Chemotherapy-induced peripheral neuropathy (CIPN) is a common side-effect in colorectal cancer (CRC) patients treated with oxaliplatin [1
]. Oxaliplatin can cause both acute and chronic CIPN. Symptoms of chronic CIPN include distal paresthesia, tingling sensations and numbness. Chronic CIPN predominantly affects sensory nerves and can lead to long-term disability [1
]. Occurrence and severity of chronic CIPN are related to the cumulative dose and dose-intensity of the treatment [1
]. Six to eight months after the end of oxaliplatin treatment, 40–60% of the patients still suffer from CIPN [4
]. In order to minimize the detrimental effects in CRC patients, it is important to understand which factors can influence the development and severity of CIPN.
Magnesium and calcium are proposed to be important in the etiology of CIPN, because they are both involved in electric excitability of neurons and muscle contraction [8
]. Low circulating levels of magnesium, but not calcium, before treatment have been associated with more severe CIPN in CRC patients [3
]. Besides circulating levels of magnesium and calcium, several studies focused on intravenous administration of magnesium and calcium and the severity of CIPN [9
]. The clinical observational study of Gamelin et al. found a lower occurrence and severity of CIPN in CRC patients who received magnesium and calcium in comparison to patients who did not receive magnesium and calcium for several reasons [9
]. Other observational studies in CRC patients did not find an association between intravenous magnesium and calcium infusions and CIPN [10
Several randomized-controlled trials (RCTs) [11
] studied the effect of intravenous magnesium and calcium infusions on CIPN, but results are inconclusive. Grothey et al. reported a protective effect of magnesium and calcium on the prevalence of CIPN in 102 colon cancer patients [12
]. The prevalence of CIPN was 22% in the magnesium and calcium group compared to 41% in the placebo group (p
= 0.04) [12
]. On the contrary, four other RCTs conducted among 27–353 CRC patients, did not find a protective effect of magnesium and calcium infusions on CIPN [13
]. So far, no consensus about the use of magnesium and calcium infusions to reduce or prevent CIPN has been reached [17
Most studies conducted so far focused on acute CIPN during and directly after treatment. It has been shown that further progression of CIPN can occur months after the end of treatment [1
]. Moreover, the associations between dietary magnesium or calcium intake and the prevalence and severity of chronic CIPN have not been described so far. Dietary intake in relation to CIPN is important as dietary magnesium intake is the main contributor to the magnesium status. Further insights into the relation between diet and CIPN may provide feasible opportunities for dietary strategies directed against CIPN in cancer patients. In this prospective cohort study, we assessed the association between habitual dietary intake of magnesium or calcium and the prevalence and severity of CIPN approximately six months after chemotherapy, i.e., 12 months after diagnosis, in CRC patients receiving adjuvant chemotherapy.
The aim of this study was to assess the association between magnesium and calcium intake and CIPN in a prospective cohort of CRC patients. Dietary intake of magnesium during chemotherapy was associated with a lower prevalence of CIPN. A higher dietary intake of magnesium, but not calcium, during and after chemotherapy was associated with a lower severity of total CIPN symptoms.
The prevalence of CIPN approximately six months after chemotherapy, i.e., 12 months after diagnosis, was higher than expected (81%) in our study population consisting of 196 CRC patients treated with adjuvant chemotherapy. Argyriou et al. reported a prevalence of 40% for CIPN in CRC patients six to eight months after finalizing their treatment containing OX [1
]. CIPN is related to various risk factors, including treatment schedule, dose per course, cumulative dose, time of infusion and pre-existing peripheral neuropathy [1
]. These factors likely vary between studies and countries. Furthermore, difference in the prevalence of CIPN may be explained by different methods to assess CIPN. Most previous studies used criteria of the National Cancer Institute (NCI-CTCAE) or the total neuropathy score (TNSc) to assess CIPN [4
]. These methods are based on clinical examination, while the QLQ-CIPN16 is a patient-reported assessment of CIPN. The use of the QLQ-CIPN16 is inherent to the large-scale setting of the COLON cohort study. Recent studies compared several commonly used methods to assess CIPN [29
]. A high correlation was found for the NCI-CTCAE and the EORTC QLQ-CIPN [29
]. Furthermore, we did expect a high prevalence of sensory symptoms, and not motor symptoms, since OX is mainly associated with chronic sensory CIPN [1
]. Although motor symptoms were also commonly reported in our study, it should be noted that the severity of motor symptoms was relatively low in the present study (mean score 12.5 versus 20.8 for sensory symptoms).
In the present study, we found that a higher magnesium intake was associated with a lower severity of chronic CIPN, whereas no association for calcium was found. Both magnesium and calcium are involved in electric excitability of neurons and muscle contraction [8
]. A potential explanation for the association between magnesium and the severity of CIPN is the role of magnesium in the neuromuscular system and nervous tissue conduction [32
]. It has been supposed that CIPN is caused by the stimulating effect of OX on neural excitability due to re-configuration of sodium channels in the cell membrane [33
]. Magnesium (and calcium) are hypothesized to decrease OX-induced hyper-excitability [34
], thereby limiting damage of neurons. In addition, magnesium specifically plays a role in membrane integrity and stability [32
In the present study, we focused for the first time on dietary intake of magnesium and calcium in relation to CIPN. It should be noted that magnesium levels in blood are tightly regulated [36
]. When circulating levels of magnesium are low, other tissues such as bone and muscle provide magnesium to restore circulating magnesium levels. With a low magnesium intake, body stores of magnesium could be depleted, while circulating levels are still in the healthy range [3
]. Among our study population, 65% of the patients had an intake below the estimated average requirement of 350 mg/day for men and 265 mg/day for women [28
] during chemotherapy. Hypothetically, especially patients with a low intake of magnesium could benefit from additional intake of magnesium, as a higher intake could restore depleted body stores of magnesium and thereby increases availability of magnesium in muscles and nerves. Stratified analyses for age showed a stronger association in patients aged 65 years and older. In this group the percentages of patients with a magnesium intake below the estimated average requirement was higher compared to participants younger than 65. In addition, during chemotherapy more participants had a magnesium intake below the estimated average requirement compared to before and after chemotherapy. These results indicate that an optimal magnesium status throughout treatment is important. Further studies are needed to confirm these findings and to determine the clinical relevance of the reported association between magnesium and CIPN.
The present study has some limitations. First, intake from dietary supplements was not considered because of the relative limited number of supplement users. In addition detailed data on dosage, frequency and compliance was lacking and supplement use was not consistent over the study duration. Also, the mineral content of the drinking water was not considered. Magnesium and calcium from drinking water contribute to the total magnesium and calcium intake. In the Netherlands, magnesium and calcium content in the tap water ranges from 1.7–26.2 mg/L (1–8% of the total intake) and 15–157 mg/L (1–17% of the total intake), respectively [38
]. Second, although we explored the possible interaction between magnesium or calcium and many nutrients like B vitamins, calcium, vitamin D, vitamin E and alcohol, we could not exclude the possibility that other nutrients or bioactive compounds contributed to the observed effects. Third, the prevalence of pre-existing CIPN was not taken into account. Pre-existing CIPN is a risk factor for developing chronic CIPN [1
]. Diabetes mellitus is an important cause of peripheral neuropathy [39
]. However, in the present study, adjustment for self-reported diabetes mellitus did not influence the observed associations. In addition, we have not been able to take specific information on treatment-related factors, such as cumulative dose of chemotherapy and use of specific medications that may have influenced magnesium status into account. However, in the specific setting of studies focusing on long-term (chronic) toxicities, dose is a complicated factor. Patients who received a low (cumulative) dose may have experienced severe (acute) toxicities which have resulted in a dose reduction or premature discontinuation of therapy. Because of severe toxicities, among which potentially CIPN, an increased risk of chronic CIPN on the long-term may be expected. On the other hand, patients who completed their scheduled treatment, and hence received a high (cumulative) dose, may also have an increased risk of CIPN because of extensive exposure to the cytotoxic regimens. Furthermore, although information on clinical and socio-demographic characteristics of patients who did not fill out the QLQ-CIPN16 (n
= 67, 23%) was available, it remains unknown why they did not fill out the questionnaires. It could be that these patients suffered from CIPN symptoms in their hands, resulting in selection which theoretically could decrease the validity of the present study. However, we do not expect that these non-responses had a major impact on the results of our study as the overall response rate was high (77%). The sample size of this study was relatively small (n
= 196) and restricted to CRC patients and therefore we cannot state yet if generalization of our results to other cancer patients or chemotherapeutic agents is justified. Finally, we did not measure blood levels of magnesium and calcium. It should be noted, however, that the specific objective of this study was to investigate the association between dietary intake of magnesium and CIPN. Next to that, circulating levels are tightly regulated and not representative for magnesium levels in muscles and bone [37
The present study also has important strengths. First of all, this is the first prospective cohort study which assessed the association between habitual dietary intake of magnesium or calcium and CIPN. Our data extend and complement existing evidence regarding the association between magnesium, calcium and neuropathy. Previous studies focusing on infusions with magnesium and calcium showed inconsistent findings and relied on acute exposure, while we assessed habitual, long-term intake of magnesium and calcium. In addition, previous studies focused on acute CIPN (during and directly after chemotherapy), while we focused on chronic and persistent CIPN. Therefore, this study provides an important contribution to the limited knowledge on chronic CIPN and its association with diet before, during and after chemotherapy. Furthermore, in the present study we used the 16 items of the QLQ-CIPN20 that are considered to be valid and reliable [22
]. This approach resulted in a clinically relevant estimation of the prevalence and severity of CIPN compared to the QLQ-CIPN20 [22
]. Due the availability of detailed data on diet and other clinical and lifestyle factors, we could adjust for the most plausible confounders, although residual confounding can never be fully excluded.