STUDY Therapeutic Ionizing Radiation and the Incidence of Basal Cell Carcinoma and Squamous Cell Carcinoma Michael D. Lichter, MD; Margaret R. Karagas, PhD; Leila A. Mott, MS; Steven K. Spencer, MD; The´re`se A. Stukel, PhD; E. Robert Greenberg, MD; for the New Hampshire Skin Cancer Study Group Objective: To estimate the relative risk of developing basal tempt was made to review the radiation treatment re- cell carcinoma (BCC) and squamous cell carcinoma (SCC) cords of subjects who reported a history of radio- after receiving therapeutic ionizing radiation. therapy. Overall, an increased risk of both BCC and SCC was found in relation to therapeutic ionizing radiation. Design: Population-based case-control study. Elevated risks were confined to the site of radiation ex- posure (BCC odds ratio, 3.30; 95% confidence interval, Setting: New Hampshire. 1.60-6.81; SCC odds ratio, 2.94; 95% confidence inter- val, 1.30-6.67) and were most pronounced for those ir- Patients: A total of 592 cases of BCC and 289 cases of radiated for acne exposure. For SCC, an association with SCC identified through a statewide surveillance system radiotherapy was observed only among those whose skin and 536 age- and sex-matched controls selected from was likely to sunburn with sun exposure. population lists. Conclusions: These results largely agree with those of Main Outcome Measures: Histologically confirmed previous studies on the risk of BCC in relation to ion- BCC and invasive SCC diagnosed between July 1, 1993, izing radiation exposure. In addition, they suggest that through June 30, 1995, among New Hampshire resi- the risk of SCC may be increased by radiotherapy, dents. especially in individuals prone to sunburn with sun exposure. Results: Information regarding radiotherapy and other factors was obtained through personal interviews. An at- Arch Dermatol. 2000;136:1007-1011 REATMENT WITH prolonged to previous therapeutic ionizing radia- administration of low- tion. We examined risks according to age dose ionizing radiation is at first exposure, time since exposure, con- associated with subse- dition for which irradiation was adminis- quent nonmelanoma skin tered, and site of exposure. We further as- From Nashua Dermatology cancer (NMSC), particularly basal cell car- sessed the frequency and number of T 1 Associates, Nashua, NH cinoma (BCC). Implicated treatments in- treatments, and, for those who were irra- (Dr Lichter), and the Section of clude radiotherapy of inflammatory der- diated for cancer, the amount of expo- Biostatistics and Epidemiology, matoses such as eczema, psoriasis, acne sure by dose per week and by dose per Department of Community and vulgaris, and tinea capitis.2,3 Addition- treatment course. Family Medicine, and the Norris Cotton Cancer Center ally, an increased risk of BCC has been re- (Drs Karagas, Stukel, and lated to ionizing radiation treatment of goi- RESULTS 4 5-8 Greenberg, and Ms Mott), ters, ankylosing spondylitis, acute Section of Dermatology lymphocytic leukemia, and astrocy- By design, cases and controls were compa- (Dr Spencer), Department of toma.9 Whether radiotherapy enhances rable for age and sex. The overall mean age Medicine, Dartmouth Medical risk of squamous cell carcinoma (SCC) is of cases with BCC and SCC was 58.5 years School, Lebanon, NH. The less clear. A population-based study among and 64.7 years, respectively, and 60.5 years authors have no commercial, men in Alberta, Canada, reported a 5- to for controls. About 40% of the subjects were proprietary, or financial 6-fold increase in incidence of BCC and women and 98% were white. Seven per- interests in the products or SCC associated with nondiagnostic x-ray cent of the controls and 12% of the cases companies described in this 10 article. A complete list of the exposure. Using data collected as part of reported previous ionizing radiation therapy members of the New Hampshire a large case-control study in New Hamp- for reasons other than skin cancer. Skin Cancer Study Group shire, we also had the opportunity to evalu- For BCC, we found a significantly in- appears on page 1010. ate the risk of BCC and SCC in relation creased risk associated with radiotherapy (REPRINTED) ARCH DERMATOL / VOL 136, AUG 2000 WWW.ARCHDERMATOL.COM 1007 ©2000 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021 SUBJECTS AND METHODS history of radiotherapy for skin cancer. Patients treated with ionizing radiation for skin cancer are more likely to be in the case group than in the control group. Therefore, the The case-control study group consisted of patients with BCC inclusion of these cases could bias analyses toward an as- and SCC, aged 25 to 74 years at diagnosis, who were iden- sociation with radiotherapy. We adjusted for age (as a con- tified through a population-based incidence survey of skin tinuous variable) and sex in all models. In addition, we ex- cancer conducted in New Hampshire covering diagnoses amined the potentially confounding effects of outdoor from July 1, 1993, through June 30, 1995.11 Age- and sex- exposure (hours per week spent outdoors in the summer— matched controls were selected from state drivers’ license recreationally and occupationally); cigarette smoking his- lists for those younger than 65 years and from Medicare tory (never, former, current); level of education (less than enrollment lists for those 65 years or older. college, college, graduate or professional school); and sun- An in-person interview that took 90 minutes to 2 hours sensitive skin type defined according to skin reaction to to complete was usually conducted in the subject’s home. strong sunlight for the first time in summer for 1 hour (se- Interviewers were masked to the study hypotheses and were vere sunburn with blistering, painful sunburn, mild sun- not told the case-control status of the participant. Inter- burn and some tanning, and tanning with no sunburn). We viewers asked about sun exposure history, outdoor recre- also explored the possibility that the effects of ionizing ra- ation, skin reaction to sunlight, personal use of tobacco and diation exposure may be modified by skin type. alcohol, educational background, and medical history. To We grouped anatomical location of both skin cancer document previous exposure to therapeutic ionizing ra- and radiation field to the head and neck, trunk, or limbs. diation, we asked subjects if they were ever treated with For controls, we randomly assigned a site based on the ana- x-rays along with the condition and anatomical location tomical distribution of the overall case group. Data were treated, age at and duration of treatment, and the fre- too sparse to study specific anatomical sites of involve- quency of treatments. We requested permission to obtain ment. Therefore, we computed separate ORs for skin can- the medical records of those who reported a history of ra- cers in the radiation field and at unirradiated sites. In this diotherapy. Medical records review was done without analysis, we excluded individuals whose tumor or irradia- knowledge of the subject’s case-control status or other data tion occurred at more than 1 anatomical location. collected at the interview. Lastly, we attempted to analyze the dose per week and We estimated the odds ratio (OR) and 95% confi- the dose per treatment course among those who reported dence intervals (CIs) of BCC and SCC associated with ra- treatment for cancer and for whom irradiation records were diotherapy using unconditional logistic regression.12 We available. Treatment for nonmalignant conditions gener- restricted our analysis to the 592 cases of BCC, 289 cases ally had occurred before 1970; thus, the medical records of SCC, and 536 control subjects who did not have a were no longer available. (age and sex-adjusted OR, 1.88; 95% CI, 1.24-2.87) and The difference between the ORs for the exposed and un- for SCC a borderline significant increased risk (age- and exposed sites was statistically significant for BCC (P=.01) sex-adjusted OR, 1.56; 95% CI, 0.95, 2.55) (Table 1). and borderline significant for SCC (P=.07). When we ex- Adjustment for other potentially confounding factors had amined whether the risks associated with radiotherapy no appreciable effect on the risk estimates. were modified by skin type, we found that for BCC, the The magnitude of the ORs differed according to the ORs for radiation treatment were comparable among those reported reason for treatment. Radiotherapy for acne was who tend to burn and those who tend to tan with first associated with a pronounced and statistically signifi- exposure to sunlight in the summer (among burners, cant increased risk for BCC and SCC (Table 1). A 2-fold OR,1.87; 95% CI, 0.86-4.03 and among tanners, OR, 1.96; increase in BCC risk was found in relation to radio- 95% CI, 1.18-3.26) (P value for interaction, .97). Whereas therapy for cancer, but no increased risk of SCC was found for SCC, risk was increased only among those with a ten- (Table 1). No relation was observed among those who dency to burn (OR, 3.02; 95% CI, 1.37-6.68) and was not had radiotherapy for other benign skin conditions. elevated among those who tend to tan (OR, 0.73; 95% Odds ratios for BCC and SCC according to time since CI, 0.35-1.52) (P value for interaction, .01). the initial exposure and age first treated with radiation Medical records were reviewed for 44 (79%) of the are given in Table 1. Persons whose first radiation treat- 56 subjects who reported receiving therapeutic ionizing ment occurred before they were 20 years old had a greater radiation for cancer. Of the 39 patients receiving radia- risk of BCC and SCC than those treated at older ages.