RT for High-Risk and Postoperative

Transcription

1 RT for High-Risk and Postoperative Prostate Cancer ASTRO Refresher Course 2013 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 Pre-test question 1. There are now 3 randomized studies testing adjuvant RT vs. observation for men with pt3 prostate cancer or positive margins after radical prostatectomy, each with >9 years of follow-up. Which of the following studies demonstrate a survival benefit? A. EORTC (Bolla) B. SWOG 8794 (Thompson) C. ARO 9602 (Wiegel) D. RTOG 9601 (Shipley)

4 Pre-test question 2. A 71 year old man with minimal comorbidity who presents with clinical T3, intact adenocarcinoma of the prostate, Gleason score 4+4, and PSA 22 should be treated with RT/ADT rather than ADT alone because: A. Biochemical failure at 10 years is ~75% with ADT alone, and only ~50% with RT/ADT B. Cause specific survival at 10 years is reduced by half (~24% with ADT alone, and ~12% with RT/ADT) C. Overall survival at 10 years is improved by ~5% (~65% with ADT alone, and ~70% with RT/ADT) D. All answers are incorrect; ADT alone is preferred because this man is >70 years old

5 High-Risk, Intact Prostate Cancer

6 Definitions: NCCN risk category Recurrence risk Features? surveillance, if life 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 less critical than with low or intermediate risk

7 Definitions: AJCC (2010) Stage has been replaced by prognostic group NCCN High risk corresponds to Groups IIB IV

8 General management options EBRT with long term ADT EBRT with brachytherapy +/- long term ADT Radical prostatectomy (if no fixation) and LND +/- RT ADT alone = only for men not candidates for local therapy

9 RT/ADT vs. ADT 2 large randomized trials test 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 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

10 Role of RT/ADT SPCG-7 Cause specific mortality 24% NCIC/MRC Overall survival 74% 66% 12% 10-yr BF 26/75; OS 70/61 All subsets favorably affected 7-yr PCSM 9/19 Local therapy improves survival in men with high risk disease treated with ADT Grade 3 toxicity limited with RT ( 2%); mild/moderate symptoms more common but QOL shows acceptability Risk benefit ratio greater with IMRT/IGRT?

11 Primary ADT for localized cancer Low risk Int risk High risk Cooperberg, JCO 2010 Trials may alter practice patterns (hopefully)

12 Role of RT/ADT Several randomized trials test RT/ADT vs. RT 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

13 Role of RT/ADT Other randomized trials test length of ADT RTOG 9202 (2003,2008) EORTC (2009) n Eligibility ADT Important endpoints affected 1554 T2c-4, N0; PSA< T2c-4, or N+ PSA< m vs. 4 m brfs, LC, DM, CSS [OS for GS8-10] 36 m vs. 6 m CSS, OS Canada (abs 2013) 630 T3 or PSA>20 or GS8, N0 36 m vs. 18 m None RT is conventional fractionation, Gy; whole pelvic RT for high risk patients Using conventional RT to treat locally advanced disease, there is a survival advantage with longer term ADT

14 Hormonal therapy Affects local control and distant control Distinct from surgical studies with ADT Long term ADT is better for highest risk? Improved control of micrometastases? LC more problematic in high risk patients Unknown how higher doses of RT should influence the use of concurrent ADT Retrospective analyses offer some hints until prospective studies are completed There are potential negative effects of therapy

15 Hormonal therapy Does ADT risk of cardiovascular mortality? Nguyen JAMA 2011 In 8 RCTs, ADT improved PCSS and OS without resulting in excess cardiovascular deaths Sending patients for ADT clearance is not necessary (Levine, Ca J Clin 2011)

16 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

17 RT dose n Eligibility RT dose (Gy)* FFBF at 5 y MDACC (2002,2008) Harvard/LLMC (2005,2010) Dutch (2006,2008) 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* 64/54 74 vs. 64* 71/ T1b-3, PSA<50 80 vs /61 *ADT allowed Dose escalation is supported for all risk categories It is likely that local control remains a problem even with dose escalation

18 Brachytherapy boost Retrospective data suggest favorable PSA control rates for high-risk disease Mt. Sinai IJROBP, 2004 Wheeling WV BJUI, 2011 Sydney BJUI, 2012 MSKCC Brachy 2013 n High risk pts EBRT ADT Implant FFBF 132 Med PSA 10-20, 28% with GS 8+ 14% with T3 284 Median PSA 10 Median GS 8+ 34% with T2c+ 90 Median PSA 15 25% with GS 8+ 25% T % with GS8+ No T3 45 Gy PSV only (100%) 45 Gy, Low pelvis (91%) 45 Gy, low pelvis (100%) 50.4 Gy, PSV only (100%) 9 mo (100%) ~12 mo (63%) 12 mo (100%) Pd I or Pd HDR ~9 mo I, Pd or HDR 86% at 5 yr 89% at 12 yr 94% CSS at 12 yr 80% at 5 yr 54% at 10 yr 80% at 5 yr Note contribution of patient selection and high quality implant centers

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

20 EBRT vs. EBRT/brachytherapy Retrospective comparison of EBRT (~78 Gy, n=510) and CMRT (n=448) Biochemical failure Cause specific mortality Unadjusted Kaplan Meier 40% 13% 14% 7% Adjusted Cumulative incidence HR 0.35 with CMRT HR 0.45 with CMRT Shilkrut, Cancer 2013 FFBF and CSS with combined modality RT

21 Role of ADT with escalated dose In retrospective series, ADT use is usually still associated with improved FFBF and CSS 100 High Med Low 0 Effect may be reduced with highest doses of RT Conventional RT Local failure Distant failure No ADT ADT 100 High Med Low 0 Dose escalated RT Local failure Distant failure Hypothetical model of risk of relapse: ADT use/longer duration may be less important when local control is improved, especially if local failure is the primary problem No ADT ADT

22 Role of ADT with escalated dose Magnitude of benefit may depend on dose and T-stage Study of 3,666 men treated with EBRT and varying ADT length Impact of ADT on BF is non-linear (first 6 mo >> after 18 months) >68 Gy T2 68 Gy T3 Williams IJROBP 2011 PSA response might also be helpful (D Amico Lancet Onc 2012) PCSM at 8-years is 5% if PSA nadir 0.5 (vs. 27%)

23 RT volume Pelvic nodes can be involved in high risk disease 1055 men undergoing LN evaluation: Weckermann J Urol 2006 Pubic bone Lymph node involvement goes beyond standard US template >50% of time Shih IJROBP 2005 Nanoparticle data indicate common involvement and size < 1 cm

24 RT volume Does pelvic radiation improve outcomes? RTOG 9413 (2003,2007) GETUG-01 (2007) n Eligibility Arms Important endpoints affected 1292 T2c-4 GS6+, or LN+ risk >15%; PSA<100 WP vs. PO NHT vs. AHT 444 T1b-3 Low pelvis RT vs. PORT (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

25 5-year rates late toxicity WPRT (n=309) RT volume Does pelvic radiation add toxicity? Grade 2 GI GU Grade 3 GI GU 15% 15% 4% 3% Mini-pelvis (n=170) 9% 15% 1% 2% Prostate (n=131) 7% 6% 0% 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 Note: Classic ADT trials did include pelvic lymph nodes

26 Summary: High risk, intact prostate cancer Role of RT+ADT established by RCTs Long term ADT superior to short term ADT Dose escalation likely provides further benefit Brachytherapy boost may be an attractive alternative in select cases Pelvic nodal RT (2D) thus far demonstrates an unfavorable risk-benefit ratio The standard of care may change with incorporation of newer technology (IMRT, IGRT), and new drugs Trials have been designed to address these issues

27 Post-operative Prostate Cancer

28 Outcomes after prostatectomy Overview Risk factors %bned-10 y 8 centers Karakiewicz Urol 2005 N= Med fu 25 mo bned 61% at 10 y 0% adj RT + margins ECE, +/- margins SVI, +/- margins LNI, +/- margins 36 25/46 12/20 14/8 Wash U Roehl J Urol 2004 n= Med fu 65 mo bned 68% at 10 y 6% adj RT Stage ct3 Gleason score 8 ECE, +/- margins SVI /62 26 LN 12 Baylor Hull J Urol Med fu 47 mo bned 75% at 10 y +margins ECE alone SVI n=1000 0% adj treatment LN 7 U Chicago Orvieto BJU 2006 n= Mean fu 76 mo bned 86% at 10 y 0% adj treatment +/- margins SVI 60/90 ~50 ( 50% highlighted)

29 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 90% n= Age 65 y Med preop PSA ~10 Postop PSA <0.2 in 66% n= Age 65 y Median preop PSA ~9 Postop PSA 0.2 in 100% RT techniques 60 Gy Gy 60 Gy Conventional Conventional 3D conformal Prostate bed Prostate bed Prostate bed Within 4 mo Within 4 mo Within 3 mo Median fu 10.6 y 11.5 y 9.3 y

30 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, pt3a 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

31 Role of adjuvant RT Adjuvant RT for all pt3 and +margins? YES (adjuvant) Supported by Level I evidence Risk of significant morbidity is low Might allow for: lower RT doses, smaller volumes, less need for ADT with RT, with similar or better result than salvage therapy (?) No (early salvage) RCTs did not test adjuvant vs. early salvage Early salvage adjuvant RT (?) Perhaps not all benefit equally from adjuvant RT Avoid overtreatment, reduce risks and costs Salvage RT is also effective for a rising PSA post-operatively

32 Salvage RT Retrospective data support salvage RT Stephenson JCO 2007 Trock JAMA 2008 Cotter Cancer 2011 n Patients Treatment Important endpoints affected 1540 RT in all men Median PSA % margin+ 22% GS 8+; 3% N1 635 Observation or RT Median PSA ~0.8 43% margin + 28% GS 8+; 20% N1 519 Observation or RT 59% margin + 29 GS 8+; No N1 Median 64.8 Gy 14% ADT Median 66.5 Gy 12% ADT Median 66 Gy 16% ADT FFBF-6 y 32% RT improves CSS At 10 years, ~85% vs. 62% RT improves OS Salvage RT is associated with better CSS and OS in select series

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

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

35 Early salvage RT Matched paired analysis of adjuvant and observation with early salvage (PSA 0.5) as needed (n=890) RT 65 Gy to the prostate bed only, no ADT 5-year FFBF 78% vs. 82% Median FU 47 mo Briganti Eur Urol 2012 Early salvage RT adjuvant RT; avoids overtreatment Trials are accruing to address this issue

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

37 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

38 Salvage RT: patient selection Nomogram caveats The nomogram is merely a model based on heterogeneous data using a BF endpoint What if the nomogram predicts a poor outcome? Men without biochemical control can sll have DM (Swanson, JCO 2007) and CSS Men with a fast PSA doubling me can have CSS (Trock, JAMA 2008) Selection by clinical factors may not need to be as refined as once thought Patient selection would ideally be better defined with factors other than clinical disease parameters

39 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 Low sensitivity with low PSA; indeterminate findings possible RIS (e.g. Prostascint) Not routinely 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

40 Salvage RT: Endorectal MRI Local recurrences as seen on endorectal MRI: Liauw IJROBP men evaluated for salvage RT, median PSA 0.3 Radiographic abnormalities in prostate bed in 24% Likelihood correlated with prert PSA Abnormalities seen on T2 MRI (90%) > DWI or DCE Unclear whether MRI findings should influence patient selection or treatment

41 Optimizing salvage RT Data driven approach towards intensification of therapy to improve outcomes Quality of data is weaker compared to intact prostate cancer RT dose RT volume Combined ADT Available data Retrospective Retrospective Limited prospective, and Retrospective

42 RT dose Can dose escalation be extrapolated from the intact setting? Despite less certainty with target location, there exists a dose response 70 Gy Higher RT doses may 65 Gy compensate for a higher pre-rt PSA PSA 1, 70 Gy = PSA 0.6, 65 Gy King IJROBP 2012 Ohri IJROBP 2011

43 RT dose Select retrospective series and dose escalation King (IJROBP 2008) Siegmann (Str Onk 2011) Bernard (IJROBP 2010) Ost (Eur Urol 2011) Goenka (Eur Urol 2011, IJROBP 2012) n RT dose FFBF Comments Gy 60 Gy 70.2 Gy 66.6 Gy >66.6 Gy <64.8 Gy Gy (all IMRT) Gy <70 Gy (Mix of IMRT and 3D RT) 58% at 5 y 25% at 5 y 88% at 2 y 71% at 2 y 57% at 5 y 46% at 5 y 39% at 5 y Higher dose improves FFBF Higher dose improves FFBF (but patients selected by PSA decline >20%) Higher dose improves FFBF 56% at 5y IMRT to 76 Gy is safe Gr2+ toxicity 8% GI, and 22% GU at 5 yr ~37% at 7 y Higher dose did not improve FFBF IMRT to 70 Gy reduces late GI toxicity Gr2+ toxicity 2% GI, 17% GU (IMRT) at 5 yr Gr2+ toxicity 10% GI, 17% GU (3D) at 5 yr Higher dose is associated with better biochemical control in several series; IMRT may reduce late toxicity

44 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 Prostate bed Whole pelvis Moghanaki Cancer 2013

45 RT volume Retrospective series and nodal radiation n Volume FFBF Comments Kim (Cl Pr Ca 2004) Pelvic LN Bed only ~50% at 10 y WPRT does not improve FFBF Spiotto (IJROBP 2007) Pelvic LN Bed only 47% at 5 y 21% at 5 y Benefit of WPRT only in select group (pt3, GS 8-10, preop PSA >20 with ADT) Moghanaki (Cancer 2013) Pelvic LN Bed only 82% at 5 y 69% at 5 y Benefit of WPRT only in select group (pre RT PSA 0.4; HR 0.47 for bned) Alongi (RadOnc 2009) IMRT to WP 3D to WP -- IMRT reduces acute GI toxicity Acute Gr2+ toxicity 7% ugi, 3% LGI (IMRT) Acute Gr2+ toxicity 22% ugi, 9% LGI (3D) Pelvic RT is associated with better biochemical control in select men; IMRT may reduce acute toxicity Await results from RTOG 0534

46 Use of ADT Prospective, randomized studies n Eligibility RT ADT Important endpoints RTOG 9601 (ASTRO 2010) 771 pt2-3n0 with PSA Gy 2 years (bicalutamide) vs. none ADT with salvage RT DM FFBF-7 y (57/40), DM-7 y (7/13) RTOG 8531 (2005) 173 N1 subset includes postop Gy Indef (LHRH) vs. none ADT with salvage RT OS FFBF-5 y (54/33), DM, CSS, OS 9601: ADT (150 mg bicalutamide x 2 y) DM Other studies are accruing to evaluate ADT: Study Accrual goal Eligibility Arms MRC PR10 N= RTOG 0534 N= PSA <0.4 PSA ; T2-3N0, GS 9 Adj vs early salvage RT with 0 vs 4 vs 24 mo ADT PBRT vs. PBRT/ADT vs. WPRT/ADT (ADT for 4-6 mo)

47 Use of ADT Prospective, single arm studies Sunnybrook (2009) Sunnybrook (2009) SWOG S9921 (2011) n Eligibility RT ADT Important endpoints 78 pt3 or R Gy 75 pt3 or R1, PSA detectable 481 PSA >15, pt3b, N1, GS8-10, R Gy Only in 27% 2 years (adj CAB/LHRH) 2 years (adj CAB/LHRH) Adjuvant: FFBF-5 y 100% Salvage: FFBF 5-y 85% 2 years (CAB) FFBF-5 y 93% Salvage: FFBF 5-y 92%, 7-y 79% Excellent FFBF with long term ADT in comparison to other published studies without ADT Retrospective data are generally supportive for ADT with salvage RT for FFBF but results are mixed ADT impact may be influenced by dose and volume considerations

48 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 IMRT/3D treatment likely better than 2D treatment and may facilitate dose escalation Treatment factors including volume and dose likely have impact Multi-institutional Belgium

49 Toxicity (Symptom Scores) Do we need to wait for continence recovery? Patient reported QOL surveys can still show improvement in continence after RT Corbin, PRO in press Post-op IMRT does not clearly worsen continence

50 NCCN Post-op Guidelines Treatment Guidelines pt3, +margins PSA undetectable (Node negative) PSA detectable RT or observation Consider: Bone scan, CT/MRI/US, PSA DT, biopsy If no distant disease: RT +/- ADT, or observation Standard of care allows for wide interpretation Adjuvant RT not routinely recommended Use of imaging, RT, and ADT are at clinician discretion

51 UCMC Post-op RT Guidelines pt3, +margins PSA 0.05 (Node negative) PSA detectable (Node negative) Node positive Proposed Treatment Guidelines 64 Gy at 2/fx IMRT to prostate bed Favor adjuvant > salvage RT in highest risk, younger patients with reasonable urinary recovery Enroll on RTOG 0534; otherwise 68 Gy (2/fx) IMRT to the prostate bed If unfavorable: 50.4 Gy (1.8/fx) IMRT to pelvic lymph nodes Gy (1.8/fx) IMRT to the prostate bed 4 months of ADT Gy (1.8/fx) IMRT to pelvic lymph nodes 68.4 Gy (1.8/fx) IMRT to the prostate bed 4+ months of ADT Post-op RT and choice of dose, volume, ADT: consider risk factors, comorbidity, and patient preference

52 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

53 Planning guidelines DVH relationships are much 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% DVH relationships may eventually be determined using prospectively recorded late toxicity

54 IGRT How much does the prostate bed move? Study of prostate bed beacon transponders (n=20) Suggested margins based on setup error: LR SI AP Skin markings 0.9 cm 1.3 cm 1.5 cm Bony anatomy 0.5 cm 1.3 cm 0.9 cm Real time tracking >5 mm motion in 32% for >1 sec, and 11% for > 30 sec (of 638 treatments) 18 of 20 patients with at least one such episode (90%) Setup uncertainty can be significant Klayton, IJROBP 2012

55 IGRT options Bony anatomy Ultrasound Surgical clips or fiducial markers in prostate bed (kv) Cone beam CT Comments Most widely available imaging modality Occasional patient may have widely varied setup; PTV margin ~ cm not always reliable Readily adjust for bladder filling; No additional radiation exposure Inter-observer variability in setup Can be easily seen and quickly imaged Does not evaluate soft tissue anatomy See entirety of prostate bed volume More time on treatment table

56 On treatment imaging IGRT can be valuable: differential rectal filling Reference (CT simulation) Daily cone beam CT Differential rectal filling

57 On treatment imaging IGRT can be valuable: differential bladder filling Daily cone beam CT #1 Daily cone beam CT #2 urination Differential bladder filling Setup to prostate bed requires a 2 cm bony anatomy shift Prostate bed and bones are aligned as on CT simulation

58 Conclusions: EBRT for postop prostate Adjuvant RT is better than watchful waiting 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

59 Post-test question 1. There are now 3 randomized studies testing adjuvant RT vs. observation for men with pt3 prostate cancer or positive margins after radical prostatectomy, each with >9 years of follow-up. Which of the following studies demonstrate a survival benefit? A. EORTC (Bolla) B. SWOG 8794 (Thompson) C. ARO 9602 (Wiegel) D. RTOG 9601 (Shipley)

60 Post-test question 2. A 71 year old man with minimal comorbidity who presents with clinical T3, intact adenocarcinoma of the prostate, Gleason score 4+4, and PSA 22 should be treated with RT/ADT rather than ADT alone because: A. Biochemical failure at 10 years is ~75% with ADT alone, and only ~50% with RT/ADT B. Cause specific survival at 10 years is reduced by half (~24% with ADT alone, and ~12% with RT/ADT) C. Overall survival at 10 years is improved by ~5% (~65% with ADT alone, and ~70% with RT/ADT) D. All answers are incorrect; ADT alone is preferred because this man is >70 years old