Urashima et al. (2019): Effect of Vitamin D Supplementation on Relapse-Free Survival Among Patients With Digestive Tract Cancers The AMATERASU Randomized Clinical Trial

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Title	Effect of Vitamin D Supplementation on Relapse-Free Survival Among Patients With Digestive Tract Cancers The AMATERASU Randomized Clinical Trial
Topic	Vitamin D
Author	Urashima, M, Ohdaira, H, Akutsu, T, Okada, S, Yoshida, M, Kitajima, M, Suzuki, Y
Year	2019
Journal	JAMA
DOI	https://doi.org/10.1001/jama.2019.2210

Brief summary

The study included 417 patients with carcinomas of the digestive tract. They were randomly divided into 2 arms. One arm received 2000 IU of vitamin D daily and the other arm a placebo. No differences were found between the arms for relapse-free survival at 5 years or overall survival. An analysis of patients with vitamin D levels in the mid-range at baseline showed benefits in 5-year relapse-free survival for the arm receiving supplemental vitamin D. It is unclear how long patients received vitamin D. About 10% of patients stopped taking vitamin D during the study, but all but one patient was followed up until the end of the study.

In der Studie wurden 417 Patienten mit Karzinomen des Verdauungstrakts eingeschlossen. Diese wurden zufällig in 2 Arme eingeteilt. Ein Arm erhielt täglich 2000 IU Vitamin D und der andere Arm ein Placebo. Es wurden keine Unterschiede zwischen den Armen gefunden für Rückfallfreies Überleben nach 5 Jahren oder allgemeines Überleben. Eine Analyse von Patienten mit einem Vitamin D Spiegel im mittleren Bereich zum Studienbeginn zeigte Vorteile beim 5-Jahres Rückfall freien Überlebens für den Arm die zusätzlich Vitamin D erhielt. Unklar ist wie lang die Patienten Vitamin D erhielten. Etwa 10% der Patienten stoppten während der Studie die Einnahme, jedoch wurden bis auf einen Patienten alle bis zum Ende der Studie nachbeobachtet.

Study Design

Prospective / Retrospective Prospective: forward-looking, examples include clinical trials, cohort studies, and long-term observational studies;</br>Retrospective: backward-looking, relying on existing data, examples include case-control studies and retrospective cohort studies	Prospective
Monocentric / Multicentric Monocentric: conducted in one center/ hospital; </br>Multicentric: conducted in multiple centers/ hospitals	Monocentric
Blinding No: Open, all parties are aware of group assignments;</br>Single: one party is unaware of group assignments (generally participants);</br>Double: two parties are unaware of group assignments (generally the participants and the researchers); </br>Triple: concealing group assignment from additional parties	Double
Is randomized	Yes
Cross-over Participants alternate between different treatment groups or conditions over a specified period, allowing each participant to serve as their own control	No
Number of arms	2

Study characteristics

Inclusion criteria	A histopathological diagnosis of epithelial carcinoma of the digestive tract (esophagus, stomach, small intestine, colon, and rectum), clinical stages I to III; aged 30 to 90 years at entry; diagnosis and initial surgery at the International University of Health and Welfare Hospital; not taking vitamin D supplements or active vitamin D; and no history of urinary tract stones
Exclusion criteria	Tumors that were not resectable by surgery, serious post-operative complications before starting supplementation, pathological diagnosis other than epithelial carcinoma (such as malignant lymphoma and sarcoma), and pathological stage 0 or IV
N randomized	417
Analysis PP: Per Protocol analysis, i.e. only participants included who adhered to the study protocol.</br>ITT: Intention-to-treat analysis, i.e. all randomized participants included regardless of any drop-outs or changes in assignment.</br>mITT: modified Intention-to-treat analysis can refer to analyses in which participants with missing outcome data are excluded or it can refer to analyses in which only participants who received at least one treatment dose are included. In this case, participants dropped out of the study prematurely for reasons unrelated to the treatment.	PP Analysis, ITT Analysis
Specifications on analyses	All patients who underwent randomization were included in the analysis; Relapse- and death-related outcomes were assessed according to randomization arm whether or not supplements were taken, whereas adverse events were assessed only in patients who continued to take the supplements (per protocol)
Countries of data collection	Japan
LoE Level of evidence	?
Outcome timeline Data collection times	T0: baseline Every month for the first 6 months Every 2 months for the second 6 months Every 3 months thereafter until 5 years After 5 years, follow-up continued to occur every 3 to 6 months depending on a patient’s condition as judged by the surgeon in charge

Characteristics of participants

Setting Refers to cancer therapy setting.</br>- Curative therapy: aims to completely eradicate a disease and achieve a full recovery; </br>- Neo-adjuvant therapy: form of curative therapy, given before the primary treatment for cancer (usually surgery); </br>- Adjuvant therapy: form of curative therapy, given after the primary treatment for cancer (usually surgery); </br>- Palliative therapy: focuses on providing relief from symptoms and improving the quality of life for patients, without necessarily targeting the underlying disease; </br>- Active surveillance: involves close monitoring of disease progression without any intervention (typically used for prostate cancer);</br>- No therapy setting: Patients who completed therapy/are currently not in cancer treatment, cancer survivors.	Curative
Types of cancer "Other Cancers" means that only a subpopulation was specified, but further unspecified cancer types were included	Colorectal Cancer, Stomach Cancer, Gastrointestinal Cancers - Esophageal Cancer
Cancer stages Early Stage: generally refers to cancer that is localized to the area where it started, mostly stages I and II;</br>Advanced Stage: cancer that has spread beyond its original site, mostly stages III and IV, with stage IV indicating distant metastasis	Early Stage, Advanced Stage
Specifications on cancer stages	Stages I to III
Comorbidities	Hypertension, Diabetes mellitus, Endocrine disease, Cardiovascular disease, Chronic kidney disease, Asthma, Orthopedic disease
Current cancer therapies	Chemotherapy, Radiation therapy
Specifications on cancer therapies	Preoperative and postoperative chemotherapy was administered to patients with stage II and III esophageal cancer; postoperative chemotherapy was administered to patients with stage II and III gastric cancer and all patients with stage III colorectal cancer; Local radiation or molecular-targeting therapy was combined with chemotherapy for selected patients with relapse
Previous cancer therapies	Chemotherapy
Gender	Mixed
Gender specifications	Intervention arm: n=173 (69%) male, n=78 (31%) female placebo arm: n=103 (62%) male, n=63 (38%) female
Age groups	Adults (18+)
Age groups specification	Median age: 66 years

Arms

Arm type Active control: group receives active treatment; </br>Passive control: for example treatment as usual, waiting control, no treatment	Intervention
Number of participants (arm) N randomized	251
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	24
Drop-out reasons	n=1 lost to follow-up within 6 month, n=23 stopped study medication (n=14 for nonmedical reasons, n=9 for medical reasons)
Intervention	Vitamin D
Dosage and regime	Vitamin D3 supplementation, 2000 IU/d, after surgery until the end of the trial
One-time application	No
Duration in days For long-term interventions, the number of days is an estimation.</br>A value of -999 indicates that the exact duration cannot be extracted from the study due to ambiguous or incomplete information. See Outcome timeline or Dosage and regime for further information.	-999
Side effects / Interactions	n=3 fractures (1.3%), n=2 urinary stones (0.9%); no patients developed hypercalcemia during the follow-up period

Arm type Active control: group receives active treatment; </br>Passive control: for example treatment as usual, waiting control, no treatment	Placebo
Number of participants (arm) N randomized	166
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	19
Drop-out reasons	stopped study medication (n=10 for nonmedical reasons, n=9 for medical reasons)
Intervention	Placebo
Dosage and regime	Placebo after surgery until the end of the trial
One-time application	No
Duration in days For long-term interventions, the number of days is an estimation.</br>A value of -999 indicates that the exact duration cannot be extracted from the study due to ambiguous or incomplete information. See Outcome timeline or Dosage and regime for further information.	-999
Side effects / Interactions	n=5 fractures (3.4%); no patients developed hypercalcemia during the follow-up period

Outcomes

RFS (Recurrence-Free Survival)

Outcome type As specificed by the authors	Primary
Outcome specification	Relapse-free survival = elapsed time from the date of randomization (ie, time from starting the study medication to the earliest date of cancer relapse or death due to any cause)
Type of measurement	Observation
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	NA
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	Overall: No significant differences

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	some concerns
Bias due to deviation from intended intervention (assignment to intervention)	low risk
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	some concerns
Bias in measurement of the outcome	low risk
Bias in selection of the reported result	low risk
Other sources of bias	NA
Overall RoB judgment	high risk

OS (Overall Survival)

Outcome type As specificed by the authors	Secondary
Outcome specification	5-year overall survival = elapsed time from the date of randomization (ie, time from starting the study medication to the date of death due to any cause), as well as incidence of relapse, cancer- specific death, and noncancer death
Type of measurement	Observation
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	NA
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	Overall: No significant differences

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	?
Bias due to deviation from intended intervention (assignment to intervention)	?
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	?
Bias in measurement of the outcome	?
Bias in selection of the reported result	?
Other sources of bias	?
Overall RoB judgment	?

Vitamin D level

Outcome type As specificed by the authors	Others
Outcome specification	NA
Type of measurement	Blood Test
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	NA
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	Overall: Subgroupanalysis: low (<20 ng/mL (n=173)), middle (20-40 ng/mL (n=232)), or high (>40 ng/mL (n=5)) serum levels of 25(OH)D at baseline In middle-baseline-level subgroup, 5-year relapse-free survival significantly higher in intervention arm than in placebo arm (85% vs. 71%; HR for relapse or death, 0.46; 95% CI, 0.24-0.86; p=.02) In low-baseline-level subgroup no significant differences In high-baseline-level subgroup no further analyses because of small number of patients Overall survival was not significantly different between the arms in both the middle subgroup and the low subgroup Post hoc analysis: Cumulative incidence of relapse was not significantly different In the subgroup with middle baseline levels of 25(OH)D, the cumulative incidence of relapse was significantly lower in the intervention arm than in the placebo arm (subdistribution HR, 0.44; 95% CI, 0.21-0.89; p=.02) No significant difference for the cumulative incidence of relapse in the low-baseline-level subgroup Age adjusted analysis: hazard of relapse or death was significantly less in intervention arm compared with the placebo arm, with an adjusted HR of 0.66 (95% CI, 0.43-0.99; p=.048) but hazard of death was not significantly different Analyses adjusted for stage I disease status did not show any significant differences No ignificant associations for gender, age groups, body many index, site of cancer, disease stage and adenocarcinoma vs. nonadenocarcinoma

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	?
Bias due to deviation from intended intervention (assignment to intervention)	?
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	?
Bias in measurement of the outcome	?
Bias in selection of the reported result	?
Other sources of bias	?
Overall RoB judgment	?

Funding and Conflicts of Interest

Funding	Supported by the Ministry of Education, Culture, Sports, Science, and Technology in the Japan-Supported Program for the Strategic Research Foundation at Private Universities, funding from the International University of Health and Welfare Hospital, and Jikei University School of Medicine
Conflicts of Interest	According to authors no conflict of interest

Further points for assessing the study

Sample

Power analysis performed	?
- Sample size corresponds to power analysis	?
- Reasons for insufficient sample size based on power analysis	?
If no power analysis performed: at least moderate sample size (n >= 30 per arm)	?
Ethnicity mentioned	?

Alternative Explanation

Other explanations for an effect besides the investigated intervention	?
- Possibility of attention effects	?
- Possibility of placebo effects	?
- Other reasons	?

Statistics

Correct use of parametric and non-parametric tests Testing for normal distribution only necessary if parametric tests are used, NI: use of parametric tests without report of normal distribution testing	?
Correction for multiple testing	?
Measurement of compliance	?
Consistent reporting in numbers (figures, flowchart, abstract, results)	?
Comprehensive and coherent reporting	?
Cross-over	?
- Sufficient washout period	?
- Tested for carry-over effects	?
- Tested for sequence effects	?

Interpretation of results

Effect sizes reported (clinical vs. statistical significance)	?
Side effects systematically recorded	?
Side effects considered in result interpretation	?
Ethics votum	?

Additional Notes

PRO:

• Ethics vote
• Power analysis (duration about 7 years, if 80 per year and a total of 400 required)
• Intention to treat analysis (except for side effects)
• Adherence was asked at each visit, occasional calls from coordinator and review when a new pack was issued every 6 months
• If vitamin D supplementation was necessary, intervention was stopped, but subjects were followed up
• Note that subgroup analyses should be interpreted with caution due to multiple testing
• Follow-up rate 99.8%

CONTRA:

• Adherence self-report only
• 10% stopped intervention