Relationship of Vitamin D Monitoring and Status to Bladder Cancer Survival in Veterans

ArticleinSouthern medical journal 106(2):126-30 · February 2013with58 Reads
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Abstract

Veterans of the armed forces, like most population groups, have a high prevalence of vitamin D deficiency, which may be associated with adverse outcomes in several types of cancer. Ultraviolet irradiation is inversely linked with the risk of bladder cancer, presumably through enhanced vitamin D synthesis. We hypothesized that variations in vitamin D status and monitoring predict adverse outcomes in bladder cancer among veterans. A retrospective analysis of data in the Veterans Integrated Service Network-9 (southeastern United States) was performed for patients diagnosed between October 1, 1999 and February 29, 2008. Age, tobacco exposure, body mass index, and latitude and seasonality of sampling were included as variables in addition to serum vitamin 25(OH)D levels. Monitoring of vitamin D and vitamin D levels and status were closely linked to survival in bladder cancer. Both the chances of survival and longevity improved with enhanced vitamin D status and monitoring. Veterans with bladder cancer had better outcomes if the initial vitamin D level was higher and had more monitoring of the vitamin. Initial vitamin D levels were more strongly related to outcomes than follow-up levels. The link between vitamin D and outcomes remained after adjusting for background variables such as age, body mass index, latitude, seasonality, and tobacco exposure. Findings suggest that adequate vitamin D levels early in the course of the disease provide the best opportunity to improve outcomes. Ensuring that veterans with bladder cancer have adequate vitamin D reserves with appropriate monitoring may play a role in improving outcomes in bladder cancer.

Full-text

Available from: Beth A Bailey
Relationship of Vitamin D Monitoring and
Status to Bladder Cancer Survival in Veterans
Alan N. Peiris, MD, Beth A. Bailey, PhD, and Todd Manning, BA
Objectives: Veterans of the armed forces, like most population groups,
have a high prevalence of vitamin D deficiency, which may be asso-
ciated with adverse outcomes in several types of cancer. Ultraviolet
irradiation is inversely linked with the risk of bladder cancer, pre-
sumably through enhanced vitamin D synthesis. We hypothesized that
variations in vitamin D status and monitoring predict adverse outcomes
in bladder cancer among veterans.
Methods: A retrospective analysis of data in the Veterans Integrated
Service Network-9 (southeastern United States) was performed for
patients diagnosed between October 1, 1999 and February 29, 2008.
Age, tobacco exposure, body mass index, and latitude and seasonality
of sampling were included as variables in addition to serum vitamin
25(OH)D levels.
Results: Monitoring of vitamin D and vitamin D levels and status were
closely linked to survival in bladder cancer. Both the chances of survival
and longevity improved with enhanced vitamin D status and monitor-
ing. Veterans with bladder cancer had better outcomes if the initial
vitamin D level was higher and had more monitoring of the vitamin.
Initial vitamin D levels were more strongly related to outcomes than
follow-up levels. The link between vitamin D and outcomes remained
after adjusting for background variables such as age, body mass index,
latitude, seasonality, and tobacco exposure.
Conclusions: Findings suggest that adequate vitamin D levels early in
the course of the disease pro vide the best opportunity to improve out-
comes. Ensuring that veterans with bladder cancer have adequate vitamin
D reserves with appropriate monitoring may pla y a role in impro ving
outcomes in bl adder cancer.
Key Words: bladder cancer, monitoring, veterans, vitamin D
V
itamin D deficiency is a global phenomenon that has
become more marked recently.
1
Evidence points to pos-
sible survival and longevity benefits at higher vitamin D
levels.
2
Vitamin D deficiency is prevalent in veterans of the
armed forces, and monitoring and treatment of this deficiency
remains suboptimal.
3
Deficiency also appears closely aligned
with increased healthcare costs.
4
Vitamin D deficiency may have deleterious effects in
several types of cancer.
5
For example, some preliminary data
indicate a link between circulating vitamin D and bladder
cancer, a cancer with a major economic burden.
6
Ultraviolet B
irradiation was independently and inversely associated with
incidence rates of bladder cancer after controlling for per capita
cigarette consumption and per capita health expenditure.
7
The present investigation was initiated to study how vi-
tamin D status and monitoring may predict outcomes in
veterans with bladder ca ncer. We hypothesiz ed that vitamin D
monitoring and sta tus par am eters would be linked to survival
status and length of survival in veterans with bladder cancer
irrespective of other risk factors.
Methods
Participants and Procedures
The present study was conducted at a healthcare facility
in the Depar tment of Veterans Affairs (VA). The research and
deve lopment committee at the VA Medical Center (VAMC),
as well as the institutional review board at the affiliated
Key Points
& This study examined the link between vitamin D status and
monitoring and adverse outcomes in bladder cancer in a large
sample of veterans.
& Both survival and longevity were predicted by enhanced vi-
tamin D status and monitoring.
& Initial vitamin D lev el predicted better outcomes, and effects
remained after adjusting for background v ariab les.
& Findings suggest that adequate vitamin D levels early in the
course of the disease provide the best opportunity to improve
outcomes, and adequate vitamin D reserves with appropriate
monitoring may play a role in improving outcomes in bladder
cancer.
Original Article
126 * 2013 Southern Medical Association
From the Mountain Home VA Medical Center and East Tennessee State
University, Mountain Home and Johnson City, Tennessee.
Reprint requests to Dr Alan N. Peiris, Department of Internal Medicine,
Mountain Home VA Medical Center, Medicine Service-111, Mountain
Home, TN 37684. Email: peiris@etsu.edu
The authors have no financial relationships to disclose and no conflicts of
interest to report.
Accepted September 6, 2012.
Copyright * 2013 by The Southern Medical Association
0038-4348/0Y2000/106-126
DOI: 10.1097/SMJ.0b013e3182824d00
Copyright © 2013 The Southern Medical Association. Unauthorized reproduction of this article is prohibited.
Page 1
university-approved procedures and protocol. Patient data
from 6 VAMCs l oca ted in the southeastern US in Vet eran s
Integrated Service Network-9 were included. From October 1,
1999 through Februar y 29, 2008, 5926 patients of the tota l
493,831 patients examined at the 6 VAMCs during this time
period were diagnosed as having bladder cancer.
Serum 25(OH)D was determined via immunochemilumi-
nometric assay (Labcorp, Burlington, NC). Vitamin D was
examined as both a continuous and dichotomous variable with
deficiency classified as 25(OH)D G20 ng/mL.
8
The month of
assessment also was recorded. The additional data extracted
included age, sex, race, body mass index (BMI), tobacco use and
zip code. The latitude of residence was determined by zip codes,
as previously reported, using the VA Planning Systems Support
Group Web site.
9
Finally, survival status at 4 years and length of
survival for those who did not survive also were recorded.
Patients with bladder cancer with data for all variables of
interest were included in the analysis. The final sample size of
4126 patients from the VAMCs at Huntington, West Virginia;
Lexington and Louisville, Kentucky; and Memphis, Mountain
Home, and Tennessee Valley, Tennessee.
Data Analysis
Data were obtained electronically through a database query
after removal of personal information and statistical analyses
were performed using PASW version 18.0 (IBM, Armonk, NY).
All of the variables were checked for outliers and normality of
distribution before analyses were performed. Outlying values on
vitamin D level were identified and recoded to 3 standard
deviations above the mean for subsequent analysis. t Tests and W
2
analyses were used to examine bivariate associations.
Controlled analyses, multiple regression for the continuous
outcome variable of interest (length of survival), and logistic
regression for the dichotomous outcome variable (survival sta-
tus) also were performed. Seven potential control variables were
available. Sex could not be used because of the lack of variance
(ie, sample almost exclusively men) and race could not be used
because it was missing for more than 10% of the sample.
The remaining variables of age, tobacco use, BMI, sea-
sonality of vitamin D testing, and latitude of residence were
examined for bivariate associations with the two outcomes
variables. The age, tobacco use, BMI, and latitude variables were
significantly associated (P G 0.10) with one or both outcomes
(ie, with survival status or length of survival) and were included
as possible confounders in regression analyses.
Results
Participant characteristics are presented in Table 1. The
4126 patients in the study sample were almost exclusively men
and mostly white. More than one-third used tobacco products
and the average participant was slightly overweight (ie, BMI
925). Vitamin D was not routinely tested in this sample, but
when it was, vitamin D deficiency (25(OH) G20 ng/mL) was
common.
The first question of interest was whether having had vi-
tamin D checked predicted improved outlook among patients
with bladder cancer. As can be seen in Figures 1 and 2, those
who had vitamin D testing (n = 630) were 67% more likely to
survive than those who did not (W
2
= 204.6; P G 0.001). Among
those who did not survive (n = 2025), those who had vitamin D
testing (n = 145) survived more than 2 years longer than those
Table 1. Participant characteristics
Characteristics
Percentage or mean
(range)
Background
Male sex, % 99
White race, %* 84
Body mass index 26.3 (10.3Y58.9)
Tobacco use, % 38
Latitude of residence 36.71 (24.69Y61.08)
Medical
Survival, % 51
Length of survival, mo
40.6 (0Y147.7)
Vitamin D testing, % 15
Vitamin D follow-up testing, %
57
Deficient initial vitamin D status, %
§
41
Initial vitamin D level, ng/mL 24.5 (4.3Y107.0)
Deficient first follow-up vitamin D
status, %
§||
23
First follow-up vitamin D level, ng/mL 29.9 (7.8Y88.0)
*Race missing for 11% of patients.
Þ
Calculation includes only those who did not survive.
þ
Percentage of those who had an initial vitamin D test.
§
Patients with 25(OH) values G20 ng/mL considered deficient.
||
Available only for those with at least two vitamin D tests.
Fig. 1. Bladder cancer survival rates by initial vitamin D defi-
ciency and monitoring status (N = 4126).
Original Article
Southern Medical Journal
&
Volume 106, Number 2, February 2013 127
Copyright © 2013 The Southern Medical Association. Unauthorized reproduction of this article is prohibited.
Page 2
who did not undergo testing (t = 9.54; P G 0.001). Analyses
controlling for potentially confounding background factors are
presented in Table 2. As can be seen, even after we controlled
for confounding factors, vitamin D testing still predi cted sur-
vival and days to death.
The second question of interest was whether increased
number of vitamin D tests or continued monitoring of vitamin
D predicted better outcomes among patients with bladder
cancer. Number of tests was analyzed continuously, in addition
to looking at having three or more tests (ie, at least two follow-
up tests). The number of tests was significant ly correlated with
days until death (r =0.220;P G 0.001), indicating that the more
tests that a patient underwent, the longer he was likely to survive.
In addition, patients who survived underwent significantly more
vitamin D tests than those who did not survive (0.59 vs 0.15, t =
12.66; P G 0.001). Bivariate differences in survival by grouped
number of vitamin D tests are presented in Figures 1 and 2. Two
or more follow-up vitamin D tests were associated with sig-
nificantly increased likelihood of survival (W
2
=93.1;P G 0.001),
and compared with those with fewer tests, those with at least two
follow-up tests lived more than 4 years longer after a bladder
cancer diagnosis (t =9.11;P G 0.001).
Controlled analyses were run for continuous number of
vitamin D tests predi cting both sur vival and days to death.
These results are presented in Table 3. As can be seen, even
after controlling for potentially confounding background fac-
tors, number of vitamin D tests was associated with both
survival and days to death after bladder cancer diagnosis.
The final study question was whether higher levels of
vitamin D led to better outlook for patients with bladder cancer.
Vitamin D deficiency in relation to outlook was examined for
both initial vitamin D status (Fig. 1) and vitamin D status at first
follow-up testing. Those who were initially vitamin D deficient
were significantly less likely to survive than those who were not
initially deficient (W
2
= 10.44; P = 0.001), but among those who
did not survive, initial vitamin D status was unrelated to length
of survival (t = 0.96; P = 0.337); however, follow-up vitamin D
status was unrelated to either survival status or length of sur-
vival (P 9 0.10). Controlled analyses predicting survival from
Fig. 2. Months of survival by initial vitamin D deficiency and
monitoring status (N = 2025).
Table 2. Regression results predicting outlook from
vitamin D testi ng status of patients with bladder cancer
Outcome, predictor RR
2
change P
Survival status
Background factors 0.311 0.097 G0.001
Age, y 0.172
BMI G0.001
Tobacco use 0.988
Latitude of residence 0.001
Vitamin D tested 0.346 0.023 0.001
Length of survival
Background factors 0.307 0.094 G0.001
Age, y G0.001
BMI 0.001
Tobacco use G0.001
Latitude 0.074
Vitamin D tested 0.358 0.033 G0.001
Separate regressions were performed for survival status (logistic regression)
and length of survival (multiple regression). For the length of survival analysis,
only those patients who did not survive (n = 2025) were included. Background
variables were entered together on the first step, followed by vitamin D testing
status on the second step. BMI, body mass index.
Table 3. Regression results predicting outlook from
number of vitamin D tests in patients with bladder cancer
Outcome, predictor RR
2
change P
Survival status
Background factors 0.313 0.098 G0.001
Age, y 0.027
BMI G0.001
Tobacco use 0.001
Latitude of residence 0.001
No. vitamin D tests 0.379 0.046 G0.001
Length of survival
Background factors 0.307 0.094 G0.001
Age, y G0.001
BMI 0.001
Tobacco use G0.001
Latitude 0.074
No. vitamin D tests 0.364 0.038 G0.001
Separate regressions were performed for survival status (logistic regression)
and length of survival (multiple regression). For the length of survival analysis,
only those patients who did not survive (n = 2025) were included. Background
variables were entered together on the first step, followed by number of vitamin
D tests on the second step. BMI, body mass index.
Bailey et al
&
Relationship of Vitamin D to Bladder Cancer Survival in Veterans
128 * 2013 Southern Medical Association
Copyright © 2013 The Southern Medical Association. Unauthorized reproduction of this article is prohibited.
Page 3
initial deficiency status (Table 4) revealed that even after
controlling for potentially confounding background factors,
initial vitamin D deficiency was associated with decreased
likelihood of survival after bladder cancer diagnosis.
Discussion
To our knowledge, this is the first published report indi-
cating that vitamin D status and monitoring predict significant
outcome differences in bladder cancer in veterans of the armed
forces. Veterans with bladder cancer who underwent vitamin D
testing were significantly more likely to survive than those who
did not. Moan et al reported that prognosis of internal cancers is
best for cases diagnosed in the seasons of the year with the best
vitamin D status (eg, summer).
10
Our findings are consistent
with this concept and are also supported by ecological studies by
Grant.
11
Among those veterans who did not survive, those who
had vitamin D testing survived significantly longer than those
who did not ha ve testing. Interestingly, vitamin D deficiency
remained a significant risk factor for adverse outcomes after
adjusting for age, adiposity, tobacco exposure, latitude, and
seasonality, predicting not only survival but also days to death.
The vitamin D receptor is ubiquitous and studies have
demonstrated its presence in bladder cancer.
12
In one prospec-
tive study of male smokers, lower serum 25(OH)D levels were
associated with an increased risk of bladder cancer
13
; however,
not all studies have found a link between vitamin D and cancer.
After a median follow-up of 8.0 and 7.9 years, the Women’s
Health Initiative study provided evidence that multivitamin use
has little or no influence on the risk for common cancers in
postmenopausal women.
14
This ma y relate to dosage because
many multivitamins do not contain substantial amounts of vi-
tamin D. Grant and Peiris have reviewed the data linking vitamin
D status to bladder cancer and concluded that both the risk and
survival after diagnosis of this cancer may be linked to vitamin D
deficiency, especially in ethnic minorities.
15
Among the veterans who did not survive, initial vitamin D
status was unrelated to length of survival, and follow-up vitamin
D status did not predict survival status or length of survival. This
suggests that it is perhaps important for these patients to be made
vitamin D replete before or at least at the time of diagnosis.
Attempts to improve vitamin D levels after diagnosis may be less
effective in improving survival status or longevity.
The number of vitamin D tests was significantly correlated
with days until death, indicating that the more tests a patient
underwent, the longer he was likely to survive. In addition,
patients who survived had significantly more vitamin D tests
than those who did not survive. At least one follow-up vitamin
D test was associated with significantly increased likelihood of
survival and significantly longer time of survival for those who
died. The same was true for two or more follow-up tests,
and the effects were even greater with three or more tests. We
must consider the possibility that it may not be the vitamin D
monitoring per se but that monitoring was a proxy for better
overall care or better adherence to treatment recommendations
or even a more direct result of survival time.
The present study also raises the interesting question if
plausible mechanisms of action exist to support a role for vi-
tamin D in bladder cancer. Vitamin D receptor (Fok-I) poly-
morphisms have been linked to the genetic risk of bladder
cancer.
16
Furthermore, the patients with FT and fT haplotype
have a lower risk of developing bladder cancer than those with
other haplotypes.
16
The antiproliferative effect of calcitriol and its analogues
may be related to their effect on cell differentiation. The ap-
pearance of antigen CD14 and CD11b expression after exposure
to calcitriol and its new analogues confirms their effect on cell
differentiation.
17
Vitamin 1,25D3 potentiates gemcitabine and
cisplatin-mediated growth inhibition in human bladder cancer
models in vitro and in vivo, which involves p73 induction and
apoptosis.
18
These results suggest that calcitriol inhibits pro-
liferation and induces apoptosis in human bladder tumor cells
in vitro and may have therapeutic potential in bladder cancer. In
vivo studies using an N-methylnitrosourea-induced model of
bladder cancer demonstrate that early institution of intravesical
calcitriol therapy after carci nogen exposure results in fewer
tumors, which also are less likely to be multifocal, high grade,
or invasive.
19
Vitamin D also may improve cancer-specific
survival by mechanisms that promulgate antiangiogenesis
20
and antimetastases actions.
21
This study has several limitations as a result of its retro-
spective nature. Most important, because the study was cor-
relational, no definitive conclusions can be made regarding a
potential causal link between vitamin D status and monitoring
and bladder cancer outcomes. In addition, management of
vitamin D status in the private sector could not be accounted
for, but it may have influenced findings related to both total
costs and monitoring, because some veterans have both private
and VA healthcare providers. Furthermore, it is possible that
the study sample may not be representative of all veterans and
may be skewed toward a more symptomatic group that is more
likely to be tested for vitamin D deficiency. The possibility that
vitamin D status is a marker for chronically ill patients exists;
however, similar degrees of vitamin D deficiency have been
Table 4. Logistic regression results predicting survival of
patients with bladder cancer from initial vitamin D level
Predictor RR
2
change P
Background factors 0.311 0.097 G0.001
Age, y 0.172
BMI G0.001
Tobacco use 0.988
Latitude of residence 0.001
Initial vitamin D deficiency status 0.348 0.024 0.001
Background variables were entered together on the first step, followed by vi-
tamin D deficiency status on the second step. BMI, body mass index.
Original Article
Southern Medical Journal
&
Volume 106, Number 2, February 2013 129
Copyright © 2013 The Southern Medical Association. Unauthorized reproduction of this article is prohibited.
Page 4
noted in many apparently healthy populations across the globe.
Prospective randomized controlled studi es are needed to con-
firm applicability of our findings to all veterans and the general
population of all patients with bladder cancer.
Conclusions
Findings from the present study suggest that vitamin D
deficiency may contribute to adverse outcomes in veterans with
bladder cancer. Moreover, achieving higher vitamin D values
early in the course of the disease may be better than trying to
achieve replete status after diagnosis. In addition, vitamin D
emerged as a significant risk factor independent of more tra-
ditional risk factors such as age, seasonality, latitude, and to-
bacco use. Pending prospective studies to confirm these
findings, we believe that all veterans with bladder cancer
should have a 25(OH)D level checked with appropriate re-
placement as needed. In addition, efforts should focus on
preventive measures to bring patient vitamin D to replete levels
before serious health problems emerge. Given the minimum
cost of vitamin D replacement, emerging benefits, and the low
risk of toxicity, we agree with the recent Endocrine Society
recommendations that daily intake of 1000 to 2000 IU vitamin
D
3
is a good starting point.
22
Immediate implementation of this
recommendation will likely benefit patients with bladder
cancer and possibly other cancers.
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Relationship of Vitamin D to Bladder Cancer Survival in Veterans
130 * 2013 Southern Medical Association
Copyright © 2013 The Southern Medical Association. Unauthorized reproduction of this article is prohibited.
Page 5
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