title: Rituximab versus a watch-and-wait approach in patients with advanced-stage, asymptomatic, non-bulky follicular lymphoma: an open-label randomised phase 3 trial.
abstract: BACKGROUND
  Patients with advanced-stage, low-tumour-burden follicular lymphoma have conventionally undergone watchful waiting until disease progression. We assessed whether rituximab use could delay the need for chemotherapy or radiotherapy compared with watchful waiting and the effect of this strategy on quality of life (QoL).
  
  
  METHODS
  Asymptomatic patients (aged ≥18 years) with low-tumour-burden follicular lymphoma (grades 1, 2, and 3a) were randomly assigned centrally (1:1:1), by the minimisation approach stratified by institution, grade, stage, and age, to watchful waiting, rituximab 375 mg/m(2) weekly for 4 weeks (rituximab induction), or rituximab induction followed by a maintenance schedule of 12 further infusions given at 2-monthly intervals for 2 years (maintenance rituximab). On Sept 30, 2007, recruitment into the rituximab induction group was closed and the study was amended to a two-arm study. The primary endpoints were time to start of new treatment and QoL at month 7 (ie, 6 months after completion of rituximab induction). All randomly assigned patients were included in the analysis of time to start of new treatment on an intention-to-treat basis. The main study is now completed and is in long-term follow-up. The study is registered with ClinicalTrials.gov, NCT00112931.
  
  
  RESULTS
  Between Oct 15, 2004, and March 25, 2009, 379 patients from 118 centres in the UK, Australia, New Zealand, Turkey, and Poland were randomly assigned to watchful waiting or maintenance rituximab. 84 patients were recruited to the rituximab induction group before it was closed early. There was a significant difference in the time to start of new treatment, with 46% (95% CI 39-53) of patients in the watchful waiting group not needing treatment at 3 years compared with 88% (83-92) in the maintenance rituximab group (hazard ratio [HR] 0·21, 95% CI 0·14-0·31; p<0·0001). 78% (95% CI 69-87) of patients in the rituximab induction group did not need treatment at 3 years, which was significantly more than in the watchful waiting group (HR 0·35, 95% CI 0·22-0·56; p<0·0001), but no different compared with the maintenance rituximab group (0·75, 0·41-1·34; p=0·33). Compared with the watchful waiting group, patients in the maintenance rituximab group had significant improvements in the Mental Adjustment to Cancer scale score (p=0·0004), and Illness Coping Style score (p=0·0012) between baseline and month 7. Patients in the rituximab induction group did not show improvements in their QoL compared with the watchful waiting group. There were 18 serious adverse events reported in the rituximab groups (four in the rituximab induction group and 14 in the maintenance rituximab group), 12 of which were grade 3 or 4 (five infections, three allergic reactions, and four cases of neutropenia), all of which fully resolved.
  
  
  CONCLUSIONS
  Rituximab monotherapy should be considered as a treatment option for patients with asymptomatic, advanced-stage, low-tumour-burden follicular lymphoma.
  
  
  BACKGROUND
  Cancer Research UK, Lymphoma Research Trust, Lymphoma Association, and Roche.
authors.affiliation: Department of Haematology, University College Hospital, London, UK. Electronic address: kirit.ardeshna@uclh.nhs.uk.
authors.forename: Kirit M
authors.initials: KM
authors.lastname: Ardeshna
authors.affiliation: Cambridge Clinical Trials Unit-Cancer Theme, Medical Research Council Biostatistics Unit Hub for Trials Methodology, Cambridge, UK.
authors.forename: Wendi
authors.initials: W
authors.lastname: Qian
authors.affiliation: Cancer Research UK and UCL Cancer Trials Centre, London, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Smith
authors.affiliation: Cancer Research UK and UCL Cancer Trials Centre, London, UK.
authors.forename: Nivette
authors.initials: N
authors.lastname: Braganca
authors.affiliation: Cancer Research UK and UCL Cancer Trials Centre, London, UK.
authors.forename: Lisa
authors.initials: L
authors.lastname: Lowry
authors.affiliation: Cancer Research UK and UCL Cancer Trials Centre, London, UK.
authors.forename: Pip
authors.initials: P
authors.lastname: Patrick
authors.affiliation: School of Nursing, Midwifery, and Social Work, University of Manchester, Manchester, UK.
authors.forename: June
authors.initials: J
authors.lastname: Warden
authors.affiliation: Cancer Research UK and UCL Cancer Trials Centre, London, UK.
authors.forename: Lindsey
authors.initials: L
authors.lastname: Stevens
authors.affiliation: Department of Haematology, East Kent Hospitals, Canterbury, UK.
authors.forename: Christopher F E
authors.initials: CF
authors.lastname: Pocock
authors.affiliation: Department of Haematology, Leicester Royal Infirmary, Leicester, UK.
authors.forename: Fiona
authors.initials: F
authors.lastname: Miall
authors.affiliation: Department of Medicine, Royal Marsden Hospital, London, UK.
authors.forename: David
authors.initials: D
authors.lastname: Cunningham
authors.affiliation: Department of Haematology, Western General Hospital, Edinburgh, UK.
authors.forename: John
authors.initials: J
authors.lastname: Davies
authors.affiliation: Haematological Malignancy Diagnostic Service, St James' Institute, Leeds, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Jack
authors.affiliation: MRC Clinical Trials Unit, London, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Stephens
authors.affiliation: Department of Lymphoproliferative Diseases, Maria Sklodowska-Curie Memorial Institute and Cancer Centre, Warsaw, Poland.
authors.forename: Jan
authors.initials: J
authors.lastname: Walewski
authors.affiliation: Cerrahpasa Medical Faculty, Department of Internal Medicine Division of Hematology, Istanbul University, Istanbul, Turkey.
authors.forename: Burhan
authors.initials: B
authors.lastname: Ferhanoglu
authors.affiliation: Department of Haematology, Westmead Hospital, University of Sydney, Sydney, NSW, Australia.
authors.forename: Ken
authors.initials: K
authors.lastname: Bradstock
authors.affiliation: UCL Cancer Institute, London, UK.
authors.forename: David C
authors.initials: DC
authors.lastname: Linch
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D058846:Antibodies, Monoclonal, Murine-Derived / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D058070:Asymptomatic Diseases; D001315:Australia; D018450:Disease Progression; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005060:Europe; D005260:Female; D006801:Humans; D057194:Intention to Treat Analysis; D053208:Kaplan-Meier Estimate; D008224:Lymphoma, Follicular / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D009520:New Zealand; D018579:Patient Selection; D016016:Proportional Hazards Models; D011788:Quality of Life; D012307:Risk Factors; D000069283:Rituximab; D013997:Time Factors; D016896:Treatment Outcome; D057832:Watchful Waiting
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D000069283:Rituximab