title: Randomized trial of the cardioprotective agent ICRF-187 in pediatric sarcoma patients treated with doxorubicin.
abstract: OBJECTIVE
  We conducted an open-label, randomized trial to determine whether ICRF-187 would reduce doxorubicin-induced cardiotoxicity in pediatric sarcoma patients.
  
  
  METHODS
  Thirty-eight patients were randomized to receive doxorubicin-containing chemotherapy (given as an intravenous bolus) with or without ICRF-187. Resting left ventricular ejection fraction (LVEF) was monitored serially with multigated radionuclide angiography (MUGA) scan. The two groups were compared for incidence and degree of cardiotoxicity, response rates to four cycles of chemotherapy, event-free and overall survival, and incidence and severity of noncardiac toxicities.
  
  
  RESULTS
  Eighteen ICRF-187-treated and 15 control patients were assessable for cardiac toxicity. ICRF-187-treated patients were less likely to develop subclinical cardiotoxicity (22% v 67%, P < .01), had a smaller decline in LVEF per 100 mg/m2 of doxorubicin (1.0 v 2.7 percentage points, P = .02), and received a higher median cumulative dose of doxorubicin (410 v 310 mg/m2, P < .05) than did control patients. Objective response rates were identical in the two groups, with no significant differences seen in event-free or overall survival. ICRF-187-treated patients had a significantly higher incidence of transient grade 1 serum transaminase elevations and a trend toward increased hematologic toxicity.
  
  
  CONCLUSIONS
  ICRF-187 reduces the risk of developing short-term subclinical cardiotoxicity in pediatric sarcoma patients who receive up to 410 mg/m2 of doxorubicin. Response rates to chemotherapy, event-free and overall survival, and noncardiac toxicities appear to be unaffected by the use of ICRF-187. Additional clinical trials with larger numbers of patients are needed to determine if the short-term cardioprotection afforded by ICRF-187 will reduce the incidence of late cardiac complications in long-term survivors of childhood cancer.
authors.affiliation: Pediatric Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-1928, USA.
authors.forename: L H
authors.initials: LH
authors.lastname: Wexler
authors.forename: M P
authors.initials: MP
authors.lastname: Andrich
authors.forename: D
authors.initials: D
authors.lastname: Venzon
authors.forename: S L
authors.initials: SL
authors.lastname: Berg
authors.forename: L
authors.initials: L
authors.lastname: Weaver-McClure
authors.forename: C C
authors.initials: CC
authors.lastname: Chen
authors.forename: V
authors.initials: V
authors.lastname: Dilsizian
authors.forename: N
authors.initials: N
authors.lastname: Avila
authors.forename: P
authors.initials: P
authors.lastname: Jarosinski
authors.forename: F M
authors.initials: FM
authors.lastname: Balis
authors.forename: D G
authors.initials: DG
authors.lastname: Poplack
authors.forename: M E
authors.initials: ME
authors.lastname: Horowitz
mesh_terms: D000293:Adolescent; D000328:Adult; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects*; D002317:Cardiovascular Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002648:Child; D004317:Doxorubicin / Q000009:adverse effects*; D005260:Female; D006321:Heart / Q000187:drug effects*; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D018241:Neuroectodermal Tumors, Primitive, Peripheral / Q000188:drug therapy; D011929:Razoxane / Q000493:pharmacokinetics / Q000627:therapeutic use*; D012208:Rhabdomyosarcoma / Q000188:drug therapy; D012509:Sarcoma / Q000188:drug therapy* / Q000401:mortality; D012512:Sarcoma, Ewing / Q000188:drug therapy; D012983:Soft Tissue Neoplasms / Q000188:drug therapy*; D013318:Stroke Volume / Q000187:drug effects; D015996:Survival Rate; D000637:Transaminases / Q000097:blood
chemical_list: D000903:Antibiotics, Antineoplastic; D002317:Cardiovascular Agents; D011929:Razoxane; D004317:Doxorubicin; D000637:Transaminases