1. Cardiovascular Morbidity Following Modern Treatment for Hodgkin Lymphoma: Age- and Sex- Specific Estimates of Risk in the Doxorubicin Era. D. Hodgson 1, M. Pintilie 1, L. Yun 2, S. Ahmed 1, J. Sussman 3, E. Yu 4, M. Crump 1, R. Meyer 5, R. Tsang 1. 1 Princess Margaret Hospital, Toronto, ON, Canada, 2 Institute for Clinical Evaluative Sciences, Toronto, ON, Canada, 3 Jurvavinski Cancer Centre, Hamilton, ON, Canada, 4 Toronto Western Hospital, Toronto, ON, Canada, 5 National Cancer Institute Clinical Trials Group, Kingston, ON, Canada

2. Background Doxorubicin-based chemotherapy improves the survival of Hodgkin lymphoma (HL) patients, and has become a standard component of initial treatment. Doxorubicin is directly toxic to myocardium. Almost all studies of cardiac morbidity among HL patients precede the widespread use of this cardiotoxic drug. Most existing studies do not provide age and sex-adjusted estimates of absolute risk. Most focus on cardiac death, a blunt measure of treatment-related toxicity.

3. Purpose Evaluate the cardiac morbidity in a large population of HL patients treated in the modern (i.e. doxorubicin) era. –Evaluate the impact of the transition to doxorubicin-based chemotherapy on incidence cardiac morbidity. –Provide absolute risk estimates for identifiable patient groups.

4. Methods 3,964 adult HL patients treated in Ontario from 1988-2003 identified in Ontario Cancer Registry. 19 Hospitals involved in the initial treatment of > 10 cases were selected. HL treatment data abstracted from the medical records of a random subcohort of patients (N=1,083). CIHI hospitalization registry to identify hospital admissions with primary cardiac diagnoses, based on ICD-9 and ICD-10 codes.

5. Methods Expected CV hospitalization rates in the general population estimated from a random sample Ontario citizens matched on age, sex and neighbourhood of residence to the subcohort (1:6). Competing risks models were used to estimate the cumulative incidence of cardiovascular hospitalizations.

6. Table 1. Characteristics of Hodgkin lymphoma subcohort, and general population controls matched on age, sex, and geographic region within Ontario.

7. Table 1 continued

8. Overall Survival of Subcohort Figure 1. Overall survival of Hodgkin lymphoma subcohort (N= 1,088) randomly sampled from a cohort of 3,964 patients treated in Ontario 1988-2003.

9. 15-Year Incidence of Cardiac Hospitalization by Treatment Age at HL Dx Table 2. The 15-year cumulative incidence of cardiac hospitalizations among HL patients and age- and sex- matched general population. The risk is higher among males, older patients, and patients receiving both doxorubicin and mediastinal RT. The incidence among patients receiving doxorubicin alone is not significantly different than the risk among those receiving mediastinal RT alone.

10. General population Figure 2. Cumulative incidence of cardiac hospitalization among patients treated at age 40 years (A, females; B, males). All HL treatment groups have a significantly higher incidence than the age- and sex- matched general population. There difference between doxorubicin alone and mediastinal RT alone was not significantly different.

11. General population

12. Multivariable Analysis (Ontario Population as Referent) <0.001 Table 3. Multivariable model of patient and treatment factors associated with the risk of cardiac morbidity. Adding interaction terms exploring possible multiplicative synergy between doxorubicin and mediastinal RT were not significant.

13. Other Findings Few patients did not have some exposure to cardiotoxic agents: –“Other” chemotherapy was also cardiotoxic –“Other” RT was not (but few patients received this alone) Interaction terms exploring synergystic activity of RT + doxorubicin were not significant. Other cardiac risk factors (smoking, hypertension, elevated cholesterol) were significant predictors in analysis of subcohort alone without general population (HR = 1.62, p=0.04)

14. Conclusions Both Mediastinal RT and doxorubicin-based chemotherapy appear to increase the risk of delayed cardiac morbidity. –Combined doxorubicin + mediastinal RT has highest risk –MI, ischemic heart disease most common reason for admission Males, older age (>30 years at HL Dx), and those with other cardiac risk factors at greatest absolute risk. –Ongoing work to help identify survivors who may benefit most from cardiac screening (i.e. stress echo).

15. Conclusions (con’t) Results support the rationale for ongoing trials using involved node RT (INRT), which may reduce cardiac dose in patients requiring mediastinal RT. Dose-risk relationship between doxorubicin/RT dose and long-term risk is being investigated.

16. Acknowledgements Canadian Institutes of Health Research Cancer Centres and local collaborators Sameera Ahmed Conchita Bulos Adrianne Hasler Krystyna Tybinkowski Linda Dignem