ss tt.. ii sstvvaan uuniiveerrsityyszasz...˘ˇ ˇ department of biotechnics, st.istvan university,...

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Department of Biotechnics, St.Istvan University, Hungary, [email protected]

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The results are strongly indicating the feasibility and the benefit of the oncothermia showing a valid treatment potential and safe application. Oncothermia is a potential way to escape from the present impasse situation and treat brain gliomas successfully. Performing prospective, randomized clinical trials in the future is mandatory. A well designed Phase I study is shown in our other paper [8].

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Support of OncoTherm Ltd. is appreciated.

56,55%60,32%70,00%

108,33%

100,00%

0,00%0,00%5,00%

100,00%

100,00%

0,00%

20,00%

40,00%

60,00%

80,00%

100,00%

120,00%

Dec 99 Jan 00 Feb 00 Mar 00 Apr 00 May 00 Jun 00 Jul 00

Rel

ativ

e tu

mor

-siz

e

date

Tumor

Perifocal eodema

CASE 2. (Groenemeyer Institute, [Witten-HerdeckeUniversity], Bochum, Germany) [12]

Patient: 38y, male. Diagnosis: Astrocytoma, WHO III.inoperable Hydrocephalus occlusus, neurofibromatosis. Radiation: 40 Gy (fractional, 2 Gy/d), Medication: Fortecotin 4 mg (16.02.00 - 28.03.00.) Oncothermia:2-3/week, 60m/each) Result: partial remission, improved quality of life, (perifocal edema had been vanished).

Only oncothermia

After 4th oncothermiaShuntocclusion

25.12.1999 15.02.2000 22.05.2000 03.07.2000 12.09.2000 08.12.2000 16.02.2001 24.04.2001

Oncothermia + 6x radiation

Before radiation and oncothermia

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22.03.01

22.03.01

29.06.01

29.06.01

CASE 1. (Groememeyer Institute, [Witten-Herdecke University], Bochum, Germany) [13]

Patient: 11y male. Diagnosis: April 2003 anaplastic ependymoma WHO III bithalamic. Treatment: Since April 2003 multiple chemotherapy: massive progress, low Karnofsky Score (KS). Oncothermia applied, (2-3 times 60 m/each week, 20 sessions). Result: Growing KS, no progression, status became stable.

SEER (Surveillance, Epidemiology, and End Results) by the National Cancer Institute USA, April 2000; EUROCARE Statistical database of cancer in the European Union; MRC (Medical Research Council, Brain Tumor Working Party); [18]; RTOG (Radiation therapy Oncology Group, [17]; EORTC (European Organisation for Research and Teratment of Cancer) [16]; RT = Radiotherapy, PCV = Procarbazine + CCNU(Lomustine) + Vincristine, TMZ = Temizolomid

St. Istvan UniversitySt. Istvan UniversitySt. Istvan UniversitySt. Istvan University

[1] Fisher PG, Buffler PA: Malignant gliomas in 2005. Where to GO from here?, Editorials, JAMA 293:615-617, 2005[2] Szasz A, Szasz O, Szasz N: Physical background and technical realization of hyperthermia, in: Locoregional Radiofrequency-Perfusional- and Wholebody-Hyperthermia in Cancer Treatment: New clinical aspects, (Eds: Baronzio GF, Hager ED), Springer Science Eurekah.com, 2005 [3] Hager ED, Dziambor H, App EM, Popa C, Popa O, Hertlein M: The treatment of patients with high-grade malignant gliomas with RF-hyperthermia. Proc ASCO 2003; 22:118, #47, Proc Am Soc Clin Oncol 22: 2003 [4] Hager ED, H Sahinbas, DH Groenemeyer, F Migeod: Prospective phase II trial for recurrent high-grade malignant gliomas with capacitive coupled low radiofrequency (LRF) deep hyperthermia, ASCO 2008, Journal of Clinical Oncology, 2008 ASCO Annual Meeting Proceedings (Post-Meeting Edition). 26:2047, 2008 [5] Sahinbas H., Grönemeyer D.H.W., Böcher E., Lange S.: Hyperthermia treatment of advanced relapsed gliomas and astrocytoma, The 9th International Congress on hyperthermic oncology, St. Louis, Missuri, ICHO, April 24-27, 2004 [6] Sahinbas H, Groenemeyer DHW, Boecher E, Szasz A: Retrospective clinical study of adjuvant electro-hyperthermia treatment for advanced brain-gliomas, Deutche Zeitschrifts fuer Onkologie, 39:154-160, 2006 [7] Fiorentini G, Giovanis P, Rossi S, Dentico P, Paola R, Turrisi G, Bernardeschi P: A phase II clinical study on relapsed malignant gliomas treated with electro-hyperthermia, In Vivo. 20:721-724, 2006 [8] Wismeth C, Hirschmann B, Pascher C, Dudel C. Szasz A, Bogdahn U, Hau P: Transcranial electro-hyperthermia combined with alkylating chemotherapy in patients with realpsing high-grade gliomas – Phase I clinical results, Poster presentation, STM2009, Tucson, Arizona[9] Szasz, O., Andocs, G., Szasz, A. (2008). Thermally induced effects in oncothermia treatment, Symposium on Biophysical Aspects of Cancer, Electromagneticmechanisms, (in memoriam H. Froelich), Prague, 1-3. July, 2008, submitted to Electrom. Bio. Med.[10] Andocs G, Szasz A: Preliminary results of Oncothermia induced apoptosis in nude-mouse inoculated human-glioblastoma cells, Results of hyperthermia, Seminar, St. Istvan University, Aug. 24., 2005. (in Hungarian) [11] Sahinbas H, Baier JE, Groenemeyer DHW, Boecher E, Szasz A: Retrospective clinical study for advanced brain-gliomas by adjuvant oncothermia (electro-hyperthermia) treatment, 2006 www.gimt-online.de/uploads/media/Therapieergebnisse_Giloma_Studie_01.pdf[12] Szasz A., H.Sahinbas, A.Dani: Electro- hyperthermia for anaplastic astrocytoma and gliobastoma multiforme ICACT 2004, Paris, 9-12. February, 2004[13] Sahinbas H.: EHT bei Kindern mit Hirntumoren und nicht-invasive Messverfahren am beispiel von Hirntumoren, Symposium Hyperthermie, Cologne, 15-16 Oktober 2004[14] Hager E.D.: Response and survival of patients with gliomas grade III/IV treated with RF capacitive-coupled hyperthermia, ICHO Congress, St. Louis USA 2004 [15] Varkonyi A Dani A, : Electro-hyperthermia treatment of malignant brain tumors, Results of hyperthermia, Seminar, St. Istvan University, Aug. 26-27., 2003. (in Hungarian) [16] Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn, MJB, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO: Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma, The New England J. of Med., 352:987-996, 2005[17] Scott CB, Scarantino C, Urtasun R, et al: Validation and predictive power of Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis classes for malignant glioma patients: A report using RTOG 90-06. Int J Radiat Oncol Biol Phys 40:51-55, 1998[18] Medical Research Council Brain Tumor Working Party: Randomized Trial of Procarbazine, Lomustine, and Vincristine in the Adjuvant treatment of High-grade Astrocytoma: A Medical Research Council Trial, J. Clin. Oncol. 19:509-518, 2001 [19] Hager E.D.: Clinical Response and Overall Survival of Patients with Recurrent Gliomas Grade III/IV Treated with RF Deep Hyperthermia – An Update, ICHS Conference, Shenzhen, China, 2004 [20] Sahinbas H, Szasz A: Electrohyperthermia in brain tumors, Retrospective clinical study, Annual Meeting of Hungarian Oncology Society, Budapest November 3-5, 2005

Data published in ASCO at 2003 [3] shows 106m (n=9) median survival time (MST) for AA and 20m (n=27) for GBM patients. At newest ASCO presentations [4] 38.2m (n=53) and 20.3m (n=126) was observed for AA and GBM patients, respectively. Witten-Herdecke University published [5] 70.2m (n=17) and 25.2m (n=19) as well as [6] 26.1m (n=40) and 16m (n=92) data for AA and GBM MST, respectively. HTT-Med MST results [5] were 36m (n=8) and 14m (n=10) for AA and GBM, respectively. The very advanced relapsed cases show [7] 9m MST (n=12) for GBM.

The treatment method is transcranially applied modulated RF-current capacitive coupled at 13.56 MHz carrier frequency, (Oncotherm, EHY2000+) [2]. The applied protocol was unified step-up heating, 40-150 W RF-power with water-bolus cooling. Treatment is applied in combination with chemo- and/or radio-therapy or used as monotherapy if the conventional therapies fall. Data are collected from GBM andanaplastic astrocytoma (AA) published observational studies.

None of the established state-of-the-art treatments in malignant primary brain tumors, especially in glioblastoma multiform (GBM), could show effective or commonly accepted curative potential until today. The editorial question of JAMA [1] in 2005 is actual even now: “Where to go from here?” Our objective showing feasible way to go, summarizing the results obtained till now by modulated electro-hyperthermia (oncothermia) in various clinics in EU.

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Control

Oncothermia

GL261 tumor tissue in the brain

It is effective on low temperatures also Consequence: applicable for brain [9]

It is well focused [10], Consequence: it is well localized

Due to the low temperature It is applicable near the eye

A well designed Phase I study shows the safety of the method [8]. The dose escalation has no extra hazard even in very frequent applications.

(individual tuning)

Important factors:• Tuning-automaching• Modulation• Applicator system• Safety systemRF

sourceRF

source

MATERIAL(dielectric loss)

ener

gy

(recent photo, 21.09.2006)

Carcinoma of sinus sphenoidalis , inoperable, Case from: Prof. Helmut Renner, Nurnberg, Germany(recent photo, 21.09.2006)

Carcinoma of sinus sphenoidalis , inoperable, Case from: Prof. Helmut Renner, Nurnberg, Germany

Non-Hodgkin lymphoma, Case from: Prof. Alexander Herzog, Nidda Bad Salzhausen, Germany

Before oncothermia 17.11.2003 After oncothermia; 21.04.2004

Kar

now

ski I

ndex

[%]

0

10

20

30

40

50

60

70

80

December 2003 January 2004 March 2004 May 2004

date

Karnofsky Index

CASE 3. (Dr. Dieter Hager, Bad Bergzabern, Germany [Biomed Clinic]) [14]

Patient: 38y, male. Diagnosis: Anaplasticastrocytoma, WHO III. (CT-scan and stereotactic biopsy), inoperable. Radiation: 60 Gy (fractional, 2 Gy/d), (03-04/97, progression). Medication: etherlipids (ET18OCH3) and boswellia serrata. Oncothermia: 2/week, (4 in a cycle), cycles start: 08/97, 10/97, 11/99, 02/00. Result: partial remission, improved quality of life,

CASE 5. (Groenemeyer Institute, [Witten-Herdecke University], Bochum, Germany) [11]

Patient: 26y, female. Diagnosis:1997 Grad I re. frontal + central; 2/00 Metastasis Recitives: bifrontal and central, Anaplastic Astrocytoma WHO III/IV. Radiation: 3/00-2/01 seed implants 25 Gy + external radiotherapy 25 Gy, progression. Other therapies: Oncothermia 03.04.01 – 05.05.01 (Monotherapy), from 05.05.01 Oncothermia + Systemic Chemotherapy: Temodal during 21 days 100 mg/Kg KG 21 days/ 1week. Result: Complete remission 2001

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Survival time (months)

1201101009080706050403020100

Cum

ulat

ive

surv

ival

1,1

1,0

,9

,8

,7

,6

,5

,4

,3

,2

,1

0,0

Survival time (months)

1201101009080706050403020100

Cum

ulat

ive

surv

ival

1,1

1,0

,9

,8

,7

,6

,5

,4

,3

,2

,1

0,0

Anaplastic astrocytoma

Glioblastoma multiforme

Censored

MST medium survival time

No of Cases: 35 (f:11m:25): Censored: 8 (22,2%) Events: 28, Rang e: 95% Confidence Interval

14289204116611LF -RF -DHT

20101585847261319Progressio

31102019717106291823Dx of

Disease

maxminMSTmaxminMSTmaxminMST

Grade IVGrade IIIGrade III+IVMST from

Time of



14289204116611LF -RF -DHT

20101585847261319Progression

31102019717106291823Dx of

Disease



Time of



14289204116611LF -RF -DHT

20101585847261319Progressio

31102019717106291823Dx of

Disease



Time of



14289204116611LF -RF -DHT

20101585847261319Progression

31102019717106291823Dx of

Disease



Time of

Censored

CASE 4. (Dr. Akos Varkonyi, [HTT-Med Clinic], Budapest, Hungary) [15]

Patient: 45y female. Diagnosis: June 2007 anaplasticastrocytoma WHO III. Inoperable, progression on radiotherapy, Treatment: Oncothermia monotherapy, February 1998 and second cycle in June 1998. Result:Complete remission

Anaplastic astrocytoma106

38.2 36

70.2

26.1

9 53 8 17 400

20

40

60

80

100

120

[3] [4] [5] [5] [6]

references

med

ian

su

rviv

al ti

me

(m)

0

120

number of patients (#) at base of the columns

Glioblastoma multiforme

20 20.3

25.2

1416

9

27 126 19 10 92 120

5

10

15

20

25

30

[3] [4] [5] [5] [6] [7]references

med

ian

su

rviv

al ti

me

(m)

0

300

number of patients (#) at base of the columns

Reference [3]

Oncothermia studyBrain gliomas,

Dr. Sahinbas et. al.

Oncothermia studyBrain gliomas,

Dr. Sahinbas et. al.

Average median survival from data-banks

11.35 month

Average median survival from data-banks

11.35 month

74.5%

Pat

ien

t num

ber

12.1

14.6

9.5

12.1

14.6

9.5

19.8

296 287 339 335

140

296 287 339 335

140

296 287 339 335

140

296 287 339 335

140200

400

600

800

1000

1200

1400

1600

200

400

600

800

1000

1200

1400

1600

12.1

14.6

9.5 1011.3

12.1

14.6

9.5

12.1

14.6

9.5

12.1

14.6

9.5

296 287 339 335

140

296 287 339 335

140

1578

296 287 339 335

140

296 287 339 335

140

0

5

10

15

20

25

Med

ian

su

rviv

al(m

)

0

5

10

15

20

25

Med

ian

su

rviv

al(m

)

0

5

10

15

20

25

Med

ian

su

rviv

al(m

)

SEER (Surveillance, Epidemiology, and End Results) by the National Cancer Institute USA, April 2000MRC (Medical Research Council, Brain Tumor Working Party)RTOG (Radiation therapy Oncology Group, EORTC(European Organization for Research and Treatment of Cancer)

RT = Radiotherapy,

PCV= Procarbazine+CCNU(Lomustine)+Vincristine, TMZ= Temizolomide

SEER (Surveillance, Epidemiology, and End Results) by the National Cancer Institute USA, April 2000MRC (Medical Research Council, Brain Tumor Working Party)RTOG (Radiation therapy Oncology Group, EORTC(European Organization for Research and Treatment of Cancer)

RT = Radiotherapy, RT = Radiotherapy,

PCV= Procarbazine+CCNU(Lomustine)+Vincristine, PCV= Procarbazine+CCNU(Lomustine)+Vincristine, TMZ= TemizolomideTMZ= Temizolomide

0

5

10

15

20

25

Med

ian

su

rviv

al(m

)

EORTC RT EORTC RT+TMZ MRC RT total MRC RT+PCVtotal

RTOG total

Clinical study

0EORTC RT EORTC RT+TMZ MRC RT total MRC RT+PCV

totalRTOG total

Clinical study

0

200

400

600

800

1000

1200

1400

1600

200

400

600

800

1000

1200

1400

1600Brain-gliomas (all grades)Brain-gliomas (all grades)Brain-gliomas (all grades)Brain-gliomas (all grades)Brain-gliomas (all grades)Brain-gliomas (all grades)Brain-gliomas (all grades)Brain-gliomas (all grades)

[18] [17][16] [16][18]

[11]

Brain glioma 1y survival [%]

45.437.8

86.2

73.8 71.7

n=140n=28970 n=35n=29n=14452

20

40

60

80

100

SEER Eurocare HTT Clinic BioMed Clinic GroenemeyerClinic

first

yea

r su

rviv

al [

%]

[15] [19] [20]

Brain glioma median survival [month]

11.49 11.3

23.63 23

19.8

n=140n=28970 n=35n=29n=1578

5

15

25

SEER RTOG HTT Clinic BioMed Clinic GroenemeyerClinic

Brain glioma median survival [month]

11.49 11.3

23.63 23

19.8

n=140n=28970 n=35n=29n=1578

5

15

25

SEER RTOG HTT Clinic BioMed Clinic GroenemeyerClinic[17] [15] [19] [20]

Med

ian

surv

ival

[mon

th]

19

14.4

<50 y >50 y

Present study Present study

16

9.5 9.5 10.2

MRC RT MRC RT+PCV

SEER

9.5 9.5 10.2

MRC RT MRC RT+PCV

SEER

13.7

9.7

RTOG

<50 yRTOG>50 y

13.7

9.7

RTOG

<50 yRTOG>50 y

Present study

Clinical study

Glioblastoma multiforme (WHO IV) Results of the clinical studies

0

2

4

6

8

10

12

14

16

18

20

Med

ian

surv

ival

(m)

Glioblastoma multiforme (WHO IV) Results of the clinical studies

0

2

4

6

8

10

12

14

16

18

20

Med

ian

surv

ival

(m)

0

2

4

6

8

10

12

14

16

18

20

surv

ival

(m)

0

50

100

150

200

250

0

50

100

150

200

250Median survival (m)

226 223

92

47 45

Number of pts.5801

226 223

92

47 45

Number of pts.5801

SEER (Surveillance, Epidemiology, and End Results) by the National Ca ncer Institute USA, April 2000; MRC(Medical Research Council, Brain Tumor Working Party); RTOG (Radiation therapy Oncology Group, EORTC(European Organisation for Research and Teratment of Cancer ); RT = Radiotherapy , PCV = Procarbazine+CCNU(Lomustine)+Vincristine , TMZ = Temizolomide

[18][17]

[18] [11]

ss tt.. ii sstvvaan uuniiveerrsityyszasz...˘ˇ ˇ department of biotechnics, st.istvan university,...

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