Cardiotoxicity with rituximab, cyclophosphamide, non-pegylated liposomal doxorubicin, vincristine and prednisolone compared to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone in frontline treatment of patients with diffuse large B-cell lymphoma: A randomised phase-III study from the Austrian Cancer Drug Therapy Working Group [Arbeitsgemeinschaft Medikamentöse Tumortherapie AGMT](NHL-14)

Eur J Cancer. 2016 May;58:112-21. doi: 10.1016/j.ejca.2016.02.004. Epub 2016 Mar 15.


Background: Chemoimmunotherapy containing rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) is the standard treatment for diffuse large B-cell lymphoma (DLBCL). Doxorubicin may induce early and late cardiotoxicity. Non-pegylated liposomal (NPL) doxorubicin may reduce cardiotoxicity.

Patients and methods: Patients with untreated CD20+ DLBCL were randomised to conventional R-CHOP chemoimmunotherapy or rituximab, cyclophosphamide, non-pegylated liposomal doxorubicin, vincristine and prednisolone (R-COMP) with doxorubicin substituted by NPL-doxorubicin. Left ventricular ejection fraction (LVEF) and N-terminal pro B-type natriuretic peptide (NT-proBNP) levels were measured before each treatment cycle and after the end of treatment.

Results: The mean LVEF of 178 and 158 measurements in the R-COMP and R-CHOP arms was 63.31% and 62.25%, respectively (P = 0.167). During treatment the LVEF measurements were below 50% in 10/218 (4.6%) in the R-COMP arm and 31/196 (15.8%) in the R-CHOP arm (P<0.001). Thirty-six of 40 (90%) patients in the R-COMP arm, but only 24/36 (66.7%) in the R-CHOP arm had all NT-proBNP levels below 400 pg/ml during and at the end of treatment (P = 0.013). There were more serious adverse events in the R-CHOP arm (26 versus 40, P = 0.029). Infections were more common (15 versus 28) in the R-CHOP arm.

Interpretation: In patients with normal cardiac function, six cycles of R-CHOP resulted in a low rate of early cardiotoxicity. NPL-doxorubicin did not reduce cardiotoxicity, although cardiac safety signals were elevated in R-CHOP compared to R-COMP.

Funding: Cephalon provided the Arbeitsgemeinschaft Medikamentöse Tumortherapie with NPL-doxorubicin and an unrestricted grant, but was not involved in the study protocol, data acquisition, data analysis or the writing of the paper.

Keywords: Cardiotoxicity; Chemotherapy; Diffuse large B-cell lymphoma.

Publication types

  • Clinical Trial, Phase III
  • Comparative Study
  • Multicenter Study
  • Randomized Controlled Trial

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects*
  • Austria
  • Biomarkers / blood
  • Cyclophosphamide / adverse effects*
  • Disease Progression
  • Disease-Free Survival
  • Doxorubicin / adverse effects
  • Doxorubicin / analogs & derivatives*
  • Female
  • Heart Diseases / blood
  • Heart Diseases / chemically induced*
  • Heart Diseases / diagnosis
  • Heart Diseases / physiopathology
  • Humans
  • Lymphoma, Large B-Cell, Diffuse / drug therapy*
  • Male
  • Middle Aged
  • Natriuretic Peptide, Brain / blood
  • Peptide Fragments / blood
  • Polyethylene Glycols / adverse effects
  • Prednisolone / adverse effects*
  • Proportional Hazards Models
  • Remission Induction
  • Risk Factors
  • Rituximab / adverse effects*
  • Stroke Volume / drug effects
  • Time Factors
  • Treatment Outcome
  • Ventricular Function, Left / drug effects
  • Vincristine / adverse effects*
  • Young Adult


  • Biomarkers
  • Peptide Fragments
  • liposomal doxorubicin
  • pro-brain natriuretic peptide (1-76)
  • Natriuretic Peptide, Brain
  • Polyethylene Glycols
  • Rituximab
  • Vincristine
  • Doxorubicin
  • Cyclophosphamide
  • Prednisolone