Long-Term Risk of Skin Cancer Among Childhood Cancer Survivors: A DCOG-LATER Cohort Study

Abstract

Background: Skin cancer is common after radiotherapy among childhood cancer survivors (CCSs). We studied risks and risk factors for subsequent skin cancers, with emphasis on radiation dose, exposed skin surface area, and chemotherapeutic agents.

Methods: The DCOG-LATER cohort study includes 5-year Dutch CCSs diagnosed 1963-2001. Subsequent skin cancers were identified from record linkages with the Netherlands Cancer Registry and Dutch Pathology Registry. Incidence rates were compared with general population rates. Multivariable Cox regression models were used, applying a novel method of case-control sampling enabling use of tumor location in cohort analyses. All statistical tests were two-sided.

Results: Among 5843 CCSs, 259 developed 1061 basal cell carcinomas (BCCs) (standardized incidence ratio [SIR] = 29.8, 95% confidence interval [CI] = 26.3 to 33.6; excess absolute risk per 10 000 person-years (EAR) = 24.6), 20 had melanoma (SIR = 2.3, 95% CI = 1.4 to 3.5; EAR = 1.1), and 10 had squamous cell carcinoma (SIR = 7.5, 95% CI = 3.6 to 13.8; EAR = 0.8). Cumulative incidence of BCC 40 years after childhood cancer was 19.1% (95% CI = 16.6 to 21.8%) after radiotherapy vs 0.6% expected based on general population rates. After a first BCC, 46.7% had more BCCs later. BCC risk was associated with any radiotherapy to the skin compartment of interest (hazard ratio [HR] = 14.32, 95% CI = 10.10 to 20.29) and with estimated percentage in-field skin surface area (26-75%: HR = 1.99, 95% CI = 1.24 to 3.20; 76-100%: HR = 2.16, 95% CI = 1.33 to 3.53, vs 1-25% exposed; Ptrend among exposed = .002), but not with prescribed radiation dose and likelihood of sun-exposed skin-area. Of all chemotherapy groups examined, only vinca alkaloids increased BCC risk (HR = 1.54, 95% CI = 1.04 to 2.27).

Conclusion: CCSs have a strongly, 30-fold increased BCC risk. BCC risk appears to increase with increasing skin surface area exposed. This knowledge underscores the need for awareness by survivors and their health care providers.

Figure 1.

Cumulative incidence of basal cell carcinoma in 5-year childhood cancer survivors of the DCOG-LATER cohort and the expected cumulative incidence from the general population, separately for those who had received radiotherapy (age at diagnosis before 5 years and 5–17 years) and those who had not received radiotherapy. A) Cumulative incidence with time since childhood cancer diagnosis as the time scale. B) Cumulative incidence with attained age as the time scale. Cumulative incidences were estimated in the presence of death as a competing risk and compared between subgroups of survivors with pairwise Pepe-Mori tests. Pepe-Mori test P values for comparison of cumulative incidences at 40 years since childhood cancer for each category are as follows: <.001 for no radiotherapy vs radiotherapy, diagnosed before age 5 years; <.001 for no radiotherapy vs radiotherapy, diagnosed age 5–17 years; and .25 for radiotherapy, diagnosed age before 5 years vs radiotherapy, diagnosed age 5–17 years. Pepe-Mori test P values for comparison of cumulative incidences at attained age 45 years for each category are as follows: <.001 for no radiotherapy vs radiotherapy, diagnosed before age 5 years; <.001 for no radiotherapy vs radiotherapy, diagnosed age 5–17 years; and .004 for radiotherapy, diagnosed before age 5 y vs radiotherapy, diagnosed age 5–17 years. All statistical tests were two-sided.

Figure 2.

Cumulative incidence of basal cell carcinoma in 5-year childhood cancer survivors of the DCOG-LATER cohort and expected cumulative incidence from the general population according to period of childhood cancer diagnosis. A) Cumulative incidence with time since childhood cancer diagnosis as the time scale. B) Cumulative incidence with attained age as the time scale. Cumulative incidences were estimated in the presence of death as a competing risk and compared between subgroups of survivors with pairwise Pepe-Mori tests. Pepe-Mori test P values for comparison of cumulative incidences at 15 years since childhood cancer for each childhood cancer diagnosis period are as follows: .89 for 1963–1984 vs 1985–1994, .32 for 1963–1984 vs 1995–2001, and .24 for 1985–1994 vs 1995–2001. Pepe-Mori test P values for comparison of cumulative incidences at attained age 25 years for each childhood cancer diagnosis period are as follows: .05 for 1963–1984 vs 1985–1994, .37 for 1963–1984 vs 1995–2001, and .31 for 1985–1994 vs 1995–2001. All statistical tests were two-sided.