Chemotherapy in the CNS:

 
Dr. M.A. Raja,
Medical oncologist,  Apollo Hospitals, Chennai , India.

The use of anticancer drugs in the treatment of intracranial tumors and spinal tumors is established for many forms of primary tumors. There have been many instances of unequivocal responses to chemotherapy among patients with anaplastic gliomas. Nevertheless, the impact chemotherapy in the CNS has been slight.

Chemotherapy is indicated for high-grade malignant gliomas as an adjuvant to surgery and radiotherapy or surgery in recurrent tumors.  Median survival time (MST) with surgery alone is 14 weeks and with radiotherapy, it is 36 weeks. Single agent chemotherapy improves MST to 51-73 weeks. The initial co-operative study in 1978 found no change in MST after adjunctive chemotherapy with BCNU in anaplastic gliomas, but an increased number of 18 month survivors. The influence of molecular genetics is recognized as markers of progression predicting response to therapy & predicting survival. There have been reports that suggest that anaplastic oligdenroglioma showed 100% response rate to chemotherapy when there is combined 1p & 19q LOH.

Chemotherapeutic Agents:

Nitrosoureas is the most common and effective drug. They act by alkylating tumor DNA at the O-6 position of guanine, thereby and interfering with DNA replication. The most common drugs in this class are BCNU (Bischloroethylnitrosourea/carmustine), CCNU (Cyclohexylchloroethylnitrosourea/lomustine), and procarbazine. Others such as, PCNU, ACNU, and methyl-CCNU have not found to be superior. Brain tumor study group in the 1970s has defined BCNU as the standard against which newer forms of therapy are compared. CCNU , by its pharmacologic similarity and ease of administration (since it is taken orally) has been preferred by many.

Mustard derivatives, such as, cyclophosphamide and L-phenylalanine mustard (melphalan) are the other major class of alkylating drugs. They alkylate DNA at a different site. Hence their spectrum of activity is different from that of nitrosoureas. Cyclophosphamide has shown activity against recurrent gliomas at high doses, and melphalan, against oligodendrogliamos and neuronal tumors, such as medulloblastoma and pineoblastoma.

DNA-Synthesis Inhibitors, such as, Cis-diaminedichloroplatinum II (cisplatin), have been impressive in a number of human cancers. Cisplatin has activity against both recurrent gliomas and newly diagnosed anaplastic gliomas. It is also effective against CNS germ cell tumors.

Antimetabolites, such as, methotrexate ( a folic acid antagonist), 5-fluoracil, 6-mercaptopurine, and cytosine arabinoside (ara-C), as a class are relatively inactive against CNS tumors.

Natural products, such as, vinca alkaloids ( vincristine and vinblatine ), the topoisomerase II inhibitors etoposide (VP-16), and veniposide (VM-26), the antitumor antibiotics such as adriamycin and actinmycin D, and the recently introduced, taxol, have been used in the treatment of brain and other forms of cancer. Multidrug resistant phenotype appears to produce cross- resistance to many of these natural product anticancer drugs.

 

Temozolomide (TMZ) is a novel oral alkylating agent and readily crosses blood brain barrier. Temozolomide is currently approved in USA for the treatment of patients with AA at first relapse. 

Temozolomide may block cellular replication by inhibiting DNA methylation. Temozolomide has been shown to have an inhibitory action on enzymes such as esterase & glyoxalase. Temozolomide has been shown to decrease the activity of ATase & inhibition of ATase enhances the action of Temozolomide. 

TMZ is administered at 75 mg/sq m/day daily for 6 weeks, with concomitant RT (2-Gy fractions to 60 Gy total)

Maintenance dose of TMZ is 200 mg/sq for 5 days in every 28d cycle for max of 6 cycle. 

Temozolomide is rapidly & completely absorbed after oral administration; peak plasma concentration occurs in 1 hour. Temozolomide is rapidly eliminating with a mean elimination half - life of 1.8 hrs & exhibits linear kinetics over the therapeutic dosing range. Food reduces the rate & extent of temozolomide absorption.

Population pharmacokinetic analysis indicates that age (range 19 - 78 yrs) has no influence on the pharmacokinetic of temozolomide. Pediatric patients (3 - 17 yrs of age) & adult patients have similar clearance & half - life values for temozolomide.

Temozolomide is associated with fewer side effects and improved quality of life. Caution should be exercized when temozolomide is administrated to patients with severe hepatic impairment.

 

In recurrent GBM, and anaplastic astrocytomas,  Temozolomide, has, reportedly shown complete response in 8%, partial response in 27%, stable response in 27%, and no response in 38%.

 

Other Chemotherapy Agents are being tested or used for primary and recurring tumors.

Tamoxifen, a breast-cancer drug, may also be beneficial in a minority of patients with glioma when administered continuously at high doses. More research is needed to determine which patients may benefit.

 

High-dose thiotepa along with bone marrow or stem cell transplantation is being tested for newly diagnosed aggressive oligodendroglioma as an alternative to radiotherapy. Although some patients have prolonged disease-free survival time, thiotepa

has very toxic side effects, including encephalopathy, liver damage, severe weight loss, and a drop in blood platelet count.

High-dose thiotepa along with bone marrow or stem cell transplantation is being investigated for recurrent aggressive oligodendroglioma.

 

Paclitaxel (Taxol), a drug used for breast cancer, is also being investigated for gliomas. It is showing promise for patients with recurrent gliomas. In one study, paclitaxel with stereotactic radiosurgery improved results for patients with glioblastoma multiforme.

 

Topo I inhibitors block topoisomerase I, an enzyme involved in cell replication. Clinical studies have shown that the topo I inhibitors topotecan and irinotecan injure brain tumor cells. Combinations of topo I inhibitors with standard chemotherapy drugs may prove to be active for some patients. A 2002 study also suggested that it may help some children with malignant glioma, medulloblastoma, and ependymoma. Studies in 2001 and 2002 also suggest this might be an important agent in radiochemotherapy.

 

Marimastat is a unique drug that inhibits the enzyme metalloproteinase, which may play a role in brain cancer. The drug is being used in patients with glioblastoma multiforme who have completed treatment with surgery and radiotherapy. Combinations with temozolomide may prove to be beneficial.

 

Limiting factors:

Serious toxic side effects include myelosuppression (mostly with alkylating agents), renal, hepatic, and lung fibrosis.

Methotrexate toxicity results from direct brain injury, although the mechanism is not known.  It is manifested in both acute and chronic effects.  Whereas oral methotrexate has minimal neurotoxicity, intrathecal methotrexate can cause meningeal irritation characterized by fever, nuchal rigidity, headache, nausea, and vomiting.  Examination of the CSF will reveal a pleocytosis, although all cultures remain negative.  This syndrome usually resolves without treatment.  Subacute encephalopathy, characterized by altered mental state and, frequently, hemiparesis, can occur with high-dose systemic or intrathecal methotrexate.  It is self limited.  The delayed toxicity of methotrexate is leukoencephalopathy, occurring in those who have received intrathecal methotrexate, particularly after brain radiation therapy.  The clinical picture is one of progressive encephalopathy with dementia, ataxia, and focal neurological findings. Radiographic imaging reveals diffuse tissue density abnormality of the cerebral white matter.  There is no effective treatment of this complication. 

Vinca alkaloids, such as vincristine and vinblstine, are associated with a peripheral neuropathy that can involve the cranial nerves. 

Cisplatin is commonly associated with tinnitus and hearing loss, seen in 9% and 6% of patients, respectively.  In addition, a self-limiting encephalopathy can be seen after treatment with cisplatin.  It must be distinguished from signs related to hydration preceding drug administration or electrolyte imbalances induced by the drug. 

A reversible encephalopathy can accompany ifosfamide administration. 

Cerebellar dysfunction can result from high-dose intravenous cytarabine; this drug can also cause encephalopathy when injected intrathecally. 

High doses of 5-fluorouracil can cause cerebellar dysfunction that is usually reversible. 

L-Asparaginase is associated with spontaneous sagittal sinus occlusion. 

Blood brain barrier (BBB) is often blamed for the failure of chemotherapy. The endothelial cell membrane of cerebral capillaries is permeable to hydrophilic substances < 200 Dalton sand to lipophilic non-ionized substances <450 daltons,  so many agents cannot pas across the membrane.  In the centre of the tumor the BBB may be disrupted, but in the border area of infiltrating cells the BBB is intact.

Controversy exists regarding the blood brain barrier. Most agents with significant activity against CNS tumors readily cross the BBB. The non sugar containing nitrosureas such as carmustine BCNU, which cross the BBB are effective whereas the sugar containing nitrosureas are less effective. On the other hand, the barrier is clearly disrupted in many of these tumors as measured by contrast enhancement on CT and MRI.

Pharmacokinetic considerations for intra cranial but non parenchymal tumors and extramedullay spinal tumors are less dependant on the ability to cross the blood brain barrier because many of these tumors gain blood supply from meningeal blood vessels that are significantly more permeable than those of the brain.

Cell cycle kinetics, and histological heterogeneity (Different cell lines different stages of cell differentiation within a single tumor) play  important roles in the response to chemotherapy.

Neovascularization  (abnormal tumor vessels) often show thrombotic obstruction. 

Altered microenvironment  may explain poor in vivo effects of treatment compared to good in vitro results.

Drug delivery:

Regional drug delivery produces more drug exposure than does the systemic intravenous and oral routes. With respect to the intracranial and spinal tumors the regional drug delivery takes the form of intra CSF therapy, intraarterial infusion, and intratumoral therapy. Therapy by CSF route is used to treat the meningeal neoplasia resulting from the primary of secondary tumor invasion of the subarachnoid space. Intratumoral therapy is regional therapy applicable for the cystic tumors with a narrow rim of surrounding tumor. Therapy by the intraarterial and intratumoral routes is not established in CNS tumors.

Nitrosoureas are mostly used because of their lipophiilicity. BCNU as a single drug shows the best effect and has been extensively investigated (Kaye,1992; Brandes,1991). It has been proven to be as effective as combination therapies, except vincristine combinations which show a better result in anaplstic gliomas (Levin,1990; Shapiro,1989). In order to overcome nitrosourea resistance, multidrug protocols have been tested, which showed promising results in recurrent anaplastic astrocytomas and not in GBMs.Toxic side effects were significantly higher.

BBB modification by intracarotid mannitol administration is claimed to have better response.

Electrochemotherapy (ECT) is an investigative technique; it applies high-voltage pulses to deliver drugs across cancerous tissues, including those of the brain.

 

Transplantation Procedures and High-Dose Chemotherapy is another investigative technique.

Chemotherapy destroys not only cancer cells, but also healthy cells, including special blood cells in the bone marrow called stem cells, which are immature cells from which all blood cells develop. Transplantation procedures using bone marrow or stem cells allow high-dose chemotherapy to be administered while protecting blood cells.

Targeted therapy: With the exception of lymphomas and germ cell tumors, chemotherapy has not made a significant impact on survival of primary CNS tumors, nor has it replaced other modalities as definitive therapy. With greater understanding of underlying molecular pathogenesis of tumors, application of specifically targeted therapy is becoming a reality. 

Glioblastomas which as mentioned, constitute the majority of primary CNS tumors, may arise de novo as seen mostly in elderly, or evolve from lower grade astrocytomas, as is not uncommon in younger patients. Interestingly, it appears that the underlying molecular changes are quite distinct.

In the scenario wherein gliomas evolve to a higher grade, p53 gene plays a key role. This is a tumour suppressor gene located in chromosome 17p13.1. This is the most frequently altered gene in human cancer (50% of all cancers and 30% of gliomas). p53 has a primary role in cell cycle control, DNA repair after radiation damage, and apoptosis induction. Therapies to target mutant p53 have been developed. eg. antisense adenoviral vectors, ONYX-15 an oncolytic virus, while other p53 targeting agents help to increase chemosensitivity. 

In de novo gliomas, epidermal growth factor receptor (EGFR) overexpression plays a key role, and is seen in about 40% of gliomas overall. EGFR gene is located in chromosome 7p11-p13, and mediates cell growth and proliferation by activating phosphatidyl inositol 3 kinase P13-K pathway. EGFR overexpression also inhibits apoptosis, which promotes cell survival and tumorigenesis. Several therapies targeting the EGFR gene like ZD1839 and erlotinib are now being tested in phase II trials in gliomas. 

Angiogenesis is the formation of new microvasculature by capillary sprouting. This results in microvascular proliferation, which with necrosis is one of the hallmark histological characteristics of glioblastoma multiforme. The most important angiogenesis regulator is vascular endothelial growth factor (VEGF), the gene for which is located in chromosome 6p 21.3. VEGF also increases vascular permeability. VEGF inhibiting agents like SU5416 are being evaluated in Phase I/II trials. 

Platelet derived growth factor (PDGF) is a key element of embryonic development, and a potent mitogen for glial cells, neurons, endothelial, and connective tissue cells. Binding of PDGF to its receptor activates ras pathway, thereby initiating signals for cell growth and inhibition of apoptosis. PDGF also supports tumor angiogenesis by inducing VEGF expression. Imatinib mesylate (used in chronic myeloid leukemia by targeting bcr-abl gene) is a PDGF inhibitor, and so is suramin. Both are being currently tested in phase II trials.

Ras is a cytoplasmic protein located at the inner surface of the cell membrane, integrating diverse cellular signaling events including DNA synthesis. Ras mutation is seen in at least 30% of all tumours. In gliomas, while ras mutations are rare, ras overactivity is common. This leads to cell proliferation, thus offering another target for treatment. Ras inhibitors are being tested in clinical setting.

Protein kinase C (PKC) is a family of serine/threonine kinases involved in signaling pathways that induce cellular growth and differentiation. PKC overexpression strongly correlates with growth rate of gliomas. Antisense oligonucleotides targeted against PKC have shown significant reduction in tumour proliferation. Tamoxifen is a PKC inhibitor and can induce response rates up to 30% in gliomas. More potent and specific PKC inhibitors UCN-01, bryostatin 1, ISIS 3521 are currently undergoing clinical trials.  

It is hoped that targeted therapy, possibly combined with cytotoxic chemotherapy will improve the outcome of treatment of these tumors.

Chemotherapy of tumor types: 

 

Glioblastoma multiforme

Recent Phase III randomized trial by EORTC/NCIC has demonstrated that Temozoleamide used concurrently with radiation therapy (75 mg/m2 daily) and adjuvant 150-200 mg/m2 q 28 days for 6 cycles produces median survival of 15 months and 2 year survival of 26%, the best yet. 

 

Malignant Astrocytomas

A number of drugs have efficacy as an adjuvant treatment along with radiation. Efficacy has been shown for BNCU, CCNU, procarbazine, streptozotocin, the combination of CCNU, procarbazine, and vincristine as PCV, and the combination of ciplatin and BCNU. Major known factors that influence the outcome include the age, performance status, and the extent of surgical resection at the onset of therapy. The adjuvant chemotherapy after surgery and radiation increases both the time to progress and the survival. BCNU is usually given intravenously at a dose of 200mg/m2 every 6 weeks. The 25% survival for BCNU is around 20 months and for PCV (a combination of procarbazine, CCNU, and vincristine), it is better at 28 months. Results of ongoing randomized trials with temozoleamide are pending, though it clearly has activity in this disease. 

 

Oligodendrgliomas

Chemotherapy is limited to the treatment of recurrent will differentiated and moderately anaplastic oligodendrogliomas and in the primary adjuvant treatment of highly anaplastic oligodendrogliomas with surgery, and radiation. Reports recommend a combination of CCNU, procarbazine, and vincristine (PCV). It appears that this form of gliomas is more chemosenstive. Melphalan has also been impressive.

 

Ependymomas

There are very few chemotherapeutic trials in ependymomas as a primary adjuvant treatment. Most published series of chemotherapy for recurrent differentiated or anaplastic ependymomas. They are treated with a variety of agents either singly or in combinations. The best single agents in this disease have been BCNU and dibromodulcitol, with combined response plus stable disease rates of 75% to 78% and median time to progression of 13 to 16 months. Other agents used alone and in combination are vincristine, cisplatin/carboplatin, CCNU, procarbazine, etoposide, and ifosfamide) with about 20-30% partial response or stable disease, and median duration of response 6 to 10 months.      

 

Medulloblastomas

Medulloblastomas are responsive to a variety of antineoplastic agents, including vincristine, nitrosoureas, procarbazine, dibromodulcitol, cyclophosphamide, methotrexate, platinum compounds, and various drug combinations. Single agent responses vary from 20-100% with best responses reported for vincristine, CCNU, procarbazine, and cyclophosphamide. A randomized postoperative trial with postirradiation nitrogen mustard, PCV, procarbazine, and prednisone versus radiation therapy alone for newly diagnosed medulloblastoma found that the combined modality treatment had a statistically significant increase in overall survival rate at 5 years compared with patients treated with radiation therapy alone (74% vs. 56%). The general consensus is that survival benefit is seen in high risk cases when chemotherapy is given as adjuvant.

 

Primary CNS lymphomas

All primary CNS lymphomas are B cell origin and most are of the diffuse large cell type. The current recommendation is for initial chemotherapy followed by radiation therapy. High dose methotrexate (usually around 3 Gm/m2) has been shown to be effective. Cytosine arabinoside (Ara-C) is another drug with good activity. The standard chemotherapy for such lymphomas outside the CNS which is CHOP (cyclophosphamide, adriamycin, vincristine, and prednisone) is not very effective.

 

Germ cell tumors

Most common germ cell tumor of the CNS is germinoma which is highly radiosenstive and does not require chemotherapy. However, other cellular elements in a germ cell tumor, such as endodermal sinus tumor, teratoma, or choriocarcinoma, are often treated with chemotherapy. The adjuvant multidrug therapy with agents like cisplatin, etoposide, and bleomycin together with high dose radiotherapy have produced excellent overall survival rates.

 

Other tumors

There is no established role for chemotherapy in pituitary adenomos, craniopharyngiomas, cerebellopontine angle tumors, chordomas and choroid plexus pappiloma and carcinomas.

Chemotherapy is reserved only for the intransigent recurrences of meningiomas or for the histologically malignant meningiomas. The agent that are tried are akin to the primary sarcoma regimens such as the combinations of cyclophosphamide, doxorubiein, and VCR, and DTIC and doxorubiein.

 
 

 

 

 

 

 

 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 


 

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