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
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.
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
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.
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.
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.
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.
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
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.
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,
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
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.
side effects include myelosuppression (mostly with alkylating agents),
renal, hepatic, and lung fibrosis.
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.
such as vincristine and vinblstine, are associated with a peripheral
neuropathy that can involve the cranial nerves.
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.
encephalopathy can accompany ifosfamide administration.
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
is associated with spontaneous sagittal sinus occlusion.
Blood brain barrier (BBB)
is often blamed for the failure of chemotherapy.
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,
(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
Altered microenvironment may explain poor in vivo effects of
treatment compared to good in vitro results.
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
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).
order to overcome nitrosourea resistance, m
protocols have been tested,
which showed promising results in recurrent anaplastic astrocytomas and
not in GBMs.Toxic side effects were significantly higher.
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.
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.
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
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.
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:
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.
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
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
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.
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.
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.
There is no established role
for chemotherapy in pituitary adenomos, craniopharyngiomas,
cerebellopontine angle tumors, chordomas and choroid plexus pappiloma and
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.