title: High-dose therapy with autologous stem cell transplantation versus chemotherapy or immuno-chemotherapy for follicular lymphoma in adults.
abstract: BACKGROUND
  Follicular lymphoma (FL) is the most common indolent and second most common Non-Hodgkin`s lymphoma (NHL) in the Western world. Standard treatment usually includes rituximab and chemotherapy. High-dose therapy (HDT) followed by autologous stem cell transplantation (ASCT) is an option for patients in advanced stages or for second-line therapy, leading to improved progression-free survival (PFS) rates. However, the impact of HDT and ASCT remains unclear, as there are hints of an increased risk of second cancers.
  
  
  OBJECTIVE
  We performed a systematic review with meta-analysis of randomised controlled trials (RCTs) comparing HDT plus ASCT with chemotherapy or immuno-chemotherapy in patients with FL with respect to overall survival (OS), PFS, treatment-related mortality (TRM), adverse events and secondary malignancies.
  
  
  METHODS
  We searched CENTRAL, MEDLINE, and EMBASE as well as conference proceedings from January 1985 to September 2011 for RCTs. Two review authors independently screened search results.
  
  
  METHODS
  Randomised controlled trials comparing chemotherapy or immuno-chemotherapy with HDT followed by ASCT in adults with previously untreated or relapsed FL.
  
  
  METHODS
  We used hazard ratios (HR) as effect measures used for OS and PFS as well as relative risks for response rates. Two review authors independently extracted data and assessed the quality of trials.
  
  
  RESULTS
  Our search strategies led to 3046 potentially relevant references. Of these, five RCTs involving 1093 patients were included; four trials in previously untreated patients and one trial in relapsed patients. Overall, the quality of the five trials is judged to be moderate. All trials were reported as randomised and judged to be open-label studies, because usually trials evaluating stem cell transplantation are not blinded. Due to the small number of studies in each analysis (four or less), the quantification of heterogeneity was not reliable and not evaluated in further detail. A potential source of bias are uncertainties in the HR calculation. For OS, the HR had to be calculated for three trials from survival curves, for PFS for two trials.We found a statistically significant increased PFS in previously untreated FL patients in the HDT + ASCT arm (HR = 0.42 (95% confidence interval (CI) 0.33 to 0.54; P < 0.00001). However, this effect is not transferred into a statistically significant OS advantage (HR = 0.97; 95% 0.76 to 1.24; P = 0.81). The subgroup of trials adding rituximab to both intervention arms (one trial) confirms these results and the trial had to be stopped early after an interim analysis due to a statistically significant PFS advantage in the HDT + ASCT arm (PFS: HR = 0.36; 95% CI 0.23 to 0.55; OS: HR = 0.88; 95% CI 0.40 to 1.92). In the four trials in previously untreated patients there are no statistically significant differences between HDT + ASCT and the control-arm in terms of TRM (RR = 1.28; 95% CI 0.25 to 6.61; P = 0.77), secondary acute myeloid leukaemia/myelodysplastic syndromes (RR = 2.87; 95% CI 0.7 to 11.75; P = 0.14) or solid cancers (RR = 1.20; 95% CI 0.25 to 5.77; P = 0.82). Adverse events were rarely reported and were observed more frequently in patients undergoing HDT + ASCT (mostly infections and haematological toxicity).For patients with relapsed FL, there is some evidence (one trial, N = 70) that HDT + ASCT is advantageous in terms of PFS and OS (PFS: HR = 0.30; 95% CI 0.15 to 0.61; OS: HR = 0.40; 95% CI 0.18 to 0.89). For this trial, no results were reported for TRM, adverse events or secondary cancers.
  
  
  CONCLUSIONS
  In summary, the currently available evidence suggests a strong PFS benefit for HDT + ASCT compared with chemotherapy or immuno-chemotherapy in previously untreated patients with FL. No statistically significant differences in terms of OS, TRM and secondary cancers were detected. These effects are confirmed in a subgroup analysis (one trial) adding rituximab to both treatment arms. Further trials evaluating this approach are needed to determine this effect more precisely in the era of rituximab. Moreover, longer follow-up data are necessary to find out whether the PFS advantage will translate into an OS advantage in previously untreated patients with FL.There is evidence that HDT + ASCT is advantageous in patients with relapsed FL.
authors.affiliation: Cochrane Haematological Malignancies Group, Department I of Internal Medicine, University Hospital of Cologne, Cologne,Germany. markus.schaaf@gmail.com.
authors.forename: Markus
authors.initials: M
authors.lastname: Schaaf
authors.forename: Marcel
authors.initials: M
authors.lastname: Reiser
authors.forename: Peter
authors.initials: P
authors.lastname: Borchmann
authors.forename: Andreas
authors.initials: A
authors.lastname: Engert
authors.forename: Nicole
authors.initials: N
authors.lastname: Skoetz
mesh_terms: D058846:Antibodies, Monoclonal, Murine-Derived / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D003131:Combined Modality Therapy / Q000379:methods / Q000401:mortality; D018572:Disease-Free Survival; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006801:Humans; D007155:Immunologic Factors / Q000627:therapeutic use; D008224:Lymphoma, Follicular / Q000401:mortality / Q000628:therapy*; D016609:Neoplasms, Second Primary / Q000209:etiology; D016032:Randomized Controlled Trials as Topic / Q000401:mortality; D012008:Recurrence; D000069283:Rituximab; D014182:Transplantation, Autologous; D014916:Whole-Body Irradiation / Q000379:methods*
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D007155:Immunologic Factors; D000069283:Rituximab