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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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