Therapy
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