Radiation

Transcription

Radiation

Klinik und Poliklinik für Strahlentherapie und Radiologische Onkologie
Cancer Cure by radiation treatment:
research and clinical outcome
Prof. Dr. Michael Molls
Klinik für Strahlentherapie und Radiologische Onkologie
Klinikum rechts der Isar, Technische Universität München
Prague, 24.06.2013
© Molls
Radiation Oncology/ Clinical Characteristics
 Radiation treatment of all malignant diseases including carcinomas,
sarcomas, brain tumors and lymphomas (adults, children)
 Curation, palliation
© Molls
Radiation Oncology/ Research and Innovations
 Radiation Biology of Normal and Malignant Tissues
 Physics, Informatics, Engineering
 Clinical Studies
© Molls
Department of Radiation Oncology of TU München
Treatment of 1.500 patients per year
Biology group
Prof. Multhoff
Physics group
Prof. Wilkens
Medicine group
Prof. Molls/ PD Röper
© Molls
Department of Radiation Oncology of TU München
professors
5 (2 guests)
physicians
23 ±
physicists
10 ±
biologists
10 ±
technicians
20 ±
nurses
14 ±
management assistants and secretaries
8±
students (doctor thesis, mostly students of medicine)
40 ±
guest scientists
variable
- 4 linear accelerators; neutron radiation treatment at the research reactor of TUM
- brachytherapy (afterloading, seeds)
- treatment planning including software packages, CT, MRT, PET, simulator device
- polyclinics
- ward (24 ± beds; chemotherapy in addition to radiation, special radiation concepts,
etc.)
© Molls
Cancer Treatment
Surgery
removes the local tumor, invasive
Radiation oncology
irradiates the local tumor and kills the cancer
cells, non invasive with the exception of
interventional radiation treatment
(brachytherapy)
Medical oncology
i. v. application of medicaments
(chemotherapy, etc.), compared with radiation
the cell kill of medicaments is much lower
© Molls
Tumor control by radiation (e.g. head and neck cancers)
Palliative
Curative
3 weeks radiation treatment
7 weeks radiation treatment
Radiation
kills
cancer cells!
Palliation/ pain relief
tumor control of a
metastatic neck
lymph node
Curation
complete regression
of a larynx cancer
© Molls
High precision radiation treatment: eradication of tumor and
optimal sparing of normal tissues
tumor
© Molls
Multileaf Collimator
The moving of the
leafs is precalculated
and takes place during
radiation
Shaping of the beam
in dependance of
tumor contour
© Molls
Linear accelerator with multileaf-collimator
© Molls
Radiation treatment in
Prostate cancer
patient: H. G.
age: 73 Jahre
cT1c cN0 cM0 G2
Gleason Score: 6
biopsies: 1/8 positiv
© Molls
Treatment planning: Primary curative radiation therapy of prostate
cancer (Textbook “Radiation Oncology” 2009, Bamberg, Molls, Sack)
microscopic tumor
organ movement
prostate
urethra
position variations
(35 radiation treatments)
The periphery of the tumor
must not move out of the beam
during radiation treatment!
(Tumors are mostly located in
the posterior part of the
prostate)
The front third of the rectum is
located within the high dose
area, independent of the type
of radiation (photons, protons)
© Molls
 Prostate
 Rectum
 Femur
IMRT
inhomogenous
fluence for all
fields, allowing
for very
complex dose
distributions
Isodoses (%)
 30
3D
 50
 70
 90
 95
 100
© Molls
Dose distribution/ IMRT
© Molls
DVH: Dose-Volume-Histogram
Vol %
DVH tumor
 IMRT
 3D
Dose %
© Molls
Vol %
DVH rectum
 IMRT
 3D
Dose %
© Molls
Vol %
DVH urinary bladder
 IMRT
 3D
Dose %
© Molls
Fractionation schedule in curative radiation treatment of
prostate cancer
About 35 to 40 single fractions with single doses of 2 Gy
CONVENTIONAL FRACTIONATED RADIATION TREATMENT
© Molls
Radiation induced death of cancer cells
(2 Gy reduce the cell number by 50%, theoretical example)
day
dose
cell number
1
2 Gy
500.000
2
4 Gy
250.000
3
6 Gy
125.000
4
8 Gy
62.500
5
10 Gy
31.250
16
32 Gy
16
20
40 Gy
1
23
46 Gy
0,12
© Molls
Image Guided Radiation Therapy (IGRT) with Cone Beam CT
Volumetric acquisition of CT images in one rotation
© Molls
Lateral shift
Left-Right
Longitudinal shift
Cranial- Caudal
Vertical shift
Ventral-Dorsal
Yaw, pitch and roll are used in
aerospace to define a rotation
between a reference axis
system and a vehicle-fixed axis
system
© Molls
Prostate cancer/ IMRT
Results
8-year disease-free survival
(no PSA recurrence)
Late side effects
97% bei ≥ 80 Gy
85% bei 76 Gy
58% bei ≤ 70 Gy
Grade III side effects:
4% GI (bleeding)
6% Uro (urinary retention, bleeding)
No grade IV side effects!
(early stage:
<T2b, PSA < 10, Gleas. Sc. < 7)
Side effects are reversible in
approx. 50% of the patients
Leibel et al. Semin Oncol, 2003
Geinitz … Molls et al., Radioth. Oncol, 2006
© Molls
Side effects:
Radiation of the urethra cannot be avoided
Inflammation of urethra (in any type of treatment: photons, protons, seeds)
© Molls
Side effects
Acute side effects:
inflammation during radiation treatment
Late side effects:
might occur after months and persist
might impair the quality of life
© Molls
Tolerance doses in dependence on irradiated volume
TD5/5 in Gy
1/3 Vol
2/3 Vol
Spinal cord
50 (≤ 10 cm)
47 (~ 20 cm)
Brain
60
50
45
Kidney
50
30
23
Lung
45
30
17.5
Heart
60
45
40
Liver
50
35
30
Oesophagus
60
58
55
Stomach
60
55
50
Small Intestine
50
40
Colon
55
45
Rectum
3/3 Vol
60 (100 cm3)
TD5/5: probability of complications in 5% of irradiated patients within 5 years after radiation
© Molls
Fractionation schedule in stereotactic radiation treatment
Several comparatevily high single doses (7 Gy ±)
STEREOTACTIC FRACTIONATED RADIATION TREATMENT
© Molls
Lung cancer: stereotactic radiation treatment
 High dose to the tumor
 Excellent sparing of the lung
 3 x 12.5 Gy (periphery)
 5 x 7.0 Gy (central)
 60% isodose
 Margins: 4 - 6 mm and
depending on breathing
movements
V20 (ipsilateral lung volume/ 20 Gy): 8 %
Dmean (ipsilat. lung): 5.7 Gy
© Molls
Lung carcinoma, 92 patients
Local control (no progression in CT or PET)
1y
88%
2y
3y
Local recurrence free survival
Local recurrence free survival
p = 0,04
1y
100% vs. 83%
83%
2y
100% vs. 77%
83%
3y
100% vs. 77%
T1: 3 cm or less
T2: > 3 cm
complete remission
after 18 months
Zimmermann … Molls, Acta Oncol 2006
Andratschke … Molls et al., Radiother Oncol 2011
© Molls
Schedule in radiosurgery
1 single, stereotactic radiation treatment with a comparatevily
high single dose (16 – 20 Gy)
RADIOSURGERY
© Molls
Radiosurgery
1993: renal cell-Ca
1994: brain metastasis, operation
1995: recurrency, hemianopsia
1995
LINAC- Radiosurgery, 20 Gy
6,5% of patients with single
brain metastases are long term survivors
2010: CR
(Kondziolka et al. 2005)
© Molls
© Molls
Stereotactic RT
Gamma-Knife
PERFEXION
Varian True Beam
Cyber-Knife
Vero
LINAC mit Micro-MLC
GyroKnife
TomoTherapy
© Molls
Cure rates in early cancer stages
Radiotherapy
Operation
Chemotherapy
alone
alone
alone
66 – 79 % (10-y)
75 – 85 %
Ø
6 – 50 % or more
Stereotact. Radiotherapy
30 – 80 %
Ø
75 – 80 %
(preservation of voice)
~ 75 %
Ø
63 – 91 %
74 – 91 %
Ø
Anus
60 – 80 %
(preservation of continence)
results comparable
to RT
Ø
Skin
up to 100 %
up to 100 %
Ø
Prostate
Lung
Larynx
Cervix uteri
Ø: no data in the literature: CHEMOTHERAPY alone is unable to cure solid tumors of adults (exception:
testicular carcinomas)
© Molls
cancers: radiation versus medical treatment
according to Minchinton & Tannock,
Nature Reviews Cancer 2006
Molls et al. in: The Impact of
Tumor Biology on Cancer
Treatment and Multidisciplinary
Strategies, Springer, 2009
Medicaments
radiation
source
Radiation
© Molls
Quantitative CELL KILL
tumor
cells
Tannock, Lancet 1998, Nature 2006
1010
6 cycles chemotherapy
108
106
104
surgery
102
0
0
1
2
3
4
macroscopic tumor: > 106 – 107 cells, tumors ≥ 5 mm
microscopic tumor: 1 – 106 cells, tumors < 5 mm
5
6
months
© Molls
Radiation Biology: tumor and normal tissue
•
Cell kill
•
Mechanisms of cell kill
•
4 R's (Repair of DNA, Repopulation, Reoxygenation, Redistribution)
•
RT/ ChT
•
Protection of normal tissues
© Molls
Cell death/ clonogenic survival
© Molls
Cell survival curve for
4 human tumour cell lines:
HX142, neuroblastoma
HX58, pancreas
HX156, cervix
RT112, bladder carcinoma.
from Steel (1991)
© Molls
Relative Radiosensitivity
Hypoxia reduces the radiosensitivity of tumor tissues
Partial Pressure of Oxygen - mmHg
Withers, in: Principles and Practice of Radiation Oncology, Lippincott/Philadelphia, pp.64-96, 1992
© Molls
pO2 measurements
%
25
patient 1
normoxic
20
15
10
5
0
0
10
20
30
40
50
60
pO2 (mm Hg)
%
25
patient 2
hypoxic
20
15
10
5
0
0
10
20
30
40
50
60
pO2 (mm Hg)
Blood Perfusion and Microenvironment of Human Tumors (Molls, Vaupel), Springer 1998
© Molls
Hypoxic Subvolume (HSV) and Prognosis
Head & Neck cancer, 59 patients
Overall survival [%]
(Stadler ... Molls, IJROBP, 1999)
HSV ≤ 6 cm³ n = 33 (14 RT, 19 RChT)
HSV > 6 cm³ n = 26 (13 RT, 13 RChT)
Months
© Molls
Imaging of Hypoxia by PET/ CT
[18F]FAZA (Azomycin arabinoside)
CT
axial
cor
sag
PET/CT
Fusion
Hypopharyngeal SCC
(Piert et al., TUM)
4 h after inj.
T/B ratio 3.2
© Molls
Dose Painting
Maximizing
dose to
hypoxic
subvolumes
(FAZA-PET)
© Molls
Dose painting in 2 hypoxic subvolumes
2.5 Gy
2 Gy
Grosu … Molls IJROPB 2007
© Molls
Experimental arm
Inclusion criteria
SCC
Oral cavity
Oropharynx
Hypopharynx
Stage III-IV
Inoperability
Age: > 18 years
R
A
N
D
O
M
I
S
A
T
I
O
N
5 fractions / Week
Radiotherapy
DEV = GTV( – 3mm)
DEV 2,3 Gy ad 80,5 Gy
Chemotherapy
Cisplatin 20 mg/m²
Control arm
5 fractions / Week
Radiotherapy
GTV2.0 Gy ad 70.0 Gy
Chemotherapy
Cisplatin 20 mg/m²
DEV – dose escalated volume
GTV – gross tumor volume
TRANSLATIONAL PART OF THE STUDY (TUMOR HYPOXIA)
Investigating whether tumor hypoxia can be visualized by 18F-FMISO-PET
before start of radiation treatment and whether the PET hypoxic subvolumes of a single tumor
are constant over a time axis of 2-3 days
(Molls and Pigorsch, 2010
sponsoring by DFG)
© Molls
The 3 main questions
•
Improves dose escalation the locoregional tumor control?
•
Is there a volume or a hypoxia effect in dose escalation?
•
How reliable is the PET visualization of tumor hypoxia?
(Molls and Pigorsch, 2010)
© Molls
Munich Centre for Advanced Photonics (MAP)/ LMU, TUM, MPI
2006 – 2018: ca. 65 Mio. €
Medical
Applications
Laser-generated particle
beams for tumor therapy
Medical imaging with brilliant X-rays
Imaging of biomolecules
Real-time analysis and control of
molecular processes
Developing electronics to their ultimate limits
(frequency of light)
Controlling electron motion in
microscopic systems
Investigating quantum phenomena for
information technology
Probing fundamental laws of nature
with unprecedented accuracy
Development of high-power lasers for
the production of laser-generated X-rays
and particle beams
MAP has established close
cooperation between health
professionals and physicists.
Co-funded by Siemens Healthcare.
worldwide networking
© Molls
MAP
The mission of MAP
Only about 50% of cancer patients
can be cured
The number of cancer patients
increases with increasing life
expectancy of modern societies
Improving cancer cure is a big
medical and socio-economic
challenge in research
The scientific cooperation between
physicists, physicians and
biologists in MAP offers innovative
perspectives to significantly
improve cancer cure
D. Yach et al., JAMA 291, 2616 (2004)
© Molls
Vision of MAP
Clinical evidence
Imaging
Today
 Solid tumors at a size of about 106 – 107
cells (about 1mm3) have not yet
metastasized. Thus, efficient local
treatment in very early cancer stages is
curative!
 Limited efficiency of medical cancer
treatment
Macro
107
Strategy to combat cancer
 Early tumor detection (diameter of 1mm)
Micro
Future
Imaging
 Local radiation therapy with ions is curative
and spares normal tissues
 Cost efficiency is important to ensure
sustainability
Gordon Steel, Basic Clinical Radiobiology, 2002
© Molls
Phase-Coherent X-ray Imaging
Experiments performed using the Synchrotron/ Grenoble (Group of: F. Pfeiffer/ TUM)
conventional CT
heart
phase-coherent X-rays
Synchrotron
phase-contrast CT
mouse
heart
mouse
brain tumor/ rat
Better contrast of soft tissues: Advantage for the visualization of smaller tumors (1 mm tumor!)
Perspectives: in vivo histology
© Molls
Depth Dose Curves: X-rays and protons
Dose
Theoretical advantage of protons: better sparing of normal tissues
Depth
© Molls
Setup of the cell irradiation experiment with the ATLAS laser
Protons are produced via high intensity laser interaction with the
DLC (Diamond like Carbon) target
The mini-quadrupole magnets act as an energy filter and produce a line focus of energy
5.3 ± 0.15 MeV.
The dose distribution is assessed using radiochromic film (Gafchromic EBT2)
Bin et al. Applied Physics Letters, 2012
© Molls
First biological results: DNA damage after laser irradiation
γ-H2AX
Exemplary dose map of the line focus
RBE: 1.3 ± 0.3 relative to 200 kV X-rays
The RBE obtained in this study for laser-driven protons is in
agreement with RBE values in conventional proton beams
Single shot irradiation up to 7 Gy
γ-H2AX: red, 53BP1: green:
DNA double strand breaks
Bin et al. Applied Physics Letters, 2012
© Molls
Vision of MAP: Laser based Image Guided Radiation Therapy
Today
Future/ Laser
Linac with CT
protons
brilliant
x-rays
ions
intetgrated system for
imaging and radiation
treatment (tumors of
smaller and larger sizes)
www.varian.com
© Molls
… from bed to bench,
and from bench to bed …
© Molls
Thank you
© Molls
RESEARCH (Klinik für Strahlentherapie/ TU München)
MEDICAL PHYSICS (High precision radiotherapy, X-rays, protons and heavy ions)
1. Intensitiy Modulated and Image Guided Radiotherapy with TOMOTHERAPY
Multimodal Image-Guided Helical Tomotherapy – a novel method for high precision radiation treatment
PD Dr. Frank Zimmermann, PD Dr. Anca-Ligia Grosu, PD Dr. Carsten Nieder, Prof. Dr. Peter Kneschaurek, Prof. Dr. Michael Molls
DFG, 2006-2010
2. High Precision Radiotherapy
Exploration of dose escalation protocols for the treatment of early stage lung cancer and solitary lung and liver metastases by
hypofractionated stereotactic radiotherapy
Prof. Dr. Hans Geinitz, PD Dr. Nicolaus Andratschke, Dr. Sabrina Astner , Prof. Dr. Peter Kneschaurek
Bayerisches Staatsministerium für Umwelt, Gesundheit und Verbraucherschutz, 2010-2013
3. DFG Cluster of Excellence: Munich Centre for Advanced Photonics (MAP) (M. Molls: Co-Speaker of the Cluster)
The radiooncological sub-projects of the MAP cluster are devoted to the development of laser generated proton- and heavy ion therapy
including dosimetry and radiobiological investigations
Prof. Dr. Michael Molls, PD Dr. Barbara Röper; Dr. Thomas Schmid, Prof. Dr. Peter Kneschaurek; Prof. Dr. Fridtjof Nüsslin, Prof. Dr. Jan Wilkens
The junior research group "Advanced Technologies in Radiation Therapy“ of the MAP cluster investigates the physical aspects of
radiotherapy with laser-accelerated particle beams (protons, heavy ions) by developing new concepts for dose delivery and treatment
planning
Prof. Dr. Jan Wilkens
DFG, 2007-2012
4. A Unified Framework for Biological Optimization in Ion Beam Radiation Therapy
Development of biologically-guided treatment planning strategies for ion beams including their radiobiological effectiveness
Prof. Dr. Jan Wilkens
DFG, 2011-2014
© Molls
BIOLOGY I (Immunity and tumor biology, targeted therapy)
1. Helmholtz Zentrum München, Clinical Cooperation Group: Innate Immunity in Tumor Biology
Tumor immunology and development of innovative treatment strategies targeting on heat shock proteins in different cancer entities
Prof. Dr. Gabriele Multhoff
Helmholtz Zentrum München, 2007-2015
2. Tumor-specific membrane transport and export of Hsp70
Analysis of intra- and extracellular trafficking of heat shock proteins in tumors
DFG, 2006-2008
3. EU-TRANSNET
Identification of genomic and biological markers as predictive/ diagnostic/ therapeutic tools for use in allogeneic stem cell
transplantation: Translational research towards individualised patient medicine
EU, 2006-2008
5. EU-STEMDIAGNOSTICS
Development of new diagnostic tests, new tools and non-invasive methods for the prevention, early diagnosis and monitoring of graft
versus host disease in haematopoietic stem cell transplantation (intra- and extracellular trafficking of heat shock proteins)
EU, 2007-2010
6. BMBF BioChance Plus
Development of a targeted drug delivery systems based on immuno-liposomes and tumor-specific Hsp70 membrane expression
Prof. Dr. Gabriele Multhoff, Dr. Claus Botzler
BMBF, 2005-2008
© Molls
7. SFB824/1: Imaging for Selection, Monitoring and Individualization of Cancer Therapies
Sub-Project: Hsp70 antibody and peptide for in vivo imaging of tumors
DFG, 2009-2013
8. MOBITUM: Watching Tumor Biology by Molecular Imaging
Sub-Project: Validation,engineering, and humanization of recombinant Hsp70 Fab fragment for monitoring of tumor growth and
metastatic dissemination during radioimmunotherapy
Prof. Dr. Gabriele Multhoff, Prof. Dr. Arne Skerra
BMBF, 2008-2012
9. Leading-Edge Cluster m4 – Personalized Medicine and Targeted Therapies
Sub-Project: Determination of immune- and tumor-parameters in tumor patients
BMBF, 2010-2013
BIOLOGY II (X-rays, protons and heavy ions radiation biology; tumor hypoxia and micromilieu)
1. RS225 X-ray Source
The RS225 (Gulmay) is used for experimental irradiation of cells and tumors in mice
DFG, 2010
2. Translational DFG Multicenter Cooperation Group “Hypoxia”
Sub-Project: Influence of hypoxia and irradiation on the plasminogen activation system and VEGF in squamous cell carcinomas
Dr. Christine Bayer, Prof. Dr. Michael Molls
DFG, 2006-2010
© Molls
3. MOBITUM: Watching Tumor Biology by Molecular Imaging
Sub-Project: "Hypoxia": Validation of tumor hypoxia as an approach to biology adapted radiotherapy (BART)
Dr. Sabrina Astner, Prof. Dr. Michael Molls
BMBF, 2008-2012
4. KVSF: Kompetenzverbund Strahlenforschung
Sub-Project: Individual sensitivity towards irradiation and genomic instability
Prof. Dr. Gabriele Multhoff, Prof. Dr. Mike Atkinson
BMBF, 2009-2012
5. EU-CARDIORISK: The mechanisms of cardiovascular risks after low radiation doses (M. Molls: project leader)
Work package: Project Management
PD Dr. Nicolaus Andratschke, Prof. Dr. Michael Molls, Fa. GABO:mi
Work package: Irradiation, preparation of tissue samples and primary cell culture of endothelial cells
Prof. Dr. Gabriele Multhoff, PD Dr. Nicolaus Andratschke
Work package: Training and Dissemination
PD Dr. Nicolaus Andratschke, Prof. Dr. Michael Molls, Fa. GABO:mi
EU-EURATOM (FP7, 12 international project partners), 2008-2011
6. DFG Cluster of Excellence: Munich Centre for Advanced Photonics (MAP) (M. Molls: Co-Speaker of the Cluster)
The radiobiological sub-project of the MAP cluster is devoted to in vitro and in vivo investigations with continous and pulsed protons and
heavy ions (different "end points" such as DNA-repair, apoptosis, tumor regrowth and others)
Prof. Dr. Michael Molls, PD Dr. Barbara Röper; Dr. Thomas Schmid,
DFG, 2007-2012
© Molls
CLINICAL TRIALS
1. Randomized Multicenter Trial
Does selective radiation dose escalation and tumor hypoxia status impact the locoregional tumor control after radio-chemotherapy of head
and neck tumors?
Dr. Steffi Pigorsch, Prof. Dr. Michael Molls (principal investigators)
DFG, 2009-2012
Targeted Natural Killer (NK) cell based adjuvant immunotherapy after radiochemotherapy of patients with Non Small Cell lung cancer
Prof. Dr. Gabriele Multhoff; Prof. Dr. Michael Molls (principal investigators)
BMBF, 2009-2013
Intraoperative Radiation Therapy in Breast Cancer (International Study Group)
Dr. Steffi Pigorsch, Dipl.-Phys. Sabine Schill, Prof. Dr. Michael Molls (local responsibility)
International and in house funding, 2005-2012
4. Phase II Trial
Optimization of local radiation treatment in soft tissue sarcoma by innovative radiation techniques
PD Dr. Barbara Röper, Prof. Dr. Michael Molls (principal investigators)
Wilhelm Sander-Stiftung, 2010-2012
© Molls
Phase-coherent X-Rays
Protons/ heavy ions
Today
(highly expensive)
2x Soccer stadiums
1x Soccer stadium
Diagnostic with phase-coherent
x-rays
Therapy with protons/ heavy ions
Tabletop Laser (ATLAS)
Future
(cheap)
Hospital room size
© Molls

Radiation

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