**3. Discussion**

Several randomized studies showed a significant increase in the overall and disease-free survival of GBM patients receiving LHT [75, 76]. Seventy-nine patients with newly diagnosed glioblastoma were randomized to receive either interstitial high-frequency hyperthermia in combination with brachytherapy or interstitial brachytherapy alone. The median time to disease progression was longer and the median overall survival was higher in the LHT + brachytherapy group than in the group with brachytherapy alone (35 vs. 57 weeks and 76 vs. 85 weeks, respectively) [75]. Based on the study, interstitial high-frequency hyperthermia for GBM treatment was approved by the Food and Drug Administration (FDA). However, the invasive nature of LHT limited its use by two procedures to prevent complications associated with the installation of antennas and determined the impossibility of combining LHT with external beam radiation therapy.

The effectiveness of magnetic hyperthermia combined with fractionated stereotactic radiotherapy for recurrent GBM was evaluated in a large two-center study [76]. Patients underwent stereotaxic intratumoral injection of a fluid containing magnetic nanoparticles (MNPs), followed by heating in an alternating magnetic field. Side effects were moderate, and no serious complications were observed. The median overall survival time from the diagnosis was 23.2 months. Thus, thermotherapy involving the use of alternating magnetic field in conjunction with MNPs was proven to be an effective method for treating patients with GBM. However, current limitations to the use of magnetic hyperthermia for thermotherapy of GBM patients include the high concentration of MNPs required to generate hyperthermia precluding the use of MRI, as well as the effective delivery of the MNPs [77].

selective and sustained rise of serum alkaline phosphatase (ALP) activity that was noted in 13 (43.3%) patients. When the level of serum ALP activity was 2.5 times higher than the normal limits, chemotherapy temporarily stopped, and the correction with hepatic protectors was

Hematologic toxicity in the form of grade 1/2 leukopenia, grade 1/2 thrombocytopenia, and grade 1 anemia was observed in 10 (33.3%) patients. Grade 3/4 leukopenia and thrombocytopenia were diagnosed in two (6.7%) patients. Clinical manifestations of grade 3/4 hematological toxicity were characterized by increased hemorrhage, microhematuria, and thrombocytopenic purpura. In one patient, hematoma formation in the tumor bed required surgery. There were no cases of febrile neutropenia. In the cases of grade 3/4 hematologic toxicity, chemotherapy with a reduced dose of temozolomide continued after achieving absolute neutrophil count of >1500 cells/μl and platelet count of >100,000 cells/μl. There were no cases

Grade 1–2 infectious complications after the completion of chemotherapy were revealed in three (10%) patients. These complications were manifested by chronic pyelonephritis, bronchitis, and oropharyngeal candidiasis and were managed by antibacterial and antifungal therapy. Within a month after completion of TCRT, two patients developed severe infections (pneumonia), requiring hospitalization and prescription of antibiotic therapy. Both patients

Acute radiation-induced skin damage was observed in all patients. Allopecia was observed in 29 (96.7%) patients, and a second-degree skin radiation reaction was observed in one case (3.3%). Complications associated with hyperthermia in the form of thermal injury of skin (up to 2 cm in diameter) were diagnosed in three (10%) patients. They did not cause deterioration in the physical status of patients. Treatment was conservative, and interruption or cessation of treatment was not required. One patient developed inconsistency of a postoperative scar with the formation of a cerebrospinal fluid leak. In this case, the excision and suture of the liquor fistula were performed, liquorrhea was stopped, and TCRT was successfully completed.

Several randomized studies showed a significant increase in the overall and disease-free survival of GBM patients receiving LHT [75, 76]. Seventy-nine patients with newly diagnosed glioblastoma were randomized to receive either interstitial high-frequency hyperthermia in combination with brachytherapy or interstitial brachytherapy alone. The median time to disease progression was longer and the median overall survival was higher in the LHT + brachytherapy group than in the group with brachytherapy alone (35 vs. 57 weeks and 76 vs. 85 weeks, respectively) [75]. Based on the study, interstitial high-frequency hyperthermia for GBM treatment was approved by the Food and Drug Administration (FDA). However, the invasive nature of LHT limited its use by two procedures to prevent complications associated with the installation of antennas and determined the impossibility of combining LHT with

of chemotherapy termination because of hematological toxicity.

176 Glioma - Contemporary Diagnostic and Therapeutic Approaches

received dexamethasone at a dose of 16 mg/day intramuscularly.

performed.

**3. Discussion**

external beam radiation therapy.

Modern systems for performing deep LHT allow for noninvasive heating of the tumor. In such systems, the electrical parameters of the circuit are automatically measured and individually adjusted to ensure control and high efficiency of the procedure. Temperature monitoring in tumor tissue is provided by calculation based on the measurement of absorbed energy and tissue impedance [66, 68].

There are a number of disadvantages of LHT: the excessive heating of subcutaneous fat, instability in a radiofrequency field and its dependence on the size of electrodes, their location, distance between them, and on the dielectric parameters of tissues, as well as the ease of the formation of the "hot spots," that is, the maximum electrical field in places with a high dielectric contrast [64, 78, 79].

There are published data indicating that the conductivity of the cerebrospinal fluid is at least four to six times higher than that of the gray and white matter. Thus, it is reliable to predict the presence of "hot spots" along the gray matter-cerebrospinal fluid (CSF) boundary, as well as along white matter-CSF boundary. Moreover, the induced electric field distribution is highly nonuniform. The electric field direction plays a significant role: the internal and near-surface electric field is higher in a tissue with low conductivity and lower in a tissue with high conductivity. As a result of tissue heterogeneity, the electric field in the brain does not decrease smoothly with distance from the transducers, as it would in a homogeneous tissue. In addition, electric field "hot spots" can occur far from the arrays, giving rise to a complex spatial distribution [80, 81].

This nonuniformity of the electric field determines high safety requirements for LHT, as it has a number of negative effects on neuronal structures and functions, causing disturbances in electrochemical depolarization, transmembrane ion transport, and destruction of cellular signaling mechanisms and mitochondrial functions. Despite the fact that irreversible changes in the protein structure occur at temperatures above 40°C [55, 56], this temperature threshold also activates heat shock proteins to increase thermal tolerance and enhance cell protection [82]. Since irreversible changes in normal nerve tissue are detected after hyperthermia at 42–42.5°C for 40–60 min [56, 57], the brain temperature should not exceed 42°C.

The attempts to use noninvasive magnetic resonance thermometry during transcranial radiofrequency LHT were unsuccessful, because it was impossible to combine an electromagnetic LHT device with an MRI system. Invasive thermometry for LHT is time-consuming, uncomfortable, and risky for the patient. Considering these data, we conducted a study simulating radiofrequency deep LHT using a realistic bioequivalent phantom. Results of thermometry showed that the temperature in the normal brain substance and cerebrospinal fluid did not exceed the physiologic parameters. The rise in the tumor temperature enhanced the efficacy of radiotherapy [83].

hyperthermia showed an increase in progression-free survival rates. Overall survival rates also tended to increase. Given the absence of severe complications, it is necessary to continue

The work has been financially supported by the Fundamental Research Program of the

1 Cancer Research Institute, Tomsk National Research Medical Center of the Russian

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, Olga V. Gribova1

, Irina A. Miloichikova1,3,

Concurrent Thermochemoradiotherapy in Glioblastoma Treatment: Preliminary Results

, Evgeny L. Choynzonov1,2,

http://dx.doi.org/10.5772/intechopen.76264

179

research to achieve statistically significant results.

Russian Academy of Sciences, project No. 093.

Nataliya D. Turgunova1,3 and Polina V. Surkova<sup>1</sup> \*Address all correspondence to: ranigor@mail.ru

2 Siberian State Medical University, Tomsk, Russia

Academy of Sciences, Tomsk, Russia

10.1007/978-3-319-28305-0\_7

10.1002/ana.22425

\*, Valery A. Novikov<sup>1</sup>

, Evgeny G. Grigoryev1

3 National Research Tomsk Polytechnic University, Tomsk, Russia

Tumors of Head and Neck. 2014;**3**:12-20 [in Russian]

**Acknowledgements**

**Author details**

Anastasiya I. Ryabova<sup>1</sup>

Zhanna A. Startseva<sup>1</sup>

**References**

Several clinical studies on transcranial radiofrequency hyperthermia for relapsed malignant brain tumors showed a low frequency of objective response (from 7 to 25% of cases) and the median overall survival time of 6–9 months after the onset of hyperthermia [84–86]. It was difficult to determine the effectiveness of treatment, since there were no data on the overall survival from the time of surgical treatment.

A preliminary analysis of the results of this uncontrolled cohort clinical trial showed that at a median follow-up of 12 months, the median progression-free survival was 9.6 months in patients who received TCRT (CI 95%: 7.2–19.0 months). These results were better than those described in the randomized study conducted by Stupp [30], who reported that the median disease-free survival time was 6.9 months (95% CI: 5.8–8.2 months) and 7.1 months (95% CI: 5.9–8.2 months) in GBM patients treated with Stupp regimen and tumor-treating fields, respectively [30, 37]. The median overall survival time of patients included in the study was 23.4 months. However, the result was not statistically significant because the median follow-up was up of 12 months.

Given a small number of patients included in the study, the evaluation of molecular-genetic prediction factors (IDH mutations and MGMT methylation) was important to avoid errors associated with a disproportionate number of patients with a favorable prognosis. The molecular-genetic features of tumors in patients enrolled in the study could not be the cause of improved survival. However, the study demonstrated a high frequency of subtotal tumor resections, which was a negative predictor factor [1].

Since radiofrequency hyperthermia was administered locally, an increase in the systemic side effects of chemotherapy compared with the frequency described in the population was not determined. The appearance of neurologic toxicity during chemotherapy with temozolomide not described in the previous studies [30] was more likely to be associated with an increase in edema and ischemic disorders. This was confirmed by the fact that neurological toxicity was mainly observed during the second course of chemotherapy, when external beam radiation dose accumulated. However, none of the patients had evidence of ischemic stroke.

Concurrent hyperthermia and chemoradiotherapy did not result in an increased frequency of local injuries associated with transcranial local radiofrequency hyperthermia [79]. However, it is necessary to pay attention to the fact that during TCRT, one patient developed a fistula in the area of a postoperative scar, which indicated an impairment of reparative processes.
