Int. J.

Cancer: 125, 11551160 (2009) ' 2009 UICC

Cod liver oil, other dietary supplements and survival among cancer patients with solid tumours
2 Guri Skeie1*, Tonje Braaten1, Anette Hjartaker , Magritt Brustad1 and Eiliv Lund1 1 Institute of Community Medicine, University of Troms, Troms, Norway 2 Cancer Registry of Norway, Oslo, Norway

The effect of various dietary supplements on chronic diseases and mortality has been widely studied, but few convincing results have emerged from studies in well-nourished populations. In Norway, both cod liver oil and other dietary supplements are frequently used. In the Norwegian Women and Cancer cohort study, we explored if supplement use before diagnosis affected survival of cancer patients with solid tumours. We performed Cox proportional hazards analyses, adjusting for age at diagnosis, smoking and stage. Cod liver oil was the most frequently used dietary supplement, followed by multivitamins and -minerals. Whole year daily use of cod liver oil was associated with lower risk of death in patients with solid tumours [RR 5 0.77 (95% CI 0.610.97)] and in lung cancer patients [RR50.56 (95% CI 0.340.92)]. Also daily and occasional use of other dietary supplements decreased the risk of death among lung cancer patients [RR 5 0.70 (95% CI 0.490.99) and 0.55 (95% CI 0.310.97)]. More research is needed to clarify the association; meanwhile adjustment for dietary supplement use should be performed in survival analyses of lung cancer patients. ' 2009 UICC Key words: cancer patients; survival; dietary supplements; cohort study; Norway

CLO is the second most important dietary source of very-longchain fatty acids in the Norwegian diet (after sh) and women in the highest quartile of very-long-chain fatty acid intake have a more than tripled intake of vitamin D compared with those in the lowest quartile.17 Intake of these nutrients alone or in combination has been associated with a range of health effects and mortality.1825 The main source of vitamin D is solar ultraviolet B-radiation which induces vitamin D3 production in the skin.18 From 51 degrees north and northwards, there is a period each year with no or very low cutaneous production, which increases in length with latitude.26 All of Norway is north of this latitude, so in periods of the year dietary intake of vitamin D is necessary to cover the requirements.27,28 The aim of this study was to compare the survival of female cancer patients with solid tumours according to use of CLO and other dietary supplements before diagnosis. We present overall survival for all solid tumours, and separate estimates for patients of the most frequent cancer sites: breast, colorectum and lung. Material and methods The Norwegian Women and Cancer study was initiated in 1991, and is a national, population-based cohort study. The study design, population and procedures have been described elsewhere, together with aspects of external validity.29 This article reports information collected between 1996 and 1999, partly from the second part of the baseline mailing (19961997), and partly from a second mailing (19981999). In total, 68,518 women lled in a self-administered questionnaire including a semi-quantitative food-frequency questionnaire (FFQ) and questions on demographic variables, reproductive factors, lifestyle factors, medication, different illnesses, smoking, physical activity, education and income. Body mass index (BMI) was calculated as weight (kg) divided by the square of the height (m2). Dietary questionnaire and calculations The FFQ covered the habitual diet in the previous year, with special attention to the consumption of sh and sh products.30 The questionnaires applied in the baseline and the second mailing had comparable sections of dietary information, but with some differences, especially in sweet foods. It included 6678 food items typically consumed in Norway, several questions on CLO and other dietary supplements (see details below) and 3 questions on alcohol intake, but did not cover the entire diet. Frequencies were asked per day, week, month or year as appropriate, typically with 67 alternatives. A more detailed description of the core dietary questions and their validation has been published elsewhere.3033 Daily intake of nutrients and energy was calculated using values from the Norwegian Food Composition table.34 This table
Grant sponsor: The Norwegian Foundation for Health and Rehabilitation (EXTRA funds) and the Norwegian Cancer Society. *Correspondence to: Institute of Community Medicine, University of Troms, N-9037 Troms, Norway. Fax: 147-77644831. E-mail: guri.skeie@uit.no Received 5 January 2009; Accepted after revision 26 February 2009 DOI 10.1002/ijc.24422 Published online 11 March 2009 in Wiley InterScience (www.interscience. wiley.com).

Dietary supplement use is increasing and several studies have shown higher use among cancer patients than in the general population.1 Dietary supplements comprise a wide range of products of differing composition. Studies of their effects on primary prevention of chronic diseases, as well as mortality, have generally failed to demonstrate benecial effects in well-nourished populations.27 Clinical trials have also been stopped early due to no preventive effects and suggestions of negative health effects, a recent example is the SELECT study.8 The second WCRF/AICR expert report summarized that there is not enough evidence yet for giving specic advice to cancer survivors, neither on supplement use nor on other dietary factors. They, therefore, suggest that survivors follow general cancer preventive advice, which is not taking supplements, but try to meet nutritional needs through diet alone.6 The American Cancer Society has developed guidelines for nutrition and physical activity during and after cancer treatment, even though they know that the scientic evidence is incomplete.9 During and after cancer treatment, a standard multiple vitamin and mineral supplement containing approximately 100% of the daily value is recommended, since it might be difcult to eat a diet with adequate amounts of micronutrients in those times. However, no evidence was found to suggest that nutritional supplements lower risk of recurrence. Use of high-dose supplements is discouraged.9 There is some concern that high-dose antioxidant supplements might interfere with radio- or chemotherapy treatments, though this is somewhat controversial.9,10 Dietary supplement use is common in Norway, and the most commonly taken dietary supplement is cod liver oil (CLO).1114 Typically 35% of the female adult population takes it daily at least during winter. Also other supplements are taken frequently and 4060% of Norwegian women report use of other supplements.11,15 Compared with healthy women, Norwegian breast cancer survivors did not have a signicantly higher consumption of CLO, but used other dietary supplements at a higher frequency.16 The difference was limited to those surveyed rather shortly (15 years) after diagnosis.
Publication of the International Union Against Cancer

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SKEIE ET AL.
TABLE I TYPES OF DIETARY SUPPLEMENTS USED BEFORE DIAGNOSIS BY LUNG CANCER PATIENTS AND OTHER CANCER PATIENTS WHO REPORTED SUPPLEMENT NAMES Supplement type Lung cancer patients (n 5 87)1 % n Other cancer patients (n 5 239)1 % n

includes data on CLO, but not on other dietary supplements. CLO (liquid and capsule concentrates) was, therefore, the only dietary supplement included in the nutrient calculations. No dietary supplements database was available to conrm the content of the other dietary supplements. However, supplement names were extracted from all lung cancer patients and a random selection (22.5%) of other cancer patients (not restricted to solid tumours) who had reported this. Based on the names, main ingredients and frequency of use, the other dietary supplements were classied in 9 categories (Table I). Multivitamins and -minerals were the most frequently used other dietary supplement type, followed by vitamin Bs and C. The pattern of use did not differ between the 2 groups. Cod liver oil and other dietary supplement use For about 2/3 of the cohort there were initial yes/no questions on liquid CLO use, CLO capsule use and use of other dietary supplements. Next, the participants were asked separate questions on how often they took liquid CLO, CLO in capsules and other dietary supplements: never/seldom, 13 times a month, once a week, 26 times a week or daily. For about 1/3 of the cohort no initial yes/no questions were asked, and the option 26 times a week was split into 23 times and 46 times a week. All participants were asked separate frequency questions about CLO use (liquid and capsules) in the winter and the rest of the year. Finally, a question on CLO dose was asked, the alternatives were 1 teaspoon, 1/2 tablespoon or 1 tablespoon for liquid CLO, and the number of CLO capsules was queried. For other dietary supplement there was an open-ended question about supplement name(s), but no question on dose. A previous analysis have shown that use of CLO is associated with several sociodemographic factors, self-reported health issues and intake of sh, fruit and vegetables in our cohort.11 For the current analyses, 4 groups of CLO-users were created based on the categories in the questionnaire and the previous paper11: nonusers, occasional users, seasonal daily users and whole year daily users. Participants were classied as non-users if they never took CLO, or did so less frequently than once a week during winter and the rest of the year. Occasional users were dened as participants taking CLO 16 days per week either during the winter months or the rest of the year or both. Seasonal daily users were dened as subjects taking CLO daily either during winter or the rest of the year. Whole year daily users were those taking CLO daily both in the winter and the rest of the year. The analyses did not discriminate between CLO consumed in liquid and capsule form. Daily users of CLO taking the recommended dose will cover their vitamin D requirements. For other dietary supplements the categories were non-users, occasional users and daily users. These categories were constructed in a similar fashion as the CLO-categories, but without seasonal variation. To check the combined effect of CLO and other supplements, a new variable combining the two was created. Non-users of both types of supplements were the reference category, the other categories were: occasional users of one or both types (including any combination of occasional/non-use, occasional/occasional and occasional/daily), daily users of CLO (whole year or seasonal) not using other supplements, daily users of other supplements not using CLO, and daily users of both CLO and other supplements. Study population Information on cancers was obtained by linkage to the Cancer registry of Norway and information about death was obtain from the Central Person Registry, both using the individually unique national registration numbers. The Regional Committee for Medical Research Ethics and the Norwegian Data Inspectorate approved the study. All participants provided informed consent. The study population was the subsample of the cohort who was diagnosed with their rst cancer after the 19961999 questionnaire, and before January 1, 2007, N 5 4,242. Exclusions were

Multivitamins/minerals Vitamin B Vitamin C Ginseng/Q10 Vitamin E Single minerals Herbs/plants Other Not specic Total

38.5 15.6 14.1 10.4 5.9 5.9 5.2 3.0 1.5 100.0

52 21 19 14 8 8 7 4 2 135

38.2 11.4 12.8 9.7 6.7 8.1 4.5 7.2 1.4 100.0

137 41 46 35 24 29 16 26 5 359

1 Since several patients took more than one supplement, the number of supplements taken is greater than the number of patients.

based on implausible energy intakes (<2,500, >15,000 kJ/day)30 (N 5 52), missing information on smoking (N 5 87), missing information on CLO frequency or amount (N 5 325), and missing information on frequency of other supplements, (N 5 132). A further 20 patients were diagnosed upon death and did not contribute follow-up time and 629 patients did not have stage information (including 239 non-solid tumours). Finally, 2,997 women were included in the analyses; 1,226 with breast cancer [International Classication of Diseases version 7 (ICD-7), code 1700-1709], 399 with colorectal cancer (ICD-7, code 1530-1549), 217 with lung cancer (ICD-7, code 1620-1629) and 1,155 with other solid tumours. The vital status was censored December 31, 2007, and by then 748 participants had died, of these 121 had breast cancer, 143 had colorectal cancer and 160 had lung cancer. Statistical analyses The Cox proportional hazards model was used to calculate hazard ratios for mortality with corresponding 95% condence intervals (CI). Assumptions for the Cox proportional hazards model were tested and met. The hazard ratios are interpreted as estimates of relative mortality risks (RR), and the term survival is used analogously to mortality risk. Time since diagnosis was used as the primary time-variable. KaplanMeier plots were constructed to describe the survival function. Survival differences between groups were assessed for statistical signicance by the log-rank test. Differences between categories of CLO and other supplement use were tested in analyses of covariance (age at diagnosis) and Cochran-Mantel-Haenzels test adjusted for age at diagnosis (smoking and stage). All analyses were done in SAS Software Package (version 9.1). The level of signicance was set to 0.05. The associations between cancer survival and CLO and other dietary supplements use, respectively, were rst examined in ageadjusted analyses. A set of potential confounders were tested individually in a model with age and supplement use, and whenever a change in risk by supplement use was observed, the variable was included in the multivariate models. The criterion for effect was a change in the estimate for supplement use of 5% or more in the multivariate adjusted model. The following variables were tested for confounding effects: stage, BMI, smoking status, physical activity, age at rst birth, parity, region of residence, education, prevalence of certain diseases (myocardial infarction, stroke, high blood pressure, heart failure and diabetes), self-reported health, alcohol consumption, total fat, total energy, vitamin C, vitamin D, beta-carotene, alpha-tocopherol, selenium, dietary bre, fruits, vegetables, fatty sh and lean sh. Only smoking status and stage affected the estimates. The nal models, therefore, only included age at diagnosis (continuous, in years), smoking (never, former, current) and stage (localized, regional metastases, distant metastases). Interaction between smoking and dietary supplement use

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was tested by including an interaction term in the models for total cancer. Results Mean age at diagnosis was 58.4 years, but there were differences among the cancer sites, and breast cancer patients were younger (Table II). More than half of the solid tumours were detected at a localized stage, but there was considerable variation among cancer sites. Most breast tumours were localized (57.3%), most colorectal tumours were found with regional metastases (64.9%) and tumours in the lung were most frequently detected when distant metastases had occurred (45.6%). For all patients (n 5 2,997), breast cancer patients (n 5 1,226) and colorectal cancer patients (n 5 399), the distribution between current, former and never smoking before diagnosis was fairly even, but among lung cancer patients (n 5 217) only 3.9% were never smokers. Among all patients, 46.6% used CLO at least occasionally before diagnosis, with slight variations between the cancer sites. The frequency of other supplement use before diagnosis was similar, 47.1%, also with slight variation between cancer sites. Some differences were observed across categories of CLO and other supplement use (results not shown). Nonusers and occasional users of CLO were younger (58 years) than seasonal (59 years) and whole year (61 years) daily users (p < 0.001). Smoking was signicantly associated with CLO use, p 5 0.005. There were more current smokers among nonusers (38.9%) than occasional users (28.2%). Occasional users of other supplements were younger at diagnosis (56 years) than nonusers and daily users (59 years, p < 0.001). Stage was signicantly associated with other supplement use (p 5 0.02). Occasional users were more often diagnosed in a localized stage of disease (57% of the cases vs. 52% in nonusers and daily users), and less often with distant metastases (9 vs. 14% and 11%). One-year survival rate differed vastly, for breast cancer it was 98.4%, for colorectal cancer 86.7% and for lung cancer 47.0%. In Figure 1 KaplanMeier plots for all solid tumours (Fig. 1a) and lung cancer (Fig. 1b) describe the survival function for the categories of CLO use, and gures 1c and 1d have corresponding plots for categories of other dietary supplement use. For CLO use there were no differences either for all solid tumours or for lung cancer. One-year survival rate for all solid tumours was 89.8% for whole year daily users, 88.9% for seasonal daily users and occasional users and 87.4% for nonusers. For lung cancer, it was 57.6% for all year daily users, 56.1% for seasonal daily users, 40% for occasional users and 42.4% for nonusers. For other dietary supplements there was a signicant association between category of use and survival. The log-rank test for all solid tumours was signicant (p 5 0.002), and occasional users had the best survival. The 1-year survival was 89.3% among daily users, 91.1% among occasional users and 86.9% among nonusers. Also for lung cancer there was a signicant association (p 5 0.02) and occasional users had the best survival. One-year survival rate was 52.8% for daily users, 58.3% for occasional users and 41.3% for nonusers. As can be seen from the gures, the tendency was that the curves diverged more as time since diagnosis increased. Table III shows the relative risks of dying among cancer patients with solid tumours depending on category of CLO use and category of other supplement use. Whole-year daily use of CLO was associated with improved survival among cancer patients with solid tumours, RR 5 0.77 (95% CI 0.610.97). No associations were evident for breast or colorectal cancer patients, but lung cancer patients using CLO daily the whole year had a signicantly reduced risk of death, RR 5 0.56 (95% CI 0.350.92). Occasional users of other dietary supplements had the lowest risk of death, both for all solid tumours and for the specic cancers studied, but the risk reduction was only signicant for lung cancer patients, RR 5 0.55 (95% CI 0.310.97). For lung cancer patients, the risk estimate for daily users was also similar, RR 5 0.70 (95%

CI 0.490.99). There was no interaction between smoking and use of CLO or other supplements. More than half of those who died did so within 1 year of diagnosis. Specic causes of death were complete until December 31, 2005, and 95% of the deaths were due to cancer. Exclusion of those diagnosed less than 1 year after study entry did not affect the estimates. When use of CLO and other dietary supplements were combined into one variable daily use of both CLO and other dietary supplements was associated with improved survival in lung cancer patients, RR 5 0.57 (95% CI 0.350.94; results not shown). Discussion In this study, daily use of CLO and other dietary supplements before diagnosis, alone or in combination, was associated with reduced risk of death among lung cancer patients. Survival was also increased for cancer patients with solid tumours who were whole-year daily users of CLO and for lung cancer patients using other dietary supplements occasionally. Our study is not the rst to nd increased survival in lung cancer patients taking dietary supplements.3537 In a small crosssectional study a random selection (n 5 36) of postoperative nonsmall cell lung cancer patients were invited to complete a food frequency questionnaire and donate a blood sample.35 The vitamin-users had signicantly longer median disease-free survival at the time of the study compared with nonusers, 41 vs. 11 months (p 5 0.002). The second study was a prospective study of nonsmall cell lung cancer patients in the Mayo Clinic lung cancer cohort.36 The 1,129 participants received a supplement questionnaire 6 months after diagnosis, and later at regular intervals. The relative risk of death was 0.54 (95% CI 0.440.65) among current users compared to non-users. After adjustment for stage, grade, treatment modality, age, gender, smoking history at diagnosis and timing of questionnaire, the RR increased to 0.74 (95% CI 0.60 0.91, p < 0.01). Median survival was 4.3 years for users vs. 2.0 years for nonusers. Similar results were found in patients with small cell lung cancer, RR 5 0.65 (95% CI 0.431.00).37 In all these studies, multivitamins were the most frequently reported supplements. Other studies have looked at biochemical or clinical indices of nutritional status in relation to survival of lung cancer patients. One study found that in early stage non-small cell lung cancer patients, higher levels of circulating vitamin D was associated with improved survival.38 However, the authors could not replicate the results in advanced stage nonsmall cell lung cancer patients.39 Another study found that nutritional status on diagnosis affected long term survival after lobectomy for lung cancer.40 Currently, the bulk of evidence on diet and cancer relates to primary prevention, and cancer survivors are advised to follow general cancer preventive strategies.6 At least 2 studies, including one Norwegian study, have found that CLO supplementation lowers lung cancer incidence.41,42 To our knowledge, no randomized control study of CLO supplementation and cancer incidence or survival has been performed. Given that randomized controlled trials have demonstrated no effects or increased incidence of lung cancer in supplementation studies in well-nourished populations,43,44 our results may be somewhat surprising. However, these studies used pharmacological doses of specic nutrients, and cannot easily be compared with ours. The French SU.VI.MAX study on the other hand used a combination of antioxidant vitamins and minerals at nutritional doses in a general population, and found reduced total cancer risk and total mortality in men, but not in women.45 Incidentally, the difference in cancer rates was highest for cancers of the respiratory tract. The SU.VI.MAX study found no differences in cancer rates for women, and suggested that this was due to the higher baseline concentrations of some antioxidant nutrients in women.45 It is

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TABLE II CHARACTERISTICS OF ALL STUDY PARTICIPANTS AND PARTICIPANTS WITH THE MOST FREQUENT CANCER TYPES Characteristic All patients with solid tumours (n 5 2,997) Breast cancer patients (n 5 1,226) Colorectal cancer patients (n 5 399) Lung cancer patients (n5 217)

Age at diagnosis (years, mean) 58.4 Stage (%) Localized 52.4 Regional metastases 35.4 Distant metastases 12.2 One-year survival rate (%) 88.2 1 Smoking before diagnosis (%) Never smokers 34.8 Former smokers 29.3 Current smokers 35.9 Cod liver oil use before diagnosis (%)1 Nonusers 53.4 Occasional users 10.2 Seasonal daily users 24.0 Whole-year daily users 12.4 Other dietary supplement use before diagnosis (%)1 Non-users 52.9 Occasional users 10.6 Daily users 36.5
1

56.6 57.3 40.0 2.7 98.4 37.4 31.5 31.1 52.5 10.4 24.6 12.5 51.5 11.1 37.4

61.1 25.3 64.9 9.8 86.7 33.3 36.5 30.2 58.6 6.4 24.0 11.0 55.9 9.1 35.0

60.3 17.5 36.9 45.6 47.0 3.9 12.6 83.5 56.4 11.6 18.1 13.9 55.7 11.7 32.6

Smoking, cod liver oil and other supplement use are adjusted for age at diagnosis.

FIGURE 1 KaplanMeier survival plot (a,b) for all solid tumours and lung cancer according to cod liver oil (CLO) use, respectively; (c,d) for all solid tumours and lung cancer according to other dietary supplement use.

likely that our participants had lower intakes of antioxidant vitamins from foods than the French women4648 and therefore might benet from supplementation as the French men did. Also, the frequency of smoking among Norwegian women is much higher than in French women.49 There are pros and cons to assessing supplement use before diagnosis. Prediagnosis assessment helped assuring complete follow-up, including also those who died shortly after diagnosis, and would often not be included in patient cohorts. Prediagnosis assessment might also be a better indication of long-term use, as cancer patients are known to initiate dietary supplement use after diagnosis.1

One reason for taking supplements might be self medication, either for preventive or curative effects. We excluded those who had a period shorter than 1 year between the questionnaire and diagnosis in case some of the participants had initiated supplement use as a response to early symptoms. However, this had no effect on survival estimates, and it is not likely that supplement users were in poorer condition than nonusers. Given the higher proportion of occasional supplement users diagnosed with a localized disease, it is more likely that at least a fraction of the supplement users was more health conscious, went more often to the doctor and was diagnosed earlier. Still, even after adjustment for stage the supplementation effect remained for lung cancer patients.

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TABLE III RELATIVE RISKS WITH 95% CONFIDENCE INTERVALS OF MORTALITY AMONG CANCER PATIENTS WITH SOLID TUMOURS BY CATEGORY OF COD LIVER OIL (CLO) AND OTHER DIETARY SUPPLEMENT USE1 Use of cod liver oil and other dietary supplements All solid tumours, 748 deaths Breast cancer, 121 deaths Colorectal cancer, 143 deaths Lung cancer, 160 deaths

Nonusers of CLO Occasional users of CLO Seasonal daily users of CLO Whole year daily users of CLO Nonusers of other dietary supplements Occasional users of other dietary supplements Daily users of other dietary supplements
1

1.00 (ref) 1.05 (0.811.36) 0.98 (0.821.16) 0.77 (0.610.97) 1.00 (ref) 0.83 (0.621.10) 0.94 (0.801.09)

1.00 (ref) 1.37 (0.752.51) 0.95 (0.611.48) 1.30 (0.732.30) 1.00 (ref) 0.66 (0.321.33) 1.01 (0.691.47)

1.00 (ref) 0.46 (0.181.13) 0.98 (0.671.44) 0.82 (0.481.41) 1.00 (ref) 0.65 (0.301.43) 1.19 (0.841.69)

1.00 (ref) 1.16 (0.711.88) 1.03 (0.671.59) 0.56 (0.350.92) 1.00 (ref) 0.55 (0.310.97) 0.70 (0.490.99)

Adjusted for age at diagnosis and smoking (never, former, current) and stage (localized, regional metastases, distant metastases).

The use of prediagnosis as opposed to postdiagnosis supplement information may also be drawback, since some of the patients might change (most likely increase) their supplement use after diagnosis. Whether pre or postdiagnosis use is most relevant depends on what is the critical period for inuencing survival, and whether short-term or long-term use is most important. If the most relevant period for supplementation is after diagnosis, it is likely that our results underestimate the effect of supplementation, as some of the patients most likely have initiated supplementation. On the other hand, if a certain level of the nutrients or long-term supplementation is required for an effect, dietary supplement use before diagnosis might be more relevant for the association with survival. And if dietary supplement use only is an indicator of a set of health behaviours or beliefs, prediagnosis use might be more important, as these characteristics probably are stronger in those who already take supplements before diagnosis, than in those who initiate use afterwards. Unfortunately, no dietary supplement database was available to conrm the contents of the dietary supplements other than CLO used in our study, so it is not possible to attribute the observed association to antioxidants, or any particular nutrient. Since both CLO and other supplements seem to have similar effect, and since multivitamins and -minerals were most frequently reported among other supplements, it is possible that the observed associations are more due to health consciousness than particular nutrients. The dominance of multivitamins and -minerals suggests that the majority of the other dietary supplements contained nutritional, not pharmacological doses of nutrients. Also, for other dietary supplement use the association with occasional use was as strong as that with daily use, so dose might not be the relevant factor. This adds to the health consciousness argument. Still, our results apply only to the lung cancer patients, not the breast or colorectal cancer patients. At study entry, 83.5% of the lung cancer patients were current smokers and 12.6% former smokers, and at least not in that sense having a healthy lifestyle.

Dietary supplement users and nonusers differ on several health related variables.11,5056 In our sample, CLO users were more often never smokers. We tested a long list of covariates to adjust for confounding variables, but only smoking and stage had a signicant effect. Still we cannot rule out that there is some residual confounding. The tests for interaction between smoking and supplement use were negative, i.e. the effect of using CLO or other dietary supplements on mortality risk did not differ among smokers and ex-smokers compared to never smokers. This study has several strengths: the patients originated from a nationally representative sample of Norwegian women, with cancer-rates closely mirroring those in the general population.29 The participants answered several questions on CLO and other supplements, and a range of background variables was covered. A limitation is the lack of treatment information, and the limited number of cases which did not allow for analyses by tumour histology or cancer sub type. Due to the low number of cases in some categories of use the statistical power is limited, and the condence intervals wide. In conclusion, this study has shown that in lung cancer patients taking dietary supplements before diagnosis was associated with better survival. Whether this is due to benecial effects of supplements, or differences between supplement users and nonusers cannot be determined. More research is needed to understand the interplay between nutrients, whether in food or supplements and cancer survival. Meanwhile, in countries where dietary supplement use is common, analyses of survival in cancer patients, particularly lung cancer patients, should take dietary supplement use into account. Acknowledgements Guri Skeie was supported by EXTRA funds from the Norwegian Foundation for Health and Rehabilitation and the Norwegian Cancer Society.

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