Cardiovascular Morbidity following Modern Treatment for Hodgkin Lymphoma: Age- and Sex- Specific Estimates of Risk in the Doxorubicin Era

Doxorubicin-based chemotherapy improves the survival of Hodgkin lymphoma (HL) patients, and has become a standard component of initial treatment. However, most studies of cardiac morbidity among HL patients precede the widespread use of this cardiotoxic drug, and do not provide age and sex-adjusted estimates of absolute risk. From the Ontario Cancer Registry, we identified 3,964 adult HL patients treated in Ontario from 1988-2003. Patient records were linked to a Provincial hospitalization registry to identify hospital admissions for cardiovascular (CV) diagnoses. Information regarding HL treatment was abstracted from the medical records of a random subcohort of patients (N = 1,023). 765 patients in the subcohort (75%) received doxorubicin-based chemotherapy, most commonly ABVD; 493 (48%) received mediastinal RT. Expected CV hospitalization rates in the general population were estimated from a random sample of 6,136 Ontario citizens matched on age and sex to the subcohort. Competing risks models were used to evaluate treatment-related effects in the subcohort and estimate the cumulative incidence of CV hospitalizations. Median age at HL diagnosis = 35 years. Median follow-up =10.2 years (1 month - 19 years). 332 HL patients (8.4%) had ≥1 CV hospitalization, a rate significantly greater than in the general population (HR 1.4, p<0.001). The 15-yr cumulative incidence of a CV admission among HL patients vs. population controls was 13.5% vs. 8.9% for males, and 8.8% vs. 4.6% for females. In competing risk models, for patients aged 35 years at treatment the estimated 15-yr cumulative incidence of CV hospitalization was lowest among receiving neither mediastinal RT nor doxorubicin (males = 5.9%; females = 4.0%). Males and females receiving mediastinal RT alone at age 35 had an estimated 15-yr incidence of CV hospitalization of 9.3% and 6.3%, respectively. Patients treated with 1-3 cycles of doxorubicin-based chemotherapy prior to mediastinal RT had a higher predicted 15-yr incidence (males = 11.9%; females 8.1%), while the highest rate was among those treated with 4-5 cycles of doxorubicin-based chemotherapy prior to mediastinal RT (males =17.9%; females =12.3%). This study provides estimates of the risk of CV morbidity that are more clinically relevant to contemporary HL treatment than most currently published estimates. While doxorubicin-based chemotherapy improves survival compared to RT alone, it may increase in the long-term risk of cardiac toxicity among those also requiring mediastinal RT. These results support the use of short-course chemotherapy among selected patients, and the investigation of involved-node RT for patients with mediastinal involvement.