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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

• Paclitaxel:– Symmetrical painful paresthesia– Numbness stocking/glove distribution– Decreased vibration sensation– Occasional weakness– Sensory ataxia– Gait disturbance

• Pronounced impairment of light touch fibers (A-beta), intermediate impairment of A-delta fibers, and relative sparing of C-fibers

(Dougherty et al, 2004)

Persistence of symptoms

• After administration of ~ 530 mg/m2, 71% of patients had neuropathic symptoms– 63% did not experience recovery of symptoms at

follow-up (Park et al, 2010)

• Final severity of symptoms correlated with vibration and DTR evaluations, not pin, strength, or autonomic signs (Cavaletti et al, 2004)

• CIPN in treatment predictive of persistent neuropathic pain (Reyes-Gibby et al, 2009)

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Vinca Alkaloids

• Vincristine, Vinblastine• Used for hematologic, lymphatic, and

solid tumors (breast, kidney, brain, lung)

• Mitotic inhibitor• Binds to tubulin, inhibiting microtubule

assembly• Direct axonal toxicity

(Silva et al, 2006)Siau et al, Exp Neurol. 2006

In rats with chemotherapy-induced neuropathic pain, partial denervation of the epidermis

Signs and Symptoms of Vincristine neuropathy

• Loss of ankle reflexes first

• Paresthesias in fingers and toes• Weakness in great toe extension, ankle

dorsiflexion, wrist extension• Autonomic neuropathies – constipation,

urinary incontinence• Vibration sensation rarely impacted

Predictors of toxicity

• Level of toxicity often seems unpredictable

• Low CYP3A5 expression may lead to decreased metabolism and increased neuropathy (Egbelakin et al, 2010)

• Hepatic insufficiency• Charcot-Marie Tooth

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Medical Management

• Dose reductions

• Neuroprotective agents• Treatment of neuropathic pain

• NCCN Task Force Report: Management of Neuropathy in Cancer

(Stubblefield et al, JNCCN 2009)

Dose Reductions

• Disease specific– In children dose-reductions for vincristine

AALL0331 and AREN0532• Severe neuropathic pain• Foot drop• Vocal cord paresis

– In children with neuroblastoma or liver tumors, dose reductions for grade 4 toxicities only, indicating severe impact on function

Neuroprotective Agents: Benefit shown in human trials

• Vitamin E (platinums)– 600mg BID– Antioxidant– Mitigates platinum-based toxicity (Pace et al, 2010)

– Separate study on taxane or taxane + platinum demonstrated no benefit (Kottschade et al, 2010)

• Ca++/Mg++ (platinums)– Facilitate sodium channel function– Bonds oxylate– Reduces oxaliplatin acute toxicity

• Glutamine– Up-regulates nerve growth factor– Studies with small samples found

decreased neuropathy in patients treated with paxitaxel or oxaliplatin using 10 mg TID or 15 mg BID

– Other studies demonstrating no effect (ovarian cancer 500 mg TID) (Loven et al, 2009)

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Other agents with promise

• Acetyl-l-carnitine– Paclitaxel (Xiao and Bennett, 2008)

• Vitamin B12/B6– NCT00659269 – ongoing clinical trial

including vincristine, taxanes, and platinum compounds

• Interleukin-6– Cisplatin, paclitaxel, and vincristine (Callizot

et al, 2008)

• Melatonin– Small study of Breast cancer patients on

taxanes, 21 mg daily decreased severity of symptoms (Nahleh et al, 2010)

• Erythropoietin– Mouse model � reduced DNA damage in

neurons from cisplatin (Yoon et al, 2009)

• Progesterone or dihydroprogesterone– Nerve abnormalities recovered more quickly

in rats treated with Docetaxel (Roglio et al, 2009)

Treatment of Neuropathic Pain

• Tricyclic antidepressants (amitriptylin)– 9 CPGs recommend as primary treatment

• Gabapentin– Double-blinded controlled cross-over trial with no

benefit– Other small trials with minor benefit

• Pregabalin– One trial, greater benefit than GP or AMT (Mishra,

2012)

• Topical baclofen, amitryptyline, and ketamine– Ongoing trial, NCT00516503

Assessment of Neuropathy

• Impairment Measures

• Related Measures– Related Impairments– Functional Limitations

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CIPN Measures

• NCI-CTC: physician based adverse event scales– Not sensitive for mild/moderate neuropathy

• Adults: – Patient Neurotoxicity Questionnaire– Modified Total Neuropathy Score (mTNS)– Pain Rating – VAS, NRS, McGill

• Children and Adolescents:– Ped-mTNS

Ped-mTNS• Brief Interview

– Sensory function (tingling or buzzing, numbness/ can hardly feel, pain/hurt)

– Motor function (walking/stairs, buttoning buttons)

– Autonomic Function

• Clinical Exam– Pin Sensibility

– Vibration

– Light Touch

– Strength

– Deep Tendon Reflexes

Grading

Based on extent of symptoms/loss since CIPN is thought to be a length-dependent neuropathy:

Pin Sensibility: _____0 Normal1 Reduced in fingers/toes2 Reduced up to wrist/ankle3 Reduced up to elbow/knee4 Reduced above elbow/knee

• In patients with ALL, Lymphoma, Other Solid Tumors (not CNS)

• Cases n= 60• ped-mTNS score 9.2 +/- 4.3• Controls mean score 1.4 +/- 1.4Subjective symptoms

% with deficit Mean

Sensory symptoms 30% 0.4

Motor Symptoms 50% 0.9

Autonomic symptoms

39% 0.8

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Clinical Symptoms % with deficit Mean

Light Touch 50% 1.2

Pin Sensation 50% 0.6

Vibration 38% 0.8

Strength 98% 1.9

Deep Tendon Reflexes

100% 2.8

Relation to Function

• Neuropathy and Balancers = -0.585, p < 0.001

• Neuropathy and Manual Dexterityrs = -0.514, p < 0.001

Scale Psychometrics

• Internal ConsistencyItem-Total Correlations all > 0.3 Chronbach’s Alpha 0.76

• Inter-rater Reliability (n=10)ICC = 0.98

• Test-retest Reliability (n=10)ICC = 0.99

Ped-mTNS by Diagnostic Category

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Related Impairment Measures

• Pain– PedIMMPACT recommendations:

Faces Pain Scale- revised for 5 – 12 yearsVisual analog scale (VAS) for ages 13-21

• Range of Motion– Ankle dorsiflexion

• Foot position/ Arch Measures– Hindfoot position

• Functional Limitation Measures– Balance – BOT-2, Dynamic Gait Index,

Berg– Endurance – 6-minute walk test– Gait

Gait Impairments• Foot slap

• Flat foot • Decreased step

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

Treatment (non-CNS)

• CIPN 93%• Ankle DF PROM < 5º 39%• Ankle DF AROM < 5º 63%• Strength Deficits 50%• 6MW below 3rd percentile 74%• Balance Impairment 74%• Gait Impairment 85%

Physical Therapy Intervention for Children with CIPN

Historical interventions Historical results

Daily heelcord stretching -Loss of ankle ROM

-Midfoot collapse

-Hindfoot valgus

Off-the-shelf dorsiflexion

stretching splints

night and sedentary time

-Maintains or slight increase in

DF ROM

-Midfoot collapse

-Hindfoot valgus

Hinged AFOs worn daytime

and/or nighttime

-Varied results in ankle DF

ROM

-Collapsed midfoot

-Hindfoot valgus

Current ROM/Posture/Gait Intervention

Intervention Results

Solid ankle AFO worn

23/24 hours until full DF

ROM and normal or mild

foot slap gait pattern

Wean out slowly to

SMO/FO/no orthotic with

AFO worn at night

- Increased ankle DF ROM to

normal

-Absent or minimal collapse

in midfoot

-Neutral to minimal hindfoot

valgus.

-Normalized gait pattern in

AFO and after intervention

barefoot

--COMPLIANCE!

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.017

.000

.017

.034

.025

.033

Adolescents and adults orthotics

• ROM loss without severe foot integrity loss

• Consider carbon toe-off• May need serial casting for ROM at end

of treatment

Criteria for AFO wean

• Normal ankle ROM• Barefoot heel-toe gait pattern• 6 MWT assessment

– 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

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Balance interventions• Single leg stance work

– Step stance, kicking ball, soccer ball stop, Yoga, Wii fit, popping bubbles with feet, etc

– watch foot position and hip lean

• 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.