NanoTherm In Adjuvant Therapy of Glioblastoma Multiforme

Glioblastoma multiforme (GBM), the most common and malignant primary brain tumor in adults is classified as a World Health Organisation (WHO) grade 4. Surgical removal of the tumor is the primary method of treatment. Unfortunately, because GBM is a disease of the entire brain, total resection is not possible. Therefore, the use of radiotherapy and/or chemotherapy is considered as Stupp protocol. Patients with recurrent GBM will be included in the ANCHIALE study.

The goal of the trial is to evaluate the efficacy and tolerance of using the NanoTherm therapy system in recurrent GBM.

The main questions it aims to answer are:

1. how NanoTherm therapy influences overall survival, and progression free survival;
2. what is the tolerance of NanoTherm therapy in terms of side effects (allergies, intracranial bleeding, infections, brain edema, increased intracranial pressure) and quality of life.

Participants will undergo:

* initial visit, considering the inclusion/exclusion criteria, neurological examination, and surveys regarding daily functioning and quality of life;
* standard neurosurgical operation aimed, if possible, complete removal of the recurrent GBM and administration of NanoTherm ASI - a sterile suspension of iron oxide nanoparticles. A catheter will be implanted allowing for measurement of temperature during the first activation in the magnetic field;
* between the 6th and 10th day after tumor resection, a standard computerized tomography (CT) scan of the head will be performed for routine postoperative evaluation;
* after the first activation (10th day), the catheter will be removed;
* subsequently, for 6 times, the patient will be subjected to the variable magnetic field of the NanoActivator® to induce hyperthermia - activations will be conducted on the 10th, 14th, 17th, 21st, 24th, and 28th day;
* for up to 2 years post-procedure, a CT scan with an evaluation of treatment efficacy will be performed;
* during follow-up visits for up to 2 years after the surgical procedure, a neurological examination, assessment of adverse symptoms, number of hospitalizations, number of medical visits, clinimetric assessment regarding quality of life, neurological deficit and degree of disability will be conducted.

Researchers will compare NanoTherm group with patients undergoing Stupp protocol treatment for the abovementioned effects.

Glioblastoma multiforme (GBM) is the most frequent glial tumor (glioma). The epidemiology of brain gliomas depends on many factors such as age, gender, genetics, environment, and lifestyle.

According to statistics, in developed countries, brain gliomas account for about 2% of all tumors. In the USA, there are approximately 12,000 new cases of brain gliomas annually, and in Europe, there are about 25,000. The average age of individuals diagnosed with brain gliomas is 64 years, although they can occur in all age groups. However, the majority of cases are diagnosed in individuals between 45 and 70 years of age. The global incidence rate is 3.7/100,000 for men and 2.6/100,000 for women. A higher incidence rate is observed in highly industrialized countries. It is estimated that gliomas account for 30 to 40% of all intracranial tumors. Approximately 50% of adult gliomas are the most malignant form - Glioblastoma multiforme G4.

In 2009, 1444 new cases of malignant brain tumors were recorded in men and 1362 in women in Poland. Men have a slightly higher risk of developing brain gliomas than women. The presence of genetic and hereditary factors, including mutations in genes related to DNA repair and cell cycle control, increases the risk of developing gliomas. Risk factors for the development of gliomas include exposure to ionizing radiation and viral infections (cytomegalovirus), smoking, alcohol abuse, overweight, lack of physical activity, as well as exposure to certain chemicals such as pesticides and solvents.

Recommendations for the treatment of Glioblastoma multiforme include:

Surgical removal of the tumor as the primary method of treatment. Unfortunately, considering the fact that Glioblastoma multiforme is a disease of the entire brain, complete tumor resection is not possible. Therefore, the use of radiotherapy and/or chemotherapy is considered. This treatment is used according to the protocol published by Stupp in 2005.

Radiotherapy: Radiotherapy is used to destroy the remaining tumor cells after the tumor removal. It can be used after surgery or as a standalone treatment, especially in cases where the tumor cannot be surgically removed. The total dose according to the Stupp protocol is 60 Gy and is administered in fractions of 2 Gy per day for 5 days (Monday to Friday) for 6 weeks.

Chemotherapy: In the Stupp protocol, temozolomide is used during radiotherapy: 75 mg/m2 of body surface area per day for 7 days a week. After the completion of radiotherapy, temozolomide is used as adjuvant therapy - 6 cycles of 150-200 mg/m2 of body surface area for 5 days every 28 days.

However, the clinical effects of using the Stupp protocol are not fully satisfactory. The two-year survival rate after the full Stupp protocol (radio- and chemotherapy) is 26.5% of patients, and after using only radiotherapy, it is 10.4% of patients.

Supportive treatment methods used in the treatment of Glioblastoma multiforme so far include thermotherapy - hyperthermia and nanotherapy.

Hyperthermia involves:

* the use of elevated temperature to increase the effectiveness of radio- and chemotherapy
* thermoablation, in which the use of high temperatures - above 45°C - causes direct damage to tumor cells,
* magnetic hyperthermia (MHT), e.g. NanoTherm® Therapy (NTT), which has been registered in Europe as a method of treating Glioblastoma multiforme in cases of tumor recurrence Nanotherapy uses magnetic nanoparticles (MNP), which are used in diagnostic and therapeutic procedures.

Hyperthermia and thermotherapy have been treatment methods studied in cancer patients and magnetic hyperthermia induced using nanoparticles is becoming the subject of increasingly advanced research.

In a phase III study, the use of tumor-treating fields (TTF) was evaluated as a first-line therapy in patients with Glioblastoma multiforme. Low-power electromagnetic fields using long waves are directed at the tumor area using external electrodes. According to the report from the Institute for Quality and Efficiency in Health Care (IQWiG), this method resulted in a 5-month extension of the overall survival of patients with Glioblastoma multiforme compared to patients treated with temozolomide, and the tolerance of the treatment was acceptable.

On the other hand, NanoTherm therapy represents a promising form of thermotherapy leading to an extension of survival, especially in cases of Glioblastoma multiforme recurrence. In the study by Maier-Hauff et al., it was shown that the average overall survival of patients undergoing NanoTherm therapy after recurrence was 13.4 months, which was longer (P\<0.01) than in patients treated according to the Stupp protocol (6.2 months). The overall survival after the initial diagnosis of Glioblastoma multiforme was also longer (23.2 versus 14.6 months; P\<0.01). The benefit observed in both groups of patients was attributed to the use of NanoTherm therapy.

Therefore, among the sought-after new methods of treating Glioblastoma multiforme that could increase the effectiveness of the current treatment, NanoTherm therapy is a procedure that significantly increases the survival and quality of life of patients. For this reason, it is planned to conduct this study, the aim of which is to determine the effectiveness and tolerance of using nanoparticles in cyclic hyperthermia as adjuvant therapy in patients with Glioblastoma multiforme.

The main goal of the treatment for each patient with Glioblastoma multiforme is to prolong survival time and improve the quality of life. According to the literature, the median overall survival of these patients is 9 - 12 months.

Patients with recurrent glioblastoma multiforme WHO G4 will be included in the ANCHIALE study.

Study Objective:

The aim of the ANCHIALE study is to prepare a registry that allows for the evaluation of the efficacy and tolerance of using the NanoTherm therapy system in cases of recurrent glioblastoma multiforme.

Study Principles:

During the initial visit, a qualification for treatment will be conducted, taking into account the inclusion and exclusion criteria, i.e., indications and contraindications for the NanoTherm therapy system. Additionally, an interview, neurological examination, and surveys regarding daily functioning and quality of life will be conducted.

After qualifying a patient for the study, he or she will undergo standard neurosurgical operation aimed at partial or, if possible, complete removal of the recurrent brain tumor. Then, in the place of the removed tumor, NanoTherm ASI will be administered in a quantity of either 112 or 335 mg/ml of iron particles. This is a sterile suspension of iron oxide nanoparticles in sterile water, characterized by a high specific ability to absorb heat associated with its superparamagnetic properties. At the site where the thickest layer of nanoparticles (NanoTherm® ASI) is applied, a catheter will be implanted allowing for measurement and control of temperature during the first activation in the magnetic field of the NanoActivator®.

Between the 6th and 10th day after the neurosurgical procedure, a standard computerized tomography (CT) scan of the head will be performed for routine postoperative evaluation.

After the first activation (10th day post-implantation of NanoTherm® ASI), the catheter will be removed. Subsequently, cyclically, for 6 times, the patient will be subjected to the variable magnetic field of the NanoActivator® to induce hyperthermia, i.e., increase the temperature of the site after the removed tumor and the surrounding tissues. Activations will be conducted on the 10th, 14th, 17th, 21st, 24th, and 28th day. The heat released by the nanoparticles (NanoTherm® ASI) into the surrounding tissue causes destruction or damage to the cells of the glioblastoma multiforme (hyperthermia effect), increasing their susceptibility to radiotherapy and chemotherapy.

The patient will then be subjected to detailed observation for 2 years. Observation will include visits conducted on the 60th, 90th, 150th, 210th, 270th, and 360th day after surgery, and then every 3 months up to 2 years post-procedure.

On the 6th - 10th, 90th, 150th, 210th, 270th, and 360th day after surgery, and then every 3 months up to 2 years post-procedure, a CT scan with an evaluation of treatment efficacy will be performed. The treatment effects on CT will be analyzed using RANO (Response Assessment in Neuro-oncology) scale.

During follow-up visits on the 60th, 90th, 150th, 210th, 270th, and 360th day, and then every 3 months up to 2 years after the surgical procedure, a neurological examination, assessment of adverse symptoms, number of potential hospitalizations, number of medical visits, clinimetric assessment regarding quality of life (EuroQuality of Life-5 dimensions 5- levels \[EQ-5D-5L\], Neurologic Assessment in Neuro-Oncology \[NanoScale 2\]), and clinimetric assessment regarding neurological deficit and degree of disability will be conducted (modified Rankin scale, Barthel index).

The results from NanoTherm group will be compared to patients undergoing standard neurosurgical treatment for the abovementioned effects.

Eligibility Criteria:
Inclusion Criteria:

1. Recurrence of glioblastoma multiforme.
2. Age \> 18 years.
3. Informed written consent to participate in the study.
4. Karnofsky performance score ≥ 60.
5. Expected survival time \> 6 months.
6. Failure of standard treatment according to the Stupp protocol.
7. Cardio-respiratory fitness - allowing to stay for 60 minutes in a lying position in the field activator.

Exclusion Criteria:

1. Pregnant or breastfeeding women.
2. More than 3 foci of glioblastoma multiforme.
3. Tumor invasion of eloquent or motor areas.
4. Subependymal contrast enhancement in the adjacent brain ventricles.
5. Concurrent immunotherapy for glioblastoma.
6. Metal implants within ≤ 40 cm of the planned exposure field: metal dental fillings/restorations, cervical spine implants, metal elements left after previous craniotomies, metal elements used in osteosynthesis after orthopedically treated injuries, vascular ports with metal components.
7. Electronic implants: pacemakers, cardioverter defibrillators, cochlear implants, deep brain stimulation (DBS) electrodes.
8. Allergy/hypersensitivity to aminosilanes, iron oxide, acetic acid.
9. Planned or current treatment with electromagnetic field in the Optune®TTF system.
10. Claustrophobia not amenable to control.
11. Painful conditions, musculoskeletal system diseases that prevent staying in a lying position.