Stern RS, Lunder EJ. Risk of Squamous Cell Carcinoma and Methoxsalen (Psoralen) and UV-A Radiation (PUVA)A Meta-analysis. Arch Dermatol. 1998;134(12):1582-1585. doi:10.1001/archderm.134.12.1582
To assess the risk of squamous cell carcinoma (SCC) and the relation of dose to risk among groups of patients with psoriasis exposed to psoralen–UV-A (PUVA).
Four electronic databases were searched from 1984 to 1998.
In addition to the PUVA Follow-up Study, we included all English-language studies from the United States and Europe with at least 150 patients enrolled, who were followed up for at least 5 years as identified from our bibliographic search.
A custom-designed questionnaire was used to extract data from each of the articles. For each study, if possible, we determined the incidence of basal cell carcinomas and SCCs and the incidence rate ratio of SCC among patients exposed to low-dose (we defined as <100 treatments or 1000 J/cm2) compared with high-dose PUVA (>200 treatments or 2000 J/cm2). Exact methods were used to calculate the incidence rate ratios.
In addition to our study, we identified and reviewed 8 other studies. Overall, the incidence among patients exposed to high-dose PUVA was 14-fold higher than among patients with low-dose exposure (95% confidence interval, 8.3-24.1); a greater dose-dependent increase in risk than that observed in the PUVA Follow-up Study.
Although the incidence of SCC reported among groups of PUVA-treated patients followed up for at least 5 years varies greatly, compared with the risk in low-dose patients, long-term high-dose exposure to PUVA was consistently observed to significantly increase the risk of SCC in all studies reviewed.
ORAL PSORALEN–UV-A radiation (PUVA) is an effective and widely used treatment for psoriasis. First used more than 20 years ago, PUVA is recognized as one of the most valuable treatments for psoriasis.1 Psoralen–UV-A is, however, mutagenic and is considered a standard for photocarcinogenesis studies in animals.2 In 1975, the first 1380 patients to be treated with PUVA for psoriasis in the United States enrolled in a long-term prospective study of PUVA therapy (The PUVA Follow-up Study).3- 5 Reports from this multicenter study have demonstrated that in this population long-term exposure to PUVA increases the risk of squamous cell carcinoma (SCC) and that this risk increases with greater exposure to PUVA.4,5 These findings have been controversial. Other groups in the United States and Europe have published their findings based on observations of groups of patients with psoriasis (and in some cases other diseases) who have had long-term exposure to PUVA but whose overall exposure to PUVA has been lower.6- 13
The published studies of the occurrence of skin cancer among patients exposed to PUVA vary substantially in their methods, population studied, and results. We undertook a meta-analysis of 8 studies published in the English language from groups other than the PUVA Follow-up Study5 which provided information on the occurrence of nonmelanoma skin cancer (in a group of at least 150 patients primarily with psoriasis followed up for at least 5 years.6- 13 Based on the data available from these articles, we calculated the incidence of SCC, the relation of incidence to level of exposure to PUVA, and the ratio of SCC to basal cell carcinoma (BCC) overall and according to level of exposure to PUVA. To assess the extent to which these findings concerning SCC risks and PUVA therapy are consistent, we compared the individual and aggregate findings of these 8 studies6- 13 with the published findings from the PUVA Follow-up Study.5
Using the MEDLINE, Healthstar, Aidsline, and Cancerlit databases, we attempted to ascertain all studies published reporting on the nonmelanoma skin cancer experience for patients primarily with psoriasis exposed to oral PUVA with an average follow-up of at least 5 years. We initially identified 49 studies. For cohorts that had been subject to multiple analyses over time, we relied only on data from the most recent publication identified by us in March 1998. We limited our analysis to studies from the United States and Europe that enrolled at least 150 patients followed up at least 5 years and published after 1984. In addition to the PUVA Follow-up Study, we identified 8 studies that met these criteria. For each study, we abstracted the following types of data: number of patients enrolled, number followed, person years of follow-up, average age at enrollment, and percentage of male. We also attempted to determine the number of individuals and years of exposure among patients exposed to high and low doses of PUVA. Whenever it was possible, we defined high dose as more than 200 treatments or 2000 J/cm2 and low dose as less than 100 treatments or fewer than 1000 J/cm2. If data in the study were not available in a format that permitted analysis using either of these definitions for dosage, the definition of high- and low-dose PUVA as defined by the author(s) of the individual study was used. On the basis of the tumor experience reported in each article, we attempted to calculate an overall incidence rate for SCC as well as incidence rates per 1000 person-years among patients exposed to high and low doses of PUVA. From these data we then calculated the incidence rate ratios (IRRs) for high- vs low-dose exposure groups (ie, the ratio of the incidence of tumors per 1000 person-years of follow-up) in the high-dose group compared with that in the low-dose group. To calculate summary IRRs and estimate the confidence intervals for individual report results we used exact methods.14,15 We also calculated the ratio of BCCs to SCCs overall, and according to level of exposure to PUVA for each study and overall, and compared these ratios with the ratio we have reported for the PUVA Follow-up Study.5
Table 1 provides a summary of the characteristics of the patient populations in the 9 studies analyzed. Except for the PUVA Follow up Study,5 all studies were retrospective cohort studies. Six of the 8 studies reported on completeness of follow-up.6- 9,11,13 The percentage of patients eligible for follow-up who had complete follow-up ranged from 43% to 78%. The PUVA Follow-up Study followed up more than 90% of patients for at least 5 years.5 The study by Lindleof et al10 was unique, since it used record linkage between a registry of PUVA-exposed patients and the Swedish Cancer Registry. It is likely to have complete ascertainment. In addition to the PUVA Follow-up Study, studies reported average age at enrollment.6,9- 11 These ages were not substantially different from each other or the PUVA Follow-up Study5 (average age range, 43-50 years). Males outnumbered females in 5 of the 7 studies with these data provided, including the PUVA Follow-up Study.5 The PUVA Follow-up Study5 and the study by Chuang et al7 were based in the United States. The remaining 7 studies were of European populations.6,8- 13 Nearly all patients studied were of European ancestry.
The average duration of follow-up, study group size (Table 1), and extent of exposure to PUVA varied greatly among the studies. As a result, both the number of tumors expected and the precision of estimates vary greatly among studies. Table 2 lists the incidence per 1000 person-years for SCC overall and among patients exposed to high and low levels of PUVA. The incidence of SCC varied greatly among studies, even within dose groups. Among high-dose patients, all other studies reported incidence rates substantially less than the 65 per 1000 person-years calculated for high-dose patients in the PUVA Follow-up Study.5 For 4 of 8 studies reporting results among patients with low-exposure to PUVA, no SCCs were noted.6,8,11,12 Every study noted a higher incidence of SCC among members of the study group exposed to higher doses of PUVA. In addition to the PUVA Follow-up Study,5 a point estimate of the IRR for SCC for high- vs low-dose groups can be calculated for 4 studies. For these 4 studies, the IRRs ranged from 7 to 13 (high- vs low-dose PUVA). In 4 additional studies, the point estimate was infinite. For these 4 studies the lower bound of the 95% confidence interval in every case was more than 1 (ie, risk was significantly higher for high-dose patients). For the 8 studies other than the PUVA Follow-up Study, the pooled estimate of the IRR for SCC for high- vs low-dose PUVA equals 14.0 (95% confidence interval, 8.3-24.1). Therefore, the estimate of the increase in risk of SCC for high-compared with low-dose exposure to PUVA is significantly higher for these studies compared with that calculated by the PUVA Follow-up Study (IRR high vs low, 5.9).5
In addition to the PUVA Follow-up Study data,5 7 of the 8 studies6- 9,11- 13 provided incidence data on BCC. As detailed in Table 3, in 5 of 7 studies the number of SCCs detected among patients exposed to high doses of PUVA was greater than the number of BCCs.7- 13 Overall, among patients exposed to high doses of PUVA the ratio of SCCs to BCCs was 3:1 (Table 3), a ratio almost identical to the 2.7:1 ratio reported for the PUVA Follow-up Study.5 Among patients exposed to low doses of PUVA, all studies that documented BCCs detected more BCCs than SCCs (Table 3).
Using meta-analysis, we have assessed the extent to which the published findings from different patient groups with psoriasis and exposed to PUVA studied in the United States and Europe provide consistent estimates of the risk of SCC associated with high-dose exposure to PUVA. Our analysis demonstrates both striking areas of agreement as well as some substantial differences among the findings of these studies. The greatest difference in the findings among the studies we reviewed was the overall incidence of SCC. Reported incidence rates varied from 1 to 4 per 1000 person-years. These incidence rates are dramatically lower than the incidence of 20 per 1000 person-years for the PUVA Follow-up Study.5 However, once SCC incidence was stratified according to exposure to PUVA, the rates for patients exposed to high doses of PUVA were more similar, ranging from 4 to 20 SCC per 1000 person-years for the 8 other studies compared with an incidence of 65 per 1000 person-years in the PUVA Follow-up Study.5
A number of factors probably account at least in part for differences in SCC risk among studies within dose groups. First, studies varied in the characteristics of the populations studied they were from many different countries and the incidence of SCC varied greatly among the regions studied. As detailed in Table 4, even northern areas of the United States have incidence rates of SCC for men that are 5 to 8 times higher than in Sweden.16,17 Rates for women living in the northern US are 3 times those for Swedish women. Rates in the Netherlands18 and Switzerland19 are also significantly lower than estimated rates for northern areas of the United States (Table 4). For patients exposed to high-dose PUVA, adjusting for differences in baseline rates of incidence rates of SCC between the United States and Europe results in comparable incidence estimates for SCC in all European studies and the PUVA Follow-up study.5 The average dose among high-dose patients is higher for the PUVA Follow-up Study cohort5 than for the other study groups. Since risk is likely to increase with dose in a continuous fashion, the US cohort,5 who had the greatest exposure to PUVA and the highest baseline incidence of SCC, would be expected to have the highest incidence of tumors. In addition, the PUVA Follow-up Study was the only prospective study and had the highest follow-up rate. Therefore, more complete ascertainment of tumors would be expected than for other studies, except perhaps for the study of Lindelof et al.10
In the 8 studies6- 13 we reviewed, among patients exposed to low doses of PUVA, the results are consistent with those expected from published population-based incidence rates for Europe and the United States. The incidence of SCC in the PUVA Follow-up Study5 among low-dose patients is significantly higher than that estimated from population data. This finding may well reflect the substantial proportion of patients in this cohort with exposure to other carcinogens that are likely to increase SCC risk.5
There are at least 3 findings that support a dose-dependent increased risk of SCC in association with PUVA use that are consistently noted among all studies we reviewed. Within all studies with adequate data, the incidence of SCC is significantly higher among patients exposed to higher doses of PUVA compared with those with lower-dose exposure. None of the studies reviewed provide data to suggest that differences in the distribution of other risk factors for squamous cell cancer between high- and low-dose exposure groups within a study would explain the observed dose-related increase in risk. Also, the higher ratio of SCC to BCC among patients with higher-dose exposure to PUVA than patients with lower-dose exposure supports high-dose PUVA exposure as a risk factor for SCC. In fact, the ratios of SCC to BCC for the other studies are nearly identical to those noted for the PUVA Follow up Study in each PUVA dosage group.5
As with all meta-analyses and secondary analyses of data, our analysis has a number of important limitations. First, there may well be factors not reported or recognized by us that might explain the higher risk of SCC among high- compared with low-dose PUVA patients in any study we reviewed. Such factors might include older age or a higher proportion of males in the high-dose group, factors that were only adjusted for in the PUVA Follow-up Study5 and the analysis of Lindelof et al.10 The proportion of patients with exposure to carcinogens other than PUVA is also likely to be higher among high- than low-dose patients. If one assumes a similar effect for other studies attributable to these exposures to that which was observed in the PUVA Follow-up Study,5 the pooled estimate of increase in the risk of SCC for high- vs low-dose PUVA patients would be nearly identical in the 8 other studies and in the PUVA Follow-up Study.
Taken together, all the studies we analyzed provide evidence that high-dose exposure to PUVA increases the risk of SCC. However, because of the limited size of the cohorts exposed to high doses of PUVA and limited duration and completeness of follow-up, the number of patients developing SCCs is sufficiently small that these studies do not provide substantial additional data to address the morbidity of SCCs that arise in association with PUVA treatment. These studies also provide some reassuring information. At least within an average of 8.6 years and a maximum of 13 years of follow-up,5 the pooled data suggest that low levels of exposure to PUVA are unlikely to greatly increase the risk of SCC.
Accepted for publication July 24, 1998.
This study was supported by grant NO1-AR4-2214 from the National Institute of Arthritis, Musculoskeletal and Skin Diseases, Bethesda, Md.
A complete list of the articles excluded from our meta-analysis is available on request from us.
Reprints: Robert S. Stern, MD, Department of Dermatology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Ave, Boston, MA 02215 (e-mail): email@example.com.