Intravenous iron and iron deficiency anemia in patients with gastrointestinal cancer: A systematic review

Background Iron deficiency anemia (IDA) is a prevalent hematological complication associated with gastrointestinal (GI) cancers due to an increased loss of iron and decreased iron absorption. The purpose of this systematic review is to evaluate the use of parenteral iron to treat IDA in patients with GI cancer. Methods PubMed, Cochrane, EMBASE, CINHAL and Scopus were searched from January 1, 2010 to September 29, 2023 with no language restrictions. We excluded editorials, case reports, abstracts, conference papers, and poster presentations. Studies were included if they discussed IDA, GI neoplasms, use of iron supplementation (with or without erythropoietin-stimulating agents [ESAs]), defined anemia and had an adult patient population. We assessed the efficacy of parenteral iron in comparison to other iron supplementation methods when treating IDA in patients with GI cancer. The Cochrane Risk of Bias Tool 2 (RoB 2) and the Risk Of Bias In Non-randomized Studies of Interventions (ROBINS-I) assessment tools were used to assess the quality of the included studies. Moreover, the Cochrane Effective Practice and Organization data collection form was used to collect pertinent study information. Results Our search yielded 3,969 studies across all databases. Twenty-one studies were included (6 randomized control trials; 15 non-randomized studies). Of the 15 studies evaluating hemoglobin (Hb) response, seven studies found an increase in Hb levels when patients were treated with IV iron. The 14 studies evaluating red blood cell (RBC) transfusion rates found conflicting differences in RBC transfusion needs when treated with IV iron. Studies analyzing health related outcomes typically found an increase in quality of life and decreased post-operative complications. Discussion This review demonstrates improved outcomes of IDA in patients with GI cancer treated with IV iron instead of other iron supplementation methods. Timely diagnosis and appropriate IDA management can greatly improve quality of life in this patient population, especially if myelosuppressive chemotherapy is required.


Introduction
Luminal gastrointestinal (GI) cancers (i.e., cancers of the esophagus, stomach, large and small intestine) represent 26% of global cancer incidence, and 35% of all cancer-related deaths [1].A common hematological complication associated with luminal GI cancers both at diagnosis and during treatment is anemia, defined by the World Health Organization (WHO) as hemoglobin (Hb) of less than 12 g/dL in women, and less than 13 g/dL in men [2,3].The cause of anemia in cancer patients is multifactorial in nature, and can be attributed to comorbidities such as bleeding, hemolysis and nutritional deficiencies [4], such as iron deficiency.The prevalence of iron deficiency anemia (IDA; defined as anemia associated with iron deficiency) in patients with GI cancer ranges from 7% to 42% [5].
The etiology of IDA in patients with GI cancer can be attributed to increased loss of iron (i.e., bleeding) and decreased iron absorption [6].Systemic inflammation caused by GI malignancy can lead to increased levels of hepcidin, which in turn inhibits iron absorption in the GI tract and iron release from bodily stores [7].Cytokines associated with systemic inflammation characteristic of GI malignancy also directly inhibit erythropoietic activity, which in combination with poor iron absorption and release, may further worsen IDA [7,8].In addition, myelosuppressive chemotherapy and/or radiotherapy can impair normal hematopoiesis, decreasing systemic iron utilization, directly resulting in anemia [7,8].Ultimately, multiple factors contribute to IDA associated with GI cancer, contributing the overall difficulty of treating the condition in this patient population.
In patients with GI cancer, IDA is associated with increased risk of mortality, poor response to anticancer treatment, lower overall and progression free survival, fatigue, and poor quality of life (QoL) [9][10][11][12].Targeted treatment of anemia in patients can both improve prognosis and QoL [13].Common treatment approaches in this patient population include red blood cell (RBC) transfusions, erythropoietin stimulating agents (ESA) and iron supplementation.Despite available treatment options, approximately 60% of patients with anemia do not receive any treatment [2].Potential reasons for patient undertreatment may include -poor optimization of care across the patient journey, unclear guidelines, and inadequate testing for anemia and IDA [2].
Treatment of anemia with RBC transfusions should be used cautiously as use is associated with increased risk of morbidity and mortality in cancer patients [14].ESAs offer a means of reducing the need for RBC transfusions but only 30-75% of patients may respond to treatment and use may increase the risk of thromboembolic events [14].Furthermore, intravenous/parenteral (IV) iron alone or in combination with ESAs presents itself as an effective treatment for anemia, while also reducing the need for RBC transfusions [15].Oral iron supplementation is also commonly prescribed to address IDA in the cancer population; however, evidence suggests oral iron does not reduce the risk of RBC transfusion, most likely due to either malabsorption of oral iron, non-adherence, slow bioavailability and repletion [16].
The 2018 European Society for Medical Oncology (ESMO) clinical practice guidelines [17] recommend that RBC transfusions only be used in patients with severe anemia-related symptoms, and ESAs only be employed when patients undergoing chemotherapy have had their iron deficiency corrected.Additionally, the American Society of Clinical Oncology (ASCO)/ American Society of Hematology (ASH) recommends that ESAs be offered only to patients whose cancer treatment is not curative in intent and with Hb <10 g/dl [18].However, this recommendation is based on a lack of evidence indicating whether a particular patient population receiving ESAs is at greater or lesser risk of harm particularly in terms of progression/reoccurrence and overall survival [18].The current lack of specific guidelines leaves physicians without clear directives for treating IDA in patients with GI cancers.Moreover, the existing general guidelines [17,18] do not advise on the use of parenteral iron supplementation, with or without ESAs, nor do they address the appropriate timing for administering treatment to patients.In addition, existing systematic reviews predominantly focus on the use of parenteral iron supplementation for treating chemotherapy-induced anemia, and the addition of parenteral iron to ESAs in cancer patients more broadly [16,19,20].To our best knowledge, no systematic review exists to date, that examines the use of IV iron in patients with GI cancers with respect to when patients are being diagnosed with IDA, when they are being treated, how they are optimally treated, and the benefits of treatment.
Therefore, given the heightened prevalence of IDA in this patient population, the purpose of this systematic review is to evaluate the use of IV iron to treat IDA in patients with GI cancer.

Methods
This systematic review was performed following the Cochrane Training Handbook guidelines, as well as the Preferred Reporting for Systematic Reviews and Meta-Analyses (PRISMA) 2020 checklist [21,22].This review was not registered, and the review protocol is not available.

Search strategy
A search using the following databases: PubMed, Cochrane, EMBASE, CINHAL, and Scopus was conducted.The search terms included but were not limited to: "iron deficiency", "anemia", "gastric cancer", "ESA therapy*", "intravenous iron" and "iron studies".Randomized control trials (RCTs), systematic reviews, observational studies, case studies, and cohort studies, from January 2010 to September 2023, with no specified language restrictions were retrieved.Studies were excluded if they were editorials, case reports, abstracts, conference papers or poster presentations.

Study selection
Studies were reviewed if they included the following: 1) iron deficient anemia, 2) gastrointestinal neoplasms, 3) iron supplementation alone (i.e., intravenous iron or parenteral iron, oral iron) or in conjunction with ESAs, 4) defined anemia and the symptoms associated with anemia, and 5) an adult (� 18 years of age) population.Additionally, literature published before 2010 was excluded from this systematic review as the use of large dose, IV iron formulations like ferric carboxymaltose (FCM) and iron isomaltoside became readily available for the correction of anemia in 2010 [23].
The web-based software, Covidence TM , was used by two authors (SN and NS) to screen studies and extract data [24].A standardized eligibility checklist was used to screen the title, abstract and full-text of studies; removing ineligible studies throughout the process.Any conflicts that arose were discussed and resolved between the authors (SN and NS).

Data collection and quality assessment
The Cochrane Effective Practice and Organization data collection form was used to curate a standardized extraction sheet to collect the study information needed from each extracted article [21].
The Cochrane Risk of Bias Tool 2 (RoB 2) was used to assess risk of bias among eligible RCTs [25].RCTs were assessed and given an overall judgement of low risk-, some concerns-, or high risk of bias [25].Moreover, the Risk Of Bias In Non-randomized Studies of Interventions (ROBINS-I) tool was used to assess the quality of non-RCT studies [26].The non-RCT studies were given an overall judgement of low, moderate, serious, or critical risk of bias [26].The risk assessment for this study was completed individually by reviewers (SN and NS).Visualization of risk-of-bias assessments were generated using the robvis online tool [27].

Statistical analysis
Statistics used in the study were expressed as means, medians, standard deviations (SDs), interquartile ranges (IQRs), and 95% confidence intervals (CI) for any relevant study variables.

Results
Twenty-one studies published between January 1, 2010 and October 1, 2023 met the inclusion criteria and were included in the final analysis.A summary of the screening process can be found in Fig 1 .Of these studies, six RCTs compared IV iron supplementation to standard of care or compared two IV iron interventions to one another.The remaining 15 studies were of non-randomized design (10 retrospective, 5 prospective).
All studies included a comparator arm, except for Bojesen et al. [28], Lima et al. [29] and, Verhaeghe et al. [30] where all patients received IV iron.Of the RCTs, Keeler et al. [31], Keeler et al. [32], and Talboom et al. [33] compared ferric carboxymaltose (FCM) to oral iron, while Laso-Morales et al. [34] compared FCM to iron sucrose (IS), and Ng et al. [35] compared iron isomaltoside to standard of care.The comparator arms in 11 studies [36][37][38][39][40][41][42][43][44][45][46] were patients who received no specific treatment or oral iron.Of note, Quinn et al. [47] compared the efficacy of a new anemia management intervention in which patients were given FCM, and then retrospectively compared to pre-intervention patients.IV iron treatment was provided preoperatively in 17 studies and postoperatively in four studies.A complete summary of the studies can be found in Tables 1 and 2.

Quality assessment
Five of six randomized trials had a low risk of bias.Keeler et al. [32] had a high risk of bias as patients were not blinded to the study group that they were in.The complete quality assessment of the included RCTs can be found in Fig 2.
Of the 15 non-randomized studies, 11 studies had a 'Moderate' risk of bias, primarily attributable to appropriately controlled baseline confounding factors, missing data, deviations from intended interventions, and lack of information to assess bias within certain domains.Four studies had a 'Serious' risk of bias, likely due to the presence of confounding factors without appropriate statistical considerations, as well as a lack of information.A summary of the risk of bias assessment of non-randomized studies can be found in Fig 3.

Outcomes
Key outcomes were determined a priori after examination of relevant literature and considerations of the research question.Three key outcomes were identified: Hb response, RBC transfusion needs, and other applicable health outcomes (e.g., disease free survival (DFS), mortality, morbidity, overall survival (OS), quality of life (QoL), length of hospital stay (LOS), and safety/ adverse events).

Hemoglobin response
All RCTs except Keeler et al. [32], captured Hb response.Fung and colleagues [44] reported a mean difference of 6.1 g/dL (p = 0.040) when comparing patients with colorectal cancer (CRC) who received 20 mg/kg (up to 1000mg) of iron isomaltoside compared to patients who received standard care.Keeler et al. 2017 [31] reported a median increase in Hb of 1.55 g/dL (IQR; 0.93-2.58) in patients with CRC who received 1000 mg or 1500 mg of parenteral FCM at least 14 days prior to surgery compared to an increase of 0.5 g/dL (IQR; -0.13-1.33) in patients who received oral ferrous sulfate twice daily until surgery (p<0.001).In the investigation conducted by Laso-Morales et al. [34] patients with CRC either received a single 1000 mg dose of IV FCM on postoperative day two or 200 mg of IV Iron sucrose every 48 hours from postoperative day two to discharge.Patients with esophagogastric adenocarcinoma in the investigation conducted by Ng et al. [35] received a single 1000 mg dose of iron isomaltoside prior to the initiation of chemotherapy or received standard of care.Laso-Morales et al. [34], Ng et al. [35], and Talboom et al. [33] found no significant differences in Hb levels between the intervention and comparator groups.Of the 15 non-randomized studies, 11 studies assessed serum Hb levels.Bojesen et al. [28] reported a mean increase in Hb of 2.13 g/dL (95% CI: 1.71-2.55g/dL; p<0.0001) after four weeks in patients with CRC who received iron isomaltoside prior to surgery.In addition, Lima et al. [29] reported an absolute increase in mean Hb of 0.9 g/dL (SD 1.3) from baseline to 12-14 weeks (p = 0.001) in patients with CRC who received 1000 mg of IV FCM every study visit (12-13 weeks) until anemia or ID was corrected.In contrast, Verhaeghe et al. [30] reported no significant increase in Hb in patients with GI malignancies who received at least one dose of IV FCM preoperatively after a four week follow up period [30].
Two studies comparing IV iron to oral iron reported an increase in Hb.Calleja et al. [36] reported a greater increase in Hb in patients with colon cancer who received IV FCM (median dose of 1000 mg given 28.5 days preoperatively) compared to patients who received varying doses and formulations of oral iron (1.5 g/dL vs. 0.5 g/dL; p<0.0001) between diagnosis of anemia and hospital admission for surgery, and between diagnosis and 30 days postoperatively (3.1 g/dL vs. 1.5 g/dL; p<0.0001).In addition, the percentage of patients with Hb<10 g/dL was significantly lower in the intervention group at hospital discharge (61.6% vs. 75.7%,p<0.05) compared to the oral iron group (36).Laso-Morales et al. [48] reported a greater increase in Hb in patients with CRC who received IV iron sucrose of varying dose compared to patients who received oral elemental iron (2.0±1.5 g/dL vs. 1.1±1.2g/dL; p = 0.001) from postoperative day one to postoperative day 30.However, the prevalence of anemia was greater and more severe in the IV iron group (p = 0.027) [48].
Jeong et al. [37], Kam et al. [38], Quinn et al. [47], Titos-Acros [40], Ploug et al. 2022 [46], Ploug et al. 2023 [45], and Wilson et al. [41] compared IV iron to no specific treatment or standard of care.Jeong and colleagues [37] observed a mean increase of Hb of 3.2 g/dL in patients with gastric carcinoma who received IV iron sucrose every other day in 300 mg doses until total target dosage was given (target dosage calculation can be found in Table 1) compared to an increase of 2.5 g/dL in the no specific treatment group (p = 0.029) six months post-operatively (treatment was initiated post-operatively).Kam et al. [38], and Ploug et al. 2022 [46] reported no difference in mean preoperative Hb levels in patients with CRC who received IV iron or no specific treatment.However, the IV iron groups had a higher median Hb rise of 1.9 g/dL vs. a rise of 0.6 g/dL in the no specific treatment group (p<0.001).In addition, Quinn et al. [47] reported that mean Hb levels were significantly lower in patients with CRC with uncorrected anemia (no treatment or oral iron) compared to patients with corrected anemia (received 1000 mg of IV FCM) on postoperative day three (9.5 g/dL vs. 10.9 g/dL, p = 0.004).Titos-Acros [40] reported mean Hb at discharge was lower in patients with colon cancer who received 100-200 mg of IV iron saccharose postoperatively, compared to those who did not (10±1.1 g/dL, vs. 10.6±1.2 g/dL; p = 0.012).Furthermore, Wilson and colleagues [42] reported that patients treated with 1000-2000 mg of IV FCM or IV maltoside less than 6 weeks preoperatively had a significant increase in Hb compared to the usual care group (1.05 g/dL vs. 0.16 g/ dL; p<0.001).

RBC transfusion needs
Five randomized studies reported changes in RBC transfusion needs.Four studies, Fung et al. [44], Keeler et al. [31], Ng et al. [35], and Talboom et al. [33] reported no significant differences in blood transfusion needs between IV iron and standard of care.Laso-Morales et al. [34] also reported no significant differences in RBC transfusion needs in patients with CRC.However, it is important to note that this study compared two different IV iron products.
Six non-randomized studies reported changes in RBC transfusion needs.Of the studies that compared IV iron supplementation to oral iron supplementation, Calleja et al. [36] reported that patients in the IV iron group required less RBC transfusions when compared to patients in the oral iron group (9.9% vs. 38.7%;OR: 5.9.95% CI: 2.9-11.1,p<0.001).In contrast, Laso-Morales et al. [48] reported higher transfusion needs in the IV iron group compared to the oral iron comparator group (15% vs. 4%, p = 0.040), however, the prevalence and severity of anemia (as indicated by Hb levels on day of surgery) were higher amongst those in the IV iron group.Furthermore, Quinn et al. [47] reported that prior to the introduction of the anemia management intervention, patients with anemia were 17 times more likely to require perioperative RBC transfusions.In addition, postoperative RBC transfusion rates were 38% in patients who received oral iron or no specific treatment, compared to 0% in patients whose anemia had been corrected by IV iron, and 3.5% in patients without anemia [47].Kangaspunta et al. [43], Ploug et al. [46], Titos-Acros [40] reported no difference in RBC transfusion needs between the IV iron group and no IV iron group in their investigations.

Hb levels
The mean Hb change from baseline to before surgery was higher in the IV iron group than the control group (mean difference of 6.1 g/dL, p = 0.040) IV iron had significant impacts on the perioperative changes of Hb, ferritin, and TSAT concentrations in IDA patients with colorectal cancer

Blood transfusion rates
The number of patients needing RBC transfusions during the perioperative period was 2 in the IV iron group and 6 in the control group (p = 0.235)

Iron parameters (Serum ferritin, TSAT)
Ferritin level changes from baseline to before surgery was largely in favour of the IV iron group (mean difference of 296.9 μg/L, P<0.001) The TSAT concentration was higher in the IV iron group compared to the control group with a mean difference of 4.8% (P<0.001)

Postoperative complications
There was no differencein grade of complication severity between groups from recruitment to outpatients (P = 0�995) or in complication rate over the same period (P = 0�305).The same was true for grade (P = 0�083) and rate (P = 0�091) of infective complications.

Postoperative length of hospital stay
Postoperative length of hospital stay was 6 days for both groups (IQR 4-9 and 5-10 days for oral and intravenous groups respectively; P = 0�950) Serum TSAT, ferritin, and hematocrit levels were similar at baseline but significantly higher in the IV iron group at day of admission and postoperative timepoints

Postoperative complications
The postoperative cumulative complication rate at 6 months was not statistically significant with 48% in the IV iron group and 57% in the oral iron group (p = 0.22)

Postoperative length of hospital stay
There was no difference in the total length of stay between IV iron and oral iron groups (p = 0.55)
No difference in serum iron was found between poor responders and responders at week 1, 2 or 4

Postoperative complications
Twenty-one patients (34%) developed a postoperative complication within the first 30 days after surgery.Not responding sufficiently to treatment was associated with higher baseline Hb (P = 0.049) and lower body mass index (P = 0.036) but did not remain significant after correction for multiple testing.

Postoperative length of hospital stay
The median length of stay was 3 days (IQR 3-6 days, range 1-36 days).

Kam, 2020
IV IS OR IV iron isomaltoside vs.
No iron therapy Hb <10 g/dL Hb <12 g/dL after recent transfusion

Hb levels
No statistically significant difference in mean preoperative Hb level between two groups.IV iron group had a higher median Hb rise of 1.9 g/dL vs. 0.6 g/dL in non-IV iron (P<0.001).
Patients with severe anemia (Hb<9.02g/dL) had the largest increase in Hb after 4 weeks.
IV iron can significantly increase Hb levels in IDA patients before colorectal surgery and reduce RBC transfusions.

Blood Transfusion Rates
8 patients in the IV iron group required blood transfusion compared to 30 in the non-IV iron group (P = 0.006).

Blood Transfusion Rates
No significant difference in number of patients with red blood cell transfusion prior to IV iron (42.1% in IV iron and 41.9% in non-IV iron, p = 0.987) Laso-Morales, 2017 IV IS OR IV FCM vs.Oral iron or no iron Hb<13 g/dL for all patients

Postoperative complications
There was no difference in RBCT rates between patients with anemia on IV iron and those on standard care (16% vs. 17%; p50.865).
IV iron was more effective in treating preoperative anemia and reducing infection rate than standard of care Infection rates were lower among IV iron treated patients (18% vs. 29%; p<0.05).IV iron did not reduce postoperative blood transfusions but was more effective than standard care in treating preoperative anemia.

Postoperative length of hospital stay
No significant differences in length of stay (Continued ) IDA management pathway resulted in improved perioperative Hb levels with reduction in perioperative transfusion.

Blood Transfusion Rates
Postoperative transfusion rates were 38% in patients with uncorrected anemia, compared to 0% in corrected anemia and 3.5% in patients who were non-anemic.

Postoperative complications
There were seven postoperative transfusions in the entire cohort: two in patients who were non-anemic (3.5% transfusion rate), two in patients with iron deficiency (13% transfusion rate) and three in patients with uncorrected anemia from other causes (a 50% transfusion rate).

Postoperative length of hospital stay
The difference in length of stay between patients with corrected anemia and patients who were nonanemic was non-significant (p = 0.472).

Iron deficiency rates
Treatment resulted in a preoperative IDA correction rate of 60% (nine of fifteen).Based on the findings, the median increase in Hb over a 28-day period was 0.5 g/dL.This is not a significant difference but may be due to the inadequate dosing schemes.The response to IV iron depends on the

Patient health related outcomes
Four randomized studies collected data on patient health related outcomes.Laso-Morales et al. [34] reported no significant differences between LOS between the IV FCM group and the IV IS group, but did note that the infection rate was lower in the IV FCM group (9.8% vs. 37.2%).Ng et al. [35] reported a marked increase in QoL parameters such as physical and emotional well-being, as well as anemia-specific QoL, with total scores for these indices exceeding the minimum clinically important difference (defined as a difference of one standard deviation from baseline), while no improvement was reported in patients receiving standard of care.In addition, Keeler et al. [32] reported that 11 QoL components (e.g., physical and functional well-being, self-care, pain and disability, general health, etc.) increased by a clinically significant margin in the IV iron group, compared to only one component showing an increase in the oral iron group.Furthermore, patients in the IV iron group had higher median total scores (168, IQR:160-174 vs. 151, IQR:132-170) in the FACT-An than the oral iron group at the time of the outpatient appointment (2-3 months postoperatively) [.] Talboom et al. [33] reported no significant differences in postoperative complications and LOS between patients with CRC who received treatment with IV iron compared to patients receiving oral iron.Eight non-randomized studies captured data on various health outcomes.Calleja et al. [36] reported that the IV iron group had a significantly shorter mean length of hospital stay compared to the no-IV iron group (8.4±6.8 days vs. 10.9±12.4days; p<0.001).In addition, Calleja and colleagues [36] reported no adverse events (e.g., deaths, hypersensitivity, or other serious reactions) and there was no difference in post-surgical complications (e.g., suture dehiscence, paralytic ileus, hemoperitoneum, rectal bleeding, thromboembolism, etc.) at 30 days postoperatively [36].Kangaspunta et al. [43] reported that patients with colon cancer treated up to 60 days preoperatively with 500-1000 mg of IV FCM had less post-operative complications (33.9% vs. 45.9%,p = 0.045), and no difference in LOS, 30-and 90-day mortality between the two groups.Laso-Morales et al. [48] reported no significant differences in postoperative infections, LOS, and complication rates between the two groups, but did report a significantly lower rate of postoperative infection in patients receiving IV iron compared to standard care patients (18% vs. 29%; p = 0.018).Ploug et al. 2022 [46] reported higher rates of surgical complications (25% vs. 8%; p = 0.01) in patients with CRC who received IV iron isomaltoside compared to patients who did not receive IV iron treatment.Ploug et al. 2022 [46] also reported no significant difference in LOS (p = 0.74) between the treatment and control group in their investigation.Quinn et al. [47] reported morbidity rates as similar across all groups, but did not provide the data.In addition, LOS was longer for patients with uncorrected anemia compared to patients with corrected anemia (13.2 days vs. 7.2 days; p = 0.019) (47).Wilson et al. [41] treated patients with CRC with 1000-2000 mg of IV FCM or iron (III) maltoside and found no significant difference in 1-, 3-, and 5-year OS between the IV iron and non-IV iron groups.Ploug et al. 2023 [45] reported that five-year recurrence of CRC was 13.5% in the IV iron group vs. 16.7% in the control group, and found that postoperative mortality rates (5 year follow up period) was 13.5% in the IV iron group compared to 2.8% in the control group, but, these claims were not tested for statistical significance.

Discussion
Each included study was used to draw conclusions about the following key findings: Hb levels, RBC transfusion needs, iron parameters and patient QoL.Sixteen studies included in this review evaluated Hb response among patient populations at varying timepoints.Five studies found no significant difference in Hb levels between the IV iron groups and the comparator groups whereas ten studies found a statistically significant increase in Hb levels among the groups receiving IV iron treatment.In contrast, one study reported lower mean Hb levels at discharge among patients with colon cancer receiving IV iron treatment when compared to the group receiving usual care [40].Titos-Arcos et al., suggest that this finding is due to bone marrow in patients physiologically requiring more time to increase Hb levels postoperatively [40].
Eleven studies assessed the need for RBC transfusion in patients receiving IV iron compared to those receiving standard care.Two studies found a significant decrease in blood transfusion rates in groups receiving IV iron.In contrast, one study expected no significant differences in RBC transfusion rates between the study groups due to the use of two forms of active iron treatment, which would influence the need for blood transfusions [34].The other eight studies found no significant difference in transfusion rates between study groups, despite increases in Hb levels in IV iron treatment groups.Keeler et al. explain this outcome as an insufficient duration of preoperative IV iron therapy which could resultantly influence transfusion rates [31].Moreover, Ploug et al. found that 75% of RBC transfusions given to patients during the duration of the study were delivered in patients with Hb levels above the amount outlined in the transfusion guidelines, suggesting the need for more restrictive transfusion practices to avoid unnecessary RBCTs [46].Other studies found no significant difference in RBC transfusion rates due to discrepancies at recruitment in which the need for transfusion was already low at recruitment among the groups or comparator arms had higher preoperative Hb levels, reducing the need for transfusions.Further research should address these limitations and have transfusion rates as a primary endpoint to produce more definitive findings on RBC transfusions.
A total of twelve studies analyzed a variety of patient health outcomes.Across these studies, findings generally revealed no significant difference in LOS, post-operative complications, and OS between IV iron groups and control groups.Two RCT studies measured an increase in QoL in the groups receiving IV iron treatment and two non-randomized studies revealed a decrease in post-operative infections in IV iron groups.Ploug et al., found higher rates of surgical complications in the group receiving IV iron treatment however, the two groups had similar OS and LOS rates.
A systematic review by Jones et al. reveals an improvement in Hb levels when patients with anemia who had surgery are treated with IV FCM [49].All 10 RCT studies analyzed in the review found an improvement in Hb concentration from baseline to the end of the study in both the preoperative FCM (Hb concentration increase from 1.3 g/dL to 4.7 g/dL) and postoperative FCM setting (Hb concentration increase from 1.7 g/dL to 3.2 g/dL) (49).Moreover, a retrospective study by Cancado et al., evaluated the effects of administering IV iron sucrose (IS) infusions in an IDA (as defined by WHO guidelines) patient population by providing patients with a weekly dose of 200 mg IS until patients received a total iron dose (calculated by weight and Hb levels of the patient) or when they had a Hb concentration of greater than 14.0 g/dL [50].Hb concentration in patients increased significantly between the baseline and end of study (Mean change: 3.29 g/dL (women) and 4.58 g/dL (men)) [50].These results coincide with the findings of this review as most of the studies show a significant increase in Hb levels in patients receiving IV iron treatment opposed to other iron supplementation methods.These findings reveal the strong efficacy of IV iron in effectively increasing Hb levels in patients with IDA.
Hallet et al. systematically reviewed four studies to assess the effects of perioperative iron supplementation on RBC transfusion needs in patients undergoing elective GI surgeries [51].The study found that although fewer patients required transfusions when given iron supplementation, the observations were statistically insignificant [51].However, the findings of their systematic review may be underpowered, as the results were based on four studies with small sample sizes which may not provide an accurate effect estimate of iron supplementation [51].Based on our systematic review findings, most studies that evaluated RBC transfusion rates as an outcome of interest found no significant difference between groups.However, a multicenter cohort study by Calleja et al. found that patients in the group receiving IV FCM (n = 111) needed less RBC transfusions than patients receiving oral iron supplementation (n = 155) (OR: 5.9, 95% CI: 2.9-11.1,p<0.001) [36].Therefore, additional studies need to be conducted to assess the impact of IV iron and comparator iron types on blood transfusion rates to validate and strengthen the current evidence available.Furthermore, valid clinical endpoints, such as Hb rise, effective iron repletion, less RBC transfusion, morbidity, QoL and hospital length of stay for inpatient assessments, should be assessed in these studies.
Iron parameters were another key factor explored in studies evaluating the efficacy of IV iron treatment in IDA correction.Jones et al. found that in the preoperative setting, IV iron intervention revealed a 15-35% increase in TSAT levels from baseline and an increase in serum ferritin levels from 19 μg/L at baseline to 229-558 μg/L [49].Additionally, they found that in the postoperative setting, there was a 7.2-20% increase in TSAT and a serum ferritin increase from 19 μg/L to 114-571 μg/L [49].In our review, seven studies assessed iron parameters (serum ferritin and TSAT) to evaluate the difference in these biomarkers after treating patients with IV iron.All studies found a statistically significant increase in ferritin and TSAT levels of patients receiving IV iron compared to comparator groups.However, a limitation to these study findings is the use of serum ferritin as an indicator IDA improvement in cancer patients.Ferritin levels are found to be elevated in the cancer patient population due to the cancer's inflammatory nature [52].The elevated levels of serum ferritin in cancer patients could be due to the abnormal production and release of ferritin from tumour cells [53].Thus, the sensitivity of ferritin as a prognostic value for iron deficiency is low and studies should refrain from using this parameter as an indicator of iron levels in cancer patients.
QoL is an important factor that is often overlooked when treating IDA and assessing patient performance in an oncology population [36].A review written by Strauss and Auerbach evaluated the importance of using validated patient reported outcome tools (FACT measurement system) to assess QoL [34].They found IV iron (IV ferric gluconate) to be the most effective treatment for IDA in cancer patients which resulted in an improvement in patient FACT scores [34].One RCT assessed in their review by Henry et al. looked at the impact of IV iron on FACT-Fatigue scores in patients with anemia receiving chemotherapy [36].All patients in the trial received epoetin alfa once a week for four weeks, then an adjusted dose based on their protocol [36].These patients were randomized into three groups: no iron (ESA alone), oral iron sulfate with ESA, or IV ferric gluconate with ESA [36].Researchers found that patients receiving IV ferric gluconate reported a significant improvement in the FACT-Fatigue scale (MID = 3) compared to patients receiving oral iron or no iron [36].In our systematic review, we found that the information on QoL specifically in patients with GI cancer was limited.Only two studies evaluated QoL as an outcome of interest.Keeler et al., found that the QoL Fact-An scores were higher in patients receiving IV iron compared to oral iron (FACT-An total score (oral iron 151 (132-170 [69-183]); IV iron 168 (160-174 [125-186]); p = 0.005))) [32].However, these conclusions may not be meaningful due to the small sample size (n = 116) of the study [32].More QoL research should be conducted in the GI cancer population to gain a stronger understanding of QoL improvement when given iron supplementation.
The strengths of this systematic review include the comprehensive and inclusive search strategy that was approved by an oncologist specializing in GI cancers, as well as a hematologist.This review assessed a total of 2,363 studies across five databases with no restrictions to language or publication types.Two authors (SN and NS) independently screened the eligibility of each of the studies to minimize selection bias.Moreover, the two authors (SN and NS) conducted separate data extractions for studies that passed the initial screening phase to ensure all pertinent information was collected and all studies followed the eligibility criteria of the review.Furthermore, the quality of both RCTs and non-RCTs were assessed using Cochrane's RoB 2 and ROBINS-I tools.The risk assessment revealed the limitations of the studies included in this systematic review and helped curate a thorough understanding of the missing findings in current publications.
This systematic review presents some limitations.Due to the varying interventions, comparators, populations, clinical endpoints, iron formulation, dosing schemes and settings evaluated in each RCT, the results of the review produced heterogeneous findings and thus, made it difficult to conduct a meta-analysis.Additionally, the studies assessed in this review used different time points of data collection, included patients undergoing different surgical approaches, and different cancer types, making it difficult to make valid comparisons between findings.Some studies also assessed outcomes that did not provide meaningful conclusions, such as the use of serum ferritin as a prognostic parameter in this patient population.Moreover, majority of studies in this review were potentially underpowered due to their small sample sizes.This review was not registered through PROSPERO or any other systematic review database, which is an additional limitation.
Overall, to strengthen the findings in this field, research should be conducted using larger sample sizes to validate findings prior to making conclusive statements on the efficacy of the intervention being used.Additionally, research evaluating the efficacy of IV iron should use iron parameters that are solely influenced by iron intake in patients with IDA (eg.Hb levels, RBC transfusion rates, serum iron, and TSAT) to ensure findings are resultant of the type of iron patients receive opposed to co-factors such as chemotherapy.More studies should also follow patients for a longer duration of time to assess the long-term impacts of IV iron on QoL and other important outcomes such as survival in this patient population.Another important consideration future researchers should incorporate in their research is the drug availability of IV iron compared to oral iron and how physicians can implement an IV iron infusion center in a feasible manner, especially as there are newer IV iron formulations (e.g., ferric derisomaltose) requiring shorter infusion times.
The findings of this systematic review reveal the importance of addressing the prevalence of IDA in a GI oncology patient population.Patients should receive timely diagnosis and management of ID prior to undergoing cancer treatments to avoid postoperative complications related to anemia, including myelosuppressive chemotherapy dose reductions, and to improve overall QoL.More research in this field will help create an international set of guidelines to ensure best clinical practices to improve IDA in patients with GI malignancies.