Cancer-Related Anemia (CRA) is a common complication in cancer patients, with an incidence rate of 30%–90%. Its causes are complex, including tumor-related bleeding, chemotherapy-induced myelosuppression, iron utilization disorders caused by chronic inflammation, and iron deficiency due to malabsorption. Anemia not only reduces patients’ quality of life (e.g., fatigue, shortness of breath, impaired cognitive function) but also affects chemotherapy tolerance and tumor treatment outcomes. As an oral iron supplement, ferrous gluconate, with advantages of relatively low gastrointestinal irritation and stable bioavailability, plays an adjuvant role in correcting iron deficiency in CRA. It can be used alone or in combination with erythropoiesis-stimulating agents (ESAs) to improve iron stores, increase hemoglobin levels, and support tumor treatment. This article systematically analyzes its core value in the adjuvant treatment of CRA from aspects of mechanism of action, applicable scenarios, administration protocols, and safety management.

I. Core Mechanisms of Ferrous Gluconate for Cancer-Related Anemia

Abnormal iron metabolism in CRA is mainly characterized by the dual problems of "iron deficiency" and "iron utilization disorder": on one hand, tumor bleeding and chemotherapy-induced myelosuppression lead to iron loss or reduced iron synthesis; on the other hand, tumor-related chronic inflammation increases hepcidin levels, which inhibit intestinal iron absorption and macrophage iron release, resulting in "functional iron deficiency" (normal iron stores but inability to be utilized by the bone marrow). By specifically supplementing absorbable iron and improving iron metabolism disorders, ferrous gluconate provides raw materials for erythropoiesis. The specific mechanisms are as follows:

1. Supplementing Absorbable Iron to Directly Correct Absolute Iron Deficiency

In the gastrointestinal tract, ferrous gluconate dissociates into divalent iron ions (Fe²⁺), which are absorbed into the bloodstream via the "divalent metal transporter 1 (DMT1)" in the small intestinal mucosa. After binding to transferrin, Fe²⁺ is transported to the bone marrow hematopoietic microenvironment. In the bone marrow, Fe²⁺ participates in hemoglobin synthesis: it combines with protoporphyrin IX to form heme, which then assembles into hemoglobin, promoting red blood cell maturation and directly increasing hemoglobin (Hb) levels to alleviate anemia symptoms (e.g., fatigue, decreased exercise tolerance). This supplementary effect is particularly critical for "absolute iron deficiency" (serum ferritin < 30 ng/mL, transferrin saturation (TSAT) < 15%) caused by tumor bleeding (e.g., melena in gastrointestinal tumors) or insufficient iron intake due to chemotherapy (e.g., nausea and vomiting affecting food intake).

2. Improving Iron Stores to Alleviate Functional Iron Deficiency

Tumor-related chronic inflammation increases hepcidin, causing iron to "accumulate" in the liver and macrophages and become unavailable to the bone marrow (manifested by normal or elevated serum ferritin but TSAT < 20%). Through continuous iron supplementation, ferrous gluconate can partially counteract hepcidin’s inhibitory effect on iron absorption—even if hepcidin elevation reduces intestinal iron absorption efficiency, a sufficient amount of Fe²⁺ can still enter the blood through passive diffusion and other pathways. This gradually increases transferrin saturation (TSAT), enhancing the amount of iron available to the bone marrow and preventing impaired erythropoiesis due to "insufficient iron raw materials." It is particularly suitable for patients with mild inflammatory status (C-reactive protein (CRP) < 10 mg/L).

3. Synergizing with Erythropoiesis-Stimulating Agents (ESAs) to Enhance Therapeutic Response

ESAs (e.g., epoetin alfa, darbepoetin alfa) are first-line treatments for moderate to severe CRA, as they stimulate the proliferation and differentiation of bone marrow hematopoietic stem cells. However, ESAs require adequate iron stores to function. In cases of iron deficiency, ESAs may exhibit "treatment resistance" (i.e., increased ESA dosage without significant Hb elevation). The combination of ferrous gluconate and ESAs provides the material basis for ESA-mediated erythropoiesis by supplementing iron. This not only accelerates the rate of Hb increase (e.g., from 5 g/L per week to 8–10 g/L per week) but also reduces ESA dosage (usually by 20%–30%), lowering the risks of ESA-related hypertension and thrombosis.

II. Applicable Scenarios and Administration Protocols of Ferrous Gluconate in Cancer-Related Anemia

Iron metabolism status varies significantly among CRA patients. The application of ferrous gluconate requires comprehensive evaluation based on patients’ anemia severity, iron metabolism indicators, tumor type, and treatment stage to avoid iron overload or insufficient treatment due to blind supplementation. The core applicable scenarios and protocols are as follows:

(I) Applicable Scenarios

Mild Iron-Deficiency CRA (Hb 100–120 g/L): Suitable for patients with serum ferritin of 30–100 ng/mL, TSAT of 15%–20%, and no significant gastrointestinal intolerance. It is especially appropriate for patients with gastrointestinal tumors (e.g., gastric cancer, colorectal cancer) accompanied by mild bleeding or mild myelosuppression after chemotherapy (e.g., mild decreases in white blood cells and platelets). It can be used alone as an oral iron supplement to avoid early use of ESAs.

Adjuvant Iron Supplementation for ESA Therapy: For patients with moderate to severe CRA (Hb < 100 g/L) receiving ESAs, if baseline serum ferritin < 200 ng/mL or TSAT < 20%, combination with ferrous gluconate is necessary to supplement iron stores and prevent ESA treatment resistance. Even with normal baseline iron stores, "increased iron consumption" may occur during ESA therapy due to accelerated erythropoiesis, requiring continuous iron supplementation to maintain TSAT at 20%–30% and serum ferritin at 200–500 ng/mL.

CRA Patients Intolerant or Contraindicated to Intravenous Iron: Some patients have allergic reactions (e.g., rash, dyspnea) to intravenous iron (e.g., iron sucrose, deferoxamine) or have contraindications such as severe hepatic and renal insufficiency (e.g., cirrhosis, eGFR < 30 mL/min/1.73 m²) or active infection (e.g., neutropenic fever after chemotherapy). For these patients, ferrous gluconate serves as a safe alternative, particularly suitable for elderly patients or those with poor underlying health conditions.

Maintenance Iron Supplementation During Cancer Recovery: After cancer treatment, if patients still have mild anemia (Hb 110–120 g/L) and low iron stores (serum ferritin < 100 ng/mL), long-term low-dose ferrous gluconate can be used to maintain iron stores, prevent anemia recurrence, and improve quality of life during recovery (e.g., enhancing exercise tolerance, reducing fatigue).

(II) Administration Protocols

1. Dose Determination

The dose of ferrous gluconate is calculated based on "elemental iron." The routine recommended dose for CRA patients is 100–200 mg of elemental iron per day, administered orally in 2–3 divided doses (e.g., each tablet containing 0.3 g ferrous gluconate, corresponding to 35 mg elemental iron; 2–3 tablets per dose, 3 times daily). The specific dose should be dynamically adjusted according to iron metabolism indicators:

Early Treatment Stage (First 4 Weeks): If serum ferritin increases by < 50 ng/mL and TSAT increases by < 5%, and the patient has no significant gastrointestinal discomfort, the dose can be increased to 200–300 mg of elemental iron per day.

After Treatment Targets Are Met (Hb ≥ 120 g/L, TSAT 20%–30%, Serum Ferritin 200–500 ng/mL): Adjust to 50–100 mg of elemental iron per day for maintenance to avoid iron overload (which increases the risk of liver damage and infection, especially unfavorable for patients with liver cancer or cholangiocarcinoma).

2. Administration Method

To improve bioavailability, factors affecting iron absorption should be avoided while considering patient tolerance:

Administration Time: Priority is given to taking on an empty stomach (1 hour before meals or 2 hours after meals), as calcium, phytates, and tannic acid in food bind to Fe²⁺ to form insoluble complexes, reducing absorption efficiency. For patients with severe gastrointestinal reactions after chemotherapy (e.g., nausea, abdominal distension), administration can be adjusted to after meals (bioavailability decreases by approximately 20%–30%, but gastrointestinal irritation is reduced).

Combination with Vitamin C: Take with 200–500 mg of vitamin C daily. Vitamin C reduces Fe³⁺ in the gastrointestinal tract to Fe²⁺, doubling iron absorption efficiency without increasing the risk of gastrointestinal adverse reactions. This is particularly suitable for patients with poor appetite and insufficient vitamin C intake after chemotherapy.

Avoid Interfering Substances: Do not take with calcium-containing preparations (e.g., calcium carbonate, calcium tablets), phosphate binders (e.g., sevelamer), or tetracycline/quinolone antibiotics (an interval of ≥ 2 hours is required), as these substances significantly inhibit iron absorption. There is no direct interaction between chemotherapeutic drugs (e.g., cisplatin, carboplatin) and iron supplements, but it is recommended to separate their administration by ≥ 1 hour to avoid increasing gastrointestinal burden.

3. Treatment Course and Monitoring

The course of iron supplementation for CRA patients is determined by the tumor treatment cycle and anemia correction targets, usually divided into "treatment phase" and "maintenance phase":

Treatment Phase: Lasts 6–8 weeks. Monitor complete blood count (Hb, hematocrit) and iron metabolism indicators (serum ferritin, TSAT) every 2–3 weeks until Hb reaches 120–130 g/L (to avoid excessive Hb increasing the risk of thrombosis) and iron metabolism indicators meet targets.

Maintenance Phase: After reaching targets, if chemotherapy is still ongoing or continuous iron loss exists (e.g., tumor bleeding), continue 50–100 mg of elemental iron per day for maintenance. Monitor indicators every 4–6 weeks to prevent anemia recurrence after discontinuation.

III. Safety Management and Adverse Reaction Management in Ferrous Gluconate Use

Due to poor underlying health conditions (e.g., chemotherapy-induced gastrointestinal mucosal damage, hepatic and renal dysfunction), cancer patients are more prone to adverse reactions when using oral iron supplements. Targeted safety management is required to balance efficacy and tolerance.

(I) Common Adverse Reactions and Management Strategies

1. Gastrointestinal Reactions (Incidence 30%–50%)

Manifestations include nausea, abdominal pain, abdominal distension, diarrhea, or constipation—the most common adverse reactions, mostly occurring in the early treatment stage (first 2 weeks). Management strategies include:

Gradual Dose Adjustment: Start with a low dose (e.g., 50 mg elemental iron per day), increase by 50 mg every 3–5 days, and gradually reach the target dose to allow the gastrointestinal tract to adapt. For example, patients with severe nausea after chemotherapy can start with 35 mg elemental iron per day (1 ferrous gluconate tablet) and increase the dose if no discomfort occurs.

Symptomatic Treatment: For constipated patients, prefer osmotic laxatives (e.g., lactulose, polyethylene glycol) and avoid stimulant laxatives (e.g., senna) that may aggravate intestinal damage. For patients with diarrhea, take smectite powder to protect the intestinal mucosa and supplement probiotics (e.g., bifidobacteria) to regulate intestinal flora and reduce the duration of diarrhea.

Dosage Form Adjustment: If tablets are poorly tolerated, switch to liquid formulations (e.g., ferrous gluconate oral solution). Note that liquid formulations may cause tooth staining (which can be relieved by rinsing the mouth with water after administration).

2. Hepatic and Renal Effects (Rare)

Long-term high-dose administration (> 300 mg elemental iron per day) may cause iron deposition in the liver, especially in patients with liver cancer or hepatitis. Regular monitoring of liver function (e.g., ALT, AST) is required. If liver dysfunction occurs (ALT elevation > 2 times the upper limit of normal), discontinue the drug or reduce the dose. No dose adjustment is needed for patients with renal insufficiency (eGFR < 60 mL/min/1.73 m²), as ferrous gluconate is mainly excreted in feces and imposes little burden on the kidneys.

3. Allergic Reactions (Incidence < 1%)

Manifestations include rash and pruritus; severe cases may present with urticaria or angioedema. Discontinue the drug immediately, administer oral antihistamines (e.g., loratadine, cetirizine) to relieve symptoms, and consider switching to other iron supplements (e.g., iron polysaccharide complex) or evaluating the possibility of intravenous iron use (strict allergy testing is required).

(II) Safe Medication for Special Populations

Elderly Cancer Patients (> 65 Years Old): With declined gastrointestinal function and hepatic/renal function, the recommended initial dose is 50 mg elemental iron per day, increasing by 50 mg every 2 weeks. Strengthen constipation monitoring (elderly patients have a higher incidence of constipation, which may induce cardiovascular events) and use mild laxatives preventively.

Patients with Concurrent Gastrointestinal Tumors (e.g., Gastric Cancer, Esophageal Cancer): Oral iron supplements may aggravate mucosal irritation due to tumor-induced gastrointestinal mucosal damage. Administer after meals and avoid concurrent use with acid suppressants (e.g., omeprazole) (acid suppressants increase gastric pH and reduce Fe²⁺ stability; an interval of ≥ 2 hours is required). If necessary, combine with gastric mucosal protectants (e.g., sucralfate).

Patients with Neutropenia (ANC < 1.0 × 10⁹/L after Chemotherapy): Strictly avoid iron overload (which increases infection risk). Discontinue the drug when serum ferritin > 500 ng/mL, and strengthen oral and intestinal cleaning to reduce infection triggers.

IV. Precautions for Synergy Between Ferrous Gluconate and Cancer Treatment

In the adjuvant treatment of CRA, ferrous gluconate needs to be used synergistically with tumor treatments (chemotherapy, targeted therapy, radiotherapy) and other supportive drugs to avoid interactions affecting efficacy or increasing toxicity. The core precautions are as follows:

1. Interaction with Chemotherapeutic Drugs

Most chemotherapeutic drugs (e.g., paclitaxel, docetaxel, fluorouracil) have no direct pharmacokinetic interaction with ferrous gluconate, but attention should be paid to:

Avoid concurrent administration with cisplatin or carboplatin (separate by ≥ 1 hour), as cisplatin itself easily causes nausea and vomiting, and combined use with iron supplements may aggravate gastrointestinal reactions.

In cases of severe chemotherapy-induced myelosuppression (e.g., platelets < 50 × 10⁹/L, Hb < 80 g/L), prioritize anemia correction (e.g., red blood cell transfusion) and resume iron supplementation only after bone marrow function recovery to prevent iron overload due to unutilized iron.

2. Synergy with Targeted Drugs

Some targeted drugs (e.g., the anti-angiogenic drug bevacizumab) may increase the risk of tumor bleeding, exacerbating iron loss. Strengthen monitoring of iron metabolism indicators (every 2 weeks) and supplement ferrous gluconate promptly to maintain TSAT ≥ 20%, avoiding anemia affecting targeted therapy tolerance.

3. Coordination with Radiotherapy

Radiotherapy may cause gastrointestinal mucosal damage (e.g., radiation esophagitis, radiation enteritis). Administer oral iron supplements after meals to avoid empty-stomach irritation of damaged mucosa. If severe mucosal inflammation occurs (e.g., dysphagia, diarrhea), temporarily discontinue oral iron supplements and switch to short-term intravenous iron supplementation until inflammation is relieved, then resume oral administration.

As an adjuvant therapeutic drug for cancer-related anemia (CRA), ferrous gluconate corrects absolute and functional iron deficiency by supplementing absorbable iron, provides raw materials for erythropoiesis, and synergizes with erythropoiesis-stimulating agents (ESAs) to enhance therapeutic response while reducing ESA dosage and adverse reaction risks. Its applicable scenarios cover mild iron-deficiency CRA, ESA adjuvant therapy, intravenous iron alternative, and recovery-phase maintenance, making it particularly suitable for patients with poor gastrointestinal tolerance or weak underlying health conditions. In clinical application, efficacy can be optimized through "gradual dose adjustment, empty-stomach administration combined with vitamin C, and dynamic monitoring of iron metabolism indicators," while targeted management of gastrointestinal reactions and avoidance of drug interactions balance efficacy and safety. In the future, with in-depth research on CRA iron metabolism mechanisms, the combined application of ferrous gluconate and anti-inflammatory drugs (e.g., hepcidin inhibitors) may become a new direction, further improving iron correction efficiency in CRA and providing stronger support for tumor treatment and quality of life improvement in cancer patients.