A prospective study of intravenous iron effectiveness on quality of life and functional outcomes in patients with cancer.

Introduction
Anemia is defined as a reduction in circulating erythrocytes or hemoglobin concentration below established thresholds1. The incidence and prevalence of anemia among cancer patients are high, ranging from 13% at diagnosis to nearly 67% during chemotherapy, as reported by the European Cancer Anemia Survey2. In addition, about 13% of initially non-anemic patients may develop anemia during the course of therapy3. While multiple etiologies contribute to cancer-related anemia (CRA), including anemia of chronic disease and treatment-related marrow suppression, iron deficiency (ID) is recognized as a frequent and potentially correctable cause4,5. Indeed, ID has been identified as a major contributor to CRA, particularly in low- and middle-income settings6, and is associated with impaired performance status and poor prognosis7.
CRA adversely affects patients’ functional capacity and quality of life (QoL), with hemoglobin levels below 12 g/dL being closely linked to fatigue, reduced physical activity, and decreased daily functioning8,9. The burden of anemia includes a wide range of symptoms: fatigue, lethargy, dyspnea, anorexia, and impaired concentration, which markedly limit patients’ ability to engage in physical and social activities10,11. It was also reported that even in the absence of anemia, ID can also cause these symptoms12. Iron, a vital micronutrient, underpins a variety of critical physiological functions, particularly those related to oxygen (O₂) delivery and utilization. Beyond its role in erythropoiesis, iron acts as a cofactor for a range of enzymes, playing a crucial role in cellular respiration, oxidative phosphorylation, nitric oxide pathway, and the citric acid cycle. Depleted iron impacts mitochondrial function, leading to energy production inefficiencies. Furthermore, it can result in aberrations in sarcomere structure, compromising muscle contractility13–17. So, reduced exercise tolerance and cardiorespiratory compromises are also well-known consequences of ID2.
Regarding these, correcting iron status would be of clinical importance by means of functional status and hence QoL in patients with cancer. A recent systematic review confirmed that FCM is effective and well tolerated, offering advantages over iron sucrose by enabling rapid hemoglobin and ferritin improvement with the convenience of delivering higher iron doses in fewer infusions18. However, to the best of our knowledge, there is no study to assess QoL and cardiorespiratory fitness in cancer patients with ID who underwent iron supplementation before and after. Therefore, we aimed to assess and investigate potential associations between QoL and the functional status of patients with ID. We hypothesized that patients’ physical performance would be greater after iron supplementation compared to their baseline values.

Methods

Study design
This study was designed as a prospective observational study. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guideline was followed in reporting19. This study was held between March and October 2023. All procedures and measurements in this study were performed according to the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Ethical approval was granted by Bakircay University Ethical Board of Clinical Studies with the 2023/939 protocol number before the enrollment of patients. Informed consent was obtained from each patient prior to participation in this study.

Patients
Patients who were candidates for iron supplementation and suffered from ID were screened and invited to participate in this study. The inclusion criteria were set as follows: Being a volunteer to participate, having suffered from ID according to the Hemoglobin (Hb) and iron levels, and being a candidate for intravenous iron replacement (IR). ID was defined as ferritin < 30 µg/L and/or transferrin saturation (TSAT) < 20%; in the presence of inflammation, ferritin < 100 µg/L with TSAT < 20% was considered functional ID4,5. Anemia was defined according to WHO criteria as hemoglobin < 13.0 g/dL in men and < 12.0 g/dL in women20. Detailed medical histories, including previous iron therapies and underlying health conditions, were taken into account to evaluate the eligibility of the participants. Exclusion criteria were set as having mental/cognitive deficits, a higher comorbidity index, underlying factors causing anemia, not having independent ambulation skills, advanced restrictive/obstructive pulmonary problems, or unstable angina, and having no communication skills in the Turkish language.
Patients did not receive any specific instructions regarding daily walking duration, step count, or exercise prescription during the follow-up period; physical activity habits were not modified as part of the study protocol.

Iron replacement
Ferric Carboxymaltose (FCM) was administered according to a standard fixed-dose regimen recommended in the product guidelines and international practice. Specifically, patients with hemoglobin < 10 g/dL received 2,000 mg, while those with hemoglobin ≥ 10 g/dL received 1000 mg. These fixed doses were selected instead of the Ganzoni formula, which was not applied in this study. In our hospital’s routine clinical workflow, patients with ID anemia are referred for FCM replacement by the treating clinicians, and the administration follows a standardized protocol. Accordingly, this study was observational in nature, and no intervention outside routine practice was performed. FCM was prepared by diluting the appropriate dose in a sterile 0.9% sodium chloride solution under aseptic conditions, with a final concentration not exceeding 2 mg/mL. Patients were monitored for any adverse reactions throughout the infusion and for a minimum of 30 min post-infusion. Preparation and administration were carried out by nurses according to standard protocols and manufacturer recommendations, while the investigators only recorded the relevant safety data. All adverse events were recorded and reported as per the study protocol. Patients underwent follow-up assessments to monitor the response to FCM treatment. Hematological parameters, including hemoglobin levels, ferritin, transferrin saturation, and mean corpuscular volume (MCV), were measured at regular intervals post-infusion. For study analyses, follow-up blood samples were obtained 4–6 weeks after the first dose of IV iron supplementation, a timeframe chosen to allow for a clinically meaningful hemoglobin increase. The efficacy of FCM in correcting ID and improving anemia-related parameters was assessed.

Quality of life
The quality of life (QoL) of patients was measured via the Short Form 36 (SF-36). It consists of a total of 36 items, each of which should be scored according to the Likert scale. It was developed by Ware et al.21. Its reliability and validity among cancer patients were reported to be suitable among Turkish cancer survivors22. Physical functioning, role limitations due to physical and emotional problems, mental health, general health perception, bodily pain, social functioning, and vitality health concepts are reported to be assessed via SF-36. The higher score represents better QoL or vice versa. Baseline SF-36 and six-minute walk test (6MWT) assessments were performed prior to the first dose of IV iron replacement. Follow-up assessments were scheduled 4–6 weeks after the first infusion, depending on the patient’s hemoglobin level. Patients assessed outside this time frame (< 4 or > 6 weeks), as well as those who missed the scheduled follow-up despite having baseline data, were excluded from the study.

Cardiorespiratory fitness
The 6MWT was used to evaluate cardiorespiratory fitness according to the American Thoracic Society Guideline23. Briefly, a 30-m indoor corridor setting was established. Each patient was informed before the test that they walk as fast as they could for six minutes. The Pulse oximeter (Nonin Medical, Model 2500, Plymouth, USA) was used to measure vital signs such as heart rate and saturation. Subjective dyspnea and perceived fatigue were evaluated using the Modified Borg Scale (0–10), a validated measure of exertional symptoms24 which has also been applied in Turkish clinical populations25. Subjective dyspnea and perceived fatigue were assessed during the six-minute walk test using the Modified Borg Scale in accordance with standard 6MWT procedures. However, these measures were collected primarily for safety monitoring and assessment of acute exertional responses and were not predefined as formal study endpoints. Given their effort-dependent and transient nature, they were not included in the longitudinal outcome analyses. An oral command was given during the test, and each patient was monitored closely. They were also informed that they could stop or rest during the test when feeling bad. These tests were taken three times as follows: before, after, and during the recovery phase. The total walked distance (TWD) was recorded in meters. The reliability of the 6MWT among the cancer population was reported as 0.9326.

Endpoints
While the physical functioning and vitality (energy/fatigue) subscales of SF-36 are most directly related to the effects of iron metabolism disorders, these were chosen as primary endpoints. Secondary endpoints were hematological parameters, six-minute walking distance, and other subscales of SF-36.

Statistical analysis
The data was shown as means and standard deviation, or numbers and percentages, whether the data was continuous or categorical. The normality of the data was checked via the Kolmogorov-Smirnov test. A paired t-test or Wilcoxon signed rank test was used to analyze the data before and after iron supplementation, whether the data was distributed normally or not, respectively. Independent samples t-test or Mann-Whitney U test were used to compare two independent variables. A p-value was considered significant below 0.05. Statistical analyses were performed via IBM SPSS v.20 (IBM Corp, Armonk, USA). Given the observational design, several steps were taken to mitigate potential sources of bias. The study used a prospective within-subject pre–post comparison, thereby reducing inter-individual variability. Follow-up assessments were standardized to a narrow 4–6 week window after intravenous iron administration to minimize temporal confounding. Although patients were receiving concurrent oncologic treatments as part of routine care, no changes in anticancer therapy were initiated specifically for study purposes during the assessment period. Due to the limited sample size, multivariable adjustment was not performed; however, baseline clinical characteristics and treatment status were carefully documented to allow transparent interpretation of potential confounding effects. Given the exploratory nature of this prospective observational study, no formal a priori sample size calculation was performed. However, a post-hoc power analysis demonstrated sufficient statistical power (> 99%) for the primary endpoints (SF-36 physical functioning and vitality). However, the study was not specifically powered to detect changes in secondary endpoints such as the 6MWT. For secondary analyses, no formal adjustment for multiple comparisons was applied. This approach was chosen to avoid excessive type II error in a small, hypothesis-generating observational study. Patients with missing data were excluded from the final analysis. No imputation methods were applied, and analyses were conducted using a complete-case approach.

Results
Thirty patients were enrolled (Fig. 1). A post-hoc power analysis with means and standard deviations (57.5 ± 19.5 vs. 75.3 ± 17.3, correlation among repeated measures 0.712 for physical functioning; 49.6 ± 17.8 vs. 66.0 ± 16.1, correlation among repeated measures 0.738 for energy/fatigue), within 95% confidence interval, revealed > 99% power for both primary endpoints. Consequently, recruitment was stopped at 30 patients to use time and resources efficiently.

Baseline demographics and clinical characteristics are summarized in Table 1. The age range was broad (35–82 years; mean 57), with a near-equal gender distribution. The cohort was heterogeneous regarding tumor type and stage, with most patients having received multimodal treatment. The majority maintained good performance status (ECOG 0–1 in 73%), while 20% were at Stage 4. During follow-up, 33.3% experienced disease progression, more often metastatic (23.3%) than local (10%).

Most iron replacement occurred during the follow-up period (46.7%); others received it during chemotherapy, TKI, or immunotherapy. Iron studies showed low mean serum iron and transferrin saturation, along with low median ferritin, confirming ID. Distribution was non-parametric, with occasional very high ferritin values (e.g., 499 µg/L and 821 µg/L).
As shown in Table 2, variations in iron status parameters between microcytic and normocytic patients were subtle and not statistically significant, indicating uniform ID across subgroups.

Following intravenous iron replacement, hematological parameters and QoL scores improved significantly: hemoglobin, hematocrit, red blood cell count, MCV, and MCH all increased (p < 0.001), accompanied by a marked rise in ferritin and transferrin saturation. Functional outcomes (6MWT) showed modest but non-significant improvement in six-minute walk distance (p = 0.108). The same table also demonstrates significant gains in several SF-36 domains, particularly physical functioning (p < 0.001), energy/fatigue (p < 0.001), and emotional well-being (p = 0.008). Other domains improved numerically without statistical significance (Table 3).

Discussion
In this prospective cohort of cancer patients with ID, intravenous iron replacement led to significant gains in hematologic indices and in key QoL domains - particularly physical functioning and vitality -while the 6MWT showed only a non-significant trend toward improvement. These findings suggest that correcting ID can translate rapidly into better patient-reported outcomes, even when short-term objective exercise performance does not change. Recent inpatient feasibility work showed that a single 1000-mg dose of FCM increases hemoglobin in hospitalized cancer patients with ID, although patient-reported QoL endpoints were difficult to capture, underscoring the need for prospective ambulatory data focusing on QoL and function. Our findings not only align with this inpatient evidence of hemoglobin gains after single-dose FCM but also extend those observations by documenting early, clinically meaningful improvements in SF-36 physical functioning and vitality in an ambulatory cohort within 4–6 weeks27. To contextualize the clinical relevance of the observed changes, previous studies have suggested that a difference of approximately 5–10 points in SF-36 subscale scores represents a minimal clinically important difference (MCID) in chronic disease and oncology populations28. Grönkvist et al.29 also reported 2.62 to 4.69 points as MCID in SF-36 in patients with chronic pain. Therefore, it is plausible to conclude that the improvements observed in physical functioning and vitality in our sample exceeded those reported thresholds, supporting the clinical meaningfulness of these changes beyond statistical significance.
Comparable evidence has emerged in oncology populations. In the IVICA randomized trial of anaemic colorectal cancer patients, preoperative intravenous FCM led to greater increases in hemoglobin and clear improvements in multiple QoL domains compared with oral iron. Long-term follow-up of the same cohort demonstrated that these benefits translated into improved overall survival after surgery30,31. In palliative oncology settings, Yeung et al. reported that intravenous iron increased hemoglobin and reduced transfusion requirements by 55%, supporting its role as a feasible and effective alternative to blood transfusion in advanced cancer patients32. A systematic review focusing on patients with gastrointestinal malignancies also reported that parenteral iron improved anemia and, in some cases, led to enhanced QoL33. Consistent with these observations, Abdel-Razeq et al. demonstrated in a pilot study that IV iron monotherapy, even without concomitant ESA therapy, significantly increased hemoglobin and reduced transfusion needs in chemotherapy-treated cancer patients34. These findings reinforce and extend our results, underscoring that the benefits of intravenous iron extend beyond hematologic indices to clinically meaningful improvements in QoL. Similarly, the CAMARA prospective cohort showed that correction of ID in patients with mixed solid tumors improved both hematologic parameters and QoL10. Mechanistically, Koh and colleagues emphasized that transferrin saturation (TSAT) is the most reliable marker of functional ID in oncology and a pragmatic biomarker to guide intravenous iron use, with improvements in TSAT aligning with better clinical and QoL outcomes35. In a large, randomized trial, Bastit et al. demonstrated that in chemotherapy-induced anemia, adding IV iron to darbepoetin alfa significantly improved hematopoietic response rates and halved transfusion requirements compared with darbepoetin alone, without additional toxicity36. Similarly, Pedrazzoli et al. found that in chemotherapy-related anemia without baseline ID, the addition of IV iron to darbepoetin alfa significantly increased hematopoietic response and reduced transfusion requirements compared with darbepoetin alone, with no added safety concerns37. In contrast, Steensma et al. found no additional benefit of IV iron over oral or no iron when given together with darbepoetin alfa in chemotherapy-associated anemia, indicating that improvements in fatigue and QoL cannot be attributed to IV iron in that setting38. More recently, Noronha et al. showed that in chemotherapy patients not receiving erythropoiesis-stimulating agents (ESAs), IV iron was not superior to oral iron in hemoglobin or QoL outcomes39. Collectively, these studies indicate that the benefits of intravenous iron on fatigue and QoL are context dependent, more consistent in surgical and supportive care settings, while results in active chemotherapy populations are heterogeneous. Our outcomes (robust SF-36 improvement with a non-significant 6MWT change) fit within this pattern.
Beyond oncology, evidence from chronic heart failure, pulmonary hypertension, and COPD shows that intravenous iron improves exercise capacity, reduces hospitalizations, and enhances QoL13,16,17,40–43. Mechanistically, iron availability supports mitochondrial respiration and muscle contractility; deficiency impairs oxygen utilization and skeletal/cardiac performance13,16,17. These biological pathways likely explain the symptomatic improvements seen after iron repletion.
An important explanatory point is the relative sensitivity of outcome measures. Early after treatment, QoL metrics may capture symptomatic change sooner than field walking tests, which are influenced by treatment toxicity, deconditioning, and comorbidities. This is supported by a recent network meta-analysis by Liu et al., which analyzed 22 randomized controlled trials in surgical patients and concluded that assessment windows around 4–6 weeks are optimal for capturing both hemoglobin recovery and patient-reported improvements, whereas earlier functional tests, such as the 6MWT, may underestimate benefit44. Our protocolized follow-up at 4–6 weeks and the pattern of results (clear QoL gains; modest, non-significant 6MWT change) are consistent with these observations. In contrast, a universally accepted minimal clinically important difference for the six-minute walk test in oncology populations has not been firmly established. For instance, Cantarero-Villanueva et al.45 reported 54 m and 41.6 m total walked distance in patients with breast cancer during chemotherapy and after chemotherapy, respectively. Granger et al.46 reported 43 m as MCID in lung cancer patients, while Falz et al.47 reported 31 m in colorectal cancer patients. In other chronic conditions, MCID values ranging from approximately 20–50 m have also been proposed. Bohannon et al.48 reported 14–30 m change in total walked distance might be clinically meaningful in diverse pulmonary diseases. The modest, non-significant increase (467 m vs. 482 m; pre-FCMm and post-FCM, respectively) observed in our study did not reach these thresholds, which may reflect limited statistical power, short follow-up duration, or the influence of concurrent cancer therapies.
Iron indices also matter for interpretation. In inflammatory states typical of cancer care, ferritin may be elevated and insensitive to functional iron restriction, whereas transferrin saturation (TSAT) reflects iron immediately available for erythropoiesis and muscle metabolism4,5. Low TSAT is common in oncology and correlates with fatigue and activity limitation; improvement in TSAT with treatment aligns with better QoL10,11. Our cohort’s gains in SF-36 vitality and physical functioning are compatible with this pathophysiology.
Finally, our data emphasize that normal or high MCV does not exclude ID in cancer. We observed no significant differences in iron-status markers between microcytic and normocytic subgroups, underscoring the need to evaluate iron, TIBC, and TSAT alongside hemoglobin when CRA is suspected. Intravenous iron has been feasible and generally well tolerated in oncology cohorts, including studies of FCM given with or without ESAs, although results in chemotherapy contexts remain mixed and require tailored patient selection34,38,39,49.
The marked hemoglobin improvement in our cohort likely reflects the strict inclusion of patients with confirmed ID and administration of full replacement doses of FCM. Baseline hemoglobin was mostly in the mild-to-moderate anemia range, where IV iron typically elicits a rapid response if marrow reserve is intact. Although pre-existing ID before cancer could not be fully excluded, all patients had documented deficiency at study entry, underscoring the clinical relevance of our findings in the oncologic setting.
Several limitations should be acknowledged. First, the observational nature of the study without a parallel control group precludes causal inference regarding the effects of FCM. Although the prospective design and within-patient comparisons reduce some sources of bias, residual confounding—particularly from concurrent oncologic treatments such as chemotherapy, targeted therapy, or immunotherapy—cannot be fully excluded. Second, this study may have been underpowered to detect statistically significant changes in secondary endpoints, particularly the 6MWT. The absence of a significant difference in 6MWT distance should therefore be interpreted with caution, as it may reflect limited statistical power rather than a true lack of functional improvement. In addition, the heterogeneous nature of the cohort, including different cancer types, stages, and ongoing treatments, may have affected measurable effects on objective functional outcomes. In this regard, exploratory subgroup analyses were not performed due to the limited sample size and the risk of generating unstable or misleading results. Larger, adequately powered studies are required to evaluate potential differential effects across tumor types or disease stages. The follow-up interval of 4–6 weeks represents another limitation. While this timeframe is appropriate for capturing hematologic responses to intravenous iron, it does not allow assessment of the durability of quality-of-life or functional improvements. Longer follow-up periods would be necessary to determine whether these early gains are sustained over time and translate into longer-term functional or prognostic benefits. On the other hand, the absence of formal correction for multiple testing may increase the risk of type I error in secondary outcomes; therefore, these findings should be considered exploratory and interpreted accordingly. Nevertheless, the study reflects real-world supportive care practice, enhancing external validity. Future randomized controlled trials comparing intravenous iron with oral iron or no supplementation are required to confirm causality and to define optimal patient selection and timing relative to anticancer therapy. Limitations include a modest sample size, tumor-type heterogeneity, and potential variability in 6MWT performance relative to anticancer treatment timing. A longer follow-up would clarify durability and whether short-term QoL gains translate into functional or survival benefits, as suggested in IVICA31. In conclusion, intravenous iron replacement in cancer patients with ID produced clinically meaningful improvements in QoL and hematologic indices within 4–6 weeks. Future randomized studies should refine patient selection (with TSAT as a central biomarker), define optimal timing relative to oncologic therapy, and test longer-term effects on function, adherence, and outcomes.

Conclusion
In this prospective cohort of patients with cancer and ID anemia, IV iron replacement produced clinically meaningful improvements in hemoglobin and in QoL domains, particularly physical functioning and vitality within 4–6 weeks, while changes in six-minute walk distance showed only a non-significant trend. These data support routine assessment of iron status in oncology, with transferrin saturation as a pragmatic biomarker of functional ID, and consideration of intravenous iron as part of supportive care when appropriate. Larger randomized trials should confirm durability, quantify effects on objective functional capacity and survival, and optimize patient selection and timing relative to anticancer therapy.