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Oncothermia as monotherapy A.Szasz Dept. Biotechnics, St.Istvan University, Hungary Spontaneous tumor regression (or even curing) by heat/fever effects believed by many patients and it is under intensive debate for a long time in the professional literature also. As early as in the beginning of the last century 185 spontaneous regressions were collected [1] and also collection of cases were published in early 1960’s: 202 cases were collected within 4 years [2], while 98 cases shown also in the middle of that decade [3]. Many surprising spontaneous remission were described in a monograph [4]. Few years ago the famous “Armstrong effect” [5], had been in focus of the topic. The literature of the spontaneous remission of cancer is impressive, and all of them somehow connected to the fever or heat [6], [7], [8], [9]. Large number of clinical cases are collected for study the topic: 176 cases between 1900–1960, [10], [11]; 489 cases described from 1900–1987 [12]; and a large meta-analysis was applied for about 1000 cases [13]. In fact the classical hyperthermia as monotherapy was applied in many studies at the historical time of hyperthermia. In ancient applications, no other treatment facilities were available, [14]. Hyperthermia alone is a popular (almost unique) application for in-vivo experiments like [15]. In former times many human clinical trials were performed as monotherapy applications [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34]. At the design of the clinical trials in hyperthermic oncology it was counted as an option, but the results of the combined therapies was found better [35]. In an extended study the localized hyperthermia alone has been used for the treatment of cancer in cases of recurrences in which previously administered conventional therapies have failed [36]. 57 patients with 60 lesions have been treated by microwave and radiofrequency methods, twice a week, 6-8 times. Complete response (CR) was obtained in ten cases (16.6%) and partial response (PR) in 14 (23.4%). Higher rates of CR were observed in the chest wall (38.5%) compared with the head and neck area (11.4%), trunk (l0%), and limbs (none). Adenocarcinoma was the most responsive histologic type (40%). Squamous cells carcinoma had 7.7% CR. The only case of undifferentiated carcinoma showed CR; there were none on five sarcomas. Long-term local control (24 months) was approximately 7%. Oncothermia is typical complementary treatment for GS methods, first of all for radioand chemotherapy but growing number in pre- and postoperative applications as well. We have to strictly emphasize: while the GS therapies could be applied with the chance of success, oncothermia could be only complementary for these, sensitizing, boosting their effects and reducing their (sometimes severe) side effects. 1 However, oncothermia was provided many times as monotherapy in the cases when no other “gold standard” (GS) treatments facility is applicable. Some of the cases are blocking the complementary applications (organ [like liver, kidney] failure, low blood count, severe side effects of GSs, psycho-rejection, very low immune status, definite refractory cases etc.). In such situation oncothermia could be applied as monotherapy. It has consequences: 1. In this meaning oncothermia is palliative from the point of view of GS. Effect of this palliation could be immediately observed on the quality of life and measured by Karnofski Performance Score (KPS). 2. The obtained results in palliative approach of oncothermia are many times curative in these cases as well. It could even resensitize by oncothermia the anyway refractory GS, and so they could be reapplied complementary again. 3. Patients treated by oncothermia all are in advanced stages, many times terminal. 4. Evidence based statistics are not available when GS is failed, the cases are very individual, patients have frequently co-morbidities, low immune status, low KPS and almost all individuals are psychologically frustrated. Oncothermia for them is a “last hope” treatment. 2 Some cases can be cited for monotherapy: Esophagus carcinoma. Department: Department of Radiology and Microtherapy, University of WittenHerdecke, Bochum, Germany. Investigators: Prof.D.Gronemeyer & Dr.H.Sahinbas. Patient: M, 46 y, male, Diagnosis: 4/00, Esophagus-Ca. Therapies: 1. Surgery: 4/2000. 2. Chemotherapy: Multiple CxT, 3. Radiotherapy: (50 Gy) from 01.08.2001, Result 1: recidiv. Anastomiosen recidiv / Multiple bougienage and Anastomose, Full block of food-passage, low KPS Oncothermia: monotherapy from 27.09.2001 –23.11.2001 Result 2: Complete remission (CR) Free-food passage 01.08.01. 29.11.2001 after 6x oncothermia 17.01.2002 after 12x oncothermia 3 Liver metastasis from sigma carcinoma primary Department: Department of Radiology and Microtherapy, University of WittenHerdecke, Bochum, Germany. Investigators: Prof.D.Gronemeyer & Dr.H.Sahinbas Patient: A.K, 61 y, male; Diagnosis: 11/97, Sigma-Ca. Tumor-classification: pT3 N1 M0; Size: 4 x 5 cm, Metastasis: hepatic; Therapy (for metastasis): Oncothermia alone (no chemotherapy or other was available) Result: Partial remission (PR) tumor and tumor marker regression 4 Astrocytoma, WHO III. Institute: HTT-Med Polyclinicum, Budapest, Hungary, Investigator: Dr. A.Varkonyi, June 1998, after 2nd session of oncothermia June 1997, before oncothermia Patient: P.I. 45 y, female; Diagnosis: Anaplastic astrocytoma; Stage: WHO III; Treatment: Oncothermia monoterapy from June 1997 Result: Complete remission (CR) 5 Astrocytoma, WHO III. Institute: Biomed Clinic, Bad Bergzabern, Germany. Investigator: Dr. Dr. D. Hager Patient: K.D. male, Diagnosis: Anaplastic astrocytoma, Stage: WHO III Treatments: Surgery: Sept./2000 Excision of tumor, Radi ation: Sept.-Nov. 2000 postoperative radiation. Chemotherapy: Sept.2000-Jan.2001 (BCNU+VM-26). Recurrence: Febr.2001 (4x1.5 cm). Oncothermia: Febr. 2001 with Thal. & bosw. s. Result: Complete Remission (CR) 6 Astrocytoma, WHO II. Institute: Institute of Microtherapy, University Witten Herdecke, Germany. Investigators: Prof.Dr.D.Gronemeyer & Dr.H.Sahinbas Patient: W. B. 49y, Female. Diagnosis: Astrocytoma WHO II. Treatments: Surgery: 1. January 1999 2. October 1999 Radiation: 1. Nov.-Dec.1999 60 Gy 2. July 2001 30 Gy Chemotherapy: July 2001; 12 Cycles Temozolomide; Result 1: recurrence July 2002 Oncothermia: monotherapy. 10 July.-24.July, 2002. 8 x sessions, 60 min Result 2: Histologicly tumor-free, only necrotic tissue Before oncothermia After oncothermia (monotherapy) Only necrotic tissue 7 Astrocytoma, WHO III. Institute: Biomed Clinic, Bad Bergzabern, Germany. Investigator: Dr. Dr. D. Hager Patient: F.M. male. Diagnosis: Anaplastic astrocytoma, Stage: WHO III Treatments: Surgery: 1. Jun.2001 Subtotal resection 2. Aug.2001 Relapse, subtotal resection again Radiation: Sept.-Oct. 2001 postoperative radiation (TD 60 Gy) Chemotherapy: Jan.2002-Jun.2002, Temodal (7cycles) Result 1: Progressive disease (PD) Oncothermia: Since. Jun.2002 with Thal. & bosw. s. & ELP Result 2: Complete Remission (CR) MRI 21.06.2002 MRI 11.06.2004 MRI 21.06.2002 8 Astrocytoma, WHO III. Institute: Biomed Clinic, Bad Bergzabern, Germany, Investigator: Dr.Dr. D.Hager Patient: C.C. male. Diagnosis: 09/93 Anaplastic astrocytoma, Stage: AAC WHO II, Inoperable. Treatments: Radiation: 10-12/93 (TD 54 Gy). Result: Recurrence 07/94; AAC WHO III Chemotherapy: 08/94 – 07/95 (5xPCV). Result: Progression, 01/96, (MRI) Oncothermia, (monotherapy) Since 01/96 Results: 1. Central necrosis with perifocal edema, decrease in vascularization 12/96; MRI. 2. Partial Remission; 12/97. 3. No change (NC); MRI, since 11/98. 4. Follow up: till 06/04 (MRI) 9 Pediatric ependymoma, WHO III Institution: Institute of Microtherapy, University Witten Herdecke, Germany Investigator: Prof. Dr. D. Gronemeyer & Dr. H. Sahinbas, Patient K.K. 10 y, (boy), Diagnosis: progressive ependymoma, bithalamic. Stage: WHO III, Treatments: conventional: 1st surgery, 2nd chemotherapy, 3rd radiotherapy and chemotherapy. Failed all, Karnowfsky score down to 30%. Oncothermia (since 09.Dec.2003) (monotherapy), 60 min, 2-3 times weekly, 21.04.2004 after 1st session of oncothermia 17.11.03. before oncothermia 17.11.03. before oncothermia 21.04.2004 after 1st session of oncothermia Karnowski Index [% ] Karnofsky Score 80 70 60 50 40 30 20 10 date 0 December 2003 January 2004 March 2004 May 2004 10 Intrahepatic bile-duct carcinoma Institution: Markusovsky Hospital, Szombathely, Hungary. Investigator: Dr. A.Csejtey & Mr.P.Lorentz. Diagnosis: Intrahepatic bile-duct carcinoma, inoperable. Therapy: Oncothermia as monotherapy with concomitant supportive vitamins only. Prognosis: overall median survival 6 months. Due to the patient’s status, no any other therapies was possible. Oncothermia started (June14.2007) Tumor-progression (May 08.2007) Definite tumor-regression (December 19, 2007) 11 Clinical study for liver metastasis from colorectal cancer primary [37] (n=80) Institute: Biomed Clinic, Bad Bergzabern, Germany. Investigator: Dr.D.Hager Histology: Adeno-carcinoma, Prior liver resection: 16%, All patients had metastases. Median survival [months] number of patients 30 25 24.4 20 15 10 21.5 24.1 80 80 80 60 50 11 30 Oncothermia Oncothermia + alone chemotherapy after failure of (various) prior treatments 40 20 5 0 100 All therapies Expected survival (historical) 0 patient number median survival [months] Prior chemotherapy unsuccessful, 37.5% of patients had palliative chemotherapy concomitantly with oncothermia, others had monotherapy. Oncothermia alone was more successful than with concomitant chemotherapy. The reason is probable the low immune status of the patients with advanced diseases, and the intolerable side effects. 12 Advanced hepatocellular carcinoma (HCC) phase II study [38] (n=22) Institute: Department of Oncology, Spedali Civili, Brescia, Italy. Investigator: Prof.VD.Ferrari. Patient characteristics: Number of patients: 22. Stage C (of BCLC classification). Nonoperable: 68%. Portal vein-thrombosis: 70%. Distant metastasis: 9%. Oncothermia treatment: 60 min/session, 2 sessions/week. 10 sessions/cycle, Median 1.5 cycle (1-4), 80-140 W (41-47oC) Local clinical response 80 Quality of life: better 50% 70 72 60 50 40 30 23 20 5 10 0 0 CR PR NC Concomitant chemotherapy Toxicity 80 70 PD 70 68 64 60 60 50 50 36 40 40 30 30 18 20 14 10 20 10 0 0 Not observable Erithema Subcutan adipose burn Concomitant oxalyplatine (50 mg) No concomitant chemotherapy 13 Far-advanced liver metastases (various primary tumors) [39] Institute: Clinic & Institute of Radio-Oncology, Zentralkrankenhaus Reinkenheide, Bremerhaven, Germany. Investigator: Prof.H.Aydin Topic: Far advanced liver metastases various kind of primer tumors. Concomitant therapies were applied whom it was possible. Oncothermia: 2x / week. Concomitant chemotherapy: Vinorelbine (20 mg/m2/week) Concomitant radiotherapy: 10MV, 1.5-1.8 Gy fractional radiation 5x /week, overal dose: 21-24 Gy. Protocols: Therapy / week-days Radiotherapy + Oncothermia Mon. Tue. Wed. Thu. Fri. RT RT OT RT RT OT RT Number of patients 16 CHT Chemotherapy + Oncothermia OT OT 8 Oncothermia monotherapy OT OT 4 Local control (overall response) 80 75% Oncothermia + Radiotherapy Oncothermia +Radiotherapy: 81% 70 Oncothermia + Chemotherapy (Vinorelbine (20mg/m2/week) Oncothermia + Chemotherapy: 38% 60 Oncothermia alone 62% Oncothermia as monotherapy: 25% 50% 50 40 31% 30 25% 25% 19% 20 13% 10 0 0 0 CR 0 5/16 1/8 PR 0 8/16 2/8 1/4 SD 3/16 5/8 3/4 PD The most advanced refractory cases were treated by monotherapy oncothermia alone. Probable this is one of the factors of the result. 14 References [1] Rohdenburg (1918) Fluctuations in the growth energy of tumors in man, with esspecial reference to spontaneous recession. J Cancer Res; 3:193-225 [2] Fauvet J. (1964) Spontaneous cancer cures and regressions. Rev Prat. Jun 11;14:2177–2180 [3] Boyd W. (1966) The spontaneous regression of cancer. 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