Why are Muni predictions so bad

The adult gliomas

Background: Brain tumors are among the ten most common fatal malignancies. Although there are no screening or preventive examinations, timely and effective diagnosis and therapy will affect the further course of the glioma. The therapy is ideally carried out by highly specialized centers. However, the course for this is set by the family doctor or specialists in various fields. An update of the basic knowledge on this topic seems necessary because the basic knowledge and the diagnostic-therapeutic possibilities have expanded considerably in recent years.

Method: Selective literature research (PubMed and Cochrane Library) and use of the guidelines of the German Societies for Neurosurgery, Neurology and Radiation Therapy

Results and conclusion: The neuroradiological diagnosis with the help of magnetic resonance tomography provides, in addition to the high-resolution morphological representation, additional biological and functional information, but still cannot replace the histological diagnosis. Extensive tumor resection has clear advantages for the overall survival of the patient. New molecular markers enable a prognostic assessment of the course of the disease. Chemotherapy has a permanent place in the therapy concepts for various tumors. With a median survival of 14.6 months for glioblastoma, for example, the prognosis remains poor.

Gliomas make up about 30 to 40 percent of intra-cranial tumors. About half of adult gliomas are glioblastomas. The incidence of primary brain tumors in the United States is estimated at 10 in 100,000 people per year and a gender distribution of 6: 4 (male to female). Gliomas are typical tumors of middle age, with a peak between 40 and 65 years of age (1).

Etiologically, only 1 to 5 percent of gliomas can be classified as hereditary (e1, 2). The origin of sporadic gliomas, however, is largely unknown. Only ionizing radiation is consistently considered to be a high risk factor for its development, with a relative risk rate of up to 22 (for example 23 patients out of 9,720 examined out of an epidemiologically expected 1.06 patients) (e1, 2).

Although gliomas are rare, they are of great importance in medicine due to their often poor course. As a result of their considerable variety of symptoms, they can be relevant for different disciplines. Due to numerous new findings on this tumor group, an up-to-date overview of the basic knowledge on this specialized topic is to be given.

learning goals

Learning objectives for the readers of this article are:

  • Get to know important aspects of the different manifestations of these tumors
  • Understand the basics of diagnosis and treatment including supportive measures
  • To gain insights into newer and future therapy strategies.

A selective literature search (PubMed and Cochrane Library) with the main terms “glioma” and “brain neoplasm” was carried out as the basis for this review article. The current guidelines of the participating professional societies as well as our own scientific studies and clinical experience were taken into account.

Neuropathology

The brain's own tumors are mostly of neuroepithelial origin. The largest subgroup is the glioma. According to the predominant cell type, these are divided into astrocytomas including glioblastomas, oligodendrogliomas, ependymomas and oligodendroglial / astrocytic mixed tumors. Rare mixed tumors have glial and neural tumor components.

According to the WHO (World Health Organization) classification of brain tumors, gliomas are currently classified into grades I to IV (Table 1gifppt). The WHO classification has historically developed, based on the work of Bailey and Cushing (e3), from various classification systems for brain tumors, taking into account histopathological and prognostic data, to the current system from 2007 (2).

Gliomas usually grow in a diffuse infiltrating manner within the white matter, so that they are often not directly visible on the brain surface. The gyri, however, appear splayed and flattened. In the peripheral area, the vessels are often massively dilated, while in the tumor center, especially in aggressive gliomas, thrombosed blood vessels are noticeable. Gliomas grow preferentially in the cerebral hemispheres; in children they also often occur in the brain stem or cerebellum. A tumor growth over the bar in both frontal poles is called a butterfly glioma. 5 to 10 percent of glioblastomas already appear multiple at the time of diagnosis (3). The tumor is usually surrounded by a marked edema in the white matter.

Pilocytic astrocytomas represent a special case, as low-grade WHO grade I tumors, predominantly of childhood, have a distinct tumor biology and should not be mixed with diffuse astrocytomas of WHO grades II to IV.

The ability of the glioma cells to migrate is essential for the aggressiveness of gliomas. Therefore, on the one hand, it is impossible to completely remove gliomas by local measures such as surgery. On the other hand, this also hinders cytotoxic therapies, since migrating cells are less often in the division phase, which is sensitive to cytotoxic drugs, compared to non-migrating cells.

Diagnosis

Clinical examination

Brain tumors can cause virtually any neurological disorder. The type of disorder does not depend on the histology but on the location of the tumor (e4). In principle, local symptoms such as paresis, sensitivity, visual or speech disorders are differentiated from general signs of intracranial pressure such as headache, vomiting, congestive papilla or changes in consciousness. Typical symptoms are seizures, focal or generalized, which occur more frequently in low-grade gliomas.

A rapid increase in clinical symptoms can indicate malignant growth or a CSF circulatory disorder. In the case of glioblastomas, the duration of symptoms prior to diagnosis is only 7 percent longer than a year (e5), while for astrocytomas the duration of symptoms over a year was given as 34 percent (e6). Occasionally, initial symptoms appear suddenly (apoplectiform), which can be caused by tumor hemorrhage.

Acute symptoms of life-threatening intracranial entrapment are headache, vomiting, and increasing impairment of consciousness leading to unconsciousness. After unconsciousness occurs, pupillary dysfunction and extension synergisms can occur. Basically, both slow and fast growing tumors can lead to entrapment and be fatal. Gliomas rarely metastasize, even if histologically classified as highly malignant (e7)

The Karnofsky Performance Score (classification of the general condition in the case of tumor diseases, for example) should be determined for each examination, which, together with the age of the patient, has a significant influence on the later overall prognosis and should be taken into account for the complete diagnostic and therapeutic planning.

A CSF examination is not of great importance. At best, it can be helpful in differential diagnosis in the event of suspected lymphoma, brain abscess or germ cell tumor and to clarify the question of diffuse tumor cell seeding.

Early detection, prevention or screening examinations are of no importance in the case of gliomas. Specific tumor markers are not available. In the differential diagnosis, cerebral haemorrhage, circulatory disorders, inflammation, abscesses, trauma consequences, CSF circulatory disorders and psychiatric, endocrinological or metabolic diseases should be considered.

General neuroradiological aspects

Cross-sectional imaging methods are mainly used, with magnetic resonance tomography being clearly superior to computed tomography.

The reasons for this are:

  • greater sensitivity
  • higher soft tissue contrast
  • better expansion assessment
  • Display option in three room levels

In principle, T2- and T1-weighted, native and contrast-enhanced sequences as well as a Fluid Attenuated Inversion Recovery (FLAIR) examination should be performed for brain tumor diagnostics. A representation in three planes (axial, sagittal, coronal), if necessary a T2 gradient echo (T2 * [* denotes a special T2 sequence]) for the detection of blood / calcifications or diffusion weighting to differentiate glioma / abscess are recommended. The layer thickness should not exceed 5 to 6 millimeters (e8).

Intravenous contrast medium should always be applied in order to better delimit the mass in its extent and against the perifocal edema, to differentiate high-grade from low-grade gliomas / tumor parts or vital from non-vital tumor tissue, or to detect small satellites (e9).

Postoperatively, tumor residues can be detected in the early phase (maximum 48 hours) of barrier-disrupted tumors (4). Computed tomography can be helpful for tumors with calcification or bone infiltration.

Newer investigation methods

MR proton spectroscopy enables measurable metabolite signal intensities (N-acetyl-
Aspartate, choline, creatine, lactate, lipids) better differentiation between neoplastic and non-neoplastic brain lesions, for example cerebral infarction, and a certain degree of glioma (e10). The relative cerebral blood volume (rCBV) allows conclusions to be drawn about the malignant transformation of low-grade gliomas and the outcome (recurrence-free or overall survival) (e11, 12).

Functional magnetic resonance imaging (fMRI) enables the visualization of brain activity due to changes in blood flow and increased nerve cell activity. Active (finger tapping, speech) or passive (sensorimotor nerve stimulation) paradigms can be used, for example, to visualize motor / sensitive cortical areas or language lateralization. With the help of the diffusion tensor image
The relationship between the tumor position and larger orbit systems, for example the pyramidal orbit, can be visualized ("fiber tracking") (e13) (Figure 2jpgppt). If the MR-morphological appearance is atypical, these methods are regularly used in routine diagnostics for better differential diagnostic delineation of individual lesions or for sub-
used to support neurosurgical operation planning.

A more specific identification of the regions of the strongest anaplasia and thus possibly a more targeted biopsy is possible with the (amino acid) PET / SPECT compared to the MRI. PET / SPECT is also more specific than MRI in differentiating between recurrence and post-therapeutic changes such as radionecrosis (e14, 15).

therapy

The therapy of gliomas is currently already very differentiated, mainly depending on the histological diagnosis, and will be further individualized in the future. What is certain is that the prognosis of a glioma generally depends on the histological classification, the tumor grade, the Karnofsky performance score as well as neurological deficits and the age of the patient. Other new molecular markers such as LOH ("loss of heterozygozity") from 1p / 19q, the methylation of the promoter of MGMT- (methylguanine methyltransferase) or the mutation of IDH (isocitrate dehydrogenase) -1 meanwhile enable a more extensive prognostic assessment (Table 2gifppt). For the following special tumor groups, the currently guideline-compliant therapy steps are shown. For grade III and IV tumors, the recommendations correspond to evidence class 1b. Due to the considerably longer survival times and the necessary follow-up periods for grade I and II tumors, only recommendations of evidence class 3 have so far existed (for an overview, see Table 3gifppt).

Special tumors

Pilocytic astrocytomas (WHO grade I)

The pilocytic astrocytoma classically occurs in the cerebellum of children and is usually located around the fourth ventricle. Cases beyond the age of 30 are rare. Typically, a cystic mass is found neuroradiologically with a nodular, strongly inhomogeneous contrast medium-absorbing part. Opticochiasmatic tumors are predominantly non-cystic and show homogeneous contrast enhancement (5). The treatment of choice is total macroscopic resection. If this is not possible, adjuvant radiation therapy can be discussed, although the benefit is still unclear. The prognosis is excellent with recurrence-free survival times of well over 20 years. Cases of malignant transformation have been documented extremely rarely (6, e16).

Low grade gliomas (WHO grade II)

Low-grade gliomas are preferably temporal or frontal (sub-) cortical. They are T2-weighted homogeneously hyperintense, T1-weighted slightly hypointense, mostly without perifocal edema and without contrast enhancement. A contrast enhancement that occurs in the course of the disease is an image-morphological correlate of a malignant transformation. An infarct or gliosis is possible in the differential diagnosis, so histological confirmation through an open tumor resection or stereotactic needle biopsy is recommended. Additional neurological failures should be avoided at all costs during the surgical procedure.

All modern intraoperative aids can be used sensibly (7):

  • Neuronavigation
  • open MRI
  • intraoperative electrophysiological monitoring
  • Voice monitoring when the patient is awake ("awake surgery")

The preoperative functional diagnostics can include:

  • the magnetic encephalogram (MEG)
  • the functional MRI (f-MRI)
  • the MRT "fiber tracking"
  • the functional-topographical mapping through implanted electrodes

In circumscribed, symptomatic and surgically easily accessible grade II gliomas, resection as complete as possible is the primary treatment of choice. McGirt et al. found 5-year survival rates of up to 95% in their study (e17). It can be assumed with sufficient certainty (evidence level 2b) that gross total resection improves overall survival (OS) in both low-grade gliomas and glioblastomas (e17).

Immediate postoperative radiation therapy could not be shown to have any advantage over waiting behavior with regard to overall survival time (8). The only advantages are with regard to the time to tumor progression. Especially in younger patients (< 40 jahre),="" mit="" einer="" primär="" besseren="" prognose,="" kann="" daher="" nach="" der="" histologischen="" sicherung="" eine="" „wait="" and="" see“-strategie="" bevorzugt="" werden.="" bei="" ausgewählten="" patienten="" mit="" einem="" streng="" umschriebenen="" tumor="" kann="" die="" stereotaktische="" brachytherapie="" mit="" jod="" 125="" eine="" alternative="" darstellen="">

The standard therapy for progressive low-grade gliomas is fractionated radiation therapy as low-dose irradiation with 45 or 50.4 Gy (10) after a possibly previous surgical tumor resection. Advantages of chemotherapy as an alternative or in combination with radiotherapy for diffuse astrocytoma grade II have not yet been proven.

Newly diagnosed WHO grade III gliomas

The newly diagnosed WHO grade III gliomas include anaplastic astrocytomas, oligoastrocytomas and oligodendrogliomas. These inhomogeneous masses in T2 and T1 show moderate, spotty contrast enhancement. The oligodendroglial tumors also often show calcification (T2 *; CT) and a rather low level of perifocal edema (5).

Histological confirmation is essential, as grade III tumors cannot be differentiated from grade II tumors radiologically, and an oligodendroglial portion cannot be clearly verified either. If the location permits, the operation should be performed as an open microsurgical tumor resection that is as extensive as possible (11).

In the subsequent postoperative therapy, the combination of chemotherapy and radiation therapy is not an advantage over individual therapies in terms of overall survival (12). There is also no difference between these individual therapies, radiation versus chemotherapy (multicenter study by the neuro-oncological working group of the German Cancer Society, NOA-04 study [11]). The median overall survival in the NOA-04 study was 72.1 months after radiation therapy and 82.6 months after chemotherapy, with no statistically significant difference. There was also no difference between chemotherapy with temozolomide or procarbazine. However, if one considers the possible side effects and long-term effects, advantages for adjuvant chemotherapy with temozolomide after primary surgery could be derived from these data.

The NOA-04 study confirmed the long-known significant prognostic advantage for the histological evidence of an oligodendroglial portion. In addition, the positive prognostic factors such as 1p / 19q-LOH, MGMT promoter methylation and IDH-1 mutation were impressively confirmed.

Newly diagnosed glioblastomas

In accordance with the histopathological multiformity, neuroradiological magnetic resonance tomography offers a very variable appearance, predominantly a centrally necrotic, strongly marginal, contrast-enhancing mass with pronounced perifocal edema (illustration 1gifppt).

In the differential diagnosis, metastases, abscesses, or lymphomas should be considered (4). A histological confirmation of the diagnosis is essential; the required surgical procedure can be performed either as a stereotactic biopsy or as a microsurgical resection.Only in recent years has it been possible to prove in studies that patients really benefit from extensive tumor resection (13, e18). In particular, the multicenter study by Stummer et al. showed significantly longer survival under fluorescence-assisted microsurgery with 5-aminolaevulinic acid (5-Ala) for patients in whom no contrast-enhancing tumor residues could be detected with the help of magnetic resonance imaging shortly after the operation (median survival of 16.7 months versus 11.8 months, p< 0,0001) (14,="" e19).="" bei="" der="" standardmäßig="" mikrochirurgischen="" operation="" kann="" eine="" operative="" mortalität="" von="" unter="" 2 %="" und="" eine="" permanente="" neurologische="" morbidität="" von="" unter="" 5 %="" erreicht="" werden="" (15).="" aufgrund="" der="" erheblichen="" migrationsfähigkeit="" von="" gliomzellen="" ist="" eine="" r0-resektion="" von="" glioblastomen="" praktisch="" nicht="" möglich="" und="" folglich="" eine="" weitere="" anschlusstherapie="" erforderlich.="">

According to a study published in 2005 by Stupp et al. published study by the European Organization for Research and Treatment of Cancer (EORTC) and the National Cancer Institute of Canada (NCIC), the post-
Surgical radiation therapy with accompanying temozolomide chemotherapy for six weeks with subsequent adjuvant temozolomide therapy (six cycles in a 28-day rhythm) defined as the new standard. The median survival time was increased from 12.1 to 14.6 months (p = 0.001) (13). Most side effects are rather moderate, for example a maximum of 1 percent of patients suffer from grade 3 to 4 vomiting. Severe myelosuppression (grade 3 to 4) can occur in up to 16% of cases (13).

During irradiation, total doses of around 55 to 60 Gray (1.8 to 2 Gy fractions) are administered concentrated on the target tumor volume with sharply decreasing doses in the areas of the brain rim (16). Whole-brain radiation is now considered obsolete.

In a subgroup evaluation of the Stupp study, the importance of MGMT promoter methylation as a predictive, molecular marker for the response to temozolomide and probably also for any type of therapy could be shown for the first time. The mean survival of the patients with methylated MGMT promoter was 21.7 months (versus 12.7 months), the 2-year survival was 46% (versus 13.8%) (17).

Recurrent gliomas (WHO grade III and IV)

The data on relapse gliomas are less informative and mostly only refer to small phase II studies. Re-operation is generally recommended:

  • when the tumor is easily accessible
  • a significant reduction in the remaining residual tumor mass is to be expected
  • Due to the localization of the tumor, a postoperative improvement in the neurological condition can be assumed
  • and the general condition of the patient is satisfactory.

For individual patients with circumscribed lesions, renewed, most likely hyperfractionated (e.g. 4 × 5 Gy) radiation therapy or stereotactic one-time radiation therapy can be considered (e20, e21).

The decision to repeat chemotherapy must be made on an individual basis. In principle, a prognostic improvement can be assumed through renewed chemotherapy, for example with nitrosoureas (ACNU) or PCV combination therapy. In particular, increasing the dose of temozolomide to 150 mg / m² alternating weekly led to an increase in median progression-free survival to 21 weeks compared to 13 weeks in a historical control group (18). The quality of life of the patients is very different in individual cases and cannot be predicted.

Supportive therapy

Corticosteroids

A typical side effect of brain tumors is the perifocal, vasogenic edema, which can significantly increase the tumor's space-occupying effect. Targeted drug therapy for this edema with dexamethasone can quickly improve neurological deficits and the overall condition of the patient (e22 – e24). This very effective therapy was proposed in 1961 by Galicich et al. was introduced (e25) and has been used widely since then. The authors are not aware of a high-quality randomized controlled study on this, so that all recommendations for this therapy are ultimately empirical in nature. Due to the numerous significant side effects in long-term therapy, however, the application should be reduced as quickly and as much as possible.

As an alternative to dexamethasone, an experiment with boswellia acids, an incense extract, makes sense. This phytotherapeutic, which can be obtained from international pharmacies in Germany, can significantly reduce peritumoral edema of up to 40% or at least reduce the dose of dexamethasone in some patients (19, e26).

Antiangiogenic therapy with bevacizumab also reduces perifocal edema by reducing vascular permeability. An application for supportive therapy is certainly not to be recommended at the moment. Future studies will show what improvement in quality of life can actually be achieved with this (20).

Antithrombotic therapy

Patients with malignant gliomas have a significantly increased risk of leg vein thrombosis and pulmonary embolism. The use of anticoagulant drugs such as heparins or, better still, low molecular weight heparins is therefore also used in many clinics and also in the early postoperative phase, although these drugs are not approved for use after brain operations. However, practical experience has shown that the actual risk of suffering an intracranial hemorrhage in the situation described is relatively low. However, data on this topic are only available from several smaller studies that describe no intracranial bleeding in up to 50 patients each (e24, e27). The prescription of anticoagulants of the phenprocoumon type is less advisable and should, if possible, not be started before four weeks after the operation (e28).

Anticonvulsants

About 50 percent of glioma patients experience epileptic seizures in the course of their illness. Focal seizures predominate over generalized seizures. While the anticonvulsant potency is largely the same, the interactions with cytostatics such as temozolomide administered in parallel are caused by enzyme induction or inhibition. With the newer anticonvulsants like lamotrigine, topiramate or levetiracetam these interactions are less than with the older ones like phenytoin, carbamazepine or valproic acid. The newer anticonvulsants, which are also generally better tolerated, have other disadvantages such as, for example, the slow possibility of increasing the dosage of Lamotigen or the (still) considerable therapy costs for levetiracetam. Although there are no meaningful studies on this subject, for practical reasons, anticonvulsant treatment is advisable after the first seizure has occurred and a glioma is suspected (e24). General postoperative or general anticonvulsant prophylaxis in patients with gliomas is not recommended (e29).

New approaches to treatment

With knowledge of the molecular genetic changes, targeted molecular genetic therapeutics were developed. Inhibitors of “epidermal growth factor receptor” (EGFR) such as gefitinib or erlotinib, integrins such as cilengitide and tyrosine kinase such as imatinib have so far shown little success (21).

However, the first positive results were obtained from the inhibition of angiogenesis with bevacizumab, a VEGF antibody, in combination with irinotecan. Some phase I / II studies showed a significant increase in the six-month progression-free survival rate of up to 43% for glioblastomas and up to 59% for anaplastic gliomas compared to 15% and 31% in a historical control group (20). However, a significant change in overall survival could not be demonstrated. Among other things, a randomized, controlled study by the Radiation Therapy Oncology Group (RTOG) is to further clarify these results on a larger scale.

Furthermore, antisense oligonucleotides against TGF-β2, an extremely immunosuppressive cytokine, were applied locally via a catheter inserted into the tumor. Particularly in the case of WHO grade III astrocytomas, a possible treatment option seems to be emerging (22), which is being examined in an international, multicenter phase III study. Other immunotherapy studies, with passive or active methods, have been able to demonstrate all the prerequisites for immunotherapy in the brain and confirm its feasibility in principle, but so far there has been no evidence of an emphatic clinical success (e30, e31).

This also applies to gene therapy, which offers interesting options both as a direct and an indirect variant (e32).

The intratumoral infusion of exotoxins or oncolytic viruses has so far remained far below expectations (e33, e34).

In the future of neuro-oncology, research is unlikely to find an optimal therapeutic approach for all patients, including those with the same tumor type. Rather, an individualized therapy based on molecular classification will gain the greatest importance.

Conflict of interest

PD Schneider received financial support as part of joint study projects from: Merck and Antisense-Pharma,

Prof. Mawrin received support for congress trips and for research projects from the following companies: Merck, Pfizer, Wyeth and DAKO

Dr. Scherlach and Prof. Skalej supervised the Sapphire study of Antisense-Pharma GmbH as radiologists.

Prof. Firsching declares that there is no conflict of interest within the meaning of the guidelines of the International Committee of Medical Journal Editors.

Manuscript dates
Taken in: October 6, 2009, revised version accepted on August 9, 2010

Address for the authors
PD Dr. med. Thomas Schneider
Neurosurgery Clinic
Otto-von-Guericke University Magdeburg
Leipziger Strasse 44

39120 Magdeburg

Email: [email protected]

Summary

Gliomas in Adults

Background: Primary brain tumors are among the ten most common causes of cancer-related death. There is no screening test for them, but timely diagnosis and treatment improve the outcome. Ideally, treatment should be provided in a highly specialized center, but patients reach such centers only on the referral of their primary care physicians or
other medical specialists from a wide variety of fields. An up-to-date account of basic knowledge in this area would thus seem desirable, as recent years have seen major developments both in the scientific understanding of these tumors and in clinical methods of diagnosis and treatment.

Methods: Selective search of the pertinent literature (PubMed and Cochrane Library), including the guidelines of the German Societies of Neurosurgery, Neurology, and Radiotherapy.

Results and Conclusion: Modern neuroradiological imaging, in particular magnetic resonance imaging, can show structural lesions at high resolution and provide a variety of biological and functional information, yet it is still no substitute for histological diagnosis. Gross total resection of gliomas significantly improves overall survival. New molecular markers can be used for prognostication. Chemotherapy plays a major role in the treatment of various different kinds of glioma. The median survival, however, generally remains poor, e.g. 14.6 months for glioblastoma.

Citation style
Schneider T, Mawrin C, Scherlach C, Skalej M, Firsching R: Gliomas in adults. Dtsch Arztebl Int 2010; 107 (45): 799-807. DOI: 10.3238 / arztebl.2010.0799

@Literature marked with "e":
www.aerzteblatt.de/lit4510

The German version of this article is available online:
www.aerzteblatt-international.de

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