Linking DVH-parameters

to clinical outcome

Richard Pötter,

Medical University of Vienna,

General Hospital of Vienna, Austria

Outline

• DVH parameters for HR CTV (D90) and OAR (2 ccm)

„simple“ integration of 3D EBRT and Brachytherapy

• Clinical endpoints: local failure, morbidity

• Material: mono/multi-institut. series of consecutive patients

• Method: Prospective evaluation of clinical outcome (Vienna)

3D assessment of failures and morbidity + link

• Results: links between DVH parameters and outcome

CTV D90 and local control

OAR 2 ccm and morbidity

• Conclusions and limitations

Overview of adaptive target concepts in cervix cancer

3

ICRU/GEC ESTRO

report 88

under publication

Fig. 5.9-11

2cc1cc

0.1cc

Bladder

Rectum

ICRU 38 Ref. Points

GTV

Sigmoid

3D-based Dose Volume

Parameters for OAR

2 cm3

0.1 cm3

CLASSICAL MAX DOSE : in 3D

no clinical relevant endpoint

FIXED VOLUME: tolerance dose (total dose)-

“minimum dose to the most exposed tissue”*

*GYN GEC ESTRO Recommendations(II) Radiother Oncol 2006

1cc/2cc:teleangiectasia (20 mm x 20 mm x 5 mm)

0.1 cc: 3D“maximum dose“: ulceration(fistula)

• 145 consecutive patients

141 with MRI assisted cervix cancer brachytherapy

• 18 local recurrences (18/145: crude 12%)

• Analysis of recurrence topography and morbidity in 3D

relation to HR-CTV and D90

• 3D Dose-volume-effect relationships

Linking DVH-parameters to clinical outcome HR CTV and GTV and Recurrence (Vienna)

Analysis (n=141, FIGO: IB-IVA, median follow-up=51 months)

523 treatment plans / 608 fractions

Dimopoulos et al. IJROBP 2009

Summary dose values HR CTV (EQD2)

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 - -

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

Depending on treatment period

(experience, modification of application)

D90: 81 Gy (98-00) – 90 Gy (01-03)

Linking DVH-parameters to clinical outcome HR CTV and GTV and Recurrence

3D Analysis of recurrence topography

FIGO stage IIB

a b

B

R

GTV

HR CTV

84 Gy EQD2

c

GTVDG

B

R

GTV DG

B

d e

C

C

f

a b

B

R

GTV

HR CTV

84 Gy EQD2

c

GTVDG

B

R

GTV DG

B

d e

C

C

f

Diagnosis Diagnosis Brachytherapy

6 mths after treatment 6 mths after treatment 9 mths after treatment

Dimopoulos et al. IJROBP 2009

18%

22%

Pötter R. et al Radiother Oncol 2007 81 Gy vs. 90 Gy in HR CTV

Vienna experience

Linking DVH-parameters to clinical outcome HR CTV/Tumour

Analysis (n=141, FIGO: IB-IVA, median follow-up=51 months) D90 for the HR-CTV and probability of local control

1

Pro

ba

bili

ty o

f lo

ca

l co

ntr

ol

0 10 20 30 50 40 90 100 70 60 80 110 120 130 140 0

0.1

0.2

0.3

0.5

0.4

0.9

0.7

0.6

0.8

D90 (HR CTV)

Entire population (n=141)

Tumours > 5cm (n=76)

Dimopoulos et Radioth & Oncol 2010

D90 HR CTV 90 Gy EQD2

90% probability for local control

D90 HR CTV 70 Gy EQD2

65% probability for local control

a) b)

c) d)

Figure 1

Vienna 2001-2008: 156 patients Mean D90: 93 Gy, 91 Gy for tumozurs >5 cm, 96 Gy 2-5 cm

Radioth & Oncology in press

Multicenter studies with IGABT in cervix ca.

STIC

• Prospective

• 2D vs. 3D (CT)

– Non random.

– Availability

• Completed

• 2005-2008

• 20 centers

• 705 pts

• Def. EBRT+BT

• Preop BT

• Preop. EBRT+BT

Embrace

• Prospective

• Phase IV (MRI)

• Accruing

• 2008-2013

• 27 centers

• 800 pts

• Def. EBRT+BT

Retro Embrace

• Retrospective

• Before Embrace

• Collecting

• 2011-2012

• 12 centers

• 700 pts

• Def. EBRT+BT

Lindegaard ESTRO 2012

DVH parameters & outcome

based on multi-centre experience

Study HR CTV Bladder Rectum Sigmoid 2y Local 2y G3-G4

D90 (Gy) D2cc (Gy) D2cc (Gy) D2cc (Gy) Control BL+GI

STIC 3

Def EBRT+BT

n=201

73 70 61 58 79%(74) 1%(14)

EMBRACE

n=731/800 88 77 64 63 >90% ?

Retro

EMBRACE

n=584/698

84 79 63 63 91%

3y 6%

Lindegaard ESTRO 2012

Retro EMBRACE: Sturdza et al. ESGO 10/2013

69 local failures out of 731 patients,

median follow-up: 44 months

Actuarial Local Control

@ 3 years:

Stage 1B: 98%

Stage 2B: 95%

Stage 3B: 79%

Actuarial Local Control

@ 3 years: 91%

@ 5 years: 88%

FIGO

stage

Total no Local

failure

only

Local and

systemic

failure

Local and

regional

failure

Local,

regional

and

systemic

failure

Overall

local

failure

No

evidence

Of any local

disease

Mean D90

HRCTV

(Gy)

Actuarial

LC at 3

years %

Actuarial

LC at 5

years %

IA 2 0(0) 0(0) 0(0) 0(0) 0(0) 0(0) 100 100

IB 123 0(0) 0(0) 2(2) 0(0) 2(2) 121(121) 93.24±16.7 98 98

IIA 42 1(0) 1(1) 0(0) 1(1) 3(2) 39(40) 88.3±15.4 97 94

IIB 368 14(11) 5(3) 4(3) 5(4) 28(21) 340(347) 87.5±14 93 91

IIIA 23 1(1) 3(2) 0(0) 1(1) 5(4) 18(19) 83.4±11.8 71 71

IIIB 145 19(15) 4(4) 1(1) 4(4) 28(24) 117(121) 83.4±13 79 75

IVA 23 1(1) 0(0) 0(0) 2(2) 3 (3) 20(20) 77.92±23 76 76

IVB 5 0(0) 0(0) 0(0) 0(0) 0(0) 5(5) 78.26±13

Total 731 36(27) 13(11) 7(6) 13(11) 69(56) 662(676) 87.6±14.6 91 89

() Number of recurrences at three years

Table 3.Local failures in any form and D90 for HRCTV stage based

RetroEMBRACE Evaluation, to be published

Sturdza et al. 2013

Months to event

Survival Function

1.0

0.8

0.6

0.4

0.2

0.0

Local control

Overall survival

697 557 421 307 184 117

697 604 463 350 228 139

91%

85%

87.5%

79%

Figure 1: Actuarial LC and OS for 698 patients

with median 32 months F/U.

Absolute numbers for Local failures: 63 patients

(23 persistent diseases, 40 true local recurrences);

234/698 patients died.

Figure 6. Actuarial stage related overall survival at 3 years

and 5 years: stage IB: 88% & 83%, II A: 83% & 80% ,

IIB: 78% & 70%, IIIA: 54% & 42%, IIIB: 58% & 45%

and IV A: 43% and 32% .

Pro

bab

ilit

y

Months after treatment

100%: tumor < 4 cm

95.3%: tumor > 4 cm

HR-CTV D90 > 60 GyEQD2

40.0%: tumor > 4 cm

HR-CTV D90 < 60 GyEQD2

P = 0.001

HR-CTV D90 need more than 60 GyEQD2 (WP 30 Gy + ICBT 5.8 Gy x 4 to HR-CTV)

Correlation between HR-CTV D90

and local control : NIRS

2011 JASTRO Kato

0

.2

.4

.6

.8

1

0 12 24 36 48 60 72

D90≧ 58 GyEQD2 (n=21)

Pro

ba

bili

ty

Months

95%

70%

p=0.0470

D90 < 58 GyEQD2 (n=21)

0

.2

.4

.6

.8

1

0 12 24 36 48 60 72

Pro

ba

bili

ty

Months

Group 1

Group 2

Group 3

100%

92%

61%

Group 1 tumor size< 4cm (n=13)

Group 2 tumor size ≧ 4cm で

D90 ≧ 58 GyEQD2 (n=13)

Group 3: tumor size ≧ 4cm で

D90 < 58 GyEQD2 (n=16)

p=0.0884

(JSGO 48th Ohno et al.)

D90: 58GyEQD2 WP 30Gy/15fr + ICBT5.5Gy x 4fr (HR-CTV D90)

Correlation between HR-CTV D90

and local control : Gunma University

Dose Effects: local control multi-centre data, retrospective (RetroEMBRACE)

Figure 1.2.4: Relationship between EBRT-C+BT dose and local control from retroEMBRACE patients

(Tanderup et al, unpublished data)

Figure 1.2.4: Relationship between

EBRT-C+BT dose and local control from

retroEMBRACE, n=592 patients

(Tanderup et al, unpublished data)

LOCAL CONTROL - CLINICAL DATA

DOSE AT POINT A vs. D90 IN IMAGE BASED HR-CTV

Vienna experience, Rad&Onc 2011 (RetroEMBRACE)

EARLY DISEASE IB

DOSE

Pt A / D90 HR

BEST STANDARDS AIM/Vienna 2011

(RetroEMBRACE)

75 Gy / 90+ Gy

90-95%

100%/100% (98%)

ADVANCED

DISEASE

IIB

80 Gy / 90+ Gy

70-85%

95-100%/96% (95%)

IIIB

85 Gy / 90 Gy

50-65%

85-90%/86% (79%)

Expected Improvement through Image Guided Adaptation:

5-40%: IB: 5-10%; IIB lim: 10-20%; IIb ext/IIIB: 20-40%

Summary dose values OAR (EQD2)

Mean Gy Intracavitary1 interstitial2 145 patients3

Bladder D2cc 83 83 95

ICRU 75 73 72

Rectum D2cc 64 66 65

ICRU 69 71 67

Sigmoid D2cc 63 67 62

1 Kirisits et al Int J Radiat Oncol Biol Phys 2005

2 Kirisits et al Int J Radiat Oncol Biol Phys 2006

3 Pötter et al Radiother Oncol 2007 treatment period 1998-2003

145 consecutive patients with MRI assisted cervix cancer brachytherapy

prospective assessment of morbidity

Analysis of morbidity topography in 3D

for organs and

subgroups

2 ccm organ volume

(1 ccm, 0.1 ccm)

3D Dose-volume-

effect relationships

Linking DVH-parameters to clinical outcome morbidity (Vienna)

(n=141, FIGO: IB-IVA, median follow-up=51 months) 523 treatment plans / 608 fractions

P. Georg et al. IJROBP 2011;

LENT/

SOMA

G1 G2 CR*

G1/2 G3

G4

CR*

G3/4

Bladder 7 10 20% 1

2

4%

Rectum 2 6 9% 2 0

2%

Sigmoid 0 1 1% 0 2

2%

*CR: actuarial complication rate

D2cc = 81 Gy EQD2

D1cc = 90 Gy EQD2

D0.1cc= 108 Gy EQD2

ventral

dorsal

high dose area

corresponding to 0.1cc

Georg et al. IJROBP 2011

Endoscopic mapping

Incid

en

ce

VR

S >

3

0

10

20

30

40

50

60

70

80

90

100

Dose [Gy]

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

Incid

en

ce

LE

NT

/SO

MA

> 2

0

10

20

30

40

50

60

70

80

90

100

D2 ccm

D1 ccm

D0.1 ccm

DICRU

Dose volume effects

for rectal morbidity applying

GEC ESTRO recommendations

VRS: Vienna Rectoscopy

Score

Clinical late Effects

LENT SOMA score

Georg et al. Radioth&Oncol 2009

N = 35 patients

with rectosigmoidoscopy

Koom et al. IJROBP 2007

P. Georg et al. IJROBP 2011

Dose Volume Effect for sigmoid for 2 ccm (?)

0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

1

0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160

D2cc (Sigmoid)

P

0/2 0/1 0/9 0/7 0/15 0/22

1/280/24

0/11

0/10

2/10

0/2

Sigma

N=141

0

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

sc

ore

mean VS

common observation

Topographical interfractional

changes

In addition: No clear

correlation in endoscopy study

(2007) Sturdza et al. Boston 2008

Uncertainties in assessing sigmoid DVH parameters Assessment of sigmoid topography changes between

HDR-brachytherapy fractions

“Is the worst case assumption valid for the sigmoid colon?”

Results

23/44 common observations between observers

• 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

little or no movement

Sturdza et al. Boston 2008

Dose effect bladder

P. Georg et al. 2011 IJROBP

(Vienna data)

Significant dose response

for Bladder D2cc

on urinary incontinence (frequ)

(EMBRACE)

Linking DVH-parameters to outcome

Bladder - evaluation

Bladder wall(bw)

Position

P = 0.006

Low

bw

Medium

bw

With Side effect 10 3

No Side effect 6 15

Arie et al./Berger et al., Vienna 2008/10

Bladder D2cc ≤100 Gy >100 Gy

G1-G4 13% (12/94) 17% (8/47)

Rectum D2cc ≤75 Gy >75 Gy

G1-G4 4% (5/116) 20% (5/25)

Sigmoid D2cc ≤75 Gy >75 Gy

G1-G4 1% (1/119) 9% (2/22)

Weak overall dose volume effect for all patients, e.g. 2 ccm (Georg et al. 2010, in press)

for 34 patients with D 2 ccm > 90 Gy

RetroEMBRACE

Fokdal et al. 2013 Publication under preparation

RetroEMBRACE Fokdal et al. 2013 Publication under preparation

Vaginal dose assessment and reporting

DVH parameters have HIGH uncertainty for representative vaginal dose estimation

They are influenced by the resolution of

sectional imaging, contouring accuracy and applicator reconstruction

Berger et al, IJROBP 2007

Vaginal morbidity was not (significantly) correlated to

any DVH-parameters which were applied in

3D MRI-based cervical cancer brachytherapy

bleeding teleangiectasia

shortening fibrosis

LENT SOMA 1 or 2

0,0 20,0 40,0 60,0 80,0 100,0 months after RT

0,0

0,2

0,4

0,6

0,8

1,0

pe

rce

nt

ACTUARIAL LATE SIDE EFFECTS (LENT/SOMA)

G1 / G2

G3 / G4

Upper vagina

n=145 G1/G2= 114

G3/G4= 5

Fidarova et al. Radioth&Oncol 2010

ICRU/GEC ESTRO Report 88 under publication Fig. 6.1/Fig. 8.11

Vaginal morbidity and radiation doses

at 5 mm

60-115 Gy

65 Gy ICRU

rectovag. P

50 Gy

37 Gy

4 Gy

(Westerveld et al.

Vienna 2013)

DVH Parameters and Reference Points,

variations in application

ICRU/GEC ESTRO

report 88

under publication

Fig. 6.4, Fig. 8.8

Dose Effects: vaginal morbidity multi-centre data, prospective (EMBRACE)

Vaginal morbidity

(shortening /stenosis)

and dose in 446 patients

(EMBRACE, Doctor reported outcome) (Kirchheiner et al, ESTRO Geneva 2013,

unpublished data)

Such dose effect correlations

also possible

for Patient reported outcome (?)

see Bergmark et al. 1999, 2002,

recent endometrium work

CONCLUSIONS AND LIMITATIONS (IGABT)

Linking DVH parameters to clinical outcome

• D90 HR CTV and local control: strong link

• 2 ccm for rectal morbidity (ICRU Point): strong link

• 2 ccm for bladder morbidity: some link

improvement by location assessment?

• 2 ccm for sigmoid morbidity: weak link

improvement by movement assessment?

• Any DVH parameter for vaginal morbidity: no link so far

improvement by ICRU rectovaginal Point strong link

Limitations: limited prospective study data

multicenter study: RetroEMBRACE/EMBRACE