Occurrence of multiple subsequent neoplasms in long-term survivors of childhood cancer: a report from the childhood cancer survivor study

Abstract

Purpose: Childhood cancer survivors experience an increased incidence of subsequent neoplasms (SNs). Those surviving the first SN (SN1) remain at risk to develop multiple SNs. Because SNs are a common cause of late morbidity and mortality, characterization of rates of multiple SNs is needed.

Patients and methods: In a total of 14,358 5-year survivors of childhood cancer diagnosed between 1970 and 1986, analyses were carried out among 1,382 survivors with an SN1. Cumulative incidence of second subsequent neoplasm (SN2), either malignant or benign, was calculated.

Results: A total of 1,382 survivors (9.6%) developed SN1, of whom 386 (27.9%) developed SN2. Of those with SN2, 153 (39.6%) developed more than two SNs. Cumulative incidence of SN2 was 46.9% (95% CI, 41.6% to 52.2%) at 20 years after SN1. The cumulative incidence of SN2 among radiation-exposed survivors was 41.3% (95% CI, 37.2% to 45.4%) at 15 years compared with 25.7% (95% CI, 16.5% to 34.9%) for those not treated with radiation. Radiation-exposed survivors who developed an SN1 of nonmelanoma skin cancer (NMSC) had a cumulative incidence of subsequent malignant neoplasm (SMN; ie, malignancies excluding NMSC) of 20.3% (95% CI, 13.0% to 27.6%) at 15 years compared with only 10.7% (95% CI, 7.2% to 14.2%) for those who were exposed to radiation and whose SN1 was an invasive SMN (excluding NMSC).

Conclusion: Multiple SNs are common among aging survivors of childhood cancer. SN1 of NMSC identifies a population at high risk for invasive SMN. Survivors not exposed to radiation who develop multiple SNs represent a population of interest for studying genetic susceptibility to neoplasia.

Fig 1.

Survivors with multiple neoplasms after first subsequent neoplasm (SN) when SN1 is (A) nonmelanoma skin cancer (NMSC), (B) breast cancer, (C) meningioma, (D) thyroid cancer, (E) soft tissue sarcoma (STS), and (F) CNS malignancies (Malig). Gold, blue, and black boxes represent subsequent malignant neoplasms (SMNs), NMSCs, and benign neoplasms, respectively. NHL, non-Hodgkin's lymphoma.

Fig 2.

(A) Cumulative incidence of second subsequent neoplasm (SN2) after occurrence of first SN (top line) with 95% CI and of second subsequent malignant neoplasm (SMN2; bottom line) after occurrence of first SMN (SMN1) with 95% CI; (B, C) cumulative incidence of SN2 after SN1 by primary pediatric cancer diagnosis. HD, Hodgkin's disease; NB, neuroblastoma; NHL, non-Hodgkin's lymphoma; STS, soft tissue sarcoma.

Fig 3.

Conditional cumulative incidence of (A) second subsequent breast neoplasm after occurrence of first subsequent breast neoplasm and of (B) second subsequent nonmelanoma skin cancer (NMSC) after first subsequent NMSC, conditioned on time of 0 (gold line), 6 (blue line), 12 (gray line), or 24 (black line) months (mo) from first subsequent breast neoplasm or NMSC. SN, subsequent neoplasm.

Fig 4.

Cumulative incidence of a subsequent malignant neoplasm among radiotherapy-exposed patients after nonmelanoma skin cancer (NMSC) as first subsequent neoplasm (SN; blue line) and subsequent malignant neoplasm (SMN) as SN1 (gold line).