l z n i a r a y rd t re G point of view i n ac e C...

Interdisciplinary Cardiac Imaging Center [IC]2 Med.University Graz/Austria

• Clinical results

• MR-bound hybrid hyperthermia

• Radiology or "everything flows"

• Perspectives

MR-bound hybrid hyperthermia from a radiological

point of view

Interdisciplinary

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ardiac maging

Cent e

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"Give me the power to produce fever and I'll cure

all disease"

"Quae medicamenta non sanant, ferrum sanat.Quae ferrum non sanat, ignis sanat.

Quae vero ignis non sanat, insanobilia reportari oportet."

Parmenides (2,500 years ago)


point of view


Interdisciplinary

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"Structure is a sure guide to function"

"No physiological theory can be true unless it gives a complete

and final explanation of all points of structure"

Sir Arthur Keith

Br.Med.J., 1:361,1918


point of view

Interdisciplinary

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4

HyperthermiaEffective or not?

Esophageal Cancer Malignant Melanoma

GBM

Head & Neck Cancer Head & Neck CancerCervical Cancer

Sugimachi K et al. Int J Hyperthermia 1992 Overgaard J et al. Lancet 1995 Sneed PK et al. IJROBP 1998

van der Zee C et al. Lancet 2000 Valdagni R et al. IJROBP 1994 Valdagni R et al. IJROBP 1994

Courtesy of Oliver Ott

5


Bladder Cancer

Cervical Cancer

Head & Neck Cancer

Anal Canal Carcinoma

Colombo R et al. J Clin Oncol 2003Harima Y et al. Int J Hyperthermia 2001

Datta NR et al. Int J Hyperthermia 1990 Kouloulias V et al. Am J Clin Oncol 2005


6

Advanced Cervical CancerInternational Phase III-Trial

FIGO IIB-IVA

or

N+ (pelvis)

RANDOM

RCT + Brachy

+ Hyperthermia

RCT + Brachy

Westermann et al. Cancer 2005;104:763-70


Courtesy of Peter Wust

Shim coils

Gradient coils

Shielding

Body coil

MR patient table

SIGMA eye applicator

Movable HT patient table

on rails

HT patient table

The Principle of Hybrid Hyperthermia

EVALUATION


Progression over time of mean MR temperature of the liver (PRF method,

navigation-assisted breathhold technique)


Tem

pera

ture

dif

fere

nce

Time (minutes)

Typical MR temperature distributions

under clinical conditions

After

12 minutes

After

51 minutes

treatment


Vo

xel

Vo

xel

Tumor

Tumor

Tumor necrosis

Tumor necrosis

M.glut.med.left M.glut.med. right

M.glut.med.left M.glut.med. right

Tumor necrosis

M.glut.med.leftM.glut.med.right

Tumor

Tumor

Rectum

Muscle

1000 W

Sarcoma with high temperatures

MR temperature


Perfusion distribution before and during partial-body hyperthermia

(Patient with peritoneal carcinosis of colorectal carcinoma)

Before first

hyperthermia

During

second

hyperthermia


before during after hyperthermia

Blood Flow Velocity in Large VesselsDuring Hyperthermia of Rectal Cancer


Hybrid hyperthermia of soft-tissue sarcoma

MR TEMPERATURE [deg] FLOW [ml/100g/min]

Basal under hyperthermia

Tumor center

Perfusion of the tumor decreases under hyperthermia, especially around the edge

Increase

(adductor)

Increase

(extensor)Decrease

(tumor edge)


• Change of tumor blood supply

• Acidosis of carcinogenic cells

• ATP reduction in tumor

• Cell wall destruction through "thermodynamic

pressure"

• Cell necrosis

Several functional mechanisms of hyperthermia (I):


Large vs. small arteries (relative flow)

Flo

w (

rela

tive)

Time

Sli-3-Aorta

Sli-5-Aorta

Sli-3-small

Sli-4-small

Sli-5-small

RF on

RF off

Temperature-dependent functional changes

H. Sahimbas 09/2008

Temperature

Effect

Moderate

Blood flow

Vascularity

Angiogenesis

Glycolysis

Metabolism

Oxygenation

Tissue acidosis

Cytoskeleton

Permeability

Macro molecule

Radical

Genetic regulation*

Repair mechanisms

Bioenergetic (ATP)

Necrosis/Lysis

Intermediary Extreme Ablative

• Reduction of DNA replication speed

• Endothelial swelling and microthromboses

(angiogenetic block)

• Increase of heat shock protein production

• Synergies with other therapies

Several functional mechanisms of hyperthermia (II):

With chemotherapy (reinforcing)

• ↑ Cellular cytostatica uptake

• ↑ Intracellular metabolism

• ↑ Reaction rate of chemotherapeutic

Substances

• ↓ DNS repair mechanisms

With radiotherapy (supplementary)

• Effective in hypoxic areas

• Effective in G2 and S phase

Several synergy effects of hyperthermia

It‘s

Simultaneous Visualization

of

Structure and Function

Resolution

Spatial: < 1 mm3 Time: < 100 ms Functional: < 1cm3

What is Radiology?

"What we call Structures are Slow

Processes of Long Duration.

What we call Functions are Fast

Processes of Short Duration."

Koestler nach H.N. Wagner Jr.

J. Nucl. Med. 1991,32:561-564

What is Structure, what is Function?

"Cognition is not static, it is a

process.

Even the object of cognition,

that which is perceived, is

modified in this process and

changes."

F. Cramer

Cognition as mental

and molecular process

VCH – Weinheim, 1991

MR hybrid hyperthermia

• Without "toxicity"

• Temperature measurement – complex process

• Numerous morphological & functional changes

in the tumor and environment

• Circulatory stress (BP ↓, HF ↑)

Radiological (diagnostic) view (I):

MR offers:

• Excellent morphology with tissue characterization

• Temperature measurement

• Blood flow and organ perfusion measurement

• Permeability measurement

• Tissue oxygenation and pH measurement

• Spectroscopic metabolism examination

• Tissue vitality assessment

Radiological (diagnostic) view (II):

Perspectives:

• Sentence from Parmenides

• Basic (patho)physiological understanding

• Results of phase II and III of (MR-bound)

hybrid hyperthermia studies

Excellent!

Radiological (diagnostic) view (III):

Regional Hospital – Uniklinikum Graz

Motion (§ 21 GeoLT) 03/19/2009 No. 2820/1

"The parliament resolves:

The state government is requested to contact

the Styrian Hospital Association to initiate the

necessary action to be able to offer hyperthermia

treatments in Styria."

Prerequisite:

Interdisciplinary cross-sector cooperation of:

Radio and chemo oncologists, radio-diagnosticians,

physicists, chemists, physiologists, pathologists,

immunologists, biologists, computer scientists,

statisticians, mathematicians, bioengineers, etc.

Radiological (diagnostic) view (IV):


Acknowledgements:

Peter Wust Rüdiger Wessalowski Jacoba van der Zee

Rolf Issels Gerard van Rhoon Johanna Gellermann

Oliver Ott Martin Wadepohl Gerhard Sennewald

Rolf Sauer


point of view

Interdisciplinary

C

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ardiac maging

Cent e

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Thank you for your attention!

R. Rienmüller


point of view

Interdisciplinary

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Cent e

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Muscle 1 Muscle 2

Tumor 1

Tumor 2

1400 W 1500 W 1000 W

Relapse (rectal carcinoma): stabilization

MR temperature


Time sequences of mean MR-temperatures (rectal cancer recurrence)


Hybrid hyperthermia of rectal carcinoma relapse

FLOW [ml/100g/min]

Hyperthermia can also increase perfusion in parts of the tumor.

Basal During /after hyperthermia


MR temperature distribution over time in one layer (liver)


Tem

pera

ture

dif

fere

nce

Time (minutes)

Perfusion [ml/min/100ml]Peritoneal carcinosis

20

0

Before 1st HT

Under 2nd HT

20

0


3636


Breast Cancer Peritoneal Carcinomatosis

Superficial Tumours

Verwaal VJ et al. J Clin Oncol 2003Vernon CC et al. IJROBP 1996

Jones E et al. J Clin Oncol 2005


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Advanced Cervical CancerCombined Radiation and Deep Regional Hyperthermia

� Patients: n = 114

� FIGO: Stage IIB – IVA

� Treatment: Radiotherapy ± Hyperthermia

� 3-year results

van der Zee et al. Lancet 2000;335:1119-25 Courtesy of Oliver Ott

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Advanced Cervical CancerDutch hyperthermia trial: Long term results (12y)

van der Zee et al. Lancet 2000;335:1119-25 Courtesy of Oliver Ott

39

Advanced Cervical CancerDutch hyperthermia trial: Long term results (12y)


Ctyotoxic effect of hyperthermia in vitro

Tubiana et al. 1990

Hyperthermia as radiosensitizer

Overgaard 1989

Hyperthermia as chemosensitizer

Chinese Hamster Zellen

Bleomycin für 1 h

1,00E-04

1,00E-03

1,00E-02

1,00E-01

1,00E+00

0 10 30 50

Bleomycin (ug/ml)

Surviving Fraction

Ratio

37 °C

41 °C

43 °C

Streffer 1990

Chinese Hamster Cells

Bleomycin for 1 hr.

Molecular and functional effects and associated biological end products of hyperthermia

Perfusion, Reoxygenation (pO2), Hypoxia, Immune Status, Antigenity, Sensitization, Pharmacokinetics

Issels, 2002

Principle of MR thermography during phase difference measurement (vis-à-vis reference measurement at time t = 0)

� Temperature dependency of proton resonance frequency of water of -0.01 ppm/°C, i.e., -0.64 Hz/°C (at 1.5 T, 64 MHz)

� Use of gradient echo sequence with long echo time TE = 20 ms, corresponding to a phase shift of -4.6°/°C

� Disturbances independent of echo time (temperature-dependent runtime differences, RF effects) are eliminated via double-echo (5 ms, 20 ms) (B1 effect)

� Water bolus and/or fat tissue used for drift correction (B0 correction)


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