We identified 14,358 survivors (median age at last follow-up, 31.9 years; range, 5.6 to 56.3 years), who accrued a total of 327,297 person-years of follow-up time, with a median of 23.0 years from diagnosis (range, 5.0 to 37.6 years). Within this cohort, radiation exposure was common (occurring in 67.9% of those who consented to release their medical records). Additional characteristics of the cohort are listed in and in Appendix Table A3
(online only). Within this cohort, 1,382 people (9.6%) developed SN1, with a total of 9,387 person-years of follow-up time. Among these 1,382 SN1 occurrences, 386 (27.9%) developed an SN2. Of those with SN2, 153 (39.6%) developed greater than two SNs. In addition, 735 (5.1%) of the 14,358 members of the cohort developed SMN1, 68 (9.3%) of whom developed SMN2.
Characteristics of the CCSS Cohort: Entire Cohort, Survivors With Subsequent Neoplasms, and Survivors With Subsequent Malignant Neoplasms
NMSC was the most common SN (1,104 total episodes; Appendix Table A4
, online only) and occurred as SN1 in 485 survivors (A), 61 (12.6%) of whom subsequently developed an invasive SMN. Other important patterns were identified. Of 176 participants who had a breast neoplasm as SN1, 37 developed a new breast neoplasm as SN2 (B). Multiple subsequent meningiomas were common (C). Thyroid cancer, soft-tissue sarcomas, and CNS malignancies were frequently observed as SN1 and preceded a variety of additional SNs (D to F).
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, (more ...)
Among survivors with SN1, the cumulative incidence of SN2 was 33.4% (95% CI, 30.3% to 36.5%) at 10 years, was 38.8% (95% CI, 35.1% to 42.5%) at 15 years, and was 46.9% (95% CI, 41.6% to 52.2%) at 20 years (A). When SN1 was an SMN, the cumulative incidence of developing SMN2 after SMN1 was 12.4% (95% CI, 9.1% to 15.6%) at 15 years (A). The cumulative incidence of SN2 was highest among survivors of a primary Hodgkin's lymphoma (50.3% at 15 years; 95% CI, 44.1% to 56.6%) or CNS malignancy (44.5% at 15 years; 95% CI, 33.4% to 55.6%; B and C). Among survivors exposed to radiation as therapy for their primary cancer, the cumulative incidence of SN2 was 41.3% (95% CI, 37.2% to 45.4%) at 15 years from SN1 compared with 25.7% (95% CI, 16.5% to 34.9%) for those not treated with radiation (Appendix Table A5
, online only). Similarly, among patients with SMN1 who were not exposed to radiation, the cumulative incidence of SMN2 was 22.8% at 10 years.
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 (more ...)
Within this cohort, there were 252 breast lesions (n = 189 invasive, n = 61 in situ, and n = 2 benign). The cumulative incidence of developing a second breast SN was 20.7% (95% CI, 14.7% to 26.7%) at 10 years from the time of development of the initial breast SN (A). Because of a significant rate of synchronous breast lesions, cumulative incidences of a second breast neoplasm conditioned on time from first breast SN of 6, 12, and 24 months were 12.6% (95% CI, 7.3% to 18.0%), 10.4% (95% CI, 5.2% to 15.7%), and 9.6% (95% CI, 4.4% t0 14.8%), respectively, at 10 years from initial breast SN. The cumulative incidence of developing a second NMSC at 10 years from the first NMSC was 49.0% (95% CI, 43.5% to 54.5%). Because multiple lesions at presentation were common, when conditioned on time from first NMSC (B) of 6, 12, and 24 months, the cumulative incidences of a second NMSC were 40.8% (95% CI, 34.7% to 46.9%), 38.2% (95% CI, 32.0% to 44.4%), and 33.8% (95% CI, 27.3% to 40.3%), respectively, at 10 years from first NMSC.
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), (more ...)
Among survivors who received radiation and developed an SN, 414 had NMSC as SN1, whereas 570 had an invasive SMN as SN1. The cumulative incidence of an additional invasive malignancy (ie, SMN) was 20.3% (95% CI, 13.0% to 27.6%) at 15 years after NMSC compared with 10.7% (95% CI, 7.2% to 14.2%) after SMN1 () and was potentially influenced by the survival estimates for those with an invasive SMN as SN1 (45.4% at 15 years; 95% CI, 37.0% to 53.8%) that were lower than for those with NMSC as SN1 (79.0% at 15 years; 95% CI, 68.4% to 89.6%).
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).
The limitation of incomplete information regarding treatment for SNs and SMNs is recognized. provides multivariable models evaluating risk factors (ie, demographic, treatment exposure for primary cancer, health behaviors, family history) associated with the cumulative incidences of multiple SNs and multiple SMNs after SN1 and SMN1, respectively. Exposure to radiation for the primary cancer was associated with cumulative incidence of SN2 (subdistribution HR, 2.16; 95% CI, 1.32 to 3.55). However, radiation appeared protective from SMN2 (subdistribution HR, 0.48; 95% CI, 0.25 to 0.94; cause-specific HR, 0.41; 95% CI, 0.20 to 0.85). Note that the radiation-exposed survivors had a lower survival estimate at 10 years from SMN1 (56.1%; 95% CI, 49.8% to 62.4%) compared with those who had no radiation exposure (64.3%; 95% CI, 49.6% to 79.0%). Additionally, older age at SN1 (≥ 30 years) was associated with higher cumulative incidence of developing an SN2 compared with those younger than 30 years of age (HR, 1.9; 95% CI, 1.28 to 2.82). Women were more likely than men to develop SMN2 (HR, 2.53; 95% CI, 1.23 to 2.51). However, when breast neoplasia as SMN2 was removed from analysis, association with female sex did not reach statistical significance (HR, 1.57; 95% CI, 0.70 to 3.50). Having a first-degree relative with cancer and being a current smoker were associated with an increased cumulative incidence for multiple SMNs, but the associations were not statistically significant at the.05 level.
Multivariable-Adjusted Subdistribution Hazard Ratios for Development of SN2 From Time of SN1 and for SMN2 From Time of SMN1