Cause-Specific Mortality and Second Cancer Incidence after Non-Hodgkin Lymphoma: A Report from the Childhood Cancer Survivor Study.

Background: Second primary malignancies and premature death are a concern for patients surviving treatment for childhood lymphomas. Despite in-depth reports on second cancer risk after Hodgkin lymphoma, there is limited published information on clinical, demographic, and treatment risk factors for second malignant neoplasms (SMNs) or deaths after non-Hodgkin lymphoma (NHL).

Methods: We assessed mortality and SMNs among 1,082 five-year survivors of NHL in the Childhood Cancer Survivor Study, a multi-institutional North American retrospective cohort study of pediatric cancer survivors diagnosed between 1970 and 1986 before age 21. We searched the National Death Index for dates and causes of death and inquired about SMNs in periodic questionnaires, with confirmation of all reported SMNs by a study pathologist. We calculated standardized mortality ratios (SMRs) and standardized incidence ratios (SIRs) based on United States population rates. We calculated relative risks (RRs) for death and SMNs by demographic, clinical, and treatment characteristics using proportional hazards modeling. Medical physicists determined organ exposure to radiation therapy (RT) based on clinical RT records.

Results: There were 87 deaths among 5-year survivors (SMR=4.2, 95% confidence interval (CI): 1.8, 4.1). Leading causes of death were NHL (n=21), solid tumors (n=17), circulatory diseases (n=12), and leukemia (n=10). There were elevated rates of mortality due to NHL, solid tumor SMNs, leukemia, cardiac disease, and pneumonia. The mortality rate remained elevated beyond 20 years after NHL. Risk factors for death included NHL relapse (RR=8.5), doxorubicin (RR=1.8), bleomycin (RR=4.1), platinum agents (RR=4.0), and cardiac RT exposure (RR=1.8). There were 31 SMNs, including 27 solid tumor SMNs (SIR=3.9, 95%.CI: 2.6, 5.7), specifically SMNs of the breast (n=6, SIR=9.1), thyroid (n=6, SIR=9.4), oral cavity and pharynx (n=3), brain and nervous system (n=3), bone (n=2) and urinary bladder (n=2). Risk factors for solid tumor SMNs were female sex (RR=3.1), mediastinal NHL disease (RR=5.2), and breast RT exposure (RR=4.3). Overall cumulative incidence of solid tumor SMNs from 5 to 20 years after NHL diagnosis was 0.03 (95% CI: 0.02, 0.05).

Conclusions: We identified a four-fold risk of mortality and three-fold risk of SMNs in a large cohort of pediatric NHL survivors relative to the general U.S. population. Survivors of childhood NHL, particularly those treated with chest RT, may be at continued increased risk of early mortality and solid tumor SMNs. Health care providers responsible for this population should remain alert to second cancers and other severe late health outcomes.