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Vitamin D supplementation shows limited benefit in patients with gastrointestinal cancers
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Vitamin D3 supplementation moderately prolonged PFS and, to a limited extent, RFS among patients with certain gastrointestinal cancers, according to results of two separate studies published in JAMA.
The randomized phase 2 SUNSHINE trial examined the impact of high-dose vs. standard-dose vitamin D3 supplementation during chemotherapy on PFS among patients with advanced or metastatic colorectal cancer. The researchers found no statistically significant difference in PFS when comparing groups treated with either dose; however, multivariate analysis revealed a statistically significant lower risk for disease progression or death among patients in the high-dose vitamin D3 group.
The randomized, single-center AMATERASU trial evaluated RFS among patients with stage I to stage III digestive tract cancers who received vitamin D3 supplementation or placebo. The study showed a slight, albeit not statistically significant, increase in 5-year RFS among those who received vitamin D3.
“Vitamin D has demonstrated antiproliferative, antiangiogenic, proapoptotic, anti-inflammatory and immunomodulatory effects in cell lines and animal models of colon cancer. Epidemiologic studies in patients have also shown an association between higher plasma levels of vitamin D and improved survival in colorectal cancer and, in particular, in metastatic colorectal cancer,” Kimmie Ng, MD, MPH, director of clinical research at Dana-Farber Cancer Institute and lead author of the SUNSHINE study, told HemOnc Today.
SUNSHINE trial
In the double-blind, multicenter SUNSHINE trial, Ng and colleagues randomly assigned 139 patients (mean age 56 years; 43% women) with advanced or metastatic colorectal cancer in a 1:1 ratio to receive high-dose vitamin D3 (loading dose of 8,000 IU/day for the first cycle, followed by 4,000 IU/day for subsequent chemotherapy cycles) or standard-dose vitamin D3 (400 IU/day) plus concurrent chemotherapy.
Median follow-up was 22.9 months (interquartile range [IQR], 11.8-34.5).
Results showed median PFS of 13 months (95% CI, 10.1-14.7; 49 PFS events) for those who received high-dose vitamin D3 compared with 11 months (95% CI, 9.5 to 14; 62 PFS events) for those in the standard-dose group. Multivariable HR for PFS or death was 0.64 (1-sided 95% CI, 0-0.9).
Researchers observed no significant differences between the high-dose and standard-dose groups in tumor objective response rate (58% vs. 63%) or median OS (24.3 months for both groups).
“High-dose vitamin D3 supplementation improved PFS when added to standard chemotherapy for patients with previously untreated, metastatic colorectal cancer,” Ng told HemOnc Today. “Even after controlling for potentially confounding variables, high-dose vitamin D3 led to a significant 36% improvement in PFS.”
AMATERASU trial
The double-blind, placebo-controlled AMATERASU trial included 417 participants (mean age, 66 years; 66% men) randomly assigned in a 3:2 ratio to receive either 2,000 IU/day vitamin D3 or placebo after undergoing surgical resection for a digestive tract cancer (esophageal, 10%; gastric, 42%; colorectal, 48%).
Researchers followed patients for a median of 3.5 years (IQR, 2.3-5.3 years), with a maximum follow-up period of 7.6 years.
Results showed 5-year RFS of 77% for those in the vitamin D3 group compared with 69% in the placebo group (HR for relapse or death = 0.76; 95% CI, 0.5-1.14). Relapse or death occurred among 50 patients (20%) in the vitamin D3 group compared with 43 patients (26%) in the placebo group. The death rate of 15% was identical in both groups (n = 37 in vitamin D3 group vs. n = 25 in placebo group).
Five-year OS was 82% in the vitamin D3 group compared with 81% in the placebo group (HR for death = 0.95; 95% CI, 0.57-1.57).
Although the differences in OS and RFS did not reach statistical significance, there was a significant increase in 5-year RFS when broken down by patients’ baseline serum 25(OH)D levels. Five-year RFS for patients with a serum 25(OH)D level between 20 ng/mL and 40 ng/mL was 85% in the vitamin D3 group compared with 71% in the placebo group (HR for relapse or death = 0.46; 95% CI, 0.24-0.86).
Mitsuyoshi Urashima MD, PhD, MPH, professor of molecular epidemiology at Jikei University School of Medicine in Tokyo and lead author of the AMATERASU study, told HemOnc Today that the overall eight percentage-point difference in RFS, although not statistically significant, suggests there is a role for vitamin D3 supplementation in the treatment of gastrointestinal cancers.
“Vitamin D is not effective in all patients with cancer, but [it] may improve the prognosis [for some] patients with cancer,” Urashima said.
Clinical impact
Ng told HemOnc Today that her group’s results need confirmation from the larger randomized phase 3 SOLARIS trial that will begin later this year through the Alliance for Clinical Trials in Oncology cooperative group.
“In the current era of very expensive and often quite toxic chemotherapy and targeted drugs, vitamin D represents a potentially important addition to the armamentarium of treatment options for [patients with] colorectal cancer, particularly with respect to safety and cost,” she said. “Consequently, if our results are confirmed in the upcoming large phase 3 randomized trial opening later this year, then this research will have a global impact on the care of patients with colorectal cancer.”
Urashima touted vitamin D3’s low cost, safety and availability as reasons why it should be considered as a supplement to cancer therapies, despite the limited association with RFS seen in his group’s study.
“In contrast to adjuvant chemotherapy and molecular targeting medicine, vitamin D is a natural compound that is essentially nontoxic and cost-effective to produce. By simply being exposed to sunlight (eg, exercising outside), patients can increase their 25-hydroxyvitamin D levels at no cost and may potentially decrease the risk for relapse and improve survival,” he told HemOnc Today. “Because vitamin D has few side effects, prescribing vitamin D3 for patients may be a good choice even if the effect of vitamin D on the survival of patients with cancer [is] not significant.”
In an editorial accompanying the studies, Elizabeth L. Barry, PhD, associate professor of epidemiology at Geisel School of Medicine at Dartmouth, and colleagues found the results of both studies to be similar with respect to PFS and RFS, with null results for OS.
“It may be tempting to interpret the preliminary findings regarding recurrence- and progression-free survival as specific antineoplastic effects of vitamin D3 supplementation,” Barry and colleagues wrote. “However, higher vitamin D levels have been associated with substantially decreased mortality and morbidity among hospitalized patients with a range of non-neoplastic diseases as well as with cancer. Thus, the findings of the two trials may reflect relatively broad biological effects of vitamin D.”
Barry and colleagues said further trials with longer follow-up and biological measurements “to clarify underlying mechanisms” are needed to evaluate and confirm the findings of both studies. – by Drew Amorosi
For more information:
Kimmie Ng, MD, MPH, can be reached at Dana-Farber Cancer Institute, 450 Brookline Ave., Boston, MA 02215; email: kimmie_ng@dfci.harvard.edu.
Mitsuyoshi Urashima MD, PhD, MPH, can be reached at Division of Molecular Epidemiology, Jikei University School of Medicine, Nishi-shimbashi 3-25-8, Minato-ku, Tokyo 105-8461, Japan; email: urashima@jikei.ac.jp.
Disclosure: Ng reports grants from Celgene, Consano, Genentech, Gilead Sciences, NCI, Pharmavite, Tarrex Biopharma and Trovagene; and personal fees from Bayer, Eli Lilly, Genentech, Seattle Genetics and Tarrex Biopharma. Urashima reports no relevant financial disclosures. Please see the studies for all other authors’ relevant financial disclosures. Barry and the other editorial authors report no relevant financial disclosures.
Perspective
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David Ilson, MD, PhD
The oncology literature is replete with retrospective studies indicating that higher serum vitamin D levels may correlate with reduced cancer risk. However, whether vitamin D level is merely a reflection of other health-related issues and not directly impactful on cancer development or treatment outcomes remains to be determined.
Even if low vitamin D levels correlate with increased cancer risk or impact on treatment, this does not mean that correcting or supplementing the deficiency will improve outcomes. Randomized clinical trials to test a vitamin D supplement hypothesis are required to substantiate retrospective data.
Ng and colleagues previously reported that patients treated in the metastatic colorectal cancer trial CALGB 80405 who had higher baseline vitamin D levels had significantly improved OS and PFS compared with lower baseline vitamin D levels. This appeared to be independent of other prognostic factors, including KRAS mutation status.
Based on this observation, they now report results of the SUNSHINE trial treating patients with metastatic colorectal cancer with a high-dose vitamin D3 supplement vs. a standard dose, combined with mFOLFOX6 and bevacizumab (Avastin, Genentech). In this randomized phase 2 trial, there was a nonsignificant increase of 2 months in PFS with no impact on antitumor response or OS.
Although high-dose vitamin D3 supplementation did achieve the desired increase in vitamin D levels, there was no correlation of a potential greater impact in patients who had the lowest baseline vitamin D levels. Despite the weakness of this observation, a phase 3 trial testing high-dose vitamin D3 added to chemotherapy among patients with metastatic colorectal cancer is planned.
Investigators for the AMATERASU trial evaluated vitamin D3 supplementation vs. placebo among patients undergoing curative treatment for gastrointestinal tract cancers, predominantly colorectal cancer. Vitamin D3 did not significantly improve 5-year RFS, the primary trial outcome, compared with placebo (77% vs. 69%) and 5-year OS was nearly equivalent (81% vs 82%). Like the SUNSHINE trial, there was no differential impact among patients with the lowest baseline vitamin D levels. The authors also observed no impact on potential genetic polymorphisms of either vitamin D receptors or vitamin D binding proteins.
These two negative trials reinforce the caveat about drawing conclusions from retrospective data and shed needed sunlight on the ongoing debate about the value of vitamin D supplementation and cancer therapy.
Reference:
Ng K, et al. J Clin Oncol. 2015;doi:10.1200/jco.2015.33.15_suppl.3503.
Perspective
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Jimmy J. Hwang, MD
Substantial observational and retrospective data over the past several decades have suggested a correlation between vitamin D levels and outcomes among patients with cancer and, in particular, colorectal cancer.
Several prospective randomized studies published this year have not confirmed the anticipated benefits of supplementing vitamin D3 with a therapeutic intent, targeting patients with established cancer or at high risk for recurrence after the resection of a malignancy. Each of these studies had limitations: for example, sample size for the SUNSHINE and AMATERASU trials and heterogeneity in the AMATERASU trial. These affect and limit interpretation of their results.
There were also notable differences between the studies. Both studies used different patient populations — the SUNSHINE trial was limited to patients with metastatic colorectal cancer receiving initial chemotherapy, whereas the AMATERASU trial included patients with resected stage I to stage III gastrointestinal malignancies, including colorectal, gastroesophageal and small-bowel carcinomas.
In addition, the SUNSHINE trial investigated high-dose (4,000 IU twice daily for one cycle, then 4,000 IU daily) vs. standard-dose vitamin D3 supplementation of 400 IU daily, with the former clearly increasing vitamin D levels. The AMATERASU study investigated vitamin D3 supplementation of 2,000 IU daily vs. placebo.
Despite these limitations and differences, these studies did yield some intriguing findings that appear to confirm preclinical studies and hypotheses, and the results should provoke further investigation.
Although neither trial met its primary endpoint, they were close, suggesting that larger studies may have demonstrated a significant benefit. However, there were discordant results regarding whether patients who had low baseline vitamin D levels derived some benefit from supplementation, with only the AMATERASU study showing there may be such a benefit. The SUNSHINE study showed that patients with a lower BMI (perhaps less obese) derived a benefit from high-dose supplementation.
Perhaps the most intriguing finding was from the SUNSHINE trial, which showed that high-dose vitamin D3 supplementation may decrease diarrhea — because fewer patients (1%) in the high-dose supplementation arm had severe (grade 3 or greater) diarrhea than patients who received standard supplementation (12%) — without causing other significant toxicities. The frequency of diarrhea in the standard supplementation group seemed somewhat higher than expected, so this difference may simply be a chance finding resulting from a relatively small study population. However, the difference in the frequency of diarrhea may also reflect a potential role for vitamin D in the maintenance of gut health, as suggested by preclinical studies.
Regardless, this finding raises the possibility that vitamin D3 supplementation may have a palliative benefit in patients receiving chemotherapy and presents a route to improve the therapeutic index of chemotherapy, a notion worthy of further investigation.
Reference:
Froicu M, et al. BMC Immunol. 2007;doi:10.1186/1471-2172-8-5.
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