**4.4. Some clinical results**

46 Hyperthermia

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.

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

**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

only A-lesion, surprisingly, the C lesion is also suppressed

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 [160].

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

be shown when randomized controlled trials are not possible, [348]. The challenges of evaluation appear forcefully in case of patients with advanced stages having inoperable (or partly resected) tumors, having relapsed malignancies, patients who are resistant on the gold-standard treatments, etc. Oncothermia is facing to this challenge as well.

Local Hyperthermia in Oncology – To Choose or not to Choose? 49

 Special cases are treated on Intend-to-Treat population. This makes the patient selection not objective enough, but the dominantly metastatic patient's spectrum compensates for this lack of selection. In this case, we have an automatic selection of advanced (many

 The generally low quality of life (QoL) in combination of supportive therapies weaken the measurability of oncothermia alone. However, due to the fact that oncothermia is not proposed as monotherapy, the combination objectively measures the benefit, if the

 The patients are treated with oncothermia in their very advanced, metastatic states. The local oncothermia treatment, of course, concentrates on definite localizations, (primary or metastatic) which again lowers the full measurability of the oncothermia in the development of the cancer. This is the main reason why oncothermia measures first of all the overall survival rates, which are good objective parameters of the treatment

 The quality of life (QoL) of the patients is an important characteristic of such a method as oncothermia. In a generally controlled and randomized study a trial effect exists [356], which is not the case in oncothermia applications. However, it could be negative outcome, that in a strict competitive market the opinions are not independent and objective [357]

On the above bias structure the characteristics of the clinical studies could be described as – Single arm, open label, observational for intention-to-treat (ITT) population, dominantly for the patients in late/advanced stages, where the conventional methods have failed. Mostly the survival rate was the studied endpoint. The inclusion criteria were the inoperable and in progression after chemo- and/or radio-therapy. Exclusions were only the well-known, above

The oncothermia challenge is its use when the conventional treatments are unsuccessful. In consequence, its effect could be active only in a small (last) fraction of the overall survival. When patients have long overall survival by the conventional treatments alone, oncothermia is applied only in the last stage of the disease so objectively the life-elongation by

To make an objective evaluation, we have special considerations how to get the evidences from the available information pool and find the objective evidences. It is a complex challenge, having four basic approaches. These methods highlight the objective information

1. **Fast course case comparison.** Use the survival of the rapid, fast course cases (most advanced, drastically quickly developing cases) in comparison with large databases. (Only the survival is considered as relevant parameter, the clinical outcomes

2. **Comparison of clinics.** Compare the obtained data of the independent clinics, using the

3. **Quality of life comparison.** Collect the data about the quality of life and the adverse

and their parallel results make the obtained data evidence-based. The five legs are:

and of course the conflict of interest could make considerable bias [358], [359].

supportive therapies alone would not be successful at all.

times terminal) cases.

efficacy in general.

described contraindications of oncothermia.

(responses) are not studied as evidences.)

effects limiting the application of oncothermia.

same protocol for the same cohort.

oncothermia can not be observed.

We have to make special attention evaluating of the clinical results performed by oncothermia. The complications make definite challenges to objective evaluation. The main challenges are:

	- Inoperable lesion
	- Radio-resistant
	- Chemo-resistant (refractory)
	- Improper blood-counts
	- Liver-failure
	- Kidney failure
	- Psycho-resistance

In most of the cases the complex combination of the above problems occurs. Due to these conditions, oncothermia is applied in higher line of the therapies. This sequence of the treatments is mostly determined by the individual decisions of the physicians [349], usually without having help from any evidence based statistical approvals.


 Special cases are treated on Intend-to-Treat population. This makes the patient selection not objective enough, but the dominantly metastatic patient's spectrum compensates for this lack of selection. In this case, we have an automatic selection of advanced (many times terminal) cases.

48 Hyperthermia

challenges are:

be shown when randomized controlled trials are not possible, [348]. The challenges of evaluation appear forcefully in case of patients with advanced stages having inoperable (or partly resected) tumors, having relapsed malignancies, patients who are resistant on the

We have to make special attention evaluating of the clinical results performed by oncothermia. The complications make definite challenges to objective evaluation. The main

 Oncothermia is applied in higher (usually third and subsequent) treatment-lines, boosting or resensitizing the effect of the conventional therapies. Oncothermia is mostly applied in cases when the conventional therapies fall. In most of the cases oncothermia

In most of the cases the complex combination of the above problems occurs. Due to these conditions, oncothermia is applied in higher line of the therapies. This sequence of the treatments is mostly determined by the individual decisions of the physicians [349],

 Usually it is applied in palliative care; many patients are in terminal phase. This patient care has very limited statistical evidence based trials; the medical decision-making

 Only few controlled randomized clinical trials are available for oncothermia. The results have to be concluded from observational studies and from the historical and data-base comparisons. USA- and EU-databases (SEER [352], Eurocare [353]) are mostly used. Due to the not solved problem between the hypothesis check confidence of evidence based medicine and the observational studies [354], [355], this data-comparison is acceptable. Make the result as objective as they could be, we compared the collected results of the same localizations and the same protocols from various clinics. The

common significant difference from the databases can be accepted as evidence. In the case of long-survivals, we have to consider, that oncothermia is taken only in a small fraction of the overall survival. The patients are treated by oncothermia in their definite late stages, after prognosis "no curative help" by continuing the gold-standards alone. In consequence, the long overall survival generally is not the result of the oncothermia, but the selection of the patients in their end. Oncothermia effect in these cases can be negligible, irrespective of its real efficacy. The chance to measure the efficacy is the first year survival rate (%), when the patients with the most aggressive kind of the given cancer do not survive the following year after the diagnosis. If they start the oncothermia in the first year, the survival-rate result can be an objective sign of

usually without having help from any evidence based statistical approvals.

processes are usually well tailored to the individual patients [350], [351].

gold-standard treatments, etc. Oncothermia is facing to this challenge as well.

therapy is applied when the patient has/is




the efficacy.


On the above bias structure the characteristics of the clinical studies could be described as – Single arm, open label, observational for intention-to-treat (ITT) population, dominantly for the patients in late/advanced stages, where the conventional methods have failed. Mostly the survival rate was the studied endpoint. The inclusion criteria were the inoperable and in progression after chemo- and/or radio-therapy. Exclusions were only the well-known, above described contraindications of oncothermia.

The oncothermia challenge is its use when the conventional treatments are unsuccessful. In consequence, its effect could be active only in a small (last) fraction of the overall survival. When patients have long overall survival by the conventional treatments alone, oncothermia is applied only in the last stage of the disease so objectively the life-elongation by oncothermia can not be observed.

To make an objective evaluation, we have special considerations how to get the evidences from the available information pool and find the objective evidences. It is a complex challenge, having four basic approaches. These methods highlight the objective information and their parallel results make the obtained data evidence-based. The five legs are:


4. **Create a quasi-control arm**. Patients having no benefit from oncothermia could form a quasi-arm for control. The "no benefit" category could be defined when the patient survival is short from the time of the first oncothermia treatment.

Local Hyperthermia in Oncology – To Choose or not to Choose? 51

Median overall survival of

responding patients (m)

Median overall survival of

non-responding

patients (m)

Reference

[373]

[376]

[377]

[373]

Study

Refractory bone-metastases study, Phase

Colon cancer study, , Phase II, prospective, three arms, randomized

Rectum cancer study, Inoperable→operable, Phase II,

Phase II, retrospective

Phase II, retrospective

Phase II, retrospective

Kidney cancer study, Phase II,

Liver metastases from various origin,

Liver metastases from various origin, Comparative study, Phase II, retrospective

Liver metastasis form colorectal origin,

Liver metastasis form colorectal origin,

retrospective

retrospective

II, retrospective

Number of patients

Rectum 92 57.1 58 21 Colon 114 44.2 109.8 23.2

Clifford TCM 53 75 Monotherapy 50 81 Combined therapy 51 91

With radiotherapy 16 81 With chemotherapy 8 38 Monotherapy 4 25

Passive arm 53 11 Active arm 80 91 24.1 With chemotherapy 30 80 21.5 Monotherapy 50 92 24.4

1st year survival (%)

Breast cancers 103 97.1 52.1 45 274.8 10.9 [160] ,

Colorectal cancer () 218 84.9 28.5 [160] , [373] Sigma 12 34.1

Esophagus study, Phase II, retrospective 12 41.7 28.5 35 29.4 8.5 [160],

Median overall survival (m)

Resposnding patients/ratio

(%)

11 90.9 [374]

154 [375]

7 71 [378]

39 84.6 35.9 48 78.4 33.7 [160],

25 20.5 [379]

28 [374]

80 86.0 24.1 [380]

15 23 80 [381]

5. **Parametric evaluation.** Use the available latest statistical knowledge to find the relevant parameters of the survivals and use the best fit of the parametric distribution for evaluation.



evaluation.

Study

Glioma (WHO IV) Study, Phase II,

Recurrent glioblastoma study, Phase II, retrospective,

Advanced, relapsed brain gliomas, Phase

Brain glioma WHO III-IV, Phase I, safety

Head and neck study, Phase II.

Bone-metastases, monotherapy,

Phase II, retrospective

prospective, two arms

II, retrospective

prospective

retrospective

4. **Create a quasi-control arm**. Patients having no benefit from oncothermia could form a quasi-arm for control. The "no benefit" category could be defined when the patient

5. **Parametric evaluation.** Use the available latest statistical knowledge to find the relevant parameters of the survivals and use the best fit of the parametric distribution for

1st year survival (%)

Brain gliomas 27 86.2 23.6 43 66.2 18.2 [360],

Brain-glioma study Phase II, Retrospective 140 71.7 [362], Astrocytoma [363] 40 25.8 80 40.2 20.2

Glioma study, Phase II, retrospective 36 60.0 [366]

Glioma study, Phase II, retrospective 179 [367]

Median overall survival (m)

Resposnding patients/ratio

(%)

45 15 [160],

19 68.0 21.8 59 32.6 12.4 [365]

12 10 25 [368]

15 [369],

64 92.2 26.1 [160],

6 100 40.1 [160],

Median overall survival of

responding patients (m)

Median overall survival of

non-responding

patients (m)

Reference

[361]

[364]

[370], [371], [372]

[373]

[373]

survival is short from the time of the first oncothermia treatment.

Number of patients

Glioblastoma 92 16 73 21.9 13.1

Active arm 9 65 14.5 43 66.2 18.2

Diffuse astrocytoma 8 52.9

Passive arm 36 40 11

Astrocytoma 9 106 Glioblastoma 27 20

Astrocytoma 53 100 103 Glioblastoma 126 76 16


Local Hyperthermia in Oncology – To Choose or not to Choose? 53

Median overall survival of

responding patients (m)

Median overall survival of

non-responding

patients (m)

Reference

Study

Soft tissue sarcoma study, Phase II,

Urinary bladder cancer study, Phase II,

*4.4.1. Comparison of brain studies* 

(more than 25% increase) of oncothermia.

**Table 1.** Summary of the studies made by oncothermia treatment

treatments of the aggressive pancreas tumors.

Stomach cancer study, Phase II,

retrospective

retrospective

retrospective

[397] as well.

weighted mean.

Number of patients

1st year survival (%)

Esophagus study, Phase II, retrospective 7 6.8 100 [378]

We show, as spectacular examples, two important categories in comparison with the literature: the sensitive extra-cranial (non-invasive) brain glioma treatments and the

Some more open-label, single arm, monocentric, retrospective and intention-to-treat frame oncothermia studies were published at professional conferences, [393], [394], [395], [396],

The comparison of the median survivals for anaplastic astrocytoma and for glioblastoma multiform obtained by different clinics shows good correlations. Their glioblastoma multiform (WHO IV) results are ranging from 14-25.2 months median survival (weighted mean is 19.1 months), while the literature ([352], [398], [399], [400]), uses only 10.5 months

According to the RTOG classifications [401], we divided the patients into two groups: age under- and over-50 years. By this division in cases of glioblastoma oncothermia has 14.4 and 19 months for over and under 50 years of ages, [397]; while RTOG has 9.7 and 13.7 months, [401]; respectively. The method shows successful applications in pediatric cases as well, [402]. The results are pretty coherently above the statistical values of the large databases SEER [352] and the gold-standard radiotherapy (RT) and RT+PCV [398]. The results of oncothermia show

The first-year survival rates compared to SEER [352] and EUROCARE [353] databases as well as to the recent chemotherapy of Temozolomide also show significant advantages

advantages in comparison with the publications on Temozolomide [399], [400], too.

Median overall survival (m)

Resposnding patients/ratio

(%)

16 100 35.9 31 115.3 31.3 [160]

68 58.9 14.4 [160]

18 85.0 36.5 73 42.0 22.6 [160]


**Table 1.** Summary of the studies made by oncothermia treatment

We show, as spectacular examples, two important categories in comparison with the literature: the sensitive extra-cranial (non-invasive) brain glioma treatments and the treatments of the aggressive pancreas tumors.
