Plasma 25-Hydroxyvitamin D Levels and Survival in Patients with Advanced or Metastatic Colorectal Cancer: Findings from CALGB/SWOG 80405 (Alliance)

Abstract

Purpose: Previous studies have suggested that higher circulating 25-hydroxyvitamin D [25(OH)D] levels are associated with decreased colorectal cancer risk and improved survival. However, the influence of vitamin D status on disease progression and patient survival remains largely unknown for patients with advanced or metastatic colorectal cancer.

Experimental design: We prospectively collected blood samples in 1,041 patients with previously untreated advanced or metastatic colorectal cancer participating in a randomized phase III clinical trial of first-line chemotherapy plus biologic therapy. We examined the association of baseline plasma 25(OH)D levels with overall survival (OS) and progression-free survival (PFS). Cox proportional hazards models were used to calculate hazard ratios (HRs) and confidence intervals (CIs), adjusted for prognostic factors and confounders.

Results: At study entry, 63% of patients were vitamin D deficient (<20 ng/mL) and 31% were vitamin D insufficient (20-<30 ng/mL). Higher 25(OH)D levels were associated with an improvement in OS and PFS (P trend = 0.0009 and 0.03, respectively). Compared with patients in the bottom quintile of 25(OH)D (≤10.8 ng/mL), those in the top quintile (≥24.1 ng/mL) had a multivariable-adjusted HR of 0.66 (95% CI, 0.53-0.83) for OS and 0.81 (95% CI, 0.66-1.00) for PFS. The improved survival associated with higher 25(OH)D levels was consistent across patient subgroups of prognostic patient and tumor characteristics.

Conclusions: In this large cohort of patients with advanced or metastatic colorectal cancer, higher plasma 25(OH)D levels were associated with improved OS and PFS. Clinical trials assessing the benefit of vitamin D supplementation in patients with colorectal cancer are warranted.

Trial registration: ClinicalTrials.gov NCT00265850.

Conflict of interest statement

Disclosure of Potential Conflicts of Interest:

R.M.G. declares consulting for Merck KGaA. C.S.F. declares consulting for Agios, Bain Capital, Bayer, Celgene, Dicerna Pharmaceuticals, Eli Lilly and Company, Entrinsic Health Solutions, Five Prime Therapeutics, Genentech, Gilead Sciences, KEW, Merck & Co., Merrimack Pharmaceuticals, Pfizer, Sanofi, Taiho Pharmaceutical, and Unum Therapeutics. He also serves as a Director for CytomX Therapeutics and owns unexercised stock options for CytomX Therapeutics and Entrinsic Health Solutions. Other authors declare no conflicts of interest.

©2019 American Association for Cancer Research.

Figures

Figure 1.

Kaplan-Meier curves for (A) overall survival and(B) progression-free survival according to quintile of plasma 25-hydroxyvitamin D. Patients in quintiles 2 to 4 were combined for ease of graphic viewing.

Figure 2.

Multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for (A) overall survival and (B)progression-free survival, comparing the highest to lowest quintile of plasma 25-hydroxyvitamin D, across strata of potential effect modifiers. Adjusted for age (continuous), sex (female, male), race (white, black, other, unknown), Eastern Cooperative Oncology Group (ECOG) performance status (0, 1, 2), prior adjuvant chemotherapy (yes, no), chemotherapy backbone [leucovorin, fluorouracil, and oxaliplatin (mFOLFOX6); leucovorin, fluorouracil, and irinotecan (FOLFIRI)], assigned treatment arm (bevacizumab, cetuximab, bevacizumab + cetuximab), RAS mutation status (wild-type, mutant, unknown), body mass index (continuous), physical activity (continuous), season of blood collection (summer, fall, winter, spring, unknown), and geographic region of residence (southern US, midwestern/western US, northeastern US, Canada, unknown), excluding the stratification variable. MET, metabolic equivalent.