Prevention of Oxaliplatin-Induced Peripheral Sensory Neuropathy by Carbamazepine in Patients with Advanced Colorectal Cancer

Lersch, C.; Schmelz, Renate; Eckel, Florian; Erdmann, Johannes; Mayr, Martina; Schulte‐Frohlinde, E.; Quasthoff, Stefan; Großkreutz, Julian; Adelsberger, Helmuth

doi:10.3816/ccc.2002.n.011

Cited by 72 publications

(52 citation statements)

References 17 publications

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“…The other approach was to block the action of oxaliplatin on sodium channels with carbamazepine or gabapentin or to chelate oxalate by i.v. infusions of calcium and magnesium, the latter now being widely used in clinical practice (9,37,38).…”

Section: Discussionmentioning

confidence: 99%

Predictive Factors of Oxaliplatin Neurotoxicity: The Involvement of the Oxalate Outcome Pathway

Gamelin¹,

Capitain

Morel³

et al. 2007

Clinical Cancer Research

112

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Purpose: Oxaliplatin displays a frequent dose-limiting neurotoxicity due to its interference with neuron voltage-gated sodium channels through one of its metabolites, oxalate, a calcium chelator. Different clinical approaches failed in neurotoxicity prevention, except calcium-magnesium infusions. We characterized oxalate outcome following oxaliplatin administration and its interference with cations and amino acids. We then looked for genetic predictive factors of oxaliplatininduced neurotoxicity.Experimental Design: We first tested patients for cations and oxalate levels and did amino acid chromatograms in urine following oxaliplatin infusion. In the second stage, before treatment with FOLFOX regimen, we prospectively looked for variants in genes coding for the enzymes involved (a) in the oxalate metabolism, especially glyoxylate aminotransferase (AGXT), and (b) in the detoxification glutathione cycle, glutathione S-transferase k, and for genes coding for membrane efflux proteins (ABCC2). Results: In the first 10 patients, urinary excretions of oxalate and cations increased significantly within hours following oxaliplatin infusion, accompanied by increased excretions of four amino acids (glycine, alanine, serine, and taurine) linked to oxalate metabolism. In a further 135 patients, a minor haplotype of AGXT was found significantly predictive of both acute and chronic neurotoxicity. Neither glutathione S-transferase k nor ABCC2 single nucleotide polymorphisms we looked for were linked to neurotoxicity. Conclusion: These data confirm the involvement of oxalate in oxaliplatin neurotoxicity and support the future use of AGXTgenotyping as a pretherapeutic screening test to predict individual susceptibility to neurotoxicity.Oxaliplatin, a platinum-based chemotherapeutic agent with a 1,2-diaminocyclohexane (DACH) carrier ligand, displays a characteristic pattern of neurotoxicity, which is the most frequent dose-limiting toxicity, with an acute onset of distal dysesthesia and/or paresthesia, induced or exacerbated by cold and prolonged muscular contraction after a voluntary contraction. Although these symptoms that occur during or short after infusion are transient and generally mild, when treatment is continued, a persistent sensory peripheral neuropathy can develop, eventually causing superficial and deep sensory loss, sensory ataxia, and functional impairment (1). The mechanism of chronic neurotoxicity evoked by some authors is close to that of cisplatin-being the progressive accumulation of a heavy metal, the DACH platin, in neurons and the implication of the detoxication system of glutathione (2).However, clinical neurophysiologic examinations and nerve biopsy studies have shown that patients displaying sensory symptoms have no signs or very mild signs of axonal degeneration (1). Oxaliplatin has a direct ''pharmacologic'' effect on the excitability of sensory neurons and muscle cells that has not previously been described with other platinum agents (3). Furthermore, the acute symptoms induced by oxaliplati...

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Section: Discussionmentioning

confidence: 99%

Predictive Factors of Oxaliplatin Neurotoxicity: The Involvement of the Oxalate Outcome Pathway

Gamelin¹,

Capitain

Morel³

et al. 2007

Clinical Cancer Research

112

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“…to achieve a serum-level of 3 -6 mg l À1 ) according to the preliminary results of a pilot study (Lersch et al, 2002).…”

Section: Treatment Schedulementioning

confidence: 99%

Capecitabine plus oxaliplatin as first-line treatment in patients with advanced biliary system adenocarcinoma: a prospective multicentre phase II trial

et al. 2008

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This prospective multicentre phase II study characterises the toxicity and activity of first-line capecitabine and oxaliplatin combination therapy (CAPOX) in advanced biliary system adenocarcinomas. Patients received oxaliplatin (130 mg m À2 , day 1) plus capecitabine (1000 mg m À2 b.i.d., days 1 -14) every 3 weeks. Patients were stratified prospectively into two groups based on location of the primary (gallbladder carcinoma (GBC) or extrahepatic cholangiocarcinoma (ECC) versus intrahepatic mass-forming type cholangiocarcinoma (ICC)). Sixty-five patients were evaluable. The response rate in 47 patients with GBC/ECC was 27% (4% complete responses), and in 23 patients (49%) stable disease (SD) was encountered. In 18 patients with ICC, we observed no objective responses, but 6 patients (33%) had SD. Median survival was 12.8 months (95% CI, 10.0 -15.6) for patients with GBC or ECC (GBC: 8.2 months; 95% CI, 4.3 -11.7; ECC: 16.8 months; 95% CI, 12.7 -20.5), and 5.2 months (95% CI, 0.6 -9.8) for ICC patients. In both cohorts, therapy was well tolerated. The most common grade 3 -4 toxicity was peripheral sensory neuropathy (11 patients). Our data suggest that the CAPOX regimen is a well-tolerated and active treatment option for advanced ECC and GBC but might produce poorer results for ICC.

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“…Neither calcium or magnesium infusions, nor neuromodulatory agents have proved sufficiently effective to become routine treatments of acute or chronic neuropathy (10,11). An alternative therapeutic approach is to target an upstream phenomenon, that is, the generation of oxidative stress by oxaliplatin.…”

Section: Introductionmentioning

confidence: 99%

Treatment of oxaliplatin-induced peripheral neuropathy by intravenous mangafodipir

Coriat¹,

Alexandre²,

Nicco³

et al. 2013

J. Clin. Invest.

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Background. The majority of patients receiving the platinum-based chemotherapy drug oxaliplatin develop peripheral neurotoxicity. Because this neurotoxicity involves ROS production, we investigated the efficacy of mangafodipir, a molecule that has antioxidant properties and is approved for use as an MRI contrast enhancer.Methods. The effects of mangafodipir were examined in mice following treatment with oxaliplatin. Neurotoxicity, axon myelination, and advanced oxidized protein products (AOPPs) were monitored. In addition, we enrolled 23 cancer patients with grade ≥2 oxaliplatin-induced neuropathy in a phase II study, with 22 patients receiving i.v. mangafodipir following oxaliplatin. Neuropathic effects were monitored for up to 8 cycles of oxaliplatin and mangafodipir. Funding.

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Prevention of Oxaliplatin-Induced Peripheral Sensory Neuropathy by Carbamazepine in Patients with Advanced Colorectal Cancer

Cited by 72 publications

References 17 publications

Predictive Factors of Oxaliplatin Neurotoxicity: The Involvement of the Oxalate Outcome Pathway

Predictive Factors of Oxaliplatin Neurotoxicity: The Involvement of the Oxalate Outcome Pathway

Capecitabine plus oxaliplatin as first-line treatment in patients with advanced biliary system adenocarcinoma: a prospective multicentre phase II trial

Treatment of oxaliplatin-induced peripheral neuropathy by intravenous mangafodipir

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