Megasun

W B GrantInsufficient evidence exists to link sunbed use to risk of melanoma for other than those with skin phenotype I

William B. Grant, Ph.D. Sunlight, Nutrition, and Health Research Center (SUNARC)

Abstract

A recent meta-analysis found that risk of cutaneous malignant melanoma (CMM) was significantly correlated with sunbed use. However, some of the observational studies included in the meta-analysis included individuals with skin phenotype at increased genetic risk of CMM without adjustment for skin phenotype, and many other risk-modifying factors were not considered in most of the studies. To examine the role of skin phenotype in the meta-analysis, the five studies from the UK were treated separately in a meta-analysis that did not adjust for any confounders from any study. In the original study, the odds ratio (OR) of CMM with respect to sunbed use was 1.15 (95% CI, 1.00-1.30). In this study, the similar OR was 1.20 (95% CI, 1.03-1.38). The OR for the five UK studies was 2.09 (95% CI, 1.14-3.84), while the OR for the other 14 studies was 1.09 (95% CI, 0.96-1.24). Thus, when studies in which a large fraction of the cases have an increased genetic risk for CMM based on skin phenotype are removed from the analysis, the risk of CMM is no longer significant. There are many risk factors for CMM that are generally not considered in such observational studies, including the beneficial effects of ultraviolet-B irradiance, vitamin D, and a good diet (low fat, high fruits and vegetables), so it is doubtful that such studies could be used to establish a link between CMM and sunbed use. Those with skin phenotype I should be discouraged from using sunbeds.

Introduction

The recent systematic review of the association of sunbed use with cutaneous malignant melanoma (CMM) and non-melanoma skin cancer found that sunbed use was associated with risk of CMM and squamous cell carcinoma.1 In addition, first exposure to sunbeds before 35 years of age was associated with a significantly increased risk of CMM. However, whether the evidence presented and available from other studies is strong enough to make such a recommendation is highly questionable.

Does the meta-analysis of risk of CMM with respect to sunbed use make an accurate assessment of the risk? A careful consideration suggests that it does not: research has identified many risk-modifying factors for CMM. Table 1 summarizes the risk-modifying factors for CMM that have been identified to date. Not all the factors have been fully verified, but there is reasonable observational evidence to support all of them. Many of these factors were unknown as risk modifying factors for CMM when many of the studies on sunbed use in Ref. 1 were conducted. Thus, the relevant data were not collected and the different studies cannot be combined in a meta-analysis with great confidence that the result will be meaningful.

However, the primary problem is failure in some studies to account for skin phenotype. Those with Fitzpatrick skin phenotype I (those who burn easily and do not tan at all)20 have a greatly increased risk of CMM from UV irradiance, in part due to a genetic predisposition.

Data and methods

In order to examine the role of skin phenotype in the meta-analysis of CMM related to sunbed use, the studies used in Ref. 1 (Refs. 7, 21-39) along with an additional recent study were incorporated into a new meta-analysis in which the studies were segregated according to some information on skin phenotype and whether the data used in Ref. 1 had been corrected for the known confounders. The two earliest UK studies used data that were not adjusted for confounders.

Statistical Analysis

Meta-analyses were performed using a random-effects model. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to estimate pooled exposure effects. All statistical tests were two-sided, and the cutoff for statistical significance was set at p < 0.05. Weights presented (Tables 1 and 2) represent individual estimates of exposure effect (weighted averages) weighted by assessment of precision of the estimates. Statistical analyses were performed using RevMan software.40 In this work, the unadjusted data were used since it was deemed too difficult to obtain all of the information required to use adjusted data. In addition, it is noted that 11 of the original studies were not adjusted for confounders.

The data were used in the following meta-analyses as follows: all of the original 19 studies; those plus Ref. 39; the original 19 studies less the five UK studies; those plus Ref. 39; the original 19 studies less the two earliest UK studies; those plus Ref. 39. Thus, even though unadjusted data are used, it will be possible to compare with the results in Ref. 1.

Results

The results of several meta-analyses of CMM with respect to sunbed use are presented in Table 2 and in Figures 1 and 2. By omitting any adjustments for confounders, the OR of the original 19 studies increased by 0.05 or 0.06 with the addition of Ref. 39. However, by omitting two or five UK studies, the OR decreased by 0.07 or 0.11, respectively. The OR for the five UK studies was 2.09 (95% CI, 1.14-3.84). Thus, it is apparent that the UK studies were responsible for the OR of CMM risk with respect to sunbed use being apparently statistically significant. With them removed, the statistical significance disappears.

Discussion

These results indicate that when studies largely influenced by inclusion of people with skin phenotype I without adjustment for skin phenotype are removed from the meta-analysis, no statistically significant relation is found between sunbed use and risk of CMM. This result is consistent with the recent large-scale European study which also made a similar finding.38

However, even if the meta-analysis OR showed a significant risk, the meta-analysis is based on observational studies. In addition to the problems with not accounting for confounding factors, there may well be a bias introduced for those who use sunbeds versus those who do not. Those who use sunbeds probably also often tan in solar ultraviolet (UV) light and may have other lifestyle habits or genetic predisposition that could increase their risk of CMM.

The health literature has many examples where relying on observational studies led to flawed health policy decisions. Use of hormone replacement therapy (HRT) for postmenopausal women is a well-known example of confounding factors that colored findings based on observational studies. In 1991, a meta-analysis of 16 observational studies reported that 15 found a reduction in risk of coronary heart disease for use of HRT.41 A quantitative overview of all studies taken together yielded a relative risk of 0.56 (95% CI, 0.50–0.61), and taking only the internally controlled prospective and angiographic studies, the relative risk was 0.50 (95% CI, 0.43–0.56). By 2000, a prospective study found that coronary heart disease risk was lower, but risk of stroke was much higher, thereby canceling the beneficial effect for cardiovascular disease.42 This finding was recently confirmed.43 Eventually, Nelson et al.44 determined that there were many adverse effects from HRT, and its use then declined dramatically.

Although the authors of Ref. 1 discussed the adverse roles of both ultraviolet B (UVB; 280–315 nm) and UVA (315–400 nm) with respect to risk of CMM, they omitted any discussion of the beneficial roles of UVB in reducing the risk of CMM. There is a growing body of literature indicating that vitamin D reduces the risk of CMM. The case for vitamin D was outlined recently.4 Dietary vitamin D was found inversely correlated with incidence of CMM.5 CMM was inversely correlated with non-melanoma skin cancer along with 16 other types of cancer in an ecologic study of cancer mortality rates in Spain.13

Tanning is also protective against CMM.6,8 Tanning was reported to generate increased induced protection factor of around 2 after 2 weeks of daily suberythemal UV doses in skin types II and III.45 Another study reported induced protection factor values of 3.46 The benefits of the induced tan or melanogenesis include both protection against penetration of UVA and increased ability to repair DNA damage.8

Sunbed use can confer health benefits. Vitamin D production in sunbeds that have 4%–5% of the UV spectral output in the UVB region has been well documented.47 However, advocating the use of sunbeds for vitamin D production would be premature until careful studies are conducted. Such studies should include time in sunbeds for maximum vitamin D production, which peaks after a few minutes because of photogradation at wavelengths out to 330 nm.48

Examining the policy issues related to sunbed use in light of the foregoing discussion is useful. European countries limit UVB to 1.5% of total UV radiation.49 When UVB-rich lamps were used in Norway and Sweden before 1983, sunbed use was not associated with increased risk of CMM.37 In the United States, lamps may have up to 5% UVB, which is similar to midlatitude, midday solar UV radiation. Thus, European countries should reexamine the prescribed limit to UVB output in sunbed lamps.

In conclusion, a meta-analysis of the risk of CMM with respect to sunbed use does not support the evidence that sunbed use is a risk factor for CMM when the confounding factor of skin phenotype is considered.

References

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2.. Moan J, Dahlback A, Setlow RB. Epidemiological support for an hypothesis for melanoma induction indicating a role for UVA radiation. Photochem Photobiol. 1999;70:243–7.

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4. Osborne JE, Hutchinson PE. Vitamin D and systemic cancer: is this relevant to malignant melanoma? Br J Dermatol. 2002;147:197–213.

5. Millen AE, Tucker MA, Hartge P, et al. Diet and melanoma in a case-control study. Cancer Epidemiol Biomarkers Prev. 2004;13:1042–51.

6. Kennedy C, Bajdik CD, Willemze R, et al. The influence of painful sunburns and lifetime sun exposure on the risk of actinic keratoses, seborrheic warts, melanocytic nevi, atypical nevi, and skin cancer. J Invest Dermatol. 2003;120:1087–93.

7. Bataille V, Winnett A, Sasieni P, et al. Exposure to the sun and sunbeds and the risk of cutaneous melanoma in the UK: a case-control study. Eur J Cancer. 2004;40:429–35.

8. Agar N, Young AR. Melanogenesis: a photoprotective response to DNA damage? Mutat Res. 2005;571:121–32.

9. Lang J, Hayward N, Goldgar D, et al. The M53I mutation in CDKN2A is a founder mutation that predominates in melanoma patients with Scottish ancestry. Genes Chromosomes Cancer. 2007;46:277–87.

10. Garland FC, White MR, Garland CF, et al. Occupational sunlight exposure and melanoma in the U.S. Navy. Arch Environ Health. 1990;45:261–7.

11. Gandini S, Sera F, Cattaruzza MS, et al. Meta-analysis of risk factors for cutaneous melanoma: II. Sun exposure. Eur J Cancer. 2005;41:45–60.

12. Berwick M, Armstrong BK, Ben-Porat L, et al. Sun exposure and mortality from melanoma. J Natl Cancer Inst. 2005;97:195–9.

13. Grant WB. An ecologic study of cancer mortality rates in Spain with respect to indices of solar UV irradiance and smoking. Int J Cancer. 2006;120:1123–7.

14. Garland CF, Garland FC, Gorham ED. Rising trends in melanoma. An hypothesis concerning sunscreen effectiveness. Ann Epidemiol. 1993;3:103–10.

15. Bentham G, Aase A. Incidence of malignant melanoma of the skin in Norway, 1955-1989: associations with solar ultraviolet radiation, income and holidays abroad. Int J Epidemiol. 1996;25:1132–8.

16. Agredano YZ, Chan JL, Kimball RC, Kimball AB. Accessibility to air travel correlates strongly with increasing melanoma incidence. Melanoma Res. 2006;16:77–81.

17. Freedman DM, Sigurdson A, Doody MM, et al. Risk of melanoma in relation to smoking, alcohol intake, and other factors in a large occupational cohort. Cancer Causes Control. 2003;14:847–57.

18. Odenbro A, Gillgren P, Bellocco R, et al. The risk for cutaneous malignant melanoma, melanoma in situ and intraocular malignant melanoma in relation to tobacco use and body mass index. Br J Dermatol. 2007;156:99–105.

19. Grant WB. A meta-analysis of second cancers after a diagnosis of nonmelanoma skin cancer: additional evidence that solar ultraviolet-B irradiance reduces the risk of internal cancers. J Steroid Biochem Mol Biol. 2007 Jan 5; [Epub ahead of print]

20. Pathak MA. In memory of Thomas Bernhard Fitzpatrick. J Invest Dermatol. 2004 Feb;122(2):xx–xxi.

21. Adam SA, Sheaves JK, Wright NH, et al. A case-control study of the possible association between oral contraceptives and malignant melanoma. Br J Cancer. 1981;44:45–50.

22. Swerdlow AJ, English JS, MacKie RM, et al. Fluorescent lights, ultraviolet lamps, and risk of cutaneous melanoma. BMJ. 1988;297:647–50.

23. MacKie RM, Freudenberger T, Aitchison TC. Personal risk-factor chart for cutaneous melanoma. Lancet. 1989;2:487–90.

24. Dunn-Lane J, Herity B, Moriarty MJ, Conroy R. A case control study of malignant melanoma. Ir Med J. 1993;86:57–9.

25. Holman CD, Armstrong BK, Heenan PJ, et al. The causes of malignant melanoma: results from the West Australian Lions Melanoma Research Project. Recent Results Cancer Res. 1986;102:18–37.

26. Osterlind A, Tucker MA, Stone BJ, Jensen OM. The Danish case-control study of cutaneous malignant melanoma. II. Importance of UV-light exposure. Int J Cancer. 1988;42:319–24.

27. Zanetti R, Rosso S, Faggiano F, et al. [A case-control study of melanoma of the skin in the province of Torino, Italy] Rev Epidemiol Sante Publique. 1988;36:309–17. French.

28. Walter SD, Marrett LD, From L, et al. The association of cutaneous malignant melanoma with the use of sunbeds and sunlamps. Am J Epidemiol. 1990;131:232–43.

29. Garbe C, Weiss J, Kruger S, et al. The German melanoma registry and environmental risk factors implied. Recent Results Cancer Res. 1993;128:69–89.

30. Autier P, Dore JF, Lejeune F, et al. Cutaneous malignant melanoma and exposure to sunlamps or sunbeds: an EORTC multicenter case-control study in Belgium, France and Germany. EORTC Melanoma Cooperative Group. Int J Cancer. 1994;58:809–13.

31. Westerdahl J, Olsson H, Masback A, et al. Use of sunbeds or sunlamps and malignant melanoma in southern Sweden. Am J Epidemiol. 1994;140:691–9.

32. Holly EA, Aston DA, Cress RD, et al. Cutaneous melanoma in women. I. Exposure to sunlight, ability to tan, and other risk factors related to ultraviolet light. Am J Epidemiol. 1995;141:923–33.

33. Chen YT, Dubrow R, Zheng T, et al. Sunlamp use and the risk of cutaneous malignant melanoma: a population-based case-control study in Connecticut, USA. Int J Epidemiol. 1998;27:758–65.

34. Westerdahl J, Ingvar C, Masback A, et al. Risk of cutaneous malignant melanoma in relation to use of sunbeds: further evidence for UV-A carcinogenicity. Br J Cancer. 2000;82:1593–9.

35. Naldi L, Gallus S, Imberti GL, et al. Sunlamps and sunbeds and the risk of cutaneous melanoma. Italian Group for Epidemiological Research in Dermatology. Eur J Cancer Prev. 2000;9:133–4.

36. Kaskel P, Sander S, Kron M, et al. Outdoor activities in childhood: a protective factor for cutaneous melanoma? Results of a case-control study in 271 matched pairs. Br J Dermatol. 2001;145:602–9.

37. Veierod MB, Weiderpass E, Thorn M, et al. A prospective study of pigmentation, sun exposure, and risk of cutaneous malignant melanoma in women. J Natl Cancer Inst. 2003;95:1530–8.

38. Bataille V, Boniol M, De Vries E, et al. A multicentre epidemiological study on sunbed use and cutaneous melanoma in Europe. Eur J Cancer. 2005;41:2141–9.

39. Han J, Colditz GA, Hunter DJ. Risk factors for skin cancers: a nested case-control study within the Nurses’ Health Study. Int J Epidemiol. 2006;35:1514–21.

40. Review Manager (RevMan) [Computer program]. Version 4.2 for Windows. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2003.

41. Stampfer MJ, Colditz GA. Estrogen replacement therapy and coronary heart disease: a quantitative assessment of the epidemiologic evidence. Prev Med. 1991;20:47–63.

42. Grodstein F, Manson JE, Colditz GA, et al. A prospective, observational study of postmenopausal hormone therapy and primary prevention of cardiovascular disease. Ann Intern Med. 2000;133:933–41.

43. Lawlor DA, Smith GD. Cardiovascular risk and hormone replacement therapy. Curr Opin Obstet Gynecol. 2006;18:658–65.

44. Nelson HD, Humphrey LL, Nygren P, et al. Postmenopausal hormone replacement therapy: scientific review. JAMA. 2002;288:872–81.

45. Sheehan JM, Cragg N, Chadwick CA, et al. Repeated ultraviolet exposure affords the same protection against DNA photodamage and erythema in human skin types II and IV but is associated with faster DNA repair in skin type IV. J Invest Dermatol. 2002;118:825–9.

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47. Tangpricha V, Turner A, Spina C, et al. Tanning is associated with optimal vitamin D status (serum 25-hydroxyvitamin D concentration) and higher bone mineral density. Am J Clin Nutr. 2004;80:1645–9.

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Table 1. Risk-modifying factors for CMM

Risk

Risk reduction

Reference

UVA

 


2,3

 


UVB

4

 


Vitamin D

5

Sunburning

 


6

Skin type I, II

Skin type III, IV

7

 


Melanogenesis

8

Gene among Scots

 


9

 


Chronic solar UV irradiance

6, 10-13

Sunscreen use

 


14

Travel to sunny locations

 


15, 16

High-fat diet

Fruits, vegetables

5

 


Smoking

17-19

 

Table 2. Summary of the results of meta-analyses calculations using various sets of studies

Conditions

Ref. 1

OR, starting with original set in Ref. 1

OR, starting with original set in Ref. 1

plus Ref. 39

Original set (Refs. 7, 21-38)

1.15 (95% CI, 1.00-1.30)

1.20 (95% CI, 1.03-1.38)

1.21 (95% CI, 1.05-1.39)

Original set less 2 UK studies (Refs. 21, 22)

 


1.13 (95% CI, 0.99-1.29)

1.14 (95% CI, 1.00-1.30)

Original set less 5 UK (Refs. 7, 21-24)

 


1.09 (95% CI, 0.96-1.24)

1.10 (95% CI, 0.98-1.25)

Five UK studies (Refs. 7, 21-24)

 


2.09 (95% CI, 1.14-3.84)

 


William B. Grant, Ph.D.
Sunlight, Nutrition, and Health Research Center (SUNARC)
P.O. Box 641603
San Francisco, CA 94164-1603, USA
www.sunarc.org

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