7 th July CRH talk Dr George Hruby Senior Staff Specialist Sydney Cancer Centre

Outline of Talk IGRT (Image Guided Radiation Treatment) as applied to prostate cancer Update the Sydney Cancer Centre HDR (high dose rate) brachytherapy programme

Introduction Dose escalation confers significant disease control benefit in localised prostate cancer. 7 RCTs show 10-20% improvement in FFF with increased dose. Caveat… -EBRT – landmark MD Anderson trial – FFF 78% in 78Gy arm v 59% for 70Gy -HDR brachytherapy as a boost

CT simulation

CT sim

Dual energy Linac with MLC

Conformal Radiation treatment Up until recently, EBRT has relied on a single planning CT “snap-freeze” taken before treatment starts. Regular X-rays (port films) were performed to ensure the pelvic bony anatomy was in the same position But – required bigger margins to account for organ motion - Could not visualize the prostate itself or its relationship to OAR (organs at risk) eg rectum/bladder

treatment

EBRT

Reducing target uncertainty Rectal balloon Flatus tubes Image Guidance Trans-abdominal ultrasound (BAT) Cone beam CT Fiducial markers Brachytherapy

Prostate: EBRT Fiducials In house feasibility trial of fiducial markers 2007/8 Ethics approved for 25 patients 1 st 5 patients – feasibility alone Current 20 – daily “on line” localization Feasibility study completed early 2008 Standard practice since early 2008

Fiducial marker insertion Picture of Probe/Insertion

$ 200

Rectal Gas

L oss Gas between AP and Lat

Image “matched” to bone

Matched to fiducials

Results Slightly more invasive Very Feasible (even with prosthetic hip) RTs enthusiastic, if 3mm or greater mis- match in any 1 plane, we correct in all 3 planes Adds about 5 mins to 5 field prostate treatment (OTT in bunker from 9 to 14 mins)

Where to next ? Fiducials Now our standard treatment for intact prostate Daily “on-line” seed matching allows tighter margins in all 3 planes hence safe dose escalation to 78Gy with 3D-CRT Same process crucial for IMRT 80Gy

TRUS

Setting up

HDR brachytherapy

HDR Brachytherapy

RPA experience First Case: January th patient treated Over 200 implants since technique introduced. Team: ROs (Hruby, Patanjali), Urologists, Anaesthetics (JL), RTs, physics, nursing.

Benefits of HDR Conformality (and effects on normal tissues) Radiobiologic advantage (low alpha/beta ratio of prostate cancer suggests hypofractionated treatment could improve response) Shorter overall treatment time (patient convenience) Recent systematic review of 3 modalities of dose escalation showed superiority of HDR as a boost (vs IMRT or seed brachy boost) – Pieters 2009

Study Methods Data collected prospectively (outcomes, toxicity, QOL) Patients were considered for HDR boost if they had localised prostate cancer with intermediate or high risk features, AND were suitable for anaesthesia with a reasonable life expectancy (~10years)

Radiation Technique First 67 patients: 6.5Gy x 3# Since then 2 separate implants for all patients Dose escalation over last few yrs: 8.5 Gy x 2, 9 Gy x2, currently 9.5 Gy x2 EBRT: 46Gy in 23# (prostate and seminal vesicles only)

Failure Biochemical failure defined by Phoenix definition (PSA nadir + 2) OR clinical failure, any of Radiological evidence lymphatic or distant disease LR on DRE, imaging or biopsy Need for salvage treatment (LHRH)

Patient Characteristics Median age 68 (46-79) Median PSA = 12 (3 – 43) 31, 58, and 11 men had Clinical T1, 2 and 3 disease, respectively GS 3+4 (36), 4+3 (42) Intermediate risk: n=65 High risk: n=35

Androgen Ablation 95 patients received neo-adjuvant and/or concomitant hormones 80 for 6 months 14 for 12 to 24 months 1 patient 3 months only

Results Median F-up 49 months (17 to 85) No data beyond 2 years for 3 patients OS 99% (one patient died of an MI)

Results continued 15 patients failed – 7 biochemical and 8 clinical. DFS rate intermediate risk = 90.8% high risk = 74.3% To date, no patients have developed clinically apparent LR or metastatic disease.

Acute toxicity Acute effects: 69% of patients had grade 1-2 acute urinary toxicity; 54% GI effects (no grade 3 or 4) Three patients had post op PEs; another patient was admitted to CCU with post op AF.

Late toxicity GU – rate of urethral stricture 8% (only one of these pts required more than one intervention) GI – 8% mild (gd 1) toxicity, 3% grade 2, No grade 3 or 4. Erectile function preservation rate 72% (53/75 patients who were potent at baseline had satisfactory EF post treatment)

How do the results compare? Comparable to large international series (the largest pooled analysis Galalae reported DFS of 69% and 88% for high and int risk respectively at 5yrs) Toxicity also similar to that reported elsewhere (including Sullivan’s data on urethral strictures and most prostatectomy data)

Discussion points Young cohort, median age 68 -Good preservation of EF (age and microvasc disease recently proven to be risk factors in post RT ED) -PSA bounce – tends to occur in younger patients, probably reflecting testosterone recovery (6% in our cohort)

Change in toxicity Profile Shift in radiation related toxicity from rectum to urethra -MD Anderson gd 2+ rectal toxicity 26% in high dose arm (vs 13% in std arm) -Rates of urethral stricture comparable to other studies but still higher than seed brachy (up to 5.5%) EBRT (1-4%) and IMRT (3%)

High risk patients 74% DFS However patients with more than one adverse feature (T3+, PSA>20, GS 8-10) all failed - Micro-mets ? Individualisation of treatment – androgen deprivation and radiation volumes (? treating pelvic nodes in these pts)

Evolution of Protocol Shift from 3 fractions to 2 (out-patient tmt, eliminates problem of inter-fraction catheter displacement, ?better for patients – patient survey analysis pending) Dose escalation (19Gy in 2#; ? 15Gy in 1#) Fiducial markers – to quantify and account for intra-fraction catheter displacement (may be some time before we see if this translates into improved toxicity profile)

Planning CT scout

Pre treatment Film