4/8/2013 1 Chemotherapy-Induced Peripheral Neuropathy in Children and Adolescents: Pathophysiology, Medical Management, Assessment, and Rehabilitation Laura Gilchrist PT, PhD Lynn Tanner PT Action of Chemotherapeutic Agents • Known to act on rapidly dividing cells • Paradox that non-dividing neurons are susceptible to damage • PNS cells especially vulnerable: – Sensory and autonomic cells lie outside the blood-brain barrier – Long axons dependent on axonal transport and supportive glial cells – Programmed cell death pathways particularly sensitive to DNA damage • Three presumed sites of attack: – Distal axonopathy: dying back or retraction of endings – Ganglionopathy: death of the cell body, especially in the dorsal root ganglion – Myelinopathy: destruction of the myelin sheath
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Chemotherapy-Induced Peripheral Neuropathy in Children and
Adolescents: Pathophysiology,
Medical Management, Assessment, and Rehabilitation
Laura Gilchrist PT, PhDLynn Tanner PT
Action of Chemotherapeutic Agents
• Known to act on rapidly dividing cells• Paradox that non-dividing neurons are
susceptible to damage• PNS cells especially vulnerable:
– Sensory and autonomic cells lie outside the blood-brain barrier
– Long axons dependent on axonal transport and supportive glial cells
– Programmed cell death pathways particularly sensitive to DNA damage
• Three presumed sites of attack:– Distal axonopathy: dying back or retraction
of endings– Ganglionopathy: death of the cell body,
especially in the dorsal root ganglion– Myelinopathy: destruction of the myelin
sheath
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(Images courtesy of Dr. Patrick Dougherty at M. D. Anderson Cancer Center, processed in collaboration with the laboratory of Dr. William Kennedy at the University of Minnesota)
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Platinum-based Drugs
• Cisplatin, oxaliplatin, carboplatin
• Used in solid tumors especially lymphomas, colorectal cancers, lung tumors
• Platinum accumulates in the dorsal root ganglion cells � primarily sensory neuropathy
• Forces usually non-dividing cells back into the cell cycle � apoptosis
• Oxaliplatin: Acute neurotoxicity common
– Cold-induced paresthesias, dysthesias, or pain primarily of the hands and face
– Calf cramping with walking– 96% of patients had symptoms
immediately after each chemotherapy cycle
– Thought to be due to impact of oxalate salts on sodium channels
(Attal et al, 2009)
• Chronic neuropathy– After treatment cessation, 40% of patients
have complete resolution of symptoms– Remaining signs of neuropathy in the
extremities• 50% decreased/absent DTR• 50% vibration deficits• 30% fine touch deficits• 61% thermal or pin prick deficits• 44% paresthesias• No pain or motor deficits• <10% with residual cold dysthesias
(Attal et al, 2009)
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Prediction for Recovery?• Cold-evoked symptoms that last >4 days after 3rd
cycle predicted chronic neuropathy
(OR 22, CI 1.54-314.74)• Enhanced pain response to cold predicted severity
of chronic neuropathy(OR 39, CI 1.8 – 817.8) (Attal, 2009)
• Recovery half-life in the hands 6.8 yrs, no observed
recovery in the feet
(Brouwers et al, 2009)
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Taxanes• Used heavily for breast cancer• Microtubule-stabilizing agents• Accumulation of microtubules in
Schwann cells, cell bodies, and axons • Spontaneous discharge from A-fibers
and C-fibers• Intra-epidermal degeneration• Micro-glial activation in SC
length• Wide base of support• Toe walking• Steppage pattern• In-toeing • Out-toeing
Functional Impairments Evidence
• 415 Survivors 10+ years post tx. of ALL were > 1.3 S.D. lower than norms– 15.4% balance (SOT)– 3.6% mobility (TUG)– 46.5 % gait (6MWT)
• ADF ROM < 5 degrees in 33%Ness KK, Hudson MM, Pui CH, et al. Neuromuscular
impairments in adult survivors of childhood acute lymphoblastic leukemia associations with physical performance and chemotherapy doses. Cancer, 2012; 118(3):828-38.
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Prevalence of Impairments in Pediatric Cancer Patients on
– Decrease AFO time and increased walk time without foot slap
– Demonstrate muscular endurance
• Consider night wear if still on chemotherapy
• Stress functional use of closed chain DF
Muscle Weakness Intervention• Peripheral strength
– Ankle T-band– Standing DF holdwith object balance– Tip toe statues– Jumping high for push off– Jumping down-ecc. control– Toe grasping– Foot “caves”– Dorsiflexion tug-of-war
• Unstable surface – standing, tandem stance, single leg stance
• Eyes closed• Balance beam or line
– forward, backward, tandem
Motor function• Stairs
– Ankle mechanics
• Dynamic gait challenges– Surfaces, direction changes
• Plyometrics– Using ankle or quad/ham?
• Running– Push off
• Screen fine motor skills
Intervention Evidence• Ankle stretching and strengthening
program improved DF PROM and knee extension strength, but did not improve measurements of mobility (Marchese, 2004)
• Review of exercise interventions in patients with pediatric cancer (Huang & Ness, 2011)
– 15 small intervention trials showed improvements in cardiopulmonary fitness, muscle strength and flexibility, and physical function
Summary
• CIPN is an established side effect of cancer treatment in both pediatrics and adults
• Accurate assessment is important in medical treatment decisions
• Knowledge of cancer treatment and assessment of CIPN is important in PT assessment and intervention
• Progress is being made in PT intervention in both peds and adults, however there is much to be learned
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References
• Argriou at al, Crit Rev Oncol 2012; 82:51-77• Attal N et al, Pain 2009; 144:245-252• Brouwers EE et al, Acta Oncol 2009;48(6):832-41.
• Dougherty PM et al, Pain 2004;109:132-142.• Dzagnidze A et al, J Neurosci 2007;27(35):9451-7• Egbelakin A et al, Pediatr Blood Cancer 2010; E pub
Nov. 11• Cavaletti G et al, Ann Oncol 2004;15(9):1439-42.
• Callizot N et al, Cancer Chemother Pharmacol 2008; 62(6):995-1007.
• Loven D et al, Eur J Cancer Care 2009; 18(1):78-83.
• Mishra et al, Am J Hosp Palliat Care 2012;29:177-82• Nahleh Z et al, Clin Med Insights Oncol 2010; 4:35-41.• Pace A et al, Neurology 2010; 74(9):762-6.
• Park SB et al, Muscle Nerve 2010; E pub Dec 9.• Reyes-Gibby CC et al, J Pain 2009; 10(11):1146-50.• Roglio I et al, J Periph Nerv Syst 2009;14:36-44.
• Siau C et al, Exp Neurol. 2006; 201(2):507-14.• Silva A et al, J Periph Nerv Syst 2006; 11(3):211-6.• Stubblefield MD et al, JNCCN 2009; 7(S5)S1-S26.
• Xiao WH and Bennett GJ, Pain 2008;135:262-70.• Yoon MS et al, BMC Neurosci 2009;10:77.