Second Cancer Risk in Female Survivors of Hodgkin Lymphoma: A National Cohort Analysis Across Treatment Eras

Purpose Subsequent primary malignancies (SPMs) are the leading cause of long-term treatment-related mortality in Hodgkin lymphoma (HL). Although treatments have evolved substantially over recent decades, few studies have demonstrated reductions in SPM risks following modern treatments, nor how such changes should inform survivorship care and screening. We analyzed SPM risks in a large female cohort of childhood and adult patients with HL treated over a 60-year period. Materials and Methods This population-based cohort study included 7,428 women diagnosed with HL before age 36 years in England and Wales from 1954 to 2010, with follow-up through 2018. SPMs were ascertained via national cancer registry linkages. Standardized incidence ratios (SIRs), absolute excess risks, and multivariable models were used to assess temporal trends and associations with treatment. Results During a median follow-up of 20.2 years, 1,200 women developed 1,467 invasive cancers (SIR, 3.3 [95% CI, 3.1 to 3.5]), most commonly breast, lung, and thyroid cancers. Solid tumor risks were the highest following radiotherapy, with a strong dose-dependent response. Alkylator use with radiotherapy was associated with reduced risks of breast cancer but increased risks of GI cancers. Solid cancer risks decreased by 25% between treatment periods 1954-1989 and 2000-2010. The decrease was attenuated and nonsignificant after adjustment for radiotherapy but not affected by adjustment for chemotherapy. No decline was observed for hematologic malignancies. Cumulative incidence of SPMs reached 36% at 50 years. Conclusion Female patients treated in more recent eras have a substantially lower long-term risk of solid SPMs largely attributable to the reduced use, dose, and improvement in radiotherapy. Nevertheless, persistently elevated risks remained beyond 50 years of follow-up, particularly for lung and breast cancer, underscoring the need for lifelong surveillance and targeted screening of survivors.