24° CORSO RESIDENZIALE DI AGGIORNAMENTO con il patrocinio dell’Associazione Italiana di Radioterapia Oncologica (AIRO) Moderna Radioterapia, Nuove Tecnologie e Ipofrazionamento della Dose 17 marzo 2014: Oltre l’alfa/beta: ipotesi di coinvolgimento dell’endotelio e modelli predittivi dell’effetto nei trattamenti ultra-ipo-frazionati (lineare-cubico ecc.)

1. Oltre l’alfa/beta:
ipotesi di coinvolgimento dell’endotelio
e modelli predittivi dell’effetto nei
trattamenti ultra-ipo-frazionati
(lineare-cubico ecc.)
Dinapoli N, Cilla S, Diletto B

2. Historically
• By the 1930s fractionated radiotherapy (1-3 Gy per
fraction) has been the major regimen of radiotherapy
• Tumor response and normal tissue damage are governed
by 4 Rs
Reoxygenation
Repair of sublethal damage
Redistribution of cell in the cell cycle
Repopulation of cells
• Introduction of LQ model in 1980s to calculate cell
killing by different total dose, size of fraction and
fraction number

3. Why reconsider high dose fractions?
• Evidence that it can be very effective (SRS of
brain metastases, SBRT for lung, breast, liver,
prostate and spine)
• Evidence of low α/β in some sites (breast,
prostate)
• Lower cost of whole treatment
• Patient convenience and demand

4. Radiobiological principles at high doses
• Response predicted by LQ model is really linear at
higher doses?
• Mixed tumor cell populations with different response
characteristics?
• Increased apoptosis?
• Immunological effects?
• Vascular damage?

5. The LQ model
β
α
Basic Clinical Radiobiology, fourth edition, Joiner M and Van der Kogel A. Hodder Arnold Edition 2009
-ln (S) = αD + βD2

6. The lethal-potentially lethal (LPL)
damage model
Curtis SB. Radiat Res. 1986 May;106(2):252-70.

7. • Based on experimental and theoretical considerations, the LQ model
is a reliable mechanistic plausible model for dose range from 2 to 10
Gy
• Above 10 Gy would become less accurate but, based on animal data,
still accetable for doses per fractions of 15 to 18 Gy
• To date there is no evidence of problems when LQ was been applied
in the clinic
Semin Radiat Oncol 2008; 18:234-9

8. • LQ model is derived mostly in vitro at doses below those used in
radiosurgery
• Clinically underestimates tumor control observed at radiosurgical
doses
• Do not reflect the vascular and stromal damage produced at high
doses per fraction
• Ignores the impact of radioresistant subpopulations of cells (stem
cells)
Semin Radiat Oncol 2008; 18:240-3

9. Semin Radiat Oncol 2008; 18:240-3

10. Tumor blood vessels
RakeshK Jain. Nature Medicine 9, 685 - 693 (2003)

11. Tumor blood vessels
• Single-layer endothelial cells often separated by gaps
• Frequently devoid of innervations and so unable to
autoregulate in response to external stresses (ionizing
radiation)
• the blood perfusion is sluggish and intermittently
stationary
• the abnormal features account for the hypoxic,
nutritionally deprived and acidic intratumor
microenvironment
SH Lewitt et al. (eds.), Technical Basis of Radiation Therapy. Springer-Verlag Berlin Heidelberg 2012

12. Wong HH, et al. Radiology. 1973 Aug;108(2):429-34
Walker 256 tumors grown in legs
of Sprague-Dawley rats
Single dose radiation of 30 Gy
Vascular effects at high doses

13. Vascular effects at high doses
Park HJ et al. Radiat Res. 2012 Mar;177(3):311-27.
Functional Intravascular
Volume
Walker 256 tumors grown in legs
of Sprague-Dawley rats
Single dose radiation of
2-5-10-30-60 Gy

14. Vascular effects at high doses
Song CW et al. Proceedings of the 51° Annual ASTRO Meeting, Chicago, Nov. 1-5, 2009. Abstract #2859
Functional Intravascular Volume
and vascular permeability
Walker 256 tumors grown in legs of
Sprague-Dawley rats
Irradiation with
20 Gy in 1, 4 or 8 daily fractions

15. Vascular effects at high doses
Park HJ et al. Radiat Res. 2012 Mar;177(3):311-27.
2 different breast cancer patients
Endothelial cells from normal
breast or cancer
In vitro radiation survival curves

16. Vascular effects at high doses
Park HJ et al. Radiat Res. 2012 Mar;177 (3):311-27.

17. Ceramide and radiation-induced endothelial cell death
Kolesnick Ret al. Oncogene, 2003, 22: 5897-906

18. • In several organs in vivo (alveolar septi of the lung,
intestinal mucosa, central nervous system)
• The damage of the endothelium is confined to the
microvasculature
• Endothelial apoptosis is an early event after exposure,
peaking at 4-10 h after irradiation and is dose dependent
Ceramide and radiation-induced endothelial cell death
Kolesnick Ret al. Oncogene, 2003, 22: 5897-906

19. Ceramide and radiation-induced endothelial cell death
Kolesnick Ret al. Oncogene, 2003, 22: 5897-906

20. Ceramide and radiation-induced endothelial cell death
Garcia-Barros M et al. Science 2003; 300: 1155-59

21. Single Dose Radiation (> 8-10 Gy)Single Dose Radiation (> 8-10 Gy)
Tumor Cell DamageTumor Cell Damage
Tumor Cell DeathTumor Cell Death
Tumor ResponseTumor Response
Endothelial Membrane AlterationsEndothelial Membrane Alterations
ASMaseASMase
SM
Ceramide
Endothelial ApoptosisEndothelial Apoptosis
Microvascular DysfunctionMicrovascular Dysfunction
Modified from: Fuks Z et al. Cancer Cell 2005, 8: 89-91

22. Fractionated Radiation (1.8 –3Gy/fraction)Fractionated Radiation (1.8 –3Gy/fraction)
Tumor Cell DamageTumor Cell Damage
Tumor Cell DeathTumor Cell Death
Tumor ResponseTumor Response
Cell Death SignalsCell Death Signals
Endothelial ApoptosisEndothelial Apoptosis
Microvascular DysfunctionMicrovascular Dysfunction
Modified from: Fuks Z et al. Cancer Cell 2005, 8: 89-91
Hypoxia/Reperfusion/ROS
HIF-1 Translation
VEGF / bFGF
Hypoxia/Reperfusion/ROS
HIF-1 Translation
VEGF / bFGF

23. • A 3-dimensional computer simulation developed and fitted to response data
from 90 pts treated by LINAC radiosurgery for 1-3 brain metastases with
median dose of 20 Gy
• Oxygen supply, tumor cell division (cell cycle time 5 days),
neovascularization, tumor cell kill by single dose irradiation and time-
dependent vascular occlusion were modeled by Monte-Carlo simulation
techniques
• To determine the impact of the two possible effects on tumor response: the
cytotoxic and the vascular effects

24. Clonogenic
Hypoxic
Necrotic
Vessels
Clonogenic
Hypoxic
Necrotic
Vessels

25. Kocher Met al. Radiother Oncol 2000; 54: 149-56

26. • The observed response rate of brain metastases to single dose
radiosurgery requires the assumption of a major effect of radiation
on tumor vasculature
• The dose response characteristics of the brain metastases can by no
way explained by the LQ model of tumor cell kill alone, even if the
typical dose distribution and the decreased radiosensitivity of the
hypoxic cells are considered

27. The Linear Quadratic Cubic Model
Joiner M. Quantifying cell kill and survival. In: Basic Clinical Radiobiology. 4th edition,
Joiner M and Van der Kogel A. Hodder Arnold London, 2009
-ln (S) = αD + βD2
– γD3
γ = β/3DL

28. The Universal Survival Curve
• Alternative model termed USC (Universal Survival Curve) by
hybridizing the LQ model and the classical multi-target model

29. The Universal Survival Curve
BED: the total dose delivered in an infinite number of infinitesimally small dose
fractions that has the same biologic effect as the dose-fractionation scheme in
question
Park C. et al. Int J Radiat Oncol Biol Phys. 2008 Mar 1;70(3):847-52.

30. The Universal Survival Curve
Park C. et al. Int J Radiat Oncol Biol Phys. 2008 Mar 1;70(3):847-52.

31. The Universal Survival Curve
• The UCS provides an empirically and clinically well-justified
rationale for SBRT while preserving the strenght of the LQ model for
the conventional fractionated radiotherapy
Park C. et al. Int J Radiat Oncol Biol Phys. 2008 Mar 1;70(3):847-52.

32. The Universal Survival Curve
Park C. et al. Int J Radiat Oncol Biol Phys. 2008 Mar 1;70(3):847-52.