Risk of Cardiac-Specific Mortality in Patients with Lymphoma Treated with Radiotherapy

Abstract

The mainstays of treatment for Non-Hodgkin (NHL) and Hodgkin (HL) lymphoma are chemotherapy, radiotherapy (RT), or a combination of both. Thanks to improvements in treatment options many patients outlive their diagnosis by several decades. As treatments are de-intensified and cardiac sparing techniques have improved, the impact of RT on cardiac mortality should be re-visited. In this study, we sought to investigate the potential association between thoracic irradiation and cardiac-specific mortality (CSM) in patients with lymphoma. We hypothesized that receipt of RT would be associated with higher risk of cardiac death. The Surveillance Epidemiology and End Results (SEER) database was queried to identify all patients with HL and NHL with a thoracic primary site from 1975 to 2018. Kaplan Meier estimators were used to analyze cardiac-specific survival. Cohorts were balanced using inverse probability treatment weighing (IPTW). Hazard ratios were calculated using multivariate cox regression analysis. The following treatment eras were defined for analysis: pre-1995, 1995-2003, post-2003, to roughly correspond to the adoption of 3D conformal RT (3DCRT) and intensity-modulated RT (IMRT). We identified 10,602 patients, of which 8,088 (76%) had NHL and 2,514 (24%) had HL. Seventy-three percent of patients received chemotherapy and 38% received RT. Median follow up was 11.2 years. Forty-eight percent of patients were alive at last follow up, 6.6% had died from cardiac-specific causes, and 45% had died of other causes. Patients who received RT were had a lower risk of CSM (HR = 0.64, p < 0.01). However, IPTW survival analysis revealed no difference in the risk of cardiac death between the treatment cohorts (HR = 1.00, p = 0.99). Multivariate cox regression analysis identified female sex (HR = 0.73, p <0.01), age younger than 40 (HR = 0.27, p <0.01), and diagnosis after 1995 (HR = 0.31, p <0.01) to be associated with a lower CSM. In patients who received RT, we found that the risk of CSM was a higher (HR = 2.66, p <0.01) in those treated in the pre-1995 era and lower (HR = 0.32, p < 0.01) in the post-2003 era when compared to patients treated between 1995-2003. Additionally, receipt of RT was associated with a lower risk of all-cause mortality (HR 0.82, p<0.01). Our IPTW analysis shows that patients with thoracic lymphoma treated with RT have a similar risk of cardiac death to patients who did not receive RT, and an improved OS. Known cardiovascular risk factors like male sex and older age were associated with higher risk of cardiac death in patients receiving RT. We also found that patients treated with RT pre-1995 had higher CSM compared to those treated in 1995-2003 and those treated after 2003 had the lowest CSM, possibly in part attributable to the adoption of newer RT techniques. These findings may help clinicians counsel patients with lymphoma on the optimal modality of therapy and the possibility for late treatment effects in the modern era.