Brain cancer treatment in Germany

The symptoms caused by primary tumours and by metastatic tumours are the same. Many symptoms are related to raised intracranial pressure:

• headache:
• change in mental status;
• focal neurological symptoms.

Headache is the most common symptom. It is most intense when patients wake from deep non-rapid-eye-movement sleep (usually a few hours after falling asleep), because hypoventilation, which increases cerebral blood flow and therefore raises ICP, is greatest in this phase of sleep. The headache is also progressive and may become worse when lying down and during the Valsalva manoeuvre. When ICP is very high, the headache may be accompanied by vomiting, sometimes preceded by nausea. Papilloedema develops in about 25% of patients with a brain tumour, but it may be absent even when ICP is raised. In infants and small children, raised ICP leads to an increase in head size. If ICP rises sufficiently, brain herniation may occur.

The second most common symptom is deterioration in mental status. Its manifestations include drowsiness, apathy, personality changes, behavioural changes and cognitive impairment, particularly with malignant brain tumours. Epileptic seizures are possible (more often with primary brain tumours, less often with metastatic ones). Impaired consciousness may be a sign of the onset of brain herniation, of brainstem involvement or of diffuse bilateral cortical damage.

Focal brain dysfunction can cause a number of symptoms. Focal neurological symptoms, endocrine disturbances and focal seizures (sometimes with secondary generalisation) develop depending on where the tumour is located. Focal signs often suggest the location of the tumour. Nevertheless, local deficits sometimes do not correspond to the site of the tumour. Examples of such false localising signs are:

• unilateral or bilateral paresis of the lateral rectus muscle of the eye, caused by raised intracranial pressure and compression of the sixth cranial nerve;
• ipsilateral hemiplegia, caused by the contralateral cerebral peduncle being pressed against the edge of the tentorial notch (Kernohan's notch phenomenon);
• a visual field defect on the side of the tumour due to ischaemia of the contralateral occipital lobe.

Some tumours cause inflammation of the meninges, leading to subacute or chronic meningitis.

Neurological deficit can arise for the following reasons:

• invasion of the tumour into brain tissue and destruction of that tissue;
• direct compression of the underlying tissue by the tumour;
• raised intracranial pressure;
• bleeding inside or outside the tumour;
• cerebral oedema;
• obstruction of the venous sinuses of the dura mater;
• impaired drainage of cerebrospinal fluid;
• impaired absorption of cerebrospinal fluid in leukaemia or carcinoma involving the meninges;
• impaired arterial blood flow;
• in some cases — paraneoplastic syndromes.

In a malignant tumour, new blood vessels develop that may bleed or become occluded.

Benign tumours are characterised by slow growth. They can become quite large without obvious symptoms, which is often related to the absence of cerebral oedema. Malignant primary tumours grow quickly but rarely spread beyond the CNS. Death results from local growth of the tumour and can therefore follow the growth of both benign and malignant tumours. For prognosis, then, the difference between malignant and benign CNS tumours matters less than it does for tumours elsewhere in the body.

• securing the airway;
• dexamethasone for raised intracranial pressure mannitol for herniation;
• definitive treatment – removal of the tumour, radiotherapy, chemotherapy or combined treatment.

Patients in a coma or with impaired airway reflexes undergo endotracheal intubation. Brain herniation due to a tumour is treated with intravenous mannitol at a dose of 25–100 g and with corticosteroids (for example, dexamethasone 16 mg intravenously, then 4 mg orally or intravenously every 6 hours), and such patients are intubated. Surgical decompression, with removal of the mass, is carried out as early as possible.

When intracranial pressure is raised because of a tumour but there is no herniation, corticosteroids are given (for example, dexamethasone in the same regimen as is used for herniation, or prednisolone 30–40 mg orally twice a day)

Treatment of the tumour depends on its type and location. Surgical excision is used both for diagnosis and as a palliative measure. With benign tumours it can lead to a cure. Tumours that infiltrate the brain parenchyma require multimodal treatment. Radiotherapy is necessary, and chemotherapy sometimes gives a good result.

Treatment of metastatic disease includes radiotherapy and sometimes stereotactic radiosurgery. In patients with solitary metastases, surgical removal of the tumour before radiotherapy improves the outcome.

Radiotherapy to the head and neurotoxicity

For diffuse or multifocal tumours, diffuse irradiation of the whole head is given, while well-demarcated tumours are treated locally. Local radiotherapy may be external beam (three-dimensional conformal radiotherapy targeting the tumour and largely sparing healthy brain tissue) or stereotactic – brachytherapy with implantation of iodine-125 (125I) or iridium-192 (192Ir) isotopes into the tumour, as well as the gamma knife or a linear accelerator. In brachytherapy, radioactive isotopes of iodine-125 (125I) or iridium-192 (192Ir) are implanted into or next to the tumour. Gliomas are treated with conformal radiotherapy; the gamma knife or a linear accelerator is used for metastases. Delivering radiotherapy daily increases its effectiveness and reduces the neurotoxic effect on normal CNS tissue.

The degree of neurotoxicity depends on:

• the cumulative radiation dose;
• the single dose;
• the duration of therapy;
• the volume of tissue treated;
• individual susceptibility.

Because individual susceptibility can vary widely, it is quite difficult to predict the development of radiation neurotoxicity. Symptoms of toxicity may develop within the first few days after treatment (acute), within the first months (delayed) or after several months or years (late). In rare cases, irradiation is followed by the development of gliomas, meningiomas or peripheral nerve sheath tumours several years after treatment.

Spinal cord tumours can arise within its parenchyma, destroying tissue directly, or outside the parenchyma, compressing the spinal cord or the nerve roots. They present with increasing back pain and with neurological deficit related to involvement of the spinal cord or the nerve roots. The diagnosis is established by MRI. Corticosteroids are prescribed, and surgery and radiotherapy are carried out.

Spinal cord tumours are divided into intramedullary (within the parenchyma of the spinal cord) and extramedullary (outside the parenchyma).

Intramedullary tumours

The most common are gliomas (for example, ependymomas, low-grade astrocytomas). Intramedullary tumours infiltrate and destroy the parenchyma of the spinal cord; they can extend over several spinal cord segments and cause a syringomyelic cyst (a pathological cavity in the spinal cord or the brainstem).

Extramedullary tumours

These tumours may be intradural or extradural. Most intradural tumours are benign and consist of meningiomas and neurofibromas – the most common primary tumours of the spinal cord. Among extradural tumours, metastases predominate, most often from cancer of the lung, breast, prostate, kidney or thyroid gland, or from lymphoma (for example, Hodgkin's lymphoma, lymphosarcoma, reticulum cell sarcoma).

Intradural and extradural tumours compress the spinal cord and its roots, causing neurological deficit. Most extradural tumours invade and destroy bone before they exert a compressive effect on the spinal cord. Clinical presentation

Pain is an early symptom, particularly with extradural tumours. It is progressive, is not related to physical activity and becomes worse when lying down. The pain may be localised in the back and/or radiate within a dermatome (radicular pain). As a rule, neurological disturbances develop that point to involvement of the spinal cord. Typical examples are spastic paresis, urinary incontinence, and damage to some or all of the sensory pathways at the level of the affected spinal cord segment and below. The disturbances usually appear bilaterally.

In many patients with extramedullary tumours the first complaint is pain, and in some it is loss of sensation in the distal parts of the legs, segmental neurological disturbances, symptoms of spinal cord compression, or a combination of these. Symptoms of spinal cord compression can deteriorate rapidly and lead to paraplegia and loss of bowel and bladder control. Symptoms of nerve root compression are also common, including pain, paraesthesia, loss of sensation and muscle weakness and, if the compression is chronic, muscle atrophy in the area supplied by the affected roots.

Diagnosis

• MRI

Urgent diagnosis and treatment are required in patients with segmental neurological deficit or suspected spinal cord compression.

The following symptoms suggest a spinal cord tumour:

• increasing pain, radicular pain or back pain at night that has no other objective cause;
• segmental neurological disturbances;
• neurological deficit pointing to involvement of the spinal cord or the nerve roots and having no objective cause;
• unexplained back pain in patients with a primary tumour of the lung, breast, prostate, kidney or thyroid gland, or in patients with lymphoma.

The diagnosis is made by MRI of the affected region of the spinal cord. CT myelography is an alternative, although it is less accurate.

If MRI does not reveal a spinal cord tumour, another space-occupying lesion of the spinal cord may be considered (for example, abscesses, arteriovenous malformations and paravertebral tumours). Destruction of bone, widening of a vertebral pedicle or displacement of paravertebral tissues, particularly if the tumour is metastatic, may be an incidental finding on a spinal X-ray.

Treatment

• corticosteroids;
• resection of the tumour and/or radiotherapy.

Patients with neurological involvement need corticosteroids immediately in order to reduce oedema of the spinal cord and preserve its function (for example, dexamethasone 100 mg intravenously, then 10 mg orally 4 times a day). With tumours that compress the spinal cord, treatment must be started as soon as possible.

Some well-localised primary tumours of the spinal cord can be excised surgically. About half of the patients with this condition improve. For tumours that cannot be excised, radiotherapy is used with or without surgical decompression. Extradural metastases causing spinal cord compression are usually excised from the vertebral body, after which radiotherapy is given. Non-compressive metastatic extradural tumours can be treated with radiotherapy alone, but if radiotherapy proves ineffective, surgery is indicated.

Primary brain lymphomas develop in neuronal tissue and are usually B-cell tumours. Diagnosis requires neuroimaging and sometimes CSF analysis (including the antibody titre to Epstein–Barr virus) or a brain biopsy. Treatment includes glucocorticoids, chemotherapy and radiotherapy.

The incidence of primary brain lymphomas is rising, particularly among immunocompromised and elderly people. Lymphomas tend to infiltrate the brain diffusely, often as multifocal lesions near the ventricles, although they can also be solitary lesions. Lymphomas also appear in the meninges, in the uvea of the eyeball and in the vitreous body. Most of them are B-cell tumours, often immunoblastic. Where immunity is impaired, the development of lymphomas is triggered by Epstein–Barr virus. In most cases systemic lymphoma does not develop subsequently.

Diagnosis

• MRI;
• in some cases – CSF analysis or brain biopsy.

MRI can raise suspicion of the disease. MRI findings alone cannot distinguish lymphoma from cerebral toxoplasmosis, which is common among patients with AIDS.

If meningeal symptoms are present, the CSF is examined; it may contain lymphoma cells. Where immunity is impaired, Epstein–Barr virus DNA can be detected in the CSF. If the CSF contains neither lymphoma cells nor Epstein–Barr virus DNA, a brain biopsy (open or needle) is indicated. Because lymphoma is very sensitive to glucocorticoids, giving them immediately before a biopsy risks a false-negative result.

Treatment

• corticosteroids;
• chemotherapy;
• radiotherapy.

Most primary brain lymphomas are difficult to cure because they infiltrate the brain diffusely. A dramatic improvement is usually seen immediately after corticosteroids are given. Various chemotherapy regimens are effective, particularly those that include methotrexate (intravenous infusions of high doses of the drug); with methotrexate treatment, median survival approaches 4 years. Methotrexate can also be given intrathecally, usually through a subcutaneous intraventricular device (an Ommaya reservoir). It is sometimes injected into the carotid artery under general anaesthesia, after which a 25% mannitol solution is given intravenously to increase the permeability of the blood–brain barrier.

Radiotherapy can be given after a course of chemotherapy, usually after 12-16 weeks, but sometimes, in order to reduce neurotoxicity, irradiation is postponed until the tumour recurs. Delaying it helps to lower the level of radiation toxicity.

Most pituitary tumours are adenomas. They are characterised by headache and by endocrinopathies that arise if the tumour produces hormones or destroys hormone-producing tissue. The diagnosis is established by MRI. Treatment consists of correcting any endocrinopathy and of surgery, radiotherapy or dopamine receptor agonists.

Most tumours of the pituitary and of the suprasellar region are adenomas. Pituitary tumours are rarely carcinomas. Meningiomas, craniopharyngiomas and dermoid cysts can also develop in the region of the sella turcica, and metastatic involvement is possible.

Adenomas may be secreting or non-secreting. Secreting adenomas produce pituitary hormones; many of them are <10 mm in size (microadenomas). Secreting adenomas are classified by their histological staining (for example, acidophilic, basophilic, chromophobe). The hormone produced is often related to these characteristics; thus acidophilic adenomas overproduce growth hormone, and basophilic adenomas overproduce ACTH. Overproduction of prolactin is the most common.

Any tumour that grows beyond the pituitary can compress the optic tracts, including the optic chiasm. Tumours can also compress or destroy the tissue of the pituitary or the hypothalamus, disrupting hormone production or secretion.

Clinical presentation

With a growing pituitary adenoma, headache is possible even without a rise in ICP. If the tumour compresses the optic tracts, visual disturbances develop such as bitemporal hemianopia, unilateral optic nerve atrophy and contralateral hemianopia.

Many patients develop endocrinopathies because of a deficiency or an excess of hormones. Compression of the hypothalamus with reduced release of vasopressin leads to diabetes insipidus. Excess synthesis of prolactin causes amenorrhoea and galactorrhoea in women and, less often, gynaecomastia and erectile dysfunction in men. Excess production of growth hormone before puberty leads to gigantism, and after puberty to acromegaly. Excess expression of ACTH leads to Cushing's syndrome. A rare condition, haemorrhage into a pituitary tumour, causes pituitary apoplexy, accompanied by sudden headache, loss of vision and ophthalmoplegia.

Diagnosis

• MRI with 1 mm slices

A pituitary tumour should be ruled out when there are headaches, characteristic visual disturbances and endocrinopathy. Neuroimaging with a slice thickness of 1 mm is performed. MRI is more sensitive than CT, particularly for detecting microadenomas.

Treatment

Surgical removal of the tumour where possible. Drug treatment for endocrinopathies. Endocrine disorders are treated.

Pituitary tumours that secrete ACTH, growth hormone or thyroid-stimulating hormone are excised surgically, as a rule using a transsphenoidal approach. Radiotherapy is sometimes needed for tumours that are surgically inaccessible or multifocal.

Dopamine agonists (for example, bromocriptine, pergolide, cabergoline) are effective for prolactin-producing adenomas. As a rule, surgery and radiotherapy are not required.