chemotherapy- induced peripheral neuropathy a review and update

Chemotherapy- Induced Peripheral Neuropathy

A Review and Update

Dr.Yasar Hammor MD, FRCP, MSc

Objectives

• Explain the etiology of neuropathy in cancer patients.

• Describe the manifestations of chemotherapy-induced peripheral neuropathy.

• List agents associated with neuropathy.

• Describe tools to assess neuropathy in cancer patients.

• Outline strategies to manage peripheral neuropathy associated with chemotherapy.

Questions !!

What is Chemotherapy Induced Peripheral Neuropathy CIPN ?

Group of neuromuscular symptoms that result from peripheral nerve fibers (motor, sensory,

autonomic) damage & dysfunction caused by certain neurotoxic chemotherapy agents.

What is Neuropathic pain?

Nerve pain initiated by damaged nerves, often described as sharp, tingling, burning, cold,

and/or a pins and needles

•

How common is CIPN ?

• It is a common treatment-related side effect



• Affects 30-60% of patients getting specific neurotoxic chemotherapy drug




• This percentage varies depending on regimens, duration of exposure and

assessment methods.





assessment methods.• It has the potential to result in chemotherapy dose reductions and/or early

discontinuation





assessment methods.• It has the potential to result in chemotherapy dose reductions and/or early

discontinuation

• Chemotherapy combinations with higher incidences include those that

involve platinum drugs, vinca alkaloids, bortezomib and/or taxanes

Facts

Incidence of PN is increasing :

Chemotherapy is prolonging life

Cancer is becoming a chronic, manageable diseaseMore neurotoxic drugs have been developed

Pathophysiology

• Pathogenesis of CIPN is not completely understood

• Peripheral neuropathy results from damage to the axon, myelin

sheath, or cell body

• Characterized as injury, inflammation, or degeneration of

peripheral nerve fibers

Multiple Sclerosis Resource Centre , 2008Used with permission

Pathophysiology (continued)• Chemotherapy drugs are believed to first:Damage sensory axonsThen move on to cause degeneration and dying back of axons and myelin sheaths

• CIPN is usually symmetrical

• Begins in distal end of longest axons

• Sometimes known as polyneuropathy: affects many nerves

• Toxins (including chemotherapy) are transported along the axon towards the cell body

Contributing Factors

I. Chemotherapy Agents

• High dose, high cumulative doses, or concurrent neurotoxic

chemotherapy increases risk

• Platinum drugs, Vinca Alkaloids, Taxanes, Cytarabine, Interferon,

Thalidomide, Bortezomib

Contributing Factors

I. Others

• Peripheral neuropathy from pre-existing co-morbidity (e.g. alcoholism, Vit.

B deficiency, diabetes, HIV, hypothyroidism, CTD, toxic neuropathy, post-

herpetic neuralgia)

• Tumor infiltration & compression of spinal nerves

• Paraneoplastic syndromes

• Radiation therapy involving the spine

• Surgical trauma

Common Antineoplastic Agents Known to Induce Neuropathy

Drug Incidence Onset Dose Clinical Manifestation Recovery

Cisplatin 28%–100% (overall) + paclitaxel: 7%–8% (severe)

300 mg/m2

Symmetrical painful paresthesia or numbness in a stocking-glove distribution, sensory ataxia with gait dysfunction

Partial, symptoms may progress for months after discontinuation

Carboplatin6%–42% (overall) + paclitaxel: 4%–9% (severe)

800–1600 mg/m2

Similar to cisplatin but milder Similar to cisplatin

Oxaliplatin (acute)

85%–95% (overall) any Cold-induced painful dysesthesia Resolution within a week

Oxaliplatin (persistent/ chronic)

FOLFOX: 10%–18% (severe) 750–850 mg/m2

Similar to cisplatin Resolution in 3 months, may persist long-term

Common Antineoplastic Agents Known to Induce Neuropathy ( cont..)

Drug Incidence Onset Dose

Clinical Manifestation Recovery

Paclitaxel 57%–83% (overall),2%–33% (severe)+ Cisplatin: 7%–8% (severe)+ Carboplatin: 4%–16% (severe)

100–300 mg/m2

Symmetrical painful paresthesia or numbness in stocking-glove distribution, decreased vibration or proprioception, occasionally weakness, sensory ataxia, and gait dysfunction

Resolution usually within 3 months, may persist

Abraxane (albumin-bound paclitaxel) 73% (overall)

10%–15% (severe)

Unclear Similar to paclitaxel Resolution usually within 3 weeks

Docetaxel 11%–64% (overall)3%–14% (severe)

75–100 mg/m2

Similar to paclitaxel Resolution usually within 3 months, may persisy

Consequences

• Sensory symptoms: Dys/paresthesia, hyper/hypothesia, hypo/areflexia,

pain, diminished vibratory or cutaneous sensations

Consequences



• Motor symptoms: Weakness, gait and/or balance disturbance, difficulty

with fine motor skills, wrist or foot drop

Consequences



• Motor symptoms: Weakness, gait and/or balance disturbance, difficulty

with fine motor skills, wrist or foot drop

• Autonomic symptoms: Constipation, urinary dysfunction, sexual

dysfunction, orthostatic hypotension

Consequences

• Quality of life - exacerbation of other symptoms (e.g. pain, fatigue)

Consequences


• Interference with activities of daily living (ADLs), compromised role

function at home & work (may need gradual return to work-)

•

Consequences




• Chemotherapy dose delays, reductions, discontinuation of treatment

Consequences




• Chemotherapy dose delays, reductions, discontinuation of treatment

• Patient safety – risk for falls, tripping, burns, frostbite

Features of CIPN

• CIPN is primarily polyneuropathic, with symmetric stocking-glove “dying back” distribution, with the earliest symptoms developing at the finger tips and toes

Evaluation of CIPN

• Are the symptoms due to neuropathy?

• If so, is the neuropathy a result of cancer treatment,

cancer pathology, or other causes unrelated to cancer?

• Are the symptoms severe enough to require

intervention?

• If so, what are the options for intervention or symptom

management?

• Is modification or discontinuation of the present

cancer treatment necessary?

Diagnostic Features

• Symmetrical, distal, length-dependent “glove and stocking” distribution

• Predominantly sensory symptoms (especially pain), both in frequency and

severity, rather than motor symptoms

• Onset after administration of chemotherapy, which may be progressive, rapid, or

“coasting”

• Dose-dependent

Assessment of CIPNProblems with measuring neuropathy:

• Patient difficulty with describing the uncomfortable sensations, unless they are painful

• CIPN not always been considered a pertinent side effect—usually considered a minor

problem that would eventually resolve

• Easy, simple, and usefully comprehensive tool has yet to be developed

• Limited because toxicity is determined subjectively by healthcare provider

These problems lead to unanswered questions about how to improve CIPN symptoms

Assessment of PN• Subjective assessment: Symptoms related to PN

– Evaluate sensory, motor and autonomic symptoms

• Objective assessment:

-Touch, Pinprick, vibration, & proprioception

– Reflexes, muscle strength, Gait and balance.

– Autonomic: assess bowel sounds, orthostatic blood pressures, pulse regularity

– Difficulty with fine motor skills: opening jars, buttoning

Diagnostic StudiesSerum: • HIV, herpes, Vitamin B12 deficiency, B6 toxicity, CBC diffRadiology• X-ray, CT, MRINeurodiagnostic studies• EMG• NCV • QST

CT = computed tomography; MRI = magnetic resonance imaging; EMG = electromyography; NCV = nerve conduction velocity; QST = quantitative sensory test. Galer et al, 2000; Kovacs et al, 2006.

These are only a few of the available tests and procedures to diagnose PN

Subjective and objective assessments are important to correctly diagnose PN

What is the treatment ??

Pharmacologic and Neuroprotectant Nortriptyline

– Modest benefit, small study, lack of effectiveness Amitriptyline - Failed to improve sensory symptoms, but QOL improvedGabapentin and pregabalin - Studies failed to demonstrate benefit Lamotrigine

– not effective Glutamine

–Up-regulate nerve growth factor, decrease PN in a few previous trials Alpha-Lipoic- Acid

Diabetic PN, may interfere w/ Bortezomib

QOL = quality of life.Hammack et al, 2002; Kautio et al, 2008; Rao et al, 2007; Mitchell et al, 2006; Rao et al, 2008; Cascinu et al, 1995; Cascinu et al, 2002; Smyth et al, 1997; Wang et al, 2007.

Final Recommendations:Prevention

• There are no established agents recommended for the prevention of CIPN in cancer patients undergoing treatment with neurotoxic agents.

• This is based on the paucity of high-quality, consistent evidence and a balance of benefits versus harms.

Final Recommendations:Prevention (continued)

• Clinicians should not offer the following agents for the prevention of CIPN to cancer patients undergoing treatment with neurotoxic agents:• acetyl-L-carnitine (ALC)• amifostine• amitriptyline• CaMg for patients receiving oxaliplatin-based chemotherapy• diethyldithio-carbamate (DDTC)• glutathione (GSH) for patients receiving paclitaxel/carboplatin chemotherapy• nimodipine• all-trans retinoic acid• vitamin E

Final Recommendations:Treatment

• To date, no approved effective treatment is available for CIPN

• For cancer patients experiencing CIPN, clinicians may offer duloxetine.

• No recommendations can be made on the use of:– Acetyl-L-carnitine, noting that a positive phase III abstract supported its value, but

this work has not yet been published in a peer-reviewed journal and a prevention trial suggested that this agent was associated with worse outcomes.

Final Recommendations:

Treatment (Continued)• No recommendations can be made on the use of:

– Tricyclic antidepressants; preferences.– Gabapentin, Pregabalin– A topical gel treatment containing baclofen (10 mg), amitriptyline HCL

(40 mg), and ketamine (20 mg),

Final Recommendations:Pain medication for CIPN

• Choose an agent based on the clinician’s experience and expectation of efficacy

and safety

• Titrate that agent to the maximal tolerated dose

• If a single agent is effective, then it should be continued.

• If a single agent confers partial but incomplete benefit, then a second agent with

a different mechanism of action should be chosen and added.

• Often many agents will be needed for adequate analgesia

NCI-Wad Medani-Sudan

"don't judge a book by its cover"

Sue’s Story• Supposedly chemotherapy increased my chances of living 5 years by

8%. I don’t want to live for another 5 years like this. My hands and fingers are numb. My feet are numb. My legs are numb from my knees to the bottom of my feet. I have pain, gnawing, burning, and cramping most of the time. My legs ache and feel stiff and heavy all the time. Driving is a problem, walking is a problem, Being on my feet is a problem. My hands don’t work. I feel collapsed, dizzy, and weak all day, every day, all the time. I have disabling fatigue. I feel like I have been poisoned. –

• written in 2008 by Sue, colorectal cancer survivor. (Tofthagen, 2010

chemotherapy- induced peripheral neuropathy a review and update

Health & Medicine