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:martin@dsvidf.cea.frAcknowledgments—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