Maximum Tumor Diameter is Associated with Relapse Risk in Limited-Stage Hodgkin Lymphoma: An International Study

Tumour bulk is an established prognostic factor in Hodgkin lymphoma (HL) but most patients with limited-stage (LS) HL do not have 'bulk' by standard binary definitions. In the RAPID trial, maximum tumor diameter (MTD) was associated with risk of relapse for LS-HL patients achieving PET-negativity after ABVD chemotherapy. We aimed to externally validate these findings in the H10 trial. Patients with stage I/IIA HL, without mediastinal bulk, who achieved PET-negativity with ABVD were included. 'PET-negative' patients received 3x ABVD plus radiotherapy (n=208) or 3x ABVD alone (n=211) in RAPID, and 3-4x ABVD plus radiotherapy (n=556) or 4-6x ABVD alone (n=303) in H10. Baseline MTD was measured by CT. MTD was strongly associated with event-free survival (relapse or HL-related death) in H10 (HR=1.22, 95%CI:1.07-1.38, p=0.003), a similar effect to the RAPID trial (HR=1.19, 95%CI:1.02-1.39, p=0.02), giving an estimated 21% increase in HL-risk per centimetre MTD (HRpooled=1.21, 95%CI:1.09-1.33, p<0.001). Findings were consistent when adjusting for baseline risk stratification and chemotherapy cycles. The effect sizes were similar for patients treated with chemotherapy alone (HRpooled=1.19, 95%CI:1.01-1.35, p=0.005) and combined modality treatment (ABVD plus radiotherapy; HRpooled=1.24, 95%CI:1.05-1.46, p=0.009) with no evidence of a differential effect (pinteraction=0.97). Treatment modality and MTD were independent risk factors; patients with higher MTD receiving chemotherapy alone had the greatest risk of relapse. This international validation study confirms that MTD is strongly associated with the risk of relapse for LS-HL patients achieving PET-negativity. These findings refine assessment of risk in LS-HL and can inform clinical discussions for risk-adapted application of radiotherapy. NCT00943423 and NCT00433433.