RT for High-Risk and Post- operative Prostate Cancer ASTRO Refresher Course 2014

Transcription

1 RT for High-Risk and Post- operative Prostate Cancer ASTRO Refresher Course 2014 Stanley Liauw MD Associate Professor University of Chicago Dept of Radiation and Cellular Oncology

2 Objectives Review evidence regarding the role of RT for high-risk (locally advanced) prostate cancer Review evidence regarding the role of RT after radical prostatectomy Review treatment factors which influence outcomes (disease control, toxicity) Review technical aspects of post-operative radiation planning and treatment

3 High-Risk, Intact Prostate Cancer

4 Definitions: NCCN risk category Recurrence risk Features Consider surveillance, if expectancy: Very low T1c, Gleason score 6, PSA < 10, fewer than 3 cores positive, 50% involved in each core, PSA density <0.15 ng/ml/g <20 years Low T1-2a, Gleason score 6, PSA < 10 <10 years Intermediate T2b-c OR Gleason score 7 OR PSA <10 years High T3a OR Gleason score 8 OR PSA >20 Not specified Very high (locally advanced) Metastatic T3b-4 Any nodal or distant metastasis Not specified Life expectancy estimation is less critical for men with high risk prostate cancer

5 Management of high-risk disease EBRT (+/- brachytherapy) with long term ADT Radical prostatectomy (if no fixation) and LND +/- RT ADT alone only for very-high risk disease who are not candidates for local therapy Local therapy can improve survival NCCN guidelines 2014

6 RT/ADT vs. ADT Eligibility SPCG-7 Widmark Lancet Onc 2009 T3 or T1b-2b/WHO G2-3; PSA<70; pn0 if PSA > 11 Patients n=875 78% T3 Median PSA 16 19% WHO G3 NCIC/MRC Warde Lancet 2011 T3-4, or T2 with PSA>40, or GS8 with PSA>20; cn0/nx n= % T3 Median PSA 28 18% GS 8-10 Treatment 70 Gy (no pelvic RT) Gy (45 Gy pelvis) Indefinite ADT Anti-androgen (3 mo LHRH) LHRH agonist (2+ wk anti-androgen) Median fu 7.6 y 6.0 y

7 RT/ADT vs. ADT SPCG-7 Cause specific mortality 24% NCIC/MRC Overall survival 74% 66% 12% At 10 years RT/ADT ADT p PSA failure 26% 75% <0.001 CSS 88% 76% <0.001 OS 70% 61% At 7 years RT/ADT ADT p Time to progr NR 6.8 y CSS 91% 81% OS 74% 66% 0.03 RT improves survival, with limited Grade 3 toxicity ( 2%) Perhaps a wider risk/benefit ratio with newer technology

8 What about surgery? Low risk Intermediate risk High risk RP has traditionally been reserved for lower risk disease Cooperberg, JCO 2010

9 Surgery vs. RT Retrospective studies of biochemical control n=2991, Median follow-up 56 mo T1-T2 disease: Surgery and dose escalated RT offer similar brfs Kupelian, IJROBP 2004

10 Surgery vs. RT Retrospective studies of late endpoints, including high risk disease Outcome Endpoint Reference MSKCC, n=2380 RP > EBRT Metastasis Zelefsky JCO 2010 CapSURE, n=7538 RP > EBRT Cancer mortality Cooperberg, Cancer 2010 Mayo/FCCC, n=1847 RP > EBRT (RP = EBRT/ADT) Cancer mortality Boorjian, Cancer 2011 CCF/WashU, n=10429 RP > EBRT Cancer mortality Kibel, J Urol 2012 PCOS, n=1655 RP > EBRT Cancer mortality Hoffman, JNCI 2013 HRs favor RP ( ), largest for high-risk disease

11 Surgery vs. RT Time from metastasis to cancer death depends on primary modality of therapy RP RT SEER-Medicare data n=574 with int/high risk disease Median follow-up 33 mo Shao, Eur Urol 2013

12 Limitations with comparative data Imbalances in the two groups are likely Contribution of salvage therapies can influence analysis Comparisons may be outdated (suboptimal RT dose, imaging, ADT by today s standards) Quality of life and toxicity are not considered A safe conclusion: with primary RT, maximize efforts to safely obtain local control

13 RT dose Supported by several randomized trials to improve biochemical control 78 Gy 73% at 10 y 70 Gy 50% at 10 y Kuban, IJROBP 2008

14 RT dose n Eligibility RT dose (Gy)* FFBF at 5 y MDACC (2002,2008) Harvard/LLMC (2005,2010) Dutch (2006,2013) MRC (2007) GETUG (2011) 301 T1b-3 78 vs /50 (10 y); trend FFDM and CSS 393 T1b-2b, PSA< T1b+, GS6+, PSA< T1b-3a, PSA< vs /68 (10 y) 78 vs. 68* 49/43 (10 y) 74 vs. 64* 71/ T1b-3, PSA<50 80 vs /61 *ADT allowed Dose escalation is supported for all risk categories Local control remains a problem even with dose escalation to Gy

15 RT dose 0% 0% 3% Distant failures after 78 Gy MDACC study: median follow-up 9.7 years Kuban, IJROBP 2011

16 Combination EBRT/brachytherapy 848 outcomes studies (n=14,793 high risk pts) EBRT+seeds+ADT EBRT+seeds EBRT RP Grimm, BJUI 2012 Suggestion of improved outcomes with EBRT + seeds in comparison to EBRT or RP

17 EBRT vs. EBRT/brachytherapy Dose escalation with brachytherapy boost is supported by a few smaller RCTs n Eligibility RT dose (Gy)* FFBF at 5 y Mt Vernon, UK (2007) McMaster, Ont (2005) 220 T1-T /13 fx + HDR vs. 55/20 fx 51 T2-T3 40/20 fx + HDR vs. 66/33 fx 79/64 71/39 +biopsy at 2 yr: 24/51 BED was relatively low in the EBRT alone arm UBC trial compares 46 Gy + brachy vs. 78 Gy in int/high risk disease (analysis planned in 2014)

18 Role of ADT with RT Several randomized trials test RT/ADT vs. RT High-risk Int-risk EORTC (1997,2010) RTOG 8531 (1997,2005) RTOG 8610 (1995,2001) TROG 9601 (2005,2011) Harvard (2004,2010) RTOG 9408 (2011) n Eligibility ADT Important endpoints affected 412 T3-4, WHO G3 997 T3, or N+ (non-bulky) 456 T2-4 bulky, or N+ 36 m vs. 0 m brfs, LC, DM, CSS, OS Indef. vs. none brfs, LC, DM, CSS [OS for GS7-10] 4 m vs. 0 m brfs, [LC, DM, CSS, OS for GS2-6] 818 T2b-4; N0 0 vs. 3 vs. 6 m brfs, LC [DM, CSS, OS for 6 m] 206 PSA 10-40, or GS7+, T1b-2b 1979 T1b-2b, PSA 20; cn0 6 m vs. 0 m FFbF, FF salvage, CSS, OS 4 m vs. 0 m FFbF, DM, CSS [OS for int-risk] +biopsy at 2 y RT is conventional fractionation, Gy; whole pelvic RT for high risk patients The addition of ADT (dual agent) to RT improves survival

19 Role of ADT with RT Other randomized trials test length of ADT n Eligibility ADT Important endpoints affected High-risk Int-risk RTOG 9202 (2003,2008) EORTC (2009) Quebec (abs 2013) Canadian (2004,2009) RTOG 9910 (abs 2012) 1554 T2c-4, N0; PSA< T2c-4, or N+ PSA< T3 or PSA>20 or GS8, N0 28 m vs. 4 m brfs, LC, DM, CSS [OS for GS8-10] 36 m vs. 6 m CSS, OS 36 m vs. 18 m No differences 378 Any M0 8 m vs. 3 m No differences [DFS for high-risk] 1579 GS6+PSA>10; GS7+PSA<20; T1, GS8-10, P<20 9 m vs. 4 m No differences RT is conventional fractionation, Gy; whole pelvic RT for high risk patients Using conventional RT to treat high risk disease, there is a survival advantage with longer term ADT

20 Role of ADT with RT For prostate cancer with high-risk features: ADT local control, distant control, and survival Gy Gy Int-risk High-risk 4-6 months? 4-6 months months months?

21 Dose escalated EBRT +/- ADT Retrospective analysis of 234 men treated with Gy and varying ADT > 1 year After dose escalated RT, long term ADT is associated with better biochemical and distant control Feng IJROBP 2013

22 PSA response as a prognostic variable? 10yr FFDM 86% Pre-RT PSA nadir yr FFDM 79% FFbF yr FFbF 96% 4yr FFbF 81% Pre-RT PSA halving time 2 weeks Time (months) Malik IJROBP 2011 Zelefsky IJROBP 2013 Post-RT PSA nadir 0.5 8yr PCSM 27-28% 8yr PCSM 4-7% D Amico Lancet Onc 2012 These potential biomarkers to guide duration of ADT must be further tested

23 Biomarkers as a (future) variable? 22- gene classifier for distant metastasis after RP (via RNA micro dissection) Prostate ca survival Low GC score High GC score Karnes J Urol 2013

24 Hormonal therapy

25 Hormonal therapy SEER-Medicare Veterans Affairs ADT can cause: Insulin sensitivity LDL, HDL and TG Fat mass ( lean mass) Absolute Excess Risk: 15 cases/1000 patient years Keating, JCO 2006; JNCI 2012

26 Hormonal therapy In 8 RCTs, ADT did not risk of CV mortality Nguyen JAMA 2011 Joint statement: referrals to cardiology for ADT clearance are not necessary (Levine, Ca J Clin 2011)

27 RT volume Pelvic nodes can be involved in high risk disease Incidence ~22% from extended LN dissection data Lymph node involvement goes beyond standard US template >50% of time Weckerman J Urol 2006

28 RT volume Does pelvic radiation improve outcomes? RTOG 9413 (2003,2007) GETUG-01 (2007) n Eligibility Arms Endpoints affected 1292 T2c-4 GS6+, or LN+ risk >15%; PSA<100 Whole Pelvis vs. Px only Neoadj HT vs. Adj HT 444 T1b-3 Low pelvis RT vs. Px only (ADT allowed) Trend PFS for WPRT/NHT (and PORT/AHT) None WP/NHT vs. PO/NHT p=0.066 WP/AHT p=0.022 PO/AHT p=0.75 Lawton IJROBP 2007

29 5-year rates of late toxicity RT volume Pelvic radiation adds toxicity Gastrointestinal: Grade 2 Grade 3 Genitourinary: Grade 2 Grade 3 WPRT (n=309) 15% 4% 15 3% Mini-pelvis (n=170) 9% 1% 15% 2% Prostate (n=131) 7% 0% 6% 0% P value Roach IJROBP 2006 The risk benefit ratio for 2D pelvic RT is unfavorable Today, careful patient selection and technology may influence the decision to include pelvic lymph nodes

30 Summary: High risk, intact prostate cancer Role of RT+ADT well established by RCTs Long term ADT superior to short term ADT Dose escalation improves outcomes Brachytherapy boost may be an attractive alternative in select cases Pelvic nodal RT (2D) demonstrates an unfavorable risk-benefit ratio The standard of care may change with incorporation of newer technology (IMRT, IGRT), and new drugs

31 UCMC guidelines for Intact prostate cancer Discuss: Treatment vs. no treatment, Surgery vs. RT Always weigh comorbidity (and consider surveillance) NCCN risk category: EBRT: ADT: Low-risk Intermediate risk High risk 78 Gy at 2/fx Prostate only No <50% cores 50% cores <T3 T3; GS9-10; high vol; N1 78 Gy at 2/fx Prostate/SV No 78 Gy at 2/fx Prostate/SV 6 mo 78 Gy at 2/fx Prostate/SV 6 vs. 28 mo 79.2 Gy at 1.8/fx Pelvic LN, Px/SV 28 mo brachy: Monotherapy preferred if age<65 Monotherapy preferred if age<65 Boost considered if age<65 Boost considered if age<65 Boost considered if age<65 Comorbidity can downstage treatment (~1 category) Consider protocol enrollment a priority when eligible

32 Post-operative Prostate Cancer

33 Outcomes after prostatectomy Overview Risk factors %bned-10 y 8 centers margins 36 Karakiewicz Urol 2005 Med fu 25 mo bned 61% at 10 y ECE, +/- margins SVI, +/- margins 25/46 12/20 N=5831 0% adj RT LNI, +/- margins 14/8 Wash U Stage ct3 15 Roehl J Urol 2004 Med fu 65 mo bned 68% at 10 y Gleason score 8 ECE, +/- margins 32 53/62 n=3478 6% adj RT SVI 26 LN 12 Baylor margins 36 Hull J Urol 2002 Med fu 47 mo bned 75% at 10 y ECE alone SVI n=1000 0% adj treatment LN 7 Men with +margins, pt3 disease have >50% risk of failure at 10 yrs

34 Randomized trials: adj RT vs obs EORTC SWOG 8794 ARO 9602 Bolla Lancet 2012 Thompson J Urol 2009 Wiegel JCO 2009/ GU ASCO 13 Eligibility pt2-3n0 pt2-3n0 pt3n0 ece, svi, or psm ece, svi, or psm ece, svi, psm Patients n= Age 65 y Med preop PSA 12 Postop PSA 0.2 in 70% RT techniques 60 Gy Conventional Prostate bed Within 4 mo n= Age 65 y Med preop PSA ~10 Postop PSA <0.2 in 66% Gy Conventional Prostate bed Within 4 mo n= Age 65 y Median preop PSA ~9 Postop PSA 0.2 in 100% 60 Gy 3D conformal Prostate bed Within 3 mo Median fu 10.6 y 11.5 y 9.3 y

35 Randomized trials: adj RT vs obs EORTC SWOG 8794 ARO 9602 bned 61% at 10 y ~50% at 10 y 56% at 10 y 41% at 10 y ~25% at 10 y 35% at 10 y Endpoints bpfs, LRF-10 y (7/17) Clinical PFS-10 y (~70/50) bpfs (primary) DM (~11), OS-10 y (~78) bpfs: all except age>70 cpfs: age<65, +margins On ADT- 5y (10/21) MetFS-15 y (46/38) OS-15 y (47/37) bpfs: +margins, PSA>10, pt3b, GS 7 OS: none (worse if >70) RT toxicity Acute ~20% Gr2; 5% Gr3 Any grade 24% (vs 12%) 12% Gr2; 3% Gr3 Late ~10% Gr2; 2% Gr3 proctitis, stricture, incontinence ~ 5% Gr 2; 1% Gr3

36 Quality of life Health related QOL: Adj RT vs obs. (n=217) Frequent (mild) rectal Tenderness or urgency Urinary frequency 9x/day Insufficient erectile function (Normal) Global HRQOL RT RP Global HRQOL: rating of how life is affected by your state of health Moinpour, JCO 2008

37 ASTRO/AUA joint guidelines 3 guidelines regarding adjuvant RT: Statement Clinical principle Clinical principle Grade A evidence Recommendation Counsel men on possibility of recurrence after RP Inform men that adjuvant RT can be beneficial Offer men with negative features at RP adjuvant RT Valicenti, IJROBP 2013

38 Have these RCTs changed practice? No change in use of adjuvant RT for high-risk disease Hoffman, J Urol 2011

39 Concerns with adjuvant RT exist 1. Observation group did not routinely receive early salvage RT after failure Median time 2.2 years Original protocol specified salvage treatment at LF If early salvage RT were routinely given, perhaps we would not detect a benefit with adjuvant RT Bolla, Lancet 2005

40 Subgroups: Adjuvant vs. early salvage SWOG Metastasis-FS ~30% of men were enrolled with a postop PSA >0.2 EORTC bpfs

41 Early salvage RT Matched paired analysis of adjuvant and observation with early salvage (PSA 0.5) as needed Adj RT: 5-year FFBF 82% Salv RT: 5-year FFBF 78% 65 Gy Bed alone Med PSA 0.2 at salvage n=890, Median FU 47 mo Early salvage RT adjuvant RT; avoids overtreatment Trials are accruing to address this issue Briganti Eur Urol 2012

42 Concerns with adjuvant RT exist 2. A large percentage of men may be treated unnecessarily Risks of therapy Costs of therapy Surgeons may be especially sensitive to a therapy which could compromise their patients recovery With adjuvant RT? Sanda NEJM 2008

43 Does RT adversely affect continence? Subset of men on EORTC (n=100) Pad weight measured with adj RT vs. no RT: Pre-RT Post-RT Full continence recovery was not required at randomization Rate of full continence (Grade 0) was similar in both groups at time of last follow-up Van Cangh, J Urol 1998

44 Does RT adversely affect continence? Retrospective comparison, Milan (n=361) 81% 51% RT dose 70.2 Gy at 4.5 mo after RP Suardi, Eur Urol 2013

45 The Ideal candidate for adjuvant RT (?) High risk for recurrence: Positive margins or pt3 Consider for post-rp LN+ disease Reasonably good recovery of continence Longer life expectancy Patient who understands potential pros/cons of therapy

46 The Ideal candidate for adjuvant RT (?) Hypotheses: Adjuvant RT is better because Adjuvant treatment is less toxic than salvage RT Gy without ADT vs. ~68+ Gy +/- ADT A delay in treatment might risk of DM PSA does not reliably report disease burden or growth kinetics in all cases Follow-up anxiety can be minimized Caveat: We cannot confirm that early salvage RT is an inferior approach

47 Adjuvant RT for LN+ disease Matched, retrospective comparison, Milan Preop PSA ~30; 25% had > 2 LN+ 10-y CSS 86% Adj RT 3 mo after RP; ~68.4 Gy + long term ADT 10-y CSS 70% n=703, Median follow-up 95 mo Briganti, Eur Urol 2011

48 Salvage RT Retrospective data support salvage RT vs obs Johns Hopkins JAMA 2008 Mayo Clinic J Urol 2009 Duke Cancer 2011 n Patients Treatment Important endpoints affected 635 Observation or RT Median PSA ~0.8 43% margin + 28% GS 8+; 20% N Observation or RT Median PSA % margin + 11% GS 8+; No N1 519 Observation or RT 59% margin + 29 GS 8+; No N1 Median 66.5 Gy 12% ADT RT dose not reported No ADT Median 66 Gy 16% ADT RT improves CSS 10 yr CSS, ~85% vs. 62% [best for PSA DT < 6 mo] RT reduces DM RT improves OS Salvage RT is associated with CSS and OS

49 Salvage RT FFP-6 y PSA 0.5 PSA > % 18% n=1540, Median follow-up 53 mo FFP associated with: Gleason score Pre-RT PSA LN involvement Margin status PSA DT Use of ADT Similar to intact prostate (T/N, Gleason, PSA) + two post-op factors (margins and PSA DT) Stephenson, JCO 2007

50 Salvage RT Meta-analysis of 41 salvage RT studies 2.6% loss of RFS per 0.1 ng/ml PSA Best outcomes with lower pre-rt PSA (0.2 probably better than 0.5) King IJROBP 2012

51 Salvage RT: patient selection Clinical factors are used to prognosticate outcome 6-year progressionfree probability after salvage radiotherapy Output typically 30-70% Largest impact for PSA DT, pre-rt, GS, LN status, ADT Stephenson JCO 2007 These men (e.g. short PSA DT) may actually have the biggest gain in CSS

52 New referral with a post-op PSA Post-op active surveillance analogy Weighing natural history of disease vs. life expectancy 15-y CSS 94%: BF > 3 y after RP, PSA DT 15 mo, GS < 8 Freedland JAMA 2005

53 ASTRO/AUA joint guidelines 6 guidelines regarding salvage RT: Statement Clinical principle Clinical principle Grade C evidence Grade C evidence Clinical principle Clinical principle Recommendation PSA recurrence post-op is associated with clinical failure PSA failure post-op is defined as 0.2 and rising Consider restaging men with biochemical failure Offer men with rising PSA post-op salvage RT Salvage RT is most successful for a low PSA Post-op RT has possible acute and late toxicity Limited by quality of evidence available Valicenti, IJROBP 2013

54 Salvage RT: imaging Ultrasound and biopsy Recommended? No Comment Moderate sensitivity only; only evaluates prostate bed CT abdomen/pelvis No Low sensitivity with low PSA Bone scan If PSA >10, PSADT<6 mo, velocity >0.5 ng/ml/mo; or sx RIS (e.g. Prostascint) Not routinely Low sensitivity with low PSA; indeterminate findings possible Accuracy questionable; does not predict better salvage RT response PET (C11, F18) Not routinely Accuracy low for PSA <2 MRI (Endorectal, DCE, DWI) Consider, especially for pt3 and positive margins Most favorable sensitivity and specificity (Lymphotropic nanoparticles not approved) Adapted from: Beresford, Clin Onc 2010

55 Salvage RT: Endorectal MRI Local recurrences as seen on endorectal MRI: 88 men evaluated for salvage RT, median PSA 0.3 Radiographic abnormalities in prostate bed in 24% (α PSA) Abnormalities seen on T2 MRI (90%) > DWI or DCE Still unclear whether MRI findings should influence patient selection or treatment Liauw IJROBP 2013

56 Optimizing salvage RT Data driven approach towards intensification of therapy to improve outcomes RT dose RT volume Combined ADT Available data Retrospective Retrospective Limited prospective, and Retrospective

57 RT dose Can dose escalation be extrapolated from the intact setting? 70 Gy is better than 60 Gy King IJROBP 2012

58 RT dose PSA Gy=50% PSA Gy=50% PSA Gy=35% 70 Gy 65 Gy Higher RT doses might compensate for a higher pre-rt PSA Ohri IJROBP 2011

59 RT dose Is there an upper limit to the dose response? Median pre-rt PSA 0.4 but dose 70 Gy was associated with lower rate of local failure men with LF on emri (p=0.07) n=285, Median follow-up 60 mo Goenka IJROBP 2012

60 RT dose 76 Gy to the post-operative bed 5 year FFBF 56% Toxicity: Gr2-3 GU 22% Gr2-3 GI 8% Median pre-rt PSA 0.8 n=136, Med follow-up 60 mo High dose IMRT is tolerated with limited G3 tox (Smaller, MRI defined prostate bed mm with IGRT) Ost Eur Urol 2011

61 RT volume Does inclusion of pelvic lymph nodes improve efficacy of salvage RT? With a median PSA 0.5, 23% of men had +LNs on nanoparticle MRI (Ross, Clin Imaging 2009) Shih IJROBP 2005

62 RT volume Stanford Duke/VCU Subset: pt3, GS8+, preop PSA>20 (with ADT) Subset: PSA >0.4 (no ADT) WPRT n=114, median follow-up >5 y PBRT n=139, median follow-up 4 y Spiotto IJROBP 2007 Moghanaki Cancer 2013 Certain subsets may benefit from pelvic nodal RT

63 Use of ADT RTOG pts, pt2-3n0 with PSA Gy + 2 years of bicalutamide 150 mg daily 64.8 Gy alone Median follow-up 7.1 years No difference in overall survival ADT 7-year FFBF and DM (13% vs. 7%) Shipley ASTRO 2010

64 Use of ADT Prospective, single arm studies n Eligibility RT ADT Important endpoints Sunnybrook (2009) 78 pt3 or R Gy 2 years (adj CAB/LHRH) Adjuvant: FFBF-5 y 100% Salvage: FFBF 5-y 85% Sunnybrook (2009) 75 pt3 or R1, PSA detectable Gy 2 years (adj CAB/LHRH) Salvage: FFBF 5-y 92%, 7-y 79% SWOG S9921 (2011) 481 PSA >15, pt3b, N1, GS8-10, R1 Only in 27% 2 years (CAB) FFBF-5 y 93% Retrospective ADT data generally indicate FFBF but results are mixed Randomized trials are accruing to test ADT and volume

65 UCMC guidelines for Post-op RT Always assess comorbidity (and consider surveillance) Adjuvant RT (PSA undetectable) Salvage RT (PSA detectable) Only if pt3 or margin+; N0 N1 Favorable (e.g. margin+, lower GS, older age) Unfavorable (e.g. higher GS, younger age, N1) EBRT: 64 Gy at 2/fx Prostate bed 64 Gy at 2/fx Pelvic LN, bed 68 Gy at 2/fx Prostate bed 68.4 Gy at 1.8/fx Pelvic LN, bed ADT: No, but fair to consider 4-28 mo (consider 28 mo if age <65) No 4 mo (consider 28 mo if N1 and age <65) Consider boosting emri defined or gross disease to ~72 Gy Consider protocol enrollment a priority when eligible

66 RT Modality (+/- ADT as indicated) Late Toxicity (Grade) GI Toxicity GU Toxicity References Gr2 Gr3 Gr2 Gr3 Adjuvant RT EORTC Salvage RT Standard dose 76 Gy with IMRT Comparable toxicity rates to intact setting Treatment factors including volume and dose likely have impact Multi-institutional Belgium

67 Toxicity (Symptom Scores) Patient reported QOL shows stability at 4 years Melotek, submitted

68 Toxicity (Symptom Scores) Post-op IMRT does not clearly worsen continence Corbin, PRO 2013

69 Contouring: Prostate bed Guidelines have been proposed by 4 groups Differences mainly regard coverage of anterior and superior prostate bed PMH Wiltshire, IJROBP 2007 RTOG guidelines are online for prostate bed and pelvic LNs

70 Planning guidelines DVH relationships are less established for the post-op setting compared to the intact setting RTOG 0534: Metric Goal PTV V100 95% Dmax 115% Rectum V65 Gy 35% (+10) V40 Gy 55% (+10) Bladder (minus CTV) V65 Gy 50% (+7.5) V40 Gy 70% (+7.5) Femoral heads V50 Gy 10%

71 IMRT SEER-Medicare: % 0% Goldin, JAMA Int Med 2013

72 IMRT vs. 3DCRT SEER-Medicare analysis of 251,787 men No difference in procedures or diagnosis codes between IMRT and 3DCRT Goldin, JAMA Int Med 2013

73 MSKCC IMRT vs. 3DCRT 176 pts IMRT ( 70 Gy); 109 pts 3DCRT (66-70 Gy) Treatment primarily to prostate bed alone Median follow-up 60 months Grade 2+ GI toxicity 10% 2% 17% 16% IMRT may allow for safer escalation of dose to ~70 Gy Goenka Eur Urol 2011

74 IGRT for post-op RT Bony anatomy Ultrasound Surgical clips or fiducial markers in prostate bed (kv) Cone beam CT Comments Most widely available PTV margin ~ cm not always reliable due to soft tissue movement Monitor bladder, rectal filling; No additional radiation exposure Inter-observer variability in use Easily seen and quickly imaged Does not evaluate soft tissue anatomy See entirety of prostate bed volume More time on treatment table

75 IGRT for post-op RT Surgical clips in the prostate bed Clips are reproducibly identified Rectal DVH improved with 5 mm vs 10 mm margin Song Rad Onc 2012

76 UCMC guidelines on IGRT use Post-operative RT planned Prostate bed alone Prostate bed and pelvic LNs* PTV margin, bed: No surgical clips Surgical clips No surgical clips Surgical clips 6 mm lateral 8 mm ant/post 9 mm sup/inf IGRT: kv: set up to bony anatomy; At least weekly CBCT (after d1,2 confirms reproducibility) 5 mm uniform Daily kv: set up to clips 6 mm lateral 8 mm ant/post 9 mm sup/inf kv; set up to bony anatomy At least weekly CBCT (after d1,2 confirms reproducibility) to ensure bed is within PTV margin 6 mm lateral 8 mm ant/post 9 mm sup/inf Daily kv: Set up to bony anatomy but ensure clips are within PTV margin *after initial field completed, see bed alone

77 On treatment imaging CBCT can identify differential rectal filling Reference (CT simulation) Daily cone beam CT Differential rectal filling Required a shift of > 1 cm ant/post consider daily imaging and/or replanning

78 Conclusions: EBRT for postop prostate Adjuvant RT is better than observation for men with pt3, +margins Early salvage RT (if needed) is an alternative to adjuvant RT Salvage RT is moderately effective, and could impact biochemical control and survival Uncertainty regarding timing of RT, and best use of dose, volume, ADT will hopefully be addressed with future trials