Sweatman - Brain Tumors

Question 1

What are the most common mets to the brain? Where do they occur?

Answer 1

• Lung, breast, unknown primary, melanoma, and colon
• 80% in cerebral hemispheres (more accessible for surgical intervention)
  1. 15% in cerebellum, 5% in brain stem (more problems for disease mgmt due to location)
• REMEMBER: brain mets outnumber primary neoplasms by at least 10 to 1

Question 2

What are the key points for brain met mgmt?

Answer 2

• STEROIDS: to tx brain edema and raised ICP
• ANTICONVULSANTS: to tx seizures
• DEFINITIVE TX: pts with single or multiple brain mets managed with surgery, whole brain radiotx (WBRT), or radiosurgery, alone or in combo (i.e., multimodal)
  1. If poor prognosis, maybe comfort measures only
• Future tx includes: better use of conventional and novel chemo, targeted agents, radiosensitizers, stem-cell assoc therapy, and advanced radiation techniques sparing hippocampi

Question 3

What are the guidelines for brain met chemo?

Answer 3

• Lack of level 1 evidence to support routine use of conventional chemo in mgmt of most pts w/brain mets
  1. Metastatic seminoma is still often managed with chemo and resection
• Ongoing trials are examining role of BBB-penetrating chemo agents like Temozolomide + WBRT

Question 4

What are some of the possible resistance mechanisms to chemotherapy (table)?

Answer 4

• Pharmacokinetic: issues of ADME
  1. Inability of drug to pass the BBB, and common overexpression of P-gp by tumors in the brain
• Pharmacodynamic: modification of drug target, pathway redundancy, or amplification of repair processes

Question 5

How might astrocytes be implicated in chemo resistance in the brain?

Answer 5

• Close association bt astrocytes and tumor cells via gap junctions that may impart neuroprotective gene-related effects
• Tumor cells cultured alone respond to application of chemo agent by undergoing mito depolarization, and initiating process of apoptosis
  1. Same tumor cells + astrocytes in culture survive the SAME CONC of applied chemo -> astrocytes may have capacity to interrupt apoptotic process and provide “survival signaling” in spite of chemo
• Suggests that even if a chemo agent could reach brain tissue, one should NOT expect activity of drug to parallel that in treating peripheral tumors

Question 6

What are the features of Temozolomide? Resistance? AE’s?

Answer 6

• PO, non-enzymatically activated pro-drug yielding DNA methylating agent (DNA damage) -> resistance by removal of methyl gps from O6-guanine bases by AGT (encoded by the gene, MGMT)
• AE’s: usually mild-mod myelosuppression, leukopenia, thrombocytopenia (rapidly proliferating cell pops)
  1. N/V common 1-3 hrs post-tx; chills, fever, malaise, myalgias
  2. Teratogen
• NOTE: indications in attached image (GBM and malignant melanoma NOT indications for nitrosureas)

Question 7

Why might a pts cancer be resistant to Temozolomide?

Answer 7

• One method for dealing w/DNA methylation damage is to repair it with methyl guanine methyl transferase (MGMT), as suicide repair enzyme that accepts methyl adduct and restores 3D topology of DNA to permit cell division to resume, unimpeded
• Upregulation of MGMT activity and capacity is thus a potential mech of resistance
• NOTE: while this may spare tumor cell, hematopoietic stem cells lack capacity to resist action of the drug, so dose-dependent myelosuppressive effects continue

Question 8

What are the brain tumor indications of the nitrosureas?

Answer 8

• BCNU: astrocytoma, brain mets, malignant glioma, medulloblastoma
• CCNU: malignant glioma

Question 9

What are the 2 conventional chemo agents that may be used to tx brain cancer? MOA?

Answer 9

• Nitrosureas: BCNU (Carmustine), CCNU (Lomustine)
  1. Physiochem props provide access across BBB
• MOA: alkylators
  1. BCNU decomposition products ALSO carbamolyate proteins, INH DNA repair
• Both protein adducts (alkylation + carbamolyate) contribute to carmustine toxicity
• Cross-resistance with other alkylating agents uncommon

Question 10

What are the structural features of the nitrosureas? Toxicity?

Answer 10

• Highly lipophilic and non-ionized at physiologic pH, so enter CNS in measurable concentrations
  1. Large dose to compensate for dilution effect
• LOmustine (CCNU) Oral; CArmustine (BCNU) pArenteral -> BOTH undergo extensive hepatic metab
• TOXICITY: thrombocytopenia, leukopenia, N/V, admin site rxns
  1. Pulm fibrosis and/or infiltrates; may be delayed by years
  2. Endocrine dysfunction w/brain irradiation: hyperPRL and hypothyroidism (DEC thyroxin, T4)
  3. Encephalopathy and seizures; deterioration can lead to dementia
  4. INC transaminases, alkaline phosphatase, and hyperbilirubinemia -> INC LFT’s

Question 11

What is the gliadel wafer? Utility?

Answer 11

• Local surgical application of up to 8 biodegradable discs to avoid drug toxicity and maximize concentration at intended site of action -> CARMUSTINE (BCNU)
• Implanted into tumor site after surgical excision of tumor
• Dissolve over protracted time, yielding clinically active drug concentrations in immediate area, and hopefully eradicating residual tumor at margins of excision site
• BENEFICIAL EFFECT in tx of high-grade glioma (INC survival w/o INC AE’s over placebo wafers; no apparent benefit in recurrent disease)

Question 12

What is convection enhanced delivery?

Answer 12

• Alternative approach for drug localization
• Installation of catheter and infusion under pressure of chemo agent that will diffuse into tumor + immediately surrounding tissue -> spread from catheter dependent on physiochem props of drug, and varies by agent
• Numerous technical challenges (like backflow), and some clinical trials have had disappointing results
• Devo continues

Question 13

What is chemo-fog?

Answer 13

• Chemo-related cognitive impairment (CRCI): long-term consequence of antitumor tx w/cytotoxic agents
  1. “Survivor care:” long-term needs of these pts
• Impaired verbal and visual memory, attention, conc, language, motor skills, multitasking and ability to org information -> imaging/animal studies support impaired memory and learning
• Studies suggest cytotoxics promote peripheral release of TNF-alpha in response to cellular damage: cytokine, unlike drug, CAN access BBB (in other words, even drugs like Doxorubicin that can’t access BBB, can cause these effects)
  1. In brain, TNF-alpha damages mito and produces reactive nitrogen species via glial cell-related mechanism
• Both outcomes can be blocked in animal models via admin of anti-TNF-alpha Ab