Impact of Competing Treatment Scenarios on Lifetime Disease Burden and Quality Adjusted Life Expectancy (QALE) Among Survivors of High-Risk Childhood Hodgkin Lymphoma (HR-HL): A Modeling Study Based on the St. Jude Lifetime (SJLIFE) Cohort
Authors: Bhakta Nickhill , Davies Kalatu , Turner Jesse , Chen Yichen , Flerlage Jaime , Huang I-Chan , Hudson Melissa M. , Lucas John T. , Metzger Monika , Robison Leslie L. , Wong F. Lennie 
Published: February 2020

Background: Children and young adults diagnosed with HR-HL have a 5-year survival rate of &gt;95%. Yet, as compared to the general population, survivors remain at elevated risk for therapy-related early mortality and excess long-term morbidity. Second malignancies (SMNs), cardiac disease, and pulmonary complications are major contributors to excess mortality/morbidity experienced by survivors of HL. Since several treatment regimens used for younger HR-HL all offer excellent overall survival and tolerable short-term morbidity profiles, it is not clear which is best. The objective of this study was to compare the life-long impact of treatment-related toxicity and early mortality associated with 4 common treatment scenarios used to treat HR-HL. Outcomes measured included overall life expectancy (LE), 10-year post-diagnosis QALE and cause of death.
Methods: A microsimulation model was developed using the lifetime horizon for a cohort of 10-year survivors of HR-HL treated with 4 common treatment scenarios utilized by pediatric and adult oncology groups. The data from 5522 adult 10-year survivors of childhood cancers in the SJLIFE cohort (56% males; mean age at last follow-up=35.3 years [y], range 18.9-67.9; ≥18y at study enrollment) was used to estimate the mortality risk and incidence of cardiac and pulmonary complications and SMNs as functions of age at primary cancer diagnosis, attained age, sex, race, and treatment exposures including cumulative doses of anthracyclines, alkylating agents, and bleomycin plus radiation dose to the heart and chest. Prospective and retrospective clinical assessments were used to obtain and grade late-effect outcomes using a modified Common Terminology Criteria for Adverse Events. Rates from population-based registries and published systematic analyses were used for background mortality, mortality risk from the complications and for extrapolation. Calibration was performed against SJLIFE data to ensure model consistency. Quality of life utility weights (ranging from 1 for perfect health to 0 for dead) associated with complications were estimated from the SJLIFE cohort. The mortality and incidence functions and utility weights were applied to the lifetime of 10,000 simulated HL survivors (same demographic distribution as in the 667 SJLIFE HL participants: 58% males; mean age at HL diagnosis=13.9y, range 3-25) starting at 10y after HL diagnosis to death to calculate the average LE and QALE associated with the 4 treatment scenarios.
Results: The figure shows the results for 4 scenarios based on OEPA [vincristine, etoposide, prednisone, doxorubicin] (2 cycles) plus COPDac [cyclophosphamide, vincristine, prednisone, dacarbazine] (4 cycles) and ABVD [doxorubicin, bleomycin, vincristine, dacarbazine] (6 cycles), both with and without heart and chest radiation. The average LE for the cohort assuming general population mortality risk is 80.8y (dashed line). Average LEs associated with the 4 scenarios are represented by the asterix above each bar. The average 10-year post-diagnosis QALE and the proportion of time spent living with cardiac, pulmonary and/or SMN are depicted in the colored stacked bar-chart. The decrement in average LE due to treatment for HR-HL ranged from 12.8y for OEPA/COPDac alone to 25.8y for ABVD with radiation. OEPA/COPDac based regimens without and with radiation had higher average LE (68.1y and 64.1y, respectively) and QALE (29.9y and 27.4y, respectively) compared to the ABVD regimens (LE: 60.9y and 55.0y; QALE: 25.0y and 22.7y). The addition of radiation reduced average LE and QALE in both the OEPA/COPDac (4.0y and 2.5y) and ABVD (5.8y and 2.3y) regimens and increased the proportion of the cohort who developed pulmonary disease and SMNs for all scenarios. The cohort receiving OEPA/COPDac with radiation had similar average post-10 year QALE compared to those treated with ABVD without radiation. Increased proportional mortality due to SMN was observed among the cohort exposed to ABVD.
Conclusion: Using a lifetime horizon simulation approach, we demonstrate that the OEPA/COPDac regimen results in greater average LE and QALE when compared against ABVD for HR-HL. This approach highlights a yet untapped opportunity to leverage data from survivorship cohorts by evaluating late-effect trade-offs to inform clinical trial design and aid patient decision-making when choosing between different treatment options that have similar efficacy.

Disclosures
No relevant conflicts of interest to declare.