Managing oxaliplatin-induced neurotoxicity

A fairly simple protocol of calcium and magnesium supplementation has been proposed to reduce the incidence of neuropathy.

Issue: August 1, 2006

ByLisa K. Lohr, PharmD, BCPS, BCOP

Oxaliplatin (Eloxatin, Sanofi-Aventis), a third generation platinum analogue, is an important antineoplastic agent in the treatment of colorectal cancer. It is usually given in combination with fluorouracil and leucovorin at a dose of 85 mg/m² intravenously every two weeks, but it has also been given in doses of 100 mg/m² IV every two weeks or 130 mg/m² IV every three weeks. Common adverse events seen with oxaliplatin include fatigue, nausea, diarrhea, vomiting, anemia and liver function test (LFT) increases. However, the dose-limiting toxicity is either acute or chronic neuropathy.

Acute toxicity

Lisa K. Lohr, PharmD, BCPS [photo]
Lisa K. Lohr

The acute toxicity is common and transient and occurs most commonly during or soon after the infusion of oxaliplatin. The symptoms include paresthesias or dysesthesias in the hands and feet or around the mouth and throat. Exposure to cold, such as drinking cold beverages or reaching into the refrigerator, can trigger these symptoms. In most cases, symptoms resolve within a few days of oxaliplatin administration. It has been estimated that 85% to 95% of patients experience these adverse events. Rarely, patients may experience feelings of difficulty breathing or swallowing due to pharyngolaryngeal dysesthesias. In addition, symptoms may be accompanied by muscular contractions in the jaw, hands or feet.

Chronic toxicity

The chronic neurotoxicity is related to the cumulative dose of oxaliplatin administered. Neuropathy with significant functional impairment occurs in about 10% of patients who receive a cumulative dose of 780 mg/m²(about 9 doses of 85 mg/m²). Significant functional impairment occurs in about 50% of patients who receive a cumulative dose of 1,170 mg/m² (about 13 doses of 85 mg/m²). These symptoms include paresthesias, hypoesthesia and dysesthesias primarily in the distal extremities. Early on, the symptoms resolve between cycles of oxaliplatin, but eventually the symptoms persist between cycles and worsen with subsequent cycles. The symptoms resolve slowly after discontinuing oxaliplatin, with a three-month median time to recovery from grade-3 toxicity.

Because of the unique pattern and time course of oxaliplatin-induced neuropathy, a special toxicity grading system has been proposed. In this system, grade-1 toxicity would be short-duration sensory symptoms. Grade-2 toxicity would represent symptoms that persist between oxaliplatin cycles and grade-3 sensory symptoms would be those that cause functional impairment.

Cause of neuropathy

Researchers speculate that dysfunction of the sodium channels on neural cell membranes causes oxaliplatin-induced acute neuropathy. Oxalate, having been released from the oxaliplatin, can chelate calcium ions, which affects the sodium channels of nerve cells. This results in excitability of nerve and muscle cells. Gradual platinum compound accumulation could also be responsible for chronic neuropathy since physicians have observed morphologic damage to nerve cells.

If symptoms occur, the patient should be advised to avoid exposure to cold. That includes not drinking cold beverages and protecting the body, especially the hands and feet, from cold. Lengthening the infusion from two hours to up to six hours can mitigate acute neuropathy. Moreover, lower oxaliplatin doses are less likely to cause neurotoxicity. In a palliative setting, physicians could opt for regimens without oxaliplatin or provide an oxaliplatin hiatus while neurotoxicity resolves.

table 1

Calcium and magnesium

A fairly simple protocol of calcium and magnesium supplementation has been proposed to reduce the incidence of neuropathy. A group of researchers examined calcium and magnesium IV supplementation in a retrospective, non-randomized study. A group of 161 patients being treated with oxaliplatin, fluorouracil and leucovorin for advanced colorectal cancer (1,134 cycles of chemotherapy) was identified. The oxaliplatin dose administered ranged from 85 mg/m² every two weeks, to 130 mg/m² every three weeks infused over two hours. During this time period, some patients were given IV calcium gluconate 1 g and magnesium sulfate 1 g infused over 15 minutes before and after the oxaliplatin administration. The study identified 96 patients who received the supplementation and 65 patients who did not. The major results, which were all statistically significant, are shown in table 1.

Gamelin and colleagues concluded that calcium/magnesium supplementation reduced the incidence and severity of acute and chronic oxaliplatin-associated neurotoxicity. This treatment also has the advantage of fairly easy administration, since it is given only on the day of oxaliplatin administration.

Agents to prevent neurotoxicity

Lin and colleagues reported the results of a pilot study comparing oral n-acetylcysteine (NAC) 1,200 mg given 1.5 hours prior to oxaliplatin. NAC can act to increase glutathione concentrations, which may prevent platinum accumulation. After 12 cycles of chemotherapy, only one of five patients treated with NAC experienced grade-2 to -4 neuropathy, whereas eight of nine patients given placebo suffered neurotoxicity.

An investigational agent, xaliproden (SR 57746A, Sanofi-Aventis), was studied in 649 patients with metastatic colorectal cancer being treated with oxaliplatin. Cassidy and colleagues observed the non-peptide neurotrophic agent in a 1 mg/d oral dose vs. placebo. The results are shown in table 2.

table 2

Cassidy et al. concluded that treatment with xaliproden reduced the incidence of grade-3 or -4 chronic neurotoxicity from oxaliplatin, without reducing the incidence of acute neurotoxicity.

Studies of other agents used for prevention or management of neuropathy symptoms have preliminary or conflicting data. Some of these agents include gabapentin (Neurontin, Pfizer), carbamazepine (Carbatrol, Shire US), amifostine (Ethyol, MedImmune) and glutathione.

Oxaliplatin can cause substantial neurotoxicity, which can cause serious functional changes in patients’ quality of life. Several agents show promise in the prevention or amelioration of neuropathy symptoms. However, more research is needed in this area to allow improved tolerability of oxaliplatin.

For more information:

Cassidy J, Bjarnason GA, Hickish T, et al. Randomized double blind placebo controlled phase III study assessing the efficacy of xaliproden in reducing the cumulative peripheral sensory neuropathy induced by the oxaliplatin/ FU/LV combination (FOLFOX4) in first-line treatment of patients with metastatic colorectal cancer. Abstract 3507. Presented at: 2006 ASCO Annual Meeting; June 2-6; Atlanta.

Lin PC, Lee MY, Wang WS, et al. N-acetylcysteine has neuroprotective effects against oxaliplatin-based adjuvant chemotherapy in colon cancer patients: preliminary data. Support Care Cancer. 2006;14:484-487.

Cersosimo RJ. Oxaliplatin-associated neuropathy: a review. Ann Pharmacother. 2005;39:128-135.

Grothey A. Clinical management of oxaliplatin-associated neurotoxicity. Clinical Colorectal Cancer. 2005;5(S1):S38-46.

Gamelin L, Boisdron-Celle M, Delva R, et al. Prevention of oxaliplatin-related neurotoxicity by calcium and magnesium infusions: a retrospective study of 161 patients receiving oxaliplatin combined with 5-fluorouracil and leucovorin for advanced colorectal cancer. Clin Cancer Res. 2004;10:4055-4061.

About the author:

Lisa K. Lohr, PharmD, BCPS, is a clinical pharmacy specialist in oncology at Fairview University Medical Center in Minneapolis and is the section editor for Pharmacology on Hem/Onc Today’s editorial board.