Abstract
Purpose
To assess whether higher plasma 25-hydroxyvitamin D (25[OH]D) is associated with improved outcomes in colon cancer and whether circulating inflammatory cytokines mediate such association.
Patients and Methods
Plasma samples were collected from 1437 patients with stage III colon cancer enrolled in a phase III randomized clinical trial (CALGB/SWOG 80702) from 2010 to 2015, who were followed until 2020. Cox regressions were used to examine associations between plasma 25(OH)D and disease-free survival (DFS), overall survival (OS), and time to recurrence (TTR). Mediation analysis was performed for circulating inflammatory biomarkers of CRP, IL-6, and sTNF-R2.
Results
Vitamin D deficiency (25(OH)D<12 ng/ml) was present in 13% of total patients at baseline and in 32% of Black patients. Compared with deficiency, non-deficient vitamin D status (≥12 ng/ml) was significantly associated with improved DFS, OS, and TTR (all Plog-rank<0.05), with multivariable-adjusted hazard ratios of 0.68 (95% confidence interval [CI], 0.51–0.92) for DFS, 0.57 (0.40–0.80) for OS, and 0.71 (0.52–0.98) for TTR. A U-shaped dose-response pattern was observed for DFS and OS (both Pnon-linearity<0.05). The proportion of the association with survival that was mediated by sTNF-R2 was 10.6% (Pmediation=0.04) for DFS and 11.8% (Pmediation=0.05) for OS, whereas CRP and IL-6 were not shown to be mediators. Plasma 25(OH)D was not associated with the occurrence of ≥ grade 2 adverse events.
Conclusions
Non-deficient vitamin D is associated with improved outcomes in patients with stage III colon cancer, largely independent of circulation inflammations. A randomized trial is warranted to elucidate if adjuvant vitamin D supplementation improves patient outcomes.
Keywords: colon adenocarcinoma, recurrence, survival, 25(OH)D, inflammation, biomarker
INTRODUCTION
Vitamin D is predominantly obtained from dietary intake, sunlight exposure, and supplement intake, and is hypothesized to reduce the risk of cancer progression through pro-apoptotic, antiproliferative, and antiangiogenic actions.1 However, based on current findings in humans, the US Preventive Services Task Force concluded that there is inadequate evidence on the benefit of treating asymptomatic vitamin D deficiency on cancer outcomes, and encouraged more research on the role of vitamin D in chronic diseases.2 Vitamin D deficiency is common among patients with colorectal cancer (CRC), which is the second most common cause of cancer-related death in the United States.3–5 Approximately 36% of CRC patients are diagnosed with locally advanced disease (mainly stage III).6 Our previous study showed that higher predicted vitamin D status (derived using diet and lifestyle questionnaires) was associated with decreased recurrence and improved survival among stage III cancer.7 A recent study reported an improved disease-free survival (DFS) and time to recurrence (TTR) among men with the highest tertile of measured serum 25-hydroxyvitamin D [25(OH)D)] level,.8 9 Larger studies with measured plasma 25(OH)D levels are therefore warranted.
Compelling evidence suggests that vitamin D may improve cancer prognosis through reducing inflammation,10 and higher inflammation status measured by C-reactive protein (CRP), interleukin (IL-6), and soluble tumor necrosis factor receptor 2 (sTNF-R2) is associated with worse CRC survival.11–15 In this study, we prospectively assessed the association between plasma 25(OH)D levels and clinical outcomes of patients with stage III colon cancer who were enrolled in a completed phase 3 randomized clinical trial of adjuvant chemotherapy and also explored the role of circulating inflammatory cytokines in mediating this association.
PATIENTS AND METHODS
Study population
This prospective cohort was derived from the NCI-sponsored phase III randomized trial (CALGB/SWOG 80702) in patients with stage III colon cancer who had undergone curative-intent resection. Patients were randomized to treatment with 6 vs. 12 cycles of adjuvant 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) with 3 years of celecoxib vs. placebo.16 17 A detailed trial description can be found in the Supplementary Methods. Briefly, from June 2010 to November 2015, a total of 2524 colon cancer patients were enrolled in the treatment trial. All trial patients were invited to participate in companion studies. A total of 1498 (59%) patients participated in the plasma companion biomarker study and had blood drawn before the planned treatment. And 1892 (75%) patients participated in the diet and lifestyle companion study and completed a semiquantitative food frequency questionnaire (FFQ) within the first 6 weeks of randomization (FFQ1) and again during the 14–16 months after randomization (FFQ2). The FFQ has been externally validated and collected information on 131 food items, vitamin and supplement use, and physical activity.18
A detailed flow diagram for patient enrollment and exclusion for the present study is depicted in Supplementary Figure S1. The final population included 1437 patients in the main analysis of plasma 25(OH)D, and 1643 patients in the sensitivity analysis of predicted vitamin D level, which may better reflect long-term vitamin D status. No appreciable differences were detected between these two companion study populations and the overall treatment trial population with regard to baseline characteristics and patient outcome, with a median survival of 8.6 years in all three groups (Supplementary Table S1). All patients provided written informed consent for trial participation. This study was conducted in accordance with ethical guideline of U.S. Common Rule, and Institutional Review Board approval was obtained at each participating center.
Assessment of exposure and covariates
The primary exposure was baseline plasma 25(OH)D. Plasma samples were collected by individual centers and sent on ice to the CALGB Pathology Coordinating Lab (Ohio State University, Columbus, OH). The median time from randomization to blood collection was 0.2 months (range 0–5.9 months). Plasma 25(OH)D concentrations were measured by radioimmunoassay at Heartland Assays, with a mean intraassay coefficient of variation of 4%.19 All laboratory personnel were blinded to the clinical outcomes.
A predicted vitamin D score was calculated using previously validated regression coefficients.7 20 21 Information on race and geographic region from FFQ1 was applied directly, and we used cumulative averaging values of physical activity, body mass index (BMI), and dietary and supplementary vitamin D intake from both FFQ1 and FFQ2, with weighted proportion to times between FFQ1 and FFQ2 and then between FFQ2 and DFS time.7 Median time from randomization to FFQ1 was 0.6 months (range 0–5.8 months). A full description of the covariates and plasma measurement of CRP, IL-6, and sTNF-R2 is provided in the Supplementary Methods. The mean day-to-day intraassay coefficient of variability was 3% for CRP, 8% for IL-6, and 4% for sTNF-R2.
Clinical outcomes
The primary study endpoints were DFS (calculated from randomization to disease recurrence or death from any cause), OS (calculated from randomization to death from any cause), and time to recurrence (TTR, calculated from randomization to disease recurrence). Colon cancer-specific mortality was also evaluated (calculated from randomization to death from colon cancer). Adverse events were graded using NCI Common Toxicity Criteria version 4.0.16 All patients were followed up through August 10, 2020.
Statistical analyses
There is no consensus on the definition of vitamin D deficiency, sufficiency, and excess.22 This study used the cut points recommended by the National Academy of Medicine: vitamin D deficiency was defined as plasma 25(OH)D <12 ng/ml (1 ng/ml = 2.5 nmol/L) and non-deficiency as ≥12 ng/ml, while non-deficiency was further subcategorized as inadequacy (12–19 ng/ml), sufficiency (20–29 ng/ml), and beyond sufficiency (≥30 ng/ml).23–25 Kaplan-Meier curves were calculated for DFS, OS, and TTR, and compared according to plasma 25(OH)D levels using the log-rank test. Cox proportional hazard models were conducted to assess the hazard ratio (HR) for DFS, OS, and TTR and their 95% confidence intervals (CIs) comparing predefined plasma 25(OH)D levels, adjusting for a priori defined covariates, including age (years), sex (female or male), race (White, Black, Others), BMI (<25, 25–30, >30 kg/m2), season of blood collection (winter/spring or summer/autumn), Eastern Cooperative Oncology Group (ECOG) performance status (0 or 1/2), tumor location (left-sided, right-sided, multiple), tumor stage (T1/2 or T3/4), nodal stage (N1 or N2), and assigned treatment arms (6 or 12 cycles of FOLFOX with or without Celecoxib). Multi-variable adjusted HRs of DFS, OS, and TTS by quartiles of predicted vitamin D scores were also computed. Assumptions of proportional hazards were tested and met by the product of 25(OH)D levels and the natural logarithm of time. Nonlinear trends were assessed with likelihood-ratio tests of restricted cubic splines.26 Cause-specific Cox regression was applied to estimate colon-cancer-specific mortality by treating non-cancer deaths as a competing event. Stratification analyses were conducted by covariates of interest, and sensitivity analyses were done by excluding patients with tumor recurrence or death within three months of blood collection, and by including participants enrolled both in the biomarker study and the diet and lifestyle study. Using multivariable-adjusted logistic regression, the odds ratio (OR) of significant adverse events (≥ grade 2) by plasma 25(OH)D levels was estimated.
To examine the proportion of the association of plasma 25(OH)D (modeled as continuous variable per 10 ng/ml increase) and recurrence and death that is due to circulating inflammatory biomarkers, mediation analyses were conducted using the difference method to estimate primary multivariable-adjusted HRs with and without adjustment for each specific biomarker.27 28 Percent of mediation was calculated by β coefficients from two models using the following formula: (βbiomarker-unadjusted- βbiomarker-adjusted)/ βbiomarker-unadjusted.
The Alliance Statistics and Data Management Center collected all data and confirmed data quality following Alliance policies (data locked on October 30, 2022). Statistical analyses were conducted using SAS version 9.4 (SAS Institute Inc, Cary, NC). A two-sided P value of <0.05 was considered statistically significant.
Data availability statement
De-identified patient data may be requested from Alliance for Clinical Trials in Oncology via concepts@alliancenctn.org if data are not publicly available. A formal review process includes verifying the availability of data, conducting a review of any existing agreements that may have implications for the project, and ensuring that any transfer is in compliance with the IRB. The investigator will be required to sign a data release form prior to transfer. The code is available upon proper request.
RESULTS
Among 1437 patients with stage III colon cancer, the median plasma 25(OH)D level was 21.0 ng/ml (range, 5.7–96.1 ng/ml). Vitamin D deficiency was present in 182 patients (13%) (Table 1). Vitamin D deficiency was more prevalent among Black patients (32%) than White patients (10%). Compared with patients with deficient vitamin D, patients with higher plasma 25(OH)D tended to be older, more physically active, and were more likely to have normal BMI, better ECOG performance status, and higher calcium and vitamin D intake. The study participants generally represent well the stage III colon cancer patients in the US (Supplementary Table S2).
Table 1.
Baseline characteristics of study participants by vitamin D status
| Characteristic a | Deficiency (<12 ng/ml) b | Non-deficiency |
|||
|---|---|---|---|---|---|
| Overall (≥ 12 ng/ml) | Inadequacy (12–19 ng/ml) | Sufficiency (20–29 ng/ml) | Beyond Sufficiency (≥30 ng/ml) | ||
|
| |||||
| Total number of patients | 182 | 1255 | 478 | 516 | 261 |
| Plasma 25(OH)D, ng/ml, mean (SD) | 9.8 (1.5) | 24.3 (9.7) | 16.2 (2.3) | 24.3 (2.8) | 39.0 (9.6) |
| Age in years, mean (SD) | 59.3 (10.2) | 61.4 (10.7) | 59.9 (10.3) | 61.1 (11.0) | 64.6 (9.8) |
| Sex, No. (%) | |||||
| Female | 94 (52) | 548 (44) | 183 (38) | 208 (40) | 157 (60) |
| Male | 88 (48) | 707 (56) | 295 (62) | 308 (60) | 104 (40) |
| Race, No. (%) | |||||
| White | 117 (64) | 1062 (85) | 382 (80) | 450 (87) | 230 (88) |
| Black | 51 (28) | 110 (9) | 56 (12) | 37 (7) | 17 (7) |
| Other races | 14 (8) | 83 (7) | 40 (8) | 29 (6) | 14 (5) |
| Body mass index, kg/m2, No. (%) | |||||
| <25 | 36 (20) | 360 (29) | 114 (24) | 153 (30) | 93 (36) |
| 25–30 | 55 (30) | 462 (37) | 161 (34) | 205 (40) | 96 (37) |
| >30 | 91 (50) | 433 (35) | 203 (42) | 158 (31) | 72 (28) |
| Season of blood collection, No. (%) | |||||
| Winter (December to February) | 56 (31) | 264 (21) | 117 (24) | 97 (19) | 50 (19) |
| Spring (March to May) | 59 (32) | 342 (27) | 132 (28) | 140 (27) | 70 (27) |
| Summer (June to August) | 33 (18) | 321 (26) | 106 (22) | 138 (27) | 77 (30) |
| Autumn (September to November) | 34 (19) | 328 (26) | 123 (26) | 141 (27) | 64 (25) |
| Geographic region, No. (%) c | |||||
| Southern US | 57 (31) | 422 (34) | 161 (34) | 182 (35) | 79 (30) |
| Midwestern/western US | 87 (48) | 507 (40) | 196 (41) | 200 (39) | 111 (43) |
| Northeastern US/Canada | 38 (21) | 324 (26) | 120 (25) | 134 (26) | 70 (27) |
| Unknown | 0 (0) | 2 (0) | 1 (0) | 0 (0) | 1 (0) |
| ECOG performance status, No. (%) d | |||||
| 0 | 118 (65) | 919 (73) | 334 (70) | 389 (75) | 196 (75) |
| 1/2 | 64 (35) | 336 (27) | 144 (30) | 127 (25) | 65 (25) |
| Primary tumor location, No. (%) e | |||||
| Left | 84 (46) | 609 (49) | 236 (49) | 244 (47) | 129 (49) |
| Right | 96 (53) | 625 (50) | 235 (49) | 262 (51) | 128 (49) |
| Multiple/unknown | 2 (1) | 21 (2) | 7 (1) | 10 (2) | 4 (2) |
| Tumor stage, No. (%) | |||||
| T1/T2 | 30 (16) | 246 (20) | 90 (19) | 105 (20) | 51 (20) |
| T3 | 125 (69) | 823 (66) | 305 (64) | 344 (67) | 174 (67) |
| T4 | 26 (14) | 176 (14) | 78 (16) | 63 (12) | 35 (13) |
| Unknown | 1 (1) | 10 (1) | 5 (1) | 4 (1) | 1 (0) |
| Nodal stage, No. (%) | |||||
| N1 | 127 (70) | 928 (74) | 345 (72) | 387 (75) | 196 (75) |
| N2 | 55 (30) | 327 (26) | 133 (28) | 129 (25) | 65 (25) |
| Assigned treatment arm, No. (%) | |||||
| 6 cycles of FOLFOX + Placebo | 54 (30) | 312 (25) | 116 (24) | 124 (24) | 68 (26) |
| 6 cycles of FOLFOX + Celecoxib | 47 (26) | 308 (25) | 113 (24) | 137 (27) | 62 (24) |
| 12 cycles of FOLFOX + Placebo | 48 (26) | 328 (26) | 114 (24) | 130 (25) | 63 (24) |
| 12 cycles of FOLFOX + Celecoxib | 33 (18) | 307 (24) | 135 (28) | 125 (24) | 68 (26) |
| Physical activity, MET-h/wk, mean (SD) | 8.9 (18.6) | 17.0 (27.9) | 14.3 (27.7) | 18.2 (26.3) | 19.3 (31.0) |
| Calcium intake, mg/d, mean (SD) | 819 (487) | 1097 (575) | 967 (532) | 1110 (539) | 1315 (651) |
| Calorie intake, kcal/d, mean (SD) | 1954 (942) | 1884 (802) | 1907 (820) | 1915 (844) | 1778 (667) |
| Total vitamin D intake, IU/d, mean (SD) | 245 (355) | 828 (850) | 480 (615) | 794 (745) | 1540 (976) |
| Dietary vitamin D intake, IU/d, mean (SD) | 159 (110) | 222 (147) | 211 (146) | 229 (144) | 227 (154) |
| Supplement vitamin D intake, IU/d, mean (SD) | 86 (312) | 606 (841) | 269 (599) | 565 (749) | 1313 (967) |
Abbreviation: FOLFOX, adjuvant chemotherapy with fluorouracil, leucovorin, and oxaliplatin; MET, metabolic equivalents tasks from recreational and leisure-time activities; SD, standardized deviation
Percentage may not sum to 100% in some columns due to rounding.
To convert ng/ml to nmol/l, multiply the ng/ml by 2.5.
Southern US denotes states of CA, NV, UT, CO, AZ, NM, OK, TX, LA, AR, MS, AL, FL, GA, SC, NC, VA, TN, KY, WV, D.C., DC, MD, DE, HI, GU, VI, and PR; Midwestern/western US denotes states of WA, OR, MT, ID, WY, ND, SD, NE, KS, MN, IA, IOWA, MO, WI, IL, MI, IN, and OH; Northeastern US denotes states of PA, NY, NJ, CT, RI, MA, NH, VT, ME, and AK.
ECOG: Eastern Cooperative Oncology Group, grade 0 denotes fully active, able to carry on all pre-disease performance without restriction; grade 1 denotes restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature; grade 2 denotes ambulatory and capable of all selfcare but unable to carry out any work activities, up and about more than 50% of waking hours.
Left-sided colon cancer includes cancers that arise in the splenic flexure, descending, and/or sigmoid colon; Right-sided colon cancer includes cancers that arise in the cecum, ascending colon, hepatic flexure, and/or transverse colon.
During a median follow-up time of 5.8 years, a total of 373 (26%) patients died or had a recurrence. Compared to vitamin D-deficient patients, non-deficient patients had significantly improved DFS (Plog-rank =0.02, Figure 1A), OS (Plog-rank =0.002, Figure 1B), and TTR (Plog-rank =0.049, Figure 1C). After adjusting for potential confounders, patients with non-deficient vitamin D continued to have significantly improved DFS (HR 0.68, 95% CI 0.51–0.92), OS (HR 0.57, 95% CI 0.40–0.80), and TTR (HR 0.71, 95% CI 0.52–0.98) (Table 2). Results were similar after excluding patients who died or recurred within three months after blood draw (Supplementary Table S3). A significant U-shaped dose-response relationship of 25(OH)D was found for DFS (Pnon-linearity=0.04, Figure 2A) and OS (Pnon-linearity=0.03, Figure 2B), but not for TTR (Pnon-linearity=0.87, Figure 2C). Compared to those with deficient vitamin D, patients with plasma 25(OH)D of 12 to 50 ng/ml had improved DFS and OS, but not those with higher levels (>50 ng/ml), though the sample size was small (n=25).
Figure 1.
Kaplan-Meier curves of disease-free survival (A), overall survival (B), and time to recurrence (C) by plasma 25-hydroxyvitamin D [25(OH)D] level among patients with stage III colon cancer
Table 2.
Hazard ratio of overall survival, disease-free survival, time to recurrence by plasma 25-hydroxyvitamin D level
| Deficiency (<12 ng/ml) a | Non-deficiency |
||||
|---|---|---|---|---|---|
| Overall (≥ 12 ng/ml) | Inadequacy (12–19 ng/ml) | Sufficiency (20–29 ng/ml) | Beyond sufficiency (≥30 ng/ml) | ||
|
| |||||
| No. of patients | 182 | 1255 | 478 | 516 | 261 |
| Median 25(OH)D (range), ng/ml | 10.0 (5.7–12.0) | 22.2 (12.0–96.1) | 16.3 (12.0–19.9) | 24.0 (20.0–30.0) | 36.3 (30.1–96.1) |
| Disease-free survival | |||||
| No. of events | 59 | 314 | 119 | 127 | 68 |
| Person-years | 624 | 4632 | 1789 | 1882 | 960 |
| Age-adjusted HR (95% CI) | Reference | 0.70 (0.53–0.93) | 0.71 (0.52–0.96) | 0.70 (0.52–0.95) | 0.69 (0.49–0.99) |
| Multivariable HR (95% CI) b | Reference | 0.68 (0.51–0.92) | 0.67 (0.49–0.92) | 0.68 (0.49–0.94) | 0.73 (0.51–1.07) |
| Overall survival | |||||
| No. of events | 45 | 193 | 66 | 81 | 46 |
| Person-years | 850 | 6031 | 2313 | 2472 | 1246 |
| Age-adjusted HR (95% CI) | Reference | 0.56 (0.41–0.78) | 0.53 (0.36–0.78) | 0.59 (0.41–0.85) | 0.58 (0.38–0.88) |
| Multivariable HR (95% CI) b | Reference | 0.57 (0.40–0.80) | 0.52 (0.35–0.77) | 0.59 (0.40–0.87) | 0.64 (0.41–0.99) |
| Time to recurrence | |||||
| No. of events | 49 | 266 | 100 | 110 | 56 |
| Person-years | 624 | 4632 | 1789 | 1882 | 960 |
| Age-adjusted HR (95% CI) | Reference | 0.74 (0.54–1.00) | 0.72 (0.51–1.01) | 0.75 (0.53–1.04) | 0.75 (0.51–1.11) |
| Multivariable HR (95% CI) b | Reference | 0.71 (0.52–0.98) | 0.68 (0.48–0.97) | 0.72 (0.50–1.03) | 0.78 (0.52–1.18) |
Abbreviation: 25(OH)D, 25-hydroxyvitamin D; CI, confidence interval; HR, hazard ratio
To convert ng/ml to nmol/l, multiply the ng/ml by 2.5.
Model adjusted for age (continuous in years), sex (female, male), race (White, Black and other race), body mass index (<25, 25–30, >30 kg/m2), season of blood collection (winter/spring, summer/autumn), Eastern Cooperative Oncology Group performance status (0, 1/2), tumor location (left, right, multiple/unknown), tumor stage (T1/2, T3/4), nodal stage (N1, N2), assigned treatment arm (6 cycles of FOLFOX + Placebo, 6 cycles of FOLFOX + Celecoxib, 12 cycles of FOLFOX + Placebo, 12 cycles of FOLFOX + Celecoxib).
Figure 2.
Dose-response relationship and test of non-linearity for the hazard ratio (HR) and 95% confidence intervals of disease-free survival (A), overall survival (B), and time to recurrence (C) by continuous plasma 25-hydroxyvitamin D levels, with reference to plasma 25-hydroxyvitamin D at 12 ng/ml.
Among patients who participated in the diet and lifestyle companion study, the predicted vitamin D score ranged from 16.3 to 36.4 ng/ml. Improved survival outcomes were seen among patients in the higher quartiles of predicted vitamin D scores (Supplementary Table S4), with a linear trend observed for DFS (Plinearity =0.02) and OS (Plinearity =0.0002) (Supplementary Figure S2). Similar findings were observed when the analysis was restricted to patients who participated in both the diet and lifestyle and plasma biomarker companion studies (Supplementary Table S4). A statistically significant Spearman correlation between measured plasma 25(OH)D levels and predicted vitamin D scores was observed (r2=0.34, P<0.0001).
In subgroup analyses, associations between plasma 25(OH)D levels and DFS, OS, and TTR were largely unchanged across strata of clinically relevant covariables (all Pinteraction >0.05) (Supplementary Figure S3A, S3B and S3C). Colon cancer-specific mortality was also lower in patients with non-deficient plasma 25(OH)D levels (HR 0.59, 95% CI 0.39–0.90) and patients with higher predicted vitamin D levels (Ptrend=0.02) (Supplementary Table S5).
There was no significant association between 25(OH)D levels and the occurrence of the most common ≥ grade 2 adverse events, including diarrhea, fatigue, hypertension, nausea, neutropenia, peripheral neuropathy, and thrombocytopenia (Table 3). However, in the subgroup treated with celecoxib, patients with plasma 25(OH)D of ≥ 12 ng/ml had a lower risk of fatigue (OR 0.57, 95% CI 0.33–0.97) and hypertension (OR 0.55, 95% CI 0.29–1.04), compared to those with plasma 25(OH)D <12 ng/ml.
Table 3.
Risk of selected toxicities (≥ grade 2) by plasma 25-hydroxyvitamin D levels and in subgroups defined by treatment arms, ordered by frequency
| Adverse event | All Patients a |
Patients received Celecoxib c |
Patients received placebo c |
|||
|---|---|---|---|---|---|---|
| < 12 ng/ml b | ≥12 ng/ml | < 12 ng/ml | ≥12 ng/ml | < 12 ng/ml | ≥12 ng/ml | |
|
| ||||||
| Neutrophils decrease (neutropenia) | ||||||
| No. at risk | 182 | 1238 | 80 | 631 | 102 | 607 |
| No. of events | 87 | 568 | 36 | 302 | 51 | 266 |
| Age-adjusted OR (95% CI) | Reference | 0.88 (0.64–1.20) | Reference | 1.02 (0.63–1.63) | Reference | 0.76 (0.50–1.17) |
| Multivariable OR (95% CI) | Reference | 0.91 (0.65–1.28) | Reference | 1.02 (0.62–1.67) | Reference | 0.91 (0.57–1.45) |
| Peripheral neuropathy | ||||||
| No. at risk | 182 | 1232 | 80 | 629 | 102 | 603 |
| No. of events | 63 | 446 | 23 | 233 | 40 | 213 |
| Age-adjusted OR (95% CI) | Reference | 1.10 (0.79–1.53) | Reference | 1.51 (0.90–2.52) | Reference | 0.85 (0.55–1.32) |
| Multivariable OR (95% CI) | Reference | 0.96 (0.67–1.39) | Reference | 1.33 (0.76–2.32) | Reference | 0.74 (0.45–1.22) |
| Fatigue | ||||||
| No. at risk | 182 | 1230 | 80 | 628 | 102 | 602 |
| No. of events | 54 | 349 | 27 | 157 | 27 | 192 |
| Age-adjusted OR (95% CI) | Reference | 0.92 (0.65–1.29) | Reference | 0.61 (0.37–1.01) | Reference | 1.30 (0.81–2.08) |
| Multivariable OR (95% CI) | Reference | 0.90 (0.63–1.30) | Reference | 0.57 (0.33–0.97) | Reference | 1.24 (0.75–2.05) |
| Diarrhea | ||||||
| No. at risk | 180 | 1232 | 78 | 630 | 102 | 602 |
| No. of events | 30 | 239 | 13 | 126 | 17 | 113 |
| Age-adjusted OR (95% CI) | Reference | 1.15 (0.76–1.75) | Reference | 1.15 (0.61–2.17) | Reference | 1.14 (0.65–2.00) |
| Multivariable OR (95% CI) | Reference | 1.12 (0.72–1.74) | Reference | 1.12 (0.58–2.19) | Reference | 1.12 (0.61–2.04) |
| Platelets decrease (thrombocytopenia) | ||||||
| No. at risk | 182 | 1239 | 80 | 633 | 102 | 606 |
| No. of events | 32 | 238 | 17 | 131 | 15 | 107 |
| Age-adjusted OR (95% CI) | Reference | 1.05 (0.70–1.59) | Reference | 0.88 (0.49–1.56) | Reference | 1.22 (0.68–2.20) |
| Multivariable OR (95% CI) | Reference | 0.88 (0.57–1.35) | Reference | 0.79 (0.43–1.46) | Reference | 1.07 (0.57–2.03) |
| Nausea | ||||||
| No. at risk | 182 | 1232 | 80 | 629 | 102 | 603 |
| No. of events | 31 | 216 | 15 | 113 | 16 | 103 |
| Age-adjusted OR (95% CI) | Reference | 1.07 (0.71–1.62) | Reference | 1.00 (0.55–1.82) | Reference | 1.12 (0.63–1.99) |
| Multivariable OR (95% CI) | Reference | 1.16 (0.75–1.79) | Reference | 1.09 (0.58–2.05) | Reference | 1.25 (0.68–2.30) |
| Hypertension | ||||||
| No. at risk | 174 | 1185 | 76 | 604 | 581 | 679 |
| No. of events | 26 | 136 | 16 | 82 | 10 | 54 |
| Age-adjusted OR (95% CI) | Reference | 0.72 (0.45–1.13) | Reference | 0.53 (0.29–0.98) | Reference | 0.90 (0.44–1.84) |
| Multivariable OR (95% CI) | Reference | 0.73 (0.45–1.17) | Reference | 0.55 (0.29–1.04) | Reference | 0.84 (0.39–1.80) |
Abbreviation: CI, confidence interval; OR, odds ratio
Multivariable model adjusted for age (continuous in years), sex (female, male), race (White, Black and other race), body mass index (<25, 25–30, >30 kg/m2), season of blood collection (winter/spring, summer/autumn), Eastern Cooperative Oncology Group performance status (0, 1/2), tumor location (left, right, multiple/unknown), tumor stage (T1/2, T3/4), nodal stage (N1, N2), assigned treatment arm (6 cycles of FOLFOX + Placebo, 6 cycles of FOLFOX + Celecoxib, 12 cycles of FOLFOX + Placebo, 12 cycles of FOLFOX + Celecoxib).
To convert ng/ml to nmol/l, multiply the ng/ml by 2.5.
Multivariable model adjusted for age (continuous in years), sex (female, male), race (White, Black and other race), body mass index (<25, 25–30, >30 kg/m2), season of blood collection (winter/spring, summer/autumn), Eastern Cooperative Oncology Group performance status (0, 1/2), tumor location (left, right, multiple/unknown), tumor stage (T1/2, T3/4), nodal stage (N1, N2), assigned treatment duration (6 cycles, 12 cycles).
Further adjustment of the primary multivariable model with sTNF-R2 slightly attenuated the HRs of DFS and OS, with 10.6% (Pmediation=0.04) of the association with DFS, and 11.8% (Pmediation=0.05) with OS, but not with TTR (8.4%, Pmediation=0.13) (Table 4). HRs of DFS, OS, and TTR by plasma 25(OH)D were basically unaltered after adjustment of CRP or IL-6 and both these inflammatory biomarkers did not mediate the association of plasma 25(OH)D.
Table 4.
Mediation analysis of inflammatory biomarkers on the association between plasma 25-hydroxyvitamin D and disease-free survival, overall survival, and time to recurrence a
| HR (95%CI) by plasma 25(OH)D adjusting for specific inflammatory biomarker |
HR (95% CI) by per 10 ng/ml increase of plasma 25(OH)D |
Percent mediated by biomarkers; Pmediation | |||||
|---|---|---|---|---|---|---|---|
| Deficiency (<12 ng/ml) | Inadequacy (12–19 ng/ml) | Sufficiency (20–29 ng/ml) | Beyond Sufficiency (≥30 ng/ml) | Direct effect | Indirect effect b | ||
|
| |||||||
| C-reactive protein | |||||||
| DFS | Reference | 0.67 (0.49–0.92) | 0.68 (0.49–0.95) | 0.73 (0.51–1.06) | 0.95 (0.84–1.07) | 0.95 (0.84–1.07) | 0.0%; P=1.00 |
| OS | Reference | 0.52 (0.35–0.77) | 0.60 (0.40–0.88) | 0.64 (0.41–0.99) | 0.95 (0.81–1.10) | 0.94 (0.81–1.10) | 0.0%; P=1.00 |
| TTR | Reference | 0.68 (0.48–0.97) | 0.72 (0.51–1.03) | 0.78 (0.52–1.18) | 0.97 (0.85–1.10) | 0.97 (0.85–1.10) | 0.0%; P=1.00 |
| Interleukin-6 | |||||||
| DFS | Reference | 0.66 (0.48–0.91) | 0.69 (0.49–0.95) | 0.73 (0.51–1.07) | 0.95 (0.84–1.07) | 0.95 (0.84–1.07) | 2.0%; P=0.34 |
| OS | Reference | 0.52 (0.35–0.77) | 0.60 (0.41–0.89) | 0.64 (0.41–1.00) | 0.95 (0.81–1.10) | 0.95 (0.81–1.11) | 2.7%; P=0.33 |
| TTR | Reference | 0.68 (0.48–0.97) | 0.72 (0.50–1.03) | 0.78 (0.52–1.18) | 0.97 (0.85–1.10) | 0.97 (0.85–1.10) | 1.3%; P=0.35 |
| Soluble tumor necrosis factor-receptor 2 | |||||||
| DFS | Reference | 0.67 (0.49–0.92) | 0.69 (0.50–0.96) | 0.74 (0.51–1.08) | 0.95 (0.84–1.07) | 0.96 (0.85–1.08) | 10.6%; P=0.04 |
| OS | Reference | 0.52 (0.35–0.76) | 0.60 (0.41–0.89) | 0.65 (0.41–1.01) | 0.95 (0.81–1.10) | 0.95 (0.82–1.11) | 11.8%; P=0.05 |
| TTR | Reference | 0.68 (0.48–0.97) | 0.73 (0.51–1.04) | 0.79 (0.53–1.19) | 0.97 (0.85–1.10) | 0.97 (0.85–1.10) | 8.4%; P=0.13 |
Abbreviation: 25(OH)D, 25-hydroxyvitamin D; CI, confidence interval; DFS, disease-free survival; HR, hazard ratio; OS, overall survival; TTR, time to recurrence.
All models had adjusted for age (continuous in years), sex (female, male), race (White, Black and other race), body mass index (<25, 25–30, >30 kg/m2), season of blood collection (winter/spring, summer/autumn), Eastern Cooperative Oncology Group performance status (0, 1/2), tumor location (left, right, multiple/unknown), tumor stage (T1/2, T3/4), nodal stage (N1, N2), assigned treatment arm (6 cycles of FOLFOX + Placebo, 6 cycles of FOLFOX + Celecoxib, 12 cycles of FOLFOX + Placebo, 12 cycles of FOLFOX + Celecoxib).
Model further adjusted for each specific inflammatory biomarker.
DISCUSSION
This prospective cohort study of patients with stage III colon cancer showed that non-deficient plasma 25(OH)D levels were associated with lower cancer recurrence and improved survival, and the association between 25(OH)D and survival may potentially follow a U-shaped pattern with survival benefits seen among patients with 25(OH)D levels of 12 to 50 ng/ml. We also observed that the protective effect of higher vitamin D was independent of inflammatory cytokines of CRP and IL-6 while being marginally mediated by sTNF-R2. Plasma 25(OH)D levels were not significantly associated with the occurrence of ≥ grade 2 adverse events, although a possible lower risk of fatigue and hypertension may exist with higher plasma 25(OH)D levels among patients treated with celecoxib. To our knowledge, this is the largest study to characterize the relationship between plasma 25(OH)D levels and outcomes among stage III colon cancer patients.
Higher plasma 25(OH)D levels were significantly associated with improved survival, which is consistent with findings using the predicted vitamin D score in a previous trial study of stage III colon cancer,7 and also in the current study. Sinicrope et al. reported an improved DFS and TTR by higher plasma 25(OH)D levels only among male patients with stage III colon cancer but not all patients.8 9 The present study had a relatively wide range of plasma 25(OH)D levels, which allowed us to observe a significant U-shaped association between plasma 25(OH)D and survival among the entire study population. However, this U-shaped relationship currently should be considered hypothesis-generating only, because the analysis may be underpowered for patients with plasma 25(OH)D levels of >50 ng/ml. Further studies are needed to confirm whether a true negative association exists between high plasma 25(OH)D and survival among patients with stage III colon cancer. Several other observational studies also evaluated the relationship between 25(OH)D levels and patient outcomes among patients with any stage of colon and rectal cancer; however, conflicting results were reported and none of them were adequately powered to look at patients with stage III colon cancer specifically.4 29 30 31 The U-shaped association of DFS and OS by 25(OH)D levels found in the current study may partly explain why conflicting results were seen in previous reports that used different cut-off points to define high and low 25(OH)D levels. Interestingly, we did not find a U-shaped association between predicted vitamin D scores and survival outcomes; this could potentially be attributed to the much narrower range of predicted vitamin D levels. Moreover, predicted vitamin D scores were derived from two serial questionnaires, which indirectly reflect relative levels of vitamin D status, and it is also possible that diet, physical activity, or supplementary vitamin D use could have changed after chemotherapy and led to variations in predicted vitamin D levels.
In comparison with the general population, patients with colon cancer tend to have a higher prevalence of vitamin D deficiency.3 24 Potential reasons for this difference include the fact that cancer patients or patients with more advanced tumor stage are likely to be older and have less sun exposure, lower dietary vitamin D intake, reduced physical activity, and increased obesity compared to the general population. We also noticed that Black patients had a higher prevalence of vitamin D deficiency (32%) compared to White patients (10%), which could partly explain the worse survival among Black patients in previous publications.5 32 However, in this study, both Black and White patients with higher vitamin D had improved survival compared to their counterparts with lower vitamin D levels, suggesting the importance of detecting and correcting vitamin D deficiency. Higher plasma 25(OH)D levels were mainly due to a higher intake of supplemental vitamin D, which supports future investigation of adjuvant supplement use among stage III colon cancer patients.
Our results are supported by compelling preclinical evidence showing that vitamin D may inhibit colon cancer progression through several signaling pathways.1 The active form of vitamin D, 1–25-dihydroxyvitamin D, binds to the vitamin D receptor-retinoid X receptor complex to regulate gene expression, leading to induction of apoptosis, cell differentiation, inhibition of cell proliferation, invasion, metastasis, and angiogenesis.1 Vitamin D also inhibits the production of pro-inflammatory cytokines and demonstrates anti-inflammatory actions in cancers.10 The present study did not find strong evidence that CRP or IL-6 confounded or mediated associations between 25(OH)D and colon cancer survival, suggesting that the reported association of 25(OH)D could be independent of CRP or IL-6 levels. Notwithstanding, we observed sTNF-R2 as a potential mediator in the causal pathway between vitamin D and survival, indicating potential other mechanisms. Previous studies showed that TNF-R2 not only directly promoted cancer proliferation, activated immunosuppressive cells, and supported immune escape,33 but may also work together with vitamin D to co-regulate extracellular signal-regulated kinase (ERK) and NF-κB signaling in colon cancer, which may explain the marginal mediation effect of TNF-R2 in the present study.1 33 34 These findings suggest that clinical interventions to increase plasma 25(OH)D levels or to decrease circulation inflammations may benefit colon cancer patients in the future. Further investigation of sTNF-R2 in CRC pathogenesis and underlying mechanisms of action, as well as interactions with vitamin D signaling, are warranted.
The strengths of this study include a large study population from a rigorously conducted multicenter phase III randomized clinical trial with uniform treatment and follow-up. Detailed data on lifestyle and clinical characteristics were prospectively collected using a validated instrument. In addition, direct plasma measurement of 25(OH)D levels provides reliable vitamin D status at the study baseline before chemotherapy, while a predicted vitamin D score could be more representative of longer-term vitamin D status among patients with colon cancer before and after the chemotherapy. The reduced recurrence and improved survival among patients with higher vitamin D levels measured by both direct assay and predicted vitamin D score further enhance the validity and biological plausibility of the study results.
However, several limitations deserve attention. It is possible that higher plasma 25(OH)D levels may be acting as a surrogate for other favorable prognostic factors, although higher vitamin D levels continued to be significantly associated with improved survival after adjusting for several of these factors in multivariable analyses. Plasma 25(OH)D was measured only once at the study baseline, therefore the impact of changes in 25(OH)D on patient outcome was not able to be evaluated. But similar results were found using a predicted vitamin D score that may better reflect longstanding vitamin D status. Because our study population was comprised of patients enrolled in a clinical trial, the generalizability of our results may be limited, and findings may not apply to colon cancer patients at large. Nevertheless, the relatively wide range of 25(OH)D levels in the cohort diminishes this concern and our patients were recruited from both community and academic centers throughout North America. Finally, the majority of the patients were of White race; additional studies focusing on other races are encouraged, particularly because disparities exist in vitamin D status and CRC incidence and mortality by race and ethnicity.35 36
In conclusion, this study found that non-deficient vitamin D levels are significantly associated with decreased recurrence and improved survival in patients with stage III colon cancer, independent of inflammation cytokines of CRP or IL-6. This survival benefit may be mediated in part through sTNF-R2. Additional research to understand the mechanisms of vitamin D activity is needed. Given the promising results from the present study, a randomized clinical trial of adjuvant vitamin D supplementation in patients with stage III colon cancer patients should be considered to confirm causality.
Supplementary Material
STATEMENT OF TRANSLATIONAL RELEVANCE.
Previous studies showed conflicting associations between plasma 25-hydroxyvitamin D (25[OH]D) and stage III colon cancer outcomes, and optimal levels of plasma 25(OH)D for patients with colon cancer are currently unknown. It is also unclear if the association between plasma 25(OH)D and survival is mediated or confounded by circulating inflammatory cytokines. This large cohort study nested in a phase III randomized clinical trial found that higher 25(OH)D levels were associated with decreased cancer recurrence and improved survival of patients with stage III colon cancer. A possible U-shaped dose-response pattern was observed, with plasma 25(OH)D level between 12 ng/ml and 50 ng/ml being associated with improved survival. Additionally, the protective effect of 25(OH)D was independent of circulating CRP and IL-6 but was marginally mediated by sTNF-R2. Plasma 25(OH)D may be a good prognostic predictor for survival among patients with stage III colon cancer and randomized clinical trials are needed to confirm causality and determine whether vitamin D supplementation can lead to improved outcomes.
Acknowledgment of research support:
We would like to thank the participants and staff of the clinical trials. The authors assume full responsibility for the analyses and interpretation of these data. Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award Numbers U10CA180821, U10CA180882, and U24 CA196171 (to the Alliance for Clinical Trials in Oncology), UG1CA189858, UG1CA189960, UG1CA233163 (SWOG), UG1CA233180, UG1CA233290, UG1 CA233320, UG1CA233337, UG1CA233339; https://acknowledgments.alliancefound.org; U10CA180863 and CCS Grant 707213 (CCTG); UG1CA233234 and U10CA180820 (ECOG-ACRIN); U10CA180868 (NRG); U10CA180888; R01CA205406 (to K.N.); Department of Defense (R33CA160344 to K.N.), Project P Fund (J.A.M. and K.N.), Douglas Gray Woodruff Chair Fund (J.A.M.), Anonymous Family Fund for Innovations in Colorectal Cancer (J.A.M.), and Cancer Center Support Grant/Core Grant P30 CA008748 (E.M.O). Also supported in part by Pfizer. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Abbreviations:
- 25[OH]D
25-hydroxyvitamin D
- BMI
body mass index
- CI
confidence interval
- CRP
C-reactive protein
- DFS
disease-free survival
- ECOG
Eastern Cooperative Oncology Group
- FOLFOX
fluorouracil, leucovorin, and oxaliplatin
- HR
hazard ratio
- IL-6
interleukin-6
- MET
metabolic equivalent task
- OR
odds ratio
- OS
overall survival
- TTR
time to recurrence
- sTNF-R2
soluble tumor necrosis factor-receptor 2
Footnotes
Conflicts of interest: Non-federal sponsors did not contribute to design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication. Q.S. reports consulting/advisory role from Yiviva Inc, Boehringer Ingelheim Pharmaceuticals, Inc, Regeneron Pharmaceuticals, Inc., Hoosier Cancer Research Network, Honorarium/speaker role from Chugai Pharmaceutical Co., Ltd (to Q.S.), research funds from Celgene/BMS, Roche/Genentech, Janssen, Novartis (to institution). B.M.W. reports researching grant funding from Celgene, Eli Lilly; consulting fees from BioLineRx, Celgene, and GRAIL. C.S.F. reports consulting roles for Amylin Pharmaceuticals, Astra-Zeneca, Bain Capital, CytomX Therapeutics, Daiichi-Sankyo, Eli Lilly, Entrinsic Health, Evolveimmune Therapeutics, Genentech, Merck, and Taiho; served as a Director for CytomX Therapeutics and owns unexercised stock options for CytomX and Entrinsic Health; is a co-Founder of Evolveimmune Therapeutics and has equity in this private company; had provided expert testimony for Amylin Pharmaceuticals and Eli Lilly; is an employee of Genentech and Roche. P.K. has served as a medical advisor to Biocept, Enclear Therapies, Affinia Therapeutics, SDP Oncology, Janssen, and Sintetic; has received research funding from Genentech and Novocure. R.M.G. reports consulting fees from AdaptImmune, Advanced Chemotherapy Technologies, Astra Zeneca, Compass Therapeutics, Eisai, Genentech, GSK, Inspirna, IQVIA, Merck, Sorrento, and Taiho. E.M.O reports receiving research funding (to MSK) from Genentech/Roche, Celgene/BMS, BioNTech, AstraZeneca, Arcus, Elicio, and Parker Institute; consulting in Cytomx Therapeutics (DSMB), Rafael Therapeutics (DSMB), Seagen, Boehringer Ingelheim, BioNTech, Ipsen, Merck, IDEAYA, Silenseed, Novartis, AstraZeneca, Noxxon, BioSapien, Cend Therapeutics, Thetis, Autem, Novogene, ZielBio, Tempus, Agios (spouse), Genentech-Roche (spouse), Eisai (spouse), Zymeworks (spouse). J.A.M. has served as an advisor/consultant to Merck Pharmaceutical and COTA Healthcare. K.N. reports institutional research funding from Pharmavite, Evergrande Group, Janssen Pharmaceuticals, and Revolution Medicines; and advisory board/consulting fees from SeaGen, Array Biopharma, BiomX, X-Biotix Therapeutics, Bicara Therapeutics, Redesign Health, GSK, Pfizer, and Bayer. The remaining authors declare no potential conflicts of interest.
ClinicalTrials.gov Identifier: NCT01150045
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Associated Data
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Supplementary Materials
Data Availability Statement
De-identified patient data may be requested from Alliance for Clinical Trials in Oncology via concepts@alliancenctn.org if data are not publicly available. A formal review process includes verifying the availability of data, conducting a review of any existing agreements that may have implications for the project, and ensuring that any transfer is in compliance with the IRB. The investigator will be required to sign a data release form prior to transfer. The code is available upon proper request.