Radiotherapy Overcomes Adverse Prognostic Role Of COX-2 Expression On Reed-Sternberg Cells In Early Hodgkin Lymphoma
Authors: Gutierrez Antonio , Francesc Mestre , Rodriguez Jose , Martinez-serra Jordi , Ramos Rafael , Herraez Ines , Bautista-Gili Antonia M , Bento Leyre , Garcia Lucia , Gines Jordi , Ros Teresa , Perez Albert , Lopez-Perezagua Paloma , Daumal Jaime , Besalduch Juan 
Published: October 2019

Abstract

Background
Cyclooxygenase-2 (COX-2) is an inflammatory enzyme involved in the pathogenesis and prognostic of Hodgkin lymphoma. We previously reported that expression of COX-2 on Reed-Sternberg cell is a major independent, unfavorable prognostic factor in patients with early Hodgkin lymphoma treated with ABVD (Blood 2012; 119: 6072). The relationship between COX-2 expression and poor prognosis has been associated with pathogenic phenomena such as induction of angiogenesis, chemoresistance through induction of antiapoptotic mechanisms such as up-regulation of bcl-2 or resistance to Fas, or promotion of invasion through induction of some metalloproteinases. As patients in our series were treated with ABVD +/- radiotherapy, we aim to analyze the role of radiotherapy on the adverse prognostic factor of COX-2 RS expression.

Methods
In the present study, we investigated the prognostic value of COX-2 expression in a large (N = 143), uniformly treated early Hodgkin Iymphoma (HL) population from the Spanish Network of HL using tissue microarrays. Univariate and multivariate analysis was done, including the most recognized clinical variables and the potential role of administration of adjuvant radiotherapy.

Results
Median age was 31 years; there was B-symptoms or bulky disease in 30% of patients; ECOG PS > 1 in 6%, EORTC score > 1 in 84% and 66% received radiotherapy. The expression of COX-2 defined a subgroup with significantly worse prognosis. Accordingly, the 46 (32%) COX-2+ patients had a PFS at 5 years of 72% versus 86% of COX-2- patients (P = .017). Similarly, the OS at 5 years also differed for both groups, with 82% and 94% for COX-2+ and COX-2-, respectively (P = .004). By multivariate analysis, COX-2 expression (HR = 2.76), B symptoms (HR = 2.34), and administration of RT (HR = 0.32) were independently associated with PFS, whereas only ECOG PS (HR = 9) and COX-2 RS expression (HR = 4.81) were independently associated with OS.
Considering patients COX-2+, those that received RT had a significantly better 5y-PFS (80% versus 54% if no RT; p = .008). In contrast, COX-2- patients only had a modest non-significant benefit from RT in terms of 5y-PFS (90% versus 79%; p=0.13). When compared the outcome of patients receiving RT considering the expression of COX-2 on RS we found a non-significant 10% difference in terms of PFS between COX-2+ and COX-2- patients (p=0.09) while this difference between the two groups was important (25%) in patients non receiving RT (p=0.04).

Conclusions
COX-2 RS expression is an adverse independent prognostic factor in early HL. Radiotherapy overcome the worse prognosis associated to COX-2 expression on RS acting in a chemotherapy-independent way. COX-2 RS expression may be useful to determine patients with early HL candidates to receive consolidation with RT.

Disclosures:
No relevant conflicts of interest to declare.