Oxaliplatin acute neurotoxicity and the role of Ca/Mg infusions

Oxaliplatin is a third-generation platinum compound approved for treatment of adjuvant and metastatic colorectal cancer in combination with 5-FU and leucovorin. The addition of oxaliplatin to chemotherapy regimens for colorectal cancer has increased response rates, time to disease progression and OS. Common adverse effects associated with oxaliplatin include peripheral sensory neuropathy, hypersensitivity reactions, nausea, neutropenia, thrombocytopenia, anemia, and elevated transaminases and alkaline phosphatase.

Two distinct forms of neuropathy occur with oxaliplatin (Eloxatin, Sanofi-Aventis). Acute neuropathy is transient and symptoms typically develop during or within several hours of the infusion and typically resolve between cycles. The severity and duration of symptoms may increase with continued oxaliplatin administration. Sensory symptoms associated with acute neuropathy include paresthesia, dysesthesia and hypoesthesia of the hands, feet, perioral region or throat. Patients can also experience motor symptoms including prolonged muscular contractions, tetanic spasms and fasiculations. Pharyngolaryngeal dysesthesias associated with difficulty breathing or swallowing have been reported in 1% to 2% of patients.

Symptoms associated with acute neuropathy may be induced or aggravated by exposure to cold temperatures or objects, and can occur with each oxaliplatin infusion. The incidence of acute neuropathic symptoms has been reported to be from 56% to 95% and typically not referred to as a dose-limiting toxicity. The second form of oxaliplatin-induced neuropathy is a cumulative, dose-limiting sensory neuropathy that resembles the characteristics of cisplatin-induced neuropathy. The differences in symptom onset and resolution between acute and chronic oxaliplatin neurotoxicity suggest that different mechanisms exist for each.

Acute neurotoxicity

Several mechanisms for the causes of oxaliplatin-induced acute neurotoxicity have been proposed. Acute sensory and muscular symptoms seen with oxaliplatin are not consistent with progressive neuron or muscular damage and likely result from effects on nerve and/or muscle excitability. In a phase-1 study by Wilson and colleagues, patients treated with capecitabine (Xeloda, Roche) and oxaliplatin underwent needle electromyography and nerve conduction studies. Patients demonstrated a reversible, peripheral-nerve hyperexcitability after receiving oxaliplatin, with clinical features that resemble those seen with neuromyotonia.

Symptoms of acute neurotoxicity in this study correlated with the timing of peak oxaliplatin plasma levels and terminal half-life of approximately 10 days. Involuntary muscle contractions of the hands, feet or jaw seen with oxaliplatin may be attributed to hyperexcitability of motor neurons and associated with hypocalcemia and hypomagnesemia. The inability of patients to release after voluntary contraction and correlation to cold temperatures is similar to contractions seen in inherited myotonias, which result from hyperexcitability of the muscle cell membrane. Oxalate, a metabolite of oxaliplatin, is a potent chelator of calcium and interferes with Ca–dependent voltage-gated sodium channels on peripheral neurons. By chelating Ca, oxalate interferes with sodium channel activity and leads to neuron hyperexcitability and development of symptoms of neurotoxicity.

Managing symptoms

Researchers and clinicians have tried a variety of measures to decrease the incidence, duration and severity of acute neurotoxicity symptoms associated with oxaliplatin. Management strategies have included avoidance of cold exposures, dose reduction and prolonged infusion times (four to six hours). Several pharmacotherapeutic interventions have also been tried, including carbamazepine, gabapentin, pregabalin (Lyrica, Pfizer), alpha lipoic acid, amifostine, glutathione and Ca and magnesium infusions. Ca/Mg have shown promise in recent literature in reducing the incidence and intensity of symptoms. Several proposed mechanisms support the rationale for using Ca/Mg.

Ca/Mg can modify the properties of voltage-gated sodium ion channels. Increasing the extracellular Ca concentration facilitates the closing of sodium ion channels, decreasing oxaliplatin-induced hyperexcitability of peripheral neurons and thereby decreasing symptoms of acute neurotoxicity. The addition of Ca/Mg immediately before and after oxaliplatin infusions results in chelation of the oxalate metabolite, thereby minimizing its effects on neuron channels.

Trials of Ca/Mg

After empirically using Ca/Mg infusions with oxaliplatin, a group of researchers conducted a retrospective review of 161 patients who received oxaliplatin for second-line treatment of metastatic colorectal cancer. Ninety-six patients received Ca gluconate and Mg sulfate 1 g each via IV infusion 15 minutes immediately before and after the oxaliplatin infusion (treatment group). Also, 66 patients in the control group did not receive Ca/Mg infusions with oxaliplatin.

Fewer patients stopped treatment due to any type of toxicity in the Ca/Mg group compared with the control group (33% vs. 51%; P<.02). There was no significant difference in the mean dose of oxaliplatin or treatment duration between the two groups.

The incidences of distal and lingual paresthesias, trismus, limb contractions and asthenia were significantly less with Ca/Mg compared with the control group. No cases of pharyngolaryngeal dysesthesia were reported in the treatment group vs. 9% in the control group (P=10^-8). Only 4% of patients withdrew from the study as a result of neurotoxicity in the Ca/Mg group vs. 31% in the control group (P=.000003). The researchers concluded that Ca/Mg infusions reduced the incidence and severity of acute neurosensory and neuromuscular symptoms.

Based on the results from this retrospective review, Ca/Mg infusions were built into CONcePT. CONcePT was a phase-4, randomized, prospective trial to evaluate an intermittent schedule of oxaliplatin with FOLFOX plus bevacizumab (Avastin, Genentech) compared with the conventional administration schedule of FOLFOX plus bevacizumab; in addition, the researchers evaluated neuroprophylaxis with Ca/Mg infusions. Study patients were randomly assigned to 1 g each of Ca gluconate and Mg sulfate via IV infusion for 30 minutes before and after each oxaliplatin infusion or placebo.

The trial was terminated prematurely by an independent data-monitoring committee following an interim analysis, which suggested a decreased response rate in patients who were receiving Ca/Mg infusions vs. placebo (17.3% vs. 32.9%;

P=.028). After an independent radiology review of CT scans, tumor response rates were higher in the group assigned to Ca/Mg infusions compared with placebo.

Concurrently, the North Central Cancer Treatment Group (NCCTG-N04C7) conducted a phase-3, randomized, placebo-controlled, double blind trial to evaluate the neuroprotective activity of Ca/Mg infusions with FOLFOX for adjuvant therapy of colon cancer. This study was closed after enrollment of 104 patients due to the preliminary results from the CONcePT trial. Preliminary results from this study demonstrated less grade-2 or worse neurotoxicity in patients assigned to Ca/Mg vs. placebo (22% vs. 38.5%; P=.07) according to the NCI Common Toxicity Criteria, and 28% vs. 52% (P=.01) using an oxaliplatin-specific neuropathy scale.

In a follow-up abstract, researchers reported a reduction in muscle cramps with Ca/Mg but no difference in sensitivity to cold, swallowing cold liquids and throat discomfort on days one to four following oxaliplatin infusion with any treatment cycle.

Lack of consensus

Based on the results from recent trials, there is still no consensus regarding the efficacy and safety of Ca/Mg infusions for the prevention of acute neuropathic symptoms with oxaliplatin in clinical practice. Several trials’ results have demonstrated the potential benefits of Ca/Mg infusions for preventing the development and/or decreasing the severity of symptoms experienced by patients assigned to oxaliplatin.

Based on the final results from the CONcePT trial, oxaliplatin antitumor activity does not appear to be affected by Ca/Mg; however, additional confirmatory studies have not been performed.

In clinical practice, oncologists are taking a varied approach in their use of Ca/Mg infusions with oxaliplatin. Some believe the safety concerns have been well addressed and use Ca/Mg infusions in all stages of disease (adjuvant and metastatic settings). Due to concerns over diminished efficacy of the chemotherapy, other practitioners reserve the use of Ca/Mg for patients with incurable metastatic disease. A few will reserve use until patients are unable to tolerate acute neuropathic symptoms or are responding to oxaliplatin and require continuation of treatment beyond a standard time frame.

An individualized approach that assesses the goals and duration of therapy, the patient’s ability to tolerate acute neuropathic symptoms and an overall risk vs. benefit evaluation may be the best approach in deciding whether or not a patient should receive Ca/Mg infusions with oxaliplatin-based chemotherapy.

Andrea Landgraf Oholendt, PharmD, BCOP, is a Clinical Pharmacy Specialist in Gastrointestinal Medical Oncology at The University of Texas M.D. Anderson Cancer Center.

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