**4.3. Action on far distant metastases**

44 Hyperthermia

The cleaved Caspase-3 (as important part of the apoptotic pathway) was activated (see Figure 39., [341]), as well as the death toll receptors became overexpressed (see Figure 40., [341]).

**Figure 39.** HT29 human colorectal carcinoma cell-line xenograft model in nude mice. Caspases, or cysteine-aspartic proteases or cysteine-dependent aspartate-directed proteases are a family of cysteine proteases that play essential roles in apoptosis (programmed cell death), necrosis, and inflammation

**Figure 40.** HT29 human colorectal carcinoma cell-line xenograft model in nude mice. Death receptor

Oncothermia is different from this point of view as well. It blocks the dissemination, avoids their motility due to the lazy connections with the tumor. Oncothermia makes it by the reestablishing the cellular connections (see Figure 41. [337]), which is also great success to save life. The built up connections can force not only the sticking together, but make bridges between the cells for information exchange to limit the individuality and the competitive

(the red line is for the reference value) [Reference: untreated control]

activity (the red line is for the reference value) [Reference: untreated control]

**4.2. Suppressing the dissemination of malignant cells** 

behavior of the malignant cells.

The main danger of malignancies is the metastases, attacking the organs which are crucial for life. When the tumor grows somewhere without endangering the important systems like the respiratory system, central nervous system, cardiovascular system, etc., it is not lifethreatening. These tumors are local (benign or early malignant), their elimination is possible. The real life-threatening danger is the malignancy, when the cells are disseminated from the tumor-lesion by the various transport systems (lymph, blood), or their effect becomes systemic by one of the general mechanisms of the organism.

The heavy life-threatening effect of metastases has been observed on statistical basis on colorectal adenocarcinoma collecting data for 15 years [342]. The long- term (10 years) survival was around 90% when no metastases were present, 60% in case of regional metastases and only 15% when distant metastases were developed in the patient. The bloodtransported cells can be blocked easily by the brain, lung, kidney, liver, etc., causing fatality. The challenge of the treatments is to recognize the tumor early, to avoid the metastases, and/or to block the dissemination as much as possible.

In veterinarian clinical trial of dogs having osteosarcomas without evidences of metastases, the local radiation combined complementary with whole body hyperthermia was studied. The result was surprisingly bad [343], [344]: the combined treatment was not effective on the primer tumor, but rapid and massive metastases were developed in far distance organs including the lung. This blocked the research in this direction, the veterinarian application of the hyperthermia even in combined therapies was not plasticized in veterinary field.

Local Hyperthermia in Oncology – To Choose or not to Choose? 47

the primer tumor was locally treated

**4.4. Some clinical results** 

[160].

**Figure 44.** Investigator: Prof. Dr. Seong Min Yoon, Institute: Division of Hematology-Oncology, Department of Internal Medicine, Samsung Changwon Hospital, Sungkyunkwan University, S.Korea Patient: SAsc, 72 y, male, Primer-tumor: Non-small cell lung cancer; Size: 9.5 cm right middle lobe, Metastases: in sentinel and distant lymph-nodes, Tumor-classification: cT2 cN2 M0, stage IIIB, Treatment: trimodal protocol: 28x1.7 Gy; support: 250 microgram Leukine and Oncothermia 6x; Only

Oncothermia has a long-time history with large number of documented case reports and clinical trials [160]. During more than 20 years 43 studies were performed involving more than 2000 patients altogether from 14 clinics in 4 countries (see Table 1.) Details of the clinical effects are summarized in the publications as well as in the specialized monograph

The clinical trials of oncothermia are dominantly retrospective. To develop randomized clinical trials is a challenge for patients. Patients do not agree to be in the control-arm at any case. In most of the cases they are registered for oncothermia because the other methods (conventional gold standards) failed. In these cases progression could occur anyway due to drug-resistance, organ-overload (kidney, liver, etc.), tumor-relapses, psycho-resistance, etc.

The advanced cases at the conditions described above emphasize not only the complexity of the individual situation of patients, but also underlines the fact that oncothermia is applied as the facility of the "no other is possible" many time hopeless cases providing over 3rd line treatment approach. This high-line treatment process is in general palliation (the first goal is to provide acceptable quality of life), which is an important factor for oncothermia as well. However oncothermia even in these advanced situations has curative value, and makes curative therapy in 3rd-line or over. The professional literature clearly shows the rare facility of the evidence-based clinical trials for these high-line treatments. Other evidences have to

One of the interesting, and so far not completely understood process, is the systemic effect of the local treatments called abscopal (out of the target) or bystander effect [345]. This phenomenon shows a systemic effect only by local treating, see Figure 42. The effect was shown in mice experiments [346], see Figure 43*,* and also in human, see Figure 44*.*, [347].

**Figure 42.** The mice have two distant tumors in left and right femoral region. The growths of the tumors are equal. When we treat the mice systemically with immune supporters, no change can be seen. When we treat the A tumor locally with oncothermia, that tumor does not grow so quickly as the reference C. However, when we apply the systemic immune therapy and the local oncothermia for the only A-lesion, surprisingly, the C lesion is also suppressed

**Figure 43.** E. coli LPS sc. to the dorsal region of the animal 24 h before the oncothermia treatment. 100ug LPS in 100uL Salsol solution. 30 min oncothermia with pink noise AM modulation (41-42°C tumor core temperature) Sampling: animals were sacrificed 72 h after the treatment

Local Hyperthermia in Oncology – To Choose or not to Choose? 47

**Figure 44.** Investigator: Prof. Dr. Seong Min Yoon, Institute: Division of Hematology-Oncology, Department of Internal Medicine, Samsung Changwon Hospital, Sungkyunkwan University, S.Korea Patient: SAsc, 72 y, male, Primer-tumor: Non-small cell lung cancer; Size: 9.5 cm right middle lobe, Metastases: in sentinel and distant lymph-nodes, Tumor-classification: cT2 cN2 M0, stage IIIB, Treatment: trimodal protocol: 28x1.7 Gy; support: 250 microgram Leukine and Oncothermia 6x; Only the primer tumor was locally treated
