Originally published as JCO Early Release 10.1200/JCO.2007.13.5251 on July 30 2007

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Use of Calcium and Magnesium Salts to Reduce Oxaliplatin-Related Neurotoxicity

Howard S. Hochster

New York University Cancer Institute, New York, NY

Axel Grothey

Mayo Clinic, Rochester, MN

Barrett H. Childs

Sanofi-aventis, Bridgewater, NJ

To the Editor:

We would like to apprise the Journal of Clinical Oncology readership of a recent development leading to the termination of the Combined Oxaliplatin Neuropathy Prevention Trial (CONCEPT) study for first-line therapy of metastatic colorectal cancer. The CONCEPT study was designed to evaluate potential reduction in cumulative neurotoxicity associated with oxaliplatin through intermittent administration of oxaliplatin, using the OPTIMOX concept introduced by deGramont et al¹ and the use of calcium and magnesium salts as proposed by Gamelin et al.² Patients were randomly assigned to folinic acid, leucovorin, fluorouracil, and oxaliplatin (FOLFOX) plus bevacizumab every 2 weeks until progression or toxicity versus alternating blocks of eight cycles FOLFOX with bevacizumab and biweekly fluorouracil and leucovorin infusion with bevacizumab (without oxaliplatin). In a 2 x 2 factorial design, and in a double-blinded fashion, the initial 140 patients were also randomly assigned to calcium gluconate and magnesium sulfate or placebo before and after oxaliplatin to potentially reduce neurotoxicity.

A planned review by the independent data monitoring committee, resulting in a more extensive and unplanned analysis, found that of the data from the 174 patients analyzed, those patients who received calcium and magnesium salts reported a significantly lower response rate than the placebo group. This analysis was based on investigator-determined and unconfirmed response.

Due to this finding, and as per the independent data monitoring committee recommendation, this study was closed. We are in the process of verifying all data related to this study and have convened an independent radiology committee to review all patient imaging in a blinded fashion.

Based on the findings in the CONCEPT trial, the National Cancer Institute–sponsored cancer control, phase III, North Central Cancer Treatment Group trial, N04C7, investigating the neuroprotective activity of calcium and magnesium salts versus placebo in the context of adjuvant FOLFOX therapy, was terminated.

At present, bearing in mind the preliminary and unconfirmed nature of these data, we would like our colleagues to be aware of this unexpected finding. Oncologists should recognize the possibility that calcium and magnesium may reduce the activity of FOLFOX and bevacizumab in the treatment of colorectal cancer and exercise appropriate clinical judgment when using these agents in the neuroprotective setting until definitive data are available. For the time being, we would urge that calcium and magnesium salts particularly be avoided in the adjuvant setting, where reduced efficacy could lead to reduced benefit, and be reserved for those with symptomatic acute neurotoxicity.

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment or Leadership Position: Barrett H. Childs, Sanofi-aventis (C) Consultant or Advisory Role: Howard S. Hochster, Sanofi-aventis (C), Genetech Biooncology (C); Axel Grothey, Sanofi-avents (C), Genentech (C) Stock Ownership: None Honoraria: Howard S. Hochster, Sanofi-aventis, Genentech Biooncology; Axel Grothey, Sanofi-aventis, Genentech Research Funding: None Expert Testimony: None Other Remuneration: None

NOTES

published online ahead of print at www.jco.org on July 30, 2007.

REFERENCES

1. Maindrault-Goebel F, Tournigand C, Andre T, et al: Oxaliplatin reintroduction in patients previously treated with leucovorin, fluorouracil and oxaliplatin for metastatic colorectal cancer. Ann Oncol 15:1210-1214, 2004[Abstract/Free Full Text]

2. 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 10:4055-4061, 2004[CrossRef][Medline]

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Related Correspondence

• Oxaliplatin-Related Neurotoxicity: Interest of Calcium-Magnesium Infusion and No Impact on Its Efficacy
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