Calcium and Magnesium Infusion

Examine the efficacy of purported chemoprotective agents to prevent or limit neurotoxicity of cisplatin and related agents

TYPE OF STUDY: Combined systematic review and meta-analysis

DATABASES USED: Cochrane Neuromuscular Disease Group Specialized Register, Cochrane Central Register of Controlled Clinical Trials, MEDLINE, EMBASE, LILACS, and CINAHL

KEYWORDS: Extensive list provided in article appendix

INCLUSION CRITERIA: Quasi-randomized or randomized clinical trials whose participants received cisplatin (or related compounds) chemotherapy with or without a potential chemoprotectant and were evaluated zero to six months after completing chemotherapy using quantitative sensory testing (primary) or other measures, including nerve conduction studies or neurologic impairment rating using validated scales (secondary)

TOTAL REFERENCES RETRIEVED: Sixteen randomized trials were evaluated in the initial 2006 review. In the 2010 update, 11 additional randomized trials not among the 2006 review were identified.

EVALUATION METHOD AND COMMENTS ON LITERATURE USED: Cochrane method of evaluation for risk of bias done by two authors and finalized by consensus

• N (studies) = 6
• SAMPLE RANGE ACROSS STUDIES: 14–242
• TOTAL PATIENTS INCLUDED IN REVIEW: 1,537 participants
• KEY SAMPLE CHARACTERISTICS: Patients who received cisplatin chemotherapy

Cisplatin is considered to have neurotoxic effects, with patients developing sensory neuropathy. Symptoms of pain, numbness, and tingling are observed mostly in the extremities from a distal to proximal distribution. The neuropathy experienced by patients may recover partially or may become permanent. Neuroprotective agents such as acetylcysteine, acetyl-L carnitine, amifostine, calcium and magnesium, growth factors, glutathione, ORG 2766, oxcarbazepine, and vitamin E have been tested. The five newly added randomized controlled trials included three chemoprotective agents not previously described in the 2006 review.

From the data examined in this updated review, inconclusive evidence exists for recommending any neuroprotective agent tested to prevent or limit the neurotoxicity of platinum chemotherapy.

While 1,537 participants were included in the 2010 update, few trials were amenable to meta-analysis. Clinical trials of neuroprotective agents are plagued by issues of study design, including small sample size, unclear randomization and blinding procedures, and lack of quantitative measures, especially conventional QST or electrophysiologic evaluation.

STUDY PURPOSE: To examine the efficacy of chemoprotective agents to prevent or limit neurotoxic side effects of cisplatin and related chemotherapy agents

TYPE OF STUDY: Meta-analysis and systematic review

• FINAL NUMBER STUDIES INCLUDED = 20 
• TOTAL PATIENTS INCLUDED IN REVIEW = 2459
• SAMPLE RANGE ACROSS STUDIES: 18–755
• KEY SAMPLE CHARACTERISTICS: Varied tumor types receiving platinum-based chemotherapy

PHASE OF CARE: Active antitumor treatment

There is insufficient high quality evidence to show that any agent is protective against platinum-induced neuropathy. There is some suggestion that amifostine, glutathione, and calcium and magnesium may have some effect.

• Limited number of studies included
• Low sample sizes
• There were few studies per intervention, and very few studies with small sample were included in the meta-analyses.

There is insufficient evidence to show that any agent is truly effective in protecting against neurotoxic effects of platinum-based chemotherapy. There is a continued need for well designed research using appropriate objective as well as subjective measures of neuropathy.

STUDY PURPOSE: To evaluate status of research on pharmacologic interventions for CIPN

TYPE OF STUDY: Meta-analysis and systematic review

DATABASES USED: Medline, Embase, and China National Knowledge Internet

YEARS INCLUDED: (Overall for all databases) Information for dates of search not provided, articles included were from 1995 to 2014

INCLUSION CRITERIA: The study (a) assessed CIPN in patients with cancer, (b) compared two or more drugs or placebo, (c) provided sufficient data to assess differences, and (c) assessed incidence or severity of CIPN

EXCLUSION CRITERIA: None listed

TOTAL REFERENCES RETRIEVED: 1,839

EVALUATION METHOD AND COMMENTS ON LITERATURE USED: No description of quality evaluation

FINAL NUMBER STUDIES INCLUDED: 23

TOTAL PATIENTS INCLUDED IN REVIEW: 2,298

SAMPLE RANGE ACROSS STUDIES: 20-732

KEY SAMPLE CHARACTERISTICS: All but one of the studies focused on patients getting platinum-based chemotherapy and 12 of 23 only included people with colorectal cancer.

PHASE OF CARE: Active antitumor treatment

Contrary to the title, this article does not include any commonly prescribed prescription drugs, including gabapentin, pregabalin, or duloxetine. This review included studies of amifostine, Vitamin E, calcium and magnesium infusions, and glutathione. Eighteen studies had a placebo control group and had no control group. Neither blinding nor control were needed for inclusion. Findings indicate that Vitamin E and amifostine reduce incidence of CIPN, while glutathione and amifostine reduced severity of CIPN. There was one study (n = 20) included that had patients getting amifostine who all had cervical cancer and were receiving cisplatin with radiation therapy. The authors of this original study (Gallardo et al., 1999) found no statistically significant difference in neurotoxicity between those getting amifostine and those who did not. It is therefore unclear how the authors of the meta-analysis found otherwise. There was also only a single study of glutathione versus placebo versus calcium/magnesium (n = 93, 33 of whom received glutathione) included. The original study (Dong et al., 2010) showed no significant differences in CIPN incidence or severity between the three groups. Four studies of Vitamin E, two which were placebo controlled and two with no control group.

The limitations, including lack of quality control, small sample sizes, focus on platinum use, and GI malignancies, limit the generalizability of the findings from this meta-analysis.

• Limited search
• Limited number of studies included
• No quality evaluation
• Low sample sizes

Findings from this study suggest that amifostine, glutathione, and Vitamin E may be helpful for CIPN but no recommendations for practice can be made at this time due to limitations of this meta-analysis.

STUDY PURPOSE: To provide evidence-based guidance on optimum prevention and treatment approaches in the management of chemotherapy-induced peripheral neuropathy in adult cancer survivors

TYPE OF STUDY: Systematic review

DATABASES USED: Ovid Medline (1946–April, week 2, 2013); EMBASE (1980–2013, week 16); AMED Allied and Complementary Medicine (1985–April 2013)

KEYWORDS: chemotherapy-induced peripheral neuropathy; adult cancer survivors; randomized clinical trials

INCLUSION CRITERIA: Adult cancer survivors with chemotherapy-induced peripheral neuropathy; randomized trials

EXCLUSION CRITERIA: Phase 1 trials; published in a language other than English; less than 10 patients; focused on radiation or stem cell transplant neuropathy; animal studies

TOTAL REFERENCES RETRIEVED = 1,252

EVALUATION METHOD AND COMMENTS ON LITERATURE USED: An expert panel representing neurology, nursing, medical oncology, community oncology, pain research, and genetics met through teleconference and emails to review and develop the American Society of Clinical Oncology guidelines.

• FINAL NUMBER STUDIES INCLUDED = 48
• TOTAL PATIENTS INCLUDED IN REVIEW: Treatment studies: 780; prevention studies: 3,741

PHASE OF CARE: Active antitumor treatment

Forty-two randomized clinical trials involved 19 various interventions for prevention of chemotherapy-induced peripheral neuropathy. These agents included anticonvulsants, antidepressants, vitamins, minerals, and other chemoprotectant drugs. Only six randomized clinical trials discovered six different drugs, such as antidepressants, anticonvulsants, and a topical gel, for the prevention of chemotherapy-induced peripheral neuropathy. The following are not recommended for use: acetyl-l-carnitine, amifostine, amitriptyline, calcium and magnesium, glutathione, nimodipine, ORG 2766, trans retinoic acid, rhuLIF, and vitamin E. Venlafaxine is not recommended for routine use in clinical practice. Although data support potential utility, evidence is not strong enough to suggest use. For treatment of chemotherapy-induced peripheral neuropathy, clinicians can offer duloxetine. No recommendation is made regarding ALC. Tricyclic antidepressants or gabapentin through trial use may be reasonable.  The panel felt that trying topical gel containing baclofen, amitriptyline, and ketamine would be reasonable. 

No agents were recommended for the prevention of chemotherapy-induced peripheral neuropathy, but duloxetine is moderately recommended for the treatment of chemotherapy-induce peripheral neuropathy. Even though conclusive evidence is lacking to recommend tricyclic antidepressants such as nortriptyline, gabapentin, and a topical gel containing baclofen,amitriptyline, and ketamine for treatment of chemotherapy-induced peripheral neuropathy, the expert panel agreed that offering these agents based on treatment for neuropathic pain is reasonable. The panel also recommended that patients be counseled regarding the lack of evidence in treating chemotherapy-induced peripheral neuropathy with these agents.

• Small, insufficient sample
• Inability to compare studies because of different outcomes
• Measurements and instruments used at different points in treatment

Nurses are at the frontline in assessing patients who are receiving agents with the potential for chemotherapy-induced peripheral neuropathy. Nurses should be aware of the standard of care in treating this population. Many drugs prescribed have no evidence in preventing or treating these patients. However, with these American Society of Clinical Oncology guidelines, a role for duloxetine is clear and a role for tricyclic antidepressants is possible. Nurses need to be knowledgeable about this information to better inform patients.

STUDY PURPOSE: To summarize the evidence regarding the effects of calcium and magnesium infusion to prevent peripheral neuropathy associated with oxaliplatin

TYPE OF STUDY: Meta-analysis and systematic review

• FINAL NUMBER STUDIES INCLUDED = 5
• TOTAL PATIENTS INCLUDED IN REVIEW = 694
• SAMPLE RANGE ACROSS STUDIES: 27–353
• KEY SAMPLE CHARACTERISTICS: All were on FOLFOX regimens.

PHASE OF CARE: Active antitumor treatment

Across four studies (640 patients), the relative risk of grade 2 or higher chemotherapy-induced peripheral neuropathy was 0.81; however, the z test for overall effect showed no statistical significance. The largest trial showed no difference between groups.

The findings did not show any benefit of calcium and magnesium infusions for the prevention of oxaliplatin-induced peripheral neuropathy.

• Limited number of studies included
• No quality evaluation
• Low sample sizes
• Two of the five studies had very low sample sizes.

The findings do not support the use of calcium and magnesium infusions to prevent chemotherapy-induced peripheral neuropathy.

• 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.

• 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: Advanced

APPLICATIONS: Elder care, palliative care

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.

• 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

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.

STUDY PURPOSE: To identify all observational studies that examine the role of calcium and magnesium infusions in the chemoprevention of oxaliplatin-induced sensory neuropathy in gastrointestinal cancers

DATABASES USED: PubMed, EMBASE, Science Citation Index, Expanded Chinese National Knowledge Infrastructure

KEYWORDS: Calcium gluconate; digestive system neoplasms; magnesium sulfate; neurotoxicity syndrome; oxaliplatin; oxaliplatine; eloxatine; ACT 078 L-HP; neuropathy; chemotherapeutic agent; toxicity; calcium; Ca; Ca and magnesium; Mg or Mg and oesophageal cancer; gastric cancer; stomach cancer; bowel cancer; colorectal cancer; colon cancer; rectal cancer; pancreatic cancer; hepatocellular carcinoma; liver cancer; biliary tract cancer

INCLUSION CRITERIA: Studies for meta-analysis included randomized, controlled trials and cohort studies that involved calcium and magnesium infusions in chemoprevention of oxaliplatin-induced sensory neurotoxicity in gastrointestinal cancers.

EXCLUSION CRITERIA: Letters, case studies, reviews, comments, studies on cell lines, animal studies, and any study with no control group

EVALUATION METHOD AND COMMENTS ON LITERATURE USED: National Cancer Institute Common Toxicity Criteria (NCI CTC) and oxaliplatin-specific scale (OSS) were used. Meta-analysis was done on six studies that had reported responses. A sensitivity analysis was used by repeating meta-analysis but excluding one study at a time. Odds ratio and its 95% confidence interval were calculated.

• FINAL NUMBER STUDIES INCLUDED = 16 (15 full manuscripts and one abstract)
• TOTAL PATIENTS INCLUDED IN REVIEW: 1,765
• KEY SAMPLE CHARACTERISTICS: The studies were randomized, controlled trials, prospective and retrospective, that included magnesium and calcium infusions for the prevention of chemotherapy-induced neuropathy in patients with gastrointestinal cancers. Patients had gastrointestinal, colorectal, hepatocellular, and small intestine cancers. Patients were aged 18–37 years.

• PHASE OF CARE: Survivorship
• APPLICATIONS: Pediatrics, elder care

The difference in the incidence of grade 1 oxaliplatin-induced neuropathy was statistically significant between those who received calcium and magnesium infusions and those who did not receive the treatment (NCI CTC: OR .44, 95% CI 0.31–0.62, p = 0.000; OSS: OR 0.30, 95% CI 0.20–0.45, p = 0.000). Similar results were found in the incidence of grade 2 oxaliplatin-induced neuropathy (NCI CTC: OR 0.60, 95% CI 0.46–0.77, p = 0.000; OSS: OR .45, 95% CI 0.30–0.67, p = 0.000). No difference was observed in grade 3 neuropathy in patients treated with calcium and magnesium infusions opposed to those who were not treated with calcium and magnesium infusions (NCI CTC: OR 0.67, 95% CI 0.44–1.01, p = 0.054; OSS: OR 0.66, 95% CI 0.34–1.29, p = 0.224). Overall, calcium and magnesium infusions reduced the incidence of peripheral neuropathy grades 1 and 2. This did not include the incidence of grade 3 neuropathy. The calcium and magnesium infusions did not lessen the treatment effects of oxaliplatin (OR 0.89, 95% CI 0.67–1.17, p = 0.391).

Most research in chemotherapy-induced peripheral neuropathy has focused on treatment-related side effects. Positive studies in this area are lacking. However, this analysis of six studies of calcium and magnesium infusions in the prevention of chemotherapy-induced peripheral neuropathy is promising. Large, randomized trials would need to be done to determine efficacy.

• More than likely, studies that had negative results were not published, so the authors concluded that bias could not be ruled out.
• The design of the studies varied greatly. The majority of the studies were retrospective or nonblinded observations.
• There may be a discrepancy in the results because the number of treatments, duration of treatments, cumulative doses of oxaliplatin, assessment scales, and timing of assessments varied.
• Given the small subgroup and that the analysis did not provide all of the information needed, care should be taken in interpreting the results and conclusions.

One of the limitations speaks to lack of consistency among various assessment scales for peripheral neuropathy. Whether a preventive study or treatment study, assessment is critical to patients with peripheral neuropathy. Nurses should be knowledgeable concerning various assessment scales and should use the scales from baseline through survivorship.

The purpose of the study was to evaluate the neuropathy-protective effects of calcium and magnesium infusions in patients receiving oxaliplatin.

Patients were randomized to a treatment group with calcium gluconate 1 g plus 1 g of magnesium sulfate in 100 ml normal saline infused before and after oxaliplatin, or a placebo group with infusions of normal saline.

• The sample consisted of 19 participants with a mean age of 54 years.
• The amount of men (52%) slightly outnumbered the amount of women (48%).
• All of the participants had colorectal cancer and were receiving oxaliplatin-based chemotherapy with a life expectancy of more than three months.
• Exclusion criteria included previous treatment with platinum-based chemotherapy and/or a preexisting neurologic disease or metastases.
• Seventy-eight percent of the patients received 600 mg/m² of oxaliplatin.
• The median follow-up was 8.7 months.

The study was conducted in a single-site location in Singapore.

• Active treatment
• Late effects

The study was a blinded, placebo-controlled, randomized phase II design.

Measurements included the National Cancer Institute Common Terminology Criteria for Adverse Events [version 3.0] and oxaliplatin-specific toxicity scale nerve conduction studies.

Incidence of grade 1 and 2 neurotoxicity was higher in the placebo group, but there was a higher proportion of grade 3 cumulative numbness in the treatment group. No differences were noted between groups for tingling and cold sensitivity. In addition, no difference was noted in time to onset of symptoms. Conduction studies showed lower median score at the end of the study in the treatment arm (p = 0.02). Of note, the study was ended prematurely.

This study does not provide strong evidence regarding the efficacy of calcium and magnesium infusion for the reduction of chemotherapy-associated peripheral neuropathy.

• A small sample size (less than 30 participants).
• Findings and reported conclusions can be confusing since median end of study nerve conduction scores suggested increased abnormal conduction in the treatment group, as noted by the authors.
• A correlation between nerve conduction findings and subjective patient symptoms are unclear.
• No information was provided regarding chemotherapy treatment delays or dose reductions.
• Given the question of cumulative effects, it may be more useful to look at symptoms at oxaliplatin dose levels rather than time.

Because of a small sample size, this current study does not provide strong evidence regarding use of calcium and magnesium infusions. Neuropathic symptom effects appear to be mixed, with higher prevalence of grade 3 with treatment, but overall prevalence lower with treatment. Some symptoms appear to be affected and some do not, and the relationship between nerve conduction findings and symptoms are unclear. Additional research in this area is needed to clarify the actual impact of calcium and magnesium for protective effects with neurotoxic treatment.

Participants in the treatment group received infusions of calcium gluconate and magnesium sulfate (1 g) before and after oxaliplatin. The chemotherapy protocol consisted of combination oxaliplatin, 5-fluourouracil (5-FU), and leucovorin. Three regimens of oxaliplatin were used: 85 mg/m² every two weeks, 100 mg/m² every two weeks, or 130 mg/m² every three weeks.

A total of 161 patients were enrolled in the study, with 96 placed in the treatment group and 65 in the control group.

The study had a retrospective design.

Toxicity was graded every one to two weeks by staff according to the National Cancer Institute's Common Terminology Criteria for Adverse Events and an oxaliplatin-specific neurotoxicity scale that assessed paresthesias.

Paresthesias, trismus, cramps, limb pain, and diarrhea were significantly less frequent in the treatment group. Pharyngolaryngeal dysesthesia were never reported in the treatment group versus 9% in the control group. In addition, less grade 3 toxicity was reported in the treatment group compared to the control group. At the end of oxaliplatin therapy, 65% of participants in the treatment group had no evidence of chemotherapy-induced peripheral neuropathy (CIPN) compared to 37% in the control group. By the end of treatment, 20% of patients in the treatment group showed evidence of CIPN versus 45% in the control group. Patients with grade 2 or 3 neurotoxicity at the end of treatment with oxaliplatin (85 mg/m²) recovered more rapidly from CIPN than those in the control group.

• The study was retrospective and not randomized or blinded.
• Staff who performed the assessments may have been biased in reporting.
• More patients who received either FOLFOX 4 or FOLFOX 6 regimens were included in the treatment group, making results more open to bias and placebo effect.

The purpose of the study was to determine whether calcium and magnesium infusions would prevent or ameliorate neurotoxity associated with oxaliplatin, enable a larger cumulative oxaliplatin dose delivered, ameliorate acute neuropathy associated with oxaliplatin, and whether any adverse events occurred.

Patients were randomly assigned to receive either IV calcium gluconate plus magnesium sulfate, 1 g each in 100 ml D5W for 30 minutes immediately before and after each dose of oxaliplatin, or an identical-looking placebo. Patients underwent a physical examination at study entry and before each two-week chemotherapy cycle, including an assessment for adverse events and toxicity as well as laboratory testing. Patients completed daily questionnaires before each dose of FOLFOX and for five days after completion of each cycle.

• The total sample consisted of 102 participants with a majority being men (53%) and older than age 65 (64%).
• All participants had stage II or III adenocarcinoma of the colon and were scheduled to receive six months of oxaliplatin-based FOLFOX chemotherapy.
• Exclusion criteria included a preexisting peripheral neuropathy of any grade, hypercalcemia, and having received prior neurotoxic chemotherapy.

The study was conducted in multiple outpatient settings throughout the United States.

• Active treatment
• Late effects

The study was a double-blind, placebo-controlled randomized clinical trial.

• The National Cancer Institute's Common Terminology Criteria for Adverse Events, verion 3.0
• A patient questionnaire using a 0–10 scale for sensitivity, discomfort swallowing, and muscle cramps.
• The North Central Cancer Treatment Group patient-reported outcome questionnaire to detect onset of neurotoxicity symptoms.

The study accrual was stopped before the original goal because of a data monitoring committee report regarding a similar trial in patients receiving palliative FOLFOX treatment in which interim analysis showed lower response rates in patients receiving calcium and magnesium. However, subsequent independent analysis of the data showed that initial interpretations were incorrect and that antitumor response was lower in that study's placebo group.

Results of the current study showed that the incidence of grade 2 or higher sensory neurotoxicity was significantly lower in the calcium and magnesium group on two different measurement scales (p < 0.04). In addition, onset of grade 2 or higher was significantly delayed in patients who received calcium and magnesium (p = 0.03). Patient report of numbness also was lower in the calcium and magnesium group (p = 0.021). The study intervention did not appear to have an effect of oxaliplatin-specific symptoms such as muscle cramps, throat discomfort, and cold sensitivity toxicities. No patients developed hypercalcemia.

The findings provide some support for the hypothesis that calcium and magnesium infusions can decrease oxaliplatin-related cumulative sensory neurotoxicity. The results suggest that some types of neurotoxic effects may be reduced, while no obvious effect on other symptoms is apparent.

• The study may have been underpowered because of premature closure to subject accrual.
• No information is provided regarding whether or not there were any FOLFOX dose reductions or discontinuations that also may have affected study findings.
• The authors stated that this was because of early study closure; however, why this would prevent providing any such data is unclear.

Calcium and magnesium infusion may reduce neurotoxicity associated with chemotherapy agents. Additional research in this area is needed to determine if both elements are required and what is the most effective dosages, timing, and efficacy with agents other than oxaliplatin. Research would further clarify the role of this intervention with specific neuropathic symptoms and whether this intervention is effective with various chemotherapeutic agents.

To investigate the effects of calcium and magnesium infusions on oxaliplatin pharmacokinetics and neurotoxicity

Patients were randomized to receive either 1 g calcium and 1 g magnesium IV or placebo 15 minutes before and after a two-hour oxaliplatin infusion on cycle 1, then crossed over to the other intervention on cycle 2. Blood samples were obtained at multiple time points during and after the oxaliplatin infusion for pharmacokinetic analysis. Other study measures were obtained on day 2 and at the end of treatment cycles 1 and 2.

• N = 19
• MEDIAN AGE = 62 years
• AGE RANGE = 31–77 years
• MALES: 60%, FEMALES: 40%
• KEY DISEASE CHARACTERISTICS: Colorectal adenocarcinoma—95% had stage 3 or 4 disease; patients were receiving either a XELOX or modified FOLFOX6—all received the same dosage level of oxaliplatin
• OTHER KEY SAMPLE CHARACTERISTICS: Two patients had diabetes mellitus.

• SITE: Single site 
• SETTING TYPE: Outpatient 
• LOCATION: New Zealand

• PHASE OF CARE: Active antitumor treatment

• Double-blind, placebo-controlled, crossover trial

• EMG with severity score calculation from severity of hyperexcitability and number of muscles affected—four-point severity score
• Patient questionnaire of presence or absence of acute neurotoxicity symptoms

No evidence existed of a pharmacokinetic interaction between calcium and magnesium infusions and oxaliplatin. Most patients demonstrated EMG changes about 24 hours after oxaliplatin. No differences were seen between the experimental and control conditions.

Findings did not show a benefit of calcium and magnesium infusions for prevention of neurotoxicity symptoms from oxaliplatin.

• Small sample (less than 100)

Findings demonstrate that calcium and magnesium infusions did not have a preventive effect on the development of neuropathy symptoms in patients receiving oxaliplatin. Findings also showed that EMG changes happened within 24 hours of treatment. Nurses need to be aware that neuropathic symptoms can develop very quickly and need to assess for such changes early and on a routine basis to identify patients who may need dose reduction or other interventions.

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.

The purpose was to assess the effect of calcium and magnesium infusions on incidence of neurotoxicity and clinical outcomes in patients treated in a phase III trial (CAIRO2) with oxaliplatin-based chemotherapy.

Patients who had been treated in an randomized clinical trial for advanced colorectal cancer with either capecitabine, oxaliplatin, and bevacizumab or the same regimen with the addition of cetuximab were retrospectively divided into two groups: those who had received calcium and magnesium infusion at least during the first oxaliplatin cycle and those who did not receive calcium and magnesium during cycle 1. To evaluate the impact on prevention, incidence of neurotoxicity was defined as early (occurring during the first six cycles) or late (present at the last cycle).

• A total sample of 732 participants with colon cancer were enrolled, with men (60%) outnumbering women (40%).
• The mean age of participants was 61.9 years with a range of 27–83 years.

The study was conducted in multiple outpatient facilities in Norway.

• Active treatment
• Late effects

The study was a retrospective analysis of trial data.

• The National Cancer Institute's Common Terminology Criteria for Adverse Events, version 3.0.
• An evaluation of tumor response with the Response Evaluation Criteria in Solid Tumors (RECIST).

Sample sizes were varied between groups, with 551 having received calcium and magnesium and 181 who did not. Incidence of any grade neurotoxicity was 85% in those who received calcium and magnesium and 92% in those who did not (p = 0.02), and incidence of grade 2 or higher was not significantly different between groups. Early neurotoxicity of any grade occurred more often in those who did not receive calcium and magnesium (91% versus 81%, p = 0.0002). In addition, no significant difference were noted between groups in incidence of grade 2 or higher early toxicity. All grade late neurotoxicity was lower in those who were in the calcium and magnesium group; however, incidence of grade 2or higher late toxicity was no different between groups. No difference was noted in survival or response rates between study groups.

Findings suggest that calcium and magnesium infusion may be helpful in the prevention of neurotoxicity with oxaliplatin; however, findings do not show a clear difference in more severe toxicity of grade 2 or higher.

• Limitations include the retrospective nature of the study with no appropriate control in place.
• The authors define the calcium and magnesium group as getting this infusion with the first cycle of chemotherapy; however, whether or not any of these patients or other patients got any such infusions with later cycles is unclear.
• The only outcome measure is the toxicity grading scale.
• No information is provided regarding total cumulative chemotherapy doses (whether any cycles were not provided, etc.) to evaluate any differences in symptoms according to chemotherapy dosage and cycle completions.

The findings suggest the potential effect of calcium and magnesium infusions in the prevention of neurotoxicity; however, the findings do not show any difference in terms of prevalence of higher grade neurotoxicity. Additional research in this area is needed with more definitive outcome measures.

To provide a definitive test of the effectiveness of calcium and magnesium in decreasing oxaliplatin-induced neurotoxicity

Patients randomly were assigned to receive intravenous calcium gluconate and magnesium sulfate at 1 g each in 100 ml of D5W over the course of 30 minutes immediately prior to and after each dose of oxaliplatin. Patients in the control group received a placebo that appeared identical to the study drug with the same administration timing. A third group was administered calcium and magnesium before chemotherapy and a placebo after infusion. Patients with adenocarcinoma of the colon scheduled to receive 12 cycles of FOLFOX chemotherapy including 85 mg/m² oxaliplatin every two weeks were considered for participation. Oxaliplatin dose modifications were not prescribed by the study, but dosage changes or delays were provided as recommendations. Study measures were obtained at each cycle of chemotherapy.

• N = 326 
• MEDIAN AGE = 56 years
• MALES: 48%, FEMALES: 52%
• KEY DISEASE CHARACTERISTICS: All participants were patients with colon cancer receiving either FOLFOX-4 or mFOLFOX-6 treatment.
• OTHER KEY SAMPLE CHARACTERISTICS: 85% Caucasian; majority were diagnosed with stage II disease

• SITE: Multi-site  
• SETTING TYPE: Multiple settings    
• LOCATION: More than 50 sites in the United States

• PHASE OF CARE: Active antitumor treatment

Three-group, double-blinded, placebo-controlled, randomized trial

• European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ) for Chemotherapy-Induced Peripheral Neuropathy (CIPN20)
• National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE)

There were no significant differences between the three study arms on the EORTC-QLQ CIPN20 sensory or motor neuropathy scales. There were no significant differences in neurotoxicity assessment using the CTCAE to determine time till grade 2 neurotoxicity or incidence of grade 2 symptoms. A subgroup analysis did not show evidence of benefit in groups according to age, sex, disease stage, or specific FOLFOX regimen. There were no differences in acute or chronic symptoms.

The findings of this study do not support the use of intravenous calcium gluconate and magnesium sulfate to prevent oxaliplatin-induced neuropathy.

This large, well designed trial showed no benefit of the use of a calcium gluconate and magnesium sulfate infusions to prevent peripheral neuropathy in patients receiving FOLFOX. The authors of this study state that as many as 50% of practitioners continue to use this intervention, and resources such as UpToDate suggest consideration of this intervention. Nurses can advocate that calcium gluconate and magnesium sulfate not be used for the prevention of peripheral neuropathy given the lack of evidence for its efficacy. This can save time and expense in treatment for patients receiving this type of chemotherapy. Additional similar research may be needed to examine this treatment's effects in patients at risk for peripheral neuropathy related to other chemotherapeutic agents.

This study outlines the common antineoplastic agents known to cause neuropathy and provides information on incidence, onset dosages, the signs and symptoms, and general course and patterns of resolution. Agents identified include platinum compounds, vinca alkaloids, taxanes, bortezomib, ixabepilone, thalidomide, and lenalidomide. In addition to outlining the mechanisms of neuropathy development in cancer, the study discusses neurophysiologic and objective testing, noting that findings on electromyographic (EMG) and nerve conduction studies (NCS) can lag behind clinical symptoms. The study also identifies commonly used physician-based grading systems, including the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE) and Eastern Cooperative Oncology Group (ECOG) systems, and notes that these two grading systems lack inter-rater reliability. Patient-based instruments for assessment include the Functional Assessment of Cancer Treatment (FACT) and the Patient Neurotoxicity Questionnaire (PNQ). The authors note that the routine assessment of pain secondary to neuropathy, using instruments such as the Brief Pain Inventory (BPI), is useful.

Routine assessment should be conducted and continued throughout therapy. Key points in assessment that should be included are:

• History, related comorbid conditions, alcohol use, symptoms, pain assessment, time course, and treatment delays or discontinuation from CIPN
• Physical examination
• Patient interview questions regarding sensation of numbness or tingling, pain, bothersome sensations, weakness, difficulty walking, falls, and interference with activities of daily living
• Functional skills testing, such as straight-line walking, name writing, buttoning, pegboard tests, and timed pellet retrieval.

Proposed agents for prevention of CIPN identified include:

• Agents with positive findings: vitamin E, calcium, magnesium, glutamine, glutathione, N-acetylcysteine, oxcarbazepine, xaliproden
• Agents with negative findings: amifostine, nimodipine, Org2766, rhuLIF
• Agents being tested in trials: vitamins B12, B6, acetyl-L-carnititne, alpha lipoic acid

Agents used for pain management:

• Those with negative results in CIPN, including gabapentin, amitriptyline, notriptyline
• Other agents commonly used include duloxetine, 5% lidocaine patch, opioids, tramadol

Current literature is inconclusive on the benefits of neurostimulation in treating CIPN. The authors note that evidence is scarce on efficacy of complimentary and alternative medicine (CAM) therapies and the need for appropriately powered and controlled studies in this area. However, acupuncture was identified as a promising adjunct option. The article also provides safety tips and issues for management of functional deficits in PIN, including situations in which to avoid or discontinue physical training, footwear selection, orthosis, and safety aspects of the household environment. Finally, the article addresses how autonomic neuropathy from chemotherapy occurs, but has not been well documented or studied.

• Limitations include a significant lack of evidence regarding effective management and prevention in this area.
• The review did not describe a search strategy or process to determine the quality of evidence used.

The article provides a comprehensive review of current knowledge about CIPN and common approaches toward assessment, prevention, and management. The authors do not make specific recommendations for treatment, research to validate evaluation tools, and exploration of combinations and scheduling of pain medications. In addition, testing of the safety and effectiveness of therapeutic interventions and dietary supplements are needed.