Brain Tumors -an overview:

 
Dr. A. Vincent Thamburaj,
Neurosurgeon,  Apollo Hospitals, Chennai , India.

The epidemiological study of the brain tumors world wide is limited, more so in India, due to various factors. It has been reported that the incidence range is about is 1-10/100,000 depending on the population studied. It is reported to be lowest in Mexico, and highest in Israel. The incidence of Gliomas (primary brain parenchymal tumors), the commonest brain tumor is about 5/100,000. The incidence of Meningioma, the commonest benign brain tumor, is about 1.23/100,000. Metastases constitute 30% to 50% of them.The Pediatric brain tumors form 20-30% of childhood malignancy.

 

 Pathology:

 

The etiology of brain tumors remain largely unknown, except for the hereditary form of retinoblastomas, genetically determined neurocutaneous syndromes and rare examples of tumors resulting from radiation or trauma.

However, the following factors appear to have a role:

 

Racial factors: Though brain tumors are found throughout the world,  certain varieties appear to be less frequently seen in certain races. Germinomas are more common in Japan than elsewhere in the world. Acoustic schwannomas have been reported to be rare in African Blacks.

 

Familial and genetic factors: An inborn, hereditary or inherited factor plays a role in the origin of gliomas. Oncogenes, a class of structural genes, play a decisive role in the development of neoplasms. Studies on malignant and low grade gliomas and on glioma cell lines have led to some speculative hypotheses about genetic pathways that may determine the transformation of normal glial cells to glioblastoma cells. < 5% of glioma patients have a family history of brain tumor. Several inherited diseases, such as tuberous sclerosis, neurofibromatosis type I, Turcotís syndrome, and Li-Fraumeni syndrome, predispose to the development of gliomas. However, these tumors tend to occur in children or young adults and do not account for the majority of gliomas, which appear in later years. Neurogenetic aspects are discussed elsewhere.

 

Transformation of ectopic tissue and vestigeal rests: Neoplasms, most often benign in nature, are seen to arise from vestigeal tissues. These include the teratomas and teratoid neoplasms, dermoid and epidermoid cysts, craniopharyngiomas and chordomas. These are clearly of malformative origin.

 

Age and Sex: While medulloblastomas and cerebellar astrocytomas are tumors almost entirely restricted to childhood, glioblastomas are generally seen in the adult. Primary parenchymal tumors are twice as common in males as in females, thus implicating obvious hormonal factors in the etiopathogenesis. Meningiomas are commoner in females, though some Indian and African neurosurgeons found a slight male preponderance.

 

Trauma: While head injury has been invoked in the pathogenesis of meningiomas, there is no evidence that such an injury plays any significant role in the development of a subsequent glioma. There are rare case reports of a glioblastoma occurring in the tract of a leucotomy or at the site of a gunshot wound.

 

Environmental factors: Prior cranial irradiation clearly increases the risk of subsequent intracranial neoplasms. Certain environmental factors have been tentatively linked to the development of gliomas, but they apply to few patients. Severe head trauma, chronic exposure to petrochemicals, or employment in the aerospace industry may be predisposing factors. Some reports suggest that with long term use of cell phones, there appears to be an increased risk for cases with tumors in the temporal, temporoparietal, or occipital lobe. No increased risk for brain tumors was found for medical diagnostic x-ray investigations. Brain tumors are not associated with lifestyle characteristics, such as cigarette smoking or alcohol use.

 

Irradiation: While gliomas do not appear to have resulted from previous therapeutic radiation to the head, this procedure might be an inciting factor in the production of an intracranial sarcoma. The hazard appears particularly associated with radiotherapy for pituitary adenomas and the resultant tumor is more frequently a fibrosarcoma of the dura, developing anywhere from 20 years later.

 

Chemical factors: Carcinogenic chemicals have long been employed to induce intracranial tumors in experimental animals. The most important of those are the nitrosamines-both methyl and ethyl nitrosourea. The exact mechanism of action is not clear, but may involve the binding of polycyclic hydrocarbon metabolites to guanine in DNA. It must be noted that to date no chemical carcinogen has been implicated in the production of a human cerebral neoplasm. There is no specific evidence linking human CNS tumors to chemical carcinogens.

 

Infective agents:  Experimentally a large number of viruses have been used for this purpose in animals. In man the only known virologic disorder of the brain associated with the production of bizarre astrocytes consistent with cytologic features of malignant cells, is the rare condition of progressive multifocal leucoencephalopathy. Here virions belonging to the papova group of viruses have been detected. Some patients with JC virus induced demyelination have developed multifocal astrocytomas

 

There is a wide histopathological variability (click for WHO classification) in brain tumors. Most brain tumors are named after the cells from which they develop. They may be intrinsic and arise from both the glial cells (mature and immature neuroepithelial cells), or extrinisic from the meninges, schwann cells of the nerve sheaths, and the pituitary.

Local extension from tumors of the skull or paranasal sinuses, metastasis from a distant organ, and occasionally, primary CNS lymphoma, form most of the rest. Hematological disorders, such as, leukemia, and rarely, myeloma are the other possibilities.

Hamartomas from the vestigeal remnants, and cysts are also traditionally included in brain tumor category. Other rare tumors have also been reported.

 

In fetal life and the first two years, supratentorial tumors are more common. Between 3 and 15 years infratentorial growth is much more frequent. In adults, supratentorial compartment is more commonly involved.

Intrinsic tumors produce regional parenchymal effects include, compression, invasion and destruction of surrounding brain leading to hypoxia, competition for nutrients and spread of necrosis. Diffuse Intracranial effects include elevated intracranial pressure due to tumor induced increases  in the volumes of brain, blood and CSF, vasogenic edema, infarction due to venous or arterial occlusion, and alteration in the balance of CSF production and absorption.

Extrinsic lesions, such as meningiomas, displace the brain, thereby compromising the brain function. In late stages, there may be degeneration, hemorrhage or necrosis. Peritumoral cysts arise from adhesions and accumulation of protein containing CSF, reactive gliosis, fibroblastic proliferation in the final stage of peritumoral edema or rarely as an exudate from the tumor surface, and behave like an intrinisic tumor.

There may be associated hydrocephalus which may be due to obstruction to CSF pathways, or change in CSF dynamics. It is more frequent in infratentorial lesions.

While the brain is a favorite site for metastases from tumors from the rest of the body, it is well known that central nervous system tumors do not metastasize outside the nervous system, except on rare occasions, when surgery has resulted in contact of the tumor with extracranial tissues.  

Malignant cells have been found in the veins in the neighborhood of a malignant glioma. Similarly such cells are also released into the CSF. There may be an immunological defence of the body tissue to the circulating malignant glial cells. On the contrary, the brain itself seems to be incapable of any significant degree of defence response. Though there are no lymphatic channels in the brain, mononuclear cells expressing T lymphocytes and macrophage cell surface markers have been identified in the perivascular spaces of the brain. It has also been observed that a third of all human gliomas show lymphocytic and mononuclear infiltration mostly around the blood vessels. Gliomas containing such infiltrates had a longer survival.   

There are a few reports of the presence of sensitized lymphocytes as well as humoral antibodies in patients with gliomas.  Considerable evidence indicates that tumors in man and animals can provoke an immune response in the host, thus providing the basis for employing immunotherapy in the treatment of human tumors.  In the perivascular lymphocytic collections, cytotoxic and suppressor T lymphocytes are predominant. Monocytes, macrophages with cell surface expression of major histocompatability antigens, are also present. Abnormalities in cell mediated and humoral immunity occur in patients with gliomas.  Abnormalities in cell mediated immunity are more severe in patients with higher grade gliomas.

 

 Clinical features:

 

The evolution of illness is usually insidious and progressive. Occasionally, as in intratumoral bleed, the symptoms may be acute. Shorter duration usually suggests malignancy. In most cases, the general clinical manifestations are due to elevated intracranial pressure, whereas focal signs and symptoms reflect tumor action on adjacent structures.

 

A patient with a 'brain tumor' may present with one or more of the following:

 

Symptoms and signs of raised intracranial pressure: Early morning throbbing headache which gets worse progressively suggest increased intracranial pressure, especially when associated with projectile vomiting. There may no nausea. Vomiting is more common in children. Site of headache has some importance occasionally. Pain at the back of head may indicate tonsilar herniation.

Papilledema and visual failure suggest long standing increased intracranial pressure.

Disturbed concentration, judgment, and memory, may result from increased intracranial pressure. On the contrary, most children with raised ICP, are well behaved and mature in their actions.

 

Focal or generalized epilepsy: Seizures occur in about 30% of all brain tumors, and about 50% of all supratentorial tumors. 1% of all with epilepsy have brain tumors. A tumor must be ruled out in any late on set epilepsy. It is the first symptom in 50% of temporal tumors, 78% of frontal tumors, and 93% of central tumors. Generally, seizure as the only symptom suggest a benign or low grade lesion. It may be focal or generalized. Focal seizure may suggest the site of lesion. In late stages of increased intracranial pressure seizures may occur irrespective of tumor location.

 

Symptoms related to location: Patients with left sided dominant hemispheric lesions may have language deficits, difficulty with verbal learning and memory, problems with verbal reasoning and impaired right sided motor dexterity. A higher incidence of depressive disorders along with dementia and psychotic symptoms is also seen. On the other hand, right hemispheric tumors may produce visual perceptual difficulties, difficulty in facial recognition and defects of left sided motor dexterity.

Frontal lobe lesions often results in profound changes in personality and behavior. Convexity involvement tumors may manifest with depression and  motor programming deficits and impaired speech initiative. Orbitofrontal involvement is associated with some degree of impulsivity, lack of inhibition, tendency to make puerile jokes with silly laughter, and a lack of concern. Medial frontal involvement is more likely to manifest as an inflexible attitude, apathy, and impaired motivation.

Temporal lobe lesions, most commonly, produce seizures, with olfactory and gustatory hallucinations. Impaired visual and auditory functions can occur. Inferior temporal or temporo limbic involvement leads to psychiatric symptoms, more commonly with dominant sided lesions. Involvement of insula, claustrum, and para hippocampal gyrus may produce panic attacks and anxiety.

Parietal lobe involvement is suggested by cortical sensory disturbances, such as tactile localization, joint position sense; sensory inattention, loss of awareness of the affected half of the body, may be an early feature. Progressive weakness may be seen in motor strip involvement.

In occipital lobe tumors, visual field defect is common. Cortical blindness can occur.

Features of associated hydrocephalus may be predominant in midline lesions. Sella and parasellar lesions present with visual, hypothalamic-pituitary dysfunction and neighborhood cranial nerve dysfunction may be there. Lesions near the falx may cause bilateral signs. Irritation of the supplementary motor area may result in focal seizures.

Basal ganglia lesions result in abnormal movements, rigidity or tremors.

Tumors involving the hypothalaums usually present with hypothalamic-pituitary dysfunction.

Intraventricular tumors usually present with features of hydrocephalus.

Brainstem lesions are associated with lower cranial neuropathies with hiccups and swallowing difficulties. Pupillary abnormalities can occur.Bilateral limb weakness with hypertonia and sensory disturbances may occur. Features of associated hydrocephalus may be present.

Cerebellar lesions present with incoordination and ataxia. Cognitive dysfunction may manifest in children. Cerebellopontine angle tumors , in addition to cerebellar signs, may exhibit lower cranial dysfunction.

False signs: A disturbance of blood supply to distant areas or by shifts and changes in the position of various structures may lead distant effects which may present as the primary symptoms. Abducent nerve paresis is the most common, due to its long intracranial route. However, such false signs occur only in late stages, which should be rare these days.

 

Deformity of head: Macrocrania is common in infants. Localized skull swelling due to long standing lesions may occur in adolescents. Malignant tumors may erode the skull and present as skull deformity.

 

 Investigations:

 

Skull X-rays, angiograms, ventriculograms, pneumoencephalograms have become history and been replaced with CT and MRI these days.

Magnetic resonance imaging (MRI) , introduced by  Moorey and Hinshaw in 1979, has made enormous strides and is the imaging of choice these days. MRI imaging, particularly, contrast enhanced is much more sensitive than CT due to inherent high contrast and spatial resolution, multiplanner capability. Soft tissue changes, mass effect, and the distorted anatomy are better demonstrated by T1 images. T2 images demonstrate the extent of tumor edema complex. Contrast enhanced MRI is important to assess the vascularity and the blood brain barrier(BBB) break down.

 

Computerized tomography (CT) scan, introduced by Hounfield in 1967 has equally improved in leaps and bounds. It may be an alternative when MRI is not available, and is particularly useful to study the associated bone involvement. 3D images are as informative as a MRI. Contrast enhancement, as in MRI,  indicates the vascularity and BBB breakdown. 

 

CT anigiogram and MR angiogram have replaced the conventional 4 vessel angiography. The tumor vascularity, incasement,and displacement of major vessels, and involvement of venous sinuses may be studied adequately, before surgery.

 

Limitations of structural MR/CT imaging, include, limited prognostic value, poor indicator of true extent of tumor, especially in high grade lesions, post-treatment changes (surgical, radiation) which limit capability to detect tumor recurrence, overlap in imaging appearance among tumor types and between tumors and non-neoplastic lesions, with potential implications for treatment approach.

 

Magnetic resonance spectroscopy (MRS) is a non-invasive analytical technique that has been used to study metabolic changes in brain tumors, strokes, seizure disorders, Alzheimer's disease, depression and other diseases affecting the brain.

MRS can be done as part of a routine MRI on commercially available MRI instruments. MRS and MRI use different software to acquire and mathematically manipulate the signal; the difference is the use of a state of the art technology that analyze the chemical composition of proton (hydrogen)-based molecules, some of which are very specific to nerve cells. This technology evaluates the chemical composition and integrity of functioning upper motor neurons in the brain, particularly motor neurons.

It has also been used to study the metabolism of other organs.

Unlike magnetic resonance imaging (MRI), which gives us a picture of anatomical and physiological conditions, MRS generates a frequency domain spectrum that provides information about biochemical and metabolic processes occurring within tissues. It is very useful in distinguishing destructive lesions from neoplastic processes. In addition, it provides a definition of tumor grade, aggressiveness, and relevant biochemistry. It also helps in monitoring of a successful tumor response before its regression during non-surgical treatments, and conversely the early definition of tumor recurrence. Increased choline, decreased NAA, increased lactate, increased Lipid, and decreased total creatinine, are the biochemical defects in varying degrees , common to the majority of brain tumors as measured by MRS. However, it is not reliable in irregularly shaped and cystic lesions. Recently, multi Voxel chemical shift imaging has shown promising results.

 

Positron emission tomography (PET) scan uses a small dosage of a chemical called radionuclide combined with a sugar. This combination is injected into patient. The radionuclide emits positrons. A PET scanner will rotate around a patient's head to detect the positron emissions given off by the radionuclide. Because malignant tumors are growing at such a fast rate compared to healthy tissue, the tumor cells will use up more of the sugar which has the radionuclide attached to it. The computer then uses the measurements of glucose used to produce a picture which is color coded. It is ideal for measurement of blood flow, glucose metabolism, receptor binding, DNA and protein synthetic processes and helps in distinguishing recurrent high grade tumors from radiation necrosis, and lymphoma from infectious lesions in AIDS. It is of limited value in small lesions(< 1cm).

 

Single photon emission tomography (SPECT) is more widely available and less expensive. It utilizes isotopes to study cerebral blood flow and tissue metabolism of glucose and amino acids, and helps in distinguishing recurrent high grade tumors from radiation necrosis, and lymphoma from infectious lesions in AIDS, similar to PET scan. However, it has poorer resolution and decreased sensitivity as compared to PETscan.

 

Functional MRI (fMRI) is a convenient technique for providing complimentary information to other imaging studies. fMRI offers possibility of performing these cortical localization routinely and in existing rather than new instrumentation. It is an indirect way of assessing the neuronal integrity. Neuronal activity results in a disproportionately increased cerebral blood flow in the region causing an overcompensation of the fall in oxyhemoglobin. Reduced deoxyhemoglobin and increased oxyhemoglobin levels contribute to the fMRI signal which is subsequently processed and activation maps created. fMRI has been used to map the sensorimotor cortex, visual cortex, primary auditory cortex, association areas and language regions. This preoperative mapping allows evaluation of surgical feasibility and approach. It can also provide information post surgical recovery. It can also be used to visualize epileptic focus. It is likely to replace wada test.

 

CSF Cytology, whenever possible, may give a clue to the nature of the tumor, especially in high grade lesions. In addition to neoplastic cells, tumor markers, such as alpha fetoprotein (AFP) and human chorionic gonadotropin (HCG) are useful for diagnosis and monitoring therapeutic responses.

 

Histopathology gives the final diagnosis so that optimal treatment and prognosis can now be determined.

Tumor pathology may be studied at operation (by frozen section or by cytological preparation), or in the postoperative period.

A comprehensive range of histochemical, and molecular biological tests can be performed on sections of frozen or formalin-fixed, paraffin embedded tumor tissue using light and electron microscope techniques. When a tumor is morphologically undifferentiated or anaplastic, its nature may be revealed by immunohistochemistry which demonstrates the expression of proteins that characterize particular cells. One example would be the presence of glial fibrillary acidic protein (GFAP) in astrocytic tumors and other gliomas. An alternative approach is to examine the tumor at the ultrastructral level for diagnostic cytological features, such as core vesicles in tumors of neuronal origin.       

 

 Management:

 

Symptomatic medical therapy is discussed elswhere.

 

 Surgery in some tumor types, such as meningiomas, and schwannomas, surgery may be curative. Surgery has a central role in interdisciplinary glioma management, currently representing its basic therapy (discussed elsewhere).

 

Total excision is the goal, with resultant improvement in neurology and quality of life.

The proximity of vital brain structures may limit the ideal goal of complete tumor removal with preservation of function.

Surgery may not be offered to patients who might benefit from it on the assumption that their tumor is too close to so-called 'eloquent' brain, such as the areas responsible for controlling movement or speech.

Nowadays, a variety of tools are available to help the neurosurgeon counter this problem.

 

Recent advances have made removal of a strategically located tumor possible. 

Stereotactic craniotomy (with or without a frame) involves preoperative localization the lesion stereotactically. A small superficial cortical or subcortical lesions or deep lesions that can be easily missed by conventional means; and also when  accurate localization is crucial to excise tumors in highly eloquent  areas.

 

Brain mapping, also termed cortical mapping, with awake craniotomy, uses electrical stimulation of the cortical surface to define areas of functional cortex, such as primary motor, sensory, or speech cortex. By pinpointing the exact location of these areas prior to tumor resection, the surgeon can perform a more aggressive resection and still safely avoid these structures, thereby preserving neurologic function. Recent advances in imaging techniques allow for nonivasive brain "mapping", by which the precise relationship of areas controlling brain function to a nearby tumor can be determined. One such method is functional MRI, or fMRI.

 

Neuronavigation  using, a sophisticated computer, which is capable of taking information from the CT and MRI scans is used intraoperatively in advanced centers. It creates a display on a computer screen in the operating room which the surgeon can use during surgery. It is able to use a special pointer in the area where surgery is being performed, and that location will be displayed on the screen in reference to the abnormalities on the imaging studies. During the procedure continuous exhibition of the distance as well as the orientation towards the target point minimizes unnecessary destruction of brain tissue.

MRI and CT images are superimposed on volume in the stereotactic space which allows a volumetrical tumor resection as well as staying oriented within the lesion during resection. 

 

Robotic surgery has been developed in various surgical specialties including brain and spine surgery. The evolution of robotic neurosurgery has been very rapid since the first robot assisted surgery by James M Drake in 1991. It  can perform brain surgery that was not possible till now. It is supposed to perform so accurately in areas where human hand till now was not considered absolutely safe.

The robot is guided by extremely high resolution brain scans, allowing it to work to an accuracy of a millimeter, marking it possible to operate close to vital parts of the brain. In contrast, neurosurgeons operating by hand have an accuracy of only a couple of millimeters and have to avoid various operations in case they cause permanent and possibly fatal damage. There are large areas in the brain that the surgeons are unable to operate upon.

A computer controlled robotic system that positions and inserts an 'Endoscopic Surgical Laser' through a hole in the skull 3 mm across. The robot head needs a path through the brain only 1 mm wide. Tests suggest that the robot will be able to remove a tumor in about half an hour but more complex operations may take several hours, but unlike human surgeon the robot doesn't get tired. With little damage to the skull and the brain the patients should be able to leave the hospital in 24 hours.It may be just a beginning. The uses of such a robot may be numerous.

 

Endovascular procedures have contributed in successful excision of highly vascular tumors.

Modern anesthesia have greatly helped the surgeons towards his goal.

Various multidisciplinary approaches, involving the ENT and plastic surgeons have been refined and complex skull base tumors can now be excised with satisfying outcome.

 

In 1957, Yasergil introduced Intraoperative microscope in Neurosurgery. A quality microscope in mandatory.

CUSA (cavitron ultrasonic aspirator) by Epstwein, and laser by Tew in 1983, facilitates tumor resection.

Intraraoperative endoscopy was introduced by Oppel in 1987.Neuroendoscopic techniques, even though in its infancy, have greatly reduced the morbidity in selected procedures. Use of endoscopy, during microsurgery greatly facilitates in visualization of vital neighborhood structures, such as brainstem in acoustic surgery, with minimal brain retraction. 

 

'A fool with a tool is still a fool'. All the recent advances are not a substitute for meticulous microsurgical techniques.

Various approaches and modifications are discussed in individual tumor discussions.

 

 Radiotherapy  plays a central role in the treatment of most brain tumors, whether benign or malignant. It is discussed elsewhere.  In selected, strategically located benign tumors, such as, acoustic schwannoma, radiosurgery is increasingly being used with success, especially in residual lesions. Very occasionally,  pre operative radiotherapy is employed to reduce the tumor vascularity.

 

 Chemotherapy forms an essential adjuvant therapy in gliomas. It is discussed elsewhere.

There are occasional reports on use of Tamoxifen, and Bromocriptine in meningiomas.

Use of bromocreptine is well established in pituitary prolactinomas.

 

 Genetherapy  is discussed elsewhere. Perhaps the most appealing means of curing brain tumors is to correct the underlying defects in the genes that lead to tumor control. Genes that promote growth could be turned off, those that suppress growth could be turned on, defective monitoring mechanisms could be turned on, genes that produce a beacon for the immune system could be delivered, and so on.

Gene therapy has been used successfully in mice to rid them of primary and secondary tumors. The principal problem with gene therapy as the primary treatment of brain tumors is that, in theory, every tumor cell must be treated with gene therapy. If even one cell escapes, it could regrow into a large tumor. It is in the experimental stage, with encouraging reports as an adjuvant treatment for gliomas. However, there appears to be a role in meningiomas and other benign tumors as well.

For patients with brain tumors, gene therapy offers the hope of replacing the defective genes, amplifying the immune response to cancer. The malignant phenotype of a brain tumor results from a series of mutations, including genetic deletions. Therefore, the simple paradigm of replacing a defective protein does not typically apply to children with brain tumors.

 

While it is possible to inject enough reparative genes into a tumor in a mouse to eradicate the tumor, it is quite a different thing to inject enough gene therapy into a human brain tumor, which is likely to be much larger. To date gene therapy has been shown to kill human tumor cells, unfortunately, current delivery mechanisms are inefficient and unable to deliver enough to cure the whole tumor. Nonetheless, gene therapy may well become an important future treatment of human brain tumors, alone or in combination with the above therapies. Further study is required.

 

 Immunotherapy represents a promising new class of treatments that, in theory, could confer lifelong immunity to a variety of tumors affecting the brain and is still in experimental stage as a treatment for gliomas.

In theory, the body's immune system should recognize tumor cells as abnormal and then attack and destroy them. This immune surveillance probably occurs daily and destroys many early tumor cells. A tumor cell may develop, however, that can fool the immune system by making substances that block the signals that tell the immune system to seek and destroy the abnormal cells. Or, the body's immune system may be weakened by HIV infection, drugs, or alcoholism and allow tumor cells to escape control. Animal studies have shown that a healthy immune system that is being fooled by the tumor can be taught to recognize the tumor and resume its control duties.

This is a form of therapy aimed at activating the patient's own immune system in order to kill tumor cells. This group of substances includes the interferons, interleukins, growth factors and others.

Radioimmunotherapy with Monoclonal Antibodies. Radioimmunotherapy is showing special promise as a treatment approach to brain tumors. It typically employs monoclonal antibodies (MAbs), which are genetically engineered antibodies designed to work against a specific target. MAbs are bound with radioactive substances and delivered directly into the brain and sometimes into the tumor. The MAbs are specifically designed to lock with the surface of certain cells in the tumor. Once they do so, the radioactive substances destroy the cell.

The approach is essentially mini-radiation therapy without the damage or severe side effects of standard radiation treatments.

A number of different radioimmunotherapies are being investigated, and trials of some are reporting improved survival rates in high-grade gliomas. Some experts believe this approach could prove to be the most effective therapy against these cancers.

Interleukins. Interleukins are natural proteins created by the immune system. Certain tumor cells carry receptors for specific interleukins, which are being investigated for a possible therapeutic role. For example, some drugs combine an interleukin with an agent that is toxic to cancer cells. The interleukin locks onto the receptor on the cancer cell and the toxic chemical enters the tumor with the intent to kill it. Some interleukins are also being investigated alone for their own tumor-cell killing properties.

Tumor Vaccines. Tumor cells removed from the patient are inactivated to form a vaccine; when they are transferred back to the patient, they are harmless but can elicit a powerful immunologic response against the tumor. For example, a vaccine that combines tumor proteins with the patientís nerve cells is being tested in astrocytomas.

Efforts to augment patientsí immune responses to tumors by means of enhancing agents, passive immunity, and adoptive immunity have been ineffective. Active immunotherapy by administration of interferon, interleukin-2 and/or lymphokine-activated killer cells (LAKC) however, yielded encouraging results in some trials. Since the tumors are extremely heterogeneous with respect to cell cycle, antigen-expression and growth-factor/cytokine susceptibility, immunotherapy has to be improved before it becomes apart of standard therapy protocols.

Angiostatic Therapy is a promising new technique. Many tumors produce substances that promote the growth of new blood vessels to help provide oxygen and nutrients for their nearly insatiable needs. Eventually these tumor cells become dependent on these new vessels. Substances (antiangiogenesis factors) that inhibit these blood vessels, thereby starving the tumor cells. These factors can obliterate certain malignant tumors in mice, although they have not been used in humans.

Angiogenesis inhibitors are drugs that interfere with the growth of blood vessels in the tumor, effectively starving tumors of vital nutrients and oxygen.They include the following:

Thalidomide was one of the first drugs tested. In one 2001 study of recurrent glioblastoma the one-year survival rate was 35%. Researchers are investigating different doses to improve results.

Suramin, another angiostatic agent, produced a delayed response in some patients with high-grade gliomas and was well tolerated. Antiseizure medication did not affect it. It is now being studied in combination with radiation therapy.

 

A number of similar agents are under investigation. Recent reports have suggested that these drugs may lead to a cure of cancer within two years. Although this predication may prove to be true for some tumor types, primary brain tumors are, unfortunately, composed of cells that are metabolically voracious and cells that have much more modest requirements.

Antiangiogenesis treatment, if it works, may only turn high-grade tumors into lower-grade ones. Furthermore, there are situations in which production of new blood vessels is important for health. The role of antiangiogenesis factors in humans is promising but remains to be defined.

 
 

 

 

 

 

 

 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 
 

 

 

 

 

 

 

 


 

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