title: Prognostic significance of maximum tumour (bulk) diameter in young patients with good-prognosis diffuse large-B-cell lymphoma treated with CHOP-like chemotherapy with or without rituximab: an exploratory analysis of the MabThera International Trial Group (MInT) study.
abstract: BACKGROUND
  The definition and role of bulky disease in young patients (ie, aged 18-60 years) with good-prognosis diffuse large-B-cell lymphoma (DLBCL), who have been treated with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone)-like chemotherapy with or without rituximab, remain controversial. We aimed to assess the effect of maximum tumour diameter (MTD) in these patients.
  
  
  METHODS
  Patients from the MInT (Mabthera International Trial Group) study were eligible. We analysed event-free (EFS) and overall survival (OS) after CHOP-like chemotherapy with or without rituximab, according to MTD, by Martingale residual analyses and Cox regression models. Radiotherapy was given to sites of primary bulky disease according to national standards, and to primary extranodal disease at physician discretion. The primary endpoint was EFS and the secondary endpoint was OS. Analyses were by intention to treat.
  
  
  RESULTS
  Of the 824 patients enrolled in the MInT study, the informed-consent form of one patient was missing, leaving 823 patients evaluable for intention-to-treat analysis. Data on MTD of involved sites were available for 802 patients. Martingale residual analysis showed an adverse prognostic effect of MTD on EFS and OS, which increased linearly. In a multivariable analysis with MTD as a linear regression variable, the effect of MTD was significant after CHOP-like treatment alone for EFS (hazard ratio 1.090 [95% CI 1.051-1.130], p < 0.0001) and OS (1.119 [1.057-1.184], p = 0.0001), and after CHOP-like treatment and rituximab for OS (1.089 [1.003-1.183], p = 0.043), but not for EFS (1.044 [0.991-1.099], p=0.103). For CHOP-like treatment alone, 3-year EFS ranged from 78.2% (MTD < 5.0 cm, 95% CI 68.3-85.4) to 41.3% (MTD > or = 10.0 cm, 31.8-50.4). For CHOP-like treatment and rituximab, 3-year EFS ranged from 83.2% (MTD < 5.0 cm, 72.8-89.9) to 72.7% (MTD > or = 10.0 cm, 63.8-79.7). With CHOP-like treatment alone, 3-year OS decreased from 92.9% (MTD < 5.0 cm, 84.9-96.8) to 73.5% (MTD > or = 10.0 cm, 63.9-81.0); for CHOP-like treatment and rituximab, 3-year OS decreased from 98.0% (MTD < 5.0 cm, 92.2-99.5) to 85.2% (MTD > or = 10.0 cm, 77.0-90.6). For CHOP-like treatment, any cut-off point between 5.0 cm and 10.0 cm separated two populations with a significant EFS difference (p < 0.0001 for all log-rank tests) and OS difference (p < or = 0.003 for all log-rank tests). For CHOP-like treatment and rituximab, only a cut-off point of 10.0 cm separated two populations with a significant EFS difference (log-rank p = 0.047), but any cut-off point of 6.0 cm or more separated two populations with a significant OS difference (log-rank p values 0.0009-0.037).
  
  
  CONCLUSIONS
  Rituximab decreased, but did not eliminate the adverse prognostic effect of MTD in young patients with good-prognosis DLBCL. Due to the linear prognostic effect of MTD on outcome, arbitrary cut-off points for bulky disease can be set between 5.0 cm and 10.0 cm, depending on clinical considerations. Based on this study, a cut-off point of 10.0 cm might be a suitable margin in the rituximab era to delineate those patients with bulky disease.
authors.affiliation: Saarland University Medical School, Homburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Pfreundschuh
authors.forename: Anthony D
authors.initials: AD
authors.lastname: Ho
authors.forename: Eva
authors.initials: E
authors.lastname: Cavallin-Stahl
authors.forename: Max
authors.initials: M
authors.lastname: Wolf
authors.forename: Ruth
authors.initials: R
authors.lastname: Pettengell
authors.forename: Ingrid
authors.initials: I
authors.lastname: Vasova
authors.forename: Andrew
authors.initials: A
authors.lastname: Belch
authors.forename: Jan
authors.initials: J
authors.lastname: Walewski
authors.forename: Pier-Luigi
authors.initials: PL
authors.lastname: Zinzani
authors.forename: Walter
authors.initials: W
authors.lastname: Mingrone
authors.forename: Stein
authors.initials: S
authors.lastname: Kvaloy
authors.forename: Ofer
authors.initials: O
authors.lastname: Shpilberg
authors.forename: Ulrich
authors.initials: U
authors.lastname: Jaeger
authors.forename: Mads
authors.initials: M
authors.lastname: Hansen
authors.forename: Claudia
authors.initials: C
authors.lastname: Corrado
authors.forename: Adriana
authors.initials: A
authors.lastname: Scheliga
authors.forename: Markus
authors.initials: M
authors.lastname: Loeffler
authors.forename: Evelyn
authors.initials: E
authors.lastname: Kuhnt
mesh_terms: D000328:Adult; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D058846:Antibodies, Monoclonal, Murine-Derived; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D003520:Cyclophosphamide / Q000008:administration & dosage; D018572:Disease-Free Survival; D004317:Doxorubicin / Q000008:administration & dosage; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology / Q000532:radiotherapy; D008875:Middle Aged; D009367:Neoplasm Staging; D018579:Patient Selection; D011241:Prednisone / Q000008:administration & dosage; D011379:Prognosis; D016016:Proportional Hazards Models; D018714:Radiotherapy, Adjuvant; D018570:Risk Assessment; D000069283:Rituximab; D013997:Time Factors; D016896:Treatment Outcome; D014750:Vincristine / Q000008:administration & dosage
chemical_list: D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone