Suboptimal Vitamin D levels among adult survivors of childhood cancers

Purpose: Vitamin D plays an important role in many bodily systems, with increasing evidence suggesting its importance for the prevention of chronic diseases and cancer. The identification of vitamin D levels in childhood cancer survivors becomes, therefore, particularly relevant, given that optimizing levels may contribute to the prevention of secondary malignancies and chronic diseases. Methods: A cross - sectional analysis of serum 25 - hydroxyvitamin D levels among adult survivors of childhood cancers living in New York State and surrounding areas (n = 139) was performed. Independent variables included gender, race/ethnicity, cancer site, year of diagnosis, past medical and surgical history, prior radiation therapy; prior chemotherapy, age at diagnosis, age at last clinic visit, year of last clinic visit, height, weight, body mass index, and vitamin D supplementation. Results: Overall, 34% of survivors were vitamin D deficient ( 25 demonstrated lower levels of vitamin D (p < 0.05). Vitamin D levels did not vary by age group, race, ethnicity, diagnosis, or years since diagnosis. Conclusion: Given the growing awareness of the role of vitamin D and the documented late effects of treatment for childhood cancers, the high prevalence of vitamin D deficiency within the childhood cancer survivor population is of concern. Vitamin D represents an important target for surveillance and intervention to help improve long - term outcomes of childhood cancer survivors.


Introduction
The success in treating childhood and adolescent cancers is evident by the dramatic reduction in mortality rates over the past several decades, with more than 80% of current patients now surviving for five years. 1, 2 This achievement, however, has led to a growing number of long -term survivors with new complications from their previous therapies. An extended follow up by Mertens et al. 2 , for example, found excess overall mortality of 8.4 fold when compared to age -, sex -and year -matched US population controls. Excess mortality was due primarily to secondary malignancies, followed by cardiac and pulmonary causes. 2 As a result, late effects of therapy and quality of life among adult survivors of childhood cancers have become areas of intense investigation. 3,4 include assessment of important health-related factors such as levels of Vitamin D, a fat soluble vitamin which is involved in many physiologic pathways. Emerging evidence suggests that Vitamin D levels should be greater than 30 ng/ml to achieve the desired health effects. 5 A data brief issued by the National Center for Health Statistics (NCHS) provides Vitamin D levels as assessed in the National Health and Nutrition Examination Surveys (NHANES). Findings from this survey indicate that approximately one-third of the general population were at risk of Vitamin D deficiency with levels < 20 ng/ml. 6 In a study by Forrest et al, Vitamin D status was examined using the NHANES data. Overall prevalence of Vitamin D deficiency (≤ 20 ng/mL) was found to be 41.6%; with African Americans presenting with the highest rate of Vitamin D deficiency at 82.1% and Caucasians at 30.9%. Furthermore, a significant link was found between those participants that were Vitamin D deficient and had less than a college education, poor health status, hypertension, low high-density lipoprotein cholesterol levels, and those not consuming milk. 7 A comprehensive review conducted by Holick along with other research has found a significant increase in long term cancer risk among individuals with deficient vitamin D levels. 8-12 As is clear from these findings, deficiency states are of great concern given the evidence suggesting that adequate Vitamin D levels may be important for prevention and management of type 1 and type 2 Diabetes mellitus, hypertension, and cancer. 13-16 However, research on the clinical impact of screening and treatment of Vitamin D remains inadequate. Several studies in Acute Lymphocytic Leukemia survivors have shown that patients with exposure to corticosteroids have increased bone demineralization and poor mineral homeostasis. [17][18][19] This suggests that childhood cancer survivors may be at an increased risk of Vitamin D deficiency.
Given the growing awareness of the role of Vitamin D and the documented late effects associated with treatment of childhood cancer, the issue of Vitamin D levels in the childhood cancer survivor population is of great relevance. Childhood cancer survivors are an ideal group to study Vitamin D levels, since optimizing levels may help to contribute to the prevention of secondary malignancies and chronic diseases. Childhood cancer survivors experience an increased risk of developing secondary malignancies and other chronic illnesses as a result of prior therapies. This study examines the prevalence of Vitamin D deficiency among adult survivors of childhood cancers.

Methods and Materials
Roswell Park Cancer Institute operates a Long-Term Follow -Up (LTFU) Center as part of the Department of Pediatrics which provides specialized surveillance, medical care, and counseling to former childhood cancer patients. Patients who are more than 5 years from their cancer diagnosis are seen in this outpatient center.
A cross -sectional medical chart review was utilized to abstract selected variables from patients seen in the LTFU center between 2009 and 2014. Two hundred and three patients were seen at 383 separate office visits over the period of 5 years. Sixty-four patients (31.5%) were excluded due to a lack of data on vitamin D levels leaving 139 patients (68.5%) with at least one measurement of Vitamin D who were included in the analytic data set. Among these 139 patients, 70 patients (50.4%) had Vitamin D levels available for at least 2 visits.
The main dependent variable was serum 25hydroxyvitamin D. The first Vitamin D level during the observation period was used for the analysis. Vitamin D sufficiency was defined as a serum 25 -hydroxy vitamin D level ≥ 30 ng/ml, insufficiency as a level from 20 ng ml to 29.9 ng/ml, and deficiency as ≤ 20 ng/ml. Independent variables included gender, race/ethnicity (non-Hispanic white versus all other), cancer site (leukemia, lymphoma, sarcoma, Central Nervous System (CNS), other), year of cancer diagnosis, past medical history, past surgical history, prior radiation therapy; prior chemotherapy, zip code of residence, age at diagnosis, age at last clinic visit, calendar year of last clinic visit, height, weight, body mass index (BMI, normal BMI < 25, overweight BMI 25 -29.9, and obese BMI ≥ 30), and self -reported Vitamin D supplementation / use of multivitamins. Seasons were categorized as Winter SPSS Version 21 (© IBM, Cary, NC) was used to facilitate data analyses, which included descriptive summaries and a comparison of Vitamin D status by demographic characteristics and supplementation status using chi-square tests. Vitamin D levels by supplementation status were analyzed using the Mann Whitney -U test. Analysis of variance was used to examine the relationship between mean vitamin D levels and BMI. In addition, a logistic model was constructed to examine factors associated with Vitamin D deficiency. The protocol for this research project was approved by the Roswell Park Cancer Institute Institutional Review Board.

Results
As reported above, one hundred thirty-nine patients with at least one Vitamin D assessment were identified for analysis. Clinical characteristics of childhood cancer survivors are presented in Table 1 survivors were Vitamin D deficient, 39% were classified as insufficient and 27% were classified as having sufficient Vitamin D levels. Chi -square testing revealed no significant difference in categorical Vitamin D status by gender, age group, race, cancer diagnosis, and years since diagnosis.

The distribution of Vitamin D levels based on supplementation status is shown in Figure
Median vitamin D levels among those supplemented (26.8 ng/ml) was greater than those not reporting supplementation (21.2 ng/ml, p = 0.0016, Mann -Whitney U test); however these median levels remain within the "insufficiency" range. Among the 41 patients who reported taking supplemental Vitamin D, 68.3% continued with insufficient or deficient Vitamin D levels at the subsequent draw despite supplementation.

Discussion
Examination and characterization of critical health related information in the childhood cancer survivor population is fundamental to the provision of comprehensive follow -up care. It is important to note, therefore, that the findings of the current investigation indicate that the median levels of Vitamin D (25.2 ng/ml in our sample of adult childhood cancers survivor is just above the deficiency threshold of 20 ng/ml) and well below suggested adequate levels of > 30 ng/ml. When applying thresholds for Vitamin D categories and matching age groups, patterns noted in the current study were comparable to those observed in the general population as reported in the NHANES data. 6 Specifically Despite the noted limitations, the present study is important in providing further evidence regarding the high prevalence of vitamin D deficiency/insufficiency among adult survivors of childhood cancers, and includes a substantial subset of persons > 40 years of age who are generally underrepresented in childhood cancer survivor cohorts.

Conclusion
We noted a strikingly low median level of serum vitamin D among this cohort of adult survivors of childhood cancers and high proportions of survivors with insufficient and deficient vitamin D levels. Given the documented late effects associated with therapies for childhood cancer, the issue of suboptimal Vitamin D levels among childhood cancer survivors is of substantial clinical relevance.

Funding
This study was supported by in part by Roswell Park Cancer Institute and National Cancer Institute (NCI) grants 3P30CA01605.