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Drug therapy of intracranial tumors

Primary tumors in the central nervous system (CNS) account for approx. 3.5 % of malignant tumors in adults. Tumors can arise from:
  • neuroepithelial tissue (approx. 60 %)
  • meningioma (approx. 20 %)
  • pituitary gland/sellar region (approx. 10 %) 
  • the corpus pineale region/cranial nerves (approx. 5-6 %)
  • the spinal canal (approx 4 %)

Over the years, many cytostatic regimes like PCV (procarbazine/CCNU/vincristine), monotherapy with CCNU, cisplatin-based regimes etc. have been tried in the treatment of primary brain tumors, but the results have not been good.

Oral treatment with temozolomid seems to achieve treatment results similar to the more complex cytostatic regimes and produces fewer side-effects. Temozolomid does not cause hair loss, but can cause nausea in some patients or, on rare occasions, thrombocytopenia.

The blood-brain barrier at the capillary level keeps most cytostatic agents from reaching normal brain tissue. In tumor tissue, this barrier is often broken; thus, tumors can be sensitive to cytostatic agents in varying degrees. This also applies to brain metastases. Lymphomas and germinomas are rare, but also important differential diagnoses. For these primary tumors, cytostatic agents have a central place in the treatment.

Cytostatic agents (methotrexate, cytarabin) and steroids can be administered intrathecally with spinal punction or via an implanted Ommaya-reservoir. Intrathecal treatment is especially up-to-date as prophylaxis against intracranial residue in leukemia or lymphomas. 

Neuroepithelial tumors

For grade I, II and III gliomas, chemotherapy has not so far had documented, life-extending effects, even when patient response and clinical improvement of neurological and subjective symptoms can be seen in a number of cases. For grade IV gliomas (glioblastomas), temozolomid chemotherapy could extend median survival by almost 3 months.

Peroral temozolomid for grade IV gliomas

  • Used daily, in part, in low doses as radiation-potentiating agent (concomitant use) during the entire radiation period (6 weeks).

  • Then, as adjuvant 5-day treatment at 4 week intervals.
  • Six adjuvant treatments in total, provided that no new tumor growth occurs during the treatment period.

Patients > 70 years have had no documented effect from temozolomid and therefore, are therefore usually not candidates for cytostatic treatment. However, they should be surgically treated according to the usual criteria and also benefit from postoperative radiotherapy, providing they have WHO function status 0–1–2. Other patients with glioblastoma should receive temozolomid, providing they exhibit normal hematological tolerance and absence of tumor progression during cytostatic treatment. Postoperative chemotherapy for this patient group is life-extending (median 3 months) and increases the likelihood of survival after 2 years to 25-30 %. Newer data also shows that 5 years survival increases from 3–4% till approximately 10% in patients younger than 70 years and with ECOG functional status 0-2. (15

Anaplastic (grade III) glioma

The utility of chemotherapy for anaplastic gliomas is currently unclear. In Norway, since 2004, it has been decided to give temozolomid concomitant with postoperative radiation treatment for grade III patients < 70 years of age with WHO function status 0–1–2. Palliation can be achieved, but not a cure.

Oligodendroglioma, oligo/astro mixture tumors, astrocytomas grade 1-2

Oligodendrogliomas grade II and grade III are chemosensitive and often respond to chemotherapy. Nevertheless, in randomized studies, postoperative adjuvant PCV- chemotherapy has not produced proven life-extension. Temozolomid monotherapy or PCV-chemotherapy can be used. They are assumed to be equally effective, but temozolomid produces fewer side-effects. There is no upper limit for treatment numbers for temozolomid, provided there is normal hematological and subjective tolerance and an absence of tumor progression. Remission or palliation can be achieved.

Ependymoma

Chemotherapy has no proven effects on this patient group.

Medulloblastoma

Medulloblastomas are chemosensitive tumors, and treatment with cytostatic agents improves survival for these patients. Vincristine is used as a radiation-potentiating agent for adults during the radiation period. Then eight treatment courses (cisplatin, vincristine) are administered in 6-week intervals after completed, postoperative radiation treatment. It may be necessary to reduce the cytostatic doses due to kidney and ototoxicity, bone marrow aplasia or neurotoxicity.

Brain membrane tumors (Meningiomas)

Chemotherapy has no proven effects on this patient group.

Cranial nerve tumors

Optic nerve gliomas can respond to chemotherapy. Schwannomas are treated with surgery or stereotactic radiation (based on gamma knife or linear accelerator) and chemotherapy has no place in the treatment schedule.

Primary and secondary CNS-lymphoma

Therapeutic concentrations in the CNS can be achieved with systematic, high-dose methotrexate, possibly supplemented with intrathecal methotrexate. Often given in addition to radiation treatment, but this patient group has a risk of cognitive damage after radiation treatment. A primary CNS-lymphoma can disappear temporarily after steroid treatment alone, but will return after some time. Methotrexate-based chemotherapy, possibly supplemented with radiation therapy, can cure patients with CNS-lymphoma.

Germinal cell tumors

Pure germinomas are radiation-sensitive and are regularly cured after CNS-axis radiation with a boost against macroscopic tumors. Adding chemotherapy does not improve the treatment results for pure germinomas, but increases the risk of treatment-induced toxicity. Germinal cell tumors of the non-germinoma type (non-seminoma, or secreting germinomas with beta-HCG> 50 and/or AFP> 25) should, on the contrary, primarily have cisplatin-based chemotherapy, supplemented by surgery of possible residual infiltrates. Radiotherapi may also be used following chemotherapy and surgery, or as local treatment in inoperable patients.

Tumors in the sellar area

This is a heterogeneous group of normally benign tumors (pituitary gland adenomas), which may be hormonally active. Medical treatment with bromocriptine or statins may be relevant, but pure cytostatic agents have no place in the treatment. The most important local treatment is surgery, possibly supplemented with stereotactic radiation treatment or fractionated external radiation treatment.

Brain metastases

The blood-brain barrier in metastasized vessels is usually damaged and some types of tumor tissue (germinal cell cancers, lymphomas, small-celled lung cancers and others) can respond to chemotherapy. However, primary treatment is surgery and radiation, to the extent this is considered appropriate for the patient based on their general health and neurological function.

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