Anticancer therapy induced neurotoxicity...Anticancer therapy induced neurotoxicity Berit Jordan...
Transcript of Anticancer therapy induced neurotoxicity...Anticancer therapy induced neurotoxicity Berit Jordan...
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
• 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