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
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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.
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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
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
Fisher B et al: J Neuro-Oncol 74:201-205, 2005
Delayed Neurotoxicity
O’Brien P.C. et al: Int J Rad Oncol Biol Phys 64:408-13, 2006
Fractional Delivery of Chemotherapeutic Agents Across the BBB and BTB
Local Exposure Fraction
MTX 0.017 0.18
5-FU 0.11 0.25
AZQ 0.70 0.72
BCNU 0.54 0.55
Drug Normal Brain Increased Permeability = 0.1 ml/g/min
Methods to Increase Drug DeliveryMethods to Increase Drug Delivery
• Increase delivery of systemic drug administration (intravascular drugs)
• Increase drug delivery bylocal administration(intra-CSF; intra-parenchymal-CED)
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)
Increase Delivery of Intravascular DrugsIncrease Delivery of Intravascular Drugs
Manipulating the drug(chemical modifications, prodrugs)
• 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)
Increase delivery of intravascular drugsIncrease delivery of intravascular drugs
Increase the Fraction of the Drug Reaching the Tumor: HD-Chemotherapy
• Increase plasma concentration with systemic rescue maneuvers High-dose MTX + folinic acid rescueHigh-dose Ara-C + granulocytic growth factorHigh 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.
• 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).
High Dose Chemotherapy in PCNSL
)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