Study design
The VITAMIN (VITAMin Insufficiency in oesophagogastric Neoplasms) study is a single-centre prospective cohort study with no randomisation, whereby all patients will receive supplementation. The study is performed in the Zuyderland Medical Centre (MC) in Heerlen and Sittard-Geleen, a regional centre for oesophagectomies and gastrectomies. The total duration of the study will be three years. Patients will be divided into the oesophagectomy group or in the (sub)total gastrectomy group.
Two multivitamin supplements (MVSs) have been developed, one for patients who underwent oesophagectomy (Multi-E) and one for patients who underwent gastric surgery (Multi-G). Moreover, patients will receive Calcium Soft Chew D3 as an additional supplement.
Study population
Patients older than 18 years of age that underwent oesophagectomy or gastrectomy for malignancy with no signs of recurrence of disease between 2011 and 2022 in the Zuyderland MC are eligible to participate. Exclusion criteria are wedge resection of the stomach, recurrent malignant disease, metastases and treatment with chemotherapy during inclusion and study period. Moreover, patients who are not capable of taking oral supplements will be excluded.
Study algorithm (Fig. 1, table 1)
Included patients will undergo blood withdrawal, collect faeces for faecal elastase-1 test and fill in several questionnaires at baseline (T = 0), after six months (T = 1), after twelve months (T = 2) and after 24 months (T = 3) of the start of supplement intake. Moreover, patients will receive supplements based on the type of surgery they underwent. Patients will take the MVS and Calcium Soft Chew D3 daily. Patients who take vitamin supplements in any form at baseline, will be asked to stop supplementation.
Table 1
Product composition of the Multi-E and Multi-G multivitamin supplements.
Product composition (Multi-G)
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Product composition
(Multi-E)
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Active ingredient-Vitamins
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Dosage
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RDI
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Active ingredient-
Vitamins
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Dosage
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RDI
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Vitamin A
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1200 µg
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150%
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Vitamin A
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1200 µg
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150%
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Vitamin B1
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4,4 mg
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400%
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Vitamin B1
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3,3 mg
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300%
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Vitamin B2
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2,8 mg
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200%
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Vitamin B2
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2,8 mg
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200%
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Niacin (vitamin B3)
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32 mg
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200%
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Niacin (vitamin B3)
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24 mg
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150%
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Vitamin B5
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18 mg
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300%
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Vitamin B5
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9 mg
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150%
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Vitamin B6
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1,4 mg
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100%
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Vitamin B6
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1,4 mg
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100%
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Biotin (vitamin B8)
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100 µg
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200%
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Biotin (vitamin B8)
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100 µg
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200%
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Folic acid (vitamin B11/B9)
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700 µg
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350%
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Folic acid (vitamin B11/B9)
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600 µg
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300%
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Vitamin B12
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1000 µg
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40000%
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Vitamin B12
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200 µg
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8000%
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Vitamin C
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80mg
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100%
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Vitamin C
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80 mg
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100%
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Vitamin D3
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75 µg (3000IU)
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1500%
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Vitamin D3
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75 µg (3000IU)
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1500%
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Vitamin E
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30 mg
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250%
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Vitamin E
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24 mg
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200%
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Vitamin K1
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150 µg
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200%
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Vitamin K1
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75 µg
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100%
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Active ingredient- Minerals
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Active ingredient - Minerals
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Chromium
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160 µg
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400%
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Chromium
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40 µg
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100%
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Iron
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75 mg
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535%
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Iron
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32 mg
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229%
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Iodine
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150 µg
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100%
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Iodine
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150 µg
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100%
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Copper
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3 mg
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300%
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Copper
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2 mg
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200%
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Manganese
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2 mg
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100%
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Manganese
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2 mg
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100%
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Molybdenum
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100 µg
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200%
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Molybdenum
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50 µg
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100%
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Selenium
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82,5 µg
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150%
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Selenium
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55 µg
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100%
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Zinc
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25 mg
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250%
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Zinc
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16 mg
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160%
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Legend table 1: Multi- E will be given to patients who underwent oesophagectomy and Multi-G to patients who underwent (sub)total gastrectomy. Vitamin and mineral compositions and dosage are shown of both multivitamin supplements. Both groups will receive the multivitamin supplement daily. RDI= reference intake.
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Multivitamin supplement
The oesophagectomy group will receive Multi-E and the gastrectomy group will receive Multi-G. Additionally, both groups will receive the same Calcium Soft Chew D3 prescription. All three supplements are developed by GIKAVI BV (Rotterdam, the Netherlands) based on current literature regarding nutrient deficiencies in patients who underwent surgery for EC and GC, and on the MVSs provided after bariatric surgery. The MVS will be administered once per day and Calcium Soft Chew D3 will be administered twice per day. However, due to possible interaction of calcium and iron, the Calcium Soft Chew D3 will be administered at a minimal difference of two hours from the MVS. At baseline, patients will receive supplements for 180 days. After 6 months, patients will receive supplements for another 180 days. After 360 days of supplementation, patients will receive supplements for 360 days. The supplements will be provided on the day of the hospital visit for blood analysis and collection of faeces in the hospital. Compliance will be studied by tablet count. Patients will be asked to return the packages at time point T = 1, T = 2 and T = 3.
Blood analysis
Venous blood sampling will be taken to analyse different nutrient states at all time points in the Zuyderland MC. The first venous blood sampling will be conducted before supplementation. Nutrients such as vitamins (A, B1, B6, B12, D, E, folic acid and international normalized ratio (INR)), minerals (serum iron, transferrin, ferritin, transferrin saturation, zinc, magnesium, phosphate), proteins (albumin, total protein, c-reactive protein (CRP)) and parathyroid hormone (PTH) will be analysed. Deficiencies will be classified according to current guidelines of the laboratory of the Zuyderland MC.
Faecal elastase-1 test
Faecal elastase-1 tests will be performed to diagnose EPI. Moreover, symptoms of EPI such as, bloating, steatorrhea and diarrhoea will be reported consistently. Patients will receive a special container for faecal collection by mail. The collected faeces will be returned to the hospital for
a faecal elastase-1 test. An EPI is defined as a quantity of faecal elastase-1 < 100 µg E1/g in combination with accompanying symptoms as described above.
Questionnaires
Patients will be asked to complete various questionnaires at every time point. These will be sent by e-mail or regular mail. The questionnaires used in this study regard QoL, eating behaviour and supplement tolerance. The questionnaires EQ-5D, QLQ-C30, QLCOG25 and the cancer worry scale (CWS) regard QoL (20–23). The adjusted three-factor eating questionnaire (TFEQ) regards dietary eating behaviour (24). Both the QoL questionnaires and the TFEQ questionnaires will be sent to all patients at all time points. The GIKAVI supplement tolerance questionnaire regarding the MVSs and Calcium Soft Chew D3 supplement, will be sent at T = 1, T = 2 and T = 3. A reminder will be sent to patients if the questionnaires are not completed within two weeks.
Study parameters/ endpoint
The main outcome in this study is any deficiency (yes or no) of vitamins, minerals and proteins measured in the nutrient blood levels below the specified threshold used in the Zuyderland MC. Secondary parameters include:
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Incidence of micronutrient deficiency post oesophagectomy or (sub)total gastrectomy at baseline
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Time between surgery and start of supplementation (mean in months)
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Occurrence of decreased faecal elastase-1 at any time point
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Occurrence of the following symptoms: diarrhoea (n, %), steatorrhea (n, %), bloating (n, %), which are all associated with EPI, at any time point
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QoL and vitality measured with questionnaires at all timepoints
Safety and stopping rules
The ingredients used for the MVSs and Calcium Soft Chew D3 are already safely implemented in clinical practice. Therefore, (severe) adverse events are not expected in the study population. Premature termination will occur when loss to follow up and withdrawal of individual subjects lead to insufficient data to investigate the research questions.
Statistical analysis
Sample size calculation
A sample size was calculated even though no studies have been performed with the same primary objective. Based on a Cohens’d of 0.4, a two-sided alpha of 0.05 and a power of 80% the calculated sample size is 99 per group. Considering the maximum acceptable drop-out rate of 20% in clinical studies, the number of patients needed to be included is 124 per group (oesophagectomy and gastrectomy), with a total of 248. To include this number of patients, all eligible patients from 2011 until 2022 that underwent oesophagectomy or gastrectomy in the Zuyderland MC will be invited for participation. Patients who are currently postoperatively monitored will be notified about this study during hospital visits by their supervising physician. If postoperative follow up has been ended, patients will be invited by their previous supervising physician via telephone. Since micronutrient deficiencies are not regularly monitored and treated in this population, a low drop-out rate is expected. The motivation of this population to participate is considered high and based on the response of patients during hospital visits and on the high compliance of bariatric patients who participated in a similar study design.
Data analysis
All data will be collected and analysed using Statistical Package for Social Sciences (SPSS) version 26. The primary study parameter is the presence of any deficiency (yes or no) defined as a measured value below the reference value. Multivariable linear regression analyses will be used to assess group and over time differences of individual blood value measurements. Multivariable analyses will be performed to correct for confounders.
Secondary parameters such as incidence of micronutrient deficiency (n, %), occurrence of EPI (n, %), occurrence of diarrhoea (n, %), steatorrhea (n, %), bloating (n, %), and time between surgery and start of supplementation (mean in months, standard deviation or media, interquartile range) will be compared between treatment groups using multivariable logistic regression analysis.
QoL and vitality of patients will be assessed using the EQ-5D, QLQ-C30, QLC-OG25 and CWS questionnaires according to the scoring manuals from the authors (20–23). These questionnaires will be assessed using a Mann-Whitney U test between the oesophagectomy and gastrectomy group. Over time differences between groups will be assessed separately using Friedman ANOVA and individual Wilcoxon Signed Rank tests with a Bonferroni correction as post-hoc analyses.
Ethical and regulatory considerations
The study has been approved by the medical ethics committee of the Zuyderland MC (METCZ20210146) and has been registered in the Netherlands Trial Registry (NTR) (NL9787). The study will be conducted according to the principles of the Declaration of Helsinki (10th version, Fortaleza, 2013) and in accordance with the Medical Research Involving Human Subjects Act (WMO) and other applicable guidelines, regulations and Acts. The principal and coordinating investigator will be responsible for recruitment, data collection, follow-up of included patients, completion of case report forms and adherence to the study protocol. Eligible patients will be informed about the study by their supervising physician. Informed consent will be obtained by the coordinating investigator. The project leader will be responsible for the design and conduct of the study, for the preparation of the protocol and revisions, and preparation of case report forms. Revisions of the study protocol will be communicated to all investigators. The data master file and data verification will be monitored by the Clinical Trial Centre Maastricht (CTCM). Data will be collected using individual trial case numbers processed by the electronic database program Research Manager. Patient data will be anonymized using unique participant numbers prior to data entry in Research Manager. The final dataset will be analysed by the coordinating investigator. The definition of authorship will be followed by the International Committee of Medical Journal Editors Guidelines (25). The results will be communicated via international conferences, via publications and via the NTR.