title: 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).
abstract: 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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  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.
authors.affiliation: Department of Internal Medicine 3 - Hematology and Oncology, Kepler University Hospital, Johannes Kepler University, Linz, Austria. Electronic address: michael.fridrik@akh.linz.at.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Fridrik
authors.affiliation: Medical University Vienna, Department of Medicine I, Hematology and Hemostaseology, Austria.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Jaeger
authors.affiliation: Barmherzige Schwestern Hospital Linz, Department of Medical Oncology, Hematology and Gastroenterology, Austria.
authors.forename: Andreas
authors.initials: A
authors.lastname: Petzer
authors.affiliation: University of Innsbruck, Internal Medicine V: Hematology-Oncology, Austria.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Willenbacher
authors.affiliation: Hanusch Hospital Vienna, Department of Medicine III: Hematology Oncology, Austria.
authors.forename: Felix
authors.initials: F
authors.lastname: Keil
authors.affiliation: LKH Feldkirch, Department of Internal Medicine, Austria.
authors.forename: Alois
authors.initials: A
authors.lastname: Lang
authors.affiliation: LKH Steyr, Department of Internal Medicine II, Austria.
authors.forename: Johannes
authors.initials: J
authors.lastname: Andel
authors.affiliation: Klinikum Wels-Grieskirchen, Department of Internal Medicine IV, Austria.
authors.forename: Sonja
authors.initials: S
authors.lastname: Burgstaller
authors.affiliation: Elisabethinen Hospital Linz, Department of Internal Medicine I, Austria.
authors.forename: Otto
authors.initials: O
authors.lastname: Krieger
authors.affiliation: TILAK, Clinical Epidemiology, Austria.
authors.forename: Willi
authors.initials: W
authors.lastname: Oberaigner
authors.affiliation: AKH Linz, Department of Internal Medicine I, Austria.
authors.forename: Kurt
authors.initials: K
authors.lastname: Sihorsch
authors.affiliation: Paracelsus University Hospital, Salzburg, Department of Medicine III, Austria.
authors.forename: Richard
authors.initials: R
authors.lastname: Greil
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects*; D001317:Austria; D015415:Biomarkers / Q000097:blood; D003520:Cyclophosphamide / Q000009:adverse effects*; D018450:Disease Progression; D018572:Disease-Free Survival; D004317:Doxorubicin / Q000009:adverse effects / Q000031:analogs & derivatives*; D005260:Female; D006331:Heart Diseases / Q000097:blood / Q000139:chemically induced* / Q000175:diagnosis / Q000503:physiopathology; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D020097:Natriuretic Peptide, Brain / Q000097:blood; D010446:Peptide Fragments / Q000097:blood; D011092:Polyethylene Glycols / Q000009:adverse effects; D011239:Prednisolone / Q000009:adverse effects*; D016016:Proportional Hazards Models; D012074:Remission Induction; D012307:Risk Factors; D000069283:Rituximab / Q000009:adverse effects*; D013318:Stroke Volume / Q000187:drug effects; D013997:Time Factors; D016896:Treatment Outcome; D016277:Ventricular Function, Left / Q000187:drug effects; D014750:Vincristine / Q000009:adverse effects*; D055815:Young Adult
chemical_list: D015415:Biomarkers; D010446:Peptide Fragments; C506643:liposomal doxorubicin; C109794:pro-brain natriuretic peptide (1-76); D020097:Natriuretic Peptide, Brain; D011092:Polyethylene Glycols; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011239:Prednisolone
keywords: Cardiotoxicity; Chemotherapy; Diffuse large B-cell lymphoma