**2.8. Safety and tolerability**

Treatment tolerance was assessed by monitoring changes in the functional and neurological status of patients and comparing complications from chemotherapy and radiotherapy.

Most patients had no changes in the functional performance status assessed by the Karnofsky scale before and after TCRT. In three patients with low KPS score (40%) due to neurological deficit, concurrent TCRT led to an increase in KPS score to 60%. One patient had disease progression during TCRT, and his KPS score decreased from 80 to 40%.

Changes in the KPS status before and after TCRT are shown in **Figure 5**. An increased functional activity of patients was observed; however, differences were not statistically significant (p > 0.05).

The assessment of neurological symptoms before and after TCRT showed no changes in neurological deficit in most patients. Neurological symptoms were transient in three cases and regressed after vascular therapy in two cases. Worsening of neurological symptoms was observed in three patients. One of these patients discontinued radiotherapy at a total dose of 42 Gy because of disease progression. In two remaining patients, an increase in neurological symptoms was not associated with tumor progression and was characterized by the occurrence of extrapyramidal symptoms in one case and behavioral disorders in another case. Both patients had a history of chronic cerebral ischemia. Regression of focal neurological symptoms manifested as a decrease in the severity of pyramidal symptoms was registered after TCRT

in two patients, and as an improved extremity muscle strength and regression of convulsive syndrome in one patient, thus increasing KPS status from 40 to 60%. The patient characteris-

Concurrent Thermochemoradiotherapy in Glioblastoma Treatment: Preliminary Results

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

175

Gastrointestinal toxicity manifested with diarrhea, nausea, or loss of appetite was founded in four (13.3%) patients. Grade 3/4 toxicity was not registered. Hepatotoxicity manifested by a

tics with respect to changes in neurological symptoms are shown in **Figure 6**.

**Figure 5.** Functional activity of patients before and after TCRT.

**Figure 6.** Changes in neurological symptoms after TCRT.

Concurrent Thermochemoradiotherapy in Glioblastoma Treatment: Preliminary Results http://dx.doi.org/10.5772/intechopen.76264 175

**Figure 5.** Functional activity of patients before and after TCRT.

The 1-year disease-free survival rate was 41.3 ± 10.6%. Five patients were followed up for more than 24 months. One patient developed recurrent disease 34 months after diagnosis.

**Figure 4.** Survival of GBM patients who received concurrent thermochemoradiotherapy. (A) Progression-free survival

During the follow-up period, 11 patients died. Most deaths were registered within 6–12 months (five patients) and 12–24 months (four patients). The median overall survival time was 23.4 months. The 1-year survival rate was 73 ± 8.8%. Four patients had no evidence of

Treatment tolerance was assessed by monitoring changes in the functional and neurological status of patients and comparing complications from chemotherapy and radiotherapy.

Most patients had no changes in the functional performance status assessed by the Karnofsky scale before and after TCRT. In three patients with low KPS score (40%) due to neurological deficit, concurrent TCRT led to an increase in KPS score to 60%. One patient had disease pro-

Changes in the KPS status before and after TCRT are shown in **Figure 5**. An increased functional activity of patients was observed; however, differences were not statistically significant

The assessment of neurological symptoms before and after TCRT showed no changes in neurological deficit in most patients. Neurological symptoms were transient in three cases and regressed after vascular therapy in two cases. Worsening of neurological symptoms was observed in three patients. One of these patients discontinued radiotherapy at a total dose of 42 Gy because of disease progression. In two remaining patients, an increase in neurological symptoms was not associated with tumor progression and was characterized by the occurrence of extrapyramidal symptoms in one case and behavioral disorders in another case. Both patients had a history of chronic cerebral ischemia. Regression of focal neurological symptoms manifested as a decrease in the severity of pyramidal symptoms was registered after TCRT

recurrence 24 months after completion of treatment (**Figure 4B**).

gression during TCRT, and his KPS score decreased from 80 to 40%.

**2.8. Safety and tolerability**

and (B) overall survival.

174 Glioma - Contemporary Diagnostic and Therapeutic Approaches

(p > 0.05).

in two patients, and as an improved extremity muscle strength and regression of convulsive syndrome in one patient, thus increasing KPS status from 40 to 60%. The patient characteristics with respect to changes in neurological symptoms are shown in **Figure 6**.

Gastrointestinal toxicity manifested with diarrhea, nausea, or loss of appetite was founded in four (13.3%) patients. Grade 3/4 toxicity was not registered. Hepatotoxicity manifested by a 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 performed.

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

Concurrent Thermochemoradiotherapy in Glioblastoma Treatment: Preliminary Results

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

177

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

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 dielec-

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

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

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,

42–42.5°C for 40–60 min [56, 57], the brain temperature should not exceed 42°C.

use of MRI, as well as the effective delivery of the MNPs [77].

and tissue impedance [66, 68].

tric contrast [64, 78, 79].

distribution [80, 81].

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 of chemotherapy termination because of hematological toxicity.

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

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.
