Ishibashi, K., Okada, N., Miyazaki, T., Sano, M., & Ishida, H. (2010). Effect of calcium and magnesium on neurotoxicity and blood platinum concentrations in patients receiving mFOLFOX6 therapy: A prospective randomized study. International Journal of Clinical Oncology, 15, 82–87. 

To evaluate the effectiveness of calcium/magnesium (Ca/Mg) infusions in reducing the incidence and severity of oxaliplatin-related neurotoxicity and to evaluate the effects of Ca/Mg infusions on progression-free survival and platinum plasma levels in patients with colorectal cancer

Patients with metastatic colorectal cancer were randomized and double-blinded to receive mFOLFOX6 with a Ca/Mg infusion (100 ml of 5% glucose-containing calcium gluconate of 850 mg and magnesium sulfate of 720 mg) before and after the administration of oxaliplatin or mFOLFOX6 with placebo (100 ml of 5% glucose alone) before and after administration of oxaliplatin (85 mg/m²) every two weeks for six cycles. Prior to administration, patients were assessed for adverse events according to the Common Terminology Criteria for Adverse Events (CTCAE), version 3.0, by nurses or pharmacists.

• N = 33 (17 [Ca/Mg group], 16 [control group])
• MEAN AGE = 63 years (Ca/Mg group), 64 years (control group)
• MALES: 49%, FEMALES: 51%
• KEY DISEASE CHARACTERISTICS: Histologically confirmed colorectal cancer with either unresectable metastasis or prior resection of metastatic lesions
• OTHER KEY SAMPLE CHARACTERISTICS: Bone marrow, liver, and kidney function normal in all subjects; World Health Organization performance status of 0–2; no multiple cancers or history of radiotherapy; no differences in age, sex, number of mFOLFOX6 cycles, relative dose intensity, or number of metastatic organs between placebo and Ca/Mg group

• SITE: Single site
• SETTING TYPE: Outpatient
• LOCATION: Japan-Saitama Medical Center

• PHASE OF CARE: Advanced
• APPLICATIONS: Elder care, palliative care 

Prospective, randomized, double-blind, controlled trial in patients with metastatic colorectal cancer receiving mFOLFOX6

• Adverse events were evaluated by nurses and pharmacists before the start of administration according to the CTCAE, version 3.0, and DEB-NTS, although only the data from baseline and after six cycles were provided.
• Response Evaluation Criteria in Solid Tumors (RECIST) criteria was used to evaluate treatment outcomes and compare between groups.
• Plasma platinum levels (blood samples) were drawn five minutes, one hour, three hours, and two weeks after the first cycle and five minutes, one hour, and two weeks after the fifth cycle for comparison.

Ca/Mg infusion prior to and after mFOLFOX6 did not reduce the incidence of grade 1–3 neurotoxicity using two different standardized measures for neurotoxicity (DEB-NTS and CTCAE) after the completion of six cycles; response rates, disease control rates, and median survival times were not significantly different between groups. No significant differences existed in the plasma platinum levels between groups (Ca/Mg versus placebo) at any time point using the pre-established significance value of p < 0.05. Also, no significant difference in plasma platinum levels existed in those who developed grade 2 neuropathy compared to those who developed less severe neuropathy (DEB-NTS). When comparing those who achieved a partial or complete remission with mFOLFOX6 to those who achieved no response, plasma platinum levels did not differ, suggesting that calcium and magnesium infusions did not influence the efficacy of mFOLFOX6 chemotherapy.

Ca/Mg infusions before and after oxaliplatin did not reduce the incidence or severity of neurotoxic symptoms in patients with metastatic colorectal receiving mFOLFOX6.

• Small sample (< 100)
• Risk of bias(sample characteristics)
• Findings not generalizable
• The study was terminated prematurely prior to completion of enrollment because of an interim analysis of the CONCEPT study reporting that treatment with Ca/Mg decreased antitumor activity.
• No explanation of history or presence of neurotoxic symptoms prior to the start of treatment for either group
• Unclear if patients were on medication or treatment for neuropathy
• Limited information for inclusion/exclusion criteria
• Unclear if all patients completed six cycles of mFOLFOX6
• Mann-Whitney test comparing continuous variables has limited statistical inference.
• No reliability or validity information provided for the primary measure of neuropathy (NEB-NTS)
• Lack of power to detect statistical significance because of small sample size

The administration of Ca/Mg before and after oxaliplatin as a preventive measure to reduce the incidence or severity of oxaliplatin-related peripheral neuropathy in patients with colorectal cancer receiving mFOLFOX6 for six cycles has no clinical benefit.