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Anticancer therapy induced neurotoxicity ... Anticancer therapy induced neurotoxicity Berit Jordan University Hospital Heidelberg, Department of Neurology, Im Neuenheimer Feld 410,

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  • Anticancer therapy induced neurotoxicity

    Berit Jordan University Hospital Heidelberg,

    Department of Neurology, Im Neuenheimer Feld 410, 69120 Heidelberg



  • Neurotoxicity in anticancer drugs

    tingling , burning

    Ataxia , leading to falls

    change of sensation : dysaesthesia, allodynia



    (distal) weaknessbladder



    muscle atrophy

    orthostatic hypotension

    Qualitative change of conciusness


    Cranial nerve dysfunction > ototoxicity

    PRES and vasculopathies

    Ptosis and double vision

  • Peripheral neurotoxicity :

    Chemotherapy induced polyneuropathy (CIPN)

    • 30-40% of patients receiving cancer treatment suffer from chronic CIPN

    • depends on chemotherapeutic agent, dose administered and therapy schedule

    • Individual risc factors: age preexisting neuropathy genetically determined metabolisation factors

    CIPN Incidence Grade 3/4*

    Cisplatin 30 - 68% 7 - 21%

    Oxaliplatin 68 - 92% 12 - 39%

    Vincristin 41 - 91%

    Paclitaxel 57 - 82%

    Bortezomib 36 - 64% - 30%

    *CTCAE Common termonology criteria for Adverse Events

    (Park, Goldstein et al. 2013, Staff, Grisold et al. 2017)

  • Simple neurologists thinking of nerves



    Neuronopathy /Ganglionopathy


  • CIPN: Pathogenesis

    (Park, Goldstein et al. 2013)

  • (Poly)Neuropathy

    • Mostly: „dying back“ axonopathy (or myelinopathy)

    • Symmetrical „stocking- glove“ pattern

    • Sensory with occasional motor & autonomic involvement

    CIPN: Clinical pattern due to pathogenesis

    Neuronopathy (syn. Ganglionopathy)

    • Damage of cell body (dorsal root ganglion)

    • Asymmetrical pattern

    esp. proprioception

  • CIPN: clinical signs SENSORY

    Damage of Examples Minus Symptoms Plus Symptoms

    Large fibres Cisplatin decreased vibration sense tingling

    decreased proprioception pins & needles

    Small fibres vinca alcaloids taxans thalidomide bortezomib

    Decreased pain and temperature sensation

    permanent burning, lancinating pain jabbing pain

    Small fibres: C (Heat), Aδ (Cold), both pain fibres form Tractus spinothalamicus anterior

    Remember: Only „plus symptoms may be pharmacologically treated“

    (Finnerup, Attal et al. 2015)

  • CIPN: clinical signs MOTOR

    Minus Symptoms Plus Symptoms

    (distal) weakness Fasciculations

    Hypo- to areflexia Cramps


    Deformity , e.g. pes cavus

  • CIPN: clinical signs AUTONOMIC

    Symptoms Examples

    Constipation vincristin, bortezomib, thalodomide

    Postural hypotension bortezomib

    Reduced heart rate variability

    Many ….

    Disturbance of bladder

    Delayed gastric emptying bortezomib

  • CIPN: Clinical examination

    Sensory: • Asking for positive symptoms (burning, tingling, shooting)? • numbness in hand and feet ? cotton applicator • Evoked pain ? Pin prick hyperalgesia ? toothpick

    Cold induced hyperalgesia ice pack dynamic: moving on skin cotton applicator

    • proprioception sense tuning fork

    Sensory ataxia ? Romberg, walking on line or blind

    Cotton applicator

  • CIPN: Clinical examination

    Motor: • Ankle jerks reduced ? • Walking on heels and toes

    • Atrophy of small foot and hand muscles (Extensor digitorum brevis)

  • CIPN: Neurophysiology (1)

    Sensible nerve conduction velocity (NCV)

    Reduction of sensible nerve action potential amplitude (SNAP) = Axonal damage But pitfalls: Stimulation artefacts, edema

    (Kandula, Farrar et al. 2017)

  • CIPN: Neurophysiology (2)

    ? Electromyography may verify

    • Axonal damage in motor fibres • Denervation

  • CIPN clinical characteristics

    Pain Sensory Motor Remarcs

    Cisplatin (+) +++ +

    Oxaliplatin +++* +++ + *90% acute hyperexcitability : dysaesthesia, cramps, fasciculations

    Vincristin + +++ ++ foot drop, wrist extensors at high doses;

    Paclitaxel +++ ++ ++ Acute musculosceletal pain syndrom 60%

    Bortezomib +++ +++ ++

    Ixabepilone ++ +++ ++

    Thalidomide ++ +++ ++

    Brentuximab Vedotin

    (+) ++ ++

    +++ frequently (>20%), ++ occasionally (10-20%), + rare (< 10%) (Miltenburg and Boogerd 2014)

  • CIPN : classification scales

    Contents of the EORTC QLQ-CIPN20

    Sensory scale (9 items) Tingling, Numbness, Pain Instability when walking or standing Distinguishing temperature Hearing Motor scale (8 items) Cramps, Writing, Manipulating small objects, Weakness Autonomic scale (3 items) Vision Dizziness after changing position Erection disorder

    (Cavaletti, Cornblath et al. 2013)

  • • No prevention method nor agent have been identified

    • Dose modification of chemotherapy as only preventive strategy (lowering dose, adaption of schedules)

    CIPN : Prevention

    (Hershman, Lacchetti et al. 2014)

    • Acetylcystein

    • Amifostin

    • Amitryptilin

    • Carbamazepine

    • Gluthatione (GSH)

    • Vitamin E

    • Nimodipine

    • Calcium and Magnesium

  • • Medical treament : Duloxetine (recommendation grade 2 B)

    – Dosing: 30 mg/d for one week, then 60 mg/d (120 mg possible)

    • According to treatment of neuropathic pain try to get relief of „plus- symptoms“ with membrane stabilising agents like

    Gabapentin/ Pregabalin

    Tricyclic antidepressants (Amitryptiline)

    • Local therapies:

    Topical baclofen, amitryptiline, ketamine (BAK)

    Topical low concentration menthol

    Capsaicin 8%

    CIPN treatment

    (Cavaletti and Marmiroli 2018)

  • • placebo controlled , included pt. after taxanes or platinum with CIPN according to CTCAE Grade 1 or higher and pain at least 4 out of 10 on grading scale of BPI(SV)*

    • duloxetine pts. decrease in average pain: of 1.06 (0.72-1.40) vs placebo 0.34 (95%CI, 0.01-0.66) (P=.003; effect size, 0.513)

    • Higher baseline emotional functioning (measured on EORTC QLQ-C30 subscale) predicted duloxetine response 4 times more likely to obtain a ≥30% reduction in pain (Oxaliplatin pts.)

    • Effect of duloxetine treatment has been shown to be more significant in CIPN

    due to platinum based therapies than in taxanes

    Duloxetine in CIPN

    (Smith, Pang et al. 2013, Hershman, Lacchetti et al. 2014, Smith, Pang et al. 2017)*Brief Pain Inventory-ShortForm

  • You never treat only the nerve damage, but the patient.

    Neuropathic pain may be aggravated by sleep disturbance, anxiety and depression.

    There is central sensitisation of pain.

    CIPN treatment – Consider in drug treatment

    (Lee, Jung et al. 2018)

  • CIPN: physical exercise

    Physical treatment is effective and should be focused on exercise of • Distal motor skills • Power and endurance of activity • Body coordination and balance

    (Kleckner, Kamen et al. 2018)

  • • Coasting phenomenon: worsening of symptoms after cessation of therapy, may last up to 3 months

    • partial recovery with residual deficits in most pts.

    • Drugs persisting in nerve axons after finishing therapy (paclitaxel) lead to ongoing toxicity

    • Improvement in neurophysiology is usually poor.

    • different grading scales for evaluation limit evaluation

    CIPN outcome

    (Staff, Grisold et al. 2017)

    (Wozniak, Vornov et al. 2018)

    sensory ganglion after ixapebilone

  • Central neurotoxicity

  • • an acute condition of global cerebral dysfunction in the absence of primary structural brain disease

    • Causes: metabolic, inflammatory-septic , toxic …

    • Signs of acute enc.: qualitative changes of consciousness, decreased alertness, psychosis, loss of affect (agitation).

    Focal signs possible (paresis, seizures)

    • To do: exclude infectious & metabolic cause, stroke

    • Examples: Ifosfamide (10-30%), Nelarabine


  • • Clinical signs: dizziness, ataxia, dysarthria, eye movement disorders manifesting 2-5 days after treatment initiation

    • Causes: Vincristin , Bortezomib Gemcitabine, Capezitabine, Cytarabine …

    • MRI changes inconsistent and not

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