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Strahlentherapie / Radio-Onkologie · Oxygen consumption Diffusion. Perfusion‐pO2 Model Heat...
Transcript of Strahlentherapie / Radio-Onkologie · Oxygen consumption Diffusion. Perfusion‐pO2 Model Heat...
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Ziele
• grundlegende (bio)-physikalische und technische Prinzipien beschreiben können
• Anwendungsgebiete kennen
• Fachbegriffe erklären können
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Inhalt
• Einführung Radio-Onkologie
• Arten der Strahlentherapie- Perkutan- Brachytherapie
RO
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LOG
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PHYS
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Einführung Radio-Onkologie
Krebs ist eine der häufigsten Todesursachen
Zunahme an Krebsleiden durch veränderte Altersstruktur der Bevölkerung
Eine einheitliche Erkrankung Krebs gibt es nicht: Es sind über 100 bösartige Tumore mit sehr unterschiedlichem Verhalten und Ansprechen auf Therapie bekannt.
Mortalität dank verbesserter Therapie in den letzten Jahrzehnten gesenkt
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Einführung Radio-Onkologie
Krebs entsteht, wenn die Wachstumskontrolle bei Zellen verloren geht und aggressives Wachstum eintritt. Gründe dafür sind Mutationen des Genoms durch:
• Gifte, chemische Karzinogene oder Asbestfasern• Strahlung• chronische Entzündungen• Viren (HPV: zervix-Karzinom, Epstein-Barr-Virus:
Burkitt-Lymphom)• spontane Mutationen
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Einführung Radio-Onkologie
Tumore werden unterteilt in• gutartige (benigne) Tumore: keine
Tendenz zu Metastasen• Bösartige (maligne) Tumore: Invasives
Wachstum und starke Tendenz zur Metastasierung
Es gibt dazwischen alle möglichen Abstufungen (z.B Spinaliom = semimaligner Tumor)
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Einführung Radio-Onkologie
Tumore werden unterteilt in• Karzinome (bösartige Tumore des Epithels, also
von Haut und Schleimhäuten ausgehend)• Sarkome (bösartige Tumore des
mesenchymalen Gewebe, also von Binde- und Stützgewebe sowie von peripheren Nerven ausgehden)
• Lymphome und Leukämien (bösartige Erkrankung des lymphatischen Systems und der Blutzellen nicht-solide Tumore)
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Einführung Radio-Onkologie
Die häufigsten Tumore sind• Prostatakarzinom• Brustkrebs / Mammakarzinom• Kolorektale Karzinome• Gebärmutterkarzinom• maligne Lymphome• Karzinome der oberen Schluckstrasse• Schilddrüsenkarzinome
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Heusser R et al. (2016): Schweiz. Krebsbulletin, 36, 02
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Heusser R et al. (2016): Schweiz. Krebsbulletin, 36, 02
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Einführung Radio-Onkologie
Typische Entwicklung von Tumorleiden• Tumor-Induktion• Tumorprogression• Avaskuläre Wachstumsphase• vaskuläre Phase, invasives Wachstum• Metastasierung (hämatogen, lymphogen)
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Wachstumsphasen
N(t)
Tumorwachstum
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Einführung Radio-Onkologie
Klinische Stadieneinteilung bösartiger Tumore (TNM-Klassifikation)
• T: Grösse und Nachbarschaftsbeziehung des Primärtumors (T0: Primärtumor unauffindbar, T1: kleiner Tumor (< 2 cm), T4: Tumor bricht in Nachbarorgane ein)
• N: Ausmass der regionären Lymphknotenmetastasierung (N0: keine, N3 sehr ausgedehnte Lymphknotenmetastasierung)
• M: Fernmetastasierung (M0: keine, M1: Fernmetastasen bekannt)
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Einführung Radio-Onkologie
Arten der Krebstherapie• Chirurgie• Chemotherapie (CT)• Strahlentherapie (RT)• Antikörper, Immuntherapie• Hormontherapie• Hyperthermie (beglitend zu CT und oder
RT)• …
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Einführung Radio-Onkologie
Therapieziele
• Kurativ: Tumorkontrolle bis zur totalen Tumor-Remission
• Palliativ: Bekämpfung der klinischen Symptome (Schmerzen!) steht im Vordergrund
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Einführung Radio-Onkologie
Wirkungsweise der Strahlentherapie
• Indirekt: Ionisation führt zu freien Radikalen und Peroxidbildung in der Zelle
• Direkt: Schäden auf der DNA (abhängig vom LET)
• Schäden führen zu eingeschränkter Zellfunktion
• verminderte Reparaturfähigkeit von Tumorzellen Zelltod
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LQ-Modell
2log ( )S D D
log S D
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MHR Model
Scheidegger S, Fuchs HU, Zaugg K, Bodis S, Füchslin RM (2013): Computational and Mathematical Methods in Medicine, 2013, http://dx.doi.org/10.1155/2013/587543
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MHR Model
Interphasen-Tod (frühes Apoptose-Programm)
Cell Cycle Arrest, Mitosetod
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Einführung Radio-Onkologie
Biologisch zu beacten: R’s
• Repair (Zellreparatur)• Reoxygenierung• Re-Distribution• Repopulation
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Einführung Radio-OnkologieBeeinflussung durch Fraktionierung
• Repair (Zellreparatur): Zeit zwischen den Fraktionen (kurz unvollständige Repair)
• Reoxygenierung: Folgefraktionen mehr Wirkung
• Re-Distribution: Änderung des Therapie-Ansprechens durch andere Verteilung von Zellen in unterschiedlichen Zellzyklusphasen
• Repopulation: weniger Tumorwachstum, wenn Abstände zw. Fraktionen kurz
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Biologischer Schaden: Reparatur und Dosisäquivalent
0 0.02 0.04 0.06 0.08 0.10
/ G
y
Time t / days
0
4
8
12 a
b
cd
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0
-4
-8
-12
-16
0 5 10 15 20 25
logS
Dose D / Gy
a
b cd
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Time t (days)
1 2 3 4 50lo
gS
0
-5
-10
-15
-20
-25
-30
1.00 1.05
-4
-8
-12
-16a
b
0 20 40 60 80 100
Dose D (Gy)
logS
0
-5
-10
-15
-20
-25
-30
ab
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Tumor Control Probability TCP
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TCP und NTCP: therapeutisches Fenster
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Oxygenation and TCP
Dose D / Gy
log(
S)
6020 400
0
-4
-8
-12
Dose D / Gy
TCP
6020 400
1.0
0.8
0.6
0.4
0.2
0
50 60
1.0
0.8
0.6
0.4
0.2
0
Dose D / Gy
log(
S)
6020 400
0
-4
-8
-12
Dose D / Gy
TCP
6020 400
1.0
0.8
0.6
0.4
0.2
0
50 60
1.0
0.8
0.6
0.4
0.2
0
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Oxygenation
Time t / days
V T /
V E
1.103
2.103
3.103
30201000
E = (0.1, 0.16, 0.25, 0.40, 0.63, 1.00) Gy-1 kEres = (0.2, 0.8, 1.4, 2.0) day-1
Time t / days
pO2 /
mm
Hg
30201005
30
20
10
15
25
Time t / days
V T /
V E
1.103
2.103
3.103
30201000
Time t / days
pO2 /
mm
Hg
30201000
80
40
20
60
E = 0.75 Gy-1kEres = 2.0 day-1
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Arten der Strahlentherapie
Perkutane Strahlentherapie: Von Aussen, Erzeugung eines Strahlenfeldes mit einem Teilchenbeschleuniger (z.B. LINAC), einer Röntgenröhre oder einer 60Co-Quelle
Brachytherapie: geschlossene radioaktive Strahlenquelle im Patient (Jod-Seeds bei Prostata /LDR- oder 192Ir / HDR-Brachy)
Metabolische Therapie (Nuklearmedizin, e.g. 131I für Schilddrüsenkarzinome)
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192Ir-Quelle für HDR-Brachytherapie
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Linearbeschleuniger
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Arten der Strahlentherapie
Perkutane Strahlentherapie – Strahlenarten:
• Photonen (typische Energie 6 -23 MeV)• Elektronen (typische Energien 6-23 MeV)• Protonen (z.B. Spotscanning-Methode am
PSI)• Schwerionen
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Arten der Strahlentherapie
Perkutane Strahlentherapie – ein paar Begriffe:
• konformale Bestrahlung• Intensitätsmodlulierte RT (IMRT)• Image-Guided RT (IGRT)• stereotaktische RT• intra-Operative Bestrahlung
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Arten der Strahlentherapie
Kombinierte Therapien:
• Chemoradiotherapie (CTRT)• Hyperthermie-RT• multimodale Therapien
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Hyperthermie: Oberflächenhyperthermie
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Hyperthermie: Tiefenhyperthermie
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Hyperthermie: Tiefenhyperthermie
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Brustwandrezidiv-Mammakarzinom
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Brustwandrezidiv Mamma-Ca 12Mt nach RT+HT
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Modelling the synergistic effect of HT-RT:MHR-Approach
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Proteins: Reaction kinematics(deactivation and repair)
Microscopic (proteins): molecular dynamics
Mesoscopic: repair radiationinduced damages / cell death
Local macroscopic (tissue): Tumor – host interaction
Systemic: Immune system interaction
pH immune cell activity
Perfusion acidic metabolites pH host tissue restistance
DNA repair cell death
Protein misconvolution DNA repair
T protein misconvolution
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Perfusion‐pO2 Model
Heat contentof tissue
RF power
PerfusionConvectionRadiation
Temperature
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Perfusion‐pO2 Model
Heat contentof tissue
RF power
PerfusionConvectionRadiation
Temperature
Perfusioncontrol
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Perfusion‐pO2 Model
Heat contentof tissue
RF power
PerfusionConvectionRadiation
Temperature
Perfusioncontrol
OxygenationpO2
Oxygen consumptionDiffusion
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Perfusion‐pO2 Model
Heat contentof tissue
RF power
PerfusionConvectionRadiation
Temperature
Perfusioncontrol
OxygenationpO2
Oxygen consumptionDiffusion
Perfusioncontrol parameter
Decay
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Perfusion‐pO2 Model: Perfusion Enhancement
Temperature
Perfusioncontrol parameter
Decay 2.0
1.6
1.2
0.8
0.4
0.030 60 900
time t / min
Song CW, Chelstrom LM, Haumschmild DJ (1990) : Int J Radiat Oncol Biol Phys 18, 903‐907
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Validation: Using IR Cam System
Heat contentof tissue
RF power
PerfusionConvectionRadiation
Temperature
Perfusioncontrol
0
0.5
1
1.5
2
2.5
‐30 20 70 120 170 220
1 2( )refd T Tdt
11
2
0.2 Keq
refT T
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Oxygenation
OxygenationpO2
Oxygen consumptionDiffusion
Perfusioncontrol parameter
Considered points:‐ Perfusion dependent‐ Diffusion of oxygendepending on tissueand vascularisation(diffusion distance)
2
21 2O
O
dpp
dt 21
2
3...50O
eq
p
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Result & Meaning
• Parameter estimation based on measurements of perfused and non‐perfused case
• Good agreement with literature data method o.k.
• Difficult and interesting: tissue inhomogeneity in pathological cases
27.-28. Aug 2014 SSBE 2014 – Annual Society Meeting
non‐perfused
perfused with re‐heating
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Perfusion‐pO2 Model: Oxygen Enhancement
OxygenationpO2
Oxygen consumptionDiffusion(pO2); (pO2)
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
0 20 40 60 80 100
Datenreihen1
Datenreihen2
‐factor‐factor
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Results
Heat contentof tissue
RF power
Temperature
OxygenationpO2
Oxygen consumptionDiffusion
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Results
Comparison of applying RT (2 Gy fraction) immediately after HT and applying RT 60 minutes after HT for adenocarcinoma (/ = 6), Tmax < 42 °C (!)
poorly oxygenated tumours: difference for logS = 9.1%
intermediate oxygenated tumours difference is 2.1%,
well oxygenated tumoursdifference < 0.4%.
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perkutane Strahlentherapie
Ablauf perkutane Strahlentherapie:
• Planungs-CT• Planung: PTV und Felder• Verifikation• Bestrahlung• Nachsorge
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Bildfusion: PET-MRI
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Technischer / physikalischer Bestrahlungsplan
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Bestrahlung am LINAC
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What is needed to improve RT
Experimentsin vitro
Trialsin vivo
Clinical trialsin patient
Dosimetry
Devices
ModellingData Analysis
Experimentsin silico
P P
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What is needed to improve RT
Experimentsin vitro
Trialsin vivo
Clinical trialsin patient
Dosimetry
Devices
ModellingData Analysis
Experimentsin silico
P P