low risk intermediaterisk high risk D’Amico A, IJROBP 1997

  27. bRFS in pts with favorable tumors (T1-T2A, bGS< 6, iPSA< 10 ng/ml) Kupelian PA, JCO 2002

  28. bRFS in pts with unfavorable tumors (T2b-T2c, bGS> 6, iPSA>10 ng/ml) Kupelian PA, JCO 2002

  29. Akakura K, Jpn J Clin Oncol 2006 bNED OS P=0.30 P=0.25 RP: 46 pts – EBRT (60-70 Gy): 49 pts (2 month neoadjuv DES 300mg and adjuv LHRH until progress)

  30. Characteristics of Pts with high risk prostate cancer Variable RP EBRT p-value Median Age 65.5 75.0 <0.001 bGS < 6 29 (24%) 17 (10%) 7 82 (67%) 105 (65%) <0.001 > 8 11 (9%) 40 (25%) cT-Stage <T2c 110 (90%) 70 (43%) T2c 4 (3%) 71 (48%) <0.001 >T2c 8 (7%) 21 (9%) iPSA <10 2 (1%) 44 (27%) 11-20 57 (47%) 55 (34%) <0.001 >20 63 (52%) 63 (39%) Median FU 30.5 mos 30.7 mos 0.56

  31. EAU Guidlines for follow-up after treatment with curative intent • After RP a serum PSA level > 0.2 can be associated with • residual or recurrent disease (grade B recommendation) • After EBRT a rising PSA level 2.0 ng/ml above the nadir value, • rather than a specific threshold value, is the most reliable sign • of persistent or recurrent disease (grade B recommendation) • Both a palpable nodule and rising PSA level can be signs of • local disease recurrence (grade B recommendation) Eur Urology 2008

  32. p=n.s. p=n.s. p=n.s. FFBF in high risk prostate tumors according to different scores of clinical prognostic factors iPSA cT-stage bGS (104 pts.) (46 pts.) (238 pts.) (238 pts.) (180 pts.) (46 pts.) IRE Apr 2008

  33. FFBF as a function of Age in pts with high risk prostate cancer treated with RP or EBRT (123 pts.) (159 pts.) IRE Apr 2008

  34. FFBF after RP or EBRT in pts with high risk prostate cancer p = 0,0012 (162 pts.) (122 pts.) IRE Apr 2008

  35. FFBF according to bGS ± 8 and iPSA ± 20 ng for RP and EBRT RP p=n.s p=n.s.= 0.06 (11 pts) (63 pts) (111 pts) (59 pts) EBRT p=n.s. p=0.005 (40 pts) (63 pts) (122 pts) (99 pts)

  36. FFBF of Pts with worst prognosis according to the treatment received p = 0.0161 IRE Apr 2008

  37. FFBF according to nPSA in Pts treated with EBRT p= 0.001 (10pts.) (152pts.) IRE Apr 2008

  38. FFBF of Pts treated with EBRT, RP only or RP + Adjuvant Treatment (162 pts.) p=0.62 p=0.0001 (39 pts.) p=0.06 (83pts.) IRE Apr 2008

  39. FFBF according to different scores of pathologic factors p=n.s. p=0.008 (88 pts) (25 pts) (23 pts) (71 pts) p=n.s. p=n.s. (17 pts) (8 pts) (96 pts) (103 pts)

  40. Univariate analysis of RP patient Variable 3-yr FFBF rate p-value bGS (≥8 vs <8) 72% vs 77% 0.74 cT (>T2c vs <T2c) 37% vs 77% 0.08 iPSA (>20 vs < 20) 68% vs 81% 0.06 SM+ vs SM-79% vs 72% 0.73 pGS (>8 vs <8) 53% vs 81% 0.008 pN+vs pN- 60% vs 73% 0.53 pT (>T2c vs <T2c) 72% vs 78% 0.74 Adjuv Treatm (Y vs N) 65% vs 87% 0.06

  41. Univariate analysis of EBRT patient Variable 3-yr FFBF rate p-value bGS (>8 vs <8) 77% vs 93% 0.005 cT (>T2c vs <T2c) 83% vs 93% 0.66 iPSA (>20 vs < 20) 86% vs 91% 0.26 nPSA(>0.5 vs <0.5)40% vs 94% 0. 001 Fractionation (standard vs hypo) 76% vs 96% 0.06

  42. Univariate analysis of all patients Variable 3-yr FFBF rate p-value bGS (> 8 vs < 8) 73% vs 85% 0.17 cT (>T2c vs <T2c) 74% vs 83% 0.82 iPSA (>20 vs < 20) 76% vs 81% 0.01 Age(>70 vs <70)84% vs 80% 0. 61 Treatment (RP vs EBRT) 80% vs 92% 0.001

  43. Summary of Multivariate Analysis Group Variable p-value RP pGS (<7 vs =7 vs >7) 0.04 EBRT nPSA (continuous) 0.0002 All PTS iPSA (continuous) 0.01 Treatment (RP vs EBRT) 0.007

  44. Rectal and urinary late toxicity

  45. Incidence of grade >2 late toxicity rectal hypo convent urinary hypo convent IRE, Oct 2007

  46. Radiation Proctitis Related Factors • Patient related factors • Previous history of proctitis • Previous abdominal surgery • Cardiovascular disease • Arterial hypertension • Peripheral vascular disease • Diabetes • Hemorrhoids • Prostate size • Long term ADT • Radiation related factors • Total dose • Dose per fraction • Dose/volume relationship • PTV size • RT technique • N° of RT fields • Rectal motion

  47. Non confluent multiple Telangectasia 9

  48. Freedom from rectal toxicity as a function of rectal volume receiving > 70 Gy (V70) Pollack IJROBP 2002