Despite it is acknowledged that the use of iron supplementation in addition to ESA treatment significantly improves the hematopoietic response to ESAs in dialysis patients with chronic anemia, the use of oral supplementation in cancer patients is still suboptimal . In chronic illnesses, the establishment of a permanent inflammatory status leads to the production of cytokines such as IL-1α and TNF-α, that prevents EPO production from kidneys, and the pro-inflammatory cytokine IL-6 that acts on the liver and induces the production of hepcidin. This peptide plays a key role in iron homeostasis, inhibiting intestinal iron absorption and impeding the release of iron from the stores [2, 31–33]. The presence of inflammation and, thus, high levels of hepcidin may limit the availability of circulating iron needed by RBC progenitors, hindering a correct erythropoiesis and eventually leading to the development of anemia of chronic disease [5, 34]. Thus, cancer patients, who present high or normal ferritin level, but also low circulating iron levels, may benefit from iron supplementation.
The issue of chemotherapy-induced anemia and low Hb levels in cancer patients is associated with poor physical performance status and disease-related fatigue.
Until recently (with the understanding of the mechanisms underlying FID), anemia has been largely underestimated. In 2004, an ECAM survey documented that anemia was left untreated in over 61% of cancer patients, being partly explained by a broad misconception around anemia in cancer patients (who often feature normal serum ferritin levels) and around the poor tolerability towards traditionally used iron formulations [3, 4], which is no longer applicable to newer formulations.
As a result of a growing number of studies on iron supplementation with ESAs , recent guidelines on the use of these agents  stress the importance of monitoring iron levels in patients and providing adequate supplementation in order for the patient to gain more benefit from ESA treatment, to improve Hb response, and to restore functional iron levels.
The present study specifically addressed the comparability of oral sucrosomial iron to ferric gluconate, a broadly used IV formulation, which has already been evaluated in a number of previous studies [14, 15] in combination with the long-acting ESA, darbepoetin.
Sucrosomial iron (Sideral®) is a preparation of ferric pyrophosphate conveyed and protected into a phospholipids and sucrester matrix. Differently from other formulations, it features low non-toxic dose of sucresters, which protect iron from the acid environment of the stomach and increase its permeability, allowing higher absorption of exogenous iron [22, 23]. In addition, it is characterized by an alternative route of absorption and delivery, which allows the reduction of side effects and the prevention of iron instability in the gastrointestinal tract. Preliminary studies seem to suggest that sucrosomial iron might also exert a down-regulatory effect on hepcidin in chronic inflammation . Taken together, these characteristics provide obvious advantages over other oral formulations, which have resulted less efficacious, compared to IV iron supplementation, in supporting Hb response in cancer patients receiving treatment with ESA.
Overall results showed comparable efficacy of sucrosomial iron to that of ferric gluconate in anemic patients not FID and not AID. Both IV and oral sucrosomial iron gave a good response rate (70 and 71%, respectively), with a maximum response rate achieved among patients with Hb >9 g/dL and a significantly lower response rate among patients with Hb ≤9 g/dL. This could be explained by the delicate balance involved in iron homeostasis.
In reference to the time to response, oral sucrosomial iron showed a comparable result to IV iron that was maintained for the rest of the monitoring period. Time to Hb response is an important parameter to consider in cancer patients undergoing treatment with ESA. As it is well demonstrated, ESAs are associated to severe AEs (venous thromboembolism, tumor progression, stroke, and recurrence of disease) and overall mortality [36–38]. In fact, recent guidelines such as ASCO and NCCN [10, 11] recommend that ESA should be administered for the least amount of time and at the minimum dose possible to elicit sufficient RBC levels to limit the need to turn to blood transfusions and to improve QoL. A quicker response, thus, is desirable.
An observational study by Giordano et al.  on sucrosomial iron in patients with sideropenic anemia confirmed the reduction of the typical side effects of a conventional martial treatment, determining at the same time an improvement of the patient’s anemic condition in terms of serum iron, Hb, and ferritin [24, 25, 39]. Another study by Pisani et al.  in patients with chronic kidney disease demonstrated the non-inferiority of the oral sucrosomial iron compared to IV iron therapy in terms of increase in Hb levels.
From the QoL perspective, iron supplementations represent a remarkable aid in dealing with cancer-related fatigue and preventing other related symptoms such as impaired cognitive function, headache, dizziness, chest pain, shortness of breath, nausea, and depression [6, 29, 30]. A recent German study on the overall QoL, as measured by the FACT-An total scores, showed a median anemia-related score improvement for patients receiving IV iron or ESA associated with IV iron after 12 weeks of treatment. The difference reached the level of clinical relevance (≥7 points) for patients receiving ESA associated with IV iron (106.5 to 117.5 points) . Likewise, the same tool, which is specifically validated for assessment in anemic cancer patients, was used also for our cohort.
All patients (both in the group of oral and IV supplementation) equally reported perceived benefits at 8 weeks. Parameters, such as fatigue/tiredness, general weakness, shortness of breath, feeling energetic, function, being too tired to eat, and motivation to perform daily chores, were all improved as expected with a gain in Hb level. Despite the small study population, such improvement quality of life represents a great achievement in patients with non-curable cancer, as it allows individuals to maintain function in daily life activities (in many cases these may also extend to family duties, work, etc.). The lack of differences in responses between the two groups is encouraging and confirms a comparable effect to IV as to benefits on QoL. Moreover, comparing the safety profile and efficacy of iron supplementations, the option of an effective oral supplementation in capsules may be less burdensome on the patient‘s logistics and further improve the patient’s QoL, as compared to a more invasive IV iron infusion at the out-patient clinic.
From a safety point of view, the advantages of oral sucrosomial iron supplementation are even more relevant in consideration of the recent safety warning [20, 21] on the potentially fatal effects of IV iron infusions, making an oral iron supplementation even more desirable.
From the prospective of patient management and costs involved for the healthcare system, IV infusion has also specific procedure requirements. Firstly, each IV session requires that the hematology unit reserve a transfusion station/seat for the time required for the procedure, monitor the patient (approximately 3 h), and dedicate personnel on shift during operation, which occupies resources that could be dedicated to other duties. Considering that the need for IV iron supplementation is evaluated on a patient-to-patient basis, the frequency of supplementation might imply up to three infusions per week. Secondly, IV iron can only be performed in authorized centers equipped with emergency and intensive care professionals, which excludes many patient reference centers at local level, thus, potentially discouraging physicians and patients from supplementation.
Overall, performance of oral sucrosomial iron was comparable to that of IV iron and produced comparable advantages for patients in both functional and emotional wellbeing, and Hb levels, suggesting a potential benefit also in reducing the need for transfusions for such patients and the morbidity of the malignancy.
The study was performed on a small sample size and was based on data from only two oncology centers, which limits the generalizability of the results.
Despite presenting an important bias given by the choice of treating both patients with iron deficit and true-replete patients with Hb >9 g/dL, the study provided important findings on the efficacy and safety of oral sucrosomial iron in patients treated with ESA.
Taken together, our study represents a small contribution in addressing the objectives set by ASCO (and other societies thereafter) since 2007, requesting further research to be done on iron supplementation in cancer patients treated with ESA and on iron formulation.