Serum iron levels increased by cancer chemotherapy correlate the chemotherapy-induced nausea and vomiting | SpringerLink

The emergence of new therapeutic options including 5-HT3 antagonist and an NK-1 receptor inhibitor have revolutionized the prevention of CINV [12]. However, even with modern antiemetic strategies, more than half of patients receiving HEC or MEC are affected by CINV [3, 7, 13]. Since the aim of antiemetic therapy is to minimize or eliminate CINV in all patients, current clinical options are insufficient and novel approaches to reduce CINV should be investigated.

In a healthy individual, most serum iron is bound to transferrin and the remaining non-transferrin bound iron (NTBI) fraction is extremely small [14, 15]. NTBI is potentially a toxic chemical, given its high propensity to induce reactive oxygen species, and is responsible for cellular damage producing gastroenteritis, cardiac disease, and liver injury [14,15,16,17,18,19]. Gastrointestinal toxicity is a well-known adverse effect of oral iron therapy [19]. Patients administered iron tablets for iron deficiency anemia frequently suffer from nausea or diarrhea [18], with even a small quantity of NTBI released from iron tablets likely to cause adverse effects. In the case of iron poisoning resulting from an overdose of iron tablets, gastrointestinal toxicities such as nausea and vomiting appear in patients with maximum serum iron levels of 350–500 µg/dl, and metabolic acidosis subsequently occurs as a result of free radical ions of iron [17]. Systemic toxicity potentially occurs at peak iron levels of 150–350 µg/dl [17]. High levels of serum iron do not persist for prolonged periods because excess iron in serum is rapidly distributed to tissues [8]. In this study, serum iron levels were shown to increase immediately after HEC and MEC in all patients, regardless of the chemotherapeutic regimen. Iron levels have been shown to increase to 185.87 µg/dl following treatment with FOLFOX or FOLFIRI in patients with advanced colorectal cancer, a level in accordance with that of the MEC group in our study [10]. Iron levels in the HEC and MEC groups were elevated to 231.0 ± 45.0 and 226.6 ± 44.2 µg/dl, respectively, on day 2, and nearer to 300 µg/dl in some patients, implying that serum iron had reached a considerably toxic level.

Theoretically, systemic iron toxicity is most likely when the serum iron level exceeds the iron-binding capacity. Transferrin has a strong capacity for iron binding and the saturation ratio of TIBC is normally less than 30%, with NTBI or free radical ions appearing in serum when the saturation ratio is more than 70–75% [17]. In this study, accompanied with elevated iron levels, UIBC markedly decreased and approached 0%. The saturation ratio of TIBC increased to 92.1 and 96.5% on day 2 and 95.1 and 72.3% on day 8 in the HEC and MEC groups, respectively. These findings implied that rapidly and then continuously elevated iron may produce NIBT or free radical ions, potentially causing various toxicities including nausea and vomiting in the acute and delayed phases. In contrast, iron levels were less elevated in patients treated with LEC and MIC compared with HEC and MEC. The elevation of iron observed in LEC patients on day 2 and was mild, and no significant elevation on day 8 or later was observed in patients treated with MIC consisting of tyrosine kinase inhibitors. These findings suggest that the degree of elevation of iron level seemed to be related to emetogenic risk classification.

There were several limitations to this study. First, this was a retrospective analysis and the measurement of iron was not routinely scheduled, but was instead performed in a small fraction of patients where practically necessary. Therefore, a long data collection period of over 17 years was required, and the sample size was limited. Despite these limitations, the tendency for increased iron levels to correlate with emetogenicity was evident. It should be emphasized serum iron levels were markedly increased in all patients who received HEC or MEC with no exception whether patients suffering anemia or not. It is definitely evident that iron levels were always increased by cytotoxic chemotherapy and the increased levels reached toxic range in some patients.

The mechanism by which chemotherapy is associated with elevated iron level remains unclear. One-third of iron in the human body is pooled as ferritin or hemosiderin in the liver, the spleen, and the kidneys [20]. Cytotoxic chemotherapy damages normal organs and iron may be released from pooled iron, although serum ferritin levels do not change significantly with various chemotherapeutic regimens [10, 21]. Ochiai et al. suggested that the elevation of serum iron during chemotherapy may be secondary to reduced iron consumption by erythropoiesis, leading to increased expression of hepcidin-25 and suppression of IL-6 via negative feedback [21].

In summary, we found that iron levels increased with chemotherapy according to the grade of emetogenicity. No studies to date have reported a relationship between increased iron levels and adverse effects during chemotherapy. The influence of serum iron on the adverse effects of cancer chemotherapy, in particular, when conducting clinical trials of new anticancer drugs, should therefore be investigated. This phenomenon may represent a novel approach to antiemetic treatment, as iron removal therapy using, for example, an iron-chelating drug may potentially alleviate CINV. We plan to conduct a prospective study to assess the influence of NTBI and the effect of deferoxamine as an iron-chelating drug on CINV and QOL of patients receiving cancer chemotherapy.