Tx of Brain Tumors Flashcards
How common are brain METs?
Brain metastases outnumber primary neoplasms by at least 10 to 1, and they occur in 20% to 40% of cancer patients
What primary cancers like to go to the brain?
The most common primary cancers metastasizing to the brain are lung cancer (50%), breast cancer (15%–20%), unknown primary cancer (10%–15%), melanoma (10%), and colon cancer (5%)
Where do most brain METs deposit in the brain?
80% of brain metastases occur in the cerebral hemispheres, 15% occur in the cerebellum, and 5% occur in the brain stem
Metastases implant most frequently in the cerebral hemispheres where they are more accessible to surgical intervention and least frequently in the brainstem, which site poses extreme problems for adequate disease management.
How are brain METs handled?
Patients with metastatic disease in the brain usually undergo multimodal treatment involving both surgery or radiation and chemotherapy.
Additional non-antitumoral therapy may be required to manage the problem of increased pressure within the cranium; such drugs include:
steroids and antiepileptic agents.
Whereas radiation may have a lethal effect on tumor tissue, it can also lead to damage to surrounding tissue and to a problem of swelling. Advances in radiation techniques continue to be developed to facilitate very precise targeting within this delicate and vital organ.
As you are aware, the blood brain barrier poses a significant problem for adequate penetration of chemotherapeutic agents into the brain. The vast majority of drugs are incapable of surmounting this barrier; little evidence exists of a beneficial effect on brain metastases.
Work continues on the development of agents that are suited to accessing the brain in cytotoxic concentrations, or which can be used in conjunction with whole brain radiotherapy (WBRT).
There is a lack of strong evidence to support the routine use of conventional chemotherapy in the management of most patients with brain metastases
Ongoing trials are examining the role of blood–brain-barrier penetrating chemotherapy agents such as temozolomide with WBRT, and the results to date have been mixed
What are some possible resistance mechanisms to chemotherapy in the brain?
The inability of a drug to pass across the blood brain barrier, and the common overexpression of P-gp by tumors in the brain are, of course, pharmacokinetic issues. However, basic scientific investigation would suggest that brain tissue inherently possesses some unique pharmacodynamic mechanisms of resistance
Shown here in a scanning electron micrograph is the very close association between astrocytes and tumor cells, via gap junctions. It appears that resistance to chemotherapy by the tumor cell is related not only to mechanisms within the tumor cell itself, but also to gene-related effects produced by the astrocyte.
Shown here is a simple cell culture experiment. On the one hand, tumor cells cultured alone respond to the application of a chemotherapeutic agent by undergoing mitochondrial depolarization, and initiating the process of apoptosis or programmed cell death.
However, the same tumor cells co-cultured together with astrocytes, survive the same concentration of applied chemotherapeutic agent. It would appear that the accompanying astrocytes have the capacity to interrupt the apoptotic process and to provide prevailing “survival signaling”, even in the presence of chemotherapeutic agent. This basic finding would indicate that even if a chemotherapeutic agent could reach the brain tissue, one should not expect the activity of the drug to parallel activity seen when treating peripheral tumors.
What is Temozolomide?
A PO or IV agent what is a non-enzymatically activated pro-drug that yields a DNA methylating agent
It is one of few drugs approved to treat brain tumors.
What tumors is temozolomide approved for?
Astrocytoma and glioblastoma multiforme (labeled)
malignant glioma, malignant melanoma (off-label)
What are the AEs of Temozolomide?
Myelosuppression
leukopenia and thrombocytopenia (usually only mild)
teratogenic
Recall that one method for dealing with methylation damage to DNA is to effect a repair with methylguanine methyltransferase (MGMT), a suicide repair enzyme that accepts the methyl adduct and restores normal 3-D topology of the DNA to permit cell division to resume, unimpeded. One mechanism of resistance to temozolomide is:
upregulation in MGMT activity and capacity. Whereas this may spare the tumor cell, hematopoietic stem cells lack the capacity to resist actions of the drug; this is why the drug produces dose-dependent myelosuppressive effects.
Notrosoureas, such as carmustine and lomustine, are approved for tx of what brain tumors?
Carmustine: astrocytoma, brain METs, malignany glioma, medulloblastoma
Lomustine: Malignant glioma
How do carmustine and lomustine work?
Of all the conventional chemotherapeutic agents, carmustine and lomustine, together with temozolomide, are the ones whose physicochemical properties provide for access across the blood brain barrier. As you will recall, nitrosoureas are alkylating agents.
In addition, carmustine, by virtue of its chemical structure, is also capable of carbamylating proteins to inhibit DNA repair. In other words, this drug has two mechanisms by which it can damage DNA
Describe the ADME of carmustine and lomustine
-Highly lipophilic and non-ionized (Enter the CNS in measurable concentrations)
- Lomustine oral; carmustine parenteral
- Both undergo extensive hepatic metabolism
What are Carmustine wafers
Now one way of avoiding systemic drug toxicity and maximizing drug concentration at the intended site of action is to use a local application technique. One such approach is the surgical implantation of carmustine impregnated wafers into the tumor site after surgical excision of the tumor. These wafers will dissolve over a protracted period of time, yielding clinically active drug concentrations in the immediate area and, hopefully, eradicating any residual tumor that remains at the margins of the excision site. A recent Cochrane review indicates a beneficial effect in the treatment of high-grade glioma.
An alternative approach for drug localization is a technique known as convection enhanced delivery. Describe this.
This involves the installation of a catheter and the infusion under pressure of a chemotherapeutic agent which will diffuse into the tumor and immediately surrounding tissue. The manner in which an individual drug spreads from the catheter is dependent upon physicochemical properties, and varies by agent. Numerous technical challenges remain, and hitherto, results in clinical trials with some agents have proved disappointing. Development in this area continues.
One possible mechanism for chemo fog damage in neuronal tissue is:
through cytokines, like TNF alpha, which upon liberation in the periphery through drug induced cell eradication, can access the CNS to produce damage in this distant organ. The fact that an antibody to TNF alpha is protective of brain tissue in animal models, lends strong support to this theory.
