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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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Information about Oltre l’alfa/beta: ipotesi di coinvolgimento dell’endotelio e modelli...
Health & Medicine

Published on March 15, 2014

Author: GemelliArt

Source: slideshare.net

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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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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

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

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

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?

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

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 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

• 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

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 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

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

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

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

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

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 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

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 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

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

• 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

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 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

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

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

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.

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 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.

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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