Results from this case-control study show that grape seed extract use is associated with a reduction in risk of cutaneous SCC. This effect was stronger when SCC risk factors, including sun exposure variables, were included in the model. Multivitamin use showed a borderline protective effect. The other supplements that were studied (vitamins A, C, D, and E) did not reveal any associations with SCC risk in adjusted and unadjusted models. In analyses stratified by SCC histologic subtype (in-situ vs. invasive), vitamin C appeared to have a statistically significant protective effect for in-situ SCCs only. This may suggest that vitamin C may have a protective effect that is most pronounced during the early stages of carcinogenesis, or alternatively, may reflect a spurious association due to the multiple comparisons performed. Our stratified analyses were likely underpowered, as evidenced by the substantial widening in confidence intervals.
GSE has shown promise as a chemopreventative agent in other organs, such as breast, colon, and prostate,24-27
and trials are currently underway to evaluate its efficacy in these malignancies.28
However, no epidemiologic studies, to date, have evaluated oral intake of GSE and its association with cutaneous SCC risk in humans. Nevertheless, caution should be used in recommending GSE as a long-term chemopreventative supplement. Reports of side effects of GSE supplementation have included headache, dry, itchy scalp, hives, nausea and dizziness.29
More concerning are GSEs reported effects on platelet adhesion30
which may pose additional risks in patients taking anticoagulants such as warfarin, aspirin, non-steroidal anti-inflammatory drugs, or other anti-platelet agents. Also, interactions between GSE and medicines or other supplements have not been carefully studied, and there is evidence to suggest that GSE may interfere with the cytochrome p450 enzyme system.31
Although oral administration of GSE was well tolerated in people over 8 weeks of a clinical trial,32
the long-term side effects have not been adequately ascertained.
Our finding of no statistically significant association of SCC risk with individual vitamin supplements is largely consistent with those reviewed and reported in the literature.4,33,34
Reviews of published human studies investigating the role of dietary factors in the development of keratinocyte carcinomas have not revealed any consistent association between SCC risk and exposure to vitamins A, C or E.33,34
Large prospective cohort studies have also revealed no association between SCC risk and intake of vitamins A, C or E.18,35
Pre-diagnostic serum retinol levels were not associated with subsequent risk of SCC.36
Similarly, several prospective studies using serum concentration of alpha-tocepherol did not reveal any association with subsequent risk of SCC.36-38
While one double-blind placebo-controlled trial of oral vitamin A showed a reduction in risk of first new SCC in moderate-risk subjects (HR= 0.74, 95% CI 0.56-0.99, p = 0.04),20
no beneficial effects of retinol were noted in a similar trial of high risk subjects.39
Large-scale, randomized trials have not shown any association between beta carotene supplementation and SCC risk.40-42
Although some studies have suggested that specific combinations of vitamins, such as vitamin C and E have synergistic photoprotective effects,34,43,44
results of a recent trial of a combination of nutritionally appropriate doses of vitamins C, E, beta-carotene, and the minerals selenium and zinc did not reveal any difference in incidence of non-melanoma skin cancer between supplement users and placebo users.19
Strengths of this study include a large sample size (n=830) and thorough measurement of risk factors for SCC. However, no information was ascertained on dose, frequency, duration, or brand of supplement use because supplement use was not the primary exposure of interest and our study was not powered to look at this specific association. Also, although the questionnaire was modeled off of a validated instrument on supplement use and cancer risk 45
, the accuracy of the survey instrument was not tested. Further limitations of this study include the possibility of recall bias, selection bias, and limitations of generalizability. Our control population came from respondents to the Member’s Health Survey and not from the Kaiser Permanente membership at large and may be prone to selection bias. However, previously published papers have reported that respondents to the MHS are representative of the KPNC population.46
Recall bias is also a potential problem for the self-reported variables, such as sun exposure history. Differential misclassification would result if the cancer diagnosis served as a stimulus for cases to recall supplement use more or less thoroughly than controls. However, the survey collected data on a variety of exposures and supplement use constituted a very small portion of the questionnaire (only one item among 24 items ascertained in questionnaire). The generalizability of our study may be limited because we only studied KPNC members, although previous studies have shown that the KPNC membership is highly representative of the surrounding region except for the tail ends of the income distribution.46,47
Although use of grape seed extract was reported by a small number of patients (n=17), nevertheless, a total of 2% of our study population reported its use, which may seem high for a non-vitamin, non-mineral supplement. However, previously published papers on supplement use within the KPNC adult population have shown that an estimated 32.7% of adult members used at least one non-vitamin, non-mineral supplement in the preceding 12 months, with use highest among whites greater than age 45, which constitutes the majority of our study sample.48
In summary, we found a protective effect of GSE use on cutaneous SCC risk. Future studies need to be performed to replicate these findings, and if confirmed, to ascertain the effects of dose or duration of GSE use on SCC risk. Given the potential toxicity of GSE, including platelet dysfunction, more studies are needed to establish the effect, determine optimal dosing and assess side effect profiles.