Modern Hodgkin lymphoma treatments to reduce second cancer risks: Influence of risk-adapted screening.

7053 Background: Second primary malignancies (SPMs) are the leading cause of long-term treatment-related mortality in Hodgkin Lymphoma (HL). Although substantial improvements have been made to treatments over recent decades, few studies have demonstrated reduced SPM risk, particularly following modern treatments, and how risks should inform screening. Methods: We assembled a national cohort of 7,428 women treated for HL aged <36 across England & Wales 1954-2010, with 99% complete follow-up until 2018. We analyzed SPM incidence from national cancer registry linkage. Treatment data were collated from >250 treatment centers. Standardized incidence ratios (SIRs) and Absolute Excess Risks (AERs) for SPMs were calculated, and multivariable analyses (Hazard Ratios, HR) were undertaken to assess the impact of changes in treatment and assess changing incidence trends over time. Results: Twelve hundred women (16%) developed 1,467 SPMs with mean follow-up of 22 years (range 0-62 years). Overall SIR to develop any SPM was 3.3 (95% CI 3.1-3.5), with breast cancer contributing the greatest excess risk (AER 30.8 95% CI 27.7-34.1). Radiotherapy use halved from 1954-1980 to 2000-2010 (98% to 47%) and mean dose dropped from 48Gy to 33Gy. Conversely chemotherapy use doubled from 55% to 97%, with anthracyclines used in 94% and classic alkylators in 31% of treatments in the most recent period compared with 6% and 48% respectively pre-1980. Radiotherapy conferred the greatest treatment-specific risk factor for SPMs, (SIR 3.5 95% 3.3-3.7), with a strong dose-response relationship trend (HR 1.01/Gy p<0.001), and highest relative risks seen in those treated with radiotherapy aged <15years (SIR 7.4 (95% CI 5.7-9.1). There was a 25% reduction in SPM risk from the earliest treatment period (<1990) to most recent (2000-2010) and 34% reduction in solid SPM risk (Table). The decrease in risk for SPMs became smaller and non-significant after adjusting for reduced radiotherapy use and dose (HR 0.89, p trend 0.11). There was no attenuation after adjustment for chemotherapy. Despite declining risks, risks remained significantly elevated beyond 40 years after treatment. Conclusions: Modern HL treatments are associated with a substantial reduction in SPM risks, which appears to be largely attributable to decreased radiotherapy use and dose. However large persistent excess risks, particularly for breast and lung cancers, underscore the need for targeted screening in high-risk survivors treated in more recent eras. Risk of SPMs by treatment era. SPMs & treatments Treated <1990HR (ref) Treated 1990-1999HR (95% CI) Treated 2000-2010HR (95% CI) p trend All SPMs Any treatment 1.0 0.77 (0.65-0.90 0.75 (0.57-0.99) 0.001 Adjusted for radiotherapy & dose 1.0 0.83 (0.69-1.00) 0.90 (0.63-1.28) 0.11 Solid SPMs Any treatment 1.0 0.71 (0.60-0.85) 0.66 (0.48-0.90) <0.001 Adjusted for radiotherapy & dose 1.0 0.79 (0.65-0.96) 0.81 (0.55-1.20) 0.03