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Circulating 25-Hydroxyvitamin D Levels Predict Survival in Early-Stage Non–Small-Cell Lung Cancer Patients

Wei Zhou, Rebecca S. Heist, Geoffrey Liu, Kofi Asomaning, Donna S. Neuberg, Bruce W. Hollis, John C. Wain, Thomas J. Lynch, Edward Giovannucci, Li Su, David C. Christiani

From the Departments of Environmental Health, Biostatistics, Nutrition, and Epidemiology, Harvard School of Public Health; Department of Medicine; Thoracic Surgery Unit, Department of Surgery, Massachusetts General Hospital; Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute; Channing Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, MA; and Pediatric Nutritional Sciences, Darby Children's Research Institute, Medical University of South Carolina, Charleston, SC

Address reprint requests to Wei Zhou, MD, PhD, Occupational Health Program, Harvard School of Public Health, 665 Huntington Ave, Boston, MA 02115; e-mail: wzhou{at}hsph.harvard.edu

	ABSTRACT

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Purpose: Our previous analyses suggested that surgery in the summertime with higher vitamin D intake is associated with improved survival in patients with early-stage non–small-cell lung cancer (NSCLC). We further investigated the results of circulating 25-hydroxyvitamin D (25[OH]D) levels on overall survival (OS) and recurrence-free survival (RFS) in NSCLC patients.

Patients and Methods: Among 447 patients with early-stage NSCLC, data were analyzed using Cox proportional hazards models, adjusting for age, sex, stage, smoking, and treatment.

Results: The median follow-up time was 72 months (range, 0.2 to 141), with 161 recurrences and 234 deaths. For OS, the adjusted hazard ratio (AHR) was 0.74 (95% CI, 0.50 to 1.10; P_trend = .07) for the highest versus lowest quartile of 25(OH)D levels. Stratified by stage, a strong association was observed among stage IB-IIB patients (AHR, 0.45; 95% CI, 0.24 to 0.82; P_trend = .002), but not among stage IA patients (AHR, 1.10; 95% CI, 0.62 to 1.96; P_trend = .53). Similar effects of 25(OH)D levels were observed among the 309 patients with dietary information (AHR, 0.74; 95% CI, 0.46 to 1.17; P_trend = .19). For the joint effects of 25(OH)D level and vitamin D intake, the combined high 25(OH)D levels and high vitamin D intake (by median) were associated with better survival than the combined low 25(OH)D levels and low vitamin D intake (AHR, 0.64; 95% CI, 0.42 to 0.98; P_trend = .06). Again, stronger associations were observed among stage IB-IIB than IA patients. Similar effects of 25(OH)D levels and vitamin D intake were observed for RFS.

Conclusion: Vitamin D may be associated with improved survival of patients with early-stage NSCLC, particularly among stage IB-IIB patients.

	INTRODUCTION

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Vitamin D is a steroid hormone that has long been known for its important role in regulating body levels of calcium and phosphorus, and in mineralization of bone. Vitamin D may be converted from 7-dehydrocholesterol by ultraviolet radiation (UV-B) in the skin or through limited sources from diet and supplements. Vitamin D is hydroxylated in the liver to produce 25-hydroxyvitamin D (25[OH]D), and then converted by 1-alpha-hydroxylase into 1,25(OH)₂D.¹ Recent epidemiologic studies have suggested that vitamin D may decrease the risk and mortality in various types of cancers.^1-5 However, data on lung cancer are sparse, and no epidemiologic study has ever measured circulating vitamin D concentrations directly in relation to prognosis of lung cancer or any type of cancer.

Our previous analyses demonstrated that the joint effects of surgery during the summer season and higher vitamin D intake are associated with improved survival in patients with early-stage non–small-cell lung cancer (NSCLC).⁶ To further investigate the role of vitamin D in NSCLC survival, we investigated the effects of circulating vitamin D levels on overall survival (OS) and recurrence-free survival (RFS) among 447 patients with early-stage NSCLC. Circulating 25(OH)D has a longer half-life (approximately 3 weeks), and its circulating levels have less daily variations than 1,25(OH)₂D, and is considered the better indicator of vitamin D status.^1,7 Because circulating 25(OH)D levels may only reflect the vitamin D status at the time of diagnosis or treatment initiation (short-term effect), and reported vitamin D dietary/supplement intake may reflect the longer status of vitamin D levels, we also investigated the joint effects of 25(OH)D levels and vitamin D intake. We hypothesized that patients with NSCLC with higher 25(OH)D levels at the time of diagnosis/treatment initiation who had higher vitamin D intake would have the best survival.

	PATIENTS AND METHODS

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Study Population
Eligible subjects were histologically confirmed and consecutively recruited patients with NSCLC at the Massachusetts General Hospital (MGH; Boston, MA) who were older than age 18 years. More than 85% of eligible patients participated in this study, and 96% were white. Details of this patient-case series population have been described previously.⁶ We first identified 558 incident early-stage (stages IA to IIB) patients with NSCLC recruited between 1992 and 2002, ensuring a follow-up time of at least 3 years. Sixteen patients who did not have complete follow-up or smoking information, and 95 patients who did not have serum or plasma samples were excluded from the analyses, leaving the subset of 447 incident patients with histologic diagnoses confirmed at MGH, who had their surgical resection at MGH, and who had complete outpatient records and serum or plasma samples available. The demographics and clinical and treatment characteristics of the subjects not included in the analysis were similar to those of the included subjects. This study was approved by the human subjects committee of MGH and Harvard School of Public Health (Boston, MA).

Data Collection
Twenty-five mL of peripheral venous blood were drawn for each patient at the time of initial diagnosis. Serum/plasma samples were separated and stored in –80°C freezers, and circulating 25(OH)D levels were measured using a published radioimmunosorbant assay.⁸

A modified version of detailed American Thoracic Society health questionnaire and validated semiquantitative food frequency questionnaire (FFQ) were completed for each patient at the time of recruitment.^9,10 The 126-food item FFQ has been validated in a group of white female nurses⁹ and male health professionals¹⁰ living in Boston. In the FFQ, a commonly used unit or portion size was specified for each food item or supplement, and subjects were asked about their average consumption over the past year before enrollment. Estimated average intakes for each specific food were obtained, and nutrient intake was computed using the Harvard database, which is a modification of the US Department of Agriculture Nutrition Composition Laboratory's food composition database.

Survival Measurements
OS and RFS were the end points in this study. OS time was calculated from the date of surgery to the date of last follow-up or death from any cause. RFS was defined as the time from the date of surgery to the first date of recurrence of cancer or death from any cause. Details of the verification of dates of death and dates of recurrence have been described previously.⁶ For those 14% of patients who had their primary follow-up outside of the MGH system, we contacted the primary physician to obtain follow-up information. Median follow-up time for this cohort was computed among subjects who were still alive.

Statistical Analysis
To investigate the effect of circulating 25(OH)D levels on OS and RFS, we separated the population into four groups by quartiles of 25(OH)D levels. Demographic and clinical information was compared across different 25(OH)D levels. The associations of 25(OH)D levels (or the joint effects of 25[OH]D levels and vitamin D intake) with OS and RFS were estimated using Cox proportional hazards models, controlling for multiple variables simultaneously. Trend tests were based on the integer scores of different quartile of 25(OH)D levels (from 1 to 4). Power calculations indicated that we would have 80% power (alpha [] = .05) to detect a hazard ratio of 0.65 for the highest versus lowest quartile of 25(OH)D levels among the 447 patients.

The analysis of joint effects of 25(OH)D levels and vitamin D intake on survival was limited to the 309 patients who had complete dietary information. The demographics and clinical and treatment characteristics have been shown to be similar between patients with and without dietary information.⁶ Energy-adjusted vitamin D intake values were created by regressing vitamin D intake values on total calories and obtaining the residual from this model.¹¹ The residual value was then added to the mean vitamin D intake value over all subjects to get the individual value. In the joint effects analysis, both vitamin D intake and 25(OH)D levels were divided into two groups by the median. Power calculations indicated that we would have 80% power ( = .05) to detect a hazard ratio of 0.61 for the joint effects among the 309 patients with complete dietary information (the combined high 25(OH)D levels plus high vitamin D intake v combined low 25(OH)D levels plus low vitamin D intake). All reported P values are from two-sided tests. All statistical analyses utilized SAS software, version 9 (SAS Institute, Cary, NC).

	RESULTS

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Patient, Stage, and Treatment Characteristics
Among the 447 patients with early-stage NSCLC, there were 161 recurrences and 234 deaths, including 108 deaths that occurred in the absence of reported recurrence, and 35 recurrences without death. The median follow-up time for the 213 patients still alive was 72 months (range, 0.2 to 141 months). Detailed demographic, clinical, and treatment information by different levels of 25(OH)D are presented in Table 1. The distributions of age, sex, stage, surgery type, smoking status, and pack-years of smoking were similar among patients with different 25(OH)D levels. Compared with patients with the lowest quartile of 25(OH)D levels (< 10.2 ng/mL), patients with the highest quartile of 25(OH)D levels ( 21.6 ng/mL) have higher proportions of bronchioloalveolar carcinoma (26% v 4%; P < .01) and lower proportions of squamous cell carcinoma (SCC; 21% v 32%; P < .01). In addition, a lower proportion of subjects in the highest quartile received additional radiation or chemotherapy (4% v 14%; P = .04). Circulating 25(OH)D levels were associated with the surgery season: the mean 25(OH)D levels were 14.3 ng/mL (standard deviation [SD], 8.6), 17.5 ng/mL (SD, 9.1), and 17.2 ng/mL (SD, 8.4), respectively, for patients who received surgery in the winter (November through February), spring/fall (March, April, September, and October), and summer (May through August; Kruskal-Wallis test P < .01), although the magnitude of the difference was relatively small. The distribution of patients with different 25(OH)D levels among different seasons are presented in Table 1.

Joint Effects of 25(OH)D and Vitamin D Intake
In addition to the independent effect of 25(OH)D levels, we also investigated the joint effects of 25(OH)D levels and vitamin D intake among the 309 patients who have complete dietary information, in which both 25(OH)D levels and vitamin D intake were divided into two groups by the median value. Patients with 25(OH)D levels 15.7 ng/mL and vitamin D intake 371 U/d were the reference group in comparisons (Table 4). The similar effects of the lowest two quartiles and the highest two quartile of 25(OH)D supported our analyses of stratifying the population by median level of 25(OH)D levels (15.7 ng/mL; Table 3), and subjects whose 25(OH)D levels less than 16 ng/mL (40 nmol/L) are generally defined as vitamin D insufficiency.¹² For OS, the AHR of patients with the high 25(OH)D levels and high vitamin D intake was 0.64 (95% CI, 0.42 to 0.98; P_trend = .06); and for RFS, the AHR was 0.67 (95% CI, 0.45 to 1.00; P_trend = .06). By stage, stronger joint effects were observed among stage IB-IIB patients than among stage IA patients. For OS, the AHRs of high 25(OH)D levels and high vitamin D intake were 0.50 (95% CI, 0.26 to 0.93) among stage IB-IIB patients and 0.88 (95% CI, 0.47 to 1.65) among stage IA patients; and for RFS, the corresponding AHRs were 0.55 (95% CI, 0.31 to 0.96) and 0.82 (95% CI, 0.46 to 1.51), respectively.

	DISCUSSION

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A number of factors may contribute to the variation of circulating 25(OH)D levels; among these, sunlight exposure and vitamin D intake are the most important. For many individuals who live at northern latitudes (of which the New England area is one), sunlight exposure alone in the winter may be insufficient to generate adequate vitamin D.¹⁷ We did not collect data on sunlight exposure behaviors or outdoor activities. Therefore, surgery season was used as a surrogate marker for the sunlight exposure levels. Nevertheless, regardless of the season, circulating 25(OH)D levels in this population were generally low with 50% of the subjects classified as vitamin D deficient (less than 16 ng/mL), and season was only a modest predictor of 25(OH)D levels with only about 3 ng/mL difference between winter and summer seasons. This suggests that even in the summertime, the patients in our cohort were not exposed to enough sunlight and, therefore, have low circulating 25(OH)D levels. In addition, insufficient vitamin D intake from diet and supplements, cigarette smoking, and age-related decrease in cutaneous synthesis⁵ may also have contributed to the low 25(OH)D levels in this population. The average vitamin D intake was 446 U/d (SD, 283 U/d). Although 446 U/d appears relatively adequate given current recommendations, recent evidence suggests that much higher intakes are required to avoid vitamin D insufficiency when UV-B exposure is low.^1,3 Previous studies have suggested that for older subjects who lived in regions with low UV-B levels, circulating 25(OH)D levels were generally very low. For example, in a random sample of 326 subjects (mean age, 68 years) in Oviedo, a city in northern Spain, 27% of the subjects' serum 25(OH)D levels were lower than 10 ng/mL, and 40% of the subjects' serum 25(OH)D levels were 10 to 18 ng/mL.¹⁸ In a cohort of 290 patients who were admitted consecutively to the general medical ward at MGH with a mean age of 62 years, 57% of the patients' 25(OH)D levels were lower than 15 ng/mL, and 22% of the patients' 25(OH) D levels were lower than 8 ng/mL.¹⁹ We observed a 26% improved survival for subjects with 25(OH)D levels higher than 21.6 ng/mL when compared with 25(OH)D levels lower than 10.2 ng/mL. It is possible that there would be further beneficial effect for patients with higher levels of 25(OH)D, and studies have suggested that the adequate or optimal level of circulating 25(OH)D levels is 30 ng/mL or even higher.^5,13,20

In this study, the beneficial effect of vitamin D was observed mainly among stage IB-IIB patients while not among stage IA patients. Further analysis suggested that the beneficial effect of vitamin D were stronger among stage II patients than stage IB patients, both for OS and RFS. For OS, the AHR of the highest versus lowest 25(OH)D levels was 0.68 (95% CI, 0.32 to 1.44; P_trend = .13) for the 135 stage IB patients and 0.20 (95% CI, 0.06 to 0.66; P_trend = .001) for the 80 stage II patients; for RFS, the corresponding AHRs were 0.71 (95% CI, 0.35 to 1.43; P_trend = 0.14) and 0.56 (95% CI, 0.20 to 1.57; P_trend = .06), respectively. Because of the small sample size for stage II patients, no subgroup analysis was performed for stage IIA or stage IIB patients, respectively. It is possible that the beneficial effect of vitamin D on lung cancer prognosis may be dependent on more advanced stage, seen in this study with both tumor size and lymph node involvement. The exact mechanism behind this needs further investigation.

For different histologic cell types, we observed that higher circulating 25(OH)D levels were associated with lower proportions of SCC while higher proportions of bronchioloalveolar carcinoma. This finding may be due to chance, or a heretofore unknown mechanism. A previous in vitro study did suggest there may be histologic differences for the effect of vitamin D where vitamin D inhibits growth of a lung SCC cell line, but not an adenocarcinoma cell line, and the mRNA levels of vitamin D receptor were much higher in the SCC cell line than the adenocarcinoma cell line.¹³ Finally, patients who had higher circulating 25(OH)D levels were less likely to receive adjuvant radiation or chemotherapy, suggesting that higher levels may be associated with less advanced disease.

We acknowledge several limitations in this study. This is a case series follow-up study and patients were not randomly assigned into different groups, so potentially 25(OH)D level could represent a confounder such as exercise, outdoor sunlight exposure, or correlated dietary factor. Although the overall study is large, sample sizes drop in the subgroup analyses by different stages. In addition, there is the problem of missing data. In our population, 30% of patients had missing dietary information, which may limit the generalizability of our results of vitamin D intake to all patients with early-stage NSCLC. We did not collect the information for vitamin D intake during the treatment or after the disease. Therefore, we could not investigate the beneficial effect of holding a constant high level of vitamin D. Another limitation is that diets may have changed. The FFQ inquired diet for the time period of 1 year before diagnosis. It is possible that dietary habits may have changed in the few months before diagnosis due to cancer-related symptoms, although all patients in our population were incident early-stage patients. In addition, the survival data could not distinguish between the death from lung cancer and from other causes; therefore, we assessed the all-cause of deaths instead of lung cancer specific death. Lastly, recurrence data were collected retrospectively and patients were not on a prescribed surveillance schedule.

In conclusion, this is the first study demonstrating the circulating 25(OH)D levels and the joint effects with vitamin D intake are associated with improved survival in patients with early-stage NSCLC, suggesting the importance of vitamin D in NSCLC prognosis. The results need to be confirmed in other independent studies and in randomized clinical trials.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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Although all authors completed the disclosure declaration, the following author or immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment: N/A Leadership: N/A Consultant: Bruce W. Hollis, Diasorin Stock: N/A Honoraria: N/A Research Funds: N/A Testimony: N/A Other: N/A

	AUTHOR CONTRIBUTIONS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS REFERENCES

 
Conception and design: Wei Zhou, Rebecca S. Heist, Geoffrey Liu, John C. Wain, Thomas J. Lynch, Edward Giovannucci, David C. Christiani

Financial support: Wei Zhou, David C. Christiani

Administrative support: David C. Christiani

Provision of study materials or patients: John C. Wain, Thomas J. Lynch, David C. Christiani

Collection and assembly of data: Wei Zhou, Rebecca S. Heist, Geoffrey Liu, Kofi Asomaning, Edward Giovannucci, Li Su, David C. Christiani

Data analysis and interpretation: Wei Zhou, Rebecca S. Heist, Geoffrey Liu, Kofi Asomaning, Donna S. Neuberg, Bruce W. Hollis, Edward Giovannucci, David C. Christiani

Manuscript writing: Wei Zhou, Rebecca S. Heist, Geoffrey Liu, Donna S. Neuberg, Bruce W. Hollis, Edward Giovannucci, David C. Christiani

Final approval of manuscript: Wei Zhou, Rebecca S. Heist, Geoffrey Liu, Kofi Asomaning, Donna S. Neuberg, Bruce W. Hollis, John C. Wain, Thomas J. Lynch, Edward Giovannucci, Li Su, David C. Christiani

	ACKNOWLEDGMENTS

 
We thank the following staff members: Barbara Bean, Andrea Shafer, Lucy Ann Principe, Salvatore Mucci, Richard Rivera-Massa, Siu-Ping Chin Feman, Brooke Ballantine; the generous support of Panos Fidias, MD, Bruce Chabner, MD, and the physicians and surgeons of the Massachusetts General Hospital Cancer Center.

	NOTES

 
Supported by National Institutes of Health Grants No. CA 092824, CA074386, CA090578, ES/CA 06409, and ES00002 (D.C.C.); the American Institute for Cancer Research, the Flight Attendants Medical Research Institute Young Clinical Scientist Award, and NIH Grant No. CA119650-01A1 (W.Z.); the American Cancer Society Postdoctoral Fellowship (R.S.H.); and the Doris Duke Charitable Foundation and Sue's Fund (G.L.).

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

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2. Robsahm TE, Tretli S, Dahlback A, et al: Vitamin D3 from sunlight may improve the prognosis of breast-, colon- and prostate cancer (Norway). Cancer Causes Control 15:149-158, 2004[CrossRef][Medline]

3. Giovannucci E, Liu Y, Rimm EB, et al: Prospective study of predictors of vitamin D status and cancer incidence and mortality in men. J Natl Cancer Inst 98:451-459, 2006[Abstract/Free Full Text]

4. Porojnicu AC, Robsahm TE, Ree AH, et al: Season of diagnosis is a prognostic factor in Hodgkin's lymphoma: A possible role of sun-induced vitamin D. Br J Cancer 93:571-574, 2005[CrossRef][Medline]

5. Holick MF: High prevalence of vitamin D inadequacy and implications for health. Mayo Clin Proc 81:353-373, 2006[Medline]

6. Zhou W, Suk R, Liu G, et al: Vitamin D is associated with improved survival in early-stage non-small cell lung cancer patients. Cancer Epidemiol Biomarkers Prev 14:2303-2309, 2005[Abstract/Free Full Text]

7. Gray RW, Weber HP, Dominguez JH, et al: The metabolism of vitamin D3 and 25-hydroxyvitamin D3 in normal and anephric humans. J Clin Endocrinol Metab 39:1045-1056, 1974[Medline]

8. Hollis BW, Kamerud JQ, Selvaag SR, et al: Determination of vitamin D status by radioimmunoassay with an 125I-labeled tracer. Clin Chem 39:529-533, 1993[Abstract/Free Full Text]

9. Willett WC, Sampson L, Stampfer MJ, et al: Reproducibility and validity of a semiquantitative food frequency questionnaire. Am J Epidemiol 122:51-65, 1985[Abstract/Free Full Text]

10. Rimm EB, Giovannucci EL, Stampfer MJ, et al: Reproducibility and validity of an expanded self-administered semiquantitative food frequency questionnaire among male health professionals. Am J Epidemiol 135:1114-1126, 1992; discussion 1127-1136, 1992[Abstract/Free Full Text]

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12. Need AG, Horowitz M, Morris HA, et al: Vitamin D status: Effects on parathyroid hormone and 1, 25-dihydroxyvitamin D in postmenopausal women. Am J Clin Nutr 71:1577-1581, 2000[Abstract/Free Full Text]

13. Higashimoto Y, Ohata M, Nishio K, et al: 1 alpha, 25-dihydroxyvitamin D3 and all-trans-retinoic acid inhibit the growth of a lung cancer cell line. Anticancer Res 16:2653-2659, 1996[Medline]

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Submitted May 24, 2006; accepted November 20, 2006.

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