| Reference ↗
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| Title
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Vitamin D Supplementation and Survival of Patients with Non–small Cell Lung Cancer: A Randomized, Double-Blind, Placebo-Controlled Trial
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| Topic
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Vitamin D
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| Author
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Akiba, T, Morikawa, T, Odaka, M, Nakada, T, Kamiya, N, Yamashita, M, Yabe, M, Inagaki, T, Asano, H, Mori, S, Tsukamoto, Y, Urashima, M
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| Year
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2018
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| Journal
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Clinical Cancer Research
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| DOI
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https://doi.org/10.1158/1078-0432.CCR-18-0483
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Study Note
Brief summary
This study compared the efficacy of treatment of metastatic colorectal cancer (mCRC) with standard chemotherapy alone and standard chemotherapy in combination with cholecalciferol 2000 IU daily. All but one patient had a vitamin D deficiency. The results at 46 months showed that 2,000 IU of vitamin D daily had no effect on disease-free survival or overall survival. The study has a small sample size and vitamin D intake did not always appear to follow protocol. Overall, the authors give very superficial descriptions in the study, especially when presenting the results.
In dieser Studie wurde die Wirksamkeit der Behandlung des metastasierten Kolorektalen Karzinoms (mCRC) mit alleiniger Standard-Chemotherapie und der Standard-Chemotherapie in Kombination mit Cholecalciferol 2000 IE täglich verglichen. Alle bis auf einen Patienten hatten ein Vitamin D Defizit. Die Ergebnisse nach 46 Monaten zeigten, dass 2.000 IE Vitamin D täglich keinen Einfluss auf das Überleben ohne Voranschreiten der Krankheit oder das allgemeine Überleben hatte. Die Studie hat eine kleine Stichprobengröße und die Einnahme des Vitamin D schien nicht immer dem Protokoll zu entsprechen. Insgesamt geben die Autoren sehr oberflächliche Beschreibungen in der Studie, insbesondere bei der Präsentation der Ergebnisse.
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
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Prospective
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| Monocentric / Multicentric Monocentric: conducted in one center/ hospital; </br>Multicentric: conducted in multiple centers/ hospitals
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Monocentric
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| 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
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Double
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| Is randomized
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Yes
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| Cross-over Participants alternate between different treatment groups or conditions over a specified period, allowing each participant to serve as their own control
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No
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| Number of arms
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2
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Study characteristics
| Inclusion criteria
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Histopathologically diagnosed as having NSCLC (adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, or large cell lung carcinoma); with stage IA to IIIA; aged 20 to 75 years at entry; diagnosed and operated at any one of four Jikei University Hospitals at Shimbashi, Kashiwa, Chofu, and Katsushika; with tumor totally resected; discharged without major complications; and could visit the Jikei University Hospitals (Tokyo, Japan) and be followed-up for as long as possible
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| Exclusion criteria
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Already taking a vitamin D supplement or active vitamin D; had a history of urinary tract stones; and other difficulties as judged by the surgeon in charge
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| N randomized
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155
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| 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.
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PP Analysis
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| Specifications on analyses
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Unclear: authors report intention-to-treat analyses, the results contain contradictory information
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| Countries of data collection
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Japan
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| LoE Level of evidence
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Level 2 Oxford 2011
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| Outcome timeline Data collection times
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T0: Baseline
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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.
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Curative
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| Types of cancer "Other Cancers" means that only a subpopulation was specified, but further unspecified cancer types were included
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Lung Cancer - Non-Small Cell Lung Cancer
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| 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
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Early Stage, Advanced Stage
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| Specifications on cancer stages
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IA-IIIA
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| Comorbidities
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NI
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| Current cancer therapies
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Chemotherapy
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| Specifications on cancer therapies
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Oral or injection chemotherapy was administered to the patients according to the stage, except in stage IA and tumor size less than 2 cm
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| Previous cancer therapies
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NI
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| Gender
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Mixed
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| Gender specifications
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38 (25%) female
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| Age groups
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Adults (18+)
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| Age groups specification
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Mean (SD): 68 (9)
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Arms
| Arm type Active control: group receives active treatment; </br>Passive control: for example treatment as usual, waiting control, no treatment
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Intervention
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| Number of participants (arm) N randomized
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77
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| Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date
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5
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| Drop-out reasons
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Lost to follow-up
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| Intervention
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Vitamin D
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| Dosage and regime
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Two capsules of vitamin D3 (total 1,200 IU/day), for 12 months
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| One-time application
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No
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| 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.
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365
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| Side effects / Interactions
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According to authors no side effects
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| Arm type Active control: group receives active treatment; </br>Passive control: for example treatment as usual, waiting control, no treatment
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Placebo
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| Number of participants (arm) N randomized
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78
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| Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date
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6
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| Drop-out reasons
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Lost to follow-up
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| Intervention
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Placebo
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| Dosage and regime
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Two capsule form and identical in appearance and taste, containing sesame oil, gelatin derived from swine, and glycerin, for 12 months
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| One-time application
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No
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| 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.
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365
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| Side effects / Interactions
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According to authors no side effects
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Outcomes
RFS (Recurrence-Free Survival)
| Outcome type As specificed by the authors
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Primary
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| Outcome specification
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5-year recurrence-free survival: the time from the supplement start date to the earlier date of relapse of cancer or death from any cause
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| Type of measurement
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Observation
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| 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".
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NA
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| 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".
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Overall:
No significant differences (p=0.64)
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| Risk of Bias Assessment: Cochrane RoB tool 2.0
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| Bias arising from the randomization process
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low risk
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| Bias due to deviation from intended intervention (assignment to intervention)
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low risk
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| Bias due to deviation from intended intervention (adhering to intervention)
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NA
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| Bias due to missing outcome data
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high risk
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| Bias in measurement of the outcome
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low risk
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| Bias in selection of the reported result
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low risk
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| Other sources of bias
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NA
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| Overall RoB judgment
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high risk
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OS (Overall Survival)
| Outcome type As specificed by the authors
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Secondary
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| Outcome specification
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5-year overall survival: the time from the supplement start date to the date of death from any cause
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| Type of measurement
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Observation
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| 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".
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NA
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| 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".
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Overall:
No significant differences (p=0.63)
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| Risk of Bias Assessment: Cochrane RoB tool 2.0
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| Bias arising from the randomization process
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low risk
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| Bias due to deviation from intended intervention (assignment to intervention)
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low risk
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| Bias due to deviation from intended intervention (adhering to intervention)
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NA
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| Bias due to missing outcome data
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high risk
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| Bias in measurement of the outcome
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low risk
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| Bias in selection of the reported result
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low risk
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| Other sources of bias
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NA
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| Overall RoB judgment
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high risk
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Vitamin D level
| Outcome type As specificed by the authors
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Others
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| Outcome specification
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NA
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| Type of measurement
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Blood Test
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| 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".
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Intervention arm: mean levels of 25(OH)D increased significantly from 21 to 39 ng/mL (p=0.0001),
placebo arm: no significant change (p=0.14)
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| 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".
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NA
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| Risk of Bias Assessment: Cochrane RoB tool 2.0
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| Bias arising from the randomization process
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NA
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| Bias due to deviation from intended intervention (assignment to intervention)
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NA
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| Bias due to deviation from intended intervention (adhering to intervention)
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NA
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| Bias due to missing outcome data
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NA
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| Bias in measurement of the outcome
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NA
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| Bias in selection of the reported result
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NA
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| Other sources of bias
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NA
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| Overall RoB judgment
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NA
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Funding and Conflicts of Interest
| Funding
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Supported by the Ministry of Education, Culture, Sports, Science, and Technology in the Japan-Supported Program for the Strategic Research Foundation at Private Universities and by JSPH KAKENHI grant number: 22501060
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| Conflicts of Interest
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According to authors no conflict of interest
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Further points for assessing the study
Sample
| Power analysis performed
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?
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| - Sample size corresponds to power analysis
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?
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| - Reasons for insufficient sample size based on power analysis
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?
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| If no power analysis performed: at least moderate sample size (n >= 30 per arm)
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?
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| Ethnicity mentioned
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?
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Alternative Explanation
| Other explanations for an effect besides the investigated intervention
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?
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| - Possibility of attention effects
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?
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| - Possibility of placebo effects
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?
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| - Other reasons
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?
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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
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?
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| Correction for multiple testing
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?
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| Measurement of compliance
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?
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| Consistent reporting in numbers (figures, flowchart, abstract, results)
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?
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| Comprehensive and coherent reporting
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?
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| Cross-over
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?
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| - Sufficient washout period
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?
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| - Tested for carry-over effects
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?
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| - Tested for sequence effects
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?
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Interpretation of results
| Effect sizes reported (clinical vs. statistical significance)
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?
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| Side effects systematically recorded
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?
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| Side effects considered in result interpretation
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?
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| Ethics votum
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?
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Additional Notes
?
