(Psoralen) and UV-A Radiation (PUVA) a Meta-Analysis
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STUDY Risk of Squamous Cell Carcinoma and Methoxsalen (Psoralen) and UV-A Radiation (PUVA) A Meta-analysis Robert S. Stern, MD; Elissa J. Lunder, MD Objective: To assess the risk of squamous cell carci- high-dose PUVA (.200 treatments or 2000 J/cm2). Ex- noma (SCC) and the relation of dose to risk among groups act methods were used to calculate the incidence rate of patients with psoriasis exposed to psoralen–UV-A ratios. (PUVA). Data Synthesis: In addition to our study, we identi- Data Sources: Four electronic databases were searched fied and reviewed 8 other studies. Overall, the inci- from 1984 to 1998. dence among patients exposed to high-dose PUVA was 14-fold higher than among patients with low-dose ex- Study Selection: In addition to the PUVA Follow-up posure (95% confidence interval, 8.3-24.1); a greater dose- Study, we included all English-language studies from the dependent increase in risk than that observed in the PUVA United States and Europe with at least 150 patients en- Follow-up Study. rolled, who were followed up for at least 5 years as iden- tified from our bibliographic search. Conclusion: Although the incidence of SCC reported among groups of PUVA-treated patients followed up for Data Extraction: A custom-designed questionnaire was at least 5 years varies greatly, compared with the risk in used to extract data from each of the articles. For each low-dose patients, long-term high-dose exposure to PUVA study, if possible, we determined the incidence of basal was consistently observed to significantly increase the risk cell carcinomas and SCCs and the incidence rate ratio of SCC in all studies reviewed. of SCC among patients exposed to low-dose (we de- fined as ,100 treatments or 1000 J/cm2) compared with Arch Dermatol. 1998;134:1582-1585 RAL PSORALEN–UV-A ra- posure to PUVA but whose overall expo- diation (PUVA) is an ef- sure to PUVA has been lower.6-13 fective and widely used The published studies of the occur- treatment for psoriasis. rence of skin cancer among patients ex- First used more than 20 posed to PUVA vary substantially in their years ago, PUVA is recognized as one of the methods, population studied, and results. O 1 most valuable treatments for psoriasis. Pso- We undertook a meta-analysis of 8 stud- ralen–UV-A is, however, mutagenic and is ies published in the English language from considered a standard for photocarcino- groups other than the PUVA Follow-up genesis studies in animals.2 In 1975, the first Study5 which provided information on the 1380 patients to be treated with PUVA for occurrence of nonmelanoma skin cancer (in psoriasis in the United States enrolled in a a group of at least 150 patients primarily long-term prospective study of PUVA with psoriasis followed up for at least 5 therapy (The PUVA Follow-up Study).3-5 years.6-13 Based on the data available from Reports from this multicenter study have these articles, we calculated the incidence demonstrated that in this population long- of SCC, the relation of incidence to level term exposure to PUVA increases the risk of exposure to PUVA, and the ratio of SCC of squamous cell carcinoma (SCC) and that to basal cell carcinoma (BCC) overall and this risk increases with greater exposure to according to level of exposure to PUVA. To PUVA.4,5 These findings have been contro- assess the extent to which these findings From the Department of versial. Other groups in the United States concerning SCC risks and PUVA therapy Dermatology, Beth Israel and Europe have published their findings are consistent, we compared the indi- Deaconess Medical Center, based on observations of groups of pa- vidual and aggregate findings of these Harvard Medical School, tients with psoriasis (and in some cases 8 studies6-13 with the published findings Boston, Mass. other diseases) who have had long-term ex- from the PUVA Follow-up Study.5 ARCH DERMATOL / VOL 134, DEC 1998 1582 ©1998 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/02/2021 low-up Study, studies reported average age at enroll- ment.6,9-11 These ages were not substantially different from MATERIALS AND METHODS each other or the PUVA Follow-up Study5 (average age range, 43-50 years). Males outnumbered females in 5 of Using the MEDLINE, Healthstar, Aidsline, and Can- the 7 studies with these data provided, including the PUVA Follow-up Study.5 The PUVA Follow-up Study5 and the cerlit databases, we attempted to ascertain all stud- 7 ies published reporting on the nonmelanoma skin can- study by Chuang et al were based in the United States. cer experience for patients primarily with psoriasis The remaining 7 studies were of European popula- exposed to oral PUVA with an average follow-up of tions.6,8-13 Nearly all patients studied were of European at least 5 years. We initially identified 49 studies. For ancestry. cohorts that had been subject to multiple analyses over The average duration of follow-up, study group size time, we relied only on data from the most recent pub- (Table 1), and extent of exposure to PUVA varied greatly lication identified by us in March 1998. We limited among the studies. As a result, both the number of tu- our analysis to studies from the United States and Eu- mors expected and the precision of estimates vary greatly rope that enrolled at least 150 patients followed up Table 2 at least 5 years and published after 1984. In addition among studies. lists the incidence per 1000 per- to the PUVA Follow-up Study, we identified 8 stud- son-years for SCC overall and among patients exposed ies that met these criteria. For each study, we ab- to high and low levels of PUVA. The incidence of SCC stracted the following types of data: number of varied greatly among studies, even within dose groups. patients enrolled, number followed, person years Among high-dose patients, all other studies reported in- of follow-up, average age at enrollment, and per- cidence rates substantially less than the 65 per 1000 per- centage of male. We also attempted to determine the son-years calculated for high-dose patients in the PUVA number of individuals and years of exposure among Follow-up Study.5 For 4 of 8 studies reporting results patients exposed to high and low doses of PUVA. among patients with low-exposure to PUVA, no SCCs Whenever it was possible, we defined high dose were noted.6,8,11,12 Every study noted a higher incidence as more than 200 treatments or 2000 J/cm2 and low dose as less than 100 treatments or fewer than 1000 of SCC among members of the study group exposed to 2 higher doses of PUVA. In addition to the PUVA Fol- J/cm . If data in the study were not available in a for- 5 mat that permitted analysis using either of these defi- low-up Study, a point estimate of the IRR for SCC for nitions for dosage, the definition of high- and low- high- vs low-dose groups can be calculated for 4 stud- dose PUVA as defined by the author(s) of the ies. For these 4 studies, the IRRs ranged from 7 to 13 (high- individual study was used. On the basis of the tu- vs low-dose PUVA). In 4 additional studies, the point es- mor experience reported in each article, we at- timate was infinite. For these 4 studies the lower bound tempted to calculate an overall incidence rate for SCC of the 95% confidence interval in every case was more as well as incidence rates per 1000 person-years among than 1 (ie, risk was significantly higher for high-dose patients exposed to high and low doses of PUVA. patients). For the 8 studies other than the PUVA Fol- From these data we then calculated the incidence rate ratios (IRRs) for high- vs low-dose exposure groups low-up Study, the pooled estimate of the IRR for SCC for (ie, the ratio of the incidence of tumors per 1000 per- high- vs low-dose PUVA equals 14.0 (95% confidence in- son-years of follow-up) in the high-dose group com- terval, 8.3-24.1). Therefore, the estimate of the increase pared with that in the low-dose group. To calculate in risk of SCC for high-compared with low-dose expo- summary IRRs and estimate the confidence inter- sure to PUVA is significantly higher for these studies com- vals for individual report results we used exact meth- pared with that calculated by the PUVA Follow-up Study ods.14,15 We also calculated the ratio of BCCs to SCCs (IRR high vs low, 5.9).5 overall, and according to level of exposure to PUVA In addition to the PUVA Follow-up Study data,5 7 for each study and overall, and compared these of the 8 studies6-9,11-13 provided incidence data on BCC. ratios with the ratio we have reported for the PUVA As detailed in Table 3, in 5 of 7 studies the number of Follow-up Study.5 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 ra- tio of SCCs to BCCs was 3:1 (Table 3), a ratio almost iden- RESULTS tical to the 2.7:1 ratio reported for the PUVA Follow-up Study.5 Among patients exposed to low doses of PUVA, Table 1 provides a summary of the characteristics of the all studies that documented BCCs detected more BCCs patient populations in the 9 studies analyzed.