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Iron

mildly anemic patients (Hb 12-13 mg/dL) without criteria for IVI therapy

patients treated with IVI (Hb \< 12mg/dL or Hb 12-13mg/dL with iron deficiency or risk factors for bleeding)

Both preoperative anemia (PA) and perioperative blood transfusion can contribute on poorer outcomes after colon cancer surgery. Anemia is known to be associated with a slower recovery after surgery thus often worsening short-term results, and allogenic red blood cells transfusion (ARBT) are known to promote systemic inflammatory response and affect overall and cancer-specific survival.

Patient Blood Management (PBM) systems are an evidence-based multimodal approach focused on safe and rational use of blood products, mainly through a proper PA assessment, a minimization of procedural blood loos and strict transfusion policies. Given the high prevalence of PA in patients with colorectal cancer (CRC), and its association with adverse events, it is expected that PBM implementation in said scenario carries a decrease in complications and an improved survival rate. Available literature to date supports preoperative anaemia screening and restrictive transfusion policies, nevertheless barriers exist that limit the expected implementation of PBM systems in colorectal surgery.

The present study aims to evaluate feasibility of a PBM pathway implementation in a high-volume CRC Surgery Unit based on completion of anemia screening and treatment before surgery and changes of allogenic products use along the years. The objective is to estimate the impact of a proper preoperative optimization with iron intravenous infusion (IVI) on PA measured from changes Hemoglobin (Hb) levels in comparison to those of non-anemic patients.

Perioperative Management of Preoperative Anemia in Colorectal Cancer

Perioperative Management of Preoperative Anemia in Colorectal Cancer. Effect of Intravenous Iron Treatment Within a Patient Blood Management on Colorectal Cancer Surgery

Change in serum hemoglobin concentration between baseline (at the moment of initial colorectal clinic visit) and day of surgery

Total iron dose administered from the first visit until surgery

number of complications related to IVI administration

Consorci Sanitari Integral

Nutritional and Metabolic Diseases

Anemia, Iron-Deficiency

Iron Deficiencies

Metabolic Diseases

Iron Metabolism Disorders

Anemia, Hypochromic

Anti-Inflammatory Agents

Antirheumatic Agents

Analgesics

Hematinics

Chrysarobin

Iron isomaltoside 1000

intravenous iron isomaltose 3-10 weeks before operation date. The dose will be determined by the patient's body weight: \> 50kg: 1000mg; \<50kg: 20mg/kg body weight, to be infused over 30 minutes. 2 weeks after intravenous iron isomaltoside administration, blood test for hemoglobin level and iron profile would be repeated. Subjects with hemoglobin level less than 10g/dL will receive a second dose of intravenous iron isomaltoside. The second dose would be identical to the first dose

Patient randomized to the control arm will follow the standard perioperative care and the perioperative management they received will be identical to the treatment arm except no intravenous iron isomaltoside will be given.

iron isomaltoside(Monofer®)

Iron deficiency anaemia is a common condition among colorectal surgical patient. Untreated anaemia would lead to increase in blood transfusion, surgical complications and mortality. Treatment with oral iron sulphate is poorly tolerated due to side effects. Intravenous iron supplement provides an alternative way to rapidly replace iron deficit during the preoperative period among surgical patients. Evidence is growing for its effect in rising hemoglobin level and reducing blood transfusion, at the same time supporting its safety profile.

The investigators plan for a single-centered, randomized controlled trial to examine the effect of intravenous iron compared to standard care in terms of hemoglobin level/serum ferritin increment, need for blood transfusion, duration of hospital stay, quality of recovery and surgical complication rate, as well as safety profile among colorectal cancer surgical patients in Hong Kong. The investigator propose the following pilot RCT for exploring the effect size and study process in conducting the above-mentioned large-scale RCT.

Efficacy of Preoperative Intravenous Iron in Anaemic Colorectal Cancer Surgical Patients

Efficacy of Preoperative Intravenous Iron Isomaltoside in Colorectal Cancer Surgical Patients With Iron Deficiency Anaemia Compared to Standard Care: a Pilot Randomized Controlled Trial

number of recruited patients divided by number of eligible patients x 100%

the difference between the value at diagnosis(baseline) and preoperative day (3-10weeks after diagnosis).

Units of red blood cells transfused from diagnosis to discharge

recorded and graded according to Clavien Classification of Surgical Complications

Prince of Wales Hospital, Shatin, Hong Kong

Resident trainee

Vitamins

Folic Acid

Vitamin B Complex

Vitamin B 12

Hydroxocobalamin

Trace Elements

Folinic Acid

Methylcobalamin

Folate

Vitamin B9

Vitamin B12

Cobalamin

Cyanocobalamin

Cancer patients eligible for surgery with anemia will be managed as follows:

* s-ferritin \<100 mcg/l or s-ferritin \<500 mcg/l + TSAT\<20% = i.v. iron (ferric carboxymaltose, dosage according to body weight and Hb level)
* folate \< 5 ng/ml = folate 5 mg per day for 1 month
* B12 \< 200 pg/ml = B vitamin complex 1 tablet per day for 1 month

Patients will receive combined treatment if they have multiple deficiencies simultaneously.

Patients without correctable deficiencies will not receive any treatment.

Anemic patients with ID will receive i.v. iron. Dosage will be based on Hb level and patient body weight.

Ferric Carboxymaltose Injection

Anemic patients with folate deficiency will receive folic acid 5 mg per day for 1 month

Folic acid

Anemic patients with B12 deficiency will receive B vitamin complex 1 tablet per day for 1 month

Domenico Girelli, MD

Fabiana Busti, MD

Domenico Girelli, Prof.

Alfredo Guglielmi, Prof.

Giorgio Gandini, MD

Giovanni Marchegiani, MD

Preoperative anemia is detrimental in surgical patients, and its treatment with transfusions can further worsen outcomes, including increased hospital stay and mortality. Transfusions are also highly costly. In 2010, the World Health Organization endorsed the adoption of Patient Blood Management (PBM) programs, i.e., patient-centered multidisciplinary activities, including recognition and treatment of preoperative anemia. While the latter has been proved effective in reducing transfusions in setting like elective orthopedic surgery, widespread adoption is still lacking. Moreover, little is known about surgical oncology, a particular setting posing unique challenging. This change-promoting project attempts to fill this knowledge gap by establishing a multidisciplinary team aimed at optimal management of preoperative anemia in hepatobiliary/pancreas/gastrointestinal/renal surgical oncology. The primary endpoint is the reduction of transfusions, along with safer patient outcomes as compared to the historical series.

BACKGROUND: Preoperative anemia is frequent in patients undergoing major surgery, varying from nearly 35% in elective orthopedic surgery (EOS) to \>75% in colon cancer. Mounting data have shown that anemia is independently associated with an increased risk of morbidity and mortality in surgical patients. This is true even for mild-degree anemia, which is frequently overlooked. Of note, treatment of anemia with transfusions does not ameliorate the risk but instead appears to raise further perioperative morbidity, hospital length of stay, and mortality. Transfusions have adverse immunomodulatory effects that can increase infectious complications or cancer recurrence. Indeed, it is increasingly recognized that transfusions are one of the most costly and overused treatments in modern medicine. This has led to the implementation of Patient Blood Management (PBM) programs, i.e., patient-centered, multidisciplinary activities to promote safe and evidence-based use of transfusions. Recognition and treatment of preoperative anemia is a significant pillar of PBM, with proven efficacy in certain types of surgery, i.e., EOS. This has been facilitated by recent advances in the knowledge of the pathophysiology of iron, whose deficiency represents a common and treatable form of anemia in surgical patients. Nevertheless, evidence is scanty in surgical patients with malignancies, a particular subgroup that poses unique challenges.

Hypothesis and Significance: Recognition and treatment of preoperative anemia in surgical oncology through a well-organized, multidisciplinary Anemia Clinic should decrease blood transfusions, ultimately leading to better clinical outcomes and cost savings.

METHODOLOGIES and STATISTICAL ANALYSES: Evaluation and treatment of preoperative anemia will be performed as follows: we will perform a minimum panel of exams, i.e., complete blood count (CBC), creatinine, C-reactive protein, ferritin, transferrin saturation (TSAT), and circulating folate/B12 levels, to assess the presence of anemia, and to identify potentially correctable causes. On the same day on which the patient performs lab analyses in the morning, the surgeon will alert the Anemia Clinic with the patient's ID digital code. Case-manager MD at Anemia Clinic will evaluate lab results as soon they become available (expected time 3-4 hours after blood drawing) through the e-health system. Anemic patients will be invited to attend the Anemia Clinic the day after. They will be clinically evaluated, and treatment for anemia will be immediately prescribed/performed.

Core statistical analyses regarding transfusion use and patients' outcomes will be entrusted to external independent statisticians through subcontract. The diagnostic performance of hepcidin will be investigated through Area Under the Curve Receiving Operating Characteristic (AUC-ROC) and its prognostic implications by Kaplan-Meier curves.

The duration of the presented project is calculated as 36 months and will be divided into 3 different milestones as follows:

* M1: Study organization and coordination among the Units (study protocol preparation, procedures implementation for managing patient flow across units).
* M2: 24 months of Patient Enrolment (evaluation of preoperative hematological parameters and suitable treatment, surgery, postoperative evaluation) and ad interim follow-up evaluation after 1 month from the surgery.
* M3: statistical evaluation of results, publication preparation, and evaluation of the possible implementation of new improved internal guidelines for treating anemia in cancer patients.

* Institution of an Anemia Clinic to identify all cancer patients with anemia before surgery
* Treatment of treatable causes of anemia in all cancer patients within three weeks before surgery; in particular, iron deficiency (ID), folate deficiency and B12 deficiency
* Collection of data concerning transfusions in the peri-operative period
* Collection of peri-operative outcomes such as in-hospital mortality, myocardial infarction, ischemic stroke, acute renal failure, pneumonia, or sepsis, and Hb levels at discharge
* Comparison of data relating to transfusions and outcomes with those obtained in a historical cohort of anemic patients eligible for oncological surgery for malignant tumors, matched by age, sex, and pathology enrolled in the three years 2017-2019
* Evaluation of hepcidin levels in anemic cancer patients (explorative aim)

Management of Preoperative Anaemia in Surgical Oncology

Management of Preoperative Anaemia in Surgical Oncology as a Tool to Reduce Blood Transfusion Need

Evaluate whether implementing a program for early recognition and management of preoperative anemia leads to a reduction in blood transfusions in surgical oncology compared to historical cohort enrolled before the project

Evaluate whether implementing a program for early recognition and management of preoperative anemia leads to an improvement in some patient's clinical outcomes after surgery compared to the historical cohort enrolled before the project

Evaluate whether implementing a program for early recognition and management of preoperative anemia leads to a shortening in the duration of hospitalization after surgery compared to the historical cohort enrolled before the project

Evaluate whether implementing a program for early recognition and management of preoperative anemia leads to an improvement in Hb levels at discharge compared to the historical cohort enrolled before the project

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Perioperative Management of Preoperative Anemia in Colorectal Cancer	NCT06026618	Anemia Colorectal Canc...		18 Years -	Consorci Sanitari Integral
Efficacy of Preoperative Intravenous Iron in Anaemic Colorectal Cancer Surgical Patients	NCT03565354	Anemia, Iron-De... Colorectal Canc...	iron isomaltosi...	18 Years -	Prince of Wales Hospital, Shatin, Hong Kong
Management of Preoperative Anaemia in Surgical Oncology	NCT05505006	Anemia Tumor	Ferric Carboxym... Folic acid B12	18 Years -	Azienda Ospedaliera Universitaria Integrata Verona
Management of Preoperative Anaemia in Surgical Oncology	NCT05505006	Anemia Tumor	Ferric Carboxym... Folic acid B12	18 Years -	Azienda Ospedaliera Universitaria Integrata Verona

Spots Global Cancer Trial Database for patient blood management