Oltre l’alfa/beta:
ipotesi di coinvolgimento dell’endotelio
e modelli predittivi dell’effetto nei
trattamenti ultra-ipo-fr...
Historically
• By the 1930s fractionated radiotherapy (1-3 Gy per
fraction) has been the major regimen of radiotherapy
• T...
Why reconsider high dose fractions?
• Evidence that it can be very effective (SRS of
brain metastases, SBRT for lung, brea...
Radiobiological principles at high doses
• Response predicted by LQ model is really linear at
higher doses?
• Mixed tumor ...
The LQ model
β
α
Basic Clinical Radiobiology, fourth edition, Joiner M and Van der Kogel A. Hodder Arnold Edition 2009
-ln...
The lethal-potentially lethal (LPL)
damage model
Curtis SB. Radiat Res. 1986 May;106(2):252-70.
• Based on experimental and theoretical considerations, the LQ model
is a reliable mechanistic plausible model for dose ra...
• LQ model is derived mostly in vitro at doses below those used in
radiosurgery
• Clinically underestimates tumor control ...
Semin Radiat Oncol 2008; 18:240-3
Tumor blood vessels
RakeshK Jain. Nature Medicine 9, 685 - 693 (2003)
Tumor blood vessels
• Single-layer endothelial cells often separated by gaps
• Frequently devoid of innervations and so un...
Wong HH, et al. Radiology. 1973 Aug;108(2):429-34
Walker 256 tumors grown in legs
of Sprague-Dawley rats
Single dose radia...
Vascular effects at high doses
Park HJ et al. Radiat Res. 2012 Mar;177(3):311-27.
Functional Intravascular
Volume
Walker 2...
Vascular effects at high doses
Song CW et al. Proceedings of the 51° Annual ASTRO Meeting, Chicago, Nov. 1-5, 2009. Abstra...
Vascular effects at high doses
Park HJ et al. Radiat Res. 2012 Mar;177(3):311-27.
2 different breast cancer patients
Endot...
Vascular effects at high doses
Park HJ et al. Radiat Res. 2012 Mar;177 (3):311-27.
Ceramide and radiation-induced endothelial cell death
Kolesnick Ret al. Oncogene, 2003, 22: 5897-906
• In several organs in vivo (alveolar septi of the lung,
intestinal mucosa, central nervous system)
• The damage of the en...
Ceramide and radiation-induced endothelial cell death
Kolesnick Ret al. Oncogene, 2003, 22: 5897-906
Ceramide and radiation-induced endothelial cell death
Garcia-Barros M et al. Science 2003; 300: 1155-59
Single Dose Radiation (> 8-10 Gy)Single Dose Radiation (> 8-10 Gy)
Tumor Cell DamageTumor Cell Damage
Tumor Cell DeathTumo...
Fractionated Radiation (1.8 –3Gy/fraction)Fractionated Radiation (1.8 –3Gy/fraction)
Tumor Cell DamageTumor Cell Damage
Tu...
• A 3-dimensional computer simulation developed and fitted to response data
from 90 pts treated by LINAC radiosurgery for ...
Clonogenic
Hypoxic
Necrotic
Vessels
Clonogenic
Hypoxic
Necrotic
Vessels
Kocher Met al. Radiother Oncol 2000; 54: 149-56
• The observed response rate of brain metastases to single dose
radiosurgery requires the assumption of a major effect of ...
The Linear Quadratic Cubic Model
Joiner M. Quantifying cell kill and survival. In: Basic Clinical Radiobiology. 4th editio...
The Universal Survival Curve
• Alternative model termed USC (Universal Survival Curve) by
hybridizing the LQ model and the...
The Universal Survival Curve
BED: the total dose delivered in an infinite number of infinitesimally small dose
fractions t...
The Universal Survival Curve
Park C. et al. Int J Radiat Oncol Biol Phys. 2008 Mar 1;70(3):847-52.
The Universal Survival Curve
• The UCS provides an empirically and clinically well-justified
rationale for SBRT while pres...
The Universal Survival Curve
Park C. et al. Int J Radiat Oncol Biol Phys. 2008 Mar 1;70(3):847-52.
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Oltre l’alfa/beta: ipotesi di coinvolgimento dell’endotelio e modelli predittivi dell’effetto nei trattamenti ultra-ipo-frazionati (lineare-cubico ecc.)

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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.)

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  • RC per differenti valori di radiosensibilità (a= alfa). In assenza di un effetto vascolare, per nessun valore di radiosens inserito nel modello si ottiene una deviazione significativa dai dati clinici, per i diversi tipi di mtx (solida o necrotica.
    RC in presenza dell’ effetto vascolare: scegliendo un valore di radiosens vascolare appropiato si può osservare che, per differenti tipi di mtx, l’ entità della risposta riproduce i dati clinici senza diffstat significative. Scegliendo invece un valore di radiosens vascolare troppo basso (v= 0.018) si osserva una deviazione dal dato clinico significativa.
  • Oltre l’alfa/beta: ipotesi di coinvolgimento dell’endotelio e modelli predittivi dell’effetto nei trattamenti ultra-ipo-frazionati (lineare-cubico ecc.)

    1. 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. 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. 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. 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. 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. 6. The lethal-potentially lethal (LPL) damage model Curtis SB. Radiat Res. 1986 May;106(2):252-70.
    7. 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. 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. 9. Semin Radiat Oncol 2008; 18:240-3
    10. 10. Tumor blood vessels RakeshK Jain. Nature Medicine 9, 685 - 693 (2003)
    11. 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. 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. 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. 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. 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. 16. Vascular effects at high doses Park HJ et al. Radiat Res. 2012 Mar;177 (3):311-27.
    17. 17. Ceramide and radiation-induced endothelial cell death Kolesnick Ret al. Oncogene, 2003, 22: 5897-906
    18. 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. 19. Ceramide and radiation-induced endothelial cell death Kolesnick Ret al. Oncogene, 2003, 22: 5897-906
    20. 20. Ceramide and radiation-induced endothelial cell death Garcia-Barros M et al. Science 2003; 300: 1155-59
    21. 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. 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. 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. 24. Clonogenic Hypoxic Necrotic Vessels Clonogenic Hypoxic Necrotic Vessels
    25. 25. Kocher Met al. Radiother Oncol 2000; 54: 149-56
    26. 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. 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. 28. The Universal Survival Curve • Alternative model termed USC (Universal Survival Curve) by hybridizing the LQ model and the classical multi-target model
    29. 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. 30. The Universal Survival Curve Park C. et al. Int J Radiat Oncol Biol Phys. 2008 Mar 1;70(3):847-52.
    31. 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. 32. The Universal Survival Curve Park C. et al. Int J Radiat Oncol Biol Phys. 2008 Mar 1;70(3):847-52.

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