Interventions With Inadequate Evidence as to Whether They Reduce Risk of Melanoma

Sunscreen Use and Ultraviolet (UV) Radiation Avoidance

Benefits

There is inadequate evidence to determine whether the avoidance of sunburns or the use of sunscreen alters the incidence of cutaneous melanoma.

Magnitude of Benefit: Unknown.

Harms

The harms of sunscreen use are poorly quantified but are likely to be small, including allergic reactions to skin creams and lower production of vitamin D by the skin with less sun exposure.

References:

1. Thomas VD, Aasi SZ, Wilson LD, et al.: Cancer of the skin. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds.: Cancer: Principles and Practice of Oncology. Vols. 1 & 2. 8th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2008, pp 1863-87.

Description of the Evidence

Background

Incidence and mortality

There are three main types of skin cancer:

• Basal cell carcinoma (BCC).
• Squamous cell carcinoma (SCC) (together with BCC referred to as nonmelanoma skin cancer [NMSC]).
• Melanoma.

BCC and SCC are the most common forms of skin cancer but have substantially better prognoses than the less common, generally more aggressive, melanoma.

NMSC is the most commonly occurring cancer in the United States. Its incidence appears to be increasing in some,[1] but not all,[2] areas of the country. Overall U.S. incidence rates have likely been increasing for a number of years.[3] At least some of this increase may be attributable to increasing skin cancer awareness and resulting increasing investigation and biopsy of skin lesions. The total number and incidence rate of NMSCs cannot be estimated precisely, because reporting to cancer registries is not required. However, based on extrapolation of Medicare fee-for-service data to the U.S. population, it has been estimated that the total number of persons treated for NMSCs in 2006 was about 2,152,500.[3] That number exceeds all other cases of cancer estimated by the American Cancer Society for that year, which was about 1.4 million.[4]

Melanoma is a reportable cancer in U.S. cancer registries, so there are more reliable estimates of incidence than is the case with NMSCs. In 2012, it is estimated that 76,250 individuals in the United States will be diagnosed with melanoma and approximately 9,180 will die of the disease.[5]

The incidence of melanoma has been increasing for at least 30 years.[5]

Risk Factors

Epidemiologic evidence suggests that exposure to UV radiation and the sensitivity of an individual's skin to UV radiation are risk factors for skin cancer, though the type of exposure (high-intensity and short-duration vs. chronic exposure) and the pattern of exposure (continuous vs. intermittent) may differ among the three main skin cancer types.[6,7,8] In addition, the immune system may play a role in pathogenesis of skin cancer. Organ transplant recipients receiving immunosuppressive drugs are at an elevated risk of skin cancer, particularly SCC. Arsenic exposure also increases the risk of cutaneous SCC.[9,10]

The visible evidence of susceptibility to skin cancer (skin type and precancerous lesions), of sun-induced skin damage (sunburn and solar keratoses), and the ability of an individual to modify sun exposure provide the basis for implementation of programs for the primary prevention of skin cancer.

Factors associated with increased risk of nonmelanoma skin cancer

Ultraviolet (UV) radiation exposure

Most evidence about UV radiation exposure and the prevention of skin cancer comes from observational and analytic epidemiologic studies. Such studies have consistently shown that increased cumulative sun exposure is a risk factor for NMSC.[7,8] Individuals whose skin tans poorly or burns easily after sun exposure are particularly susceptible.[7]

Factors associated with an increased risk of melanoma

UV radiation exposure

The relationship between UV radiation exposure and cutaneous melanoma is less clear than the relationship between UV exposure and NMSC. In the case of melanoma, it seems that intermittent acute sun exposure leading to sunburn is more important than cumulative sun exposure;[11] such exposures during childhood or adolescence may be particularly important.[6]

Interventions With Inadequate Evidence as to Whether They Reduce Risk of Nonmelanoma Skin Cancer

Sunscreen use and UV radiation avoidance

It is not known if interventions designed to reduce exposure to UV radiation through the use of sunscreens and/or protective clothing or through limitation of exposure time reduce the incidence of NMSC in humans. Some studies have used solar keratoses rather than invasive skin cancer as the study endpoint. It is generally felt that half or more of SCCs arise from solar keratoses. However, nearly half of SCCs occur in clinically normal skin.[12] A longitudinal study has shown that the progression rate from solar keratoses to SCC is about 0.075% to 0.096% per year, or less than 1 in 1,000 per year.[12] Moreover, in a population-based longitudinal study, there was an approximately 26% spontaneous regression rate of solar keratoses within 1 year of a screening examination.[13] Therefore, it is likely that solar keratosis is a poor surrogate endpoint in SCC prevention trials.

One very small randomized placebo-controlled study of a sunscreen (sun protection factor [SPF] 29) was conducted in 53 volunteers who had either clinical evidence of solar keratoses or NMSC.[14] Only 37 of the participants returned for the planned 2-year follow-up (attrition rate of 30%). The rate of new solar keratoses was lower after 2 years in the sunscreen group than in the placebo (base-cream) group (estimated 36% reduction in annual rate, P = .001). Another study showed that regular sunscreen use helps reduce the incidence of solar keratoses and increase remission of existing lesions.[15] In Australia, 588 persons aged 40 years and older who attended a free skin cancer screening clinic and had 1 to 30 solar keratoses were enrolled in a randomized controlled trial (RCT) assessing the effect of regular sunscreen (SPF 17) use on solar keratoses; 431 persons completed the study. Individuals in the sunscreen group developed fewer new lesions and had more remissions of existing lesions than those in the base-cream placebo group. There was an increase of 1.0 in the mean number of solar keratoses in the base-cream group versus a decrease of 0.6 in the sunscreen group (difference = 1.53; 95% confidence interval [CI], 0.81–2.25). The rate ratio of new lesions was 0.62 (95% CI, 0.54–0.71). Furthermore, in the sunscreen group, the development of new lesions and the remission of existing lesions were related to the amount of sunscreen used. Such a relationship was not observed in the base-cream group.

However, a different Australian randomized study (the Nambour Skin Cancer Prevention Trial) showed that, after 4.5 years of follow-up, there was no statistically significant difference in the incidence of BCCs or SCCs with regular SPF 16 sunscreen use. This study did not include a sunscreen placebo. Although a secondary subset analysis of the overall number of tumors showed a reduction in the frequency of SCCs on the sites of daily sunscreen application, the validity of the finding is questionable because of the possible effects of extensive multiple statistical testing.[16] An 8-year post-trial observational follow-up demonstrated statistically significant reductions in both the frequency and the overall incidence of SCCs in the regular sunscreen-use arm, but the reliability of these findings is uncertain given their occurrence outside of the controlled-trial environment.[17]

Chemopreventive agents

Beta carotene

In the Physicians' Health Study, 21,884 male physicians with no reported history of BCC or SCC were randomly assigned to take 50 mg doses of daily oral beta carotene versus placebo in a 2 × 2 factorial trial of beta carotene and aspirin.[18] Incidence of NMSCs was a secondary endpoint in the trial. After 12 years of beta carotene or placebo administration, there was no difference in incidence of either BCC or SCC. RCTs of long-term treatment with beta carotene in individuals previously treated for NMSC also showed no benefit in preventing the occurrence of new NMSCs.[16,19]

Isotretinoin

High-dose isotretinoin was found to prevent new skin cancers in individuals with xeroderma pigmentosum.[20] However, a RCT of long-term treatment with isotretinoin in individuals previously treated for BCC showed that this agent did not prevent the occurrence of new BCCs but did produce side effects characteristic of isotretinoin treatment.[21,22]

Selenium

A multicenter, double-blind, randomized, placebo-controlled trial of 1,312 patients with a history of BCC or SCC and a mean follow-up of 6.4 years showed that 200 µg of selenium (in brewer's yeast tablets) did not have a statistically significant effect on the primary endpoint of BCC development and may increase the risk of SCC and total NMSC.[23,24] The cumulative incidence of NMSC was 0.20 versus 0.16 per person year of follow-up in the selenium and placebo groups, respectively (unadjusted relative risk = 1.27; 95% CI, 1.11–1.45).

Celecoxib

The use of celecoxib as a chemopreventive agent for actinic keratosis was assessed in a double-blind, randomized, placebo-controlled trial. Two hundred forty high-risk men and women (each with 10–40 actinic keratoses and a history of previous skin cancer) received 200 mg doses of celecoxib twice daily or a placebo for 9 months with an additional 2-month follow-up. No difference was found in the incidence of actinic keratosis, but a post-hoc analysis revealed a statistically significant difference in the mean number of NMSCs per patient (rate ratio = 0.43; 95% CI, 0.24–0.75; absolute difference, 0.2 lesions per patient). The ultimate utility of celecoxib in preventing NMSCs remains unclear, given the exploratory nature of the analysis, the challenge of interpreting benefits in fractions of lesions, and the potential for serious adverse cardiovascular effects associated with long-term use of nonsteroidal anti-inflammatory drugs. However, the unexpected finding of the lack of effect of celecoxib on actinic keratosis but apparent effect on SCC and BCC incidence raises questions about the use of actinic keratosis as an intermediate endpoint for SCC and BCC and our understanding of the natural history of NMSCs.[25]

Alpha-difluoromethylornithine

Alpha-difluoromethylornithine (DFMO), an ornithine decarboxylase inhibitor used in intravenous form to treat African trypanosomiasis and in topical form to treat female hirsutism, was investigated as a chemopreventive agent in patients with prior NMSCs.[26] After a 4-week placebo run-in period, 291 volunteers who took at least 80% of their placebos were randomly assigned to oral DFMO (500 mg/m² /day) versus placebo for up to 5 years (average 4 years). At baseline, the placebo group had a higher mean number of prior NMSCs than the DFMO group (4.9 vs. 4.2; P = .1), and a longer history of NMSC (P = .002), possibly favoring the DFMO group. The primary endpoint of the study was the number of new NMSC events, and the rate was 0.44 new cancers per year in the DFMO group versus 0.61 in the placebo group (P = .07). In a subset analysis, there was a statistically significant difference in BCC events favoring the DFMO group (0.28 vs. 0.40 per year; P = .03) and no difference in SCC rates. DFMO is known to have ototoxicity, and the average hearing loss of audiograms was greater in the DFMO group, which was about 4 dB versus 2 dB (P = .003). In the DFMO group,10.8% discontinued the study drug because of a greater than 15 dB hearing loss, compared with a 4.5% discontinuation in the placebo group (P = .06). DFMO hearing loss is usually reversible. In summary, the efficacy of DFMO for skin cancer prevention is unclear, and it remains investigational for this indication.

Interventions With Inadequate Evidence as to Whether They Reduce Risk of Melanoma

Sunscreens

Results from a collaborative European case-control study and one animal study suggest that sunscreens that protect against sunburn may not protect against UV radiation–associated cutaneous melanoma.[27,28] Nonmodifiable host factors, such as propensity to burn, a large number of benign melanocytic nevi, and atypical nevi may also increase the risk of developing cutaneous melanoma.[6]

A post hoc analysis of the Nambour Skin Cancer Prevention Trial (discussed above) examined the incidence of melanoma at a median of 14.2 person-years of follow-up. In the trial, participants were randomly assigned to daily or discretionary sunscreen use from 1992 to 1996. Follow-up continued until 2006 via either active participation, in which subjects completed periodic questionnaires about new skin cancers and relevant sun behaviors, or passive participation, in which subjects' medical records were reviewed for skin cancer diagnoses; 52% of the trial participants were actively participating as of 2006. Eleven melanomas were diagnosed in the daily sunscreen arm versus 22 in the discretionary-use arm (hazard ratio [HR] = 0.5; 95% CI, 0.24–1.02), of which 3 versus 11 were invasive, respectively (HR = 0.27; 95% CI, 0.08–0.97). There was no difference in the rates of melanoma on prescribed sunscreen application sites between the two groups. This study has several important limitations: melanoma was not a planned outcome of the original trial; the CIs of the outcome estimates are very wide, indicating substantial uncertainty of the magnitude of the effect; and there is potential for the introduction of confounding with the widespread use of the passive participant option during the follow-up phase of the study.[29]

A meta-analysis of 18 studies that explored the association between melanoma risk and previous sunscreen use illustrates widely differing study qualities and suggests little or no association.[30]

Behavioral Interventions to Change Sun-Protective Practices

As noted previously, direct evidence that interventions, such as sunscreen or protection from UV light exposure, decrease the risk of skin cancer is sparse. However, given the association between UV light exposure and subsequent risk of skin cancer, counseling interventions aimed at increasing sun-protective behaviors have been examined. The U.S. Preventive Services Task Force (USPSTF) commissioned a systematic review of this evidence. Although the USPSTF review found no randomized trials directly linking counseling strategies to skin cancer reduction, it found 11 trials, rated as fair in quality, that tested the effect of interventions on sun-protective behaviors.[31] Several trials of behavioral interventions in adults, sometimes as part of an intervention addressing multiple health-related behaviors, such as smoking and nutrition, showed a short-term increase in self-reported sun-protective behaviors. However, the effect sizes were small to modest, without clear evidence that the differences were clinically meaningful.[32,33,34,35,36] Likewise, appearance-based behavioral interventions in young women have had a favorable impact on self-reported indoor tanning behavior, but no long-term follow-up or health outcomes were reported.[37,38,39] A randomized, primary care office–based counseling intervention in adolescents showed an increase in self-reported midday sun avoidance and sunscreen use in the intervention group for up to 24 months.[40] A randomized trial of a provider-based sun protection promotion counseling program for parents for their infant children showed a small increase in sun-protective actions, of questionable clinical importance according to the researchers.[41]

Nevertheless, studies of intervention strategies for reducing UV radiation exposure suggest that the best approach is education about the risks associated with sun exposure and sunburn and education about sun-protection strategies.[42,43] In one study, an educational intervention at the time of treatment for skin cancer—a time when an individual may have heightened awareness of his or her susceptibility to skin cancer—seemed to have the greatest effect.[42] However, even in such a high-risk group, it was difficult for many individuals to maintain sun-protective behaviors. In a community skin cancer screening study, researchers found that, although regular use of sunscreens was not related to personal or family history of skin cancer, it was more common among persons who perceived themselves to be at moderate or high risk of developing melanoma.[43]

Sun-protective strategies may include avoiding sun exposure at times of the day when the exposure is more intense and wearing clothing that protects skin from sun exposure. Self-examination for skin-pigmentary characteristics associated with melanoma (e.g., freckling status) may be a useful way to identify individuals at an increased risk of developing melanoma.[44] Skin type (propensity to burn after sun exposure and tanning ability), alone or with other physical characteristics, such as hair color, has been used as a measure of sun sensitivity in epidemiologic studies.[45]

In summary, a number of randomized trials and other studies have suggested that counseling or health information may have an effect on sun- or UV-protective behaviors. However, in addition to lack of information on health outcomes and relatively short follow-up times, most of the studies suffer from important methodologic problems, including the possibility of self-reporting inaccuracy, high study attrition rates, and lack of information about sustainability of the interventions.

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3. Rogers HW, Weinstock MA, Harris AR, et al.: Incidence estimate of nonmelanoma skin cancer in the United States, 2006. Arch Dermatol 146 (3): 283-7, 2010.
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9. Thomas VD, Aasi SZ, Wilson LD, et al.: Cancer of the skin. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds.: Cancer: Principles and Practice of Oncology. Vols. 1 & 2. 8th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2008, pp 1863-87.
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18. Frieling UM, Schaumberg DA, Kupper TS, et al.: A randomized, 12-year primary-prevention trial of beta carotene supplementation for nonmelanoma skin cancer in the physician's health study. Arch Dermatol 136 (2): 179-84, 2000.
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20. Kraemer KH, DiGiovanna JJ, Moshell AN, et al.: Prevention of skin cancer in xeroderma pigmentosum with the use of oral isotretinoin. N Engl J Med 318 (25): 1633-7, 1988.
21. Tangrea JA, Edwards BK, Taylor PR, et al.: Long-term therapy with low-dose isotretinoin for prevention of basal cell carcinoma: a multicenter clinical trial. Isotretinoin-Basal Cell Carcinoma Study Group. J Natl Cancer Inst 84 (5): 328-32, 1992.
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23. Clark LC, Combs GF Jr, Turnbull BW, et al.: Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin. A randomized controlled trial. Nutritional Prevention of Cancer Study Group. JAMA 276 (24): 1957-63, 1996.
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36. Geller AC, Emmons KM, Brooks DR, et al.: A randomized trial to improve early detection and prevention practices among siblings of melanoma patients. Cancer 107 (4): 806-14, 2006.
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39. Stapleton J, Turrisi R, Hillhouse J, et al.: A comparison of the efficacy of an appearance-focused skin cancer intervention within indoor tanner subgroups identified by latent profile analysis. J Behav Med 33 (3): 181-90, 2010.
40. Norman GJ, Adams MA, Calfas KJ, et al.: A randomized trial of a multicomponent intervention for adolescent sun protection behaviors. Arch Pediatr Adolesc Med 161 (2): 146-52, 2007.
41. Crane LA, Deas A, Mokrohisky ST, et al.: A randomized intervention study of sun protection promotion in well-child care. Prev Med 42 (3): 162-70, 2006.
42. Robinson JK: Compensation strategies in sun protection behaviors by a population with nonmelanoma skin cancer. Prev Med 21 (6): 754-65, 1992.
43. Berwick M, Fine JA, Bolognia JL: Sun exposure and sunscreen use following a community skin cancer screening. Prev Med 21 (3): 302-10, 1992.
44. Gruber SB, Roush GC, Barnhill RL: Sensitivity and specificity of self-examination for cutaneous malignant melanoma risk factors. Am J Prev Med 9 (1): 50-4, 1993 Jan-Feb.
45. Weinstock MA: Assessment of sun sensitivity by questionnaire: validity of items and formulation of a prediction rule. J Clin Epidemiol 45 (5): 547-52, 1992.