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Effective Treatment of Oxaliplatin-Induced Cumulative Polyneuropathy With Alpha-Lipoic Acid

Vienna University Medical School, Vienna, Austria

To the Editor:Oxaliplatin, a third-generation platinum compound with a 1,2-diaminocyclohexane carrier ligand, is a novel and widely used anticancer agent that has demonstrated synergistic activity with various other cytotoxic agents such as fluorouracil plus leucovorin.¹ In two randomized trials in patients with advanced colorectal cancer, combined treatment has resulted in high objective response rates, improved time to progression, and median survival of 16 to 19 months.^2,3 An additional hallmark of oxaliplatin represents its excellent safety profile with a specific and manageable set of toxicities.¹ When given alone or in combination with other cytotoxic drugs at its recommended dose of 85 mg/m² every 2 weeks or 130 mg/m² every 3 weeks, hematologic side effects and gastrointestinal symptoms are commonly seen but are generally mild to moderate.

The most significant adverse reaction associated with the use of oxaliplatin is a peripheral sensory neuropathy (PNP) with both acute and cumulative symptoms. Acute transient neuropathy, which can appear during or shortly after the first few infusions and usually manifests as distal and/or peroral dysesthesia, is seen in approximately 85% to 95% of patients receiving oxaliplatin.¹ These sensory symptoms, which are triggered by exposure to cold, tend to resolve spontaneously within a few hours or days. The cumulative PNP, which is characterized by paresthesia or dysesthesia ± functional impairment of the extremities, constitutes the dose-limiting toxicity of oxaliplatin and progressively develops in approximately 10% to 18% of patients when a cumulative dose of about 800 mg/m² is reached.¹

Alpha-lipoic acid (Thioctacid; Asta Medica, Frankfurt, Germany), which has been shown to be effective in both somatic and autonomic neuropathies in diabetes, normalizes endoneural blood flow, reduces oxidative stress, and improves vascular dysfunction.^4,5 In a placebo-controlled trial of symptomatic diabetic polyneuropathy, a significant relief of neuropathic symptoms was observed in patients who received alpha-lipoic acid.⁶

The aim of this study was to investigate the therapeutic potential of alpha-lipoic acid to counteract cumulative oxaliplatin-related PNP in patients with advanced colorectal cancer. After having obtained written informed consent according to institutional regulations, a total of 15 patients who had received oxaliplatin 130 mg/m² in combination with raltitrexed 3 mg/m² every 3 weeks⁷ and experienced grade 2 PNP according to the oxaliplatin specific scale were entered in this trial. The patients’ pretreatment characteristics are listed in Table 1. After a median of six chemotherapy courses (range, three to six courses) and a median cumulative oxaliplatin dose of 780 mg/m² (range, 390 to 780 mg/m²), 12 patients had grade 2 and three patients had grade 3 PNP. Neurologic symptoms were serially evaluated before treatment initiation with alpha-lipoic acid and every 4 weeks thereafter according to the above-mentioned specific scale, which takes into account both intensity and duration of symptoms.⁸ Alpha-lipoic acid 600 mg was given intravenously once a week for 3 to 5 weeks followed by 600 mg three times a day orally until full recovery of neurologic symptoms or for a maximum duration of 6 months.

Our data suggest that alpha-lipoic acid 600 mg given intravenously once a week for 3 to 5 weeks followed by 600 mg three times a day orally is able to counteract cumulative oxaliplatin-related PNP; in eight (53%) out of 15 patients who received alpha-lipoic acid, the severity of this dose-limiting oxaliplatin-related side effect could be effectively reduced. Along with the exploration of other potentially effective symptomatic treatment options, including amifostine, calcium/magnesium infusions, sodium channel blockers, gabapentin, and modified chemotherapeutic strategies such as intermittent exposure to oxaliplatin,⁹ further investigation of alpha-lipoic acid in a larger number of patients seems warranted, ideally in the form of a placebo-controlled trial.

REFERENCES

1. Culy CR, Clemett D, Wiseman LR: Oxaliplatin: A review of its pharmacological properties and clinical efficacy in metastatic colorectal cancer and its potential in other malignancies. Drugs 60: 895-924, 2000[CrossRef][Medline]

2. DeGramont , Figer A, Seymour M, et al: Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 18: 2938-2947, 2000[Abstract/Free Full Text]

3. Giacchetti S, Perpoint B, Zidani R, et al: Phase III multicenter randomized trial of oxaliplatin added to chronomodulated fluorouracil-leucovorin as first-line treatment of metastatic colorectal cancer. J Clin Oncol 18: 136-147, 2000[Abstract/Free Full Text]

4. Nagamatsu M, Nickander KK, Schmelzer JD, et al: Lipoic acid improves nerve blood flow, reduces oxidative stress and improves distal nerve conduction in experimental diabetic neuropathy. Diabetes Care 18: 1160-1167, 1995[Abstract]

5. Nickander KK, McPhee BR, Low PA, et al: Alpha-lipoic acid: Antioxidant potency against lipid peroxidation of neural tissues in vitro and implications for diabetic neuropathy. Free Radic Biol Med 21: 631-639, 1996[CrossRef][Medline]

6. Ziegler D, Hanefeld MH, Ruhnau KJ, et al: Treatment of symptomatic diabetic polyneuropathy with the antioxidant -lipoic acid. Diabetes Care 22: 1296-1301, 1999[Abstract]

7. Scheithauer W, Kornek GV, Ulrich-Pur H, et al: Oxaliplatin plus raltirexed in patients with advanced colorectal carcinoma: Results of a phase I-II trial. Cancer 91: 1264-1271, 2001[CrossRef][Medline]

8. Misset JL: Oxaliplatin in practice. Br J Cancer 77: 4-7, 1998 (suppl 4)

9. Penz M, Kornek GV, Raderer M, et al: Subcutaneous administration of amifostine: A promising therapeutic option in patients with oxaliplatin-related peripheral sensitive neuropathy. Ann Oncol 12: 421-422, 2001[Free Full Text]

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