Effect Modification of Vitamin D Supplementation by Histopathological Characteristics on Survival of Patients with Digestive Tract Cancer: Post Hoc Analysis of the AMATERASU Randomized Clinical Trial

Some coauthors of this study previously performed the AMATERASU randomized, double-blind, placebo-controlled trial of postoperative oral vitamin D supplementation (2,000 IU/day) in 417 patients with stage I to III digestive tract cancer from the esophagus to the rectum who underwent curative surgery (UMIN000001977). We conducted a post-hoc analysis of the AMATERASU trial to explore the effects of modification of vitamin D supplementation by histopathological characteristics on survival. Among patients with poorly differentiated adenocarcinoma, the 5-year relapse-free survival rate of patients supplemented with vitamin D was 91% compared with 63% in the placebo group (hazard ratio [HR], 0.25; 95% confidence interval [CI], 0.08 to 0.78; P = 0.017; P for interaction = 0.023). Similarly, the 5-year overall survival rate was 92% in the vitamin D group compared with 72% in the placebo group (HR, 0.25; 95%CI, 0.07 to 0.94; P = 0.040; P for interaction = 0.012). In contrast, there were no significant effects in other histopathological characteristics between vitamin D and placebo groups. These findings generated the hypothesis that oral vitamin D supplementation may improve both relapse-free survival and overall survival in a subgroup of patients with poorly differentiated adenocarcinoma.

Download Full-text

Effect of Vitamin D on Relapse-Free Survival in a Subgroup of Patients with p53 Protein–Positive Digestive Tract Cancer: A Post Hoc Analysis of the AMATERASU Trial

Cancer Epidemiology Biomarkers & Prevention ◽

10.1158/1055-9965.epi-19-0986 ◽

2019 ◽

Vol 29 (2) ◽

pp. 406-413 ◽

Cited By ~ 2

Author(s):

Taisuke Akutsu ◽

Shinya Okada ◽

Shinichi Hirooka ◽

Masahiro Ikegami ◽

Hironori Ohdaira ◽

...

Keyword(s):

Vitamin D ◽

Digestive Tract ◽

P53 Protein ◽

Relapse Free Survival ◽

Free Survival ◽

Digestive Tract Cancer ◽

Post Hoc Analysis ◽

Tract Cancer ◽

Post Hoc

Download Full-text

Effect of Serum SPARC Levels on Survival in Patients with Digestive Tract Cancer: A Post Hoc Analysis of the AMATERASU Randomized Clinical Trial

Cancers ◽

10.3390/cancers12061465 ◽

2020 ◽

Vol 12 (6) ◽

pp. 1465

Author(s):

Taisuke Akutsu ◽

Eisaku Ito ◽

Mitsuo Narita ◽

Hironori Ohdaira ◽

Yutaka Suzuki ◽

...

Keyword(s):

Vitamin D ◽

Digestive Tract ◽

Multivariate Analyses ◽

Controlled Trial ◽

Vitamin D Supplementation ◽

Digestive Tract Cancer ◽

Post Hoc Analysis ◽

Tract Cancer ◽

Potential Biomarker ◽

Post Hoc

Observational studies suggest that physical activity may improve, whereas sarcopenia may worsen the survival of cancer patients. It has been suggested that secreted protein acidic and rich in cysteine (SPARC), one of the myokines that is secreted into the bloodstream by muscle contraction, has tumor-suppressive effects. Based on the hypothesis that serum SPARC level may be a potential prognostic biomarker, a post hoc analysis of the AMATERASU randomized, double-blind, placebo-controlled trial of postoperative oral vitamin D supplementation (2000 IU/day) in patients with stage I–III digestive tract cancer from the esophagus to the rectum (UMIN000001977) was conducted with the aim of exploring the association between serum SPARC levels after operation and survival. On multivariate analyses adjusting serum 25-hydroxyvitamin D, vitamin D supplementation, sarcopenia, body mass index, age, sex, cancer loci, stage, and adjuvant chemotherapy, patients with SPARC levels lower than the median level had a significantly higher risk for death than those with higher levels (hazard ratio, 2.25; 95% confidence interval, 1.25–4.05; p = 0.007), whereas there were no significant associations with other outcomes including recurrence. However, on the same multivariate analyses, sarcopenia was not a risk factor for death and/or relapse. These results suggest that serum SPARC levels may be a potential biomarker for death but not cancer relapse.

Download Full-text

Effect of Vitamin D Supplementation on Survival of Digestive Tract Cancer Patients with Low Bioavailable 25-Hydroxyvitamin D Levels: A Post Hoc Analysis of the AMATERASU Randomized Clinical Trial

Cancers ◽

10.3390/cancers12020347 ◽

2020 ◽

Vol 12 (2) ◽

pp. 347 ◽

Cited By ~ 2

Author(s):

Mitsuyoshi Urashima ◽

Mai Okuyama ◽

Taisuke Akutsu ◽

Hironori Ohdaira ◽

Mutsumi Kaji ◽

...

Keyword(s):

Vitamin D ◽

Cancer Patients ◽

Digestive Tract ◽

Vitamin D Supplementation ◽

Digestive Tract Cancer ◽

Post Hoc Analysis ◽

Hydroxyvitamin D ◽

Tract Cancer ◽

25 Hydroxyvitamin D ◽

Post Hoc

Vitamin D has been shown to suppress the growth of cancer cells. Cancer cells are believed to take up bioavailable 25-hydroxyvitamin D (25[OH]D) (i.e., not bound to vitamin-D-binding protein (DBP)) more efficiently than DBP-bound 25(OH)D. Our aim was to use this bioavailable 25(OH)D, rather than total 25(OH)D, as a biomarker of vitamin D deficiency to investigate whether vitamin D supplementation improves the relapse-free survival (RFS) of patients with digestive tract cancer from the esophagus to the rectum by conducting a post hoc analysis of the AMATERASU trial (UMIN000001977). The bioavailable 25(OH)D levels were calculated via an equation using data of serum total 25(OH)D, albumin, and DBP levels, and DBP genotypes (rs7041 and rs4588). We estimated bioavailable 25(OH) levels in 355 patients. In a subgroup of patients with low bioavailable 25(OH)D levels (<median) (n = 177), 5 year RFS was 77% in the vitamin D group vs. 58% in the placebo group (hazard ratio, 0.54; 95% confidence interval, 0.31–0.95; p = 0.03), whereas no significant difference was seen in a subgroup of patients with high bioavailable 25(OH)D levels (p for interaction = 0.046). We hypothesize that vitamin D supplementation may be effective in improving RFS among digestive tract cancer patients with low bioavailable 25(OH)D levels.

Download Full-text

Vitamin D Supplementation Regulates Postoperative Serum Levels of PD-L1 in Patients with Digestive Tract Cancer and Improves Survivals in the Highest Quintile of PD-L1: A Post Hoc Analysis of the AMATERASU Randomized Controlled Trial

Nutrients ◽

10.3390/nu13061987 ◽

2021 ◽

Vol 13 (6) ◽

pp. 1987

Author(s):

Makoto Morita ◽

Mai Okuyama ◽

Taisuke Akutsu ◽

Hironori Ohdaira ◽

Yutaka Suzuki ◽

...

Keyword(s):

Vitamin D ◽

Digestive Tract ◽

Controlled Trial ◽

Vitamin D Supplementation ◽

Double Blind ◽

Digestive Tract Cancer ◽

Post Hoc Analysis ◽

Tract Cancer ◽

Postoperative Serum ◽

Post Hoc

Because vitamin D responsive elements have been found to be located in the PD-L1 gene, vitamin D supplementation was hypothesized to regulate serum PD-L1 levels and thus alter survival time of cancer patients. A post hoc analysis of the AMATERASU randomized, double-blind, placebo-controlled trial of postoperative vitamin D3 supplementation (2000 IU/day) in 417 patients with stage I to stage III digestive tract cancer from the esophagus to the rectum was conducted. Postoperative serum PD-L1 levels were measured by ELISA and divided into quintiles (Q1–Q5). Serum samples were available for 396 (95.0%) of the original trial. Vitamin D supplementation significantly (p = 0.0008) up-regulated serum PD-L1 levels in the lowest quintile (Q1), whereas it significantly (p = 0.0001) down-regulated them in the highest quintile (Q5), and it did not either up- or down-regulate them in the middle quintiles (Q2–Q4). Significant effects of vitamin D supplementation, compared with placebo on death (HR, 0.34; 95% CI, 0.12–0.92) and relapse/death (HR, 0.37; 95% CI, 0.15–0.89) were observed in the highest quintile (Q5) of serum PD-L1, whereas significant effects were not observed in other quintiles (Pinteraction = 0.02 for death, Pinteraction = 0.04 for relapse/death). Vitamin D supplementation significantly reduced the risk of relapse/death to approximately one-third in the highest quintile of serum PD-L1.

Download Full-text