4/8/2013
1
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
4/8/2013
2
(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)
The linked image cannot be displayed. The file may have been moved, renamed, or deleted. Verify that the link points to the correct file and location.
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)
4/8/2013
3
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)
The linked image cannot be displayed. The file may have been moved, renamed, or deleted. Verify that the link points to the correct file and location.
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)
4/8/2013
4
The linked image cannot be displayed. The file may have been moved, renamed, or deleted. Verify that the link points to the correct file and location.
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
4/8/2013
5
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)
4/8/2013
6
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
4/8/2013
7
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
4/8/2013
8
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
4/8/2013
9
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.
4/8/2013
10
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!
4/8/2013
11
.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
4/8/2013
12
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
4/8/2013
13
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.