{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T15:53:45Z","timestamp":1785772425178,"version":"3.56.0"},"reference-count":28,"publisher":"American Medical Association (AMA)","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA"],"abstract":"\n Importance<\/jats:title>\n \n In a phase 2 randomized clinical trial, high-dose vitamin D\n 3<\/jats:sub>\n added to standard treatment improved progression-free survival (PFS) compared with standard-dose vitamin D\n 3<\/jats:sub>\n in patients with metastatic colorectal cancer (mCRC).\n <\/jats:p>\n <\/jats:sec>\n \n Objective<\/jats:title>\n \n To determine if high-dose vitamin D\n 3<\/jats:sub>\n added to standard chemotherapy improves outcomes in patients with previously untreated mCRC.\n <\/jats:p>\n <\/jats:sec>\n \n Design, Setting, and Participants<\/jats:title>\n Double-blind phase 3 randomized clinical trial enrolling 455 patients with previously untreated mCRC, conducted in the US through the National Clinical Trials Network from October 2019 to December 2022 (database freeze: July 15, 2024).<\/jats:p>\n <\/jats:sec>\n \n Interventions<\/jats:title>\n \n mFOLFOX6 (modified FOLFOX6 [5-fluorouracil, leucovorin, oxaliplatin]) or FOLFIRI (5-fluorouracil, leucovorin, irinotecan) plus bevacizumab every 2 weeks with either high-dose vitamin D\n 3<\/jats:sub>\n (8000 IU daily\u2009\u00d7\u200914 days as loading dose followed by 4000 IU daily) or standard-dose vitamin D\n 3<\/jats:sub>\n (400 IU daily) until disease progression, intolerable toxicity, or withdrawal of consent.\n <\/jats:p>\n <\/jats:sec>\n \n Main Outcomes and Measures<\/jats:title>\n The primary end point was PFS assessed by the unstratified log-rank test. Secondary end points included objective response rate, overall survival, and toxicity. Prespecified subgroup analyses of PFS were performed according to known prognostic factors.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Among 455 randomized patients (median age, 59 years; 181 [40%] female) with median follow-up 20 months, the median PFS for high-dose vitamin D\n 3<\/jats:sub>\n (n\u2009=\u2009228) was 11.8 months (95% CI, 10.3-13.3) vs 10.3 months (95% CI, 9.4-12.2) for standard-dose vitamin D\n 3<\/jats:sub>\n (n\u2009=\u2009227) (1-sided log-rank\n P<\/jats:italic>\n \u2009=\u2009.25). There were no significant differences in objective response rate between high-dose and standard-dose vitamin D\n 3<\/jats:sub>\n (51% [95% CI, 44%-58%] vs 44% [95% CI, 37%-50%], respectively;\n P<\/jats:italic>\n \u2009=\u2009.12), or in overall survival (median, 25.6 vs 27.0 months; 1-sided log-rank\n P<\/jats:italic>\n \u2009=\u2009.66). There were no clinically meaningful differences in the most common grade 3 or greater adverse events between the high- and standard-dose groups, including neutropenia (n\u2009=\u200967 [32%] vs n\u2009=\u200962 [30%]) and hypertension (n\u2009=\u200942 [20%] vs n\u2009=\u200949 [23%]) or in incidence of vitamin D\u2013associated toxicities.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions and Relevance<\/jats:title>\n \n Among patients with previously untreated mCRC, addition of high-dose vitamin D\n 3<\/jats:sub>\n , vs standard-dose vitamin D\n 3<\/jats:sub>\n , to standard chemotherapy plus bevacizumab did not improve PFS.\n <\/jats:p>\n <\/jats:sec>\n \n Trial Registration<\/jats:title>\n \n ClinicalTrials.gov Identifier:\n NCT04094688<\/jats:ext-link>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1001\/jama.2026.9350","type":"journal-article","created":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T15:00:26Z","timestamp":1785769226000},"source":"Crossref","is-referenced-by-count":0,"title":["Addition of High-Dose Vitamin D\n 3<\/sub>\n to Standard Treatment in Patients With Metastatic Colorectal Cancer"],"prefix":"10.1001","author":[{"given":"Kimmie","family":"Ng","sequence":"first","affiliation":[{"name":"Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts"},{"name":"Associate Editor, JAMA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang-Shu","family":"Ou","sequence":"additional","affiliation":[{"name":"Alliance Statistics and Data Management Center, Mayo Clinic, Rochester, Minnesota"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tyler","family":"Zemla","sequence":"additional","affiliation":[{"name":"Alliance Statistics and Data Management Center, Mayo Clinic, Rochester, Minnesota"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadine A.","family":"Jackson","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aparna","family":"Kalyan","sequence":"additional","affiliation":[{"name":"Department of Hematology and Medical Oncology, Robert H. 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H.","family":"Schwartz","sequence":"additional","affiliation":[{"name":"Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Zuckerman","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, St Luke\u2019s Cancer Institute, Boise, Idaho"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce W.","family":"Hollis","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Medical University of South Carolina, Charleston"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eileen M.","family":"O\u2019Reilly","sequence":"additional","affiliation":[{"name":"Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey A.","family":"Meyerhardt","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, 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