title: Six versus eight cycles of bi-weekly CHOP-14 with or without rituximab in elderly patients with aggressive CD20+ B-cell lymphomas: a randomised controlled trial (RICOVER-60).
abstract: BACKGROUND
  Cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) is used to treat patients with non-Hodgkin lymphoma. Interval decrease from 3 weeks of treatment (CHOP-21) to 2 weeks (CHOP-14), and addition of rituximab to CHOP-21 (R-CHOP-21) has been shown to improve outcome in elderly patients with diffuse large B-cell lymphoma (DLBCL). This randomised trial assessed whether six or eight cycles of R-CHOP-14 can improve outcome of these patients compared with six or eight cycles of CHOP-14.
  
  
  METHODS
  1222 elderly patients (aged 61-80 years) were randomly assigned to six or eight cycles of CHOP-14 with or without rituximab. Radiotherapy was planned to sites of initial bulky disease with or without extranodal involvement. The primary endpoint was event-free survival; secondary endpoints were response, progression during treatment, progression-free survival, overall survival, and frequency of toxic effects. Analyses were done by intention to treat. The trial is registered on National Cancer Institute website, number NCT00052936 and as EU-20243.
  
  
  RESULTS
  3-year event-free survival was 47.2% after six cycles of CHOP-14 (95% CI 41.2-53.3), 53.0% (47.0-59.1) after eight cycles of CHOP-14, 66.5% (60.9-72.0) after six cycles of R-CHOP-14, and 63.1% (57.4-68.8) after eight cycles of R-CHOP-14. Compared with six cycles of CHOP-14, the improvement in 3-year event-free survival was 5.8% (-2.8-14.4) for eight cycles of CHOP-14, 19.3% (11.1-27.5) for six cycles of R-CHOP-14, and 15.9% (7.6-24.2) for eight cycles of R-CHOP-14. 3-year overall survival was 67.7% (62.0-73.5) for six cycles of CHOP-14, 66.0% (60.1-71.9) for eight cycles of CHOP-14, 78.1% (73.2-83.0) for six cycles of R-CHOP-14, and 72.5% (67.1-77.9) for eight cycles of R-CHOP-14. Compared with treatment with six cycles of CHOP-14, overall survival improved by -1.7% (-10.0-6.6) after eight cycles of CHOP-14, 10.4% (2.8-18.0) after six cycles of R-CHOP-14, and 4.8% (-3.1-12.7) after eight cycles of R-CHOP-14. In a multivariate analysis that used six cycles of CHOP-14 without rituximab as the reference, and adjusting for known prognostic factors, all three intensified regimens improved 3-year event-free survival (eight cycles of CHOP-14: RR [relative risk] 0.76 [0.60-0.95], p=0.0172; six cycles of R-CHOP-14: RR 0.51 [0.40-0.65], p<0.0001; eight cycles of R-CHOP-14: RR 0.54 [0.43-0.69], p<0.0001). Progression-free survival improved after six cycles of R-CHOP-14 (RR 0.50 [0.38-0.67], p<0.0001), and eight cycles of R-CHOP-14 (RR 0.59 [0.45-0.77], p=0.0001). Overall survival improved only after six cycles of R-CHOP-14 (RR 0.63 [0.46-0.85], p=0.0031). In patients with a partial response after four cycles of chemotherapy, eight cycles were not better than six cycles.
  
  
  CONCLUSIONS
  Six cycles of R-CHOP-14 significantly improved event-free, progression-free, and overall survival over six cycles of CHOP-14 treatment. Response-adapted addition of chemotherapy beyond six cycles, though widely practiced, is not justified. Of the four regimens assessed in this study, six cycles of R-CHOP-14 is the preferred treatment for elderly patients, with which other approaches should be compared.
authors.affiliation: Internal Medicine, Saarland University Medical School, Saarland University, Homburg, Germany. inmpfr@uniklinikum-saarland.de
authors.forename: Michael
authors.initials: M
authors.lastname: Pfreundschuh
authors.forename: Joerg
authors.initials: J
authors.lastname: Schubert
authors.forename: Marita
authors.initials: M
authors.lastname: Ziepert
authors.forename: Rudolf
authors.initials: R
authors.lastname: Schmits
authors.forename: Martin
authors.initials: M
authors.lastname: Mohren
authors.forename: Eva
authors.initials: E
authors.lastname: Lengfelder
authors.forename: Marcel
authors.initials: M
authors.lastname: Reiser
authors.forename: Christina
authors.initials: C
authors.lastname: Nickenig
authors.forename: Michael
authors.initials: M
authors.lastname: Clemens
authors.forename: Norma
authors.initials: N
authors.lastname: Peter
authors.forename: Carsten
authors.initials: C
authors.lastname: Bokemeyer
authors.forename: Hartmut
authors.initials: H
authors.lastname: Eimermacher
authors.forename: Anthony
authors.initials: A
authors.lastname: Ho
authors.forename: Martin
authors.initials: M
authors.lastname: Hoffmann
authors.forename: Roland
authors.initials: R
authors.lastname: Mertelsmann
authors.forename: Lorenz
authors.initials: L
authors.lastname: Trümper
authors.forename: Leopold
authors.initials: L
authors.lastname: Balleisen
authors.forename: Ruediger
authors.initials: R
authors.lastname: Liersch
authors.forename: Bernd
authors.initials: B
authors.lastname: Metzner
authors.forename: Frank
authors.initials: F
authors.lastname: Hartmann
authors.forename: Bertram
authors.initials: B
authors.lastname: Glass
authors.forename: Viola
authors.initials: V
authors.lastname: Poeschel
authors.forename: Norbert
authors.initials: N
authors.lastname: Schmitz
authors.forename: Christian
authors.initials: C
authors.lastname: Ruebe
authors.forename: Alfred C
authors.initials: AC
authors.lastname: Feller
authors.forename: Markus
authors.initials: M
authors.lastname: Loeffler
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D058846:Antibodies, Monoclonal, Murine-Derived; D015703:Antigens, CD / Q000276:immunology; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D003520:Cyclophosphamide / Q000008:administration & dosage; D004317:Doxorubicin / Q000008:administration & dosage; D004334:Drug Administration Schedule; D006801:Humans; D016393:Lymphoma, B-Cell / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D008875:Middle Aged; D009367:Neoplasm Staging; D011241:Prednisone / Q000008:administration & dosage; D000069283:Rituximab; D016896:Treatment Outcome; D014750:Vincristine / Q000008:administration & dosage
chemical_list: D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D015703:Antigens, CD; D000970:Antineoplastic Agents; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone