JONT Journal

Safety and adherence to the study treatment

Six patients reported grade 2 events, namely nausea, vomiting, and diarrhea, attributed to chemotherapy rather than to oral iron supplementation. Only one patient experienced chemotherapyrelated grade 3 nausea, not leading to the discontinuation of Sucrosomial® iron treatment.

Discussion

The relationship between cancer, iron metabolism, and IDA is complex. Cancer can disturb the balance of iron in the body, leading to both absolute and functional iron deficiency. Absolute iron deficiency occurs when there is a true lack of iron, whereas functional iron deficiency occurs when there is enough iron in the body, but it is not adequately available for Hb synthesis due to inflammatory processes [7].

Our study focuses on the pre-emptive use of oral SI in cancerassociated IDA patients who have adequate iron levels, with the aim of maintaining Hb levels above the threshold that would require red blood cells transfusions, thus enabling uninterrupted chemotherapy. In this way we can prevent the reduction of hemoglobin and limit the related symptoms such as fatigue, weakness, and impaired cognitive function, ultimately enhancing overall quality of life for patients [8].

Furthermore, by correcting iron deficiency and improving anemia, oral iron supplementation can help reduce the need for red blood cell transfusions [9]. This is particularly beneficial considering the risks associated with transfusions, including infections, allergic reactions, and iron overload with repeated administration [10].

Oral iron supplements are easily accessible and can be conveniently taken at home, making them a practical option for cancer patients. They also tend to be more cost-effective than intravenous iron formulations, offering a viable alternative for managing IDA in these patients.

However, the bioavailability is about 10% to 15% for ferrous iron preparations (sulfate, gluconate, fumarate, etc.), and the absorption of these formulations is negatively affected by proton pump inhibitors or antacids, or meals, or presence of an inflammatory status. In addition, a large number of patients reported gastrointestinal side effects which may lead to reduced tolerance and adherence to iron treatment [7].

Athibovonsuk et al. (2013) investigated the opportunity to give oral or intravenous iron prior to start chemotherapy in gynecologic cancer patients. The results showed that both intravenous and oral iron administration did not limit the Hb decline; a smaller median number of transfused patients was reported in the intravenous group (28,1%), respect to oral iron group, with 56.3% of transfused patients (transfusion criterion under 10 g/dL of Hb) [11].

Dangsuwan et al. (2010) obtained similar results in their study in gynecologic cancer patients with 22.7% of transfused patients in IV iron group and 63.6% in oral iron group [12].

In our study, after three months of Sucrosomial oral iron supplementation, we observed no significative drop in Hb levels, and ferritin, TSAT, and serum iron increased by 49%, 58%, and 99% respectively. Only 4 patients experienced a Hb levels below 10 g/dL during the study period. However, the decrease was limited and not less than 9 g/dl. For this reason, none of the patients required red blood cell transfusions or ESAs treatments.

Looking at the Athibovonsuk study, the results given are not comparable with ours because the transfusion threshold is different (Hb < 10 g/dL in Athibovonsuk study and Hb < 9 g/dL in our study). Anyway, if we would consider a Hb cut-off of 10 g/dL, we would obtain that in our study only 15.4% of the patients fell below this threshold.

We can try explaining why the result obtained with SI was better than that obtained with conventional iron. Historically, the use of oral iron has been problematic in cancer patients for various reasons. Factors such as inflammation, gastrointestinal side effects of cancer treatments, and interactions with other medications can affect the absorption of oral iron. Conventional iron can cause gastrointestinal side effects, including constipation, nausea, abdominal pain, and the discoloration of stools. Additionally, the side effects associated with oral iron supplements, along with the need for prolonged treatment to replenish iron stores, can impact patient adherence. The unique structure of SI, which is different from other oral formulations, protects iron from the acid environment of the stomach, increases its absorption across the intestinal epithelium, and ensures low gastrointestinal toxicity as demonstrated in multiple studies, even in patients with inflammatory bowel diseases for example [4, 13, 14].

Moreover, with traditional oral iron, elevated hepcidin levels can significantly hinder the effectiveness of iron supplementation. When hepcidin is high, it reduces the expression of ferroportin, the iron transporter protein on the basal surface of intestinal cells, effectively blocking the release of absorbed iron into the bloodstream. This leads to poor iron absorption and circulation and limits the efficacy of conventional oral iron supplements, particularly in patients with chronic disease and chronic inflammation [3].

Sucrosomial® iron offers a novel approach that may help mitigate the limitations imposed by hepcidin. With conventional iron, in conditions of inflammation, intestinal absorption is limited because the increased levels of hepcidin negatively affect the expression of ferroportin and limit the entry of iron into the blood circulation. The Sucrosome protects the iron in a phospholipid plus sucrose esters of fatty acids matrix, allowing it to be absorbed through the intestinal cells in a way that, at least partially, seems to bypass the usual pathways. In vitro studies have shown that SI absorption can occur mainly through an hepcidin-independent pathway, as it is mostly taken up as a vesicle-like structure by enterocytes and M cells via the paracellular and transcellular routes [4]. In ex-vivo experiments using isolate rat intestine and fluorescein labeled SI, it has been demonstrated that, after passing through M cells, SI was taken up by CD68+ macrophages. These experiments suggest that SI is not released to the portal blood stream, but to the lymphatic circulation (M cells route) and later to the arterial circulation, before reaching the liver [16]. This peculiar delivery system enables iron to be absorbed directly by the intestinal cells and transported across the cell membrane without relying on the traditional pathways explaining its effectiveness even in patients with elevated hepcidin. This makes it a particularly advantageous form of supplementation for individuals suffering from inflammation-related IDA, where traditional iron supplements might fail due to poor absorption [4, 16, 17].

Compared to intravenous iron, oral iron is generally considered less rapid in increasing hemoglobin levels and replenishing iron stores, especially for patients with cancer-related anemia and during ESA treatments. This is due to the direct delivery of intravenous iron into the bloodstream, bypassing absorption issues related to the gastrointestinal tract [18].

The introduction of SI into clinical practice represents a significant advancement in the management of cancer-related anemia and other trials demonstrate the efficacy of SI.

In a multicenter, open-label, phase III clinical trial conducted in patients with chemotherapy-related anemia, ESAs were administered with or without SI for 12 weeks. The study found that a higher proportion of patients supplemented with SI achieved the desired response (hemoglobin increase of >2 g/dL from baseline, without prior red blood cell transfusions in the past 28 days, or achieving a hemoglobin level of ≥12 g/dL) compared to the control group (52% vs. 31%).There were no significant differences in safety or the need for transfusions between the two groups [19].

In another study, Mafodda et al. (2017) randomized 64 patients with chemotherapy-related functional anemia (hemoglobin levels >8 g/dL and <10 g/dL, without absolute or functional iron deficiency) to receive chemotherapy and darbepoetin with either SI or intravenous iron. The study found no difference in the hemoglobin response rate between the two treatment arms, nor any differences in red blood cell transfusion requirements or changes in quality of life. However, SI was better tolerated compared to intravenous iron [20].

Conclusions

In conclusion, to our knowledge, this is the first observational study using SI in preventing Hb drop in cancer patients. This study had some limitations: the small number of patients and the absence of control group do not allow us to draw solid conclusions, but only show a trend, to be confirmed with more complete clinical trials. Supplementation with Sucrosomial® Iron seems to offer a promising new approach for managing mild cancer-related IDA in patients who do not require transfusions or ESA treatment. This addresses the critical need for more effective and tolerable iron treatments. The unique delivery system of SI, which minimizes side effects and maximizes absorption, represents a significant advancement in supporting cancer patients throughout their treatment journey [2]. As research continues to progress, SI supplementation may become a standard of care to recover iron deficiency or avoid large drop in Hb in oncology, alleviating the burden of IDA for cancer patients worldwide.

Data Availability Statement

Data supporting the findings of this study are included within the article, further inquiries can be directed to the corresponding author.

Ethics Statement

The study was reviewed and approved by Treviglio Hospital Ethics Committees (Approval No. 5/2013). The patients/participants provided their written informed consent to participate in this study.

Author Contributions

FP, RA, VL, and SB: conceptualization, methodology, resources, supervision, and project administration. FP, RA: investigation and data curation. FP and SB: statistical analysis. FP, VL and SB: writing-original draft preparation, conception and coordination of the study, full access to all data in the study, and responsibility for the integrity of the data and the accuracy of the data analysis. FP, VL and SB: writing-reviewing and editing. All authors have read and approved the final version of the manuscript for submission.

Acknowledgments

The authors would like to thank the participants of this study, and PharmaNutra S.p.A., Pisa, Italy for providing the Sucrosomial® iron supplement (Sideral® Forte). We would also like to thank Germano Tarantino and Maria Sole Rossato for their help with editing.

Funding: PharmaNutra S.p.A., Pisa, Italy will covered Article Processing Fee.

Conflict of interest

Authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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