Effect of intravenous calcium and magnesium (IV CaMg) on oxaliplatin-induced sensory neurotoxicity (sNT) in adjuvant colon cancer: Results of the phase III placebo-controlled, double blind NCCTG trial N04C7
Reviewer: Arpi Thukral, MD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: June 1, 2008
Presenter: D. A. Nikcevich Presenter's Affiliation: Mayo Clinic/ NCCTG Type of Session: Scientific
The addition of oxaliplatin to 5FU and leucovorin chemotherapy has been shown to be effective in the adjuvant setting for colon cancer in recent clinical trials.
Although oxaliplatin is relatively safe and tolerable, sensory neurotoxicity (sNT) is a dose-limiting toxicity, which can lead to the early discontinuation of oxaliplatin-based chemotherapy. It has been shown in previous studies that grade 3 oxaliplatin-induced neurotoxicity occurs in 15-20% of patients receiving the drug.
It has been observed that the clinical manifestations of oxaliplatin-induced neurotoxicity resemble those of patients with congenital mytonia or tetany, and this may be due to a unique direct effect on nerve excitability. This effect may be caused by Ca and/or Mg chelation by oxalate, an oxaliplatin metabolite. It was then proposed that IV infusion of CaMg may serve as a neuroprotectant.
In a retrospective study by Gamelin, et. al. presented at ASCO 2004, CaMg infusions with oxaliplatin was shown to reduce incidence and intensity of acute oxaliplatin-induced symptoms and possibly delay cumulative neuropathy.
The current study, NO4C7, was initiated to prospectively evaluate the effect of IV CaMg infusion on oxaliplatin-induced neurotoxicity.
Materials and Methods
Colon cancer patients undergoing adjuvant chemotherapy with 5FU and Oxaliplatin were randomized to IV CaMg vs. IV placebo. The IV CaMg was given as 1 g calcium gluconate plus 1 g magnesium sulfate pre- and post- Oxaliplatin infusion.
Patients received Oxaliplatin for 12 cycles 85 mg/m2 every 2 weeks.
Three separate methods to assess sNT were used: 1) NCI-CTC guidelines, 2) an oxaliplatin specific sNT (OSN) scale, and 3) patient questionnaires.
The primary endpoint studied was percentage of patients with grade 2 chronic sNT during or at the end of Oxaliplatin treatment. Secondary enpoints included time to onset of sNT, number of patients with acute neurotoxicity, and percentage of patients who discontinued Oxaliplatin.
A quality of life (QOL) assessment using patient questionnaires was also undertaken. The study was closed early due to a preliminary report from the CONCEPT trial suggesting that CaMg decreased efficacy of Oxaliplatin.
The trial was originally designed to accrue 300 patients, however only 104 patients were randomized due to the early closure.
102/104 patients (50 in the CaMg group and 52 in the placebo group) had started treatment and were available for an intent-to-treat analysis.
There were no differences seen in terms of patient characteristics or hematologic toxicities between the 2 groups.
On the NCI-CTC scale, the grade 2 sNT was 22% for CaMg group vs. 41% for the placebo group (p=0.0038). The CaMg group also had a prolonged time to onset of sNT compared to the placebo group (p=0.05).
On the OSN scale, the grade 2 sNT was 28% for CaMg group vs. 51% for the placebo group (p=0.018). There was also a prolonged time to onset seen for the CaMg group on this scale (p=0.025).
On QOL analysis, preliminary results show that there was a trend towards less swallowing difficulty in the CaMg group (p=0.065). There was no difference in muscle cramps between the 2 groups. The CaMg group also had a trend towards decreased tingling in the CaMg group (p-0.062).
No differences in toxicities were noted between the 2 study arms.
The results are affected by the premature discontinuation of the trial. However, despite this early termination, this study demonstrates the neuroprotective activity of CaMg on chronic neuropathy induced by Oxaliplatin.
CaMg should be a standard component of treatment with Oxaliplatin, if further studies refute the proposed idea that CaMg reduces treatment efficacy of Oxaliplatin.
CaMg has negligible toxicities, low cost, and a lack of interference with chemotherapy agents, and therefore is a tolerated and safe treatment in combination with Oxaliplatin.
This prospective study showed that the addition of IV CaMg to Oxaliplatin did reduce sNT significantly on both the NCI-CTC and OSN scales. Since sNT is a dose-limiting toxicity of Oxaliplatin and often leads to discontinuation of the treatment prematurely, IV CaMg infusion may be effective to prevent patients from discontinuing their chemotherapy treatment. It is suggested by the authors that QOL is also improved with decreased sNT, and therefore it has great implications for the well-being of patients treated with Oxaliplatin.
Although this study shows promising results for CaMg as a neuroprotectant, it should be used with caution until the issues surrounding its interference with Oxaliplatin efficacy are explored further. Reports from the CONCEPT trial by Grothey et. al. had suggested that those patients who received calcium and magnesium salts reported a significantly lower response rate than the placebo group. But this analysis was based on investigator-determined and unconfirmed response, and therefore may not be accurate and needs to be further reviewed. Future studies will be focusing on this.
Lastly, the authors did not report any significant toxicities related to CaMg infusion. However, there have been anecdotal reports of abdominal pain and acute pancreatitis associated with CaMg infusion. In humans, an association has been shown between hypercalcemia and acute pancreatitis, and this can be an issue with patients receiving CaMg. There may be a subset of patients where CaMg is not safe. It may be wise to test for amylase/lipase levels before and after treatment with CaMg.