“The risk of subsequent malignancies at 15 years after initial cancer diagnosis remained increased for those diagnosed in the 1990s, although the risk was lower compared with those diagnosed in the 1970s.”

— Lucie M. Turcotte, MD, MPH, and colleagues

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In a retrospective multicenter cohort study reported in JAMA, Lucie M. Turcotte, MD, MPH, of the University of Minnesota, Minneapolis, and colleagues found that the risk of subsequent neoplasms in 5-year survivors of childhood cancers decreased between those diagnosed in the 1970s vs the 1990s but nevertheless remained elevated vs expected incidence.¹ Reduced risk was associated with the use of reduced therapeutic radiation doses.

Study Details

The study included 23,603 5-year survivors of childhood cancer (mean age at diagnosis = 7.7 years; 46% female) diagnosed before age 21 years from 27 pediatric tertiary hospitals in the United States and Canada between 1970 and 1999, with follow-up through December 2015. The most common initial diagnoses were acute lymphoblastic leukemia (35%, all leukemia = 39%), Hodgkin lymphoma (11%, all lymphoma = 18%), and astrocytoma (9.6%, all central nervous system malignancies = 16%). Standardized incidence ratios (observed to expected number of events) were calculated using age-, sex, and year-specific U.S. cancer incidence rates from the Surveillance, Epidemiology, and End Results program. 

Treatment Changes 

During a mean follow-up of 20.5 years (374,638 person-years), 1,639 survivors experienced 3,115 subsequent neoplasms, including 1,026 malignancies, 233 benign meningiomas, and 1,856 nonmelanoma skin cancers. The most common subsequent malignancies were breast and thyroid cancers. 

Complete treatment data were available for 83% of the cohort. Between 1970 and 1999, radiation therapy use decreased from 77% of survivors to 54% in the 1980s and 33% in the 1990s, and the median radiation dose decreased from 30 Gy to 26 Gy. The proportion of patients receiving alkylating agents and anthracyclines increased over time, but median doses decreased. The proportion of children receiving epipodophyllotoxins and platinum agents increased over the 3 decades; the median cumulative dose of platinum increased in each treatment decade, whereas the median cumulative dose of epipodophyllotoxins increased in the 1980s and decreased in the 1990s.

Changes in Risk Over Time

At 15 years from initial diagnosis, the cumulative incidence of subsequent neoplasms by decade of diagnosis was 2.9% for the 1970s (P = .02 vs 1980s, P < .001 vs 1990s), 2.4% for the 1980s (P = .001 vs 1990s), and 1.5% for the 1990s. The cumulative incidence of subsequent malignant neoplasms was 2.1% for the 1970s (P = .07 vs 1980s, P < .001 vs 1990s), 1.7% for the 1980s (P = .03 vs 1990s), and 1.3% for the 1990s. The cumulative burden of subsequent neoplasms per 100 survivors was 3.6 for the 1970s (P = .02 vs 1980s, P <.001 vs 1990s), 2.8 for the 1980s (P = .001 vs 1990s), and 1.7 for the 1990s. 

Reference absolute rates for subsequent malignant neoplasms per 1,000 person-years, calculated using a fitted model for survivors with the reference group characteristics of no chemotherapy, splenectomy, or radiation therapy, male sex, and attained age of 28 years, were 4.21 for subsequent neoplasms, 1.12 for malignancies, 0.16 for meningiomas, and 1.71 for nonmelanoma skin cancers. Standardized incidence ratios for subsequent malignant neoplasms declined over treatment decades according to higher attained age. For example, standardized incidence ratios were 5.7 for the 1970s, 4.8 for 1980s, and 3.6 for 1990s among survivors attaining age 20 to 29 years (P = .004) and 5.6, 4.9, and 3.1, respectively, among those attaining age 30 to 39 years (P = .03). 

Risk Factors

In an analysis adjusting for sex, age at diagnosis, and attained age, relative rates (RRs) decreased for every 5-year increment of treatment era for subsequent neoplasms (0.81, P < .001), malignant neoplasms (0.87, P < .001), meningiomas (0.85, P = .03), and nonmelanoma skin cancers (0.75, P < .001). On multivariable analysis, female vs male sex was associated with increased risk of subsequent malignant neoplasms and meningiomas, treatment with higher doses of alkylating agents and platinum agents were associated with an increased risk of subsequent malignant neoplasms, and therapeutic radiation at all dose increments was associated with increased rates of subsequent malignant neoplasms (RRs = 1.67–2.94, P values ≤ .002), meningiomas (RRs = 10.91–34.93, P values < .001), and nonmelanoma skin cancers (RRs = 4.82–8.57, P values < .001). 

Inclusion of all treatment variables in a multivariable model significantly attenuated the era-associated reductions in rates of subsequent neoplasms (P < .001), malignant neoplasms (P < .001), meningiomas (P = .03), and nonmelanoma skin cancers (P < .001). Mediation analysis assessing whether changes in rates over time were mediated by modifications in treatment variables (ie, maximum radiation dose and all other treatments including chemotherapy doses and splenectomy) showed that radiation dose changes were the primary factor in the era-associated reductions in subsequent neoplasm rates. After adjustment for changes in radiation dose, relative rates were 0.93 (P = .02) for subsequent neoplasms, 0.96 (P = .20) for malignant neoplasms, 1.01 (P = .90) for meningiomas, and 0.87 (P = .01) for nonmelanoma skin cancers. 

The investigators concluded: “Among survivors of childhood cancer, the risk of subsequent malignancies at 15 years after initial cancer diagnosis remained increased for those diagnosed in the 1990s, although the risk was lower compared with those diagnosed in the 1970s. This lower risk was associated with reduction in therapeutic radiation dose.” ■

Disclosure: This work was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health and the National Cancer Institute. Dr. Turcotte reported no conflicts of interest. For full disclosures of all authors, visit jamanetwork.com.

Reference

1. Turcotte LM, Liu Q, Yasui Y, et al: Temporal trends in treatment and subsequent neoplasm risk among 5-year survivors of childhood cancer, 1970-2015. JAMA 317:814-824, 2017.