title: An adjuvant autologous therapeutic vaccine (HSPPC-96; vitespen) versus observation alone for patients at high risk of recurrence after nephrectomy for renal cell carcinoma: a multicentre, open-label, randomised phase III trial.
abstract: BACKGROUND
  Treatment of localised renal cell carcinoma consists of partial or radical nephrectomy. A substantial proportion of patients are at risk for recurrence because no effective adjuvant therapy exists. We investigated the use of an autologous, tumour-derived heat-shock protein (glycoprotein 96)-peptide complex (HSPPC-96; vitespen) as adjuvant treatment in patients at high risk of recurrence after resection of locally advanced renal cell carcinoma.
  
  
  METHODS
  In this open-label trial, patients were randomly assigned to receive either vitespen (n=409) or observation alone (n=409) after nephrectomy. Randomisation was done in a one to one ratio by a computer-generated pseudo-random number generator, with a block size of four, and was stratified by performance score, lymph node status, and nuclear grade. Vitespen was given intradermally once a week for 4 weeks, then every 2 weeks until vaccine depletion. The primary endpoint was recurrence-free survival. The final analysis of recurrence-free survival was planned to take place after 214 or more events of disease recurrence or deaths before recurrence had occurred. Analysis was by intention to treat (ITT). This study is registered with ClinicalTrials.gov, number NCT00033904.
  
  
  RESULTS
  48 patients in the vitespen group and 42 in the observation group were excluded from the ITT population because they did not meet post-surgery inclusion criteria; the ITT population thus consisted of 361 patients in the vitespen group and 367 in the observation group. Final analysis of recurrence-free survival was triggered in November, 2005. Re-review of all patients in the ITT population by the clinical events committee identified 149 actual recurrences (73 in the vitespen group and 76 in the observation group), nine deaths before recurrence (two in the vitespen group and seven in the observation group), and 124 patients with baseline metastatic or residual disease (61 in the vitespen group and 63 in the observation group). Thus, after a median follow-up of 1.9 years (IQR 0.9-2.5) in the ITT population, recurrence events were reported in 136 (37.7%) patients in the vitespen group and 146 (39.8%) in the observation group (hazard ratio 0.923, 95% CI 0.729-1.169; p=0.506). After continued follow-up until March, 2007, there had been 70 deaths in the vitespen group and 72 in the observation group (p=0.896); however, overall survival data were not mature, and patients continue to be followed up for survival. In predefined exploratory analyses by AJCC stage, recurrence events in patients with stage I or II disease were reported in 19 (15.2%) patients in the vitespen group and 31 (27.0%) in the observation group (hazard ratio 0.576, 95% CI 0.324-1.023; p=0.056). The most commonly reported adverse events in the vitespen group were injection-site erythema (n=158) and injection-site induration (n=153). One serious adverse event-autoimmune thyroiditis of grade 2 severity-was reported in the vitespen group; no treatment-related grade 3 or 4 adverse events were reported.
  
  
  CONCLUSIONS
  No difference in recurrence-free survival was seen between patients given vitespen and those who received no treatment after nephrectomy for renal cell carcinoma. A possible improvement in recurrence-free survival in patients with early stage disease who received vitespen will require further validation.
authors.affiliation: M D Anderson Cancer Center, Houston, TX, USA. Electronic address: cgwood@mdanderson.org.
authors.forename: Christopher
authors.initials: C
authors.lastname: Wood
authors.affiliation: University of Connecticut School of Medicine, Farmington, CT, USA.
authors.forename: Pramod
authors.initials: P
authors.lastname: Srivastava
authors.affiliation: Cleveland Clinic Foundation, Cleveland, OH, USA.
authors.forename: Ronald
authors.initials: R
authors.lastname: Bukowski
authors.affiliation: CHUQ-Hôtel-Dieu de Québec, Pavillon de Recherche de L'Hôpital I'Hôtel Dieu, Quebec City, Quebec, Canada.
authors.forename: Louis
authors.initials: L
authors.lastname: Lacombe
authors.affiliation: St Petersburg State University, St Petersburg, Russia.
authors.forename: Andrei I
authors.initials: AI
authors.lastname: Gorelov
authors.affiliation: St Petersburg Hospital 122, St Petersburg, Russia.
authors.forename: Sergei
authors.initials: S
authors.lastname: Gorelov
authors.affiliation: UMC St Radboud, Nijmegen, Netherlands.
authors.forename: Peter
authors.initials: P
authors.lastname: Mulders
authors.affiliation: Centralny Szpital Kliniczny WAM, Warsaw, Poland.
authors.forename: Henryk
authors.initials: H
authors.lastname: Zielinski
authors.affiliation: Bristol-Myers Squibb, New York, NY, USA.
authors.forename: Axel
authors.initials: A
authors.lastname: Hoos
authors.affiliation: Antigenics, New York, NY, USA.
authors.forename: Florentina
authors.initials: F
authors.lastname: Teofilovici
authors.affiliation: Antigenics, New York, NY, USA.
authors.forename: Leah
authors.initials: L
authors.lastname: Isakov
authors.affiliation: Loyola University Medical Center, Maywood, IL, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Flanigan
authors.affiliation: City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Figlin
authors.affiliation: Transave Inc, Monmouth, NJ, USA.
authors.forename: Renu
authors.initials: R
authors.lastname: Gupta
authors.affiliation: Institut Gustave Roussy, Villejuif, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Escudier
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019496:Cancer Vaccines / Q000009:adverse effects / Q000627:therapeutic use*; D018572:Disease-Free Survival; D005260:Female; D006360:Heat-Shock Proteins / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D007680:Kidney Neoplasms / Q000473:pathology / Q000517:prevention & control* / Q000601:surgery; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000517:prevention & control*; D019370:Observation; D011184:Postoperative Period; D012307:Risk Factors
chemical_list: D019496:Cancer Vaccines; D006360:Heat-Shock Proteins; C484813:vitespin