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DIAGNOSIS

The best way to visualize gliomas is by magnetic resonance tomography (MR, MRI, NMR ). Images are usually taken before and after the images are repeated at regular intervals to plan treatment and monitor progress.

The best way to visualize gliomas is by magnetic resonance tomography (MR, MRI, NMR ). Images are usually taken before and after the images are repeated at regular intervals to plan treatment and monitor progress.

Allergies to the MR contrast material are rare. However, people with claustrophobia or sensitivity to noise may have problems with the images, even though the tubes have now become larger. A mild sedative often helps. If an MRI is not possible at all due to claustrophobia or, for example, because of a pacemaker, it is possible to switch to a computer tomogram (CT). Computed tomography (CT) – short tube, X-rays, contrast medium containing iodine. Contrast agent allergies are more in addition, a pre-existing thyroid disease may require further medication. The images involve a certain amount of radiation exposure, and their informative value is somewhat lower than that of an MRI. 

In the case of unclear diagnostic results, methods are used that tell us something about the metabolism in suspicious areas:

In positron emission tomography (PET), a small amount of a substance is injected into a vein. A small amount of a substance that is consumed or incorporated by fast-growing (tumor) cells is injected into a vein. Often these are sugars or amino acids, which are radioactively marked and detected on the basis of their radiation.

Histological confirmation using biopsy material is mandatory. For differential diagnosis of inflammatory diseases, including brain abscess, germ cell tumors, primary cerebral lymphoma or brain metastases, a CSF diagnosis can be performed.

Electroencephalography (EEG) is indicated for the diagnostic of epilepsy. A diagnostic neuropsychological examination is sometimes integrated early in the diagnostic process and may include the following aspects:

  • cognitive functional areas (including higher visual perception, attention, memory, language, number processing, executive functions)
  • qualitative description of behavior
  • affect and Fatigue
  • potential ‚confounding variables‘ such as headaches, medication side effects, or a reduced willingness to exert effort 

Operation

For glioblastomas, surgery is the first step of therapy. Biopsies can be differenced from open tumor resections: 

The goal of open surgery is to remove as much tumor tissue as possible without causing without causing any harm to the patient.
However, gliomas in the brain tissue do not have a fixed limit,
so it is always necessary to re-evaluate how far to go with the operation.

A number of techniques have been developed for this purpose in the last few years developed:

 

5-ALA FLUORESCENCE

The patient will drink a pharmaceutical a few hours before the procedure, which is converted to a dye only in tumor cells.
A black light device in the operating microscope produces a reddish-orange fluorescence in the tumor cells, which the surgeon can use for orientation. The first hours after surgery with 5-ALA should be spent in relative darkness, because the drug can also cause a kind of sunburn under artificial light.

 

NEURONAVIGATION

Before surgery, images (e.g., MRIs) of the tumor are computed into a three-dimensional data set. This can be projected onto the surgical area on a screen or directly in the microscope and shows tumor boundaries or important structures that must be spared.
structures that must be spared.

 

NEUROMONITORING

During the procedure, structures in the immediate vicinity of the tumor are tested for function – usually by electrical stimulation in the tissue. If a reaction is found (e.g. activation of a muscle), the tumor removal is terminated at this site.

The extreme case of neuromonitoring is awake surgery: 

The awakened patient – who is usually painless and stress-free – is
stress-free – patient is given e.g. speech tasks during tumor removal. If the electrical stimulation leads to a short failure of the tested function, the limit of tumor removal has been reached.
is reached.

Biopsies, also known as „specimen excisions“ (PE), are used to confirm the diagnosis – either because the tumor is too unfavorably located for further excision or because one would like to clarify the suspicion of new growth after therapy by means of a specimen without open surgery or because the suspicion of new growth after therapy is to be clarified by a sample without performing an open operation. Biopsies obtain small (rice grain-sized) tissue samples and are minimally invasive. They can be performed under anesthesia, but also under local anesthesia. Biopsies are often guided by a stereotactic targeting system. Thereby either a stereotactic frame is attached to the head or neuronavigation is used.

Neuropathology

The field of neuropathology includes the histological and molecular diagnostic confirmation of the tumor tissue removed during surgery.

Brain tumors are classified into four grades (I-IV) according to the WHO classification of tumors of the central nervous system, with grade I corresponding to a benign tumor and grade IV to a malignant tumor. Glioblastoma is considered the most common malignant brain tumor in adults and by definition is a WHO grade IV tumor. Glioblastomas belong to the astrocytic tumors, i.e. they arise from astrocytes (glial cells) or their precursor cells (neural stem cells).

In many cases, tumor tissue is removed during surgery and sent directly as a so-called „frozen section“. In contrast to the material used for detailed neuropathological diagnostics, the frozen section tissue is shock-frozen. Microscopic examination of the sections with simple staining allows a rapid (within about 20 minutes) and landmark diagnosis and may potentially influence the surgical procedure. Since additional examinations (e.g. molecular pathology) are not possible with this technique – especially due to time constraints – no definitive diagnosis is made from the result of frozen section diagnostics.

The removed tumor tissue is fixed and embedded in parafin (wax), and numerous thin sections are made. The tissue is stained with various special stains. Here, in addition to microscopic diagnostics, immunohistochemical staining as well as molecular pathological examinations are performed, which enables detailed diagnostics and is also required to make a diagnosis.

Already under the microscope, glioblastoma can be diagnosed with high probability.

Typical microscopic characteristics of glioblastoma are tumor cells with long cell processes (typical of astrocytic cells), a pronounced diversity of the appearance of the cell nuclei (nuclear pleomorphism), signs of increased cell division (increased mitosis and proliferation rate), collective tumor cell death (necrosis) due to rapid growth and resulting lack of oxygen and nutrients, palisade-like arrangement of living tumor cells in the marginal area of necrosis, formation of new vessels (microvascular proliferation) to compensate for rapid growth, and possibly blockage of tumor vessels (thrombosis) due to changes in blood flow.

Advanced diagnostics with regard to various biomarkers

Immunohistochemistry, a method that uses labeled antibodies to visualize tumor-specific proteins, is used to detect mutations in the metabolic enzyme isocitrate dehydrogenase (IDH). Glioblastomas with a mutation in one of the two IDH genes (most commonly IDH 1 and very rarely IDH 2) have a significantly better prognosis compared to tumors with intact IDH (IDH wild type). IDH mutated glioblastomas are called secondary glioblastomas because they usually arise from lower grade gliomas (WHO grade II or WHO grade III). These are predominantly found in younger patients. 

Mit der immunhistochemischen Färbung können ca. 85-90% der IDH-Mutationen nachgewiesen werden. Bei immunhistochemisch negativem Befund wird bei klinischem Verdacht auf ein sekundäres Glioblastom (z.B. junges Alter, vorbekanntes low-grade Gliom) eine IDH1 und 2- Sequenzierung durchgeführt.

These two markers are detected by immunohistochemistry. Both are present in primary as well as in secondary glioblastomas, but have no prognostic relevance. They only serve to confirm the diagnosis of a glioblastoma, as they show that the tumor originates from astrocytes (GFAP) or glial cells in general (olig2).

Methyl-guanine methyl transferase (MGMT) is a DNA repair enzyme, i.e. if, for example, the genetic material of tumor cells (DNA) is damaged by radiation or certain chemotherapeutic agents, it can repair this and make the chemotherapy applied less effective. If, on the other hand, methylation of the MGMT promoter is detected, the enzyme is switched off in its function, and the tumor can accordingly no longer repair the damage to the genetic material caused by chemotherapy. This explains that MGMT-methylated tumors respond better to certain chemotherapeutic agents (e.g., temozolomide and lomustine), and thus the survival time of these patients has been shown to be prolonged by the administration of chemotherapeutic agents compared to patients with non-methylated glioblastomas. Thus, MGMT methylation status is considered an important marker of response to adjuvant radiotherapy and chemotherapy and is often helpful in making treatment decisions. The determination of MGMT methylation status is a molecular pathology diagnostic, it is performed in the context of PCR (polymerase chain reaction) or DNA sequencing.

This marker is also visualized by immunohistochemistry and indicates the division rate of the tumor cells. It has no immediate diagnostic value, but can help the neuropathologist to distinguish between a benign and malignant tumor. Malignant tumors, such as glioblastoma, have a high division rate corresponding to a high proportion of Ki67 positive tumor cells (>10%).

TERT (telomerase reverse transcriptase) is an enzyme that restores losses at the ends (so-called telomeres) of chromosomes (carriers of genetic information) after cell division.

Genetic mutations in glioblastomas can occur in the region of the TERT promoter, causing the enzyme to have increased activity, thereby promoting tumor cell growth by stabilizing the chromosome ends. Glioblastomas with a TERT mutation are associated with a poorer prognosis.

TERT mutations are found particularly in IDH wild-type glioblastomas. Mutation analysis is performed by DNA sequencing of the corresponding gene segments.

Similar to TERT, ATRX (α-thalassemia/mental retardation syndrome Xlinked-) gene controls telomere growth. Mutations in the ATRX gene can lead to ATRX loss and, unlike TERT promoter mutations, are commonly found in secondary glioblastomas.

Detection of ATRX loss is by immunohistochemical staining.

Mutations in the tumor suppressor P53 are most frequently found in secondary glioblastomas. A prognostic relevance is not known so far.

Detection is by immunohistochemical staining.

Biomarker

In general, all complementary molecular biological and immunohistochemical investigations help to distinguish between a primary and a secondary glioblastoma. The prognosis of secondary glioblastomas, which usually arise from lower-grade gliomas, is comparatively better, and younger patients are more frequently affected.

The chart on the right provides an overview of the expression of the mentioned biomarkers in primary and secondary glioblastomas.

 

Primary glioblastoma

Secondary glioblastoma

IDH

wild type

mutated

TERT-Promotor

often mutate

rarely mutated

ATRX

received expression

ATRX loss frequent

P53

rarely mutated

often mutated

Radiotherapy

Radiation therapy (radiotherapy) represents the third pillar of modern brain tumor therapy – after surgery and chemotherapy. Treatment with ionizing radiation keeps tumors under control or destroys them. So-called multimodal therapy concepts are frequently used. Here, different treatment options are combined with each other. For example, surgical removal of the tumor can be followed by combined radiochemotherapy (radiotherapy combined with chemotherapy).

In most cases, the operation is the first therapeutic step aiming at the removal of the visible tumor or at tumor reduction to milden symptoms. However, the operation does not enable complete resection of all tumor cells, and thereby often leaving microscopic residual tumor tissue.

Malignant primary brain tumors are characterized by an infiltrative growth pattern into the surrounding brain tissue. It is therefore not possible to visualize these infiltrating tumor cells with the bare eye during surgery or on preoperative imaging.

More extensive operations with the aim of removing these possible cell clusters are usually impossible, as otherwise unjustifiable neurological deficits would be caused. Therefore, the main goal of irradiation in these situations is to prevent any remaining cell clusters from further growth, or to remove visible tumor tissue that cannot be completely removed surgically due to its localization, or to treat it so that it does not grow further. In most cases, this results in the need for radiation treatment of the so-called „extended tumor region“. This means that only the area of the original tumor site and areas of possible tumor infiltration are treated with radiation therapy.

Radiotherapy is the most important treatment measure after surgery for tumors of the central nervous system.

Through intensive research by physicians, biologists and physicists, an independent discipline has developed in recent years, which, in close cooperation with the other disciplines involved, especially neurosurgery and neurology, has achieved an optimized overall treatment of brain tumors.

The development of modern irradiation devices (linear accelerators) enables irradiation of tumors located deep in the body. In this way, adjacent organs and the skin surface are largely spared. An indispensable requirement for the implementation of an optimized radiation therapy is the introduction of computer-assisted radiation planning systems that achieve an individually targeted radiation therapy with the aim of optimizing outcome rates and reducing any side effects as far as possible. The patient is placed in a virtual three-dimensional coordinate system and the rays focus the tumor area from different spatial directions. For this purpose, however, it is important to identify the tumor exactly.

Modern imaging techniques are able to do so: The tumor can exactly be differentiated from normal tissue, so that the development of high-precision radiation techniques was enabled recently.

Today, the medically applicable radiation is generated by ultra-modern „linear accelerators“. This produces „high-energy X-rays“ that are capable of penetrating into greater depths.

Modern irradiation planning systems can focus this radiation to the desired target area with the help of modern imaging techniques. Different radiation fields are used, which are irradiated from different, individually aligned directions.

Ionizing radiation causes damage to the genetic material of the irradiated cells and can thus prevent cell division and leads to cell death.

Healthy tissue possesses repair mechanisms by which damage in the genetic information can be eliminated. In cancer cells, these mechanisms often function only to a limited extent. This explains why many malignant tumors are particularly sensitive to ionizing radiation.

In radiation therapy, a high radiation dose is irradiated into a locally narrowly defined area, the so-called target volume (consisting of the tumor and its area of spread). The aim is to destroy the tumor. At the same time, adjacent radiation-sensitive organs and tissues (so-called organs at risk) have to be spared.

The dose required for tumor destruction depends on the radiation sensitivity of the correspondent tumor.

Highly malignant gliomas require a dose of up to 60 Gy, low-grade gliomas between 45 and 54 Gy. In the case of brain metastases, the entire brain is usually irradiated with up to 30 Gy.

However, depending on clinical circumstances and tumor origin, doses may vary individually.

Before starting radiotherapy, the radiooncologist determines the amount of the individual dose, the final dose and the number of individual doses (= fractions). In the vast majority of cases, the intended radiation concept is based on certain standards or on the corresponding therapy protocols for the treatment of brain tumors, especially in children.

The dose concepts are also subject to further research with the aim of achieving higher rates of cure, but also at the same time reducing risks of possible side effects.

 

Usually, the risk of side effects under radiotherapy is so low that a restriction of daily life is rarely necessary.

However, especially during the spring and summer months, care should be taken to avoid direct sunlight and wearing of sunprotection is recommended. Likewise, swimming or taking a sauna should not be avoided during the treatment period and about 4-6 weeks afterwards.

Further details are discussed with the patient by the attending radiooncologist.

Follow-up and late effects

When the irradiation therapy is finished, a control examination is usually performed. During this examination, the therapeutic outcome, possible side effects under therapy and the further procedure are discussed. This also includes information regarding any other possibly necessary medication, skin care and daily life activity.

In individual cases, additional chemotherapy may be considered. Often, a short-term follow-up appointment is scheduled, especially if side effects are observed at the end of the radiotherapy.

Further follow-up is interdisciplinary, i.e. in cooperation with neurosurgeons and neurooncologists. Furthermore, there are regular follow-up examinations, some of them are bounded to special treatment protocols and following certain schedules. Within the follow-up program, it is necessary that the attending radiooncologist consults the patient at least once a year.

Long-term therapeutic consequences can still occur after some years and might be misinterpreted by physicians that have not received specialist radiooncological training. It is not uncommon that tumor relapses are misinterpreted as a therapeutic effect. Only the radiooncologist has the training and experience to detect possible…

 

Irradiation of the tumor region

The treatment concentrates on the tumor bed including a safety margin with possible (not detectable with conventional imaging procedures = subclinical) tumor infiltration (usually 2.0 cm). To optimize irradiation, individually computer-assisted irradiation plans are compiled in order to spare as much healthy surrounding tissue as possible (e.g. for low- and high-grade gliomas). The use of individualized face masks or bite block techniques is a basic requirement to achieve an exact positioning of the head. The area to be irradiated comprises the tumor visible on CT or MRI, including surrounding areas with possible tumor infiltration. The advantages of computer-assisted radiation planning are exact localization of the area to be irradiated as well as a precise delimitation of critical organs such as the brain stem and the crossing of the optic nerves (optic chiasm). Computed tomography (CT) also obtains density values that are necessary for irradiation planning, so that an individualized, optimal field adjustment and dose distribution can be calculated.

Stereotactic single dose irradiation / linear accelerator-based systems or Gamma Knife

The aim of the stereotactic single dose treatment is to apply a clinically sufficient dose to the tumor and thereby excluding co-irradiation of normal, surrounding brain tissue. With single-dose irradiation, well-defined tumors of small size can be irradiated precisely and in high doses. Stereotactic single-dose irradiation is typically used for single brain metastases (no more than three foci), vascular malformations and benign tumors originating from the auditory nerve (acoustic neurinoma).

Linear accelerator-based systems and the Gamma Knife differ only in technical details, but not in their medical application.

The technical difference between the two systems:

Gamma Knife:
More than 200 precision-aimed Cobalt-60 sources produce a beam of radiation with a very small diameter. The bundles cross at one point, the target. The bundling is achieved using a special helmet.  

Linear accelerator supported systems:
The generated beam is confined to a very small area by a special tubular attachment. This beam is guided over several circular arcs and is concentrated in a defined intersection point (isocenter). In this way a maximum focusing is achieved (like in a burning glass).

 Whole brain irradiation (including meninges, so-called „helmet field“)

Irradiation is performed via two lateral fields that are 180 degrees apart. In the case of metastases, the target area includes the brain structures, but in the case of leukemia it also includes the external cerebral fluid spaces that extend along the outer meninges. The latter areas often have to be integrated into the therapeutic field, as tumor cells (mainly in medulloblastoma, germ cell tumors and leukemias) can be transported via the cerebral fluid flow. Inadequate detection is therefore associated with an increased risk of tumor relapse, so that a particularly carefully performed irradiation technique has a decisive effect on the treatment outcome. The remaining areas of the head (eyes/facial region, oral cavity and throat) are kept out of the irradiation field using special apertures.

Radiation treatment of the neuro axis

The brain and spinal cord are irradiated when tumor seeding to the spinal cord is observed (medulloblastoma, germ cell tumors, lymphomas). It essentially consists of the „helmet technique“ (see above) and additional spinal irradiation fields. A reproducible positioning with appropriate fixation aids is the requirement for an exact field adjustment. This is usually followed by local radiation therapy of the primary tumor site. This irradiation technique usually corresponds to the above-mentioned procedures and techniques.

Chemotherapy

Chemotherapy is defined as the treatment with so-called cytostatic drugs. Cytostatic drugs are cytotoxic agents that particularly attack fast-dividing cells such as tumor cells.

These drugs can inhibit the abnormal cell growth of tumors and thus reduce the size of the tumor or even destroy it completely. There are different categories of cytostatic drugs that attack different parts of the cell metabolism.

In some cases, several cytostatic drugs are applied together to increase the growth-inhibiting effect. Chemotherapy is a so-called „systemic“ therapy that targets the whole body and is intended to prevent tumor spreading to other organs or tissues.

The use of chemotherapy depends on the location and malignancy of the tumor.

If chemotherapy is indicated in patients with brain tumors, chemotherapy is applied after surgery and histological analysis of the tumor.

Chemotherapy is then administered either before radiation therapy („neoadjuvant therapy“), simultaneously with radiation therapy („concomitant therapy“) or after radiation therapy („adjuvant therapy“).

In some cases, application of chemotherapy is also indicated and useful without accompanying or preceding surgery or radiotherapy.

In the case of tumor recurrence or growth despite use of chemotherapy, chemotherapy is intensified or switched to another treatment regimen („recurrence therapy“).

The blood-brain barrier is a natural barrier that has the function to protect the brain from invading toxins.

For the chemotherapy of brain tumors, therefore, drugs are used that can pass this blood-brain barrier. It is very important that the drugs are „CSF-permeable“, that means, that they can enter into the cerebrospinal fluid.

This applies only for a small number of cytostatic drugs. Among the cytostatic drugs used today for brain tumors, there are in particular alkylating substances such as temozolomide or nitrosoureas (e.g. CCNU), mitosis inhibitors such as VP16 (etoposide) or platinum compounds (cisplatin, carboplatin).

Depending on the drug and therapy concept, chemotherapy can either be taken as a capsule (oral administration) or administered via the vein as an infusion (intravenous administration).

In exceptional cases, the cytostatic drug is also administered directly into the CSF system via a special reservoir. In most cases, treatment can be performed on an outpatient basis, i.e., hospitalization is not necessary. In the case of poor vein conditions, the implantation of a so-called port (special chamber which lies under the skin and is connected to a vein) may be necessary in order to infuse the medication safely. Otherwise – depending on the type of drug – skin irritation or even tissue necrosis could occur if the chemotherapy is leaking from the vein during an infusion into the surrounding tissue („extravasation“).

Chemotherapy usually proceeds in cycles, i.e. after application of the drug there are a few days or weeks where no treatment is applied.

The side effects depend on the type of chemotherapy. Basically, the problem is that chemotherapy also attacks healthy, rapidly dividing cells. The side effects of cytostatic drugs therefore affect – to varying degrees depending on the substance – the hair roots, the mucous membranes in the stomach and intestines and the hematopoietic system in the bone marrow.

This can lead to hair loss, inflammation of the oral mucosa, nausea and vomiting, diarrhea and blood count changes. A consequence of blood count changes, which often occur delayed after treatment, is the reduction of the white blood cells („leukocytes“) and thus a weakening of immune defense. Less frequent are coagulation disorders due to too few platelets (“thrombocytes”) or anemia due to a lack of red blood cells („erythrocytes“). The blood count must therefore be checked regularly during chemotherapy.

Hair loss, inflammation of the oral mucosa, nausea and vomiting, diarrhea and blood count changes may therefore occur. One consequence of the blood count changes, which often do not set in until some time after treatment, is a reduction in white blood cells („leukocytes“) and thus a weakening of the body’s defense against disease. Less frequent are coagulation disorders due to too few platelets or anemia due to a lack of red blood cells („erythrocytes“). The blood count must therefore be checked regularly during chemotherapy.

psycho-onocology

The term psycho-oncology (derived from psychology and oncology) refers to the psychological care of cancer patients. Another term can also be the so-called psychosocial oncology.

Psychooncology is thus an interdisciplinary form of psychotherapy or clinical psychology that deals with the psychological, social and socio-legal conditions, consequences and side effects of cancer.

Psychooncology has several goals:

  • Supporting patients and their families in coping with the mental and physical stress caused by the disease

  • Improve the mental well-being of patients

  • Positively change concomitant and consequential problems that arise during and as a result of diagnostics and therapy.

  • Strengthen one’s own coping skills

  • Make participation in normal life possible

The main aim of psycho-oncology is to maintain and improve the quality of life of patients and their relatives.

Tasks of psychooncology?

Psycho-oncological support can be helpful in every phase of the disease. Even if your treatment has already been completed, you should not close yourself off from seeking psycho-oncological care.

Psycho-oncology care has a variety of roles. These include:

Information and counseling

Diagnostics, in order to record the stresses and strains of patients

Therapy offers, in order to support the illness processing

Improvement and treatment of psychological, social and physical consequences of the disease

Assistance in coping with everyday life

Support in the enforcement of social benefits and in questions of social law

There are many different forms and types of psycho-oncological care.

Which one might be appropriate for you as a patient or family member depends on your needs, your stresses and your personal situation.

PSYCHO-ONCOLOGICAL CARE

The diagnosis of glioblastoma is associated with great psychological
psychological stress. This includes, for example, worries, depression as well as fear of the future and loss. Today, psychooncologists are available to help patients and their relatives with their psychological needs.

The German Brain Tumor Aid (Deutsche Hirntumorhilfe) provides opportunities and information about psycho-oncological care close to home. The focus of treatment is the quality of life of those affected. Support in coping with current problems, addressing stressful thoughts, and recognizing and mobilizing sources of strength are the goals of psycho-oncological support, which can effectively support treatment.

Likewise, a variety of offers from the regional patient groups are available to those affected and their relatives.

Individual Therapies

FIRST LINE THERAPY

In most cases, the so-called first line therapy is carried out at the time of first diagnosis of glioblastoma. Here, the so-called Stupp protocol (among others) is usually applied. The decision on which therapy is most likely to be considered for the treatment of glioblastoma at the time of initial diagnosis is made by the treating physician depending on the tumor location, the size of the tumor, its extent and the patient’s condition.

In the following – without claiming completeness or scientifically correct weighting – an overview of various forms of therapy is given:

THERAPY FOR RECURRENT TUMORS

Tumor recurrence is defined as tumor growth or newly tumor manifestation after treatment. To date, no treatment guidelines for treatment of recurrent glioblastomas exist.

Different treatment approaches in the treatment of tumor recurrence can be found. These depend on the location of the tumor, the size of the tumor, its extent and the condition of the patient. Further decisions regarding treatment are based on the tolerability of previous therapies and of course the patient’s wishes.

Recently, a vast number of studies with possible new therapeutic approaches to glioblastoma therapy have been published, leading to a huge gain of knowledge on further treatment options. It remains unclear and subject to further analysis which of these suggested protocols for treatment of tumor recurrence finds its way into recommended therapy guidelines.

A well-known contact point for information about new developments in glioblastoma therapy is the German Brain Tumour Association.

In the following – without claiming completeness or scientifically correct weighting – an overview of various forms of therapy is given:

REZIDIVTHERAPY IN THE CONTEXT OF STUDY

 

REZIDIVTHERAPY IN THE CONTEXT OF STUDY

 

Stupp-Schema

Das Stupp-Schema sieht vor, dass Patienten mit histologisch gesichertem Glioblastom einer Radio- und Chemotherapie zugeführt werden. Sie besteht aus einer fraktionierten Bestrahlung mit je 2 Gy an 5 Tagen der Woche über einen Zeitraum von 6 Wochen. Zusätzlich erhält der Patient über die Dauer der Radiotherapie täglich 75 mg Temozolomid pro Quadratmeter Körperoberfläche.

Nach der Radiotherapie erfolgen sechs Behandlungszyklen
á 28 Tage mit 150-200 mg Temozolomid pro Quadratmeter Körperoberfläche an jeweils 5 Behandlungstagen
(5/28-Zyklus).

Unterschiede DER Verfahren

Die Behandlung konzentriert sich auf das Tumorbett einschließlich eines Sicherheitssaums mit möglichem (mit üblichen bildgebenden Verfahren nicht nachweisbarem = subklinischem) Befall (in der Regel 2,0 cm).Zur Optimierung der Bestrahlung werden individuell computergestützte Bestrahlungspläne angefertigt, um möglichst viel umgebendes Gewebe zu schonen (z. B. bei niedrig- und hochmalignen Gliomen). Die Anwendung individualisierter Gesichtsmasken oder Aufbisstechniken ist Grundvoraussetzung, um eine exakte Lagerung des Kopfes zu erreichen. Das zu bestrahlende Gebiet umfasst den im CT oder MRT sichtbaren Tumor unter Einschluss von Arealen mit möglicher Tumorinfiltration. Die Vorteile der computergestützten Bestrahlungsplanung sind die exakte Lokalisierung des Bestrahlungsgebiets sowie eine präzise Abgrenzung kritischer Organe wie des Hirnstamms und der Sehbahnkreuzung (Chiasma). Die Computertomographie gewinnt für die physikalische Bestrahlungsplanung zusätzlich Dichtewerte, die für die Bestrahlungsplanung notwendig sind, sodass eine individualisierte, optimale Feldanpassung und Dosisverteilung berechnet werden kann.

Das Ziel der stereotaktischen Einzeitbehandlung besteht darin, eine klinisch ausreichende Dosis innerhalb des Tumors zu applizieren und eine Mitbestrahlung normalen, umgebenden Hirngewebes auszuschließen. Es können mit einer Einzeitbestrahlung gut abgegrenzte Tumoren geringer Ausdehnung exakt und hochdosiert bestrahlt werden. Die stereotaktische Einzeitbestrahlung kommt typischerweise bei einzelnen Hirnmetastasen (nicht mehr als drei Herde), Gefäßmissbildungen und gutartigen Tumoren, die vom Hörnerven ausgehen (Akustikusneurinome), zum Einsatz.

Linearbeschleuniger-gestützte Systeme und das Gamma Knife unterscheiden sich lediglich in technischen Einzelheiten, nicht aber im medizinischen Einsatzgebiet. Der wesentliche technische 

Unterschied zwischen beiden Systemen liegt in folgendem:

Gamma Knife:
Über 200 einzelne Telecobaltquellen produzieren ein Strahlungsbündel mit kleinstem Durchmesser. Die Bündel kreuzen sich in einem Punkt. Die Bündelung wird durch einen speziellen Helm erreicht.

Linearbeschleunigergestützte Systeme:
Der erzeugte Strahl wird mit einem speziellen röhrenförmigen Aufsatz kleinsträumig eingegrenzt. Dieser Strahl wird über mehrere Kreisbögen geführt und konzentriert sich in einem definierten Schnittpunkt (Isozentrum). Hierdurch wird eine maximale Fokussierung erreicht (wie in einem Brennglas).

Die Bestrahlung erfolgt über zwei seitliche Felder, die um 180 Grad aufeinander stehen. Das Zielgebiet umfasst bei Metastasen die Hirnstrukturen, bei Leukämien aber auch die äußeren Hirnwasserräume, die sich entlang der äußeren Hirnhäute (Meningen) erstrecken. Letztere Gebiete müssen häufig in das Therapiefeld integriert werden, da hier Tumorzellen (vorwiegend beim Medulloblastom, Keimzelltumoren und bei Leukämien) über den Hirnwasserfluss verschleppt werden können. Eine unzureichende Erfassung ist daher mit einem erhöhten Risiko für einen Rückfall der Tumorerkrankung verbunden, sodass sich eine besonders sorgfältig durchgeführte Bestrahlungstechnik entscheidend auf die Behandlungsergebnisse auswirkt. Durch spezielle Blenden wird das übrige Gewebe des Kopfes (Augen/Gesichtsbereich, Mundhöhle und Rachen) aus dem Bestrahlungsfeld herausgelassen.

Das Gehirn und der Spinalkanal werden bei Tumoren mit spinaler Aussaat bestrahlt (Medulloblastom, Keimzelltumoren, Lymphome). Sie besteht im Wesentlichen aus der „Helmtechnik“ (siehe oben) und daran anschließenden spinalen Bestrahlungsfeldern. Eine reproduzierbare Lagerung mit entsprechenden Fixationshilfen bildet die Voraussetzung für eine exakte Feldeinstellung. Anschließend erfolgt in der Regel eine lokale Strahlentherapie des ursprünglichen Tumorsitzes. Diese Bestrahlungstechnik entspricht üblicherweise der o.g. Vorgehensweise.

NÜTZLICHE INFORMATIONEN

Psychoonkologische Beratungsstelle für Hirntumorpatienten

T 03437.999 68 67

Informations- und Kontaktstelle für Hirntumor-Selbsthilfeaktivitäten 

T 03437.999 68 68

Onlineplattform zum Austausch von Hirntumorpatienten

https://forum.hirntumorhilfe.de

Hirntumor-Informationsdienst für Patienten und Angehörige

T 03437.702 702

STUPP PROTOCOL

The Stupp protocol includes that patients with histologically confirmed glioblastoma receive radio- and chemotherapy. Treatment consists of a fractionated irradiation with 2 Gy daily,  5 days a week over a period of 6 weeks. In addition, the patient receives 75 mg temozolomide per square meter of body-surface area per day for the duration of the radiotherapy.

Radiotherapy is followed by six treatment cycles of 28 days with 150-200 mg temozolomide per square meter of body-surface area for 5 days during each 28-day cycle (5/28 cycle).

Radiotherapy is followed by six treatment cycles
28 days with 150-200 mg temozolomide per square meter of body surface area for 5 treatment days each
(5/28 cycle).

TUMOR TREATING
FIELDS (TTF)

Treatment with so-called tumor treating fields (TTF) aims at slowing down cell division in brain tumors using electromagnetic waves.

After surgery and completion of radiation therapy, the patient receives a device, which mainly consists of a replaceable battery and a wave generator and can be carried in a small backpack. Electrodes are attached to the shaved head with adhesive bandages and connected to the generator, generating an electromagnetic field in the brain.

It is recommended that the therapy is continual and to remove the electrodes only for skin care.  The tumor-growth inhibiting effect of the technology has been shown in a large study.  

Tumortherapie-
felder (TTF)

Bei der Therapie mit den so genannten Tumortherapiefeldern (TTF) ist das Ziel, die Zellteilung in Hirntumoren durch
elektromagnetische Wellen zu verlangsamen.

Nach Operation und Abschluss einer Bestrahlung erhält der Patient eine Gerätschaft, die im Wesentlichen aus wechselbarem Akku und Wellengenerator besteht und in
einem kleinen Rucksack mitgeführt werden kann.
Auf die rasierte Kopfhaut werden (in der Regel vier) großflächige Elektrodenpflaster geklebt, die über Kabel mit dem Generator verbunden sind und ein elektromagnetisches Wechselfeld im Gehirn erzeugen.

Das Gerät sollte möglichst rund um die Uhr genutzt und nur zur Hautpflege abgenommen werden. Die wachstumshemmende Wirkung der Technik wurde in einer großen Studie geprüft und gilt als erwiesen.

NANOTHERM THERAPYSYSTEM

Treatment with the NanoTherm Therapysystem enables thermotherapy based on nanomedicine

TREATMENT IN THERMAL ABLATION MODE

Thermal ablation is a generic term for all procedures in which the active principle is based on direct tissue destruction by heat. In this procedure, heat is generated by the prior introduction of nanoparticles in the area of the glioblastoma and their activation by an alternating magnetic field. At temperatures above 46 degrees Celsius, which are applied for over one hour, irreversible cell damage occurs. NanoTherm® is introduced into the glioblastoma by the neurosurgeon under a surgical procedure. This is followed by a one-hour treatment in the NanoActivator® to destroy the cancer cells by locally heating the tumor.

TREATMENT IN HYPERTHERMIA MODE (COMBINATION THERAPY)

The glioblastoma is brought to a controlled temperature of at least 43 degrees Celsius for one hour with the NanoTherm® therapysystem.

For thermal coverage of the entire tumor area, higher, even thermo-ablative temperatures are usually generated inside the tumor, which can be adjusted contactless from the outside with the help of the magnetic field strength.

The temperature inside the tumor is measured and recorded by a very thin glass fiber temperature sensor during the entire treatment period.

This treatment is repeated twice a week, 6 times in total. The previously introduced nanoparticles are made to vibrate by the alternating magnetic field from outside and the tumor is heated in a controlled manner. Depending on the physiological situation, cancer cells react more sensitively to heat than healthy body cells.

The treating physician decides on his own responsibility on the admissibility of implants and metallic objects outside the treatment region, requiring a minimum distance of 40 cm from the treatment device. Present metallic objects and implants (e.g. joints, fixing screws, dentures) within the treatment region must be removed or replaced, as these materials heat up during treatment in the NanoActivator®.

Patients with non-removable medical implants such as pacemakers, defibrillators, neurostimulators, shoulder joint replacements or other non-removable metallic implants are excluded from treatment.

During treatment with the NanoTherm® therapy system in hyperthermic mode, tumor cells are sensitized to other concomitant therapies (e.g. radiation or chemotherapy) and treatmenteffectiveness is increased.

BCNU-Wafer

BCNU (camustine) is a long time known chemotherapeutic agent that is taken as a capsule for the treatment of various tumors. In order to achieve higher effective concentrations in the brain tumor while bypassing the so-called blood-brain barrier, tablets („wafers“) containing this pharmacological agent are brought into the tumor cavity during surgery. There exist a few elderly studies that revealed a good treatment effect, however a high rate of side effects put this treatment strategy up for discussion.

 

Immunotherapy

In glioblastoma, factors are released that inhibit the immune system. Immunotherapy attempts to reactivate the body’s immune system, e.g. with antibodies that deactivate this inhibitory system. Examples here are the so-called checkpoint inhibitors (antibodies against the programmed cell death receptor or its ligands, PD1 and PDL1, and antibodies against
CTLA-4). Among others, nivolumab and pembrolizumab should be mentioned here.

Another form of immunotherapy is the use of vaccines directed against certain and specific features of the tumor. Similarly, the patient’s own immune cells (usually dendritic cells) can be injected after prior collection and modification in the laboratory with the aim of having the cells directed against the tumor.

There is also the possibility of isolating the patient’s own cells (e.g. T cells) and genetically modifying them in the laboratory outside the body (e.g. coupling them to a chimeric T cell receptor) so that they are directed against specific surface features of the tumor. Subsequently, the cells are reinfused into the patient, and it is hoped to achieve a tumor-specific long-lasting immune response (so-called CAR T-cell therapy).

Another form of therapy is oncolytic viruses.
Viruses can be genetically modified to specifically replicate in and kill tumor cells. 

In addition to the direct killing of tumor cells by the virus, it has been shown that tumor cells are also eliminated indirectly by activation of the immune system. Therefore, oncolytic viruses are often mentioned in the category of immunotherapy. 

Photo-
dynamic therapy (PDT)

This is a physical process in which a light-tempfindable colorant is enriched in the tumor cells. After irradiation with light of a specific wavelength, the tumor cells are destroyed. One advantage of PDT is that this method does not interact with other procedures, i.e., radiation therapy and or chemotherapy can be performed in addition.

Targeted Therapy

This form of cancer therapy involves novel drugs that directly target specific biological, genetic and cytological properties of tumors. These include, for example, antibodies directed against specific receptors. A well-known example is bevacizumab (antibody against VEGF). In addition, there are drugs that disrupt certain metabolic sequences in the tumor and thus specifically attack the tumor (e.g. proteasome inhibitors). 

GENTHERAPY

Genetherapy in general refers to the insertion of genetic information (DNA, RNA) into body cells in order to treat certain diseases. In the field of tumor therapy, viruses or stem cells (neural or mesenchymal) are used as gene shuttles to introduce genes into the tumor cells or the tumor environment. Suicide genes are used whose protein products act as enzymes and convert so-called „prodrugs“ into toxic molecules and thus kill the tumor cells (suicide gene therapy). Alternatively, or in combination with suicide gene therapy, genes can be introduced that activate an immune response against the tumor (cytokines/chemokines).  

NanoTherm ® Therapie System

Die Behandlung mit dem NanoTherm® Therapie System ermöglicht eine Thermotherapie, die auf Nanomedizin basiert

BEHANDLUNG IM MODUS THERMOABLATION

Thermoablation ist ein Überbegriff für alle Verfahren, bei denen das Wirkprinzip auf der direkten Gewebezerstörung durch Hitze beruht. Bei diesem Verfahren wird durch die vorherige Einbringung der Nanopartikel im Bereich des Glioblastoms und deren Aktivierung durch das magnetische Wechselfeld Wärme erzeugt. Bei Temperaturen über 46 Grad, die über 1 Stunde einwirken, treten irreversible Zellschäden auf. Das Einbringen von NanoTherm® in das Glioblastom erfolgt durch den Neurochirurgen mittels eines operativen Eingriffs. Im Anschluss erfolgt eine einstündige Behandlung im NanoActivator®, um die Krebszellen durch die lokal auf den Tumor begrenzte Erwärmung zu zerstören. 

Behandlung im Modus Hyperthermie (Kombinationstherapie)

Das Glioblastom wird mit dem NanoTherm ® Therapie System für eine Stunde kontrolliert auf eine Temperatur von mindestens 43 Grad Celsius gebracht.

Zur thermischen Abdeckung des gesamten Tumorareals werden in der Regel im Innern des Tumors höhere, auch thermoablative Temperaturen erzeugt, die mit Hilfe der Magnetfeldstärke kontaktlos von außen einstellbar sind.

Die Temperatur im Innern des Tumors wird dabei mittels eines sehr dünnen Glasfaser-Temperatursensors während der gesamten Behandlungszeit gemessen und aufgezeichnet.

Diese Behandlung wird 2x pro Woche, insgesamt 6x wiederholt. Die vorab eingebrachten Nanopartikel werden durch das Wechselmagnetfeld von außen in Schwingungen gebracht und der Tumor kontrolliert aufgeheizt. In Abhängigkeit von der physiologischen Situation reagieren Krebszellen empfindlicher auf Wärme als gesunde Körperzellen.

Über die Zulässigkeit von Implantaten und metallischen Gegenständen außerhalb der Behandlungsregion, mit 40 cm Mindestabstand zur vorderen oder hinteren oberen Gehäusekante des Therapiespaltes, entscheidet der behandelnde Arzt eigenverantwortlich. Vorhandene metallische Gegenstände und Implantate (z. B. Gelenke, Fixierschrauben, Zahnersatz) innerhalb der Behandlungsregion müssen entfernt oder ersetzt werden, da sich diese Materialien während der Behandlung im NanoActivator ® aufheizen.

Patienten mit nicht entfernbaren medizinischen Implantaten wie Herzschrittmachern, Defibrillatoren, Neurostimulatoren, Schultergelenkersatz oder anderen nicht entfernbaren metallischen Implantaten sind von der Behandlung ausgeschlossen.

Bei der Behandlung mit dem NanoTherm ® Therapie System im Hyperthemie-Modus wird diese für andere Begleittherapien (z.B. Strahlen- oder Chemotherapie) sensibilisiert und deren Wirksamkeit erhöht.

BCNU-Wafer

BCNU-Wafer ist ein schon lange bekanntes Chemotherapeutikum, das bei der Behandlung anderer Tumoren als Kapsel eingenommen wird. Um im Hirntumor unter Umgehung der sogenannten Blut- Hirn-Schranke höhere Wirkstomonzentrationen zu erreichen, werden während der Operation Tabletten („Wafer“) mit dem Wirkstoff in die Tumorhöhle gebracht. Etwas ältere Studien sahen  eine Wirksamkeit, allerdings gibt das Nebenwirkungsprofil Anlass zu Diskussionen.

Immuntherapie

Beim Glioblastom werden Faktoren ausgeschüttet, die das Immunsystem hemmen. Im Rahmen der Immuntherapie wird versucht das Immunsystem des Körpers wieder zu aktivieren, z.B. durch Antikörper, die dieses Hemmsystem deaktivieren. Beispiele sind hier die sogenannten Checkpoint-Inhibitoren (Antikörper gegen den programmierten Zelltod-Rezeptor oder seine Liganden, PD1 und PDL1, sowie Antikörper gegen
CTLA-4). Hier seien u.a. Nivolumab und Pembrolizumab genannt.

Eine weitere Form der Immuntherapie ist die Verwendung von Impfstoffen, die sich gegen bestimmte und spezifische Merkmale des Tumors richten. Ebenso können dem Patienten körpereigene Immunzellen (i.d.R. dendritische Zellen) nach vorheriger Entnahme und Modifizierung im Labor mit dem Ziel, dass sich die Zellen gegen den Tumor richten, injiziert werden.

Es gibt ferner die Möglichkeit, körpereigene Zellen (z.B. T-Zellen) zu isolieren und sie im Labor außerhalb des Körpers so genetisch zu modifizieren (z.B. an einen chimären T-Zellrezeptor zu koppeln), dass sie sich gegen bestimmte Oberflächenmerkmale des Tumors richten. Im Anschluss werden dem Patienten die Zellen zurückinfundiert, und man erhofft sich eine tumorspezifische langanhaltende Immunantwort (sog. CAR T-Zellen Therapie).

Eine weitere Therapieform sind onkolytische Viren.
Viren können genetisch so modifiziert werden, dass sie sich spezifisch in Tumorzellen vermehren und diese abtöten. 

Neben dem direkten Abtöten von Tumorzellen durch das Virus hat man zeigen können, dass Tumorzellen auch indirekt durch Aktivierung des Immunsystems eliminiert werden. Daher werden onkolytische Viren häufig in der Kategorie der Immuntherapie genannt. 

Photo-
dynamische Therapie (PDT)

Dabei handelt es sich um ein physikalisches Verfahren, bei dem ein lichtempfindlicher Farbstoff in den Tumorzellen angereichert wird. Nach Einstrahlung von Licht einer bestimmten Wellenlänge werden die Tumorzellen zerstört. Ein Vorteil der PDT ist, dass diese Methode nicht mit anderen Verfahren interagiert, d.h., es kann zusätzlich eine Strahlen- und oder Chemotherapie durchgeführt werden.