Hyperthermia??? - Hyperthermie Bochum

"New Technical and Medical Methods in
Cancer Treatment"
14th March 2015 London
„ New methods in cancer: Hyperthermia –as a standalone
or in combination with other therapies for cancer
treatment"
Dr. med. Hüseyin Sahinbas MD, Ph.D
Specialist of Radiology
Specialist of Radiotherapy and Radiation-Oncology
Hyperthermia
Complementary Medicin
Prognosis of the patient as a
function of the treatment concept
1. Diagnostic time
2. Diagnostic quality
3. Operation quality
4. Chemotherapy
5. Radiotherapy
6. Hormonal treatment
7. Immunotherapy
8. Supportive care
9. Complemetary medicine
_
Survival %
General knowledge: Changes in
prognosis over time
100
90
80
70
60
50
40
30
20
10
0
Survival rates for patients with
advanced tumours
1994-2002
1978-1986
0
1
2
3
4
5
Years
6
7
8
9 10
methods
in
cancer
and
results
in last 30
years
• 5-
years Survivelrate in
•1975: 51%
•2003: 63% (USA) American cancer Society
55% (Europe)Deutsches Krebsforschungszentrum
Why INTEGRATIVE complementary
CANCER-THERAPY
• 80 – 90% all of Tumorpatients using
alternative or unconventionell Therapymethods
• more science publication`s, study`s about
- Hyperthermia
- Phytopharmacons
- Supplements
- Sports
- Psychology
- ect………
What to do now? That is the question!
Few new treatments are available:
1. Hyperthermia
2. Phytopharmacons (plant origin, herbal medicine)
- Curcuma longa
- Dichloroacetate (DCA)
- Artesunate
-Vitamines (e.g. Vitamine D)
3. Personalized cancer treatment:
e.g. testing on Tumor cells
Well-known method in bacterial infections: Antibiogram
 Replace bacteria by tumor cells  “Oncobiogram”
This allows the patient effectively tailored therapy
INTEGRATIVE complementary
CANCER-THERAPY
NatH
OrthoTx
MicrobiolTx
PsychotTx
Hyperthermia
↓
FeverTx
Cancer
HormonTx
↓
ImmunTx
↓
PhotoDTx
conventionell
OP
↓
GEN-Tx ?
RTx CTx
EM/S-Field ?
Anti-Angiogeneses
MoleculareTx
Hager et al
Very old history and knowledge on
hyperthermia:
“Those who cannot be cured by medicine can be cured
by surgery.
Those who cannot be cured by surgery can be cured by
heat.
Those who cannot be curd by heat are to be considered
incurable.”
Hippokrates of Kos (460-370 B.C.), the
famous Greek physician who became famous
for his so-called Hippokratic aphorisms, which
comprised a collection of items of practical
advice for the physicians of the time
Definition of HYPERTHERMIA??
Hyperthermia???
What can I see? Uhuh!
Dr. med. H. Sahinbas
The Kadota Fund International Forum 2004
clinical group consensus
van der Zee J, Vujaskovic Z, Kondo M, Sugahara T. Int J Hyperthermia
Overview of hyperthermia methods:
I. Active hyperthermia (fever, medical drugs)
II. Passive hyperthermia
v (device)
A. Whole Body Hyperthermia (WBH)
Mild (-39 °C)
Moderate (39-40,5 °C)
Extreme (41-42,8 °C)
Thermotherapy (~ 45°C, 15 min.)
B. „Local“ Hyperthermia“
Invasive:
RF, LITT, ECT,
Intracavitary,
peritoneal,…..
Non Invasive:
Locale (surface)
Regionale (deap)
Lokoregionale (=EHT)
T
E
M
P
E
R
A
T
U
R
E
The Kadota Fund International Forum 2004—
clinical group consensus.
van der Zee J, Vujaskovic Z, Kondo M, Sugahara T. Int J Hyperthermia.
2008 Mar;24(2):111-22.
12
Difference: regional and systemic heat
Loco-regional
Systemic (WBHT)
•Heated the area in focus
•The blood-vessels are relatively cold
•Emphasized hypoxic conditions
Capillary vessels
(stable body
temperature)
Necrotic tissue
(slightly heated)
1 mm range
•The blood delivers the heat
•The blood-vessels are relat. hot
•Moderate hypoxic conditions
Capillary vessels
(hot body
temperature)
1 mm range
Vessels are cold spots
Hypoxic tissue
(extensively heated)
Vessels are hot spots
13
Whole-body hyperthermia devices in use
heckel – HT2000 (M)
heckel – HT3000
Diffuse reflection scattering of
IR A/B
water-filtered IRA from above
in a IR heated tent
Patient covered with cotton
cloth – part of conductive heating
Head position inside or
outside the tent
Head position inside or
outside the tent
Radiation and heat-retention
phase
Radiation and heat-retention
phase
Also used for extreme WBH
(approved Intended Use)
Also used for extreme WBH
(out of the approved Intended
Use)
Ardenne IRATHERM 1000
Modification of IRAtherm 2000
Patient lying on a net
Waterfiltered Infrared A from
below
Different capacitive local Hypertermia sys.
SYNCROTHERM Italy
THERMOTRON Japan
Hyp.-Effect is depending from Temperat.
Temperatur
Effekt
Blutfluss
Vaskularität
Angiogenese
Glocolyse
Metabolismus
Permeabilität
Oxygenierung
Gewebsazidose
Zystoskelett
Makromoleküle
Radikale
Genetische Regulation*
Reparatur Mechanismen
moderat
38,5 - 40,5
°C



( )



( )
=
=
=
/
intermediär
40,5 - 41-5
°C

t







t


=
= ( )

/
Bioenergetisch (ATP)

=

=
Nekrose/Lyse
Ø
Ø
Hager at al.
extrem
41,5 - 44,0
°C
ablativ
> 45,0 °C











/





±


+++
?







-
Effects of hyperthermia with........
 Cytostatic drugs
•
•
•
Synergistic
effects of
hyperthermia
hyperthermia elevates the intra-cellular metabolism of drugs
hyprethermia increases the incorporation of cytostatic drugs
in neoplastic cells
hyperthermia raises the lavel of drug reactivity
hyperthermia suppresses DNA repair
 ionizing radiation
1.
hyperthermia acts in hypoxic areas, whereas radiation act in oxygen
enriched areas
2.
hyperthermia acts in the G2- and S-phase, whereas radiation in the Mand G2-phase
 immune-therapeutical drugs
 thermo-sensitizer
 non-thermal effects
17
increasing of CTx-effect with Hyperthermia
Potentiation of Chemotherapeutic agents
120.00
Hyperthermia and 5-FU
100.00
80.00
60.00
No therapy
5FU
Hyperthemia allone
5FU with Hyperthermia
40.00
20.00
0.00
0.00
2.00
4.00
6.00
8.00
10.00
Time [h]
12.00
14.00
16.00
18.00
Cell Controll Biomedical Laboratories 1996
increasing of CTx-effect with Hyperthermia
Mitomycin - 10
mg/ml
Aspiration cytology (Mamma CA)
105
100
tumor-cell activity [%]
95
90
85
80
only chemotherapy
75
plus electrohyperthermia
70
0
5
10
time [hours]
15
20
Chemotherapeutics with/without Hyperthermia
%
0
90
Pharynx ca. WITH Hyperthermia
50
0
Pharynx-ca. WITHOUT Hyperthermie
%
0
90
50
0 rote, braune, blaue Säule: halbe, einfache, doppelte Basiskonzentration
Scheduling of HT (41.5 oC, 2h) with CTx in Colon Ca.
25
20
Tumor Growth Delay (days)
5FU 24h >
WB-TT
15
5-FU
10
WB-TT
+ 5-FU
WB-TT
24h >5FU
WB-TT
5
0
Joan M.C. Bull, Glenna L. Scott, Frederick R. Strebel, Dwight H. Oliver, Bharat Raval, and Steven M. Koch
The University of Texas Houston Medical School, Houston, TX 77005
Cisplatin with WBHT:
• simultaneous WB-TT
 synergistic antitumor effect
• However, simultaneous cisplatin + WBHT
induces: intolerable
renal toxicity
• Whereas, cisplatin 1-48 h prior to/or
after WBH = supra-additive antitumor
effect, yet tolerable toxicity
* Baba H, et al. , Cancer Res 49: 7041, 1989.
Tumor Cures increased by Optimal Scheduling of
HT combined with Oxaliplatin (Ox)
% Tumor Cures
Joan M.C. Bull, Glenna L. Scott, Frederick R. Strebel, Dwight H. Oliver, Bharat Raval, and Steven M. Koch
The University of Texas Houston Medical School, Houston, TX 77005
60%
50%
17%
control
TT
Ox
TT +
OX
TT>
Ox
OX 3h
> TT
Ox 12h Ox 24h
> TT
>TT
WBHT increases GEMCITABINE-induced
response in metastatic breast tumor
Clinical Trial: Whole-Body Hyperthermia
Joan M.C. Bull, Glenna L. Scott, Frederick R. Strebel, Dwight H. Oliver, Bharat Raval, and Steven M. Koch
The University of Texas Houston Medical School, Houston, TX
25
increasing effect of RTx with Hyperthermia
S
U
R
V
I
V
A
L
Treatet 60 min. by 43°C, Modified from Li and Kal, 1977 /Thermoradiotherapy M.H. Seegenschmied P. Fessenden Vol. 1 1995
RADIATION + CHEMO + HYPERTHERMIA
ORDER OF TIME-APPLICATION
CISPLATIN (CDDP): FIBROSARKOMCELS IN COMBINATION WITH CDDP, RT, HT
THERAPIEGRUPPE
WACHSTUMSHEMMUNG (TAGE)
CDDP
(5mg/kg)
4.4 +/- 0.9
CDDP
(10 mg/kg)
8.0 +/- 1.7
34 °C, 30 min.
1.4 +/- 0.7
CDDP  HT
5.9 +/- 1.1
Radiatio (5 X 3 Gy)
6.3 +/- 1.5
HT  Radiatio
8.4 +/- 2.2
CDDP  Radiatio
11.7 +/- 1.8
Radiatio  CDDP  HT
13.9 +/- 2.3
CDDP  Radiatio HT
19.3 +/- 3.4
CDDP  HT  Radiatio
25.2 +/- 2.8
Source:Towle, L.R., Hyperthermia and drug resistance; Hyperthermia and Oncology, Vol.4
Chemopotentiation by Hyperthermia. 1994; 135 - 160
Publication + acceptance
…most effective radiation
sensitisers…………
Dr. med. H. Sahinbas
Summary of some Hyperthermia-Effects:
1. Direct Tumor necrosis by using heat
2. Increased blood perfusion in the healthy tissue
Blood-perfusion decrease in tumors  hypoxia
3. Oxygen and nutricient deficit in malignant tissue
4. ATP decrease in cells, energy deprivation
Anareob energy production
5. Acid milieu around the Tumor
6. Chemo- and radiation sensitivity (synergetic effect)
7. Blocking the chemo- and radiation resistance
8. Hyp.  protein expression (HSP)  surface presentation
on the Tumor cells  recognize the immune system 
Tumor lysis
9. Activates G0-phase to G1 and S-phase
10. Micro-embolisation of the Tumor vessels (angiogenetic block)
Raab, 1937; Lampert, 1948;Schmidt, 1987; Hetzel et al., 1992; Song et al., 1995; Horsman & Overgaard, 1996;
Burd et al., 1998;Rau et al., 2000
What to do now? That is the question!
Few new treatments are available:
1. Hyperthermia
2. Phytopharmacons (plant origin, herbal medicine)
- Curcuma longa
- Dichloroacetate (DCA)
- Artesunate
-Vitamines (Vitamine D)
3. Personalized cancer treatment:
e.g. testing on Tumor cells
Well-known method in bacterial infections: Antibiogram
 Replace bacteria by tumor cells  “Oncobiogram”
This allows the patient effectively tailored therapy
Vit. C and Chemotherapeutics
Additive
Supraaditive
Decreasing of SE Negative effect
Arsentrioxid
Imatinib
Cisplatin
Etoposid
(Topo II-Inhibitor).
Melphalan
Cisplatin
Tamoxifen VLDL
Vincristinsulfat
(VCS).
Bortezomib
Vincristin
Adriamycin
Homocysteinthiolakton
5-Floururacil (5-FU).
5-Floururacil
(5-FU).
Doxorubicin
Gemzitabine + Vit K3
Vinblastin
Langzeit-DNASchäden durch
Bleomycin
Doxorubicin
Cyclophosphamid
Paclitaxel
Dacarbazine
Bleomycin
VITAMIN C – Study by breast Cancer
DCA: Advantage in medicine
DCA: switches the anaerobic glycolysis based metabolism of
Cancer cells
 by inhibiting the enzyme pyruvate dehydrogenase kinase II
 leading to the reactivation of pyruvate dehydrogenase
and thus
 aerobic glycolysis leads.
 DCA stimulates the expression of the tumor suppressor
gene p53
 inhibits the
 hypoxia inducible factor-1α (HIF1a)
 Nuclear factor of activated T cells (NFAT)
 and redox-sensitive K+ channels (Kv)
suppresses growth, angiogenesis and apoptosis of tumor
Artesunate: Advantage in medicine
 Reduction of Zellangionese
 Expression of vascular endotheli. Growth fact. (= Avastin °)
 Cancer cells show fragmented mitochondria and lysosomes.
 that accumulate in the vicinity of the nucleus. This
lysosomes shift with iron leads to apoptosis.
 The effect caused by the release of hydrogen peroxide in
the vicinity of the cell nucleus and also in the mitochondria.
 Especially with chemoresistant tumor cells effectively.
Hypericin: Advantage in medicine
(St. John's wort extracts)
o widely
used as an antidepressant substance
o Apoptosis-inducing effect
o Sensitization of tumor cells to ionizing radiation and
o anti-inflammatory effects
Possible molecular mechanism of action of known properties of
hypericin antidepressant, anti-inflammatory and antineoplastic
effect by the inhibition of the proteasome and NF-kB
Vit. D3 : Advantage in medicine
Diseases associated with vitamin D deficiency:
Chronic susceptibility to infection
 Osteoporosis
 Rickets
 rheumatoid arthritis
 Tumors of breast, colon, prostate, ovary and skin
prostatic hypertrophy
 MS, epilepsy, CFS, depression and insomnia
 Vascular disease, high blood pressure
 Diabetes Type 1 and Type 2
 ……………..
 ……

Curcumin: Advantage in medicine
Curcumin slightly soluble in water
absorbed only to a very small extent
A curcumin-phospholipid complex 29-fold higher
bioavailability
Curcumin:
 induces apoptosis in a variety of cells.
 C. inhibits e.g. the synthesis of EGF (epithelial
growth factor), which is mitogenic, and lots more.
………………….
…………
Curcumin: Advantage in medicine
Clinical studies with curcumin
Preventive chemotherapy:
• familial adenomatous polyposis
• hepatocellular carcinoma (HCC)
• gastric cancer (Helicobacter pylori)
Cancertherapy: suppresses a wide variety of tumor
cells:
• pancreatic cancer, multiple myeloma, leukemia,
Myelodysplastic syndrome, lung cancer, colon
cancer, cervical cancer, CCC, breast cancer,
prostate cancer, and more.
 About 7,000 "hits" in PUB-Med.
Curcumin: Advantage in medicine
Curcumin as "chemosensitizers" in the following
Chemotherapy:
 Paclitaxel, taxol, doxorubicin, 5-FU, vincristine,
melphalan, Butyrate, cisplatin, celecoxib, vinorelbine,
gemcitabine, oxaliplatin, etoposide, Sulfinosine,
thalidomide, bortezomib,………...(daily more…..)
(Cancer Res 2007 April 15; 67 (8):. 3853-61; Nutr Cancer 2010; 62 (7): 919-30
Curcumin, a chemosensitizer and "radiosensitizer"
for tumors and chemo and radio protector protector for
normal organs.
(Goel A, Aggarwal BB. Department of Internal Medicine, Baylor University Medical Center, Texas, United
States)
Sensivitystudys with Curcumin:
Breast-Ca-Cells (ÖSTROGEN-Rezeptor: NEGATIV)
MDA-231, 48 h
120
100
% ACTIVITY
80
60
curcumin
40
paklitaksel
karboplatin
20
gemstabin
0
6,25
12,5
25
50
-20
-40
Doses (TDC)
100
200
Sensivitystudys with C+CTx:
250
% survivel
200
150
100
50
0
MCF-7 brest-ca. stem cells
24 h Therapy, ATP-Activity
Sensivitystudys Curcumin + 5-FU:
MD Andersondan
Sensivitystudys Curcumin + Radiation:
MD Anderson
What to do now? That is the question!
Few new treatments are available:
1. Hyperthermia
2. Phytopharmacons (plant origin, herbal medicine)
- Curcuma longa
- Dichloroacetate (DCA)
- Artesunate
-Vitamines (Vitamine D)
3. Personalized cancer treatment:
e.g. testing on Tumor cells
Well-known method in bacterial infections: Antibiogram
 Replace bacteria by tumor cells  “Oncobiogram”
This allows the patient effectively tailored therapy
The Problem
The response to chemotherapy (solid tumors) is
about 30% !
Principles and Practice of Oncology (Cancer: Principles &
Practice (DeVita, 8th Revised edition (REV).
Lippincott Williams & Wilkins, 1. Mai 2008
Chemoresistant Assay
Well-known method in bacterial infections:
Antibiogram
Replace bacteria by tumor cells
Oncobiogram
= Chemoresistant (Chemosensitivity) Assay
Chemosensitivity testing







to decide which drugs to use for specific cancers.
interest in personalised cancer therapy
Best effect for an individual’s cancer.
testing on patients cancer cells
Test determines the ‘accumulators’ or ‘rapid
metabolizers’
provides guidance in clinical practice.
Show more and new on Tumor biology (AB-,
Hormone-Status, genetic shifting, ect…)
48
Chemosensitivity testing and application
Adeno-Ca PANKREAS-Chemosensitivity test
Chemosensitivity testing and application
NSCLC-Chemosensitivity stest 10.11.14
The specific tumor appears to have resisting populations because of the MDR1 overexpression that can be
reversed by the use of verapamil combined with imidazole compounds (ketoconazole).
 The neoplasmatic cells have the greatest sensitivity in the alkylating agent ( Cisplatin) , in the
nucleous spindle stabilizer ( Docetaxel ) and in the antagonist ( Pemetrexed = Alimta°)
 Also can be used Cetuximab as inhibitor of EGFr, Bevacizumab as inhibitor of neo-angiogenesis,
Panitumumab as inhibitor of EGFr and Sunitinib as inhibitor of PDGF -A,-B, VEGF Rs and c-kit.
50
„ New methods in cancer: Hyperthermia –as a standalone
or in combination with other therapies for cancer
treatment"
Selected tumor entities
with hyperthermia
Dr. med. H. Sahinbas
Brest cancer studies
Mammacancer
randomisierte Phase
(Jones et al 2007 + 2005)
III und Phase I Studien
109 Patients
CP + PR
68,1 % (RTH + HT)
vs. 42,3% (RTH )
Recurrens and RT:
68,2% RTH + HT
vs. 23,5 % RTH
(Jones et. al., Journal of Clinical Oncology Vol. 23, No 13, May 1, 2005.)
In einer Erweiterung mit thermisch sensitiven Liposomen als Träger von Doxorubicin als Phase I Studie kommen die Autoren
zum bislang vorsichtigen Schluss, dass auch hier die Hyperthermie mit einer liposomalen-thermosensitiven Chemotherapie
die „Anti-Tumor-Effekte“ verstärkt. (Jones et al, June 2007, 24th Annual Meeting of ESHO, Prag, Abstracts S. 11)
Cervix cancer studies
Cervixcancer
(van der Zee, Franckena , 2007)
(randomisierte Phase III Studie mit Follow-Up)
Follow-Up Studie : Langzeiteffekt nach 12 Jahren
58 Patienten (Strahlentherapie STH +Hyperthermie HT) vs. 56 Patienten (nur STH)
* Tumor controlle:
36 % (RTH)
vs. 56 % (RTH + HT)
* Survivel after 12 years:
20 % (RTH)
vs. 37 % (RTH + HT)
(bei p= 0,02)
(Franckena et al, June 2007, 24th Annual Meeting of ESHO, Prag, Abstracts S. 18)
Bezug auf: Van der Zee J, Gonzalez Gonzalez D, van Rhoon GC, van Dijk JD, van Putten WL, Hart AA. Comparison of radiotherapy
alone with radiotherapy plus hyperthermia in locally advanced pelvic tumors: a prospective randomized multicentric trial. Lancet 200;
335: S.1119-1125
Pankreatic cancer + Hyperthermia
3 explorative trials presented at ICHO 2008: Verona, Munich and Kyoto - Japan)
Takagi et al, Kyoto: Gemcitabine plus HT
Japan
57,1% disease control (CR+PR+SD)
49 % 1 year OS
Maluto et al , Verona: Chemo /Radiation plus HT
Italy
versus
68 %
1 year OS
Gemcitabine alone
„
„
versus
„
14,3 %
30 % (p=0,024)
Chemo /Radiation alone
47 %
no more toxicity observed as in control group
Tschoep et al, Munich: Gemcitabine/CIS plus HT as second line therapy !
median progression free survival from start 2nd line therapy: 4,2 months (CI:
median
2.1-7.7)
OS: 16,9 months (CI: 11,8-22)
all presented at: ICHO conference, 10th International Congress on Hyperthermic Oncology, Munich, Germany 2008
Randomised controlled trials with HT
Tumorart
N=Studies
N= Patients
/Localisation
Radiation +
Radiation
Hyperthermia
(%)
(%)
Odds ratio
(95% CI)
(CI-Confidence ratio)
Breast
2
143
67
68
1.06 (0.52–2.14)
Cheast Wall
4
276
38
59
2.37 (1.46–3.86)
Cervix
4
248
52
77
3.05 (1.77–5.27)
Rectum
2
258
9
19
2.27 (1.08–4.76)
Bladder
1
101
51
73
2.61 (1.14–5.98)
Prostata
1
49
79
81
1.16 (0.28–4.77)
Melanom
1
70/128
31
56
2.81 (1.36–5.80)
Head &
Neck
5
274
33
51
2.08 (1.28–3.39)
Diverse
3
442
34
39
1.24 (0.84–1.82)
All Studies
23
1861
38
52
1.80 (1.50–2.16)
Journal of
Clinical
Oncology 19:
2007
Horseman /
Overgaard
Meta-Analysis
on radiation
alone
versus
radiation
plus
hyperthermia
The authors concluding: if taken all these clinical results (1861 Patienten from 23 Studies) it shows a
highly significant benefit (P< 0.0001) that confirms the rationell of a combined efficacy of radiation with
hyprthermia. That result stands besides the fact that there were quite different treatment protocols in the various
tumor entities (dito p.423).
Deep Hyperthermia by relapsed malignant gliomas
treated with RF-HT with 13.56 MHz.
University Witten/Herdecke,Departement of Radiology
Dr. H. Sahinbas, ASCO 2008
RESULTS on Gliomas
H. Sahinbas 2008 ASCO
Hyperthermia may increase overall median survival time (MST)
MST of patients with WHO grade III and IV gliomas
(Kaplan-Meier-Estimation)
MST from
1st Diagnosis of Disease
1st RF-Hyperthermia
Events
/ Censored N (%)
Grade III AA;
Grade IV GBM;
N = 53 pts
N = 126 pts
months±se [95%CI]
months±se [95%CI]
38.2±3.7 [31.2;45.0] 20.3±1.7 [15.9;22.1]
10.6±2.0 [6.7;14.4] 7.6±0.9 [5.9;9.3]
39 / 14 (26.4%)
101 / 25 (19.8%)
Survival Probability (Kaplan-Meier-Estimation)
From newly diagnosed
1 yr .
2 yrs
3 yrs
4 yrs
5 yrs
AA WHO°III; N=53
96
72
53
35
30
GM WHO°IV; N=126
82
41
23
11
11
Censored (AA): 14 (26.4%); events: 39 (73.6%) Censored (GM): 25 (19.8%); events: 101 (80.2%)
Treatment-combination (example)
Week up to 5,4 Gy
Week
"New Technical and Medical Methods in
Cancer Treatment"
14th March 2015 London
„ New methods in cancer: Hyperthermia –as a standalone
or in combination with other therapies for cancer
treatment"
Dr. med. Hüseyin Sahinbas MD, Ph.D
Specialist of Radiology
Specialist of Radiotherapy and Radiation-Oncology
Hyperthermia
Complementary Medicin