1. 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

2.  # fractions

3.  # fractions
dose/fraction
 total dose

4.  # fractions
dose/fraction
 total dose
Hypofractionated RT

5. dose/fraction Hypofractionated RT Accelerated  total dose
 # fractions
dose/fraction
 total dose
Hypofractionated RT
Accelerated
 treatment time

6. dose/fraction Hypofractionated RT Accelerated Non Accelerated
 # fractions
dose/fraction
 total dose
Hypofractionated RT
Accelerated
Non Accelerated
 treatment time
treatment time =

9. dose/fraction Hypofractionated RT Accelerated Non Accelerated
 # fractions
dose/fraction
 total dose
Hypofractionated RT
Accelerated
Non Accelerated
 treatment time
treatment time =

10. Rationnal Patient Tumor RT department Quality of life
Time for recovering professional life
Treatment coast
Biological considerations
Dose escalation
Therapeutic index
RT department
 linac time
 # treated pts
 treatment delay

11. Rationnal Patient Tumor RT department Quality of life
Time for recovering professional life
Treatment coast
Biological considerations
Dose escalation
Therapeutic index
RT department
 linac time
 # treated pts
 treatment delay

12. Rationnal Patient Tumor RT department Quality of life
Time for recovering professional life
Treatment coast
Biological considerations
Dose escalation
Therapeutic index
RT department
 linac time
 # treated pts
 treatment delay

13. Rationnal Patient Tumor RT department  linac time Quality of life
Time for recovering professional life
Treatment coast
Biological considerations
Dose escalation
Therapeutic index
RT department
 linac time
 # treated pts
 treatment delay

14. 3D Hypofractionnated RT
Durée duTTT
Dose/fraction
(Total dose)
Volume

15. Overall Treatment Time
Different teams proposed a reduction of the overall treatment time

16. Overall treatment time
Dose / fraction
Overall treatment time
However, reduction of the overall treatment time leads to a reduction the total number of fractions then increase the dose per fraction.

17. Volume

18. Volume
High dose
Small volume
Short time

21. Development Biological considerations
Dose escalation in prostate cancer
Small volume
Clinical data
Conclusion

22. Development Biological considerations
Dose escalation in prostate cancer
Small volume
Clinical data
Conclusion

23. Development Biological considerations
Dose escalation in prostate cancer
Small volume
Clinical data
Conclusion

24. Development Biological considerations
Dose escalation in prostate cancer
Prostate motion
Clinical data
Conclusion

25. Development Biological considerations
Dose escalation in prostate cancer
Prostate motion
Clinical data
Conclusion

26. Development Biological considerations
Dose escalation in prostate cancer
Prostate motion
Clinical data
Conclusions

27. Development Biological considerations
Dose escalation in prostate cancer
Prostate motion
Clinical data
Conclusions

28. Biological Equivalent Dose @ 2 Gy? =
However, the two regimens must be biologically equivalent in order to obtain the same clinical result in term of local and biochemical control.

29. Biological Equivalent Dose @ 2 Gy? =
However, the two regimens must be biologically equivalent in order to obtain the same clinical result in term of local and biochemical control.
dose/fraction
 total dose

30. Surviving cell fraction
Dose (Gy)
Surviving cell fraction
Using the linear quadratic model, we can calculate the a/b ratio

31. Surviving cell fraction
Dose (Gy)
Surviving cell fraction
Which is strongly associated with the fractionation sensitivity of the considered normal tissue or tumor.
α/ ↔ Fractionation sensitivity

32. α/ Dose range (Gy) Normal Tissue Response OTT* D/f** Low High 1 to 5
Late
Early
& Tumors +
+++
Sensitivity to
In deed, for late response normal tissue, a/b ratio is between 1 and 5 Gy with a high fractionation sensitivity,
* OTT: Overall Treatment Time
** D/f: Dose per fraction

33. α/ Dose range (Gy) Normal Tissue Response OTT* D/f** Low High 1 to 5
Late
Early
& Tumors +
+++
Sensitivity to
However, for early response normal tissue and a large number of tumors, a/b ration is higher than 10 Gy and are mostly influenced by the overall treatment time.
* OTT: Overall Treatment Time
** D/f: Dose per fraction

34. Toxicity
Efficacy
To be efficient or not to be toxic: that is the question.
All the tumors have to be considered according to the surrounding normal tissue.

35. For dose/fraction < 8 Gy
D’: biologic equivalent dose (Gy)
D : physical delivered dose (Gy)
d  : dose per fraction for D (Gy)
d’ : dose per fraction for D’ (Gy)
Linear Quadratic model gives us a biological equivalence of a hypofractionated total dose of radiation corresponding to the dose delivered through a standard fractionation of 2 Gy per fraction 5 fractions a week.

36. α/ Late responding normal tissue Tumor
Usually, the a/b ration of the tumor is bigger compare to the a/b of the late response normal tissue
α/

37. α/ Late responding normal tissue Tumor
However, in some cases, the a/b ratio of the tumor can be equal or less important
α/

38. 1.5 3 α/ Brenner DJ, Hall EJ. IJROBP 1999;43:1095
In 1999, Brener et al propose an a/b ratio for prostate cancer close to 1.5 Gy while the a/b ratio of the main critical organ at risk (the rectum) is approximately 3 Gy.
1.5 3
α/
Brenner DJ, Hall EJ. IJROBP 1999;43:1095

39. Few years later, Fowler et al highlight this discussion

40. 1< < 5 α/ Hypofractionated RT
And propose to consider the a/b ratio of the prostate between 1 and 5 Gy.
1<
< 5
α/
Hypofractionated RT

41. Development Biological considerations
Dose escalation in prostate cancer
Prostate motion
Clinical data
Conclusions
Assuming an a/b of the prostate of 1.5 to 3 Gy and using an accelerated and hypofractionnated radiation protocol, the calculated biological equivalence dose could be higher compare to the conventional delivered dose of 70 Gy.
Is dose escalation correlated with a better biochemical control?

42. Hypothesis Higher RT Doses will cause late flattening of K-M curves through a reduction in local persistence of disease [ [
%Free Of Failure
Low RT Dose
Using conventional radiation dose of 70 Gy, Morgan et al observed two different steps after external beam radiation therapy
Time After RT
Morgan PB, et al. IJROBP 2007;67:1074

43. Early drop due to micrometastatic disease
Hypothesis 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
%Free Of Failure
Low RT Dose
The first one is an early drop due to micrometastatic disease,
Time After RT
Morgan PB, et al. IJROBP 2007;67:1074

44. Hypothesis 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
%Free Of Failure
Late drop due to local persistence of disease
Low RT Dose
The second one is a late drop due to local persistence of disease
Time After RT
Morgan PB, et al. IJROBP 2007;67:1074

45. Hypothesis Higher RT Doses will cause late flattening of K-M curves through a reduction in local persistence of disease [
High RT Dose [
Early drop due to micrometastatic disease
%Free Of Failure
Late drop due to local persistence of disease
Low RT Dose
Delivering a higher dose to the prostate could avoid this second and late drop in term of biochemical relapse.
Time After RT
Morgan PB, et al. IJROBP 2007;67:1074

46. Morgan PB et al. IJROBP 2007;67:1074
All Patients
Hazard
<74 Gray
Hazard
For the entire population, the authors noticed 2 different picks for distant metastases : the first one between 2 and 4 years after radiation therapy and the second one later after 8 years.
>74 Gray
Hazard
Morgan PB et al. IJROBP 2007;67:1074

47. Morgan PB et al. IJROBP 2007;67:1074
All Patients
Hazard
<74 Gray
Hazard
For patient who received a total radiation dose less than 74 Gy, the two picks were more important
>74 Gray
Hazard
Morgan PB et al. IJROBP 2007;67:1074

48. Morgan PB et al. IJROBP 2007;67:1074
All Patients
Hazard
<74 Gray
Hazard
While delivering a higher dose (more than 74 Gy) leads to the suppression of the second wave of distant metastases recurrence.
>74 Gray
Hazard
Morgan PB et al. IJROBP 2007;67:1074

49. PSA Era Randomized Dose Escalation Trials
Authors (yr) # pts Dose (Gy) FFBF p-value
Kuban (2008)* %(10yr) %(10yr)
Zietman (2005) %(5 yr) <0.001
%(5 yr)
Peeters (2006) %(5 yr) 0.02
%(5 yr)
Dearnaley (2007) %(5 yr)
%(5 yr)
*Nadir+2 FFBF;  Neoadjuvant AD 3-6 mo.
At least, 4 international phase III clinical trials using a boost delivered either through 3D conformal therapy or Proton therapy confirm that higher delivered dose leads to achieve a significantly higher biochemical control rate

50. PSA Era Randomized Dose Escalation Trials
Authors (yr) # pts Dose (Gy) FFBF p-value
Kuban (2008)* %(10yr) %(10yr)
Zietman (2005) %(5 yr) <0.001
%(5 yr)
Peeters (2006) %(5 yr) 0.02
%(5 yr)
Dearnaley (2007) %(5 yr)
%(5 yr)
*Nadir+2 FFBF;  Neoadjuvant AD 3-6 mo.
Hypofractionated RT
At least, 4 international phase III clinical trials using a boost delivered either through 3D conformal therapy or Proton therapy confirm that higher delivered dose leads to achieve a significantly higher biochemical control rate

51. Development Biological considerations
Dose escalation in prostate cancer
Prostate motion
Clinical data
Conclusions
As we said at the beginning of this talk for breast cancer, accelerated and hypofractionated radiation therapy must be delivered on a small but well defined volume.
For breast cancer the problem is the delineation of the CTV

52. For prostate cancer, the problem is the motion of this organ.

53. Bladder & Rectal Volume Changes During RT
One of the main raison which can explain the prostate motion is the change of rectum and bladder volume during radiation treatment
Antolak JA et al. IJROBP 1998;42:661

54. Not corrected for motion
Prostate motion according to the rectum vacuity
Sigmoid Flexure R R B B
If the dose distribution CT-scan is performed while the rectum is full, P P
Ischial
Tuberosities
Not corrected for motion
Courtesy of Alan Pollack

55. Not corrected for motion
Prostate motion according to the rectum vacuity
Sigmoid Flexure R R B B
And the patient is treated with a empty rectum, the posterior part of the prostate could be missed with a low dose finally delivered on the area at high risk of local recurrence P P
Ischial
Tuberosities
Not corrected for motion
Courtesy of Alan Pollack

56. Consequences of prostate motion
In 2005, de Crevoisier et al published the results of a study comparing the biochemical control rate for patient treated with undistented (empty ) or distended (full) rectum
de Crevoisier et al, IJROBP 2005;62:965

57. Consequences of prostate motion
Hypofractionated RT
In 2005, de Crevoisier et al published the results of a study comparing the biochemical control rate for patient treated with undistented (empty ) or distended (full) rectum
de Crevoisier et al, IJROBP 2005;62:965

58. Development Biological considerations
Dose escalation in prostate cancer
Prostate motion
Clinical data
Conclusions
What about clinical data regarding Hypofractionated radiation therapy for prostate cancer

59. At the beginning of the 16th century, Guillaume Tell had to destroy an apple placed above his sun head. He had to shut shortly, precisely and efficiently.

60. Technical aspect

61. Technical aspect
RCMI +/- AT

62. Technical aspect
RCMI +/- AT
CyberKnife

63. Technical aspect
RCMI +/- AT
Curie HDD
CyberKnife

64. Results of Prospective Phase II “Soft” Hypofractionation Studies (EBRT)
Dose per fraction rise from 2,5 to 3,5 Gy for a total delivered dose of 56 to 70 Gy.
Assuming a a/b ratio of 1,5 Gy, the biochemical equivalent in 2 Gy fractions is calculated from 77 to 90 Gy.
Miles EF et al. Semin Radiat Oncol 2008;18:41

65. Ongoing Randomized Trials of “Soft” Hypofractionation (EBRT)
The Fox Chase trial is the only one to propose a dose escalation higher than 80 Gy.
Miles EF et al. Semin Radiat Oncol 2008;18:41

66. High Dose Rate Brachytherapy
Historically, the first protocol of hypofractionated boost for prostate cancer used high dose rate Brachytherapy

67. Results of Prospective Hypofractionation Boost Studies (HDR)
For low, intermediate and high risk prostate cancer, except for the Demanes study, the first time of the treatment consisted to deliver a dose of 46 to 50 Gy followed by an HDR boost in 2 to 4 fractions.

69. Different fractionation schedules using
“Hyper” Hypofractionated regimens with
CK or HDRBT
Fractionation
schedule
Tech
Dose/fx
#fxs TD Gy
1.5
α/β 3 10
Madsen
Stanford
Martinez
Demanes
Mark CK
HDR
6.70
7.20
9.50
7.25
7.50 5 4 6
33.50
36.25
38.00
43.50
45.00
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
Madsen et al. recently published their results using CK for accelerated and hypofractionated radiation therapy delivering a total dose of 33,50 Gy in 5 fractions equivalent to 78,5 Gy assuming an a/b ratio of 1,5. The HDR series present an equivalent dose higher than 100 Gy.

70. Development Biological considerations
Dose escalation in prostate cancer
Prostate motion
Clinical data
Conclusions

71. Rationale for Accelerated and Hypofractionated Treatments for Prostate Cancer

72. Time for recovering professional life
Rationale for Accelerated and Hypofractionated Treatments for Prostate Cancer
Better QoL, …
Quality of life
Time for recovering professional life
Treatment coast

73. 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

74. Biological considerations
1<
< 5
α/
So in the worst case equivalent to the a/b of the rectum and probably less
= 3

75. Biological considerations
1<
< 5
α/
Dose escalation
So in the worst case equivalent to the a/b of the rectum and probably less
= 3

77. Hypofractionated RT for Prostate Cancer?
« Soft »
« Hyper »

78. Thank you for your attention