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      Calcitriol and cancer therapy: A missed opportunity

      *

      Bone Reports

      Elsevier

      Vitamin D, Cancer, Calcitriol

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          Abstract

          The vitamin D receptor is expressed in most tissues of the body – and the cancers that arise from those tissues. The vitamin D signaling pathway is active in those tissues and cancers. This is at least consistent with the hypothesis that perturbing this signaling may have a favorable effect on the genesis and growth of cancers. Epidemiologic data indicate that vitamin D signaling may be important in the initiation and outcome of a number of types of cancer. Many studies have shown that calcitriol (1,25 dihydroxycholecalciferol) and other vitamin D compounds have antiproliferative, pro-apoptotic, anti-cell migration and antiangiogenic activity in a number of preclinical studies in many different cancer types. Unfortunately, the assessment of the activity of calcitriol or other vitamin D analogues in the treatment of cancer, as single agents or in combination with other anticancer agents has been stymied by the failure to adhere to commonly accepted principles of drug development and clinical trials conduct.

          Highlights

          • Many studies indicate that vitamin D compounds have cancer prevention and treatment properties in vitro and in vivo cancer models and epidemiologic studies note the association between low vitamin D levels and cancer occurrence and unfavorable outcome.
          • Many clinical trials in cancer patients have been done to define safety and efficacy of calcitriol and analogues and several trials suggest clinical benefit.
          • Two randomized trials of calcitriol + chemotherapy (docetaxel) in men with prostate cancer entered >1150 patients.
          • These trials did not adhere to principles of optimal trial design (choice of optimal dose of drug and balanced randomization) and the failure to execute on these findings is a missed opportunity.

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          Most cited references 155

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          Meta-analysis of observational studies of serum 25-hydroxyvitamin D levels and colorectal, breast and prostate cancer and colorectal adenoma.

          Epidemiological studies have suggested a reduced risk of several cancers associated with high vitamin D status. We performed a systematic review with meta-analyses of observational studies of serum 25-hydroxyvitamin D level and colorectal, breast and prostate cancer and colonic adenoma. The literature of December 2009 was searched without language restriction. The meta-regression analysis was done to compute dose-response effects. Because in case-control studies, serum 25-hydroxyvitamin D level is measured after the diagnosis of cancer, separate analyses for case-control and prospective studies were done. We identified 35 independent studies. The seven studies on colorectal adenomas were heterogeneous in terms of endpoint and control for major confounding factors, and we did not perform a meta-analysis of these data. The summary relative risk (SRR) and (95% confidence interval) for a 10 ng/ml increase in serum 25-hydroxyvitamin D was 0.85 (0.79; 0.91) for colorectal cancer (2,630 cases in 9 studies); 0.89 (0.81;0.98) for breast cancer (6,175 cases in 10 studies); and 0.99 (0.95;1.03) for prostate cancer (3,956 cases in 11 studies). For breast cancer, case-control studies (3,030 cases) had major limitations and obtained SRR of 0.83 (0.79; 0.87) whereas SRR of prospective studies (3,145 cases) was 0.97 (0.92; 1.03). For colorectal and breast cancer, differences between cases and controls in the season of blood draw or in overweight/obesity or physical inactivity could not explain the results. In conclusion, a consistent inverse relationship between serum 25-hydroxyvitamin D levels and colorectal cancer was found. No association was found for breast and prostate cancer. Copyright © 2010 UICC.
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            Phase II study of bevacizumab plus temozolomide during and after radiation therapy for patients with newly diagnosed glioblastoma multiforme.

            This open-label, prospective, multicenter single-arm phase II study combined bevacizumab (BV) with radiation therapy (RT) and temozolomide (TMZ) for the treatment of newly diagnosed glioblastoma (GBM). The objectives were to determine the efficacy of this treatment combination and the associated toxicity. Seventy patients with newly diagnosed GBM were enrolled between August 2006 and November 2008. Patients received standard RT starting within 3 to 6 weeks after surgery with concurrent administration of daily TMZ and biweekly BV. After completion of RT, patients resumed TMZ for 5 days every 4 weeks and continued biweekly BV. MGMT promoter methylation was assessed on patient tumor tissue. A University of California, Los Angeles/Kaiser Permanente Los Angeles (KPLA) control cohort of newly diagnosed patients treated with first-line RT and TMZ who had mostly received BV at recurrence was derived for comparison. The overall survival (OS) and progression-free survival (PFS) were 19.6 and 13.6 months, respectively, compared to 21.1 and 7.6 months in the University of California, Los Angeles/KPLA control cohort, and 14.6 and 6.9 months in the European Organisation for Research and Treatment of Cancer-National Cancer Institute of Canada cohort. Correlation of MGMT promoter methylation and improved OS and PFS was retained in the study group. Comparative subset analysis showed that poor prognosis patients (recursive partitioning analysis class V/VI) may derive an early benefit from the use of first-line BV. Toxicity attributable to RT/TMZ was similar, and additional toxicities were consistent with those reported in other BV trials. Patients treated with BV and TMZ during and after RT showed improved PFS without improved OS compared to the University of California, Los Angeles/KPLA control group. Additional studies are warranted to determine if BV administered first-line improves survival compared to BV at recurrence.
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              Association between vitamin D and risk of colorectal cancer: a systematic review of prospective studies.

              To conduct a systematic review of prospective studies assessing the association of vitamin D intake or blood levels of 25-hydroxyvitamin D [25(OH)D] with the risk of colorectal cancer using meta-analysis. Relevant studies were identified by a search of MEDLINE and EMBASE databases before October 2010 with no restrictions. We included prospective studies that reported relative risk (RR) estimates with 95% CIs for the association between vitamin D intake or blood 25(OH)D levels and the risk of colorectal, colon, or rectal cancer. Approximately 1,000,000 participants from several countries were included in this analysis. Nine studies on vitamin D intake and nine studies on blood 25(OH)D levels were included in the meta-analysis. The pooled RRs of colorectal cancer for the highest versus lowest categories of vitamin D intake and blood 25(OH)D levels were 0.88 (95% CI, 0.80 to 0.96) and 0.67 (95% CI, 0.54 to 0.80), respectively. There was no heterogeneity among studies of vitamin D intake (P = .19) or among studies of blood 25(OH)D levels (P = .96). A 10 ng/mL increment in blood 25(OH)D level conferred an RR of 0.74 (95% CI, 0.63 to 0.89). Vitamin D intake and blood 25(OH)D levels were inversely associated with the risk of colorectal cancer in this meta-analysis.
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                Author and article information

                Contributors
                Journal
                Bone Rep
                Bone Rep
                Bone Reports
                Elsevier
                2352-1872
                13 June 2018
                December 2018
                13 June 2018
                : 9
                : 110-119
                Affiliations
                Inova Schar Cancer Institute, Inova Health System, Fairfax, VA 22037, United States of America
                Author notes
                [* ]Virginia Commonwealth University, 3221 Gallows Rd., Fairfax, VA 22031, United States of America. Donald.trump@ 123456inova.org
                Article
                S2352-1872(18)30035-4
                10.1016/j.bonr.2018.06.002
                6303233
                © 2018 The Author

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                Categories
                Articles from the Special Issue on Bone Health-Vitamin D; Edited by Prof Daniel Bikle and Prof Roger Bouillon

                calcitriol, cancer, vitamin d

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