title: Four versus six courses of a dose-escalated cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) regimen plus etoposide (megaCHOEP) and autologous stem cell transplantation: early dose intensity is crucial in treating younger patients with poor prognosis aggressive lymphoma.
abstract: BACKGROUND
  Patients with aggressive lymphoma and high-risk features at the time of diagnosis are reported to have a poor prognosis with standard therapy. Attempts to improve the results achieved with the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) using second-generation or third-generation chemotherapy have failed. In the current study, the authors increased the doses and dose intensity of drugs used for the conventional first-line therapy of aggressive lymphoma and designed a Phase II randomized trial that compared four and six courses of dose-escalated CHOP plus etoposide (megaCHOEP) supported by the transplantation of peripheral blood stem cells.
  
  
  METHODS
  Eighty-four patients age < 60 years with aggressive lymphoma and elevated lactate dehydrogenase (LDH) levels were randomized to receive either 4 (Arm A) or 6 (Arm B) courses of cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone (megaCHOEP). The last three treatment courses were supported by autologous peripheral blood stem cell transplantation. Although the total doses of cyclophosphamide and etoposide were comparable, the dose intensity during the first 3 treatment courses was planned to be 2.8-fold and 2.0-fold higher, respectively, for patients in Arm A.
  
  
  RESULTS
  Thirty-seven patients in Arm A (90.2%) but only 18 patients in Arm B (69.2%) were able to complete therapy (P = 0.048). The complete response rate was 65.8% in Arm A and 50.0% in Arm B; the disease recurrence rates were 18.5% versus 61.5% (P = 0.011). Freedom from treatment failure at 2 years was 52.5% (95% confidence interval [95% CI], 36.9-68.2%) in Arm A and 23.1% (95% CI, 6.9-39.3%) in Arm B (P = 0.02). The overall survival rate was 70% (95% CI, 54.9-85.0%) in Arm A and 46.2% (95% CI, 27.0-65.3%) in Arm B (P = 0.037).
  
  
  CONCLUSIONS
  The results of the current study demonstrate that dose intensity, in particular early dose intensity, significantly influences disease control with high-dose therapy (HDT) and autologous stem cell transplantation. These results also may explain the failure of HDT with low early dose intensity to improve the results obtained with conventional chemotherapy.
authors.affiliation: Department of Hematology, AK St. Georg, Hamburg, Germany.
authors.forename: Nobert
authors.initials: N
authors.lastname: Schmitz
authors.forename: Marita
authors.initials: M
authors.lastname: Kloess
authors.forename: Marcel
authors.initials: M
authors.lastname: Reiser
authors.forename: Wolfgang E
authors.initials: WE
authors.lastname: Berdel
authors.forename: Bernd
authors.initials: B
authors.lastname: Metzner
authors.forename: Bernd
authors.initials: B
authors.lastname: Dorken
authors.forename: Michael
authors.initials: M
authors.lastname: Kneba
authors.forename: Lorenz
authors.initials: L
authors.lastname: Trumper
authors.forename: Markus
authors.initials: M
authors.lastname: Loeffler
authors.forename: Michael
authors.initials: M
authors.lastname: Pfreundschuh
authors.forename: Bertram
authors.initials: B
authors.lastname: Glass
mesh_terms: D000328:Adult; D018952:Antigens, CD34 / Q000276:immunology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D003131:Combined Modality Therapy; D003520:Cyclophosphamide / Q000008:administration & dosage; D004317:Doxorubicin / Q000008:administration & dosage; D004334:Drug Administration Schedule; D005047:Etoposide / Q000008:administration & dosage; D005260:Female; D006801:Humans; D008223:Lymphoma / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D036102:Peripheral Blood Stem Cell Transplantation; D011241:Prednisone / Q000008:administration & dosage; D011446:Prospective Studies; D015996:Survival Rate; D014182:Transplantation, Autologous; D016896:Treatment Outcome; D014750:Vincristine / Q000008:administration & dosage
chemical_list: D018952:Antigens, CD34; D014750:Vincristine; D005047:Etoposide; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone