| Literature DB >> 31023832 |
P G Vaughan-Shaw1, L Zgaga2, L Y Ooi1, E Theodoratou3,4, M Timofeeva1, V Svinti1, M Walker1, F O'Sullivan2, A Ewing1, S Johnston5, F V N Din1, H Campbell3, S M Farrington1, M G Dunlop1.
Abstract
OBJECTIVE: We assessed the effect of surgical resection of colorectal cancer (CRC) on perioperative plasma vitamin D (25OHD) and C-reactive protein (CRP) level. We investigated the relationship between circulating vitamin D level and CRC survival.Entities:
Keywords: cancer prevention; colorectal cancer; colorectal surgery; vitamin D receptor gene
Mesh:
Substances:
Year: 2019 PMID: 31023832 PMCID: PMC6943245 DOI: 10.1136/gutjnl-2018-317922
Source DB: PubMed Journal: Gut ISSN: 0017-5749 Impact factor: 23.059
Clinical characteristics of included patients
| Serial sampling study | Cohort study | Cohort study | |||
| Cohort 1 | Cohort 2 | Cohort 1 | Cohort 2 | ||
| n | 92 | 2006 | 2100 | 1687 | 1848 |
| Sampling years | 2012–2016 | 2001–2006 | 2009–2017 | 2001–2006 | 2009–2017 |
| Age (years) | 67.1 (64.4–69.9) | 60.1 (60.6–61.6) | 67.2 (66.7–67.7) | 61.5 (61.0–62.0) | 67.6 (67.1–68.1) |
| Gender (M) | 51 (55%) | 1137 (57%) | 1172 (56%) | 970 (57%) | 1024 (55%) |
| BMI (kg/m2) | 26.1 (24.8–27.5) | 26.6 (26.4–26.8) | 27.5 (27.3–27.7) | 26.6 (26.4–26.8) | 27.6 (27.4–27.9) |
| Cancer site | |||||
| Colon | 62 (67%) | 1153 (57%) | 1313 (63%) | 962 (57%) | 1161 (63%) |
| Rectum | 30 (33%) | 829 (41%) | 761 (36%) | 714 (42%) | 687 (37%) |
| NA | 0 | 24 (1%) | 56 (3%) | 11 (1%) | 0 (0%) |
| Cancer stage | |||||
| AJCC 1 | 27 (29%) | 383 (19%) | 415 (20%) | 383 (22%) | 415 (22%) |
| AJCC 2 | 31 (34%) | 666 (33%) | 692 (33%) | 666 (39%) | 692 (37%) |
| AJCC 3 | 21 (23%) | 638 (32%) | 741 (35%) | 638 (38%) | 741 (40%) |
| AJCC 4 | 7 (8%) | 268 (13%) | 167 (8%) | 0† | 0† |
| NA | 6 (7%) | 51 (3%) | 85 (4%) | 0 | 0 |
| ‘raw’ 25OHD (nmol/L) | NA* | 29.3 (28.4–30.2) | 46.5 (45.3–47.6) | 29.1 (28.1–30.1) | 46.0 (44.7–47.4) |
| May-adjusted 25OHD (nmol/L) | NA* | 33.9 (33.0–34.8) | 51.7 (50.5–52.8) | 28.8 (27.82–29.7) | 52.1 (50.9–53.4) |
| Tertile 1 | NA* | <18.5 | <37.32 | <18.1 | <38.0 |
| Tertile 2 | NA* | 18.5–34.0 | 37.3–56.5 | 18.1–33.1 | 38.0–57.9 |
| Tertile 3 | NA* | >34.0 | >56.46 | >33.1 | >57.9 |
| Sample time point | |||||
| Preoperative (months) | NA* | 0 (0%) | 560 (27%) | 0 (0%) | 486 (26%) |
| 0–12 | NA* | 1798 (90%) | 549 (26%) | 1517 (90%) | 471 (26%) |
| 12–24 | NA* | 180 (9%) | 396 (19%) | 147 (9%) | 351 (19%) |
| >24 | NA* | 28 (1%) | 595 (28%) | 23 (1%) | 540 (29%) |
| Season of sample | |||||
| Winter | NA* | 489 (24%) | 573 (27%) | 408 (24%) | 517 (28%) |
| Spring | NA* | 524 (26%) | 563 (27%) | 449 (27%) | 483 (26%) |
| Summer | NA* | 465 (23%) | 434 (21%) | 392 (23%) | 378 (20%) |
| Autumn | NA* | 528 (26%) | 530 (25%) | 438 (26%) | 470 (25%) |
| Follow-up (days) | NA* | NA | NA | 4841 | 1318 |
| Survival | |||||
| Alive | NA* | NA | NA | 978 (58%) | 1637 (89%) |
| Dead | NA* | NA | NA | 709 (42%) | 211 (11%) |
| CRC death | NA* | NA | NA | 421 (25%) | 138 (7%) |
Age at time of surgery given. Pre-illness BMI reported where available. Mean values given for summary variables except follow-up (median censored follow-up given). ‘Raw’ 25OHD was not adjusted for seasonal variation, that is, not ‘May-adjusted’.
*Repeated measures.
†AJCC 4 excluded from survival analysis.
25OHD, 25-hydroxyvitamin D; AJCC, American Joint Committee on Cancer; BMI, body mass index; CRC, C-reactive protein; NA, not applicable.
Figure 1Perioperative 25OHD and CRP in patients undergoing colorectal cancer surgery. Unadjusted 25OHD charted with CRP. Sixty-two patients undergoing colorectal cancer surgery sampled at up to six perioperative time points. Mean 25OHD and CRP for each time point category given with error bars representing SD. 25OHD, 25-hydroxyvitamin D; CRP, C-reactive protein.
May-adjusted 25OHD level in serial sampling study
| Time point | n | 25OHD (nmol/L) | Difference (nmol/L) | P value* | P value† |
| Preoperative | 92 | 48.3 (43.3–53.4) | Reference | Reference | Reference |
| Intraoperative | 30 | 38.2 (31.8–44.7) | −12.8 | 0.0004 | 7.8e-5 |
| 1–2 | 62 | 29.0 (25.1–32.9) | −17.3 | 3.6e-9 | 5.5e-7 |
| 3–5 | 58 | 29.6 (25.2–34.1) | −17.2 | 4.4e-9 | 6.5e-5 |
| 6–9 | 45 | 35.0 (28.7–41.2) | −12.7 | 3.0e-6 | 0.002 |
| 30–120 | 58 | 40.0 (34.4–45.5) | −6.4 | 0.002 | 0.04 |
| >162 | 40 | 64.9 (53.5–76.2) | 18.3 | 3.1e-5 | 2.0e-8 |
Difference in 25OHD at each time point accounts for missing samples within paired comparisons. Preoperative samples were taken median 7.5 days before surgery (range 49 to 0 day). >162 day samples taken median 225 days postoperatively (range 163–315 days).
*P values given represent paired Wilcoxon sign-rank test results with preoperative level as reference. C-reactive protein (CRP) was assayed in 70 patients preoperatively. Of these, 30 then had repeat CRP assayed in intraoperative samples while 40 patients had CRP assayed at various postoperative time points.
†P values given represent results from linear mixed model including the fixed covariates age, gender, body mass index (BMI) and CRP, and patient ID included as a random effect.
25OHD, 25-hydroxyvitamin D.
Figure 2Flow chart of study participants. Patients were sampled from the Scottish colorectal cancer study from 2000 to 2006 (cohort 1) and from 2009 to 2017 (cohort 2, recruited up to 23 February 2017). *Tx and/or Nx and/or Mx indicates pathology report and AJCC stage not available, AJCC stage 4 indicates stage at time of surgery. Cohort 2 recruited and assayed up to 23 February2017. 25OHD, 25-hydroxyvitamin D; AJCC, American Joint Committee on Cancer; CRC, C-reactive protein; LCMS, liquid chromatography–mass spectrometry.
Figure 3Difference in May-adjusted 25OHD levels by sample time point in cohorts. Mean May-adjusted 25OHD level at 0–12 months’ time point used as reference. 25OHD values scaled against reference mean and mean difference for each time point category given with error bars representing SEM. Cohort 1 (n=2006), cohort 2 (n=2100). 25OHD, 25-hydroxyvitamin D; CRC, C-reactive protein.
Unadjusted and multivariable adjusted HRs of death in cohort 1 and cohort 2 according to May-adjusted 25OHD tertile
| Model | n | Cohort 1 | |||||||
| Tertile 1 | Tertile 2 | Tertile 3 | Ptrend | ||||||
| HR | HR | 95% CI | P value | HR | 95% CI | P value | |||
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| Model 1* | 1685 | Ref | 0.84 | 0.67 to 1.06 | 0.15 | 0.74 | 0.58 to 0.93 | 0.01 | 0.05 |
| Model 2† | 1486 | Ref | 0.85 | 0.67 to 1.09 | 0.20 | 0.71 | 0.55 to 0.92 | 0.01 | 0.03 |
| Model 3‡ |
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| Model 1* | 1685 | Ref | 0.77 | 0.65 to 0.92 | 0.004 | 0.70 | 0.58 to 0.84 | 0.0001 |
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| Model 2† | 1486 | Ref | 0.77 | 0.64 to 0.92 | 0.005 | 0.69 | 0.56 to 0.84 | 0.0002 | 0.0004 |
| Model 3‡ |
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Final model is shown in bold.
*Model adjusted for age, sex and American Joint Committee on Cancer (AJCC) stage.
†Multivariable model additionally adjusted for body mass index, tumour site (colon/rectum), time between definitive treatment and sampling. Where data were missing, participants were excluded from adjusted model reflected in decreasing numbers of patients included in each sequential model.
‡Multivariable model additionally adjusted for C-reactive protein (CRP) which is not displayed for cohort 2 as only a small subset had CRP assayed. Trend—25OHD as a continuous variable. Adjustment of model 3 for dietary intake of vitamin D or vitamin D supplementation did not substantially alter observed HRs.
25OHD, 25-hydroxyvitamin D; CRC, colorectal cancer.
Figure 4Meta-analysis of HR of 25OHD tertile 3 versus tertile 1 with colorectal cancer (CRC)-specific and all-cause mortality. Adjusted HRs used for meta-analysis, adjusted for age, sex, American Joint Committee on Cancer (AJCC) stage, body mass index, tumour site (colon/rectum) and time between definitive treatment and sampling. 25OHD, 25-hydroxyvitamin D; CRP, C-reactive protein.
Figure 5Meta-analysis of HR of 25OHD tertile 3 versus tertile 1 for colorectal cancer (CRC) mortality stratified by rs11568820 genotype. Adjusted HRs used for meta-analysis, adjusted for age, sex, American Joint Committee on Cancer (AJCC) stage, body mass index, tumour site (colon/rectum) and time between definitive treatment and sampling. 25OHD, 25-hydroxyvitamin D; CRP, C-reactive protein.