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Atypical presentation of acute neurotoxicity secondary to oxaliplatin Esther Uña J Oncol Pharm Pract 2010 16: 280 originally published online 16 December 2009 DOI: 10.1177/1078155209355849 The online version of this article can be found at: http://opp.sagepub.com/content/16/4/280
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J Oncol Pharm Practice (2010) 16: 280–282
CASE REPORT Atypical presentation of acute neurotoxicity secondary to oxaliplatin Esther Un˜a, MD PhD
Neurotoxicity is the main and dose-limiting toxicity of oxaliplatin. It may produce two different syndromes, acute and chronic. We describe here a case of a patient with an acute syndrome with the particularity of affecting only contralateral hemibody to arm of infusion. A 62-year-old female diagnosed with stage IV colon cancer, underwent palliative treatment with combination of oxaliplatin (130 mg/m2 on day 1), capecitabine (1.250 mg/m2 bid on days 1 to 14 every 3 weeks), and bevacizumab. Thirty minutes after cycle 1 oxaliplatin infusion, which was into the left arm, she experienced right hemibody paresthesia with muscle cramping of her right calf. She associated dysphonia and painful jamming sensation in her
INTRODUCTION Neurotoxicity is the main and dose-limiting toxicity of oxaliplatin. It may produce two different syndromes.1 Long-term administration produces a sensory neuropathy, with loss of sensation and dysesthesia in the distal extremities. The development of this type of sensory neuropathy is correlated with the cumulative dose of oxaliplatin. But oxaliplatin also produces another form of neurotoxicity. This is a unique syndrome of acute neurosensory toxicity in up to 90% of cases, which is acute and rapidly reversible. It is characterized by appearance of striking paresthesia and dysesthesia of the hands, feet, and peroral region Clinical University Hospital, Valladolid, Spain Corresponding author: Esther Un˜a Cido´n, Medical Oncology Service, Clinical University Hospital, C/ Ramo´n y Cajal s/n, 47005 Valladolid, Spain. E-mail:
[email protected]
right upper limb with difficulty to release grip. She noted also undulating movements under the skin of her right lower extremity. She was unable to stand or walk. She was given intravenous magnesium sulfate and calcium gluconate and after 3 h all her symptoms were solved. Subsequent doses were reduced by 25% and the infusions were prolonged to 3 h and the patient tolerated well except minimal paresthesia in her right hand lasting few minutes. J Oncol Pharm Practice (2010) 16: 280–282. Key words: neurotoxicity; oxaliplatin; neuromiotonia
during or shortly after infusion. These acute symptoms last usually from a few seconds to a few hours and may be cold-triggered and increase in both duration and intensity with repeated infusions.2,3 These differences in symptoms onset and clinical spectrum suggest a distinct mechanism for these both forms of oxaliplatin-associated neurotoxicity.1 We describe here a case of a patient with this acute syndrome secondary to oxaliplatin but with the particularity of affecting only contralateral hemibody to arm of infusion.
CASE REPORT A 62-year-old female was diagnosed with neurological history of right ischemic transient attack 1 year before without neurological sequalae, and who initially presented to us with fatigue and loss of appetite. Hematological analysis showed microcitic
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10.1177/1078155209355849
˜ a: Atypical presentation of acute neurotoxicity Un
anemia with 8 g/dL of hemoglobin. She referred to passing black feces since 3 months. Upper endoscopy was fine but colonoscopy revealed an ulcerative and bleeding lesion in cecum, which had to undergo a biopsy. Pathological analysis revealed adenocarcinoma. Computerized tomography revealed disseminated multiple liver nodules. The patient underwent right hemicolectomy and she begun palliative treatment with a combination of oxaliplatin (130 mg/m2 on day 1), capecitabine (1.250 mg/m2 bid on days 1–14 every 3 weeks), and bevacizumab. An intravenous line was inserted in her left median antebrachial vein and drugs were administered through a pump as a slow infusion lasting 2 h. Thirty minutes after completion of cycle 1 oxaliplatin infusion, she experienced right hemibody striking paresthesia predominantly in her lower extremity with little muscle cramping of her right calf. She associated dysphonia and felt a painful sensation of contracture in her right upper limb with difficulty to release grip. Ten minutes after the onset of these symptoms she noted undulating movements under the skin of her right lower extremity. She was unable to stand or walk independently because she noted a marked loss of strength in the same extremity and anesthesia of this extremity. At the same time she noted that her right hand became more rigid and painful and she also complained of spontaneous jaw pain. She was given intravenous magnesium sulfate and calcium gluconate. After several minutes, the muscle contractions resolved but other symptoms persisted for three more hours. She did not have recurrences for days after. It is worth noting that the patient did not have any autoimmune disorder or previous neurological deficit nor was she taking any medications that may have predisposed her to this complication. Subsequent doses were reduced by 25% and the infusions were prolonged to 3 h and the patient tolerated well except minimal paresthesia in her right hand lasting few minutes.
DISCUSSION Oxaliplatin, which is a platinum derivative, is one of the chemotherapeutic agents widely used in the treatment of colon cancer.1 Neurotoxicity is the main and dose-limiting toxicity of this drug. It may cause two types of neuropathy such as acute and chronic. The best known toxicity is secondary to long-term administration that produces a sensory neuropathy,
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with loss of sensation and dysesthesia in the distal extremities. The development of this type of neuropathy is correlated with the cumulative dose of oxaliplatin and the chance of symptomatic improvement after stopping oxaliplatin correlates inversely with cumulative dose.1 After cessation of this drug, the chronic neurotoxicities improve in most patients within 4–6 months and will completely cure in approximately 40% of patients by 6–8 months.4 But oxaliplatin may also produce an acute neuropathy. This toxicity may begin during the infusion, i.e., within minutes to hours after infusion, or within 1–2 days after administration. It has a particularity that is the sensitivity to cold temperature exposure, which may trigger this toxicity.2,3 The acute neuropathy is usually self-limited, often solved within days.1 Although there are several cases published in the scientific literature illustrating different tables of acute neurotoxicity, neither of them have documented, to our knowledge, only hemibody toxicity5,6 after a systemic infusion with this drug. Oxaliplatin may cause a variety of acute distressing and transient symptoms almost always due to peripheral sensory nerve hyperexcitability,1 such as signs and symptoms associated with bilateral paresthesias, hypoesthesias, and dysesthesias, which begin in the feet or hands. Other frequent symptom is pharyngo-laryngo-dysesthesia accompanied by a sensation of shortness of breath without any objective evidence of respiratory distress. Although the exact mechanism that could explain these symptoms is unknown, it has been hypothesized that certain ionic channels might be involved.7 Electrophysiological studies have shown that one of the two direct metabolites of oxaliplatin, the oxalate, which is a potent calcium chelator, interferes with several ionic channels expressed on the peripheral neurons (calcium-dependent-voltage-gated Na (sodium) channels). The other metabolite, diamminocyclohexane platin, which is the active cytotoxic metabolite, has no effect on the Na channels.8,9 The hypothesis was that when oxaliplatin enters the neurons, it splits into diamminocyclohexane platin and oxalate, and the latter chelates calcium and interferes with Na-channel activity, leading to a neuronal hyperexcitability.8,9 When calcium and magnesium infusions are used as chelators of oxalate to inhibit its action on Na-channels, it has been shown, in a retrospective study, to cause a dramatic decrease of acute and chronic neurotoxicity without impact on oxaliplatin efficacy.8 This forms the backbone to use these substances to treat and prevent acute toxicity10,11 although other
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˜ a: Atypical presentation of acute neurotoxicity Un
drugs have been used to treat this toxicity such as thiamine12 and glutathione infusions.13 Sometimes the acute oxaliplatin-induced neuropathy is associated with striking signs of hyperexcitability in motor nerves similar to neuromyotonia.1,14 This syndrome is an infrequent condition characterized by muscle stiffness, slowed muscle relaxation, increased sweating, and less common paresthesia. The exact mechanism of neuromyotonia is unknown.1,14,15 It has been postulated that either persistent sodium channel activity or decreased potassium conductance can be a mechanism for producing axonal hyperexcitability and repetitive discharges in human nerve cells.9 Winquist et al.12 have documented a case about a man with metastatic transitional cell carcinoma of the renal pelvis who was treated with oxaliplatin. Ten minutes after completing the first infusion, he complained of dyspnea without respiratory distress and persistent diplopia on horizontal outward gaze affecting both eyes. In this case the patient was warmed with blankets and treated with thiamine. They did not use calcium or magnesium infusions, but after 3 h all the symptoms had been cured completely just as in our case. They planned subsequent dose reductions and prolonged infusions of oxaliplatin and demonstrated that this strategy may prevent this toxicity in cases in which dose reduction will not influence presumably therapeutic results. The particularity of our case reported here is the combination of both types of syndromes, motor and sensorial hyperexcitability, but affecting only one hemibody contralateral to the arm of infusion. If the previous right ischemic transient attack might have been played a role in this atypical presentation of acute neurotoxicity, it is unknown but perhaps subclinical neurological changes in neurons or axons after ischemia could explain this asymmetry of symptoms.16 Our observation may provide a possible explanation to patients about the importance of wide clinical spectrum of acute neurotoxicity secondary to this drug and to be aware of the preventive measures to avoid or reduce the intensity of these symptoms.
3
Leonard GD, Wright MA, Quinn MG, Fioravanti S, Harold N, Schuler B et al. Survey of oxaliplatin-associated neurotoxicity using an interview-based questionnaire in patients with metastatic colorectal cancer. BMC Cancer 2005; 5: 116.
4
Saif MW, Reardon J. Management of oxaliplatin-induced peripheral neuropathy. Ther Clin Risk Manag 2005; 1: 249–58.
5
Saif MW, Hashmi S. Successful amelioration of oxaliplatin-induced hyperexcitability syndrome with the antiepileptic pregabalin in a patient with pancreatic cancer. Cancer Chemother Pharmacol 2008; 61: 349–54.
6
Lahrmann H, Albrecht G, Drlicek M, Oberndorfer S, Urbanits S, Wanschitz J et al. Acquired neuromyotonia and peripheral neuropathy in a patient with Hodgkin’s disease. Muscle Nerve 2001; 24: 834–83.
7
Lehky TJ, Leonard GD, Wilson RH, Grem JL, Floeter MK. Oxaliplatin induced neurotoxicity: acute hyperexcitability and chronic neuropathy. Muscle Nerve 2004; 29: 387–92.
8
Pasetto LM, D’Andrea MR, Rossi E, Monfardini S. Oxaliplatin-related neurotoxicity: How and why? Crit Rev Oncol Hemat 2006; 59: 159–68.
9
Grolleau F, Gamelin L, Boisdron-Celle M, Bruno Lapied, Marcel Pelhate, Erick Gamelin. A possible explanation for a neurotoxic effect of the anticancer agent oxaliplatin on neuronal voltage-gated sodium channels. J Neurophysiol 2001; 85: 2293–97.
10
Gamelin L, Boisdron-Cell M, Morel A, Poirier AL, Berger V, Gamelin E, Tournigand C, de Gramont A. Oxaliplatin-related neurotoxicity interest of calciummagnesium infusion and no impact on its efficacy. J Clin Oncol 2008; 26: 1188–1189.
11
Hochster HS, Grothey A, Childs B. Use of calcium and magnesium salts to reduce oxaliplatin-related neurotoxicity. J Clin Oncol 2007; 25: 4028–29.
12
Winquist E, Vincent M, Stadler W. Acute bilateral abducens paralysis due to oxaliplatin. J Natl Cancer I 2003; 95(6): 488–89.
13
Takimoto N, Sugawara S, Iida A, Sakakibara T, Mori K, Sugiura M, Yamamoto M, Tanaka M, Hayakawa T, Yamamura K, Adachi M. Prevention of oxaliplatin-related neurotoxicity by glutathione infusions. Cancer Chemother 2008; 35(13): 2373–76.
14
Hart IK, Waters C, Vincent A, Newland C, Beeson D, Pongs O et al. Autoantibodies detected to expressed Kþ channels are implicated in neuromyotonia. Ann Neurol 1997; 41: 238–46.
15
Zielasek J, Martini R, Suter U, Toyka KV. Neuromyotonia in mice with hereditary myelinopathies. Muscle Nerve 2000; 23: 696–701.
16
Bostock H, Burke D, Hales JP. Differences in behaviour of sensory and motor axons following release of ischaemia. Brain 1994; 117: 225–34.
REFERENCES 1
2
Saadati H, Wasif Saif M. Oxaliplatin-induced hyperexcitability syndrome in a patient with pancreatic cancer. J Pancreas 2009; 10(4): 459–61. Gamelin E, Gamelin L, Bossi L, Quasthoff S. Clinical aspects and molecular basis of oxaliplatin neurotoxicity: current management and development of preventive measures. Semin Oncol 2002; 29(5): 21–33.
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