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
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.
