Richard Ptter Department of Radiotherapy - Medical University of - - PowerPoint PPT Presentation

ICARO MEETING: CURRENT TRENDS IN BRACHYTHERAPY VIENNA, 28 April 2009

Richard Pötter

Department of Radiotherapy - Medical University of Vienna

Potential and Limitations of Image Guided Brachytherapy of Cervix Cancer

Dose to points

‐

Point A

‐

ICRU rectum point

‐

ICRU bladder point

Dose to reference volume (60 Gy)

ICRU Report 38, 1985, Bethesda

Background X-Ray Based Brachytherapy

DOSE TO POINTS OR REFERENCE VOLUME

DOSE EFFECT RELATIONSHIP POINT A

Background X-Ray Based Brachytherapy

N=1499 Dose pt A pelvic failure Stage IB and IIA (<2 cm) 70-80 Gy <10% (>2 cm) 85-90 Gy 25-37% Stage IIB 70 Gy 50% nonbulky >80 Gy 20% bulky >80 Gy 30% Stage III unilateral ≤70 Gy 50% >70 Gy 35% Stage III bilateral/bulky < 70 Gy 60% >70 Gy 50% >85 Gy 35%

Modified from Perez et al 1998

Increasing dose, increasing local control

(a) Genitourinary (b) Rectosigmoidal

Increasing dose, increasing morbidity MORBIDITY RATES AFTER RADIOTHERAPY (EBRT+BT)

Background X-Ray Based Brachytherapy

Perez CA in Perez/Brady 1998

Point A

2cm 2cm 2cm 2cm

Point A

2cm 2cm 2cm 2cm

Point A

2cm 2cm 2cm 2cm

84 Gy 84 Gy 60 Gy

D90 = 65 Gy

Point A

2cm 2cm 2cm 2cm

84 Gy 84 Gy

D90 = 90 Gy

~ 500 Gy

R

B

HR HR-

• CTV

CTV 45 Gy EBRT + 4 x 7 45 Gy EBRT + 4 x 7 Gy BT = 84 Gy Gy BT = 84 Gy (EQD2) (EQD2) 60 Gy 60 Gy

GTV

Necessity of Introduction of 3D-images Prescription of dose to a Target Volume and dose volume constraints to organs at risk To apply to gynaecological brachytherapy

necessity of a common language

GYN GEC ESTRO RECOMMENDATIONS From 2D to 3D/4D

R

B

HR HR-

• CTV

CTV 45 Gy EBRT + 4 x 7 45 Gy EBRT + 4 x 7 Gy BT = 84 Gy Gy BT = 84 Gy (EQD2) (EQD2) 60 Gy 60 Gy

GTV

Necessity of Introduction of 3D-images Prescription of dose to a Target Volume To apply to gynaecological brachytherapy

necessity of a common language

GYN GEC ESTRO RECOMMENDATIONS From 2D to 3D/4D

Tumor at time

• f diagnosis.

GTV HR CTV IR CTV

GTV

D90 (IR CTV) D90 (HR CTV)

2cc 1cc 0.1cc Bladder Rectum ICRU 38 Ref. Points GTV Sigmoid

D0.1, 1, 2cm3 (Bladder, Rectum, Sigmoid) GTV, HR CTV, IR CTV: D90, D100

GYN GEC ESTRO Recommendations(II) Radiother Oncol 2006

TARGET OAR

Potential and Limitations of Image Guided Brachytherapy

• f Cervix Cancer

DVH parameters for Target and OAR

R

B

HR HR-

• CTV

CTV 60 Gy 60 Gy

GTV

84 Gy 84 Gy

45 Gy EBRT + 4 x 7 Gy BT 45 Gy EBRT + 4 x 7 Gy BT = 84 Gy (EQD2) = 84 Gy (EQD2)

• HR CTV of BT receives the

prescribed dose of EBRT

• High and medium dose regions
• f BT in OAR receive the prescribed

dose of EBRT D90, D100 (HR CTV) D0.1cm3, D1cm3, D2cm3 (Bladder, Rectum, Sigmoid)

Potential and Limitations of Image Guided Brachytherapy

• f Cervix Cancer

„simple“ integration of EBRT and Brachytherapy

2 4 6 10 12 14 8 20% 40% 60% 80% 100% Volume HR-CTV Bladder Sigmoid Rectum D90 D2cc D90 (HR CTV) = 7 Gy D2cc (Bladder) = 6.0 Gy D2cc (Rectum, Sigmoid) = 2.3 Gy

Overall dose (EQD2) 45 Gy EBRT + 4x7Gy HDR-Brachytherapy

D90 (HR CTV) =45+4x7= 84 Gyαβ10 D2cc (Bladder) =45+4x6= 86 Gyαβ3 D2cc (Rectum) =45+4x2.3= 53 Gyαβ3 D2cc (Sigmoid) =45+4x2.3= 53 Gyαβ3

Dose [Gy]

• D90, D100 (HR CTV)
• D0.1cm3, D1 cm3, D2cm3 (Bladder, Rectum, Sigmoid)

Potential and Limitations of Image Guided Brachytherapy

• f Cervix Cancer

„simple“ integration of EBRT and Brachytherapy

Local control TREATMENT PERIOD and SIZE

145 consecutive patients (1998-2003) Two treatment periods:

• learning: 1998-2000
• systematic

application: 2001-2003 D90 for HR CTV (mean)

• 1998-2000: 81 Gy
• 2001-2003: 90 Gy

(p<< 0.01) Pötter R. et al Radioth Oncol 2007

Potential and Limitations of Image Guided Brachytherapy

• f Cervix Cancer

3D Image Guided BT – LOCAL CONTROL

Potential and Limitations of Image Guided Brachytherapy

• f Cervix Cancer

3D Image Guided BT : DVH PARAMETERS

Mean Gy Intracavitary1 interstitial2 145 patients3 Prescribed 85 85 83 HR CTV Vol. 35cm³ 44cm³ 36cm³ HR CTV D90 87 96 86 Point A 82

• Summary

Summary volume volume and dose and dose values values HR CTV (EQD2) HR CTV (EQD2)

1 Kirisits et al Int J Radiat Oncol Biol Phys 2005, 22 pts 2 Kirisits et al Int J Radiat Oncol Biol Phys 2006, 22 pts 3 Pötter et al Radiother Oncol 2007, 145 pts

n=141, 523 treatment plans / 608 fractions

V [cm3] D100 [Gy] D90 [Gy] V [cm3] D100 [Gy] D90 [Gy] LR 18 13 ± 10 82 ± 13 113 ± 23 50 ± 24 60 ± 7 75 ± 12 No LR 123 11 ± 13 91 ± 24 124 ± 36 34 ± 23 66 ± 10 87 ± 16 p value p > 0.05 p > 0.05 p > 0.05 p < 0.05 p < 0.05 p < 0.05 Subgroup n GTV HR CTV

V [cm3] D100 [Gy] D90 [Gy] V [cm3] D100 [Gy] D90 [Gy] 1998 – 2000 71 11 ± 9 83 ± 20 113 ± 28 35 ± 20 62 ± 10 81 ± 16 2001 –2003 70 12 ± 15 97 ± 25 133 ± 38 37 ± 27 68 ± 9 90 ± 15 p value p > 0.05 p < 0.05 p < 0.05 p > 0.05 p < 0.05 p < 0.05 1998-2003 141 12 ± 13 90 ± 23 123 ± 35 36 ± 23 65 ± 10 86 ± 16 GTV HR CTV n Subgroup

Dimopoulos et al. IJROBP 2009

Potential and Limitations of Image Guided Brachytherapy

• f Cervix Cancer

HR TARGET: DVH PARAMETERS – LOCAL CONTROL

D100 [Gy] D90 [Gy] D100 [Gy] D90 [Gy] D100 [Gy] D90 [Gy] (1) 2-5cmDIAG 65 95 ± 27 131 ± 39 65 ± 11 89 ± 17 51 ± 8 65 ± 10 LR 2 92 ± 13 124 ± 19 69 ± 1 92 ± 3 53 ± 1 69 ± 1 No LR 63 95 ± 27 131 ± 39 65 ± 12 89 ± 17 51 ± 8 65 ± 10 p value p > 0.05 p > 0.05 p > 0.05 p > 0.05 p > 0.05 p > 0.05 (2) >5cmDIAG 76 86 ± 19 116 ± 29 65 ± 8 83 ± 15 55 ± 5 66 ± 8 LR 16 80 ± 12 111 ± 24 59 ± 6 73 ± 11 53 ± 5 61 ± 6 No LR 60 87 ± 20 117 ± 31 66 ± 8 86 ± 15 56 ± 4 67 ± 8 p value p > 0.05 p > 0.05 p < 0.05 p < 0.05 p < 0.05 p < 0.05 (2a) >5cmDIAG • 2-5cmBT 45 90 ± 21 122 ± 32 67 ± 8 88 ± 15 56 ± 4 68 ± 7 LR 5 90 ± 15 134 ± 29 62 ± 4 83 ± 7 52 ± 7 64 ± 4 No LR 40 90 ± 22 121 ± 33 68 ± 8 88 ± 15 56 ± 4 68 ± 7 p value p > 0.05 p > 0.05 p > 0.05 p > 0.05 p > 0.05 p > 0.05 (2b) >5 cmDIAG • >5 cmBT 31 79 ± 14 106 ± 22 61 ± 8 77 ± 13 55 ± 5 63 ± 8 LR 11 76 ± 9 101 ± 12 57 ± 7 69 ± 9 53 ± 4 60 ± 6 No LR 20 81 ± 17 109 ± 25 64 ± 7 81 ± 13 56 ± 5 65 ± 8 p value p > 0.05 p > 0.05 p < 0.05 p < 0.05 p > 0.05 p > 0.05 IR CTV Subgroup n GTV HR CTV

2-5cm >5cm

Dimopoulos et al. IJROBP 2009 n=141, 523 treatment plans / 608 fractions

Potential and Limitations of Image Guided Brachytherapy

• f Cervix Cancer

HR TARGET: DVH PARAMETERS – LOCAL CONTROL

Entire population 141 (2) >5cmDIAG 76 (2a) >5cmDIAG · 2-5cmBT 45 (2b) >5cmDIAG · >5cmBT 31 4/21 (19%) 1/24 (4%) 10/23 (43%) 1/8 (13%) 14/81 (17%) 4/60 (7%) 14/44 (32%) 2/32 (6%) D100 HR CTV < 66 Gy ≥ 66 Gy Number (and %) of LRs above or below a cut-off D90 HR CTV < 87 Gy ≥ 87 Gy 11/24 (46%) 4/21 (19%) 15/45 (33%) 3/68 (4%) 1/31 (3%) 1/24 (4%) 0/7 n Subgroup 15/73 (20%)

D90 for the HR CTV: cut-off 87 Gy EQD2 Local control 4% versus 20% D100 for the HR CTV: cut-off 66 Gy EQD2 Local control 7% versus 17%

Dimopoulos et al. IJROBP 2009 n=141, 523 treatment plans / 608 fractions

Potential and Limitations of Image Guided Brachytherapy

• f Cervix Cancer

HR TARGET: DVH PARAMETERS – LOCAL CONTROL

D90 HR CTV [Gy] Local control [%]

20 40 60 80 100 total population tumour group 2 tumour group 2b <60 60 - <80 80 - <100 100 - <120 >120 <60 60 - <80 80 - <100 100 - <120 >120 <60 60 - <80 80 - <100 100 - <120 >120

Dimopoulos et al. In press R&O 2009

Extensive disease

D90 HR CTV 86 Gy EQD2 90% probability for local control n=141, 523 treatment plans / 608 fractions

Potential and Limitations of Image Guided Brachytherapy

• f Cervix Cancer

HR TARGET: DVH PARAMETERS – LOCAL CONTROL

a b

B R

GTV HR CTV 84 Gy EQD2

c

GTVDG B R

GTVDG

B

d e

C C

f a b

B R

GTV HR CTV 84 Gy EQD2

c

GTVDG B R

GTVDG

B

d e

C C

f

Diagnosis Brachytherapy Diagnosis 6 mths after treatment 9 mths after treatment 6 mths after treatment

Dimopoulos et al. IJROBP 2009 n=141, 523 treatment plans / 608 fractions

Potential and Limitations of Image Guided Brachytherapy

• f Cervix Cancer

TARGET: DVH PARAMETERS – LOCAL CONTROL

Maximum dose: no relevant clinical endpoint in 3D brachytherapy

Fixed volumes ~ tolerance dose (overall dose) „minimal dose to the most exposed tissue“*

0.1 cc: 3D „dose maximum“: ulceration (fistula) 1 cm3/2 cm3: teleangiectasia (20 mm x 20 mm x 5 mm) >5 cc: end point fibrosis

0.1 cm3 2 cm3

*GYN GEC ESTRO Recommendations(II) Radiother Oncol 2006

2cc 1cc 0.1cc Bladder Rectum ICRU 38 Ref. Points GTV S i g m

• i

d

*

(20 mm x 20 mm x 5 mm)

Georg P et al. R&O 2009

Potential and Limitations of Image Guided Brachytherapy

• f Cervix Cancer

OAR: DVH PARAMETERS – MORBIDITY

2 4 6 8 10 12 1 %,G3/G4 GI and urinary morbidity 1998-2000 2001-2003

10% 2%

LENT/ SOMA G1, n G2, n G3, n G4, n BLADDER 7 11 1 2 RECTUM/ SIGMOID 2 7 2 2 SMALL INTESTINE/COLON 5 VAGINA 78 36 5

ACTUARIAL OVERALL MORBIDITY RATE (G3 and G4) (GASTROINTESTINAL AND URINARY) at 3 years

Pötter R. et al Radioth Oncol 2007

145 consecutive patients (1998-2003) Two treatment periods:

• learning: 1998-2000
• systematic application: 2001-2003

D2cm3 Bladder 95 Gy EQD2 Rectum 65 Gy EQD2 Sigmoid 62 Gy EQD2

Late morbidity (LENT/SOMA) actuarial 8% (G3/G4 GI+GU)

Potential and Limitations of Image Guided Brachytherapy

• f Cervix Cancer

OAR: DVH PARAMETERS – MORBIDITY

n=141, 523 treatment plans / 608 fractions

LENT/ SOMA G1 G2

CR* G1/2

G3 G4

CR* G3/4 Bladder

7 10 20% 1 2 4%

Rectum

2 6 9% 2 2%

Sigmoid

1 1% 2 2%

*CR: actuarial complication rate Pötter R. et al Radioth Oncol 2007

145 consecutive patients (1998-2003) D2cm3 Bladder 95 Gy EQD2 Rectum 65 Gy EQD2 Sigmoid 62 Gy EQD2

Potential and Limitations of Image Guided Brachytherapy

• f Cervix Cancer

OAR: DVH PARAMETERS – MORBIDITY

n=141, 523 treatment plans / 608 fractions

145 consecutive patients (1998-2003)

Rectum D2cm3 65 Gy EQD2

• P. Georg et al. GEC_ESTRO Montpellier 2007

Submitted to Radiotherapy and Oncology

Rectum N=141

Dose constraint D2cm

3

= 70-75 Gy EQD2 recommended!

Potential and Limitations of Image Guided Brachytherapy

• f Cervix Cancer

RECTUM: DVH PARAMETERS – MORBIDITY

n=141, 523 treatment plans / 608 fractions

D2cc [Gy]

20 40 60 80 100 120 140 160 180 200

Probability of rectum side effects G2-4

0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0

Topographic correlation with DVH-parameters (n=35) ventral Sagittal T2-weighted MRI Endoscopy high dose area corresponding to 0.1cc

Georg P et al. R&O 2009

Potential and Limitations of Image Guided Brachytherapy

• f Cervix Cancer

RECTUM: ENDOSCOPIC FINDINGS – MORBIDITY

Incidence VRS > 3

10 20 30 40 50 60 70 80 90 100

Dose [Gy]

30 40 50 60 70 80 90 100 110 120 130 140

D2 ccm D1 ccm D0.1 ccm DICRU Dose [Gy]

30 40 50 60 70 80 90 100 110 120 130 140

Incidence LENT/SOMA > 2

10 20 30 40 50 60 70 80 90 100

D2 ccm D1 ccm D0.1 ccm DICRU

VRS: Vienna Rectoscopy Score Clinical late Effects LENT SOMA score Koom et al. IJROBP 2007 Georg P et al. R&O 2009

Topographic correlation with DVH-parameters (n=35)

Potential and Limitations of Image Guided Brachytherapy

• f Cervix Cancer

RECTUM: ENDOSCOPIC FINDINGS – MORBIDITY

• P. Georg et al. Submitted to RadiothOncol

Low number of events Topographical interfractional changes

145 consecutive patients (1998-2003) Sigmoid 62 Gy EQD2

Dose constraint in use! D2cm³=70-75 Gy EQD2

Potential and Limitations of Image Guided Brachytherapy

• f Cervix Cancer

OAR: DVH PARAMETERS – MORBIDITY

n=141, 523 treatment plans / 608 fractions

months

60,0 48,00 36,00 24,00 12,00 0,00

probability of side effects

1,0 0,8 0,6 0,4 0,2 0,0

bladder rectum sigmoid

5-year actuarial rates for late adverse side effects (G1-4) of the rectum, bladder and sigmoid

Sturdza et al. Boston 2008 “Uncertainties in the assessment of the sigmoid dose Assessment of sigmoid topography changes between HDR-brachytherapy fractions” “Is the worst case assumption valid for the sigmoid colon?”

22 patients, 50 treatment plans, 2-3 insertions per patient 3D reconstruction

• f sigmoid topography with clay phantoms

4 observers (2 physicians, 2 physicists) Scoring system for visual assessment (VS) of the sigmoid movement between applications (scores 1-4) Scoring system for visual assessment of location of D2cc on dosimetry and expected D2cc on the clay phantom (DS),(scores 1-4)

Potential and Limitations of Image Guided Brachytherapy

• f Cervix Cancer

SIGMOID: DVH PARAMETERS – MORBIDITY

1 2 3 4

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22

Patients VS score

mean VS common observation

Easy to find or obvious change (score=3-4) in sigmoid topography between fractions in 15/22 (68%) significant movement Difficult to find or no change (score=1-2) in remaining 7 little or no movement Change present, but difficult to identify in 5 (median score=2.2) Movement of sigmoid may be vindicated: Insertion of rectal probe with movement of sigmoid Change of bowel topography Change of sigmoid filling condition Development of lymphocel after lymph-node staging

Sturdza et al. Boston 2008 Dose Constraints Sigmoid Reconsideration?

Potential and Limitations of Image Guided Brachytherapy

• f Cervix Cancer

SIGMOID: DVH PARAMETERS – MORBIDITY

“Uncertainties in the assessment of the sigmoid dose Assessment of sigmoid topography changes between HDR-brachytherapy fractions” “Is the worst case assumption valid for the sigmoid colon?”

• 1. Application (Oncentra GYN)

SIGMOID

Contours from 1. insertion related to the applicator

• 2. Application (Oncentra GYN)

SIGMOID

145 consecutive patients (1998-2003) Two treatment periods:

• learning: 1998-2000
• systematic application: 2001-2003

Bladder D2cm3 95 Gy EQD2

Bladder D2cc <100 Gy >100 Gy G1-G4 13% (12/94) 17% (8/47)

No strong evidence for

• verall dose volume

effect for all patients e.g. 2 cm

3

Potential and Limitations of Image Guided Brachytherapy

• f Cervix Cancer

BLADDER: DVH PARAMETERS – MORBIDITY

n=141, 523 treatment plans / 608 fractions

D2cc [Gy]

50 100 150 200 250 300 350 400

Probability of bladder side effects G2-4

0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0

• P. Georg et al. GEC_ESTRO Montpellier 2007

Submitted to R&O

Dose constraint in use! D2cm³=90 Gy EQD2

Comparison: patients with and without side effects (n=34)

Bladder wall(bw)

Position

P = 0.006 Lower bw Mid bw With S ide effect

10

3 No S ide effect 6

15

Arie et al., Vienna 2008

Location of high dose area in patients with D 2 ccm > 90 Gy

lower mid Dose Constraints Bladder Reconsideration?

Potential and Limitations of Image Guided Brachytherapy

• f Cervix Cancer

BLADDER: DVH PARAMETERS – MORBIDITY LIMITATION Reconsideration of dose constraints for bladder taking into account location?

Potential and Limitations of Image Guided Brachytherapy

• f Cervix Cancer

VAGINA: DOSE ASSESSMENT AND REPORTING

DVH parameters have HIGH uncertainty for vaginal dose estimation Influenced by the resolution of sectional imaging, contouring accuracy

and applicator reconstruction

Berger et al, IJROBP 2007

shortening fibrosis LENT SOMA 1/2

Fidarova et al, ESTRO 27, 2008

Upper vagina

…also for bleeding

Potential and Limitations of Image Guided Brachytherapy

• f Cervix Cancer

VAGINA: MORBIDITY AND DVH-PARAMETERS (N=26) LIMITATION Vaginal morbidity was not (significantly) correlated to any of the commonly used DVH-parameters!

• D90 HR CTV and local control:

strong relationship D90 ≥ 87 Gy EQD2 recommended

• 2 ccm

for rectal morbidity: strong relationship D2cm³ 70-75 Gy EQD2 recommended

• 2 ccm

for bladder morbidity: weak relationship D2cm³ 90 Gy EQD2 in use LIMITATION: Reconsideration of constraints after location assessment?

• 2 ccm

for sigmoid morbidity: weak relationship D2cm³ 70-75 Gy EQD2 in use LIMITATION: Reconsideration of constraints after movement assessment?

• DVH-parameters for vaginal morbidiy:

no relationship LIMITATION: Vaginal morbidity was not (significantly) correlated to any of the commonly used DVH-parameters!

Potential and Limitations of Image Guided Brachytherapy

• f Cervix Cancer

MAIN LIMITATIONS LIMITED NUMBERS LIMITED AVAILABILITY FEW (EUROPEAN) CENTERS NO PROSPECTIVE CLINICAL STUDY PROSPECTIVE CONTROLLED RESULTS AWAITED: “EMBRACE STUDY”