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Absolute Risk for Developing Most STS Low in Childhood Cancer Survivors

Jason Harris
Published: Tuesday, Nov 28, 2017

Raoul C. Reulen, PhDr
Raoul C. Reulen, PhD
While survivors of childhood cancers are at increased risk for developing soft-tissue sarcomas (STS) compared with the general population, the absolute risk for developing STS is low except for leiomyosarcoma after retinoblastoma.

Investigators analyzed data collected from the PanCare Childhood and Adolescent Cancer Survivor Care and Follow-Up Studies (PanCareSurFup). The consortium pools data on childhood cancer survivors from 13 European cohorts within 12 countries, with contributions from both population-based cancer registries and major treatment centers.

A total of 69,460 5-year survivors representing 1,126,424 person-years were included in the study. Median follow-up was 14.5 years from 5-year survival (range, 0-62 years). Investigators observed a total of 301 STS in 299 survivors. Median time from diagnosis to occurrence of an STS was 19 years. The most commonly observed STS were leiomyosarcoma (n = 80; 26.6%), fibromatous neoplasms (n = 55; 18.3%), and malignant peripheral nerve sheath tumors (MPNSTs; n = 45; 15.0%).

Overall, survivors had a 15.7-fold (95% CI, 14.0-17.6) increased risk for developing STS compared with the general population. That translates to an absolute excess risk of 2.5 (95% CI, 2.2-2.8).

“Despite attempts to reduce therapeutic exposures for specific cancers over the last few decades, the excess risk of STS did not vary across different decades of diagnosis,” wrote corresponding author Raoul C. Reulen, PhD, Centre for Childhood Cancer Survivor Studies, Institute of Applied Health Research, Robert Aitken Building, University of Birmingham, United Kingdom. “This study provides unprecedented insight into the absolute and excess risks of STS [subsequent primary neoplasms (SPN)] after childhood cancer, particularly in the long term, which is likely to be informative to both childhood cancer survivors and healthcare providers.”

Survivors of each specific type of childhood cancer were at a statistically significantly increased multiplicative (standardized incidence ratio [SIR]) and absolute excess risk (AER) of developing an STS, particularly among retinoblastoma survivors (SIR = 72.8; 95% CI, 56.1-93.0; AER = 10.5; 95% CI, 7.9-13.1).

Multivariable analysis showed that there was no statistically significant relationship between age at diagnosis or decade of diagnosis and the excess risk of STS in either multiplicative or absolute terms. The relative risk (RR) declined by 50% among survivors older than age 40 years compared with survivors aged 0 to 19 (RR = 0.5; 95% CI, 0.3-0.8; Ptrend = .002). However, the excess RR increased 2.9-fold (95% CI, 1.8-4.5; Ptrend <.001).

RR was 50% lower among patients who survived at least 45 years after their childhood cancer compared with those who survived 5 to 14 years (RR = 0.5; 95% CI, 0.2- 0.9; Ptrend = .001). In contrast, excess RR increased 3.7-fold (95% CI, 1.9-7.2; Ptrend <.001). AER was 9.1 (95% CI, 3.6-14.6) beyond 45 years after diagnosis. At 45 years from diagnosis, the cumulative incidence of developing an STS was 1.4% (95% CI, 1.1-1.6), whereas 0.1% was expected.

The SIR for developing a leiomyosarcoma was 30-fold greater among survivors of childhood cancer compared with the general public (95% CI, 23.7-37.2), corresponding to an AER of 0.7 (95% CI, 0.5-0.8). The risk was greatest among survivors of retinoblastoma (SIR = 342.9; 95% CI, 245.0-466.9) and Wilms tumor (SIR = 74.2; 95% CI, 37.1-132.8).

Investigators found that survivors diagnosed before age 5 had nearly a 100-fold risk for developing a leiomyosarcoma (SIR = 98.3; 95% CI; 74.4-127.4). There was a statistically significant decrease in risk among survivors diagnosed from age 10 to 19 years versus those diagnosed from age 0 to 4 years (RR = 0.3; 95% CI, 0.1-0.8; Ptrend = .01).

The AER among survivors of retinoblastoma increased substantially with time and age (Ptrend <.001). AER was 57.7 (95% CI, 23.3-92.1) beyond 45 years from diagnosis. Leiomyosarcomas accounted for 91.3% of all excess STS among retinoblastoma survivors beyond 45 years from diagnosis, with an AER of 52.7 (95% CI, 20.0-85.5).

Survivors were at a 12.3-fold (95% CI, 9.3-16.0) increased risk for developing a fibromatous SPNs compared with what was expected, translating to an AER of 0.4 (95% CI, 0.3-0.6). Survivors were at greatest risk for fibrosarcoma (SIR = 25.1; 95% CI, 16.5-36.5) and malignant fibrous histiocytoma (SIR = 28.3; 95% CI, 18.3-41.7).

MPNST SPNs were associated with the highest SIR for any STS subtype with a 40.6-fold (95% CI, 29.6-54.3) increased risk compared with what was expected. The corresponding AER was 0.4 (95% CI, 0.3-0.5). Almost half (47.6%) of all MPNSTs were associated with neurofibromatosis.

SIRs were highest among survivors diagnosed with central nervous system tumors (SIR = 80.5; 95% CI, 48.4-125.7), Hodgkin lymphoma (SIR = 81.3; 95% CI, 35.1-160.1), and Wilms tumor (SIR = 76.0; 95% CI, 27.9-165.4).

AERs were generally low at all years from diagnosis (AER < 1 per 10,000 person-years). Investigators did not observe statistically significant trends in excess risk related to years from diagnosis, attained age, age at diagnosis, or decade of diagnosis in multiplicative or absolute terms. The cumulative incidence of developing an MPNST reached 0.1% (95% CI, 0.07-0.14) at 30 years from diagnosis compared with the expected 0.002%.
Bright CJ, Hawkins MM, Winter DL, et al. Risk of soft-tissue sarcoma among 69,460 five-year survivors of childhood cancer in Europe [published online ahead of print November 20, 2017]. J Natl Cancer Inst. doi: 10.1093/jnci/djx235.


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