Central nervous system disorders

II./4.7.: Treatment

II./4.7.1.: Pilocytic astrocytoma (WHO: grade I.)

The treatment of pilocytic astrocytoma is surgical. The tumour is curable when removed totally, but a subtotal removal leads to a 75-85% 10-year-survival as well. Contrary to WHO II-IV tumours, the extent of the removal does not have a significant impact on the survival rate. (2) Radiotherapy and/or chemotherapy are not effective.

II./4.7.2.: Low grade glioma

In case of low grade gliomas total surgical removal is recommended if possible. The old ‘wait and see’ method is better avoided because of the chance of spontaneous malignant dedifferentiation, the development of pharmacologically not controllable epilepsy, or possible neurological symptoms. If surgical treatment is not possible (e.g. eloquent region) then a stereotactic biopsy is recommended. In case of a subtotal resection confirmed by MRI a 3D conformal 54 Gy irradiation is performed in 1.8 Gy fractions. A prospective, randomized trial initiated by the EORTC Brain Group in 1986 revealed that early, i.e. after surgery radiotherapy (RT) significantly raised the time till progression (5.3 vs. 3.4 years), but did not improve total survival (7.4 vs. 7.2 years) as compared to late irradiation administered at recurrence. Early irradiation proved to be more efficient regarding epilepsy control as well. It is important to mention that postoperative treatment is only administered in case of self-sufficient patients (KPS>70, ECOG 2, NPS 2) in this tumour type and as well in other tumours described later.

II./4.7.3.: Malignanat gliomas

In case of malignant gliomas a macroscopic surgical removal is recommended as well, which is followed by 3D conformal irradiation in a total dose of 60 Gy, in 1.8-2 Gy fractions. In tumour recurrence chemotherapy is recommended (see below), reoperation and repeated irradiations are rarely applied.

II./4.7.4.: Glioblastoma multiforme

Chemotherapy with irradiation is recommended in case of a histological diagnosis of glioblastoma multiforme. During the treatment 75 mg/m2 Temodal (temozolomide: an oral alkylating agent, which gets through the brain-blood barrier) is administered daily with 60 Gy fractionated irradiation. After a month intermission 150 mg/m2, after the second cycle 200 mg/m2 Temodal is administered daily during 5 days followed by 28 days without treatment.

In the original Supp protocol Temodal was administered for 6 months, but in the current practice the drug is administered for a minimum 1-year-long period. The treatment is well-tolerated for most of the patients. The most prevalent side-effects include leukocytopenia, thrombocytopenia, which can regenerate spontaneously, or the treatment can be continued with a lowered dosage. The efficiency of the Strupp protocol was also tested in a prospective randomized trial. During the trial data of 573 patients were analyzed. Mean survival time was 14.6 months in case of Temodal treatment, as compared to the mean survival time of 12.1 months of patients only receiving radiotherapy. The 2-year-long survival rate was 26.5% compared to 10.4%. (3) Based on the data of these patients and on the RPA classification mentioned earlier it was found that in the RPA III, IV and V groups mean survival time was 17, 15 and 10 months, respectively, while the 2-year-long survival rate was 32%, 19% and 11%, respectively. In the RPA III group mean survival time was 21 months and the 2-year-long survival rate was 43%, as opposed to the mean survival time of 15 months and the 2-year-long survival rate of 20% in the group only receiving radiotherapy. A similar significant difference was described in the RPA IV group as well (16 vs. 13 months, 28% vs. 11%), while in the RPA V class there was no significant difference between the two groups. In the same patient group the methylation state of the DNA repair O6-methylguanine-DNA-methyltransferase (MGMT) was also determined. In case the MGMT promoter was methylated, i.e. the DNA repair could not work, then Temodal treatment was significantly more effective (21.7 vs. 15.3 months mean survival).

In case of tumour recurrence or cases not responding to Temodal another alkylating agent, mostly a nitrosourea-derivative is being administered. Nitrosoureas are lipophilic agents not dependent on cell cycle, which can cross the blood-brain barrier easily. After DNA alkylation DNA cross-links are formed, which leads to blocked DNA-repair and RNA synthesis. The most often used BCNU (1,3-Bis(2-chloroethyl)-1-nitrosourea) is administered intravenously. The CCNU (chloro-2-ethyl)-1-cyclohexyl-3-nitrosourea) is administered orally, while the ACNU [1-(4-amino-2-methyl-5-pyrimidinyl) methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride] can be administered both systemically and intraventricularly. Nitrosoureas are administered in 6-week-long periods. In case of oligodendrogliomas and mixed OAs 6 cycles of PCV chemotherapy was proven to be effective, during which CCNU (Lomustine) is administered on the first day, oral procarbazine (Natulan) is used between the 8-21st days and intravenous vincrisitine is administered on the 8th and 29th days. Oligodendrogliomas and OAs with 1p19q deletion (LOH 10p1q) are chemosensitive tumours, and the survival rate of patients with such tumours is significantly higher than the survival rate of patients with tumours without the deletion. (5)

Molecular and genetic research provide a growing insight to the cell cycle regulation of tumour cells. With the help of this knowledge cell growth, proliferation, apoptosis, angiogenesis or cell invasion can all be influenced.

Monoclonalantibodies targeting the inhibition of the function of cell surface growth factor receptor molecules, angiogenic protein kinase and transcription factor are under clinical trials. Such agents are e.g. the EGFR inhibitor Erlotinib, gefitinib, the PDGFR inhibitor Imatinib, the protein kinase C and B inhibitor Tamoxifen, the invasion inhibitor Cilengitide and the VEGFR (vascular epidermal growth factor receptor) inhibitor Bevacizumab. Bevacizumab has already been approved by the FDA. The topoisomerase enzyme also plays an important role in the cell cycle regulation. The enzyme inhibition leads to a break in the DNA chain. Etoposide is an inhibitor of type II topoisomerase, while type I topoisomerase is inhibited by Topotecan and Irinotecan. Due to the complexity of cell functioning, it is most likely that a combination of agents with different targets will be the most efficient.

II./4.7.5.: Ependymoma and medulloblastoma

Ependymomas and medulloblastomas should be removed surgically. After the removal a fractionated irradiation is recommended with the irradiation of the whole neuraxis. In case of a medulloblastoma methotrexate can be administered during chemotherapy. Methotrexate is a folic acid analogue cell-cycle-dependent agent, which is hydrophilic, so it crosses the blood-brain barrier with difficulty. Methotrexate can also be administered intrathecally in case of meningeal propagation. The risks of such administration are aseptic meningitis, myelopathy and leukoencephalopathy.

II./4.7.6.: Primary central nervous system lymphoma (PCNSL)

In case of the diagnosis of PCNSL a methotrexate chemotherapy of high dosage is recommended after a stereotactic biopsy. The chemotherapy can be supplemented with procarbazine and vincristine and whole brain fractionated radiotherapy (WBRT). (10) The WBRT can be reserved for a relapse following chemotherapy as well. Irradiation is applied in a 45 Gy dose in 25 fractions. Surgical removal comes only into question in case of a significant intracranial space occupation.