Comparison of Outcomes By Age of Patients with Limited Stage Hodgkin Lymphoma Treated with ABVD Alone; A Secondary Analysis of the Canadian Cancer Trial Group HD.6 Trial

Introduction: Management options for individuals with early-stage Hodgkin lymphoma (HL) include combined modality therapy (CMT), and chemotherapy alone. The HD.6 randomized phase III trial, in which ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) alone was compared with radiation based therapy, comprises the largest prospectively collected data set of individuals with limited stage HL treated with ABVD alone with long-term follow-up [Meyer JCO 2005, NEJM 2012]. Adolescents and young adults (AYAs) with cancer are considered a vulnerable population, in part due to unique psychosocial challenges and distinct disease biology. The most common cancer observed among AYAs is HL. However, studies focusing specifically on AYAs diagnosed with limited stage HL are scarce. We sought to evaluate the impact of age on outcomes of individuals with stage IA and IIA non-bulky HL, treated with ABVD alone.

Methods: Individuals randomly assigned to ABVD chemotherapy alone on the HD.6 clinical trial formed the study population for this secondary analysis. The Kaplan-Meier life-table method was used to calculate the rates of overall survival (OS), event free survival (EFS) and freedom from disease progression (FFDP) defined as in the original trial. The primary analysis used univariate and multivariate Cox regression models with age included as a continuous variable. The following covariates were used in the multivariate analysis: age, gender, ECOG performance status (0-1 vs. ≥ 2), stage, erythrocyte sedimentation rate (ESR, < 50 vs. ≥ 50), number of nodal sites (< 4 vs. ≥ 4), white blood count, hemoglobin and lymphocyte count. Secondarily outcomes of AYAs, defined as those aged <30, and older adults aged >30 years old were compared with the use of the log-rank test for time to event endpoints and Chi-squared test for response rates, acute toxicity and chemotherapy administration. All analyses were based on the locked data base of July 15, 2011.

Results: Of 196 eligible patients assigned to ABVD alone, median age was 34 years (range 17 to 68), 106 (54%) were male and 76 (38.8%) were <30 years of age. Nodular sclerosing histology was more common in those < 30 (77.6% vs. 68.0%) while mixed cellularity was more common in the cohort ≥ 30 (23.3% vs. 17.1%).The median length of follow-up was 11 years. Univariate analysis of age as continuous variable was statistically significant for OS (HR 1.09; 95% CI 1.04 to 1.14; p = 0.0001) and EFS (HR 1.04; 95% CI 1.02 to 1.07; p = 0.0017) but not for FFDP (HR 1.02; 95% CI 0.99 to 1.05; p = 0.22) The significance of age as a continuous variable for OS and EFS was confirmed in the multivariate analysis (HR 1.09; 95% CI 1.04 to 1.14; p = 0.0001, and HR 1.03; 95% CI, 1.01 to 1.06; p = 0.007 respectively). When comparing those aged < 30 with those aged ≥ 30 years, there was no statistical difference in 12 year OS (96% vs. 93%; HR 1.89; 95% CI 0.51 to 7.01; p = 0.32), EFS (89% vs. 83%, HR 1.63; 95% CI 0.72 to 3.68; p = 0.23) or FFDP (89% vs. 86%, HR 1.23; 95% CI 0.52 to 2.87; p = 0.63). All three deaths (100%) in those under 30 were due to Hodgkin lymphoma (two disease progression and one non-protocol treatment complications). In those over 30 only three (33.3%) of the nine deaths were attributed to HL (one disease progression, one early treatment related toxicity and one non-protocol treatment complication); the remainder were due to second malignancy (4) and cardiovascular disease (2). The majority of deaths (8/12, 67%) occurred in those > 60 years at study enrolment and > 65 years at death. There was no statistical difference in overall response rates (62/76, 81.6% vs. 97/120 80.8%), acute grade 3 and 4 toxicities, or chemotherapy administration between those aged under 30, or over 30 years.

Conclusions : In this randomized phase III trial of individuals with limited stage Hodgkin lymphoma, clinical outcomes of AYAs were comparable with those of adults in middle age. However, deaths were most prominent in older patients > 60 years at the time of diagnosis and predominantly from causes other than Hodgkin lymphoma, explaining the impact of age as a continuous variable on survival but not disease progression.