2nd ESMO International Symposium on Soft tissue sarcomas

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2nd ESMO International Symposium onSoft tissue
sarcomas GISTMiland, ItalyHyperthermia
which, when, where and why?

• Rolf D. Issels
• 14.5.2008

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Hyperthermia Which?
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Hyperthermia as targeted therapy
Definition Controlled temperature elevation of
the tumor and of the surrounding tissue 40C
- 44 C Rationale Combination with Chemo-
and/or Radiotherapy
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Technical application
Thermoablation
HIFU HITT MR-Monitoring LITT
Interstitial Hyperthermia
80 - 90 C
various antennas
microwaves radiowaves ultrasound
Local Hyperthermia
43 - 45 C
capacitive systems antenna systems
Regional Hyperthermia
RHT
PBH
Part-Body Hyperthermia
antenna systems
40 - 43 C
Wust et al. , Lancet Oncology, Vol. 3 (2002)
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Technology of Regional Hyperthermia

• Electro magnetic field
• Radiofrequency
• 60-110 MHz
• 434 MHz

Spiralapplikator
Sigma 60-Applikator
Sigma Eye-Applikator
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Regional Hyperthermia in Children
Sigma-30-Applicator
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Field steering in the sigma Eye applicator
Focus
CT-Imaging Soft tissue sarcoma of the pelvis
Lamp phantom to demonstrate Field steering
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Temperature measurement of heating field
Soft tissue sarcoma of the thigh with
temperature measurement catheter
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Temperature measurement and Thermal Dose
calculation
therapeutic time (min) 0 7
14 21 28 35 42 49 56
-------------------------------------------------
----------------- 0 41,3 41,6 41,6 41,7
41,7 41,6 41,6 41,5 41,5 10 41,6 41,5
41,5 41,5 41,6 41,5 41,5 41,4 41,4 20
42,3 42,6 42,4 42,4 42,2 42,1 42,0 42,1
42,1 30 42,4 43,0 43,0 43,1 43,1 43,1
43,0 43,0 43,1 40 41,7 42,5 43,0 43,2
43,4 43,5 43,5 43,5 43,5 50 41,5 42,2
42,6 42,8 43,0 43,0 43,1 43,2 43,1 60
40,9 41,4 41,7 42,0 42,7 42,7 43,0 42,9
42,8 70 40,8 41,3 41,6 41,9 42,1 42,2
42,2 42,3 42,3 80 40,9 41,2 41,5 41,7
42,0 42,0 42,1 42,1 42,0 --------------------
-------------------------------------------------
T90 40,9 41,3 41,6 41,7 41,7 41,6
41,6 41,5 41,5 T50 41,6 41,9 42,1
42,2 42,5 42,5 42,6 42,6 42,6 T20
42,3 42,7 43,1 43,1 43,2 43,2 43,2 43,3
43,3
Temperature Analysis Index Temperature
probe position (mm)
T90
T50
T20
Temperature-Time Analysis
Integration Thermal Dose
CEM 43C T90 area under curve 7,4 min
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Correlation between thermal Dose and local
control in Canine Sarcomas
Hyperthermia combined with radiotherapy
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Correlation between thermal dose and local
response in human soft tissue sarcomas
Responders
Hyperthermia combined with chemotherapy
Non-responders
Each point represents the average temperature
analysis of 850 measured points per tumour
T20
Plt0.005
Issels et al., J. Clin. Oncol. 1990
T50-T90
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MRT Siemens Symphony/ SIGMA-Eye/BSD-2000/3D (1,5
T - 64 MHz), Wust et al. (2002)
MR-temperature
Tm
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Noninvasive Magnetic Resonance Thermography of
Soft Tissue Sarcomas During Regional Hyperthermia
Correlation With Response and Direct Thermometry
Johanna Gellermann, MD Bert Hildebrandt, MD Rolf
Issels, MD Hildegard Ganter, MD Waldemar
Wlodarczyk, PhD Volker Budach, MD Roland Felix,
MD Per-Ulf Tunn, MD Peter Reichardt, MD Peter
Wust, MD
Cancer 2006 107137382.
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Hyperthermia Where?
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(IAH)
Regional Hyperthermia Centers

• (1) Klinikum Universität München-Campus
  Großhadern
• (2) Rotkreuzklinikum München
• (3) Argirov-Klinik Starnberger See
• (4) Klinik Bad Trissl / Oberaudorf
• (5) HELIOS Schlossbergklinik / Oberstaufen
• (6) Universitätsklinik Erlangen
• (7) Charité Universitätsmedizin Berlin
• (8) Klinikum Berlin-Buch
• (9) Universität Düsseldorf
• (10) Universität Mannheim
• (11) Universität Tübingen

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Custom built
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European Society for Hyperthermic Oncology (ESHO)

• (1) Aarau (CH)
• (2) Amsterdam (NL)
• (3) Bergen (NOR)
• (4) Berlin (D)
• (5) Düsseldorf (D)
• (6) Erlangen (D)
• (7) München (D)
• (8) Rotterdam (NL)
• (9) Utrecht (NL)
• (10) Verona (I)

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Hyperthermia When?
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High-Risk Groups
S1 Primary Tumor Size 5 cm and Grade II or
Grade III and deep and Extracompartmental S2
Local Recurrence of S1 Tumor or any type of Local
Recurrence deriving from primary STS with all of
the S1 features S3 Inadequate Surgery of S1 or
S2 tumors
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Histology

• Patients with the following histological subtypes
  of tumors showing grade II or III can enter the
  EORTC 62961/ESHO RHT-95 study
• Liposarcoma (round cell and pleomorphic)
• Leiomyosarcoma
• Fibrosarcoma
• Rhabdomyosarcoma
• Synovialsarcoma
• Malignant paraganglioma
• Neurofibrosarcoma (malignant schwannoma, MPNST)
• Extraskeletal Ewing's sarcoma
• Extraskeletal osteosarcoma
• Malignant peripheral neuroectodermal tumors
  (MPNET)
• Mesenchymal chondrosarcoma
• Angiosarcoma
• Miscellaneous sarcoma
• Unclassified sarcoma (NOS)

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Study Design
S1 Primary tumor 5 cm, GII/GIII, deep,
extracompartmental S2 Local recurrence of S1
tumor
Risk- groups
R
R
A
RHT
A
RHT
Arm A
Arm A
D
D
EIA
EIA
I
I
R
R
A
A
T
T
I
I
EIA
EIA
Arm B
Arm B
O
O
N
N
Strata Center, risk group, location (extremity
vs non-extremity)
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Study Design
S3 Inadequate resection of S1 or S2 tumors
(marginal margin)
Risk- groups
R
R
A
RHT
A
RHT
Arm A
Arm A
D
D
EIA
EIA
I
I
R
R
A
A
T
T
I
I
EIA
EIA
Arm B
Arm B
O
O
N
N
Strata Center, risk group, location (extremity
vs non-extremity)
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Soft tissue sarcoma subtypes

Pathological review by the reference pathologists
of the EORTC and LMU-Munich gt90
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Hyperthermia Why?
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Temperature dependent cellular and molecular
events during regional hyperthermia
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The heat shock response and anti-tumor immunity-
Preclinical review -
Extracellular HSP by necrosis
Heat Shock
HSP Membrane expression
Necrosis
Stimulation Proliferation
Milani et al. 2005
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43-year-old male patient with a high-grade
liposarcoma before and after first cycle EIA
RHT
d0
d5
d0
Baur et al., Int. J. Hyperthermia 2003
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57-years old female patient with Leiomyo sarcoma
of the thigh after 4 cycles EIA RHT
Baur et al., Int. J. Hyperthermia 2003
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Box plot of necrosis evolution in sarcoma under
neoadjuvant chemotherapy combined with RHT
Baur et al., Int. J. Hyperthermia 2003
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Clinical Studies Soft Tissue Sarcomas
1986 1990
RHT86 metastatic STS Second-line chemotherapy
Hyperthermia
Completed N38 (J. Clin. Oncol. 1990)
Phase I/II
1991 2001
RHT 91 non resectable HR-STS First-line
chemotherapy Hyperthermia
Completed N59 (Eur. J. Cancer 2001)
Phase II
1995 2002
RHT 95 primary/recurrent HR-STS
Retroperitoneal/visceral
Completed N58 (J. Clin. Oncol. 2002)
Phase II
1998 2006
EORTC 62961/ ESHO intergroup HR-STS E vs NE
Completed N 341 (ASCO 2007)
1997
Phase III
HR-STS high risk soft tissue sarcoma RHT
Regional hyperthermia E extremities NENon-
extremities
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Regional hyperthermia (RHT) improves response and
survival when combined with systemic chemotherapy
in the management of locally advanced, high grade
soft tissue sarcomas
Early progression in patients with high-risk soft
tissue sarcomas (STS)
A phase III randomized prospective trial of
neoadjuvant chemotherapy with or without regional
hyperthermia (RHT) EORTC 62961 / ESHO RHT95
Intergroup Trial
R.D. Issels, L.H. Lindner, P. Wust, P.
Hohenberger, K. Jauch, S. Daugaard, O. Mella, M.
Kuhlencordt, P. Reichardt, S. Abdel-Rahman, M.
Schmidt , U. Mansmann, W. Hiddemann, J. Blay, J.
Verweij
L. H. Lindner, O. Mella, M. Kuhlencordt, P.
Reichardt, P. Hohenberger, S. Abdel-Rahman, M.
Schmidt, J. Verweij, J.-Y. Blay, R. D. Issels
ESHO
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Patient characteristics
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Patient characteristics
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WHO objective response evaluation (96 response
review)
p0.001

• 117 pts inevaluable for response (61 pts with
  EIA RHT / 56 pts with EIA)

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EORTC-62961 Response Evaluation 21.02.2002 by
the EORTC PR
Patient E.H. 29.03.1930 S2
after 4x EIA RHT 23.08.1999
before treatment22.04.1999
Klinikum Großhadern LMU-München
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Early Progression
S1 primary tumor 5 cm, GII/GIII S2 local
recurrence of S1 tumor S3 inadequate surgery
of S1 or S2 tumor
local progression or death of any reason
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Conclusions I

• For patients with locally advanced high-grade
  STS
• Regional hyperthermia when combined with
  chemotherapy leads to a statistically
  significant improvement in
• Tumor response
• Disease Free Survival (DFS)
• Local Progression Free Survival (LPFS)
• Chemotherapy combined with hyperthermia lowers
  the risk of early PD for all patients
  irrespective of the time point of surgery
• Patients receiving chemotherapy combined with
  hyperthermia after inadequate surgery seem to
  benefit most from the combined treatment
  regimen

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Conclusions II

• For patients with locally advanced high-grade
  STS
• Regional hyperthermia when combined with
  chemotherapy in addition to local treatment
  (surgery radiation) offers a new standard
  treatment option
• Why not?