Shunan Qi1,2, Sarah Milgrom3, Bouthaina Dabaja,3, Richard Tsang4, Mario Levis5, Umberto Ricardi5, Eldad J. Dann6, Rebecca Lopez-Alonso, Andrea Ng7, Joachim Yahalom1
1Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA,2Department of Radiation Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China,3Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA,4Department of Radiation Oncology and Biostatistics, Princess Margaret Hospital, University Health Network, University of Toronto, Toronto, Canada,5Department of Oncology, Radiation Oncology, University of Torino, Torino, Italy,6Department of Hematology and Bone Marrow Transplantation, Rambam Medical Center, Haifa, Israel,7Department of Radiation Oncology, Brigham and Women‘s Hospital, Boston, MA, USA
Purpose: Controversy exists regarding the definition and prognostic significance of bulk in advanced-stage Hodgkin lymphoma (ASHL); bulk location (mediastinum vs. other sites) maybe also of relevance. This retrospective, multi-institutional study aimed to evaluate the significance of bulk in ASHL.
Patients and methods: The complete study cohort comprised 814 ASHL (stage III/IV) patients, divided into an exploratory cohort of 683 patients treated at 5 centers between 2000 to 2010 and a validation cohort of 131 patients treated at a 6th center. Endpoints of interest included progression-free survival (PFS) and overall survival (OS). Covariates included the greatest transverse diameter of the largest mass and the site of bulky disease. SmoothHR and Kaplan-Meier analyses were used to assess for an association of PFS and OS with covariates.
Results: In the exploratory cohort (n = 683), 533 patients (78%) received chemotherapy alone. The most common chemotherapy regimen was doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD; 78% of cases). Based on SmoothHR analysis, Maximum diameter had no association with PFS and a complex, U-shaped association with all-cause mortality (Fig 1A). Using 5 cm as a cut-off for bulk, Kaplan-Meier analyses confirmed the smoothHR results, with no significant difference in PFS between the two groups and significantly better OS in the group with bulk ≥5 cm (figure 1B). The site of bulk was incorporated to divide patients into 2 groups: Mediastinal Bulk (MB)-type, defined by the presence of bulky mediastinal disease (≥5 cm) with/without bulk at another site, and Non-Bulky/Non-Mediastinal Bulk (NB/NMB)-type. The MB-type had more favorable characteristics than the NB/NMB-type, including younger age, more frequent nodular sclerosis (NS) histology, and less frequent bone marrow involvement (P < 0.001, Fig 1C). The MB-type was associated with better OS than the NB/NMB-type on univariable analysis (5-year OS 92% vs. 86%, Fig 1D; hazard ratio, 0.53; 95% CI, 0.34 to 0.84; P = 0.007). These findings persisted in the subgroup treated with chemotherapy alone and were confirmed in an independent validation cohort.
Conclusion: In ASHL, maximum tumor diameter showed no significant association with PFS, but a complex association with OS reflected by a U-shaped logarithmic HR curve. Mediastinal bulk was associated with more favorable disease characteristics and improved OS. Mediastinal bulk in ASHL may be a surrogate of a more favorable biology.