Funding sources Funding for publication of this supplement was provided by the European Skin Cancer Foundation (ESCF).
Conflicts of interest C.S. is associated with Spirig Pharma Ltd, manufacturer of topical dermatological drugs, sunscreens and skincare products. C.U. and E.S. have received funding for scientific studies from Spirig Pharma Ltd and Clinuvel Pharmaceuticals Ltd and speakers’ honorarium from Spirig Pharma Ltd.
Ultraviolet radiation (UVR) exposure from the sun and artificial UV sources has been widely acknowledged as the major culprit for skin cancer and premature skin ageing. Skin cancers are among the most dangerous (cutaneous malignant melanoma) and the most numerous (basal cell carcinoma, actinic keratosis and invasive squamous cell carcinoma) of all neoplasms in the caucasian population worldwide. Skin cancers therefore have a significant impact on public health and healthcare costs, and will continue to do so. It is obvious that adequate photoprotection – seeking shade, wearing protective clothing and using sunscreens – is the key to reducing the harmful effects of UVR in both immunocompetent and immunocompromised people. This article provides background information on UVR, photoprotection (including the concept of topical sunscreen formulations), associated concerns regarding efficacy and safety, and behavioural and educational aspects of photoprotection and skin cancer prevention in immunocompetent and immunocompromised people. Certain persistent misconceptions and mistakes regarding photoprotection are also addressed.
Ultraviolet radiation (UVR) exposure from the sun and artificial UV sources has been widely acknowledged as the major culprit for skin cancer and premature skin ageing.1–4
Skin cancers are among the most dangerous [cutaneous malignant melanoma (CMM)] and the most numerous [basal cell carcinoma (BCC), actinic keratosis (AK) and invasive squamous cell carcinoma (SCC)] of all neoplasms in the caucasian population worldwide.5–7 Furthermore, a notable increase in the incidence of these cancers is indicated.8,9 Skin cancers therefore have a significant impact on public health and healthcare costs, and will continue to do so. Corresponding cost estimates are numerous but difficult to compare as they most often reflect local situations.10,11 Nonetheless, examples are explicit, e.g. in 2003, the costs of a hospital stay in Germany were estimated to be 50–60 million Euro for CMM and 105–130 million Euro for nonmelanoma skin cancer (NMSC).12 In the near future, novel pharmacotherapeutic options will further accentuate the economic aspects of treating skin cancers.13,14
Despite knowledge on the destructive effects of UVR, enthusiasm (primarily among caucasians) remains strong for prolonged outdoor activities, vacationing in warm and sunny areas and a sustained healthy tan imparting a sense of well-being.15,16 Increased consumption of UVR by a population with basically vulnerable skin has led to the incidence of skin cancers increasing worldwide.6,7
In immunocompromised people, particularly organ transplant recipients (OTRs), the consequences of past and present sun exposure become even more conspicuous. Nearly 40% of all post-transplant malignancies are skin cancers.17 The occurrence of skin tumours has a considerable impact on the quality of life and overall survival of OTRs.18 In addition to their increased incidence in the OTR population, these tumours tend to behave more aggressively than those in nontransplant patients. Most of the cutaneous malignancies, primarily diagnosed on the sun-exposed skin of OTRs, are NMSC, with SCC and BCC accounting for more than 90% of the total.19–21 An increased incidence of skin cancer has also been observed in diseases such as inflammatory bowel disease, where active immunosuppressive agents similar to those in OTRs are used.22,23
Against this background, it becomes very obvious that adequate photoprotection is the key to reducing the harmful effects of UVR. This article provides background information on (i) UVR, (ii) photoprotection, including the concept of topical sunscreen formulations, (iii) associated concerns regarding efficacy and safety and (iv) behavioural and educational aspects of photoprotection and skin cancer prevention in immunocompetent and immunocompromised people. Certain persistent misconceptions and mistakes regarding photoprotection are also addressed.
Physics of ultraviolet radiation
UVR refers to solar radiation with wavelengths in the 200–400 nm range. Radiation in the 400–700 nm range is referred to as visible light. UVR is subdivided into UVC, UVB and UVA radiation (Fig. 1).24 Penetration of UVR into skin is wavelength dependent,25 and leads to different biological effects (e.g. sunburn, DNA damage, immune suppression, formation of free radicals, oxidative damage to DNA and other biomolecules). UVB (290–320 nm) reaching the epidermis is known as the erythemal band. The attenuating effect is designated the sun-protection factor (SPF). UVA (320–400 nm) reaching the basal layer of the epidermis and the upper dermis is known as black light. In Europe, a sunscreen product with adequate UVA protection has a dedicated UVA label as an insert, as shown in Figure 1.
Biological effects of ultraviolet radiation
UVR has a number of important biological effects on the skin, influencing the immune system and vitamin D metabolism, as well as causing DNA damage, photoageing, skin cancer and pigment changes through biologically complex mechanisms.26,27 The negative effects of UVR and their strong association with cutaneous malignancies have led to the official recognition of UVR as an environmental carcinogen.1–4 On the other hand, there are psychological effects, with many people reporting enhanced wellbeing after sun exposure, and also social influences, with 20th and 21st century fashion in some cultures dictating that a suntan is attractive and a sign of increased socioeconomic status.28
Ozone, present in the stratosphere, absorbs high quantities of shortwave UVB and UVC but only a small amount of UVA.24 The ozone concentration varies naturally according to temperature, weather, latitude and altitude. The time of day also affects the intensity of UVR. It is noteworthy that there are considerable deviations between true solar time and standard time, e.g. the difference is up to 2 h 40 min on the Spanish Atlantic coast, where noon is not at 12:00 h but rather at 14:40 h (Central European Summer Time).29
It is generally recognized that textiles are a reliable means of photoprotection. Nowadays all sun-protection programmes urge the use of appropriate clothing together with hats and sunscreens. The protective quality is highly dependent on the property of the material.30 Various authorities have advocated standardization of the protective properties against UVR.31
Bewildering arrays of various forms of sunscreen product making a wide range of claims – including nonsunscreen claims – are on the market. Just as an umbrella shields people from the unwanted effects of rain, sunscreen products spread evenly over the skin should shield people from the unwanted effects of UVR (‘photon rain’). All sunscreen products consist of a combination of UV absorbers and a carrier system (vehicle) into which they are incorporated.32,33 Sunscreens have become a quasiexclusive mode of protection, even though seeking shade and wearing protective clothing provide more protection.
Topical UV absorbers are classified into two major categories: inorganic (formerly ‘physical’) agents, such as zinc oxide or titanium dioxide, and organic (formerly ‘chemical’) agents. Depending on their absorption spectrum, they are divided into UVA (Uvinul® A Plus; BASF, Ludwigshafen, Germany), UVB (Eusolex® OS; Merck, Darmstadt, Germany) and UVA+B (Tinosorb® S; BASF) absorbers. All reduce damaging radiation by absorption, scattering or reflection (directed scattering) as shown in Figure 1. Attenuation of UVB radiation (290–320 nm, the erythemal band) reduces the most obvious effect of solar radiation, i.e. sunburn. This effect is designated the SPF. The SPF is largely a measure of UVB protection. The importance of adequate UVA protection (320–400 nm) became apparent with improved understanding of how UVA-induced damage to the skin causes immunosuppression, DNA mutations, lipid and protein oxidative damage, and photoageing via reactive oxygen species, as UVA energy interacts with endogenous photosensitizers.26,27
Photoprotection in everyday life
While the labelled UV efficacy is certainly important, perhaps even more important is the true UV protection that people will achieve when they use a product in everyday life. The ideal sunscreen is therefore a product that people will use regularly and properly. Although this sounds trivial, achieving a uniform and adequate coating of the skin is in fact quite a challenge. One key principle when formulating a highly effective sunscreen product is to ensure a uniform film of filters on the skin surface. The second, even more important, key principle is consumer/patient adherence. Adherence encompasses (i) how regularly the product is used (frequency), (ii) how much product is applied each time (dose), and (iii) how completely the UV-exposed skin is covered with product (area covered). The product must therefore have a cosmetically elegant feel which pleases the consumer/patient.
The concept of formulating a sunscreen product vehicle
The vehicle is always the sum of many different ingredients which, when mixed together and packed, yield a specific product form such as a lotion, cream, gel, stick, spray or wipe. The physicochemical properties of the ingredients determine the product form that can be created and the choice of UV absorbers that can be incorporated into it. The key formulation concept is based on polarity. In its simplest sense, ingredients and UV absorbers can be grouped on the basis of how polar they are. Very nonpolar or hydrophobic/lipophilic ingredients, such as mineral oil and silicones, are at one end of the scale and very polar or hydrophilic/lipophobic ingredients, such as water, glycerin and glycols, come at the other end. All of the ingredients used in sunscreen formulations can be ranked on this scale; as a rule, ingredients with similar polarities are mutually soluble and ingredients with very different polarities are not miscible. The same concept applies to UV absorbers – polar/hydrophilic absorbers will dissolve in polar/hydrophilic ingredients and nonpolar/lipophilic absorbers will dissolve in nonpolar/lipophilic ingredients. Materials with large differences in polarity will be immiscible. In addition, the ingredients or specific combinations thereof determine the viscosity of the product. The wide range of sunscreen formulations can therefore be described by the combination of their polarity and viscosity. Products can be categorized by whether they are water-based, oil-based, ethanol/oil-based or emulsions that contain both water and oil phases (Fig. 2). Emulsion-type vehicles include ingredients spanning a large range of polarity and can therefore take up different UV absorbers over a similar range. This allows maximum flexibility when selecting the most efficient UV absorber combination to provide optimal photoprotection quality (magnitude and wavelength range), applicability, spreadability and durability on the skin, compatibility with the skin, and skin feel (Fig. 3). Emulsion-type sunscreen products (lotions, creams) have therefore become the most common formulations on the market.
Product and skin feel
UV absorbers comprise a very large proportion of a sunscreen product formulation. The largest single component of most marketed sunscreen products is a volatile carrier material – typically water. When a layer of a sunscreen product is applied to the skin, most of the product evaporates (metamorphosis of the vehicle), leaving behind a layer of nonvolatile material consisting of UV absorber and vehicle components.35 As the product SPF increases, the UV-absorber concentration also increases (by up to 30%), leaving even more nonvolatile material behind. Even with significant work to try and mitigate the greasy, draggy and sticky effects of specific highly potent sunscreen formulations, the skin will always be left with a residual ‘coated’ feel.
Efficacy and safety of sunscreens
Controversy surrounding sunscreen efficacy and safety has stimulated a lively debate of their properties and use. Certain misconceptions and mistakes regarding photoprotection are complicating the discussion.
In terms of acute UV damage and SCC, including AK, studies have shown a direct protective effect of sunscreens in human beings.36,37 However, the protective effect of sunscreens against CMM has been debated for years. It is not surprising that case–control studies have failed to find an association between the use of sunscreens and the risk of CMM,38 especially given (i) the limited effects of older sunscreen products from the 1970s and 1980s in modifying solar UV exposure (SPF > 20, no UVA protection), (ii) longer sun exposure because of the delay in warning signs such as sunburn, and (iii) failure to apply sunscreen properly.39 More recent studies indicate an association between the use of sunscreens and a reduced risk of melanoma.40,41 It can be expected that the newer augmented sunscreen formulations will protect against CMM42 but, due to the experimental challenges involved, such benefit may not be seen for several decades.
Even though the safety of UV filters is clearly addressed in national and international regulations, the safety of sunscreen products, in particular their long-term safety, is often debated.
Adverse reactions to ultraviolet absorbers
Adverse reactions to UV filters, including allergic and irritant contact dermatitis, phototoxic and photoallergic reactions and contact urticaria, have been reported.43 Most of the adverse reactions were due to irritant rather than allergic reactions to the UV filters, to the excipients, or to a combination of the two. Despite the great increase in the use of UV filters over the past decades, there is no evidence that allergic reactions represent a common clinical problem. There is no published information on adverse reactions to UV filters in OTRs.
Endocrine effects of ultraviolet absorbers
The safety of UV filters is addressed in national and international regulations. Once sufficient safety data are available, regulatory bodies approve the UV filter and permitted concentrations. Nevertheless, there are concerns about the endocrine effect of UV filters. On the basis of animal experiments, it was concluded that daily exposure to sunscreen formulations might have oestrogenic effects in human beings.44 Questions have been raised about the methodology used, while the topical exposure to UV filters was unrealistically high compared with potential human exposure scenarios.45 The biological relevance of the oestrogenic effect of UV filters has yet not been fully established and additional long-term studies are required.46,47 Clinically relevant disturbances of hormone homeostasis have not been observed in humans.
Vitamin D deficiency and photoprotection
Ninety per cent of all requisite vitamin D is formed within the skin through the action of UVR.48 Based on clinical experiments, suppression of cutaneous vitamin D synthesis by sunscreens has been postulated.49 However, in large-scale clinical trials, the long-term use of sunscreens had little or no effect on vitamin D synthesis and did not induce osteoporosis or secondary hyperparathyroidism.50 Rigorous sun-avoidance programmes for OTRs, consisting of seeking shade/staying indoors, wearing protective clothing and using sunscreens, which are messaged to OTRs may cause vitamin D deficiency.51 In addition, the skin of elderly people is less efficient in synthesizing vitamin D under UVR.52 It is therefore important to monitor the vitamin D status in OTRs and give vitamin D supplements if necessary. The serum 25(OH)-D3 concentration is determined to assess the vitamin D status. The optimal concentration is > 75 or > 30 ng mL−1. Values of < 30 or < 12 ng mL−1 are considered highly insufficient. Vitamin D supplementation is straightforward and cost-effective. Despite the fact that correct use of sunscreens theoretically reduces vitamin D concentrations, there is no evidence of this in practice.
Misconceptions and mistakes
Certain persistent misconceptions and mistakes regarding photoprotection are ubiquitous, both in the scientific literature and on the internet.
Research and industry initially focused on improving the extent of photoprotection by increasing the SPF – defined as the minimal erythema (290–320 nm) dose (MED) of protected skin divided by the MED of unprotected skin. The SPF numbers on a product may range from as low as 2 to up to 100 and more.
The effect of the sun-protection factor
An SPF of 2 absorbs 50%, SPF 15 93·3%, SPF 30 96·7% and SPF 50+ 98·3% of UVB radiation. Many people misunderstand this statement and conclude that higher SPF numbers offer only a tiny percentage more attenuation and therefore do not provide substantial extra protection. As shown in Figure 4, it is not the UV dose (%) filtered out (or absorbed) by the sunscreen that is relevant for the characterization of UVB protection but the UV dose that reaches the skin and is responsible for sunburn. The UV dose reaching the skin is halved between SPF 15 and 30 and again between SPF 30 and 50+. This means that the protection doubles between SPF 15 and 30 and again between 30 and 50+. Nevertheless, the augmentation of the protection is limited. Products with an SPF higher than 50+ require large amounts of UV absorbers, often making them more difficult to spread, reducing the sensory attractiveness of the product, and tempting the consumer or patient to use less product. However, in real life, it can be concluded that, in the SPF range 15–50+, the higher SPF provides significant extra protection.
Calculation of protection time
In theory the SPF may be used to calculate the increased protection time by simply multiplying the SPF by the length of time it takes the unprotected consumer/patient to burn. This time depends on the skin type (e.g. type I, approx. 10 min). Computer and smartphone applications (apps) offer the option of calculating personal protection times. However, there are a number of caveats with this approach: (i) lay people are often unable to determine their own skin type, (ii) the 2 mg cm−2 sunscreen product dose, on which the labelled SPF is based, is not applied by most consumers/patients, (iii) a significant amount of the applied product is lost during many recreational activities, and (iv) the SPF on the label refers to the midday sun. These inherent uncertainties make the calculation unsuitable for everyday situations, because it may impart a false sense of security among consumers and patients.
Despite the fact that the determination of the water resistance is highly standardized and the sunscreen industry has made some effort to optimize water resistance,53–55 its relevance may be debatable. In most real-life situations, consumers or patients towel themselves down after bathing or wipe sweat off their skin after perspiring. This will also remove most of the sunscreen product from the skin and necessitate reapplication. Unfortunately, the water resistance label is popular with consumer organizations comparing different products. Its relevance is probably overvalued and may impart a false sense of security among consumers. Water resistance claims should therefore be accompanied by recommendations to reapply after swimming or sweating, immediately after towelling dry, and at least every 2 h.
Lifetime ultraviolet dose
It has been thought for many years that people get 80% of their lifetime UV dose before they reach the age of 18 years. This is a misconception. Godar et al., Krutmann, Diffey and others56–58 have shown that UV exposure is roughly equal over the years during a person’s lifetime. These findings have significant consequences for sun-protection measures. Until recently, the corresponding educational campaigns always emphasized that the use of sunscreen, sunglasses, UV-protective clothing, hats and parasols was particularly important for children and young people. As a result, adults may have concluded that sun-protection measures were less important for them, as most of the UV damage to their skin had already occurred by the time they were 19 years old. The calculations presented by Godar et al. and Diffey, however, provide evidence that continued sun protection is essential. It is quite possible that inadequate sun protection in the middle-aged and elderly causes progression of UV-induced damage sustained in childhood and adolescence to more serious lesions. To reduce the risk of skin cancer more effectively, future campaigns must make the need for lifelong UV protection absolutely clear.
Skin cancer prevention
Clinical practice guidelines all recommend UV photoprotection in immunocompetent and immunocompromised people to reduce the skin cancer risk.59,60 Advice usually includes avoidance of sunburn, intentional tanning and unnecessary UVR exposure. Sunscreens with broad-spectrum, high-factor UVB and UVA protection are recommended, together with the use of protective clothing, including broad-brimmed hats and sunglasses. But does sunscreen use translate into a reduction in skin (pre)malignancy? There is convincing evidence that sunscreens reduce AK and SCC in the general population.37 In view of the widespread uncertainty about the ability of sunscreens to prevent melanoma, recent findings from a follow-up40 of a community-based trial41,61 of sunscreen use to prevent skin cancer provide reassurance. A randomized clinical trial with liposomal sunscreen use in OTRs showed a significant reduction in AK and SCC – but not BCC – after 24 months62 (Fig. 5).
Behavioural and educational aspects of photoprotection
The photoprotection messages pushed to the public are that exposure to UVR is harmful to health (skin cancer) and has effects on skin appearance (skin ageing). The latter aspect is generally less emphasized. Despite alarming cancer statistics and evidence that most people understand the harmful effects of UV exposure, this knowledge has yet to be transformed into action. The barriers to promoting sun avoidance are societal and intertwined with the concept of a tan being beautiful.63 Several sociocultural influences such as media, family and the desire for attractiveness have been associated with tanning, ranging from improving general body image to addressing specific problems like acne.64 This discrepancy between knowledge and behaviour highlights the need for more effective strategies to inspire changes in the sun-protection behaviour of the population as a whole. Reworking the messages through unconventional and new messengers may inspire more dramatic changes in sun-protection behaviour. Health campaigns such as ‘Slip! Slop! Slap!’ and ‘SunSmart’ are popular and have proved effective in Australia. Their success has been attributed in part to their ability to intermesh outcomes, strategies and audiences by working at many levels, in many settings, and with many target groups.65 School-based educational programmes have the benefit of being incorporated into existing curricula and catching the attention of young people. Based on improvements in sun protection and covering up, it has been suggested that children respond best to educational and policy approaches in primary schools.66 The European Skin Cancer Foundation (http://www.escf-network.eu) and supporting partners have successfully implemented a project aiming at the certification of child day-care centres for their efforts in children’s sun-protection activities. The main objectives of the ‘SunPass’ project are (i) to reduce UV exposure in children, (ii) to raise the awareness of caregivers and parents, and (ii) to reduce skin cancer incidence in the long term.67
Studies have shown that OTRs have inadequate knowledge of the importance of both photoprotection and photoprotective measures.68 Multidisciplinary care teams to supervise and support OTRs are particularly well suited to provide rigorous, repetitive and persuasive instruction to patients regarding the necessity of photoprotection and the most effective means available.69 Ulrich et al.62 found that, regardless of general photoprotection education, the provision of free sunscreen and specific training in its correct application resulted in significantly better photoprotection adherence (sunscreen use 5·6 days per week, compared with 0·3 days per week in the control group), and a concomitant decline in NMSC incidence.
Management of ultraviolet-induced skin cancer
In connection with UV-induced skin cancer, the issues, findings and improvements in prevention, diagnostics, treatment, aftercare and patient or consumer education are published and discussed in very different media. In spring each year, the lay press first picks up on sun protection, then on sunscreen products, and finally skin cancer issues. The scientific literature on UV-induced skin cancer ranges from behavioural science to immunology, from pharmaceutics to physics. The challenges are rarely tackled in a holistic way and most contributions remain specialist and erratic. The authors of the present article promote a management continuum for UV-induced skin cancer that includes comprehensive awareness creation through continuous education – a prerequisite for effective prevention and conscientious aftercare. A reliable diagnosis ensures successful treatment. Completed treatment requires conscientious aftercare (Fig. 6). Such management systems may help multidisciplinary care teams to provide cost-effective assistance to both patients and the public.
It is not disputed that UVR exposure is both directly and indirectly linked to skin cancer. NMSC is the most frequent diagnosis in fair-skinned populations and the incidence is increasing worldwide. OTRs and patients using similarly active medications experience high rates of NMSC due to the immunosuppressant treatment, and their relative risk is dramatically higher than that in the immunocompetent population. As UVR is the major environmental cause of cutaneous malignancies, it is essential to protect the skin from UVR in order to prevent the development of skin cancer. The efficacy of sunscreens in reducing the damaging effects of UVR is widely and thoroughly documented. Although concerns over the long-term safety of UV filters have been raised, the benefits of sunscreens clearly outweigh their potential risks. The principal barrier to attaining these benefits is consumer/patient adherence. Failure to prevent sun-related skin damage is usually due to the way sun-protective measures are followed (e.g. wearing protective clothing or seeking shade) and the way sunscreen products are applied, rather than any technical inadequacy of the product. Investment in consumer/patient education and public health measures to increase adherence to all photoprotective measures is definitely required in the future.
What’s already known about this topic?
• Exposure to ultraviolet (UV) radiation is the main modifiable risk factor for skin cancer.
• Knowledge and awareness are critical for the protection against harmful effects of UV exposure.
What does this study add?
• Persistent misconceptions and mistakes regarding photoprotection – effect of the sun-protection factor, the calculation of protection time, water resistance and lifetime UV dose – are addressed.
• An easily comprehensible concept of formulating a sunscreen product vehicle is presented.
• A unique management continuum for UV-induced skin cancer is presented that includes comprehensive awareness creation through continuous education – a prerequisite for effective prevention and conscientious aftercare. A reliable diagnosis ensures successful treatment and completed treatment requires conscientious aftercare. Such management systems may help multidisciplinary care teams to provide cost-effective assistance to both patients and the public.