Anticancer therapyinduced neurotoxicity

Berit JordanUniversity Hospital Heidelberg,

Department of Neurology,Im Neuenheimer Feld 410, 69120 Heidelberg

DISCLOSURE OF INTEREST

none

Neurotoxicity in anticancer drugs

tingling , burning

Ataxia , leading tofalls

change of sensation : dysaesthesia, allodynia

pain

numbness

(distal) weaknessbladder

disturbances

constipation

muscleatrophy

orthostatichypotension

Qualitative change of conciusness

Seizures

Cranial nerve dysfunction > ototoxicity

PRES andvasculopathies

Ptosis anddouble 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: agepreexisting neuropathygenetically determinedmetabolisation 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

Normal

Myelinopathy

Neuronopathy /Ganglionopathy

Axonopathy

CIPN: Pathogenesis

(Park, Goldstein et al. 2013)

(Poly)Neuropathy

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

• Symmetrical „stocking-glove“ pattern

• Sensory with occasionalmotor & autonomicinvolvement

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 alcaloidstaxansthalidomidebortezomib

Decreasedpain and temperaturesensation

permanent burning, lancinating painjabbingpain

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

Remember: Only „plus symptomsmay be pharmacologically treated“

(Finnerup, Attal et al. 2015)

CIPN: clinical signs MOTOR

Minus Symptoms Plus Symptoms

(distal) weakness Fasciculations

Hypo- to areflexia Cramps

atrophy

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 damageBut 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 ++ +++ ++

BrentuximabVedotin

(+) ++ ++

+++ 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, PainInstability when walking or standingDistinguishing temperatureHearingMotor scale (8 items)Cramps, Writing, Manipulating small objects, WeaknessAutonomic scale (3 items)VisionDizziness after changing positionErection disorder

(Cavaletti, Cornblath et al. 2013)

• No prevention method nor agent have been identified

• Dose modification of chemotherapy as only preventivestrategy (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 beaggravated by sleep disturbance, anxiety and depression.

There is central sensitisation ofpain.

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

Encephalopathy

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

• Causes: Vincristin , BortezomibGemcitabine, Capezitabine, Cytarabine …

• MRI changes inconsistent and not prognostically significant

Acute cerebellar syndrome

(Wick, Hertenstein et al. 2016)

Acute cerebellar syndrome

Followingcytarabinetreatment

British Journal of Hematology 2001

• Chemotherapies aggravate tumor/ paraneoplastic coagulation disorders

• MTX: subacute “stroke like” symptoms, within 2 weeks after drug administration; 15 min- 72 hours, MRI restriction diffusion

• Asparaginase: coagulopathy with haemorrhagia, thrombosis incl. sagittal sinus thrombosis (26%), cerebral infarction (Milan 2018)

• Bevacizumab: brain ischaemia 1.2-2%

• Casual brain bleeding: sunitinib (1.5%), bevacizumab (1-3.7%)

• ! Mechanical device based treatment (thrombectomia) in brain infarction maybe effective

Stroke

(Wick, Hertenstein et al. 2016)

Figure 1

Ophthalmology 2011 118, 2093-2093.e2DOI: (10.1016/j.ophtha.2011.06.001)

• disruption of the blood brain barrier due to endothelial injury by

abrupt blood pressure changes or cytotoxic effects of chemotherapy

vasogenic oedema in posterior brain regions

• Clinical signs: confusion, visual disturbances up to blindness, seizures

• Examples: Ciclosporine!, platinum based agents, daunorubicin , vincristine , many others … targeted cancer therapies …

• usually reversible with appropriate supportive management within 2 weeks

Posterior reversible encephalopathy syndrome (PRES)

(How, Blattner et al. 2016)

PRES

MRI FLAIR, T1 with contrast(How, Blattner et al. 2016)

Cortical blindness

Pt. is not aware of vision loss becausehe recognizes visual illusions as real

Cause: bilateral damage of visual cortex

Pt. denies blindness

„Blindsight-Testing“: throwing an illusive ball

• In targeted therapies(tyrosine kinase inhibitors) and immune checkpointinhibitors

• Rare 1-2 %

• Demyelinating neuropathieswith conduction blocks

• Myasthenia gravis

Neuromuscular complications

(Touat, Talmasov et al. 2017)

• CIPN is a dose limiting side effect in cancer therapies

• Diagnoses of CIPN can mostly be established in clinical examination

• No prevention is available at at the moment

• Duloxetin shows efficacy (moderate evidence)

• Diagnosis and treatment of CIPN should include functional parameters(anxiety, depression, sleep)

• Only „plus“ symptoms of sensory neuropathy can be treated

• Spectrum of central toxicity has widened and includes immune mediatedprocesses in new cancer therapy agents

Take home messages

Cisplatin ototoxicity

Prevalence of hearing loss : 40-75% of pts. , 7-22% classified as severe, Permanent tinnitus: 20-40%

main target: outer hair cells of Corti organ, cochlear vascularized epithelial wall

dose dependent, almost always bilateral and irreversible, affects high frequencies of hearing (required for speech recognition)

Screening: audiometry including 500 – 8000 Hz at baseline, before each cycle, 3 and 6 months after chemotherapy No preventive strategy, no specific treatment Dose reduction, prefer carboplatin if possible

(Millan, Pastrana et al. 2018)

CIPN clinical characteristics

CIPN : classification scales

Table 3

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

Mechanism based pharmacologic

treatment of neuropathic pain

CIPN: Neurophysiology (2)

Axonal damage demonstrated in sural nerve