title: Prospective clinical trials of biotherapies in solid tumors: a 5-year survey.
abstract: OBJECTIVE
  To review the content and quality of prospective clinical trials of biotherapies in solid tumors.
  
  
  METHODS
  Data were collected from the literature between 1990 and 2002 on general study characteristics, patient and disease factors, study methodology, and factors related to completeness of reporting. Quality of phase II studies was evaluated by an ad hoc questionnaire. Descriptive statistics, contingency tables, and the chi-square test were applied.
  
  
  RESULTS
  A total of 334 studies were selected, of which about three quarters were multicenter, with 42.5% reporting phase I, 42.2% phase II or I/II, and 11.9% phase III or II/III studies. Only 13.7% were randomized, and a study design emphasizing statistical analysis was lacking in as many as one third. The assessment of biological endpoints was stated as the primary or secondary goal in half of these studies. Melanoma (17.1%), renal carcinoma (11.1%), gastrointestinal neoplasms (11.1%), and lymphomas (6.3%) were the most studied diseases. Immunotherapies accounted for 182 studies; the remaining 152 reported other biotherapies. Patients with (1) advanced disease (P = 0.003), (2) heavily pretreated neoplasms (P < 0.0001), (3) poor performance status (PS < 2) (P < 0.0001), were more frequently enrolled in studies of biotherapy. Biotherapies were less frequently evaluated in phase III studies (7/152) compared with immunotherapies (33/182) (P < 0.0001). A statistical study design was more frequently identified in biotherapy trials (127/152) compared with immunotherapy trials (98/182) (P < 0.0001). Biological endpoints were less frequently evaluated in phase III studies in both biotherapies (100% no vs 0% yes) and immunotherapies (81.8% no vs 18.2% yes) (P = 0.01, for biotherapies; P < 0.0001, for immunotherapies). Phase I immunotherapy studies more frequently applied biological or molecular criteria for patient selection (41.1%) than phase II (29.3%) and III (3.1%) studies (P < 0.0001).
  
  
  CONCLUSIONS
  The very wide diversity in modalities of conducting and reporting clinical trials of biotherapies of solid tumors and the presence of some methodological pitfalls suggest that the methodological standards for conducting and publishing clinical trials in biotherapies should be improved to enhance the reliability of the body of published data.
authors.affiliation: Department of Medical Oncology, ULSS2, Santa Maria del Prato Hospital, via Bagnols Ceze, Feltre (BL), Italy. ale.otto@libero.it
authors.forename: Alessandro
authors.initials: A
authors.lastname: Ottaiano
authors.forename: Ernesto
authors.initials: E
authors.lastname: Mollo
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Di Lorenzo
authors.forename: Carmela
authors.initials: C
authors.lastname: Pisano
authors.forename: Massimo
authors.initials: M
authors.lastname: Di Maio
authors.forename: Emiddio
authors.initials: E
authors.lastname: Barletta
authors.forename: Matilde
authors.initials: M
authors.lastname: Pensabene
authors.forename: Romana
authors.initials: R
authors.lastname: Segati
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Bullian
authors.forename: Guglielmo
authors.initials: G
authors.lastname: Nasti
authors.forename: Jane
authors.initials: J
authors.lastname: Bryce
authors.forename: Stefania
authors.initials: S
authors.lastname: Scala
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Castello
authors.forename: Paolo Antonio
authors.initials: PA
authors.lastname: Ascierto
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002986:Clinical Trials as Topic / Q000706:statistics & numerical data; D017321:Clinical Trials, Phase I as Topic / Q000706:statistics & numerical data; D017322:Clinical Trials, Phase II as Topic / Q000706:statistics & numerical data; D017326:Clinical Trials, Phase III as Topic / Q000706:statistics & numerical data; D006801:Humans; D007167:Immunotherapy / Q000706:statistics & numerical data*; D009369:Neoplasms / Q000628:therapy*; D018579:Patient Selection; D011446:Prospective Studies; D016032:Randomized Controlled Trials as Topic; D012189:Retrospective Studies