Wen, F., Zhou, Y., Wang, W., Hu, Q.C., Liu, Y.T., Zhang, P.F., . . . Li, Q. (2013). Ca/Mg infusions for the prevention of oxaliplatin-related neurotoxicity in patients with colorectal cancer: A meta-analysis. Annals of Oncology, 24, 171–178.

DOI Link

Purpose

STUDY PURPOSE: To determine the efficacy of Ca/Mg infusions in oxaliplatin-induced neurotoxicity
 
TYPE OF STUDY: Meta-analysis

Search Strategy

DATABASES USED: Cochrane Library (1950–2012), Cochrane Central Register of Controlled Trials (1995–2012), Cochrane Database of Systematic Reviews (2005–2012), Cochrane Methodology Register (1995–2012), Database of Abstracts of Reviews of Effects (1995–2012), Health Technology Assessment (1995–2012), National Health Service Economic Evaluation Database (1995–2012), PubMed (1966–2012), Ovid Medline (1946–2012), Embase (1988–2012), Science Citation Index Expanded (1950–2012), American Society of Clinical Oncology ([ASCO] 1996–2012), and ASCO Gastrointestinal Cancers Symposium (1996–2012). 
 
KEYWORDS: oxaliplatin, neurotoxicity, calcium, magnesium, neuropathy, peripheral, and random (search strategies changed based on database used)    
 
INCLUSION CRITERIA: Methods not well described: Retrospective and prospective studies evaluating calcium and magnesium infusions that included one primary or secondary event (primary events were instances of acute, cumulative, or total neurotoxicity; secondary events were total doses and cycles of oxaliplatin, risk ratio [RR], overall survival [OS], and progression free survival [PFS]).
 
EXCLUSION CRITERIA: The methods were not well defined. Excluded irrelevent studies and included studies of neuroprotective agents other than calcium and magnesium. Commentaries and research reviews were excluded as were studies referred to by the authors as experiment-related, although that term was not defined for readers.

Literature Evaluated

TOTAL REFERENCES RETRIEVED: 102
 
EVALUATION METHOD AND COMMENTS ON LITERATURE USED:
  • Two independent authors conducted searches. 
  • Data extraction: 102 records were retrieved, 36 abstracts were reviewed, and 12 full-text records were reviewed.
  • Seven studies were included in this meta-analysis.
  • Targeted data were extracted by authors independently.
  • Information collected included demographics, clinic pathology, chemotherapy treatment, efficacy of oxaliplatin-based chemotherapy, and effect of Ca/Mg infusions on oxaliplatin-related neurotoxicity. If a study had more than one grade criteria, only data concerning neurotoxicity incidence graded on the basis of Common Terminology Criteria for Adverse Events (CTCAE) were included.

Sample Characteristics

  • FINAL NUMBER STUDIES INCLUDED = 7 studies (4 prospective, randomized, blinded trials ; 3 retrospective clinical trials not blinded or randomized [1 Phase II, 2 phase III]) 
  • SAMPLE RANGE ACROSS STUDIES: 27–732 (214 patients in prospective studies, 956 patients in retrospective studies) 
  • TOTAL PATIENTS INCLUDED IN REVIEW: Only 1,170 of initial 1,339 analyzed because 2 studies published only a portion of patient results. Final patients included: 1,170 (802 in Ca/Mg group, 368 in control group)
  • KEY SAMPLE CHARACTERISTICS: All colorectal diagnoses, four inpatient advanced/metastatic studies, three adjuvant studies. Patients in the Ca/Mg group received before and after oxaliplatin infusions in all studies compared to placebo given or no treatment. Doses or total number of cycles were different. Two studies reported outcomes for acute neuropathy, two for neurotoxicity, one for grade 2 or greater sensory neuropathy, one for toxicity, and one for cumulative neuropathy.

Phase of Care and Clinical Applications

PHASE OF CARE: Advanced

APPLICATIONS: Elder care, palliative care

Results

Incidence of grade 3 acute neurotoxicity was significantly lower in the Ca/Mg group than in the control (odds ratio [OR] = 0.26, 95% confidence interval (CI) [0.11, 0.62], p = 0.0002). The total rate of cumulative neurotoxicity and grade 3 was significantly lower in the Ca/Mg group than in the control group (OR = 0.42, 95% CI [0.26, 0.65], p = 0.0001; OR = 0.60, 95% CI [0.39, 0.92], p = 0.02, respectively).
 
No significant differences existed among 196 patients in two combined studies in total doses and cycles of oxaliplatin significant between the Ca/Mg and control group (X difference = 246.73 mg/m2, 95% CI [3.01, 490.45], p = 0.05; X difference = 1.55, 95% CI [0.46, 2.63], p = 0.005, respectively). 
 
No significant differences existed in median PFS (MD = 0.71 months, 95% CI [−0.59, –2.01], p = 0.29), median OS (MD = 0.1 months, 95% CI [−0.41, –0.61], p = 0.7), or RRs (OR = 0.82, 95% CI [0.61, 1.10], p = 0.18).

Conclusions

Meta-analysis indicated that Ca/Mg infusions tended to decrease the incidence of oxaliplatin-induced acute and cumulative neurotoxicity. Based on two studies within this meta-analysis in which patients in the Ca/Mg arm received higher mean doses than patients in the control group, the authors infer that Ca/Mg may enhance patients’ tolerance to oxaliplatin.

Limitations

  • Inconsistent outcomes
  • Reliance on CTCAE as outcome measure
  • Blinding and randomization not consistent
  • Selective outcome reporting 
  • Possible bias from several sources
  • Data on 214 (18.29%) were from prospective, randomized trials; the remaining data on 956 were from retrospective studies.
  • Included those receiving palliative and those receiving adjuvant chemotherapy.
  • One chronic neuropathy–related outcome

Nursing Implications

Ca/Mg infusion tended to reduce the incidence of grade 3 neurotoxicity and total cumulative neurotoxicity in patients with colorectal cancer receiving oxaliplatin. However, these findings must be viewed in light of the heterogeneity of the studies included, differences in neurotoxicity outcome reporting, and recent research studies finding no neuroprotective benefit.

Legacy ID

6249