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Radiothérapie Hypofractionnée et
Cancer de Prostate
JM Hannoun-Levi
Cercle des Oncologues Radiothérapeutes du Sud /
Centre Antoine Lacassagne
2ème Congrès du CORS – Juan les Pins – 26/06/09

# fractions

# fractions
dose/fraction
 total dose

# fractions
dose/fraction
 total dose
Hypofractionated RT

# fractions
dose/fraction
 total dose
Hypofractionated RT
Accelerated

treatment time

# fractions
dose/fraction
 total dose
Hypofractionated RT

Accelerated
Non Accelerated
treatment time
treatment time =

# fractions
dose/fraction
 total dose
Hypofractionated RT

Accelerated
Non Accelerated
treatment time
treatment time =
Rationnal
Patient
Quality of life
Time for recovering professional life
Treatment coast
Tumor
Biological considerations
Dose escalation
Therapeutic index
RT department
 linac time
 # treated pts
 treatment delay
Rationnal
Patient
Quality of life
Time for recovering professional life
Treatment coast
Tumor
Biological considerations
Dose escalation
Therapeutic index
RT department
 linac time
 # treated pts
 treatment delay
Rationnal
Patient
Quality of life
Time for recovering professional life
Treatment coast
Tumor
Biological considerations
Dose escalation
Therapeutic index
RT department
 linac time
 # treated pts
 treatment delay
Rationnal
Patient
Quality of life
Time for recovering professional life
Treatment coast
Tumor
Biological considerations
Dose escalation
Therapeutic index
RT department
 linac time
 # treated pts
 treatment delay
3D Hypofractionnated RT
Durée duTTT
Dose/fraction
(Total dose)
Overall Treatment Time
Dose / fraction
Overall treatment time
Volume
Volume
High dose
Small volume
Short time
Development
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•
•
Biological considerations
Dose escalation in prostate cancer
Small volume
Clinical data
Conclusion
Development
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•
•
Biological considerations
Dose escalation in prostate cancer
Small volume
Clinical data
Conclusion
Development
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•
•
•
Biological considerations
Dose escalation in prostate cancer
Small volume
Clinical data
Conclusion
Development
•
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•
•
•
Biological considerations
Dose escalation in prostate cancer
Prostate motion
Clinical data
Conclusion
Development
•
•
•
•
•
Biological considerations
Dose escalation in prostate cancer
Prostate motion
Clinical data
Conclusion
Development
•
•
•
•
•
Biological considerations
Dose escalation in prostate cancer
Prostate motion
Clinical data
Conclusions
Development
•
•
•
•
•
Biological considerations
Dose escalation in prostate cancer
Prostate motion
Clinical data
Conclusions
Biological Equivalent Dose @ 2 Gy
=
?
Biological Equivalent Dose @ 2 Gy
=
dose/fraction
?
 total dose
Surviving cell fraction
Dose (Gy)
Surviving cell fraction
Dose (Gy)
α/ ↔ Fractionation sensitivity
α/
Dose range Normal Tissue Sensitivity to
(Gy)
Response
OTT* D/f**
Low
1 to 5
Late
+
+++
High
10 to 20
Early
& Tumors
+++
+
* OTT: Overall Treatment Time
** D/f: Dose per fraction
α/
Dose range Normal Tissue Sensitivity to
(Gy)
Response
OTT* D/f**
Low
1 to 5
Late
+
+++
High
10 to 20
Early
& Tumors
+++
+
* OTT: Overall Treatment Time
** D/f: Dose per fraction
Toxicity
Efficacy
For dose/fraction < 8 Gy
D'  D *  /   d  / /   2
D’:
D:
d :
d’ :
biologic equivalent dose (Gy)
physical delivered dose (Gy)
dose per fraction for D (Gy)
dose per fraction for D’ (Gy)
Late responding
normal tissue
Tumor
α/
Late responding
normal tissue
Tumor
α/
1.5
3
α/
Brenner DJ, Hall EJ. IJROBP 1999;43:1095
1<
α/
<5
Hypofractionated RT
Development
•
•
•
•
•
Biological considerations
Dose escalation in prostate cancer
Prostate motion
Clinical data
Conclusions
Hypothesis
%Free Of Failure
Higher RT Doses will cause late flattening of K-M curves
through a reduction in local persistence of disease
Time After RT
Morgan PB, et al. IJROBP 2007;67:1074
Hypothesis
%Free Of Failure
Higher RT Doses will cause late flattening of K-M curves
through a reduction in local persistence of disease
Early drop due to
micrometastatic
disease
Time After RT
Morgan PB, et al. IJROBP 2007;67:1074
Hypothesis
%Free Of Failure
Higher RT Doses will cause late flattening of K-M curves
through a reduction in local persistence of disease
Early drop due to
micrometastatic
disease
Late drop due to
local persistence
of disease
Time After RT
Morgan PB, et al. IJROBP 2007;67:1074
Hypothesis
Higher RT Doses will cause late flattening of K-M curves
through a reduction in local persistence of disease
%Free Of Failure
High RT Dose
Early drop due to
micrometastatic
disease
Late drop due to
local persistence
of disease
Time After RT
Morgan PB, et al. IJROBP 2007;67:1074
Hazard
Distant Metastasis
All Patients
0,002
0,001
0,000
Hazard
<74 Gray
0,002
0,001
0,000
Hazard
>74 Gray
0,002
0,001
0,000
0-2
2-4
4-6
6-8
8-10
Time Following Radiotherapy (years)
Morgan PB et al. IJROBP 2007;67:1074
Hazard
Distant Metastasis
All Patients
0,002
0,001
0,000
Hazard
<74 Gray
0,002
0,001
0,000
Hazard
>74 Gray
0,002
0,001
0,000
0-2
2-4
4-6
6-8
8-10
Time Following Radiotherapy (years)
Morgan PB et al. IJROBP 2007;67:1074
Hazard
Distant Metastasis
All Patients
0,002
0,001
0,000
Hazard
<74 Gray
0,002
0,001
0,000
Hazard
>74 Gray
0,002
0,001
0,000
0-2
2-4
4-6
6-8
8-10
Time Following Radiotherapy (years)
Morgan PB et al. IJROBP 2007;67:1074
PSA Era Randomized Dose Escalation Trials
Authors (yr)
# pts
Dose (Gy)
FFBF
p-value
Kuban (2008)*
151
150
78
70
78%(10yr)
59%(10yr)
0.004
Zietman (2005)
195
197
79.2
70.2
80%(5 yr)
61%(5 yr)
<0.001
Peeters (2006)
333
331
78
68
64%(5 yr)
54%(5 yr)
0.02
Dearnaley (2007)
422
421
74
64
71%(5 yr)
60%(5 yr)
0.0007
*Nadir+2 FFBF;  Neoadjuvant AD 3-6 mo.
PSA Era Randomized Dose Escalation Trials
Authors (yr)
# pts
Dose (Gy)
FFBF
p-value
Kuban (2008)*
151
150
78
70
78%(10yr)
59%(10yr)
0.004
Zietman (2005)
195
197
79.2
70.2
80%(5 yr)
61%(5 yr)
<0.001
Peeters (2006)
Dearnaley (2007)
Hypofractionated
RT
333
78
64%(5 yr)
331
68
54%(5 yr)
422
421
74
64
71%(5 yr)
60%(5 yr)
*Nadir+2 FFBF;  Neoadjuvant AD 3-6 mo.
0.02
0.0007
Development
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•
•
•
Biological considerations
Dose escalation in prostate cancer
Prostate motion
Clinical data
Conclusions
Bladder & Rectal Volume Changes During RT
Antolak JA et al. IJROBP 1998;42:661
Prostate motion according to the rectum vacuity
Sigmoid Flexure
R
R
B
B
P
P
Ischial
Tuberosities
Not corrected for motion
Courtesy of Alan Pollack
Prostate motion according to the rectum vacuity
Sigmoid Flexure
R
R
B
B
P
P
Ischial
Tuberosities
Not corrected for motion
Courtesy of Alan Pollack
Consequences of prostate motion
de Crevoisier et al, IJROBP 2005;62:965
Consequences of prostate motion
Hypofractionated RT
de Crevoisier et al, IJROBP 2005;62:965
Development
•
•
•
•
•
Biological considerations
Dose escalation in prostate cancer
Prostate motion
Clinical data
Conclusions
Technical aspect
Technical aspect
RCMI +/- AT
Technical aspect
RCMI +/- AT
CyberKnife
Technical aspect
RCMI +/- AT
CyberKnife
Curie HDD
Results of Prospective Phase II
“Soft” Hypofractionation Studies (EBRT)
Miles EF et al. Semin Radiat Oncol 2008;18:41
Ongoing Randomized Trials of
“Soft” Hypofractionation (EBRT)
Miles EF et al. Semin Radiat Oncol 2008;18:41
High Dose Rate Brachytherapy
Results of Prospective
Hypofractionation Boost Studies (HDR)
Risk
Authors (yr)
Groups
Median Dose (Gy)
EBRT
HDR
Median
5-year
follow-up (yr)
Biochemical
control rate (%)*
Low
Inter. & high
Elau (2000)
T1-2b, SG =6, PSA<10
50
12-16
6
96
Galalae (2004)
T1-2b, SG =6, PSA<10
46-50
16-30
5
96
Demanes (2005)
T1-2b, SG =6, PSA<10
36
22-24
7.25
90
T2c-3, SG 7-10, PSA >15
50
12-16
6
Elau (2000)
Intermediate : 1/2 factors
72
High : 3 factors
49
Martinez (2002)
T2c-3, SG 7-10, PSA =10
46
Galalae (2004)
T = 2b, SG =7, PSA =10
46-50
Demanes (2005)
23
4
16-30
5
Intermediate : 1 factor
88
High : =2 factors
69
T2b-c, SG 7, 10<PSA =20
36
22-24
7.25
T3, SG 8-10, PSA > 20
Martinez (2009)
*ASTRO definition
** 10-year biochemical control rate
87
T = 2b, SG =7, PSA =10
87
69
40
24
5.8
85 (82*)
Different fractionation schedules using
“Hyper” Hypofractionated regimens with
CK or HDRBT
Fractionation
schedule
Madsen
Stanford
Martinez
Demanes
Mark
Tech
CK
CK
HDR
HDR
HDR
Dose/fx
6.70
7.20
9.50
7.25
7.50
#fxs
5
5
4
6
6
TD
Gy
33.50
36.25
38.00
43.50
45.00
1.5
α/β
3
10
78.5
90.6
119.4
108.8
115.7
65.0
74.3
95.0
89.2
94.5
46.6
52.1
61.8
62.5
65.6
Development
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•
•
•
Biological considerations
Dose escalation in prostate cancer
Prostate motion
Clinical data
Conclusions
Rationale for Accelerated and Hypofractionated
Treatments for Prostate Cancer
Rationale for Accelerated and Hypofractionated
Treatments for Prostate Cancer
Quality of life
Time for recovering professional life
Treatment coast
Rationale for Accelerated and Hypofractionated
Treatments for Prostate Cancer
Quality of life
Time for recovering professional life
Treatment coast
Biological considerations
Dose escalation
Therapeutic index
Biological considerations
1<
α/
<5
=3
Biological considerations
1<
α/
<5
Dose escalation
=3
Hypofractionated RT for Prostate Cancer
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