Neurotoxicity

Neurotoxicity, a common side effect of cytotoxic therapy – how to protect the patient Irena Netikova General Teaching Hospital Prague the Czech Republic

Neurotoxicity - side effect of cancer therapy second in frequency to hematological toxicity

ANTINEOPLASTIC THERAPY Neurotoxicity peripheral neuropathy (CIPN) central neurotoxicity

Central neurotoxicity encephalopathy myelopathy Ifosfamide metabolic encephalopathy 5-30% of all patients

Ifosfamide induced encephalopathy Symptoms: disorientation, hallucination, catatonia, seizures and gradually worsening sensorium lapsing into coma circulatory collapse and death The risk of development advanced age, hepatic dysfunction, impaired renal function, oral use of ifosfamide and concomitant use of other central nervous systems depressants Jain S, 2001 x very active metabolism (young sportsman)

Mechanism of toxicity development Ifosfamide undergoes a secondary ‘‘deactivation’’ → dechloroethylated metabolites and chloroacetaldehyde Chloroacetaldehyde - nephrotoxicity and neurotoxicity (a) direct neurotoxic damage (b) depletion of central nervous system glutathione level (c) inhibition of mitochondrial oxidative phosphorylation resulting in impaired fatty acid metabolism

Methylene blue restores and maintains mitochondrial respiration and therefore can be used to correct or prevent acute neurotoxic effects moderate to severe cases of ifosfamide neurotoxicity prophylactically to prevent encephalopathy in high-risk conditions useful in the treatment of grade III or IV neurotoxicity ( i.v.) prophylactic or concurrent administration of methylene blue with ifosfamide requires further clinical evaluation Sarah Donegan, 2001, Klener 2000

Pharmacy of GTH Prague Rp. Methylenii Caeruleum 0,2 Aquae destil. ad 20,0 M.f.sol. D.S. 3 – 4x daily 5 ml (1 teespoon) stability 1 month protect against light i. v. administration : 50 mg methylen blue at 10 % water solution slow administration

Case report I patient L.N., 31 years dg.: 10/07 - PNET upper lip tumor without meta TNM klasifikace: T3N0M0, St.III OA: trombosis, Leyden mutation, acné vulgaris 80kg, 187cm BSA: 2,02 BMI: 22,88 FT: Vessel Due 1-0-1, Doxybene 100mg 1-0-0, Retin A 0,05%crm. smoker after 3. CHT cycle: numbness and tingling in his fingers change of mood ( agresivity)

CHT: 6 cycles VAI + RT Scheme VAI: Kytril, Dexona á 1amp./ 100ml FR day 1-5 2 g Uromitexan/ 100ml FR day 1-5 4 g ifosfamid / 1000ml G5 day 1-5 40 mg doxorubicin / 250ml FR day 1-4 800 mg Uromitexan 4 times daily after infusion, day 1-5 2 mg vincristin, day 1 Zofran Zydis 1tbl. methylen blue: 3 x 5 ml, p.o. 5 days after the 3. cycle 2 days more at home

Chemotherapy-induced peripheral neuropathy (CIPN) neuropathies cannot be treated easily protective treatment strategies have not been effective enough a consequence of antineoplastic pharmacotherapy, cancers themselves, or other diseases and medications

Peripheral neuropathy symptoms sensory nerves : pain, numbness and tingling, burning, prickling, pinching or a loss of feeling motoric nerves: weakness or paralysis of the muscles that control those nerves autonomic neuropathy: dizziness, constipation, difficulty urinating, impotence, vision changes, hearing loss

What patients feel symptoms may begin gradually glove-and-stocking distribution of sensory loss nerve hyperexcitability the skin is so sensitive that the slightest touch is agonizing heaviness or weakness in the arms and legs, an unsteady gait and can have difficulty feeling the floor beneath them

These symptoms may be disabling, adversely affecting activities of daily living and thereby quality of life

It is paradoxical that nondividing neurons and supporting cells of the peripheral nervous system are susceptible

Vulnerability reasons of peripheral nervous system sensory and autonomic neurons are contained in ganglia → lie outside the blood-brain barrier are supplied by capillaries long peripheral nerve axons are susceptible to agents, which interfere with → energy metabolism → axonal transport (microtubule–based, stuctural-based, high mitochondrial activity needed)

CIPN Neurotoxicity may develop as a consequence of treatment with : platinum analogues (cisplatin, oxaliplatin, carboplatin) taxanes (paclitaxel, docetaxel) vinca alkaloids (vincristine, vinorelbin) more recently thalidomide and bortezomib new molecularly targeted, biological agents promise to significantly reduce injury to normal tissue peripheral neurotoxicity is dose limiting

Incidence of CIPN related to: cumulative dose infusion duration individual risk factors may also influence the development and severity of neurotoxicity

What we know about risk factors As more effective multiple drug combinations are used, patients are treated with several neurotoxic drugs. Synergistic neurotoxicity has not been extensively investigated pre-existent neuropathy may influence the development of a CIPN underlying inherited or inflammatory neuropathies may predispose patients to developing very severe symptoms other factors such as focal radiotherapy or intrathecal administration may enhance PN

Mechanisms of CIPN damage to neuronal cell bodies in the dorsal root ganglion axonal toxicity via transport deficits or energy failure axonal membrane ion channel dysfunction patients treated with oxaliplatin have revealed alterations in axonal Na(+) channels prophylactic pharmacological therapies aimed at modulating ion channel activity may prove useful in reducing neurotoxicity

Development of CIPN prospective studies demonstrate that maximum symptoms and deficit may occur up to a month after discontinuation of treatment (Verstappen et al., 2005) symptoms reach a plateau at or soon after the end of treatment and improve after treatment is discontinued

The notable exceptions - platinum compounds Oxaliplatin often produces acute, reversible symptoms during the first courses of treatment all the platinum compounds produce ‘‘coasting’’ where neuropathy progresses for weeks to several months after drug treatment ends

The diagnosis of a CIPN based on: the case history the clinical and electrophysiological findings knowledge of the pattern of neuropathy associated with specific agents

Platinum compounds CIPN is closely related to total cumulative drug dose cDDP ≥ 400–500 mg/m2 of cisplatin; typically 3–6 months into treatment (Walsh et al., 1982; Thompson et al., 1984; Ozols et al., 1985) sensory CIPN with initial complaints of paresthesias in the distal extremities all sensory modalities are involved, but loss of large fiber sensory function is often prominent. → this may progress to severe sensory ataxia the neuropathy may continue to progress for several months after cessation of cisplatin and symptoms may develop as long as 3–6 weeks after the last dose of chemotherapy (Mollman et al., 1988)

autonomic neuropathy is infrequent and can cause dizziness, palpitations, or impotence (Hansen, 1990; 1992) oxaliplatin - 60–80% of patients develop a stereotyped cold-induced acute toxicity that involves reversible paresthesias in the throat, mouth, face, and hands occurring within 30–60 min

Pt compounds mechanism of action similar to alkylating agents that bind to DNA DNA damage causes aberrant re-entry into the cell cycle and apoptosis (Gill and Windebank, 1998a). concentrations in peripheral nervous tissue are similar to tumor tissue compared with much lower concentrations in brain ( Gregg et al., 1992; Screnci et al., 2000). binding of platinum to mitochondrial DNA is a potential mechanism underlying delayed neuronal death (Podratz et al., 2007)

Other alkylating agents - mild peripheral neuropathy: Cyclophosphamide, Procarbazine, Thiotepa has little or no peripheral toxicity HD Ifosfamide- CIPN occurred in about 8% of patients and central neurotoxicity is common too paresthesias and pain in the feet and pan-modal sensory loss slow and incomplete recovery occurred over years after drug withdrawal (Patel et al., 1997). Cranial nerves can be affected by intra-arterial infusion or concomitant radiation (Shingleton et al., 1982; Wilson et al., 1987).

Mitotic spindle inhibitors vinca alkaloids, taxanes, and podophyllin analogs (etoposide and tenoposide) interfere with microtubule assembly and mitotic spindle formation slows mitosis results in disordered cell division and apoptosis disruption of microtubule function in axons inhibits axonal transport → length-dependent axonal damage

neuropathy is distally predominant, symptoms begin in the lower limbs and appear later in the upper limbs sensory, motoric and autonomic fibers are all affected because the cell body is usually spared, good recovery of function can occur, especially in children and young adults peripheral rather than central neurotoxicity

Antineoplastic antibiotics Antimetabolites CIPN has not been reported

Therapy of CIPN neuropathies cannot be treated easily protective treatment strategies have not been enough effective yet

Therapy of CIPN pain Pain relievers aspirin, ibuprofen - mild symptoms more severe symptoms - NSAID (nimesulid, COX II inhibitors) and opioids (tramadol, oxycodon, morfin) Antidepressant medications - mild to moderate symptoms. amitriptyline, nortriptyline, imipramine, citalopram, venlafaxin, paroxetin and bupropion Antiseizure medications - jabbing, shooting pain carbamazepine, gabapentin, pregabalin, lamotrigin Mexiletine, a drug normally used to treat irregular heart rythmus, may help to relieve burning pain

Proposed prophylactic strategies amifostin ( Ethyol) Ndubisi, Boniface U., et al. "A Phase II Open-Label Study to Evaluate the Use of Amifostine in Reversing Chemotherapy-Induced Peripheral Neuropathy in Cancer Patients—Preliminary Findings." American Society of Clinical Oncology 1999 Annual Meeting Abstract: 2326. vitamin E glutathione A recent Cochrane review (Albers et al., 2007) concluded that there was insufficient evidence to recommend the use of any therapies for the prevention of the neuropathy caused by platin compounds

Experimental Therapeutics Acetyl-L-carnitine (ALC) the acetyl ester of L-carnitine, plays an essential role in intermediary metabolism neuroprotective and neurotrophic actions, antioxidant activity, positive actions on mitochondrial metabolism, and stabilisation of intracellular membranes ALC has demonstrated efficacy and high tolerability in the treatment of neuropathies of various aetiologies, including CIPN Maestri A et al. 2003 Claudio Pisano et al 2003

Glutamate animals experiment Glutamate significantly protected against both sensory and motor neuropathy. no intrinsic neurotoxicity with glutamate was observed and no interference with the cytotoxic efficacy of vincristine Boyle FM et al, 1996, Boyle FM et al.,1999.

Glutamine Glutamine as a neuroprotective agent in high-dose paclitaxel-induced peripheral neuropathy Stubblefield MD et al.,2005 to chemotherapy oral glutamine significantly reduces the incidence and severity of peripheral neuropathy of patients receiving oxaliplatin without affecting response and survival Florian Strassera, 2008

Glutamic acid/glutamine/glutamate The synaptically released glutamate is taken up into glial cells, where it is converted into glutamine by the glia-specific enzyme glutamine synthetase; Glutamine reenters the neurons and is hydrolyzed by glutaminase to form glutamate, thus replenishing the neurotransmitter pool In the brain, glutamine is a substrate for the production of both excitatory and inhibitory neurotransmitters (glutamate and gamma- aminobutyric acid) Glutamine is also an important source of energy for the nervous system Glutamate" is the term used interchangeably with "glutamic acid," though strictly speaking glutamate is an anionic amino acid.

Pharmacy of GTH Prague Sol. acidi glutamici 10% Rp. Acidum glutamicum 15,0 Sirupus plantaginis 45,0 Aqua purificata ad 150,0 D.S: 10 ml 3 times a day by CIPN symptoms after taxanes and oxaliplatin

Effectivity of 10% glutamic acid solution in CIPN treatment 100 40 number of 50 15 pacients 23 0 mild reduction of CIPN effective reduction of CIPN no reduction of CIPN

Thank you for your attention irena.netikova@vfn.cz

Neurotoxicity

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