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Delayed Neurotoxicity

Delayed Neurotoxicity. The cumulative risk at 5 years to develop overt dementia is 24-30% (1,2). For patients aged > 60 year the risk of dementia at 7 years is 58% (2). Multivariate analysis shows that only radiotherapy is a significant factor related to neurotoxicity (1).

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Delayed Neurotoxicity

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  1. Delayed Neurotoxicity • The cumulative risk at 5 years to develop overt dementia is 24-30%(1,2). • For patients aged >60 year the risk of dementia at 7 years is 58%(2). • Multivariate analysis shows that only radiotherapy is a significant factor related to neurotoxicity (1). • By 4 years fatal neurotoxicity rate is 10%(3). (1) Omuro A.M. et al: Arch Neurol 62:1595-1600, 2005 (2) O’Brien P.C. et al: Int J Rad Oncol Biol Phys 64:408-16, 2006 (3) Fisher B et al: J Neuro-Oncol 74:201-205, 2005

  2. Fisher B et al: J Neuro-Oncol 74:201-205, 2005 Delayed Neurotoxicity • By 4 years fatal neurotoxicity rate is 10% • Modification of the RT schedule to a25% reduction in biologically effective tumor dose (36Gy/30 fractions/3 wks) – delayed but did not eliminate fatal neurotoxicity • Reduction of RT dosedid not compromisetreatment outcome

  3. Delayed Neurotoxicity O’Brien P.C. et al: Int J Rad Oncol Biol Phys 64:408-13, 2006

  4. Local Exposure Fraction Drug Normal Brain Increased Permeability = 0.1 ml/g/min MTX 0.017 0.18 5-FU 0.11 0.25 AZQ 0.70 0.72 BCNU 0.54 0.55 Fractional Delivery of Chemotherapeutic Agents Across the BBB and BTB

  5. Methods to Increase Drug Delivery • Increase delivery of systemic drug administration (intravascular drugs) • Increase drug delivery bylocal administration(intra-CSF; intra-parenchymal-CED)

  6. Increase Delivery of Intravascular Drugs • Manipulating the drug(chemical modifications, prodrugs) • Increasing the fraction of the drug reaching the tumor (High-dose chemotherapy, intra-arterial administration) • Manipulating the capillary permeability(osmotic BBBD, chemical modification of BBB/BTB, receptor mediated transport)

  7. Manipulating the drug (chemical modifications, prodrugs)

  8. Increase delivery of intravascular drugs • Manipulating the drug(chemical modifications, prodrugs) • Increase the fraction of the drug reaching the tumor(High-dose chemotherapy, intra-arterial administration) • Manipulating the capillary permeability(osmotic BBBD, chemical modification of BBB/BTB, receptor mediated transport)

  9. Increase the Fraction of the Drug Reaching the Tumor: HD-Chemotherapy • Increase plasma concentration with systemic rescue maneuvers • High-dose MTX + folinic acid rescue • High-dose Ara-C + granulocytic growth factor • High dose chemotherapy with stem cell support • Rescue maneuvers reduce systemic toxicity and make the treatment relatively safe. • Still, systemic toxicity is the major limiting factor.

  10. High Dose Chemotherapy in PCNSL • Several studies tried to use intensive chemotherapy as the sole treatment for PCNSL but their limitations proved to be either: • A low response rate (25% CR) (single agent HD-MTX) (1) • A short duration of response(2) • A high rate of treatment-related death(9-10%) (3). (1) Herrlinger U. et al: Ann Neurol 51:247-252, 2002 (2) Abrey L..E. et al: J Clin Oncol 21: 4151-4156, 2003 (3) Pels H. et al: J Clin Oncol 21: 4489-4495, 2003

  11. Pharmacokineticsof HD-MTXHuman Studies % of treatment cycles Author I.V. MTX dose with CSF MTX level (gr/m2) > 1 mmol/L Thyss-1987 0.5 0% Thyss-1987 2.5 44% Millot -1994 5.0 66% Borsi -1987 6.0 100%

  12. Pharmacokinetics of HD-MTXHuman Studies • CSF MTX concentrations: marked interindividual variability. • Cytotoxic concentrations are obtained with marked increment of the total dose(to 6-8 gr/m2). • The mean AUC ratio (CSF/serum) MTX:1.52 - 3.0%(systemic dose: 5 - 8 gr/m2 )reflecting the poor diffusion of MTX into the CNS.

  13. MTX Pharmacokinetics • Human studies evaluated CSF MTX. • Peak CSF MTX concentrations are observed between 4-6 hrs after MTX infusion while serum levels are rapidly declining. • Do CSF MTX levels reflect parenchymal drug penetration? • CSF peak levels may reflect the sink effect or the washout of the drug from the brain and tumor extracellular space.

  14. MethotrexatePharmacokineticsin DogAfter BBBD Brain CSF Neuwelt et al, Neurosurgery 7:36-43,1980

  15. Pharmacokinetics of MTX in the ECF of Brain Tumor Plasma total MTX Plasma free MTX ECF MTX AUCECF/AUCPlasma 1.02 + 0.75 % (0.36 -2.37) i.v. MTX infusion Dukic et al, Pharmaceutical Res 16:1219-25,1999

  16. MTX Penetration in Brain Tumor Bolus Plasma Bolus ECF AUCECF/AUCPlasma i.v. bolus: 4.15 + 2.20 % i.v. infusion: 1.39 + 0.79 % Dukic et al, Europ J Cancer 36:1578-84,2000

  17. PCNSL and HD-MTX:Rapid (3 hrs) vs. Regular (6 hrs) Infusion of MTX CSF MTX Concentration Tumor Volume Relapse-Free Survival P<0.001 Regular Rapid Rapid n=16 n=13 P<0.001 Regular Higara et al, J Neurosurgery 91:221-30,1999

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