CLINICAL WORKSHOP

IMAGE-GUIDED HDR-BRACHYTHERAPY

FOR PROSTATE CANCER

Klinikum Offenbach April 27th 2014

The crux of defining risk groups

Memorial Sloan Kettering criteria vs

National Comprehensive Cancer Network criteria vs

D’Amico criteria

D´Amico et al. JAMA 1998 1872 patients with T1c-T2c (1989-1997) Median follow-up 38 months

87 % 89 %

Kupelian et al. IJROBP 2004 1866 patients with T1-T2 (1992 -1998) Radical Prostatectomy EBRT (<72 Gy vs ≥72 Gy) Permanent BRT

Biochemical relapse free survival

0

.2

.4

.6

.8

1

0 12 24 36 48 60 72 84 Time (months)

RP EBRT

PI

p=0.82

5yr 7 yr RP 83% 79% PI 82% 74% EBRT 77% 77%

Zietman et al. JAMA 2005 393 patients with organ-confined disease (1996-1999) median follow-up 66 months EBRT 70.2 Gy vs 79.2 Gy

Dose Escalation with superior Conformality

LDR vs HDR ?

?

Permanent Implant vs. Temporary Implant

• Nuclide • Energy • T1/2

• Geometry • Anatomy over time • Accumulation over time

LDR BRT

Seeds (125I, 103Pd, 131Cs)

• Nuclide • Energy • T1/2

Nuklid Energy (keV) T1/2 (days)

125I 28.0 59.49

103Pd 21.0 16.991

131Cs 30.4 9.689

Seeds (125I, 103Pd, 131Cs)

„Cold“

„Hot“

• Geometry (Dose distribution)

Dose-Accumulation ~ Time

(Prostate~Seeds)

Anatomy~Time

0 50 100 150 200 250 300 350 400 450 500 550 6000.00.10.20.30.40.50.60.70.80.91.01.1 103Pd - Seeds

125I - Seeds

Akum

ulie

rte D

osis

(% d

er R

efer

enzd

osis

)

Zeit nach Implantation (Tage)

D90 > 90 % Reference dose (145 Gy)

Time in Months

7260483624120

Actua

rial S

urviva

l1.0

.9

.8

.7

.6

Potters et al Urology 62 (6) 2003

LDR BRT

Extraprostatic Extension

*Davis et al. Cancer 85(12) 1999

105 Prostatectomy spec. Gleason 6.3 (3-9) PSA 8.6 (0.3-98)

Extraprostatic Extension

Davis et al. Cancer 85(12) 1999

LDR BRT

“…. the brachytherapy equivalent of negative margins.”

100 % Isodose

90 % Isodose

LDR BRT

• Indication

–Stage T1-T2a N0 M0

–PSA < 10 ng/ml

–Gleason-Score 2- 6

Seeds 145 Gy

[ Machtens et al. World Urol 2006 ]

Results of LDR BRT

Aspects in LDR BRT

• Radiation protection • Evaluation of the Quality of Implant after 4 weeks

possible (30 days CT)

• Influence of Edema on the implant Quality (Chen et al.,2000)

• Seed-Migration (e.g. Thorax in 55% ø Seeds/Patient (Eshleman et al. 2004)

• Indication limited: Volume (TRUS-Volumetry)

Practical advantages

HDR BRT

Physical advantages

Radiobiologic advantages

Practical advantages

Radioprotection

(No free Sources – No risk of Loss)

Cost-effective (HDR-Source and Equipment)

Physical advantages

Anatomy-oriented Target definition

(AFTER Implantation, larger volumes)

Anatomy-oriented Dose Escalation (Prostate √ Rectum, Urethra, Bladder)

Radiobiological advantages

Low α/β - value

Brenner et Hall, 1999: [EBRT vs I-125] α/β = 1.5

Fowler et al, 2001: [EBRT vs I-125/Pd-103] α/β = 1.49

Dose escalation through Hypofractionation

HDR BRT

• Indication

– any T with N0 M0

– any PSA

– any Gleason-Score

Monotherapy Low- and intermediate risk

Combined modality (as boost) Unfavorable intermediate and high risk

HDR-Brachytherapy as Boost

Microscopic regional disease

EBRT / moderate Dose

Macroscopic intraprostatic disease

BRT for Dose escalation

HDR BRT

Repair factor: α/ß = 2 Gy (1.2 Gy)

IMRT -LINAC Brachytherapy + LINAC

40 x 2 Gy = 80 Gy ~ 160 Gy

28 x 1.8 Gy = 50.4 Gy ~ 95.8 Gy 2 x 9 Gy (BT)= 18 Gy ~ 99 Gy

∑ BED 160 Gy (213) ∑ BED 194,8 Gy (295)

IMRT vs. 3D-conformal RT + HDR-BRT

Biologic Effective Dose = f (Repair factor, fractional dose, number of fractions)

CTV 1 Prostate capsule

CTV 2 Peripheral zone

CTV 3 Visible tumor

CTV-Criteria for HDR-Boost

CTV 1 whole gland defined by capsule

CTV 2 peripheral zone

CTV 3 visible tumor = GTV

Kovacs et al., 2005

Protocols: 1 Fraction / Implant:

Dinges: 2 implants (9 Gy / Implant) + 45 Gy EBRT Martinez: 2 implants (11.5 Gy / Implant) + 46 Gy EBRT Galalae: 2 implants (15 Gy / Implant) + 50 Gy EBRT Offenbach: 2 implants (10,5 Gy / Implant) + 45 Gy EBRT Multiple Fractions / Implant

Hsu 1 implant (2 x 6Gy / Implant) + 18 Gy EBRT Rodriguez: 2 implants (2 x 6Gy / Implant) + 36 Gy EBRT Pellizzon: 2 implants (2 x 6 Gy / Implant) + 45 Gy EBRT Linares: 1 implant (4 x 5.5 Gy / Implant) + 45 Gy EBRT

HDR-BOOST to EBRT

[ Martinez et al. IJROBP 2011 ]

n = 417 Patienten median FU: 8,2 J PSA ≥ 10 or GL ≥ 7 or T2b Low dose (BED) < 268 Gy High dose (BED) > 268 Gy EBRT = 46 Gy + BRT Boost (a/ß = 1.2)

Late Grade 3 genitourinary complications of 3.0 % Late Grade 3 gastrointestinal complications <0.5%

> 85 %

CTV 1 = CTV = PTV

Dose/Fx (Gy) # Fxs Total D

(Gy) BED

(a/b=1,5) % Dose EQD 2

9.5 2 19 247 57 106

10.5 2 21 275 61 118

11.5 2 23 307 65 131

Athens Consensus

Boost + EBRT 46 Gy at 2 Gy or 45 Gy at 1.8 Gy

>> 160 Gy

Case #2

HDR-Boost to EBRT “Evolution of Dose Constraints”

Kini VR et al. Use of three-dimensional radiation therapy planning tools and

intraoperative ultrasound to evaluate high dose rate prostate brachytherapy implants. Int J Radiat Oncol Biol Phys 1999; 43:571-8.

Martinez AA et al. Conformal high-dose-rate brachytherapy as monotherapy for the

treatment of favorable stage prostate cancer: a feasibility report. Int J Radiat Oncol Biol Phys 2001; 49:61-9.

Hsu IC et al. Comparison of inverse planning simulated annealing and geometrical

optimization for prostate high-dose-rate brachytherapy. Brachytherapy 2004; 3:147-52.

Case #1 Case #2

Prostate (PTV = CTV 1):

D90 ≥ 100% V100 ≥ 90% V150 35%

Urethra: D10 115% D0.1cm³ 120 % Rectum & Bladder D10 75% D0.1cm³ 80 %

HDR-Boost to EBRT

Offenbach protocol for High Risk HDR Boost to EBRT

● PTV = CTV 1 (in cT3: CTV 1+ 5.0 mm)

● BRT Boost: 2 x 10.5 Gy = 21.0 Gy upfront ● EBRT of Prostate+SV = 45.0 Gy after BRT

● Androgen deprivation for 9 months

HDR Boost to EBRT

HDR-Monotherapy

Dose escalation in locally-confined disease

HDR BRT

HDR-Monotherapy

International protocols

Martinez 1 Implantat 2 days 4x9.5 Gy 38.0 Gy Yoshioka 1 Implantat 5 days 9x6.0 Gy 54.0 Gy Corner 1 Implantat 2 days 3x10.5 Gy 31.5 Gy Mark 2 Implantate 1 day 6x7.5 Gy 45.0 Gy Offenbach 3 Implantate 1 day 3x11.5 Gy 34.5 Gy

90 %- Isodose 3D-Dose painting of Margins

LDR vs HDR

Seeds HDR

Volume Definition Pre/Peri-Implant Post-Implant

Dosimetry Pre/Peri-Implant

FIX Post-Implant

FLEXIBEL

Implementation Live Afterloading

Verification 30 days-CT Preloading

Seeds HDR

PSA < 15 ng/ml Exclusion of Mets

Gleason Score < 7 Exclusion of Mets

T-Stage T1-T2a T1-T3

Gland Volumen 45-50 cc ~ 80 cc

LDR vs HDR

Arguments pro HDR BRT

Application of a high dose in very short time ensuring radiobiological dose escalation [ Martinez et al. IJROBP 2000 ]

Intensity modulation with highest confority through Real Time Dosimetry + Inverse Planning [ Edmundson et al. IJROBP 1993 ]

Compared to EBRT no interfraction or intrafraction movement [ Martinez et al. IJROBP 2001]

[ Deutsch et al. Brachytherapy 2010]

Compared to LDR no influence of dose application by prostate deformation or seed migration

[ Edmundson et al. IJROBP 1993 ] [ Martinez et al. IJROBP 2000 ]

[ Stromberg et al. IJROBP 1995 ]

Prostate Brachytherapy in Offenbach

- History -

Prostate–Brachytherapy since 1996

Transrectal HDR-BOOST to EBRT

Beginning of new era in 2001

Transperineal HDR-MONOTHERAPY

2002-2009: 718 consecutive patients with localized prostate cancer

Transperineal Implantation under TRUS-guidance

2002-2004 (A): 1 Implant (4 x 9.5 Gy) CT- Plan (n=141)

2004-2008 (B): 2 Implants (2 x 9.5 Gy/Implant) TRUS-Plan (n=351)

2008-2009 (C): 3 Implants of 11,5 Gy TRUS-Plan (n=226)

2002-2004 (A): 1 Implant (4 x 9.5 Gy) CT- Plan (n=141)

9.5 Gy 6h 9.5 Gy 6h 9.5 Gy 6h 9.5 Gy

2004-2008 (B): 2 Implants (2 x 9.5 Gy/Implant) TRUS-Plan (n=351)

9.5 Gy 6h 9.5 Gy

9.5 Gy 6h 9.5 Gy

after 14 days 2nd implant

2008-2009 (C): 3 Implants of 11,5 Gy TRUS-Plan (n=226)

1x 11.5 Gy

after 21 days 2nd implant

after 21 days 3rd implant

1x 11.5 Gy

1x 11.5 Gy

Treatment group

Group A (9.5 Gy x 4) Group B (9.5 Gy x 4)

Group C (11.5 Gy x 3)

PTV

38.0 Gy 38.0 Gy 34.5 Gy

BED 1.5/3.0

279/158 Gy 279/158 Gy 294/162 Gy

Potential doubling time of Tpot= 42 days (Treatment completion within 42 days)

Protocol characteristics

BED 279 Gy 1.5

BED 346 Gy1.5

1 Implant (4 x 9.5 Gy)

BED 415 Gy1.5

BED 554 Gy1.5

D10 Rectum < 75 % : BED 74 Gy 10

BED 279 Gy 1.5

BED 346 Gy1.5

BED 415 Gy1.5

BED 554 Gy1.5

D10 Rectum < 75 % : BED 74 Gy 10

2 Implants (2 x 9.5 Gy/Implantat)

BED 294 Gy 1.5

BED 370 Gy1.5

3 Implants of 11,5 Gy

BED 445 Gy1.5

BED 594 Gy1.5

D 10 Rectum < 75% : BED 74 Gy 10

Patient characteristics

Group A (n = 141)

Group B (n = 351)

Group C (n = 226)

Median follow-up (months) 91.9 (45.5.-113.4) 59.3 (16.5-82.6) 25.4 (5.8-35.5) Median Gland volume (cc) 40 (20-90) 39 (16-107) 36 (11-90) Risk group (MSKCC) Low Intermediate High

103 (73.0%) 23 (16.3%) 15 (10.6%)

196 (55.8%) 81 (23.0%) 74 (21.0%)

96 (42.4%) 73 (32.3%) 57 (25.2%)

Low risk: n= 395 (55 %) Intermediate: n= 177 (25 %)

High risk: n= 146 (20 %)

Median overall follow-up 52.8 months

Evaluation

Survival estimates according to Kaplan-Maier method

Biochemical Control based on Nadir +2 (Phoenix Criteria)

Toxicity according CTC Version 3

Clinical Outcome (n=718)

97 % 95 % 90 %

98 % 96 % 94 %

93 % 90 % 84 %

95 % 93 % 93 %

Clinical Outcome (Risk Group)

Clinical Outcome (Treatment Group)

98 % 98 % 95 %

93 % 89 %

Acute Toxicity (n=718)

Group A (n= 141) Group B (n= 351) Group C (n= 226)

Toxicity Toxicity Toxicity

GI GU GI GU GI GU

Grade 4 0 % 0 % 0 % 0 % 0 % 0 % Grade 3 0.7 % 9.2 % 0 % 4.8 % 0 % 3.9 % Grade 2 0 % 15.6 % 1.7 % 16.5 % 3.5 % 17.6 % Grade 1 18.4% 46.8 % 15.7 % 48.1 % 12.3 % 36.7 %

Group A (n = 141) Group B (n = 351) Group C (n = 225)

Grade Grade Grade

2 3 4 2 3 4 2 3 4 Genitourinary Frequency/Urge 9.2% 2.1% - 4.8% 0.5% - 7.5% - - Incontinence 7.8% 0.7% 0.7% 5.1% 0.3% - 7.5% 0.4% 0.4% Retention 6.3% 2.8% - 5.4% 2.0% - 4.4% 0.8% - Errect. dysfunction 21.2% 12.0% - 15.7% 16.5% - 18.2% 19.1% - Gastrointestinal Pain 0.7% 0.7% - 0.3% 0.3% - - - - Mucositis 0.7% 3.5% - 0.8% 1.2% - 0.4% 0.4% -

Late Toxicity (n=717)

2 patients with endoscopically Grade 3 rectal necrosis: colostomy 3 patients with endoscopically grade 3 rectal mucositis: laser coagulation procedures

2 patients with incontinence indicating permanent urostomy

Results of HDR Monotherapy

Grimm et al. BJUI 2012 52.087 analysed patients Peer-reviewed journals from 2000-2011 Median follow-up of all studies ≥ 60 months