Maximum tumor diameter is associated with relapse risk in limited-stage Hodgkin lymphoma: an international study

Tumor bulk is an established prognostic factor in Hodgkin lymphoma (HL), but most patients with limited-stage (LS) HL do not have "bulk" by standard definitions. In the RAPID trial, maximum tumor diameter (MTD) was associated with relapse risk in LS-HL patients achieving positron emission tomography negativity (PET-) after doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). We aimed to externally validate these findings in the H10 trial. Stage I/IIA HL patients, without mediastinal bulk, who achieved PET- with ABVD were included. Patients received 3 ABVD plus radiotherapy (n = 208) or 3 ABVD alone (n = 211) in RAPID, and 3 to 4 ABVD plus radiotherapy (n = 556) or 4 to 6 ABVD alone (n = 303) in H10. MTD was strongly associated with event-free survival (relapse or HL-related death) in H10 (hazard ratio [HR], 1.22; 95% confidence interval [CI], 1.07-1.38; P = .003), a similar effect to that seen in RAPID (HR, 1.19; 95% CI, 1.02-1.39; P = .02), giving an estimated 21% risk increase per centimeter MTD (HRpooled, 1.21; 95% CI, 1.09-1.33; P < .001). Effect sizes were similar for patients treated with ABVD alone and ABVD plus radiotherapy, with no differential effect (pinteraction = 0.97). Treatment modality and MTD were independent risk factors; patients with higher MTD receiving chemotherapy alone had the greatest relapse risk. This international validation study confirms MTD is strongly associated with relapse risk in patients with LS-HL achieving PET- and informs decision-making around risk-adapted application of radiotherapy. The trials were registered at www.clinicaltrials.gov as #NCT00943423 and #NCT00433433.