Prevalence of functional iron deficiency in patients with malignancies and its impact on fatigue-specific quality of life.

Introduction

Iron is an important trace element. Anaemia of chronic diseases, such as cancer, is at least partially induced by deficient or inaccessible iron stores. Functional iron deficiency (FID) is also common in patients with other inflammatory or infectious conditions, chronic heart failure, chronic kidney disease, and complex medical disorders. 1 , 2 , 3 , 4 As iron regulation is disturbed in cancer and cancer-associated chronic inflammation, FID is thought to be frequent in those patients.

The main regulator of iron homeostasis is the hepatic peptide hepcidin. When hepcidin is released due to regulation of the tumour microenvironment by inflammatory cells, it binds to ferroportin (FPN), an iron exporter of intracellular iron, and induces the internalization and ubiquitin-mediated degradation of FPN. Therefore, it reduces iron absorption from duodenal enterocytes and iron efflux into the circulation from macrophages and hepatocytes. As a result of that interaction between hepcidin and FPN, serum iron will be reduced. 5 , 6 Hepcidin is up-regulated in inflammatory conditions via the interleukin 6/STAT3 (signal transducer and activator of transcription 3) pathway. 7 This leads to FID in cancer, as reduced serum iron and increased ferritin stores cause iron to be inaccessible for erythropoiesis and tissues, even though body iron stores are adequate. 5

FID may also be associated with impaired physical function, treatment-associated underperformance, as well as impaired fatigue-specific quality of life (QoL) and might therefore be an interventional target in cancer patients. 8

The European Society for Medical Oncology (ESMO) published Clinical Practice Guidelines on the management of anaemia and iron deficiency (ID) in patients with cancer. 9 FID is defined as serum ferritin (SF) ≥100 μg/l and transferrin saturation (TSAT) <20%. Absolute iron deficiency (AID) in the context of malignancies is defined as SF <100 μg/l. AID is a complete depletion of iron stores. Taken together, FID and AID both result in a reduction or unavailability of iron for erythropoiesis leading to anaemia.

The ESMO Clinical Practice Guidelines suggest treatment of FID in patients with cancer and anaemia at a Hb between 8 and 10 g/dI with a fixed dose of i.v. iron of 1000 mg complemented by erythropoiesis-stimulating agents (ESA).

Whether FID plays a role in patients with Hb between 10 and 11 g/dl or without anaemia with Hb >11 g/dl is not known. Additionally, the prevalence of ESMO-defined FID before disease-directed therapy, such as chemo-/immunotherapy, (anti-)hormonal therapy, or radiation, is also unknown.

Most studies focus exclusively on anaemia or on ID without distinguishing FID from AID, use definitions for ID and for FID other than recommended by ESMO Clinical Practice Guidelines, and report on selected populations only (e.g. specific cancer type, advanced cancer). 10 , 11 , 12 , 13 , 14 However, two recent studies used ESMO-defined FID. One study included patients with solid tumours and haematological malignancies either at any time during or without any treatment. 15 In 58% of patients ID was documented and 64% of those had FID. In the other study including patients >75 years with solid tumours, the prevalence of FID was 42% at their first geriatric assessment, and 16% of patients without anaemia had FID. 16

Whether FID might serve as an interventional target in patients with solid tumours and haematological malignancies before disease-directed therapy independent of Hb and age is not known.

To close this gap, we carried out this study as a prerequisite for the evaluation of diagnosing and potentially treating FID with i.v. iron to improve fatigue-specific QoL.

Therefore, the primary objective was to obtain data on the prevalence of ESMO-defined FID independent of Hb and age before disease-directed therapy in patients with solid tumours and haematological malignancies, and especially in patients with Hb between 10 and 11 g/dl or without anaemia with Hb > 11 g/dl.

The secondary objective was to collect data on fatigue-specific QoL analysing the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) questionnaire in order to assess the influence of FID on fatigue-specific QoL in comparison to AID and no ID. 17

Patients and methods

Study design and participants

This is a prospective, observational single-centre study, enrolling patients between March 2022 and April 2023. The study was registered with ClinicalTrials.gov ( NCT05333913 ).

Key eligibility criteria were patients with newly diagnosed or relapsed solid tumours and haematological malignancies within 4 weeks before disease-directed therapy. The decision on applying a disease-directed therapy was made by the treating physician. All patients referred were screened for eligibility and were consecutively included.

At inclusion, the following parameters were documented: age, sex, type of malignancy, and status of metastases in case of solid tumours.

Additionally, the following laboratory values were collected in a non-fasting condition: complete blood count, including Hb, mean corpuscular volume (MCV) and mean corpuscular haemoglobin (MCH), as well as reticulocyte haemoglobin content (Ret-He), SF, TSAT, C-reactive protein (CRP), and alanine aminotransferase (ALT).

Definitions of FID, AID, and anaemia were based on the ESMO Clinical Practice Guidelines on the management of anaemia and ID in patients with cancer. 9 Therefore, FID was defined as SF ≥100 μg/l and a TSAT <20%. AID was defined as SF <100 μg/l. Anaemia was defined by Hb <11 g/dl.

Malignancies were grouped into solid tumours and haematological malignancies. The former included cancer in the lung, breast, urogenital system, head and neck, gastrointestinal (GI) tract-upper, GI tract-lower, and patients with gynaecological cancers, skin and soft-tissue cancer, central nervous system cancer, and other.

QoL data were obtained at inclusion using the Functional Assessment of Cancer Therapy-Anemia (FACT-An) questionnaire. The FACT-An questionnaire consists of 47 questions to evaluate symptoms and concerns of cancer patients with anaemia within the past 7 days. Of the 47 questions, 27 are taken from the Functional Assessment of Cancer Therapy-General (FACT-G) questionnaire, while 7 questions examine specific symptoms of anaemia and 13 questions deal with fatigue. The Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) questionnaire is a subset of FACT-An consisting of the 27 questions from the FACT-G and the 13 items assessing fatigue and its impact. There are four subscale domains including physical well-being, social/family well-being, emotional well-being, and fatigue.

Patients <18 years of age, pregnant patients, and patients in need of an acute therapeutic intervention were excluded, as were patients with known ID with or without iron substitution, therapy with red blood cell (RBC) transfusions, or ESA within 8 weeks before screening.

Written informed consent was obtained from all patients. Patients unable to give informed consent due to serious underlying medical, psychiatric, psychological, familial, or geographical conditions were excluded.

Standards were reported according to ESMO GROW using the following instructions: https://www.esmorwd.org/article/S2949-8201(23)00003-6/fulltext . 18

Statistical analysis

Based on the assumption that the prevalence of FID is 10%, we calculated that 160 patients had to be enrolled to estimate the prevalence of FID with a precision of 5%. Quantitative variables are described by mean, standard deviation (SD), minimum and maximum for normally distributed data, and by median and interquartile ranges (IQR) for a non-normal distribution. Standard normal quantiles were analysed by the Shapiro–Wilk test statistic. Numbers and percentages are used for categorical variables. The prevalence of events was estimated using the Agresti–Coull 95% confidence intervals (CI). Multiple regression analysis was used to test whether iron status, sex, type of malignancy, Hb, or SF significantly predicted exam scores. Beta coefficients represent the regression coefficients for those standardized data. P values <0.05 were considered to be statistically significant. Missing data were generally not considered. Statistical analyses were conducted using various R packages, including ‘dplyr’, ‘ggplot2’, ‘ggpubr’, ‘survival’, and ‘survminer’ within the R version 4.3.1 environment (R Foundation for Statistical Computing, Vienna, Austria).

Ethics

This study protocol complied with the recommendations of the Declaration of Helsinki and was approved by the local ethics committee. Submission to the regional ethics committee took place in November 2021. All patients provided written informed consent.

Results

Patient characteristics

During the enrolment period, all patients referred to the outpatient department of haematology and medical oncology were screened for eligibility concerning the inclusion and exclusion criteria. A total of 160 patients were included in the study. All patients were intended to receive a disease-directed therapy within the next 4 weeks. A total of 146 patients were included in the final analysis, while 14 of the 160 patients were excluded. In eight patients SF levels were not available, in five iron status was only assessed after the start of the disease-directed therapy, and one patient was a duplicate.

Patient characteristics are shown in Table 1 . Table 1 Patient characteristics of the total cohort of 146 patients Variable Result Sex and age Male, n (%) 70 (48) Female, n (%) 76 (52) Median age, years (IQR) 64 (55;71) Type of malignancy, n (%) Haematological malignancies 21 (14) Solid tumours 125 (86) Lung 28 (19) Breast 26 (18) Urogenital 23 (16) Head and neck 8 (5) GI tract-upper 8 (5) GI tract-lower 8 (5) Gynaecological 8 (5) Skin and soft tissue 8 (5) Central nervous system 6 (4) Other 2 (1) Status of metastases in solid tumours, n (%) Non-metastatic disease 74 (59) Metastatic disease 51 (41) There was a slight preponderance of women ( n = 76, 52%) compared with men ( n = 70, 48%). Most patients had solid tumours ( n = 125, 86%), whereas a minority of patients had haematological malignancies ( n = 21, 14%). In those patients with solid tumours, 59% ( n = 74) had localized disease, whereas 41% ( n = 51) had metastatic disease. GI, gastrointestinal; IQR, interquartile range.

The median age was 64 years (IQR 55-71 years). There was a slight preponderance of women ( n = 76, 52%) compared with men ( n = 70, 48%).

Most patients had solid tumours ( n = 125, 86%), and a minority of patients had haematological malignancies ( n = 21, 14%). In those patients with solid tumours, 59% ( n = 74) had localized disease, whereas 41% ( n = 51) had metastatic disease. The three most prevalent solid tumours were lung cancer, breast cancer, and urogenital cancer, which occurred in 62% ( n = 77) of all patients with solid tumours.

Of the 21 patients with haematological malignancies, 6 had chronic lymphocytic leukaemia, 5 had lymphoproliferative disease, 5 had multiple myeloma, 4 had a myeloproliferative neoplasm, and 1 patient had hairy cell leukaemia.

Iron stores and haemoglobin

Laboratory values are summarized in Table 2 . Table 2 Laboratory characteristics of the total cohort of 146 patients Variable Result Hb (g/dl), mean ± SD 13.2 ± 1.8 Ret-He (g/l), median (IQR) 32.8 (31.0-34.2) MCV (fl), mean ± SD 89 ± 4.9 MCH (pg), median ± SD 29 (29-31) Serum ferritin (μg/l), median (IQR) 143 (77-297) Transferrin saturation (%), median (IQR) 20.2 (14-27) CRP (mg/dl), median (IQR) 0 (0-11) ALT (U/l), median (IQR) 21 (16-32) Mean haemoglobin level was 13.2 g/dl, within the normal range. Ret-He levels were within normal ranges. There was a wide IQR of serum ferritin level, ranging from 77 μg/l to 297 μg/l. Median transferrin saturation was 20.2% with an IQR from 14% to 27%. There were missing data in eight patients for Ret-He, in two patients for CRP, and in one patient for ALT. ALT, alanine aminotransferase; CRP, C-reactive protein; Hb, Haemoglobin; IQR, interquartile range (non-normal distribution); MCH, mean corpuscular haemoglobin; MCV, mean corpuscular volume; Ret-He, reticulocyte haemoglobin equivalent; SD, standard deviation (normally distributed data).

Mean Hb of the total cohort was 13.2 g/dl (±1.8 g/dl) which was within the normal range.

Analysing iron stores, we observed FID in 30% ( n = 44, CI 23 to 38). Anaemia with Hb < 11 g/dl was present in 10% of the assessed patients ( n = 15, CI 6 to 16). Of those, eight patients had a Hb of 10-11 g/dl (53%, CI 30 to 75), and seven patients had a Hb of 8-10 g/dl (47%, CI 25 to 70). There was no patient with a Hb < 8 g/dl. Analysing iron stores of the 15 patients with anaemia, FID was present in 66% ( n = 10, CI 42 to 85), AID was present in 7% ( n = 11, CI 0 to 32), and no ID was present in 27% ( n = 4, CI 10 to 52). Of the eight patients with a Hb of 10-11 g/dl, FID was present in five patients (63%, CI 30 to 87). Of the seven patients with a Hb of 8-10 g/dl, five patients had FID (71%, CI 35 to 92). Of the 131 patients without anaemia, 26% ( n = 34, CI 19 to 34) had FID, 38% ( n = 50, CI 30 to 47) had AID, and 36% ( n =47, CI 28 to 44) had no ID.

Of those patients with FID, the majority did not have anaemia (77%, n = 34, CI 63 to 87). Only 23% of patients with FID had anaemia ( n = 10, CI 13 to 37), half of those with a Hb of 10-11 g/dl and the other half with a Hb of 8-10 g/dl (CI 5-24).

AID was documented in 35% of all patients ( n = 51, CI 28 to 43), of which 2% ( n = 1, CI 0 to 11) had anaemia. No ID was present in 35% of all patients ( n = 51, CI 28 to 43), with anaemia in 8% ( n = 4, CI 3 to 19) ( Figure 1 ). Figure 1 Proportion of patients with functional iron deficiency (blue), absolute iron deficiency (yellow) and no iron deficiency (white) . Functional iron deficiency was observed in 30% of patients with malignancies. One half of the remaining 70% of the patients had absolute iron deficiency, the other half did not have iron deficiency.

FID was more prevalent in men compared with women (36%, CI 26 to 47, and 25%, CI 17 to 36, respectively). In contrast, AID did occur more often in women compared with men (47%, CI 36 to 58 and 21%, CI 13 to 33, respectively). Patients with FID were significantly older than patients with AID (67.5 years, IQR 62-74 years, and 56 years, IQR 50-71 years, respectively; P < 0.05).

Correlating Hb and iron stores, mean Hb was 12.6 g/l (±2.063 g/l) in patients with FID, which was significantly lower compared with patients with AID with a mean Hb of 13.5 g/l (±1.4 g/l, P = 0.01) and without ID with a mean Hb of 13.5 g/dl (± .7 g/dl, P = 0.02).

Reticulocyte haemoglobin content, red cell indices, and C-reactive protein

Ret-He was significantly lower in patients with FID (median 31 pg, IQR 29-33 pg) compared with patients without ID (33 pg, IQR 32.5-34.5 pg, P = 0.05). Ret-He in patients with FID was below the lower limit of normal (<28 pg) in only 9.4% of patients ( n = 6).

Ret-He was not significantly lower in patients with AID (median 33 pg, IQR 32-34 pg) compared with patients without ID ( P = 0.14), and was below the lower limit of normal in only three patients (6%).

The calculated parameter MCV was not significantly lower in patients with FID (mean 88.6 ± 5.1 fl) compared with patients with no ID (mean 90.1 ± 4.9 fl, P = 0.6). MCV was significantly higher in patients with no ID compared with patients with AID (mean 87.9 ± 4.51 fl, P = 0.02). MCV was below the lower limit of normal (<80 fl) in 4.5% of patients with FID ( n = 2, CI 0.4 to 16) and in 5.8% of patients with AID ( n = 3, CI 1.4 to 16).

MCH was not significantly different in patients with FID and AID (28.8 ± 2.1 pg and 29.3 ± 2.2 pg, respectively, P = 0.13). In patients with no ID, however, MCH was significantly higher compared with patients with FID (30.1 ± 1.7 pg and 28.8 ± 2.1 pg, respectively, P < 0.05).

Elevation of CRP >5 mg/l was observed in 68% of the 44 patients with FID ( n = 30), in 27% of the 51 patients with AID ( n = 14), and in 33% of the 51 patients with no ID ( n = 17). Elevation of ALT (males > 50 IU/l, females > 35 IU/l) was documented in 16% of patients with FID ( n = 7), in 6% of patients with AID ( n = 3), and in 14% of patients with no ID ( n = 7).

FID, AID, and type of malignancy

Most frequently, patients with FID had lung cancer ( n = 17). Patients with AID most frequently had breast cancer ( n = 13). Of those 51 patients with metastatic solid tumours, FID was present in 43% of the patients ( n = 22, CI 30 to 57) and AID was present in 22% of the patients ( n = 11, CI 12 to 35).

Fatigue-specific quality of life

Results of the FACT-An questionnaire were available in 132 patients. As most of our patients did not have anaemia, scores from FACIT-F as a subset of FACT-An were analysed. The median total FACIT-F score in patients with FID was 128.25 (IQR 96.38-135.38) compared with 125.33 (IQR 100.62-139.17) in patients with AID, and 128.0 (IQR 102.4-137.0) in patients with no ID ( Figure 2 ). In the multiple regression analysis, FID and AID did not predict FACIT-F scores (β = 3.5, P = 0.6, and β = −1.2, P = 0.8, respectively). Figure 2 FACIT-F-score by iron status: No ID (white), FID (blue), and AID (yellow). Median total score and IQR for FACIT-F, which shows no significant differences between the groups separated by iron status. The median total FACIT-F-score in patients with FID was 128.25 (IQR 96.38-135.38), compared with 125.33 (IQR 100.62-139.17) in patients with AID, and 128.0 (IQR 102.4-137.0) in patients with no ID. AID, absolute iron deficiency; FACIT-F, Functional Assessment of Chronic Illness Therapy-Fatigue; FID, functional iron deficiency; IQR, interquartile range; No ID, no iron deficiency.

Furthermore, when looking at the subgroup of patients with anaemia ( n = 14), FID and AID did not predict FACT-An scores ( β = 53, P = 0.3, and β = 13, P = 0.9), nor did FID and AID predict FACIT-F scores ( β = 1.5, P = 0.8 and β = −2.0, P = 0.7) in patients without anaemia.

The presence of anaemia, Hb, type of malignancy, or status of metastases did not predict FACIT-F scores nor FACT-An scores. Considering FID and AID, there was no significant prediction of any of the subscales of the FACIT-F questionnaire. In patients with FID, anaemia did not predict FACIT-F scores nor FACT-An scores.

Details are depicted in the Supplementary Material , Supplementary Tables S1-S4 , and Supplementary Figure S1 , available at https://doi.org/10.1016/j.esmorw.2025.100140 .

Discussion

Improving fatigue-specific QoL in patients with malignant neoplasms remains a major treatment goal. As malignancy is accompanied by inflammation causing FID, evaluation of the prevalence of FID and its influence on fatigue-specific QoL is essential in order to assess FID as a potential interventional target.

Evaluating 146 patients with solid tumours and haematological malignancies, the prevalence of ESMO-defined FID within 4 weeks before disease-directed therapy independent of Hb and age was 30%.

Of note, in only 23% of patients with FID ( n = 10) anaemia was present, which is still occurring more frequently in FID compared with patients with AID (2%, n = 1) and with no ID (8%, n = 4). However, the majority of patients with FID did not have anaemia (77%, n = 34).

Interestingly, when assessing the prevalence of AID and FID among 8021 adults in the United States retrospectively, Tawfik et al. found an estimated prevalence of FID of 15%, and in adults without anaemia, heart failure, chronic kidney disease, or current pregnancy, the estimated prevalence of FID was again 15%, although FID was differently defined as SF ≥30 μg/l and TSAT <20% and there are no data on other (inflammatory) comorbidities. 19 Even if the definition of FID is different from that used by the ESMO Clinical Practice Guidelines and in our study, there seems to be a relatively high prevalence of FID in American adults, although certainly much lower compared with FID in patients with solid tumours and haematological malignancies. Whether there is an association with fatigue and fatigue-associated impairment of QoL remains unclear.

In the current ESMO Clinical Practice Guidelines on the management of anaemia and ID in patients with cancer and Hb of 10-11 g/dl, ID as a potential cause of anaemia is summarized and defined by TSAT <20% and SF <100 μg/l. 9 In our study, of the eight patients with a Hb of 10-11 g/dl, five patients were diagnosed with FID (63%, CI 30 to 87). It seems therefore important to differentiate FID and AID in patients with cancer and a Hb of 10-11 g/dl, as the amount of i.v. iron supplementation is different and patients with FID should be supplemented with a fixed dose of i.v. iron of 1000 mg.

Evidence of the effect of treatment of FID in that setting is limited, as it is not distinguished from AID. Two studies, which examined the use of i.v. iron, demonstrated that patients with a Hb of 10-11 g/dl achieved an increase of Hb with or without ESA. 20 , 21 Another study randomized patients with cervical cancer and a Hb of 10-12 g/dl to receive either i.v. iron or no iron and demonstrated that patients receiving i.v. iron experienced a significantly less decline of Hb, although iron status was not recorded in this study. 22

Derived from this sparse evidence, in patients with a Hb of 10-11 g/dl and FID, treatment with a fixed dose of i.v. iron seems to be appropriate to either raise Hb or to prevent rapid decline. Patients with AID, however, should be substituted with i.v. iron according to the Ganzoni formula calculating the iron deficit in circulation and in iron stores. 23 The proposed treatment algorithm on the basis of the results of our study is depicted in Figure 3 . Figure 3 Proposed treatment algorithm for patients with cancer, anaemia, and absolute or functional iron deficiency, modified from Figure 1 in ‘Management of anaemia and iron deficiency in patients with cancer: ESMO Clinical Practice Guidelines’. 9 As functional ID does also occur in patients with a Hb of 10-11 g/dl, it should be recognized and treated with a fixed dose of i.v. iron. Absolute ID, however, should also be treated with i.v. iron, and the iron deficit should be calculated according to the Ganzoni formula. ESA, erythropoiesis-stimulating agents; Hb, haemoglobin; i.v., intravenous; ID, iron deficiency; RBC, red blood cell; SF, serum ferritin; TSAT, transferrin saturation.

Considering the 15 patients with anaemia, 66% had FID, 7% AID, and 27% had normal iron stores. Although anaemia was present in only 10% of the assessed patients, it is essential to assess iron stores in those patients as a possible and treatable cause of anaemia and to understand that FID can occur even in patients with a Hb of 10-11 g/dl.

Luporsi et al. found a comparable prevalence of FID in a study including 1221 patients with solid tumours and haematological malignancies. The prevalence of ID was 58%, and in nearly two-thirds of those patients FID was present. Most of the patients received disease-directed therapy. In contrast to our study, prevalence of ID and FID was assessed at any time during treatment. 15

Tisserand et al. evaluated iron stores in a geriatric population with solid tumours at the time of their first assessment. FID or AID was present in 65% of those patients. 16

Gluszak et al. showed an improvement in FACT-An-scores in patients with solid tumours and ID with iron substitution during disease-directed therapy independent of correction of anaemia, but there was no apparent separation of FID and AID. 24

In contrast to those studies, our study included patients ≥18 years without age limit and independent of Hb. Next to solid tumours, with localized disease or metastatic spread, haematological malignancies were included. The analysis of iron status was done before disease-directed therapy to evaluate FID as a possible target of i.v. iron supplementation at that time to improve fatigue-specific QoL.

With FID occurring in 30% of patients with malignancies independent of Hb and age, and with the proposal of FID leading or contributing to fatigue impairing fatigue-specific QoL, we next asked, whether there is an association between FID and FACIT-F-scores. We could, however, not demonstrate such an association, which remained true when a comparison of patients with and without anaemia was done.

The aetiology of fatigue is complex and not only influenced by iron status, but is dependent on several other factors, such as inflammatory cytokines, social and psychological factors, and deficiencies of vitamin B 12 , folic acid, or trace elements. 25 It seems therefore unlikely that i.v. iron supplementation in patients with FID and malignancies is of benefit regarding fatigue-specific QoL, unless anaemia is present.

The ESMO Clinical Practice Guidelines recommend supplementing a fixed dose of iron of 1000 mg in patients with a Hb of 8-10 g/dl and FID, which should be accompanied by treatment with ESA, since there is evidence that i.v. iron improves Hb response to ESA, reduces RBC transfusions, and possibly improves QoL. 9 In patients with a Hb of 8-10 g/dl and AID, i.v. iron supplementation is recommended, complemented by ESA if Hb is still <10 g/dl.

As we have demonstrated that FID can occur also in patients with a Hb of 10-11 g/dl, a fixed dose of i.v. iron only of 1000 mg should be applied to those patients. However, patients with AID with a Hb of 10-11 g/dl should receive i.v. iron according to the iron deficit calculated with the Ganzoni formula. As there is no association between FID and FACIT-F scores, we do not recommend i.v. iron in patients with Hb >11 g/dl.

Furthermore, it was demonstrated that commonly used markers of impaired iron status, such as Ret-He, MCV, and MCH, have limited clinical value regarding functionally available or stored iron in patients with malignancies.

Based on the results of our study, in patients with Hb <11 g/dl analysis of iron stores using SF and TSAT should occur to reliably diagnose FID and to treat FID in patients with a Hb of 10-11 g/dl with a fixed dose of i.v. iron of 1000 mg, and in patients with a Hb of 8-10 g/dl with a combination of a fixed dose of i.v. iron of 1000 mg and ESA.

There are several limitations to our study. The single-centre design and selection of a relatively small number of heterogeneous patients concerning type of malignancy limit the generalizability of our findings. The study was not powered to detect an association between FID and fatigue-specific QoL in certain subgroups. Additionally, TSAT was calculated using serum iron and serum transferrin in a non-fasting condition, which might overestimate FID. 26 As patients with known ID, therapy with ESA, or RBC transfusions in the last 8 weeks before disease-directed therapy were excluded, prevalence of FID and AID in patients with malignancies are likely to be underestimated.

Our population represents patients with malignancies referred for disease-directed therapy, and results cannot be extrapolated to patients in whom a disease-directed therapy does not seem to be appropriate.

Lastly, since the primary objective of our study was to obtain data on the prevalence of ESMO-defined FID in patients with malignancies independent of Hb and age, our sample size was not powered to show statistically significant differences in fatigue-specific QoL between patients with FID, AID, and with no ID. Furthermore, possible confounding factors like inflammatory cytokines, social and psychosocial factors, and substrate deficiencies other than iron were not accounted for in our analysis.

In conclusion, FID as defined by the ESMO Clinical Practice Guidelines on the management of anaemia and ID in patients with cancer occurs in patients with solid tumours and haematological malignancies before disease-directed therapy with a prevalence of 30% independent of Hb and age. As we could not demonstrate an association between iron status and fatigue-specific QoL as detected by the FACIT-F questionnaire, FID is unlikely to be an interventional target independent of Hb to improve fatigue-specific QoL.

FID does also occur in patients with a Hb of 10-11 g/dl in 63% of cases and should be treated with a fixed dose of i.v. iron. These findings, however, need further evaluation in randomized studies with a larger number of patients with malignancies. FID in patients with a Hb of 8-11 g/dl should be treated with a combination of a fixed dose of i.v. iron and ESA. In daily clinical practice, anaemia in patients with malignancies should be the focus of the diagnostic approaches evaluating anaemia and an appropriate work-up including iron status (SF and TSAT) should be carried out.

References

1 Anker S.D. Comin Colet J. Filippatos G. Ferric carboxymaltose in patients with heart failure and iron deficiency N Engl J Med 361 25 2009 2436 2448 19920054 10.1056/NEJMoa0908355

2 Cacoub P. Choukroun G. Cohen-Solal A. Iron deficiency screening is a key issue in chronic inflammatory diseases: a call to action J Intern Med 292 4 2022 542 556 35466452 10.1111/joim.13503 PMC9544998

3 Pasricha S.R. Tye-Din J. Muckenthaler M.U. Swinkels D.W. Iron deficiency Lancet 397 10270 2021 233 248 33285139 10.1016/S0140-6736(20)32594-0

4 Macdougall I.C. Bock A.H. Carrera F. FIND-CKD: a randomized trial of intravenous ferric carboxymaltose versus oral iron in patients with chronic kidney disease and iron deficiency anaemia Nephrol Dial Transplant 29 11 2014 2075 2084 24891437 10.1093/ndt/gfu201 PMC4209879

5 Muckenthaler M.U. Rivella S. Hentze M.W. Galy B. A red carpet for iron metabolism Cell 168 3 2017 344 361 28129536 10.1016/j.cell.2016.12.034 PMC5706455

6 Wang C.Y. Babitt J.L. Hepcidin regulation in the anemia of inflammation Curr Opin Hematol 23 3 2016 189 197 26886082 10.1097/MOH.0000000000000236 PMC4993159

7 Silvestri L. Nai A. Dulja A. Pagani A. Hepcidin and the BMP-SMAD pathway: an unexpected liaison Vitam Horm 110 2019 71 99 30798817 10.1016/bs.vh.2019.01.004

8 Ludwig H. Müldür E. Endler G. Hübl W. Prevalence of iron deficiency across different tumors and its association with poor performance status, disease status and anemia Ann Oncol 24 7 2013 1886 1892 23567147 10.1093/annonc/mdt118 PMC3690908

9 Aapro M. Beguin Y. Bokemeyer C. Management of anaemia and iron deficiency in patients with cancer: ESMO Clinical Practice Guidelines Ann Oncol 29 2018 iv96 iv110 29471514 10.1093/annonc/mdx758

10 Hashemi S.M. Mashhadi M.A. Mohammadi M. Ebrahimi M. Allahyari A. Absolute and functional iron deficiency anemia among different tumors in cancer patients in South Part of Iran, 2014 Int J Hematol Oncol Stem Cell Res 11 3 2017 192 198 28989585 PMC5625469

11 Osmola M. Gierej B. Mleczko-Sanecka K. Anemia, iron deficiency, and iron regulators in pancreatic ductal adenocarcinoma patients: a comprehensive analysis Curr Oncol 30 8 2023 7722 7739 37623041 10.3390/curroncol30080560 PMC10453218

12 Făgărășan V. Andraș D. Amarinei G. Absolute and functional iron deficiency in colon cancer: a Cohort study Medicina (Kaunas) 58 9 2022 1202 36143875 10.3390/medicina58091202 PMC9505715

13 Neoh K. Stanworth S. Pasricha S.R. Bennett M.I. Estimating prevalence of functional iron deficiency anaemia in advanced cancer Support Care Cancer 25 4 2017 1209 1214 27900547 10.1007/s00520-016-3511-9

14 Birgegard G. Samuelsson J. Ahlstrand E. Inflammatory functional iron deficiency common in myelofibrosis, contributes to anaemia and impairs quality of life. From the Nordic MPN study Group Eur J Haematol 102 3 2019 235 240 30472746 10.1111/ejh.13198

15 Luporsi E. Turpin A. Massard V. Iron deficiency in patients with cancer: a prospective cross-sectional study BMJ Support Palliat Care 14 2 2024 215 221 10.1136/bmjspcare-2021-002913 34330792

16 Tisserand J. Randrian V. Paccalin M. Association between iron deficiency and survival in older patients with cancer Cancers 15 5 2023 1533 36900329 10.3390/cancers15051533 PMC10000607

17 Yellen S.B. Cella D.F. Webster K. Blendowski C. Kaplan E. Measuring fatigue and other anemia-related symptoms with the Functional Assessment of Cancer Therapy (FACT) measurement system J Pain Symptom Manage 13 2 1997 63 74 9095563 10.1016/s0885-3924(96)00274-6

18 Castelo-Branco L. Pellat A. Martins-Branco D. ESMO guidance for reporting oncology real-world evidence (GROW) Ann Oncol 34 12 2023 1097 1112 37848160 10.1016/j.annonc.2023.10.001

19 Tawfik Y.M.K. Billingsley H. Bhatt A.S. Absolute and functional iron deficiency in the US, 2017-2020 JAMA Netw Open 7 9 2024 e2433126 10.1001/jamanetworkopen.2024.33126 PMC11423176 39316402

20 Toledano A. Luporsi E. Morere J.F. Clinical use of ferric carboxymaltose in patients with solid tumours or haematological malignancies in France Support Care Cancer 24 1 2016 67 75 25921449 10.1007/s00520-015-2728-3

21 Steinmetz T. Tschechne B. Harlin O. Clinical experience with ferric carboxymaltose in the treatment of cancer- and chemotherapy-associated anaemia Ann Oncol 24 2 2013 475 482 23071262 10.1093/annonc/mds338 PMC3551483

22 Kim Y.T. Kim S.W. Yoon B.S. Effect of intravenously administered iron sucrose on the prevention of anemia in the cervical cancer patients treated with concurrent chemoradiotherapy Gynecol Oncol 105 1 2007 199 204 17234260 10.1016/j.ygyno.2006.11.014

23 Ganzoni A.M. Eisen-Dextran intravenös: therapeutische und experimentelle Möglichkeiten [Intravenous iron-dextran: therapeutic and experimental possibilities] Schweiz Med Wochenschr 100 7 1970 301 303 5413918

24 Gluszak C. de Vries-Brilland M. Seegers V. Impact of iron-deficiency management on quality of life in patients with cancer: a prospective cohort study (CAMARA Study) Oncologist 27 4 2022 328 333 35380718 10.1093/oncolo/oyac005 PMC8982399

25 Thong M.S.Y. van Noorden C.J.F. Steindorf K. Arndt V. Cancer-related fatigue: causes and current treatment options Curr Treat Options Oncol 21 2 2020 17 32025928 10.1007/s11864-020-0707-5 PMC8660748

26 Cacoub P. Vandewalle C. Peoc’h K. Using transferrin saturation as a diagnostic criterion for iron deficiency: a systematic review Crit Rev Clin Lab Sci 56 8 2019 526 532 31503510 10.1080/10408363.2019.1653820

Supplementary Material

Supplementary Material

Acknowledgements

The authors would like to thank the clinical research coordinators of the Clinical Trial Unit of Luzerner Kantonsspital Luzern, Luzern, Switzerland, for their support. Special thanks to Mrs. Gaby Fahrni for her continued assistance.

Funding

The work was supported by the Foundation Sangua Cura (no grant number), https://www.sanguacura.ch .

Disclosure

The authors have declared no conflicts of interest.

Data sharing

The data that support the findings of this study are available from the corresponding author upon reasonable request.