qué debo saber de radioterapia????radioterapia? 2. como influye la radioterapia en la cirugía? ......
TRANSCRIPT
Qué debo saber de radioterapia????
Natalia Carballo
Jefe Oncología Radioterápica
1. Cómo se administra la radioterapia?
2. Como influye la radioterapia en la cirugía?
3. Modalidades de tratamiento
Proceso de
tratamiento
•
•
•
•
TC planificación
Definir estructuras
Helical 4DCT
Hax R-X
Espiración
Inspiración
1ª posición camilla 2ª posición camilla 3ª posición camilla
Adquisición imágenes 4D
DOSIMETRIA
Definir estructuras
DVH
Tratamiento
¿Cómo?
CBCT
1. Cómo se administra la radioterapia?
2. Como influye la radioterapia en la cirugía!
3. Modalidades de tratamiento
En resumen generamos: DAÑO DIRECTO Ioniza átomos de la molécula del ADN DAÑO INDIRECTO Ioniza átomos y moléculas de la célula como el agua, (produciéndose radicales libres)
SINGLE STRAND BREAK
1000 / CELL / GRAY BASE CHANGE (eg C - U) BASE LOSS
1000 / CELL / GRAY BASE MODIFICATION (eg thymine/cytosine glycol) SUGAR DAMAGE (abstraction of hydrogen atom)
INTRASTRAND CROSSLINK
INTERSTRAND CROSSLINK
DNA-PROTEIN CROSSLINK
1 / CELL / GRAY
*
DOUBLE STRAND BREAK
30/ CELL / GRAY
Radicales libres
H2O
HOH+
H+
OH*
H* OH-
e- + H2O
HOH-
PORQUE NO DAÑAMOS EL TEJIDO SANO????
ACUTE RESPONDING TISSUES (responses seen during standard therapy)
Bowel
Skin
Bone Marrow
Mucosa
LATE RESPONDING TISSUES
(responses seen after end of therapy)
Brain
Spinal Cord
Kidney
Lung
Bladder
Tissue Type response
Dose (Gy)
Surviving Fraction
20 16 12 8 4 0 0
.01
.1
1
Late Responding Tissues
Acute Responding Tissues and
Many Tumors
Physical Dose = Biological Dose
Dose (Gy)
Dose Fractionation
24 20 16 12 8 4 0 0
.01
.1
1
Surviving Fraction
Single dose Late responding tissues Single dose
Acute responding tissues
Fractionated dose Acute responding tissues
Fractionated dose Late responding tissues
Dose fractionation spares late responding tissues more than acute
responding tissues and many tumors
Efectos agudos Intestino
• Alto índice proliferativo
• Daño: Células madre de las criptas de Lieberkuhn
• Alteración Villi intestinal, inflamación, edema
Efecto directo Microvascularización
Efectos crónicos; Fibrosis TGF β1
PII S0360-3016(00)00435-1
CRITICAL REVIEW
TGF- 1 AND RADIATION FIBROSIS: A MASTER SWITCH AND A SPECIFICTHERAPEUTIC TARGET?
MICHELE MARTIN, PH.D.,* JEAN-LOUIS LEFAIX, PH.D.,* AND SYLVIE DELANIAN, M.D., PH.D.†
*Laboratoire de Radiobiologie et d’Etude du Genome, DRR, DSV, C.E.A. Saclay, France; †Service d’Oncologie- Radiotherapie,Hopital Saint-Louis, Paris, France
Radiation fibrosis is a frequent sequel of therapeutic or accidental radiation overexposure in normal humantissues. One of the main fundamental problems yet unsolved in fibrotic tissues is the origin of the chronicactivation of myofibroblastswithin these tissues. I t hasbeen postulated that this chronic activation results froma continuous production of activating factors. In this context, fibrosis could be defined as a wound wherecontinuoussignalsfor tissue repair are emitted. Cytokinesand growth factorsprobably play a central role in thisprocess. Among them, transforming growth factor- 1 (TGF- 1) isconsidered asa master switch for thefibroticprogram. This review discusses recent evidence on the critical role played by TGF- in the initiation, develop-ment, and persistence of radiation fibrosis. I t summarizes the results concerning this factor after irradiation ofvarious tissues and cells, with an emphasis on superficial fibrosis, including skin and subcutaneous tissues.Finally, recent data concerning the treatment of established fibrotic disorders of various etiology are presented,as well as the possible mechanisms involved in fibrosis regression, which show that the TGF- pathway mayconstitute a specific target for antifibrotic agents. © 2000 Elsevier Science Inc.
TGF- 1, Ionizing radiation, Fibrosis, Myofibroblast, Treatment.
INTRODUCTION
The research on radiation damage to normal tissues has
gained in enthusiasm over the past few years both in exper-
imental clinical oncology and fundamental radiobiology.
One reason was the first publications demonstrating that
such damage could be reversible. Another reason was that
the research on predictors of patient radiosensitivity had
progressed, and new tests were proposed, such as cell
growth or DNA repair capacity assays, that showed corre-
lations between in vitro radiosensitivity and the degree of
late reactions in patients treated with radiotherapy. An ad-
ditional reason was the appearance of new biological tools
that allowed progress in fundamental radiobiology. In this
context, it was important to further define late radiation
damage and the mechanisms involved in their development.
This review will focus on tissue fibrosis, which is a major
late radiation damage. We will discuss recent evidence on
the critical role of the TGF- growth factor in radiation
fibrosis and propose this factor as a major target for anti-
fibrotic agents. As both early and late damage to the skin
are often used as criteria of patient radiosensitivity, the
results obtained in skin models will be more particularly
developed.
TGF- growth factor
Transforming growth factors are a family of cellular
mediators present in mammals as three distinct isoforms of
TGF- called 1 to 3 (1–3). From gene knockout studies
in mice, it has been shown that TGF- s are essential for
survival, as the disruption of any one of the corresponding
genes results in either embryonic or perinatal lethality (4).
In this review, we will concentrate on TGF- 1, which is the
isoform most implicated in fibroproliferative diseases.
TGF- 1 was originally described as a peptide that caused
reversible transformation of rodent fibroblasts (5, 6). It was
first purified to homogeneity from human platelets (7) and
was characterized as a homodimeric peptide with a molec-
ular mass of 25 kDa. The cloning of human TGF- 1 re-
sulted in the elucidation of its precursor structure (8).
TGF- 1 is ubiquitously produced and generally secreted by
the cells as a large latent complex (9). This complex in-
cludes the TGF- 1 homodimer, the latency-associated pep-
Reprint requests to: Dr. Michele Martin, Laboratoire de Radio-biologie et d’Etude du Genome, Laboratoire Mixte CEA-INRA,Domaine de Vilvert, Jouy en Josas, 78352, cedex, France. E-mail:[email protected]—The authors thank Marie-Catherine Vozenin-Brotons and Virginie Sivan for their active participation in thework on radiation skin damage performed in the laboratory overthe last years, as well as Francois Daburon who initiated this work.They also thank for their technical assistance: Nathalie Gault,
Francoise Crechet, Yves Tricaud, Jean-Jacques Leplat, PhilippePinton, and Jean-Francois Dossin. They thank David Lawrence forcareful reading of the manuscript, and Bernard Dubray and Jean-Marc Cosset for helpful discussions. Studies developed in theLaboratoire de Radiobiologie et d’Etudes du Genome were sup-ported by EC Grant FI4P-CT95-0029 and by the Comite de Ra-dioprotection d’Electricite de France.
Accepted for publication 5 January 2000.
Int. J. Radiation Oncology Biol. Phys., Vol. 47, No. 2, pp. 277–290, 2000
Copyright © 2000 Elsevier Science Inc.
Printed in the USA. All rights reserved
0360-3016/00/$–see front matter
277
TGF β1
Biological effectiveness of RT varies with
• Size of Dose (D) - (alpha and beta)
• Size of Dose Per Fraction (d) - (alpha and beta)
• Time over which it is delivered (T)- (alpha and beta)
• Time between fractions (t)
• Volume irradiated (V)
• Quality of Radiation (Q) - RBE
• Presence/Absence of Oxygen - OER
• DNA Repair efficiency and completeness
• Cell cycle phase and level of gene activation
• Tissue/Tumor Type
Physical Dose = Biological Dose
NEJM
Ventana optima temporal para toxicidad?
1996
1996
Ventana optima temporal? AGUDOS/CRÓNICOS
Solución?????
1. Cómo se administra la radioterapia?
2. Bases biológicas/Toxicidad 3. Modalidades de tratamiento
Modalidades de tratamiento
RT Intraoperatoria
Braquiterapia
RT intraoperatoria
IORT
IORT
Disminuir la probabilidad de dejar enfermedad residual
Efecto dosis. Aumento del efecto radiobiológico
Eficiencia
Reduce el volumen irradiado
Exclusión del campo de estructuras críticas
IORT
Evidencia en el tratamiento de:
Mama, páncreas, estómago, Esófago, pulmón, recto, sarcomas de partes blandas
Tumores ginecológicos.
DEFINICIÓN
SBRT Pulmón/hepática
>1990
Desarrollo de técnicas de control respiratorio
Desarrollo de técnicas de verificación mas precisas
Adquisición imágenes de TC 4D
Clinical Example of the Maximum Intensity Projection (MIP)
The range of tumor motion, the ITV, can be estimated by contouring on the MIP
4D-CT MIP
Hax R-X
Espiración
Inspiración
1ª posición camilla 2ª posición camilla 3ª posición camilla
Adquisición imágenes 4D
GRACIAS