**1. Introduction**

The median survival time of patients diagnosed with glioblastoma multiforme (GBM) without any treatment is up to 3 months after diagnosis [1]. Modern multimodal treatment including surgery and adjuvant chemoradiotherapy with subsequent chemotherapy results in longer survival. However, the median survival does not exceed 2 years [2–4]. According to population-based studies, the overall 1-, 2-, and 3-year survival rates are approximately 40, 15, and 7–8%, respectively, and the 5-year survival rates range between 0.05 and 5.5% [1, 5–7].

Multimodal treatment including surgery and adjuvant chemoradiotherapy with subsequent chemotherapy is the mainstream treatment modality for GBM. Surgery provides material for histological and genetic examinations as well as reduces intracranial pressure in most patients with intracranial hypertension. The gross total or the subtotal tumor resection is an important prognostic factor. Surgery followed by antitumor therapy increases survival rates of these patients [19]. However, aggressive surgery within eloquent areas can worsen the neurological outcome and performance status of patients, thus decreasing overall survival [20, 21]. Moreover, the infiltrative tumor growth beyond the contrast-enhancing areas and the presence of tumor cells in the areas of perifocal edema dictate the need for further antitumor therapy [22]. Survival of patients treated with surgery alone is less than

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167

Adjuvant radiation therapy at the standard total dose of 60 Gy prolonged overall survival to 10 months. However, tumor recurrence affected about 90% of patients who received radiation therapy [1, 24]. The use of hyperfractionation or dose escalation beyond 60 Gy conferred no survival benefit. Dose escalation up to 90 Gy led to a decrease in 1- and 2-year survival rates [25, 26]. Attempts to escalate the total dose using brachytherapy and radiosurgery also

In the randomized study, concurrent chemoradiation therapy with subsequent adjuvant chemotherapy with temozolomide (TMZ) led to an increase in the overall survival of GBM patients only up to 14.5 months [30]. The use of anti-angiogenic therapy (bevacizumab) in patients with recurrent glioblastomas resulted in survival benefit, with the median overall survival rate from 19.6 to 21.5 months [4, 31, 32]. However, two large randomized phase III trials showed no improvement in overall survival between patients with newly diagnosed GBM receiving and not receiving bevacizumab. The median overall survival of these patients

In recent decades, new approaches to GBM treatment including new drugs, and various biological and physical modifiers have been actively developed. Studies on cell cultures and animal models have shown that low intensity and 200 kHz alternating electric fields have antitumor activity due to mitotic arrest and apoptosis by disrupting mitotic spindle formation during metaphase and causing dielectrophoretic movement of polar molecules during cytokinesis [34, 35]. In a large prospective randomized phase III trial, tumor-treating fields (TTFields) were compared with standard chemotherapy for patients with recurrent GBM. The trial indicated that TTFields had an equivalent efficacy when compared with palliative chemotherapy; however, the quality of life was better in the TTFields group [36]. In patients who underwent surgery and standard chemoradiotherapy, TTFields administered concomitantly with temozolomide significantly improved the median overall survival compared with temozolomide alone (20.5 vs. 15.6 months) [37]. Based on the results obtained, TTFields were included in the standard for the treatment of newly diagnosed GBM in the

Experimental studies have shown that high temperatures can directly induce damage to glioma cells and result in radio- or chemosensitization [39–43]. Unlike healthy tissues, tumors have an increased thermal sensitivity, which is caused by biophysical differences between

showed no benefit over the standard external beam radiation therapy [27–29].

6 months [23].

did not exceed 17 months [3, 33].

United States [38].

Glioblastoma multiforme is divided into primary and secondary morphological subtypes. Primary GBM accounts for 80–90% of malignant gliomas. They arise de novo and are common in older adults (mean age 55–62 years). Secondary GBMs represent progression from astrocytoma or oligodendroglioma. They manifest in younger adults (mean age 40–45 years) and have a lesser degree of necrosis [8–10]. Various genetic disorders characteristic of the primary and secondary subtypes of glioblastoma have been identified, of which the presence of IDH1/2 mutation is the most reliable molecular marker that is determined in all cases of secondary GBMs, while only about 5% of primary glioblastoma have IDH mutations [1, 11–13]. Several studies have shown that IDH1/2 mutations are positive molecular-genetic prognostic markers. IDH1/2 mutations make the tumor cells more susceptible to genetic rearrangements caused by oxidative stress, thus being a driving force for the development of gliomas. On the other hand, tumor cells containing IDH1 mutations become more susceptible to antitumor therapy, which confers cytotoxicity through the generation of reactive oxygen species [14]. Patients with glioma harboring IDH mutation show a significantly better survival than those with an IDH wild-type glioma (24–36 months vs. 9–15 months). The 5-year survival rate is nearly zero for patients with primary GBM and up to 80% for patients with secondary GBM [12, 15]. In accordance with the updated 2016 edition of the World Health Organization (WHO) Classification of Tumors of the Central Nervous System (CNS), glioblastomas are classified into glioblastoma, IDH wild-type, glioblastoma, IDH-mutant, and glioblastoma NOS. The not-otherwise specified (NOS) is reserved for situations where there is either insufficient material or the facilities for testing for the specific genotype are not available [16].

Promoter methylation of the gene encoding the DNA repair enzyme O(6)-methylguanine DNA methyltransferase (MGMT) is a favorable molecular-genetic prognostic/predictive marker for patients with GBM.Approximately 50% of newly diagnosed GBMs have MGMT gene promoter methylation. MGMT promoter methylation correlates with a low level of MGMT gene expression and may be a predictive marker of sensitivity to alkylating agents, resulting in an almost twofold increase in the median survival after chemoradiotherapy [8, 17]. In addition, the presence of mMGMT is associated with an improved survival of GBM patients regardless of the treatment strategy and reflects a generally more favorable tumor phenotype [15]. The presence of 1p19q co-deletion (loss of heterozygosity on the 1p and 19q chromosome arms) is typical for oligodendroglial tumors and indicates a more favorable prognosis. However, in patients with glioblastoma, the 1p/19q co-deletion may not be associated with survival benefit [18]. The identification of molecular-genetic biomarkers considerably increased our current understanding of glioma genesis. However, further studies are required to identify new biomarkers to define the clinical and biologic subtypes of glioblastoma [1, 8, 13].

Multimodal treatment including surgery and adjuvant chemoradiotherapy with subsequent chemotherapy is the mainstream treatment modality for GBM. Surgery provides material for histological and genetic examinations as well as reduces intracranial pressure in most patients with intracranial hypertension. The gross total or the subtotal tumor resection is an important prognostic factor. Surgery followed by antitumor therapy increases survival rates of these patients [19]. However, aggressive surgery within eloquent areas can worsen the neurological outcome and performance status of patients, thus decreasing overall survival [20, 21]. Moreover, the infiltrative tumor growth beyond the contrast-enhancing areas and the presence of tumor cells in the areas of perifocal edema dictate the need for further antitumor therapy [22]. Survival of patients treated with surgery alone is less than 6 months [23].

**1. Introduction**

166 Glioma - Contemporary Diagnostic and Therapeutic Approaches

The median survival time of patients diagnosed with glioblastoma multiforme (GBM) without any treatment is up to 3 months after diagnosis [1]. Modern multimodal treatment including surgery and adjuvant chemoradiotherapy with subsequent chemotherapy results in longer survival. However, the median survival does not exceed 2 years [2–4]. According to population-based studies, the overall 1-, 2-, and 3-year survival rates are approximately 40, 15, and 7–8%, respectively, and the 5-year survival rates range between 0.05 and 5.5% [1, 5–7]. Glioblastoma multiforme is divided into primary and secondary morphological subtypes. Primary GBM accounts for 80–90% of malignant gliomas. They arise de novo and are common in older adults (mean age 55–62 years). Secondary GBMs represent progression from astrocytoma or oligodendroglioma. They manifest in younger adults (mean age 40–45 years) and have a lesser degree of necrosis [8–10]. Various genetic disorders characteristic of the primary and secondary subtypes of glioblastoma have been identified, of which the presence of IDH1/2 mutation is the most reliable molecular marker that is determined in all cases of secondary GBMs, while only about 5% of primary glioblastoma have IDH mutations [1, 11–13]. Several studies have shown that IDH1/2 mutations are positive molecular-genetic prognostic markers. IDH1/2 mutations make the tumor cells more susceptible to genetic rearrangements caused by oxidative stress, thus being a driving force for the development of gliomas. On the other hand, tumor cells containing IDH1 mutations become more susceptible to antitumor therapy, which confers cytotoxicity through the generation of reactive oxygen species [14]. Patients with glioma harboring IDH mutation show a significantly better survival than those with an IDH wild-type glioma (24–36 months vs. 9–15 months). The 5-year survival rate is nearly zero for patients with primary GBM and up to 80% for patients with secondary GBM [12, 15]. In accordance with the updated 2016 edition of the World Health Organization (WHO) Classification of Tumors of the Central Nervous System (CNS), glioblastomas are classified into glioblastoma, IDH wild-type, glioblastoma, IDH-mutant, and glioblastoma NOS. The not-otherwise specified (NOS) is reserved for situations where there is either insufficient material or the facilities for testing for the specific genotype are not available [16].

Promoter methylation of the gene encoding the DNA repair enzyme O(6)-methylguanine DNA methyltransferase (MGMT) is a favorable molecular-genetic prognostic/predictive marker for patients with GBM.Approximately 50% of newly diagnosed GBMs have MGMT gene promoter methylation. MGMT promoter methylation correlates with a low level of MGMT gene expression and may be a predictive marker of sensitivity to alkylating agents, resulting in an almost twofold increase in the median survival after chemoradiotherapy [8, 17]. In addition, the presence of mMGMT is associated with an improved survival of GBM patients regardless of the treatment strategy and reflects a generally more favorable tumor phenotype [15]. The presence of 1p19q co-deletion (loss of heterozygosity on the 1p and 19q chromosome arms) is typical for oligodendroglial tumors and indicates a more favorable prognosis. However, in patients with glioblastoma, the 1p/19q co-deletion may not be associated with survival benefit [18]. The identification of molecular-genetic biomarkers considerably increased our current understanding of glioma genesis. However, further studies are required to identify new biomarkers

to define the clinical and biologic subtypes of glioblastoma [1, 8, 13].

Adjuvant radiation therapy at the standard total dose of 60 Gy prolonged overall survival to 10 months. However, tumor recurrence affected about 90% of patients who received radiation therapy [1, 24]. The use of hyperfractionation or dose escalation beyond 60 Gy conferred no survival benefit. Dose escalation up to 90 Gy led to a decrease in 1- and 2-year survival rates [25, 26]. Attempts to escalate the total dose using brachytherapy and radiosurgery also showed no benefit over the standard external beam radiation therapy [27–29].

In the randomized study, concurrent chemoradiation therapy with subsequent adjuvant chemotherapy with temozolomide (TMZ) led to an increase in the overall survival of GBM patients only up to 14.5 months [30]. The use of anti-angiogenic therapy (bevacizumab) in patients with recurrent glioblastomas resulted in survival benefit, with the median overall survival rate from 19.6 to 21.5 months [4, 31, 32]. However, two large randomized phase III trials showed no improvement in overall survival between patients with newly diagnosed GBM receiving and not receiving bevacizumab. The median overall survival of these patients did not exceed 17 months [3, 33].

In recent decades, new approaches to GBM treatment including new drugs, and various biological and physical modifiers have been actively developed. Studies on cell cultures and animal models have shown that low intensity and 200 kHz alternating electric fields have antitumor activity due to mitotic arrest and apoptosis by disrupting mitotic spindle formation during metaphase and causing dielectrophoretic movement of polar molecules during cytokinesis [34, 35]. In a large prospective randomized phase III trial, tumor-treating fields (TTFields) were compared with standard chemotherapy for patients with recurrent GBM. The trial indicated that TTFields had an equivalent efficacy when compared with palliative chemotherapy; however, the quality of life was better in the TTFields group [36]. In patients who underwent surgery and standard chemoradiotherapy, TTFields administered concomitantly with temozolomide significantly improved the median overall survival compared with temozolomide alone (20.5 vs. 15.6 months) [37]. Based on the results obtained, TTFields were included in the standard for the treatment of newly diagnosed GBM in the United States [38].

Experimental studies have shown that high temperatures can directly induce damage to glioma cells and result in radio- or chemosensitization [39–43]. Unlike healthy tissues, tumors have an increased thermal sensitivity, which is caused by biophysical differences between healthy and tumor cells associated with a low efficiency of ATP production in tumor cells. Under conditions of ATP deficiency, the active transport of ions through the cell membrane is violated and its membrane potential is reduced, thus resulting in higher conductivity and dielectric permittivity in cancer tissue than in normal tissue [44, 45].

has been found to act as the main stimulator of HSP expression and immune stimulation. Hyperthermia treatment at 43.5°C enhances cytotoxicity by antibodies monospecific to specific tumor antigens, suggesting that LHT is capable of enhancing specific immune responses

Concurrent Thermochemoradiotherapy in Glioblastoma Treatment: Preliminary Results

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

169

A simplified view that LHT can lead to immune suppression via induction of thermo-tolerance in tumor cells has been accepted for many years [52, 58]. It is becoming increasingly apparent that in addition to general and limited immune suppression, LHT treatment can lead to specific activation of the immune system by inducing certain modifications of the tumor cell surface and various forms of cell death. Studies have shown that even local exposure to LHT can lead to systemic tumor control by activating the innate immune system [50, 52, 58]. Despite convincing biological justifications, the enthusiasm for the clinical use of LHT as monotherapy has decreased due to the fact that heating of human tumors to cytotoxic temperatures between 42 and 45°C is difficult or almost impossible. In living tissues heated for more than a few minutes, convective heat losses occur near large blood vessels (diameter of ~0.5 mm). Such blood vessels act as a heat sink, and one can expect a temperature drop of up to 50% [63]. Blood flow provides up to 90% of heat removal. A 10-fold increase in blood flow in response to LHT can occur due to the compensatory expansion of arteries and intensive

Intratumoral blood flow varies considerably depending on the tumor type. Moreover, even within the same tumor, the distribution of the vasculature and blood flow is very heterogeneous. Contrary to the general notion that the blood flow in tumors is less than that in normal tissues, blood flow in many tumors, especially in small tumors, is actually greater than that in the surrounding normal tissues under normal conditions. Typically, the bloodstream of the tumor usually decreases as the tumor grows. While studies in small animals suggest that LHT induced a decrease in blood flow at 42–43°C, there is evidence that tumors in large animals and, more importantly, human tumors, are significantly less sensitive to LHT. In general, clinical studies do not suggest a reduction in tumor perfusion at temperatures up

An increased blood flow can increase tumor growth, as well as the risk of hematogenous metastases, suppressing the possible therapeutic effect of LHT [48, 52, 68]. However, a high blood flow can have the opposite effect: a high blood flow provides a more intensive exposure to chemotherapy and, through increased oxygenation, sensitizes tumor tissue to radiotherapy [69]. A mild temperature (39–42°C), which is not optimal for the induction of direct cell death or damage to the vascular system of the tumor, is effective in enhancing tumor response to radiation therapy or chemotherapy [70]. Many conditions that contribute to radioresistance, including hypoxia, acid medium, and S-phase of the cell cycle, either increase sensitivity to LHT or do not change it [50, 52, 70, 71]. LHT-induced increase in tumor perfusion leads to an

increased tumor tissue oxygenation and an increased tumor radiosensitivity [72].

Under the influence of LHT, both the intrinsic chemical activity of cytostatics and the degree of their penetration into cells increase due to the activation of membrane transport, and the direct effect of LHT is much higher in hypoxic tissues, in which chemoresistance is observed [47, 71].

against tumor-associated cell membrane antigens [58, 62].

perfusion, especially in normal tissues [64–66].

to 44°C [67].

As recognized in the early 1970s, the main molecular event underlying the biological effects of local hyperthermia (LHT) in a clinically significant temperature range (39–45°C) is protein damage, including denaturation, exposure to hydrophobic groups, and aggregation with proteins not directly altered by hyperthermia [46–48]. Hyperthermia (temperature above 43°C) causes a large number of macromolecular changes that lead to cell death through extensive protein denaturation and necrosis. Although significantly fewer macromolecular changes occur in the 40.5–42°C range, these changes are still numerous. They occur in different cell components and lead to apoptotic cell death [46, 48–50].

Protein aggregation and denaturation have a significant impact within the cell nucleus. Changes in nuclear proteins, especially those involved in DNA transcription, replication, and repair, cause the inhibition of replication forks and lead to chromosomal aberrations, genomic instability, abnormal chromosome segregation, and cell death [46, 47, 49–52]. Cell membranes are also extremely sensitive to heat stress due to the complex molecular composition of their lipids and proteins. Under the action of LHT, the gel-to-liquid crystal lipid phase transition occurs and the proteins lose their structure, thus resulting in an increased permeability of the cell membrane. The ion balance (Na+ , Mg2+, K+ , Ca2+) in cells and in the extracellular environment is changed, although these changes are not the main mechanism of hyperthermic cell death [49, 52].

Ion imbalance results in significant changes in the mitochondrial membrane potential and disturbance of mitochondrial respiration, causing an increase in the activity of oxygen radicals and a decrease in the level of oxygen consumption in malignant cells [52, 53]. Depolarization of the mitochondrial membrane and the resulting release of oxygen radicals change the oxidation-reduction status of cells and stability of proteins, increasing their sensitivity to LHT. The accumulation of lipid peroxidation changes the distribution of Ca2+ and activates the Ca2+ dependent apoptotic pathway. These effects contribute to the protein-unfolding effects of hyperthermia and contribute to effects observed in the nucleus [46, 49].

Irreversible changes in the structure of the protein appear to occur at a temperature of 40°C [54–57]. This temperature threshold also temporarily increases the activity of heat shock genes that encode heat shock proteins (HSPs). The effect of HSPs may depend on their location: intracellularly located HSPs have a protective function, including the correction of misfolded protein molecules, the prevention of aggregation, the transport of proteins, and the restriction of apoptosis. Intracellularly located Hsp70 can act as a cell survival protein by inhibiting the permeability of lysosomal membranes. It also protects tumor cells from monocytic cytotoxicity mediated by tumor necrosis factor [58]. However, HSPs may possess both anti-apoptotic (Hsp27, Hsp70, and Hsp90) and proapoptotic effects (Hsp60 and Hsp10) [59, 60]. Finally, cell death due to apoptosis can occur through various mechanisms and, perhaps, HSPs cannot provide protection against all these mechanisms [61]. In contrast to intracellular HSPs, membrane-bound and extracellular HSPs may have an immunostimulating effect [50]. Heat has been found to act as the main stimulator of HSP expression and immune stimulation. Hyperthermia treatment at 43.5°C enhances cytotoxicity by antibodies monospecific to specific tumor antigens, suggesting that LHT is capable of enhancing specific immune responses against tumor-associated cell membrane antigens [58, 62].

healthy and tumor cells associated with a low efficiency of ATP production in tumor cells. Under conditions of ATP deficiency, the active transport of ions through the cell membrane is violated and its membrane potential is reduced, thus resulting in higher conductivity and

As recognized in the early 1970s, the main molecular event underlying the biological effects of local hyperthermia (LHT) in a clinically significant temperature range (39–45°C) is protein damage, including denaturation, exposure to hydrophobic groups, and aggregation with proteins not directly altered by hyperthermia [46–48]. Hyperthermia (temperature above 43°C) causes a large number of macromolecular changes that lead to cell death through extensive protein denaturation and necrosis. Although significantly fewer macromolecular changes occur in the 40.5–42°C range, these changes are still numerous. They occur in different cell

Protein aggregation and denaturation have a significant impact within the cell nucleus. Changes in nuclear proteins, especially those involved in DNA transcription, replication, and repair, cause the inhibition of replication forks and lead to chromosomal aberrations, genomic instability, abnormal chromosome segregation, and cell death [46, 47, 49–52]. Cell membranes are also extremely sensitive to heat stress due to the complex molecular composition of their lipids and proteins. Under the action of LHT, the gel-to-liquid crystal lipid phase transition occurs and the proteins lose their structure, thus resulting in an increased permeability of the

ment is changed, although these changes are not the main mechanism of hyperthermic cell

Ion imbalance results in significant changes in the mitochondrial membrane potential and disturbance of mitochondrial respiration, causing an increase in the activity of oxygen radicals and a decrease in the level of oxygen consumption in malignant cells [52, 53]. Depolarization of the mitochondrial membrane and the resulting release of oxygen radicals change the oxidation-reduction status of cells and stability of proteins, increasing their sensitivity to LHT. The accumulation of lipid peroxidation changes the distribution of Ca2+ and activates the Ca2+ dependent apoptotic pathway. These effects contribute to the protein-unfolding effects of

Irreversible changes in the structure of the protein appear to occur at a temperature of 40°C [54–57]. This temperature threshold also temporarily increases the activity of heat shock genes that encode heat shock proteins (HSPs). The effect of HSPs may depend on their location: intracellularly located HSPs have a protective function, including the correction of misfolded protein molecules, the prevention of aggregation, the transport of proteins, and the restriction of apoptosis. Intracellularly located Hsp70 can act as a cell survival protein by inhibiting the permeability of lysosomal membranes. It also protects tumor cells from monocytic cytotoxicity mediated by tumor necrosis factor [58]. However, HSPs may possess both anti-apoptotic (Hsp27, Hsp70, and Hsp90) and proapoptotic effects (Hsp60 and Hsp10) [59, 60]. Finally, cell death due to apoptosis can occur through various mechanisms and, perhaps, HSPs cannot provide protection against all these mechanisms [61]. In contrast to intracellular HSPs, membrane-bound and extracellular HSPs may have an immunostimulating effect [50]. Heat

, Ca2+) in cells and in the extracellular environ-

, Mg2+, K+

hyperthermia and contribute to effects observed in the nucleus [46, 49].

dielectric permittivity in cancer tissue than in normal tissue [44, 45].

components and lead to apoptotic cell death [46, 48–50].

168 Glioma - Contemporary Diagnostic and Therapeutic Approaches

cell membrane. The ion balance (Na+

death [49, 52].

A simplified view that LHT can lead to immune suppression via induction of thermo-tolerance in tumor cells has been accepted for many years [52, 58]. It is becoming increasingly apparent that in addition to general and limited immune suppression, LHT treatment can lead to specific activation of the immune system by inducing certain modifications of the tumor cell surface and various forms of cell death. Studies have shown that even local exposure to LHT can lead to systemic tumor control by activating the innate immune system [50, 52, 58].

Despite convincing biological justifications, the enthusiasm for the clinical use of LHT as monotherapy has decreased due to the fact that heating of human tumors to cytotoxic temperatures between 42 and 45°C is difficult or almost impossible. In living tissues heated for more than a few minutes, convective heat losses occur near large blood vessels (diameter of ~0.5 mm). Such blood vessels act as a heat sink, and one can expect a temperature drop of up to 50% [63]. Blood flow provides up to 90% of heat removal. A 10-fold increase in blood flow in response to LHT can occur due to the compensatory expansion of arteries and intensive perfusion, especially in normal tissues [64–66].

Intratumoral blood flow varies considerably depending on the tumor type. Moreover, even within the same tumor, the distribution of the vasculature and blood flow is very heterogeneous. Contrary to the general notion that the blood flow in tumors is less than that in normal tissues, blood flow in many tumors, especially in small tumors, is actually greater than that in the surrounding normal tissues under normal conditions. Typically, the bloodstream of the tumor usually decreases as the tumor grows. While studies in small animals suggest that LHT induced a decrease in blood flow at 42–43°C, there is evidence that tumors in large animals and, more importantly, human tumors, are significantly less sensitive to LHT. In general, clinical studies do not suggest a reduction in tumor perfusion at temperatures up to 44°C [67].

An increased blood flow can increase tumor growth, as well as the risk of hematogenous metastases, suppressing the possible therapeutic effect of LHT [48, 52, 68]. However, a high blood flow can have the opposite effect: a high blood flow provides a more intensive exposure to chemotherapy and, through increased oxygenation, sensitizes tumor tissue to radiotherapy [69].

A mild temperature (39–42°C), which is not optimal for the induction of direct cell death or damage to the vascular system of the tumor, is effective in enhancing tumor response to radiation therapy or chemotherapy [70]. Many conditions that contribute to radioresistance, including hypoxia, acid medium, and S-phase of the cell cycle, either increase sensitivity to LHT or do not change it [50, 52, 70, 71]. LHT-induced increase in tumor perfusion leads to an increased tumor tissue oxygenation and an increased tumor radiosensitivity [72].

Under the influence of LHT, both the intrinsic chemical activity of cytostatics and the degree of their penetration into cells increase due to the activation of membrane transport, and the direct effect of LHT is much higher in hypoxic tissues, in which chemoresistance is observed [47, 71]. The mechanism of enhanced cytotoxicity can include the increase in intracellular accumulation of chemotherapeutic drugs, the inhibition of DNA repair, and S-phase cell cycle block, when cells are most sensitive to heat. In addition, LHT increases the production of free radicals and can reverse drug resistance [47, 49, 50].

Based on clinical data demonstrating the synergistic antitumor effect of noninvasive radiofrequency hyperthermia used in combination with chemotherapy and radiotherapy for tumors from various sites and recurrent glioblastomas, the goal of the study was to evaluate the effectiveness and safety of LHT combined with concurrent chemoradiotherapy for newly diagnosed glioblastoma.
