Background: Investigators from the United Kingdom (UK) have previously developed a treatment exposure-based algorithm that stratifies pediatric cancer survivors into low, medium, and high-risk groups. We sought to use the large, diverse population of the Childhood Cancer Survivor Study (CCSS) to validate risk for poor outcomes in children treated for Hodgkin Lymphoma with an emphasis on the impact of sex on long term outcomes.
Methods: Five-year survivors of childhood cancer (diagnosed between 1970-1999 at <21 years of age) were categorized into medium and high-risk groups based on treatment exposures and diagnoses. High risk was defined by receipt of transplant, doxorubicin equivalent dose ≥ 250, or direct radiation to the neck, chest, abdomen, or pelvis. The primary endpoint included cumulative incidence of grade 3-5 chronic conditions (CTCAEv4.03) conditional on reaching age 25 without the outcome. Patients were censored at age 40 and siblings used as a comparison group. Cox proportional hazards models estimated hazard ratios (HRs) and 95% confidence intervals (CI) of new onset grade 3-5 conditions adjusted for sex and race.
Results: A total of 2,131 survivors of Hodgkin Lymphoma met study criteria with a median follow-up of 22 years and median age of 36 at last follow-up. Using the above criteria, the final cohort included 241 medium and 1,890 high risk survivors. Among those who survived to age 25 without any grade 3-5 conditions, the risk of developing one by age 40 was 39.8% (95% CI 37.2- 42.5%) for high risk patients and 27.2% (19.8 – 37.2%) for medium risk patients, respectively, and 8.5% (7.5 – 9.7%) for siblings. The risk of grade 3-5 condition by age 40 in high risk patients was substantially higher for females at 50.6% (46.9 – 54.6) than for males at 29.7% (26.6 – 33.3%). In multivariable analysis the strongest predictor of grade 3-5 conditions remained female vs. male sex (HR 1.9, 95% CI 1.6 – 2.3), followed by high vs. medium risk (HR 1.7, 95% CI 1.2 – 2.4). Toxicity was not associated with race.
Conclusions: Females treated for childhood Hodgkin Lymphoma remained at nearly double the risk of long-term high grade toxicity compared to males after adjusting for treatment exposures. Patient sex may help supplement standardized risk assessment of Hodgkin Lymphoma survivors and help inform physicians attempting to determine follow-up intervals, management, and long-term surveillance of these survivors.
Michaela Dinan, Kayla Stratton, Wendy Leisenring, Yutaka Yasui, Eric Chow, Emily Tonorezos, Chaya Moskowitz, Jennifer Yeh, David Noyd, Gregory Armstrong, Kevin Oeffinger