External Beam Therapy for Low/Intermediate Risk Prostate Cancer Jeff Michalski, M.D. The Carlos A. Perez Distinguished Professor of Department of and Siteman Cancer Center
Learning Objectives Understand the role of external beam radiation therapy in the curative management of low/intermediate risk prostate cancer Understand the impact of external beam radiation therapy on quality of life
Randomized Clinical Trial S T R A T I F Y RTOG/ACOSOG/AUA Risk Group Low Intermediate Age Comorbidity R A N D O M I Z E Treatment Radical Prostatectomy Open Laparoscopic Robot Assisted External Beam 3D IMRT Proton Brachytherapy LDR HDR Does NOT exist!!!
Can we compare radiation modalities to surgical therapy? No modern clinical trials have successfully compared these modalities Physicians and patients alike unwilling to accept randomization Different definitions of cancer control Most institutions do not have combined treatment and outcome databases Patients are not comparable between modalities, even at same institution
Comparison of Outcome by Modality Kupelian, Potters et al, IJROBP 2004 (Cleveland Clinic & MSKCC Mercy Hospital)
Comparison of Outcome by Modality Kupelian, Potters et al, IJROBP 2004 (Cleveland Clinic & MSKCC Mercy Hospital)
Dose Escalation: Phase III Randomized Clinical Trial Experience MD Anderson 70 vs 78 (Pollack) Reported, N=301 PROG 70.2 vs 79.2 (Zeitman) Reported, N= 393 MRC* 64 vs 74 (Dearnaley, Sydes) Reported, N=843 Netherlands** 68 vs 78 (Lebesque, Peeters) Reported, N=669 France GETUG 70 vs 80 (Bey, Beckendorf) Completed, N=306 RTOG 70.2 vs 79.2 (Michalski) completed, N=1520/1520 *Both arms include hormone therapy **Some disease groups include hormone therapy
Dose Escalation Trial Summary Group MDA 68 vs 78 Isocenter Prescription (Gy) CTV PTV Technique Eligibility PROG 70.2 vs 79.2 Min PTV MRC 64 vs 74 Isocenter Dutch 68 vs 78 Gy Isocenter GETUG 70 vs 80 ICRU ref point RTOG 70.2 vs 79.2 Min PTV P + SV Phase I (Proton) P+5mm, 19.8 or 28.8Gy Phase II (XRT) P=SV+1cm, 50.4 Gy Low: P+ProxSV High: P+SV I:P only II:Prostate +SV (50Gy) III:Prostate +SV (68Gy) IV:Prostate +SV (full Rx) CTV1=P+SV (46Gy) CTV2=P (full Rx) 3D: P+SV 55.8Gy 3D: P to full Rx IMRT: P+prox SV Block Edge Ant-Inf 12-15mm Pos-Su 7-10mm 7-10mm 10mm to 64Gy 0mm last 10Gy 10mm to 68Gy 0-5mm final 10Gy 5-10mm 5-10mm 4F 2D to 46Gy (All) 4F 2D to 68Gy (Low) 6F 3DCRT 78Gy (High) 2Gy/fraction Proton boost 4F 3DCRT 1.8Gy 3-4F 3DCRT PTV1 4-6F 3DCRT PTV2 2Gy/day 3DCRT per institution 2Gy/day 4-6F 3DCRT 2Gy/day 3DCRT or IMRT 1.8Gy T1b-T3 ipsa=any No ADT T1b-T2b ipsa<15 No ADT T1b-T3a ipsa<50 ADT 3-6m All T-stages ipsa<60 ADT allowed ~10% short ~10% long T2-T3a T1 if GS 7 or ipsa>10 ipsa<50 No ADT T1b-T2b ipsa=10-20 (GS<7) ipsa<15 (GS7) No ADT
What is the impact of conformal therapy on toxicity? Department of and Siteman Cancer Center
Acute GI/GU Toxicity from Phase III Conformal Dose Escalation Trials Trial MD Anderson Storey/Pollack 2000 PROG Zietman 2005 Netherlands Peeters 2005 MRC Dearnaley 2007 GETUG Beckendorf 2004 Dose Acute grade 2 GI/Rectal Toxicity Acute grade 2 GU/Bladder Toxicity 70Gy 41% 36% 78Gy 43% p=0.6 29% 70.2GyE 41% 42% 79.2GyE 57% p=0.004 49% 68Gy 55% 53% 78Gy 51% p=0.2 47% 64Gy 30% 38% 74Gy 33% p=ns 39% 70Gy 56% 45% 80Gy 57% p=ns 46% p=0.8 p=ns p=0.6 p=ns p=ns
MRC RT01 Trial: Acute Bladder Toxicity Fig. 2. Acute bladder toxicity according to RTOG scale during and after RT. Dearnaley R&O 2007
Late GI/GU Toxicity from Phase III Conformal Dose Escalation Trials Trial MD Anderson Kuban/Pollack 2007 PROG Zietman 2005 Netherlands Peeters 2006 MRC Dearnaley 2007 Dose Late grade 2 GI/Rectal Toxicity Late grade 2 GU/Bladder Toxicity 70Gy 13% 8% 78Gy 26% p=0.013 13% 70.2GyE 8% 18% 79.2GyE 17% p=0.005 20% 68Gy 27% 39% 78Gy 32% p=0.2 41% 64Gy 24% 8% 74Gy 33% p=0.005 11% p=ns p=ns p=0.6 p=0.14
Freedom from Grade 2 Toxicity (RTOG Scale) Gastrointestinal Genitourinary Kuban IJROBP 2008
Percent Complication Free Rectal Toxicity Related to Rectal Dose MD Anderson Randomized Trial 100 90 80 70 60 50 40 30 20 10 0 0 12 24 36 Time (months) Storey (MD Anderson) IJROBP 2001 48 p = 0.05 60 < 25% >70 Gy > 25 % >70 Gy
IMRT vs 3DCRT DOSE SUBTRACTION
Long Term Impact of IMRT on Toxicity 3DCRT IMRT Zelefsky IJROBP 2008
IMRT vs 3DCRT in the RTOG 0126 Dose Escalation Trial >1500 pts randomized 70.2Gy vs 79.2Gy 748 evaluable patients High Dose Arm 491 3DCRT 257 IMRT Comparison to be reported Dosimetry: Organ at Risk Acute Toxicity Late Toxicity Patient Reported Outcomes (QOL) Bowel, Urinary, Sexual Accepted for Plenary Session, ASTRO 2011
Disease Outcomes with Dose Escalation Department of and Siteman Cancer Center
Randomized Dose Escalation Trials Author N Hormones Biochemical Disease Free survival Benefit Clinical Disease Free survival Benefit Overall survival Benefit Subgroup benefit Kuban, Pollack (2007) Zietman (2010) Al-Mamgani (2008) Dearnaley (2007) 301 No p=0.004 p=0.014 None PSA>10 393 No p<0.001 P<0.05* None Low, Int 664 Some p=0.02 p=ns None Int, High 843 All p=0.0007 p=0.064 None All Beckendorf (2008a) 306 No P=0.036 A P=ns P P=ns None ipsa 15 *11% v 6% received salvage hormone therapy
LONG-TERM RESULTS OF THE M. D. ANDERSON RANDOMIZED DOSE-ESCALATION TRIAL FOR PROSTATE CANCER D Kuban, S Tucker, L Dong, G Starkshall, E Huang, MR Cheung, A Lee, A Pollack MD Anderson Cancer Center Department of and Siteman Cancer Center IJROBP 2008
MD Anderson Long Term Results Kuban IJROBP 2008
MD Anderson Long Term Results Kuban IJROBP 2008
Hormone Therapy Who? Duration? Department of and Siteman Cancer Center
3DCRT alone vs 3DCRT + AST D Amico JAMA 2004
RTOG 9408: A Phase III Trial Of The Study Of Endocrine Therapy Used As A Cytoreductive And Cytostatic Agent Prior To Therapy In Good Prognosis Locally Confined Adenocarcinoma Of The Prostate S T R A T I F Y PSA 1. <4 2. 4 to 20 Grade 1. Well 2. Moderately 3. Poor Nodal Status 1. N0 2. Nx R A N D O M I Z E Arm 1 Neoadjuvant TAS 2 months before and during RT Arm 2 Therapy Alone Reported ASTRO 2009 N=2028
RTOG 9408 Population T-stage T1 49%; T2 51% PSA <4 11%; PSA 4-20 89% GS 6 61%; 7 27%; 8-10 9% Overall Survival RT alone 46% RT + Hormones 51% Rebiopsy Negative RT alone (n=404/992) 60% (241) RT + Hormones (n=439/987) 78% (344) ASTRO 2009
Hormones or Dose Escalation Department of and Siteman Cancer Center
RTOG 0815: Phase III Trial Of Dose-escalated Radiotherapy With Or Without Short-term Androgen Deprivation Therapy For Intermediate-risk Prostate Cancer S T R A T I F Y Number of Risk Factors 1. One 2. Two or Three Comorbidity 1. ACE-27 grade 2 2. ACE-27 < grade 2 RT Modality Dose escalated EBRT EBRT + LDR brachy EBRT + HDR brach R A N D O M I Z E Arm 1 Dose Escalated RT alone Arm 2 Dose Escalated RT with Short term Androgen Blockade (LHRH + AA) Intermediate risk factors: Gleason Score 7; PSA >10 but 20; T-Stage T2b-T2c. If all three AND >50% cores are positive, patient is INELIGIBLE Sample size = 1520
TREATMENT IMPACT ON QUALITY OF LIFE
Washington University Patient Population Clinical stage Gleason score Pre-Rx PSA EBRT BRACHY 87 Patients 182 Patients Pre-Rx Hormones 2 (2%) 5 (3%) T 1c T 2a T 2b T 3a T 3b 3,4 5 6 7 8,9 Range Median 39 (45%) 129 (71%) 22 (25%) 43 (24%) 12 (14%) 10 (5%) 5 (6%) 0 (0%) 9 (10%) 0 (0%) 0 (0%) 9 (5%) 3 (3%) 18 (10%) 45 (52%) 129 (71%) 27 (31%) 22 (12%) 12 (14%) 4 (2%) 0.08-53.2 0.1-22.2 7.3 5.1 Post-RT hormones 9 (10%) 2 (1%) Range 48-86 49-80 Age Median 71 70
Therapy Techniques EBRT 87 Patients 3DCRT with minimum prescription to PTV Pelvic XRT (12 patients) Mean 74.3Gy (70Gy-79.2Gy) BRACHY 182 patients Monotherapy 154 patients 103 Pd 115 Gy (17 Patients) 125 I 145 Gy (137 Patients) Combined Therapy (45 Gy EBRT) 28 patients 103 Pd 90 Gy (18 Patients) 125 I 108 Gy (10 patients)
TOTAL FACT-P Total Score Mixed Repeated Measures Model 140 135 130 125 120 115 110 1 2 3 4 5 6 7 8 QUARTER p=0.038 BRACHY EBRT
N Engl J Med 2008;358:1250-61.
Early Stage Prostate Cancer Observational Studies: The PROST-QA Consortium PROST-QA Consortium study design: Data collection: Patient-reported HRQOL and Satisfaction with cancer care baseline and 5 f/u phone interviews over 3 years (MSU CATI) Demographic/socioeconomic subject data Cancer severity Treatment details Clinical follow-up Accrual completed March 2006: 1901 subjects enrolled and eligible for follow-up 1205 patients, 696 spouse/partners >90% subject retention @ 20 months median followup Interview completion rate Pretreatment (baseline) 2 mos 6 mos 12 mos 24 mos # Beyond time after treatment 1205 1182 1079 516 # completed 1205 1107 1007 489
Characteristics of PROST-QA Patients Age Prostatectomy Brachytherapy External RT N=602 N=311 N=292 Median 59 (38-79) 65 (44-84) 69 (45-84) <60 N (%) 304 (50) 67 (21) 41 (14) 60-59 N (%) 253 (42) 149 (47) 115 (39) >70 N (%) 45 (7) 95 (30) 136 (46) p-value <0.001 Race White N (%) 547 (90) 265 (85) 238 (81) African American N (%) 31 (5) 36 (11) 47 (16) Other N (%) 15 (2) 5 (1) 2 (1) Not reported N (%) 9 (1) 5 (1) 5 (1) <0.001 Education College graduate N (%) 374 (62) 171 (54) 154 (52) 0.013 Marital status Married or partner N (%) 523 (86) 245 (78) 228 (78) <0.001 # Comorbidities Mean (SD) 0.9 (1.1) 1.3 (1.1) 1.5 (1.3) <0.001 Body Mass Index Mean (SD) 28.0 (4.5) 28.5 (5.3) 28.7 (4.9) NS PROST-QA Consortium
Cancer Characteristics of PROST-QA Patients Prostatectomy Brachytherapy External RT N=602 N=311 N=292 p-value PSA Mean (SD), ng/ml 6.7 (5.6) 5.9 (3.9 8.8 (9.9) PSA Median (range) 5.5 (0.5-71.6) 5.1 (0.6-44.0) 6.3 (0.5-99.3) PSA PSA <4, N (%) 126 (20) 69 (22) 47 (16) <0.001 PSA=4-10, N (%) 396 (65) 219 (70) 177 (60) PSA>10, N (%) 77 (12) 22 (7) 67 (22) Biopsy Gleason Score Gleason<7, N (%) 368 (61) 229 (73) 130 (44) Gleason=7, N (%) 207 (34) 77 (24) 122 (41) Gleason>7, N (%) 24 (4) 4 (1) 39 (13) <0.001 Clinical Stage Stage T1, N (%) 435 (72) 256 (82) 200 (68) Stage T2, N (%) 164 (27) 54 (17) 91(31) <0.001 Amount Cancer on Biopsy Mean Proportion of cores having cancer (SD) 0.33 (0.23) 0.26 (0.18) 0.36 (0.24) 0.002 Overall Cancer Severity Category Low risk, N (%) 266 (44) 184 (59) 79 (27) Intermediate risk, N (%) 301 (50) 120 (38) 161 (55) High risk, N (%) 32 (5) 6 (1) 51 (17) <0.001
Early Stage Prostate Cancer Observational Studies: The PROST-QA Consortium PROST-QA Cohort Characteristics Treatment Type Prostatectomy: (602) 51% Retropubic (375), Laparoscopic (110), robot-assisted (117) External (311) 23% Monotherapy (73%), with NHT (27%) IMRT (83%) Brachytherapy (292) 26% Monotherapy (88%), with ERT or NHT (12%)
Sexual Sexual Function PROST-QA 100 Prostatectomy External Brachytherapy 80 60 40 20 A B C 0 0 6 12 18 24 0 6 12 18 24 0 6 12 18 24 Follow-up (months) Nerve Sparing Non-Nerve Sparing XRT alone XRT + NHT BT alone BT+ XRT and/or NHT * --statistically significant # --statistically and clinically significant (>0.5*SD of HRQOL score)
Urinary Irritation/ Obstruction Urinary Incontinence Urinary Function PROST-QA Prostatectomy External Brachytherapy 100 80 60 40 D E F 100 80 60 40 G Nerve Sparing Non-Nerve Sparing H XRT alone XRT + NHT I BT alone BT+ XRT and/or NHT 0 6 12 18 24 0 6 12 18 24 0 6 12 18 24 * --statistically significant # --statistically and clinically significant (>0.5*SD of HRQOL score) Follow-up (months)
Bowel/Rectal Bowel/Rectal Function PROST-QA 100 Prostatectomy External Brachytherapy 80 60 40 J K 0 6 12 18 24 0 6 12 18 24 0 6 12 18 24 L Follow-up (months) Nerve Sparing Non-Nerve Sparing XRT alone XRT + NHT BT alone BT+ XRT and/or NHT * --statistically significant # --statistically and clinically significant (>0.5*SD of HRQOL score)
Vitality/Hormonal Vitality/Hormonal Function PROST-QA Prostatectomy External Brachytherapy 100 80 60 40 M Nerve Sparing Non-Nerve Sparing N XRT alone XRT + NHT O BT alone BT+ XRT and/or NHT 0 6 12 18 24 0 6 12 18 24 0 6 12 18 24 Follow-up (months) * --statistically significant # --statistically and clinically significant (>0.5*SD of HRQOL score)
% Reporting Moderate or Big Problem HRQOL related Bother @ 12 months Moderate or Big Problem 100 90 80 70 60 50 49 RP XRT BT 40 30 20 10 31 30 7 9 21 2 11 11 11 19 13 0 Sexual Urinary Bowel/Rectal Vitality Hormonal PROST-QA Consortium NEJM 2008
Comparison of HRQOL following RP, EBRT or Brachytherapy Longitudinal prospective study of 614 patients 134 Radical Prostatectomy 205 External Beam Therapy 275 Brachytherapy Instruments Medical Outcomes Study SF-36 FACT EPIC AUA-Symptom Index Non-Randomized treatment selection 2 year post treatment comparisons Ferrer (Spain) IJROBP 2008
Medical Outcomes and SF-36 Ferrer (Spain) IJROBP 2008
EPIC Urinary Ferrer (Spain) IJROBP 2008
EPIC Bowel and Sexual Ferrer (Spain) IJROBP 2008
Conclusions External Beam radiation therapy with dose escalation results in excellent biochemical disease free survival and in some studies superior clinical disease free survival compared to conventional doses. The role of hormone therapy in low and intermediate risk cancers in the context of dose escalation is under investigation. All treatments have an impact on quality of life, in various domains. The optimum treatment depends on patients perceptions of risk and expectations for functional recovery.