Health & Medical surgery

Treating Preoperative Anaemia in Colorectal Cancer Patients

Treating Preoperative Anaemia in Colorectal Cancer Patients

Methods/Design


The aim of this multicentre trial is to investigate which route of iron supplementation is superior in the treatment of iron deficiency anaemia in patients with colorectal carcinoma. By enhancing the preoperative condition of the patient, this trial aims to optimize postoperative outcome in anaemic patients. It is our hypothesis that a more profound approach of anaemia with intravenous iron will lead to a higher percentage of patients with normalization of Hb-level (>12 g/dl (7.5 mmol/l) for women and > 13 g/dl (8 mmol/l) for men) undergoing surgery, which potentially reduces morbidity, length of hospital stay, improves quality of life, decreases fatigue and could be more cost effective compared to current practice with oral substitution of iron.

In addition, an economic evaluation of intravenous iron versus oral iron will be performed. The evaluation will be performed from a societal perspective as (i) a cost-effectiveness analysis with the costs per responder to iron supplementation therapy as primary outcome and (ii) a cost-utility analysis with the costs per quality adjusted life-year (QALY) as primary outcome. The cost effectiveness analysis closely relates to clinical efficacy measure and allows for setting priorities in treatment of anaemia in colorectal cancer patients. The cost-utility analysis allows for a comparison of the societal impact of intravenous iron supplementation on post-operative recovery, such as improved health utility, shorter length of stay and earlier return to daily activities.

The Primary Aim of the FIT Trial


1) To compare the percentage of patients with normalization of Hb-level (>12 g/dl (7.5 mmol/l) for women and > 13 g/dl (8 mmol/l) for men) after intravenous versus oral iron therapy in patients undergoing curative surgery for colorectal carcinoma.

Secondary aims of the FIT trial are:

2) To analyse the effect of preoperative iron therapy (intravenous versus oral) on postoperative morbidity, length of stay, amount of blood transfusions needed and quality of life and fatigue scores.

3) To determine the cost effectiveness of preoperative intravenous iron substitution in comparison with oral substitution.

Study Design


The study is designed as a multicentre randomized clinical trial comparing ferric(III)carboxymaltose infusion with oral supplementation of ferrofumarate in the treatment of preoperative anaemia in colorectal cancer patients. Patients with a proven iron deficiency anaemia who undergo segmental colonic resection or (low) anterior resection because of M0-stage colorectal carcinoma are eligible for inclusion. Patients undergoing local excision of a rectal carcinoma (TEM/EMR/ESR) will not be included. In Fig. 1 you can find the flowchart of the FIT-trial.



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Figure 1.



Flowchart of FIT-trial





When a patient has got a proven iron deficiency anaemia and the patient does not meet the criteria for exclusion, he/she will be included in the trial. Written informed consent will be obtained from each patient. The patients' albumin and C-reactive protein (CRP) levels are used to derive a Glasgow Prognostic Score (GPS) which can be used as a predictor of post-operative outcome.

Patients will be computer randomized in random blocks of sizes 2 or 4 for either intravenous- or oral iron. Randomization will be stratified for age, colon or rectal carcinoma, open or laparoscopic operation and baseline Hb (8–10 g/dl vs 10–13 g/dl).

Apart from routine 5 year oncological follow-up, patients will be followed more intensively until 6 months after surgery as part of this trial. Hb, transferrin saturation (TSAT), ferritin, Hematocrit and CRP levels are measured at postoperative day 1, day 7, at 4, 8 and 12 weeks to monitor the anaemia. The follow-up schedule is detailed in Fig. 2.



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Figure 2.



Study follow-up




Study Procedures


Surgical procedures include all laparoscopic and open segmental resections. Patients randomized to intravenous iron will receive ferric(III)carboxymaltose dosed according to Summary of Product Characteristics (SPC) depending on body weight and Hb-level and it will be administered in one or two infusions with one week in between, prior to the operation. (also see Table 1). The maximum dose administered to the patient may not exceed 15 mg/kg and a maximum of 1000 mg may be administered per week. When the patient has a weight of lower than 35 kg, a dose of 500 mg will be given. Patients randomized to intravenous iron will receive iron infusion on the short stay/colon care unit. Ferric(III) carboxymaltose has to be infused in a period of 15 min. Patients randomized to standard care with ferrofumarate will receive three tablets of 200 mg daily from randomisation until day before surgery. This dose is conform national farmacotherapeutic protocol. When patients remain anaemic postoperatively, they will be supplied with iron according to the allocated study arm.

Study Population


The patient population consists of patients with M0-stage colorectal carcinoma and concomitant iron deficiency anaemia (Hb <7,5 mmol/l (12 g/dl) for women and Hb < 8 mmol/l (13 g/dl) for men and TSAT < 20 %) who will undergo a laparoscopic/open segmental colonic resection or (low) anterior resection. Additionally the patient should be 18 years of age or older and informed consent must be obtained. Exclusion criteria are: palliative surgery/metastasized disease, blood transfusion within one month before screening, serum ferritin above 800 μg/L, pregnancy, contraindication to use ferric(III)carboxymaltose or ferrofumarate, ASA classification higher than 3, the use of erythropoietin stimulating agents within three months before screening, chronic kidney disease (Glomerular filtration rate (GFR) <30 ml/min/m), myelodysplastic syndrome, elevated liver enzymens (more than three times normal value), hereditary hemochromatosis, thalassemia, haemolytic anaemia/chronic haemolysis.

Outcome Parameters


Our primary endpoint is the percentage of patients with normalization of Hb-level from start treatment until surgery (Hb >12 g/dl (7.5 mmol/L) for women and Hb >13 g/dl (8.0 mmol/L) for men). Our secondary endpoints are morbidity, assessed with the Comprehensive Complication index, amount of blood transfusions needed, length of stay, absolute change in HB from baseline prior to surgery and postoperatively, time needed to achieve normalization of Hb-level, change in baseline of other iron/haematological parameters (TSAT, ferritin, CRP), health-related quality of life and fatigue scores (EQ-5D, EORTC-C30, EORTC -CR29 iMCQ, BFI & iPCQ), relation between anaemia and Glasgow Prognostic Score (derived from CRP and Albumin) and cost-effectiveness of intravenous iron treatment compared to oral. Blood samples to assess Hb- and iron values will be taken at baseline, at admission, postoperative day 1, 7 and after 1-,2- and 3 months.

Sample Size Calculation


The principal analysis will be an intention-to-treat comparison of the proportions of patients with iron deficiency anaemia between the two study groups. The trial is designed as a superiority trial, hypothesizing a greater percentage of patients achieving normalization of Hb-level (called 'responder') in favour of infusion of ferric(III)carboxymaltose compared to oral iron suppletion. Our power calculation is based on the study of Seid et al., which compared ferric(III)carboxymaltose with oral ferrous sulphate in a population of post-partum women with an iron deficiency anaemia. The proportion achieving a normalization of Hb after two weeks of treatment was 55 % in the intravenous iron group and 35 % in the oral iron group. We expect that the efficacy of the iron therapy is lower in patients with a colorectal carcinoma. Therefore, the expected percentage of patients who achieve normalization of Hb-level (Hb >7.5 mmol/l (12 g/dl) for women and Hb >8.0 mmol/l (13 g/dl) for men) is 45 % in the intravenous iron group and 25 % in the oral iron group. Based on these proportions, a sample size of 89 patients per group is needed for a Chi square test to achieve 80 % power at a two sided alpha of 0.05. With an estimated loss to follow up of 10 %, a sample size of 198 is calculated. We used nQuery advisor version 7.0 to calculate the sample size.

Data-analysis


The intention-to-treat population will include all patients who give their informed consent, for whom there is confirmation of successful allocation of a randomization number, and who received at least one dose of the study medication. Statistical analyses will be performed using SPSS software for Windows version 19.

The primary endpoint, the percentage of patients with a normalised Hb-level at admission will be compared between the two study groups on a intention to treat basis. Using a two-sided Chi-square test at a significance level of 0.05. All data will be collected in an electronic database. The outcome parameters will be analysed with appropriate statistical tests by a statistician blinded for the treatment allocation using the statistical program SPSS software for Windows version 19.

Appropriate summary descriptive statistics will be determined for all secondary endpoints at each visit using raw scores. To assess morbidity the continuous scale of the Comprehensive Complication Index and the categorical Clavien-Dindo classification will be used, for which appropriate statistical tests will be undertaken (the Mann Whitney U test, in case of non-normal distribution, and the Chi squared test respectively). For continuous secondary endpoints, either analysis of variance or analysis of covariance models will be used and where necessary, the repeated measures procedure will be implemented.

Quality of life data (e.g. EORTC-C30, EORTC-CR29 and EQ-5D) will be graphically represented across all time points and analysed using a repeated measures analysis of variance. All tests based on proportions will be analysed using a logistic regression model with treatment as a factor and, where appropriate, other specified covariates to include baseline score. Time-to-event will be analysed with use of Kaplan-Meier Survival analysis and compared using the log-rank test. Where appropriate, a stratified log-rank test and Cox proportional hazard model will be used to explore the potential influences of baseline HB and other specified covariates.

The secondary efficacy analysis will be based on the Full Analysis Set (FAS) and the per protocol populations. Significance level is set at an alpha of 0.05 and no adjustment will be made for testing multiple secondary outcomes. Some significant findings are expected to occur by chance so undue consideration will not be given to any particular significant difference. Moreover, interpretation of the results will be based on patterns of differences and in conjunction with the results of the primary analyses.

Cost Analysis


Unit costing of distinct health care resources will be in accordance with national guidelines. Cost data will be derived as the product sum of health care volume data and their respective unit cost. Observed health utilities based on the EQ-5D health status profiles will be linked to the lengths of the periods in between measurements to derive QALYs. Incremental cost-effectiveness and cost-utility analyses will be performed to calculate the extra cost per additional 'responder' and the extra costs per additional quality adjusted life year respectively. Differences between groups will be assessed by calculating 95 % confidence intervals for the mean differences after non-parametric bootstrapping, drawing at least 1,000 samples of the same size as the original sample separately for each group and with replacement. A cost-effectiveness acceptability curve will be drawn to show the probability of intravenous iron supplementation being cost- effective at willingness-to-pay values up to €80,000 per QALY. Single and multi-way sensitivity analyses will be performed to study the robustness of these findings to plausible changes in key unit costs and to alternative health utility scoring algorithms. With a time horizon of six months of follow-up, no discounting of efficacy and cost data will be applied to account for time preference.

Ethics and Safety


This trial will be conducted according to the principles of the declaration of Helsinki (Fortaleza, October 2013) and in accordance with the Medical Research Involving Human Subjects Act (WMO) and other European guidelines, regulations and acts. Data management, monitoring and reporting of the study will be carried out in accordance with the ICH GCP guidelines. The medical ethical committee of the Academic Medical Centre, Amsterdam, the Netherlands, has approved the study protocol (NL50013.018.14). As this trial concerns the effectiveness of a medication a Data Safety Monitoring Board (DSMB) will be assigned. The DSMB will guard the safety of the included patients, give advice on continuation of the study upon superiority of one of the types of treatment, and will guard the methodological quality of the study.

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