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Chemotherapy Induced Peripheral Neuropathy
Chemotherapy-induced peripheral neurotoxicity (CIPN) consists of neuromuscular symptoms due to nerve damage from certain chemotherapy agents, significantly affecting patient quality of life. Despite its prevalence, with incidence rates ranging from 30% to 60%, effective prevention and treatment strategies are lacking, and many commonly used interventions lack strong evidence. Clinicians are advised to consider options like duloxetine for treatment, but no established preventative agents are recommended.
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Chemotherapy Induced Peripheral Neuropathy
- 1. Chemotherapy Induced Peripheral Neurotoxicity “CIPN” EmadShash MBBCh., MSc., MD. Medical Oncology Department National Cancer Institute, Cairo University
- 2. Don’t Expect fromme today Cover Everything!!
- 3. “The Denial Needsto Ends” A Quote that you need to remember effectively My presentation will explain, why you need to remember it!!
- 4. Questions !! What isChemotherapy 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
- 5. Pathophysiology • Pathogenesis ofCIPN 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
- 6. Features of CIPN •CIPN is primarily polyneuropathy • Symmetric stocking-glove distribution • The earliest symptoms developing at the finger tips and toes Up-to-date: Last accessed 5/20117
- 7. A short butA Common Story that we face in our practice!
- 8. Mrs. HOPE 52years old Pianist • Diagnosed with Right Breast Cancer, having the following Parameters: • Underwent Right WLE + Sentinel Lymph node dissection • T2N1 • ER +++ • PR + • Her 2 neu Score 1 + (Negative) • Ki67 68% • Referred for Medical Oncology Consultation Photo Copyright @ www.hopkinsmedicine.org
- 9. Survival Benefit fromadjuvant therapy! ONCOassist Decision support tool
- 10. Mrs. HOPE: MyFingers are my life! • …………. • Dr E: Despite we had surgery, we still need to receive adjuvant chemotherapy & radiotherapy • Mrs. HOPE: I’m already prepared, and I heard about chemotherapy side effects (Nausea, Vomiting, fatigue, hear loss, etc.……). • One last question doctor! My fingers are my life, • Would it be affected? • And if so could we prevent it from happening? • Can you give me effective medicine, if it happens? • And for how long, this feeling will last? • Dr E: hmmmmmmm, • what a difficult question to precisely answer! • I wished, she would have never asked it. • Can we keep it for later discussions!! Story Board: Courtesy of Dr Emad Shash Imagination!
- 11. What you shouldexpect to hear today about “CIPN”? Magnitude of the Problem How to properly asses? How to Prevent, if possible? How to treat? Meta- analysis Systematic Reviews Evidence Based Practice Guidelines Randomized Controlled Trials Non-Randomized Controlled Trials Cohort Studies Case Series or studies Individual Case Reports Background Information, Expert Opinion, Non EBM guidelines
- 12. What you shouldexpect to hear today about “CIPN”? Magnitude of the Problem How to properly asses? How to Prevent, if possible? How to treat? Meta- analysis Systematic Reviews Evidence Based Practice Guidelines Randomized Controlled Trials Non-Randomized Controlled Trials Cohort Studies Case Series or studies Individual Case Reports Background Information, Expert Opinion, Non EBM guidelines
- 13. CIPN: Incidence &Contributing Factors CIPN Incidence 30 % – 60 % Chemotherapeutic agent Dose Dependent Cumulative Dose exposure Other Factors
- 14. Contributing Factors Overview Platinum Drugs Taxanes Vinca Alkaloids Bortezomiab PNFrom Pre- existing Comorbidity Tumor Infiltration & Compression Radiation Therapy or Surgical Trauma Para- neoplastic
- 15. Common Antineoplastic AgentsKnown to Induce Neuropathy Drug Incidence OnsetDose 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 Carboplatin 6%–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
- 16. Common Antineoplastic AgentsKnown to Induce Neuropathy “Cont.” Drug Incidence OnsetDose 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 persist
- 17. So it’s amajor challenge that we shouldn’t deny! The question remains: How to optimally deal?
- 18. What you shouldexpect to hear today about “CIPN”? Magnitude of the Problem How to properly asses? How to Prevent, if possible? How to treat? Meta- analysis Systematic Reviews Evidence Based Practice Guidelines Randomized Controlled Trials Non-Randomized Controlled Trials Cohort Studies Case Series or studies Individual Case Reports Background Information, Expert Opinion, Non EBM guidelines
- 19. Assessment of CIPN Problemswith 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
- 20. 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
- 21. NCI CTCAE v4.0neurotoxicity Adverse event Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 Peripheral motor neuropathy Asymptomatic, clinical or diagnostic observations only; intervention not indicated Moderate symptoms; limiting instrumental ADL* Severe symptoms; limiting self-care ADL*; assistive device indicated Life-threatening consequences; urgent intervention indicated Death Peripheral sensory neuropathy Asymptomatic; loss of deep tendon reflexes or paresthesia Moderate symptoms; limiting instrumental ADL* Severe symptoms; limiting self- care ADL* Life-threatening consequences; urgent intervention indicated Death Paresthesia Mild symptoms Moderate symptoms; limiting instrumental ADL* Severe symptoms; limiting self-care ADL* NCI CTCAE: National Cancer Institute Common Terminology Criteria for Adverse Events; ADL: activities of daily living. * Instrumental ADLs include preparing meals, shopping, using the telephone, managing money. Self-care ADLs include bathing, dressing, using the toilet, taking medications.
- 22. Diagnostic Studies Serum: • HIV,herpes, Vitamin B12 deficiency, B6 toxicity, CBC diff Radiology: • X-ray, CT, MRI Neuro-diagnostic 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
- 23. What you shouldexpect to hear today about “CIPN”? Magnitude of the Problem How to properly asses? How to Prevent, if possible? How to treat? Meta- analysis Systematic Reviews Evidence Based Practice Guidelines Randomized Controlled Trials Non-Randomized Controlled Trials Cohort Studies Case Series or studies Individual Case Reports Background Information, Expert Opinion, Non EBM guidelines
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- 25. Pharmacologic Preventive Measures Anticonvulsants •Carbamazepine • Oxcarbazepine • Gabapentin • Pregabalin Antidepressants • Amitriptyline • Venlafaxine Chemoprotectants • Amifostine • Nimodipine • RhuLIF • Neurotropin • Diethyldithiocarbamate • ACTH analog ORG 2766 Vitamins, minerals, and dietary supplements • Acetyl-L-carnitine • Calcium and magnesium infusions • Glutamic acid derivatives • Glutathione and acetycysteine • Goshajinkigan (Gosha- Jinki-Gan) • Omega-3 fatty acids and alpha-lipoic acid • Vitamin E • All-trans retinoic acid We commonly Use those items, but do we really know the level of evidence!
- 26. Antidepressants & Anticonvulsants Levelof Evidence Agent Type of Study Number of patients Population End point Results Conclusion Carbamazepine 1 Open-label, non- placebo- controlled trial 36 patients Advanced colorectal cancer Peripheral neurotoxicity score No significant differences X Oxcarbazepine 2 Open-label, non- placebo controlled trial 40 patients Colon cancer Qualitative neurologic symptom and disability scores Mean total neuropathy scores were significantly lower, ? Gabapentin/ Pregabalin 3 Randomized, double-blind, placebo- controlled trial No information advanced colorectal cancer No clear methodology terminated early at an interim analysis: Pregabalin is ineffective for the prevention of CIPN XX Amitriptyline 4 double-blind trial 114 patients Receiving vinca alkaloids, platinum derivatives, or taxanes Qualitative neuropathy scale No significant differences X 1 von Delius S et al 2007, 2 Argyriou AA et al 2006, 3 Shinde SS et al 2016, 4 Kautio AL et al 2009
- 27. Venlafaxine Failed toshow Oxaliplatin neuroprotection efficacy2 • Despite it’s positive Data in Oxaliplatin-induced acute neurotoxicity1 • 50 patients were randomly assigned either to Venlafaxine or Placebo 1 Lévi F et al 1992, 2 Zimmerman C et al 2016
- 28. Chemoprotectants: Level ofEvidence Agent Type of Study Number of patients Population End point Results Conclusion Amifostine 1 “most studied neuroprotective agent” Multiple trials Cochrane Meta- analysis Patients platinum- compounds (both cisplatin and carboplatin) and taxanes Only one trial used quantitative objective measures of neuropathy as an endpoint Significantly reduced risk of developing neurotoxicity ≥ grade 2 Evidence of benefit was inconsistent across studies ?? Nimodipine 2 “calcium channel antagonist” Double blind, placebo- controlled trial 51 patients Ovarian cancer receiving cisplatin Qualitative neurologic symptom and disability scores Prematurely terminated because of increased nausea/vomiting and poor treatment compliance Neurotoxicity scores revealed significantly worse outcomes in the Nimodipine group xxx RhuLIF 3 Randomized, double-blind phase II trial 117 patients Receiving carboplatin and paclitaxel Standardized composite peripheral nerve electrophysiology scores No differences XX 1 Albers JW et al 2014, 2 Cassidy J et al 1998, 3 Davis ID et al 2005
- 29. Vitamins, Minerals &Dietary Supplements Level of Evidence
- 30. Calcium and magnesiuminfusions • Based upon an early report suggesting benefit for intravenous calcium and magnesium (IV Ca/Mg) prior to and immediately following oxaliplatin infusion. Metastatic colorectal cancer Didn’t show any significant neuropathy benefit from Ca/Mg CONcePT1 Adjuvant Setting Less acute neurotoxicity with the use of Ca/Mg supplementation N04C72 Adjuvant Setting N benefit for IV CaMg in preventing or diminishing the severity of acute or chronic neurotoxicity N08CB3 1 Grothey A et al 2012, 2 Grothey A et al 2011, 3 Loprinzi CL et al 2014
- 31. Glutathione and acetylcysteine •7 small randomized trials have addressed the protective effect of glutathione against CIPN with a platinum agent • 2014 Cochrane review concluded that glutathione significantly reduced neurotoxicity in 3 trials • However, the authors concluded that glutathione could not be recommended as a neuroprotection given the limited number of patients enrolled on these trials • A later larger trial addressing benefit in 185 patients treated with paclitaxel/carboplatin failed to demonstrate any benefit for glutathione Albers JW et al 2014, UpTodate
- 32. Vitamin E • Fivetrials of varying methodologic quality have evaluated the neuroprotective effect of vitamin E (300 to 800 mg daily) in patients treated with Taxane or platinum agents. • 2014 Cochrane review concluded that 2 vitamin E trials concluded that there was a significant reduction in the risk of neuropathy • However, the small size of the studies and the lack of objective outcome measures rendered the results inconclusive Albers JW et al 2014, UpTodate
- 33. 2014: ASCO recommendationsfor prevention of (CIPN) • There are no established agents recommended for the prevention of CIPN in patients with cancer undergoing treatment with neurotoxic agents. • Clinicians should not offer the following agents for the prevention of CIPN to patients with cancer 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 • Org 2766 • All-trans-retinoic acid • Recombinant human leukemia inhibitory factor (rhuLIF) • Vitamin E • Venlafaxine is not recommended for routine use in clinical practice. • Although the venlafaxine data support its potential utility, the data were not strong enough to recommend its use in clinical practice, until additional supporting data become available.
- 34. Some Other measuresthat could be useful in prevention! • Patients treated with oxaliplatin: • Limiting exposure to cold • Stopping and reintroducing oxaliplatin • Lengthened infusion duration • Patients treated with bortezomib: • Weekly rather than twice-weekly treatment schedules • Subcutaneous administration • Patients treated with vincristine: • Because of the high incidence of constipation, patients receiving vincristine should take prophylactic stool softeners and/or laxatives • Exercise • Cold gloves
- 35. What you shouldexpect to hear today about “CIPN”? Magnitude of the Problem How to properly asses? How to Prevent, if possible? How to treat? Meta- analysis Systematic Reviews Evidence Based Practice Guidelines Randomized Controlled Trials Non-Randomized Controlled Trials Cohort Studies Case Series or studies Individual Case Reports Background Information, Expert Opinion, Non EBM guidelines
- 36. Duloxetine and otherantidepressants Smith EM et al, 2013
- 37. 2014: ASCO recommendationsfor treatment of (CIPN) • For patients with cancer experiencing CIPN, clinicians may offer duloxetine • No recommendations can be made on the use of, however clinicians are encouraged: • It is reasonable to try a tricyclic antidepressant (eg, nortriptyline or desipramine) • Gabapentin • A topical gel treatment containing baclofen (10 mg), amitriptyline HCL (40 mg), and ketamine(20 mg)
- 38. Summary & TakeHome Message • CIPN is a major problem & real challenge in both prevention & Treatment • There are no established agents recommended for the prevention of CIPN • For patients with cancer experiencing CIPN, clinicians may offer duloxetine • The majority of other intervention commonly used doesn’t have high level of evidence, and thus every healthcare provider should reason their use.
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