title: Cisplatin, epirubicin, and vindesine with or without lonidamine in the treatment of inoperable nonsmall cell lung carcinoma: a multicenter randomized clinical trial.
abstract: BACKGROUND
  Lonidamine (LND) is an indazol-carboxylic acid derivative that selectively inhibits the energy metabolism of neoplastic cells, and increases the permeability of cell membranes. In vitro studies have demonstrated that LND can potentiate the oncolytic activity of cytotoxic drugs and is able to reverse the acquired multidrug resistance of neoplastic cells. Some clinical trials have suggested a synergism of LND with alkylating agents, cisplatin, and anthracyclines in various solid tumors.
  
  
  METHODS
  From June 1990 to June 1993, 158 previously untreated patients with Stage IIIB and IV nonsmall cell lung cancer (NSCLC) were enrolled into a multicentric randomized trial to evaluate the addition of LND to a cisplatin-epirubicin-vindesine regimen. Eighty patients in the control arm (A) received cisplatin, 60 mg/m2 intravenously (i.v.); epirubicin, 60 mg/m2 i.v.; and vindesine, 3 mg/m2 i.v. (PEV), on Day 1 every 4 weeks, whereas 78 patients in the experimental arm (B) received the same regimen with the addition of LND from 75 mg orally three times on Day 1 to 150 mg orally three times on Day 7+ until tumor progression occurred.
  
  
  RESULTS
  The experimental treatment achieved a significantly higher proportion of major responses in comparison with the control regimen (43% vs. 24%; P=0.02). The addition of LND apparently potentiated the activity of this cytotoxic treatment, particularly in patients with metastatic disease (overall response rate, 39% vs. 17%). The median time to progression (5 vs. 8 months; P=0.0007) and the median survival time (7.6 vs. 11 months; P=0.0013) were also statistically improved in Arm B. The acute toxicity of the 2 treatments was low: only 6% of patients in Arm A and 4% of patients in Arm B had to withdraw from treatment due to Grade 4 World Health Organization toxicity. The main additional side effects related to the administration of LND were epigastralgia, myalgia, asthenia, and orchialgia. However, these symptoms were mild and controlled by the concomitant administration of low doses of steroids.
  
  
  CONCLUSIONS
  The mild acute toxicity of the PEV regimen and the acceptable and nonoverlapping additional side effects of LND render our experimental therapy worthy of consideration for the management of NSCLC patients with poor performance status or low tolerance to more aggressive therapeutic approaches.
authors.affiliation: Department of Medical Oncology, G. Rummo Hospital, Benevento, Italy.
authors.forename: G P
authors.initials: GP
authors.lastname: Ianniello
authors.forename: G
authors.initials: G
authors.lastname: De Cataldis
authors.forename: P
authors.initials: P
authors.lastname: Comella
authors.forename: M D
authors.initials: MD
authors.lastname: Scarpati
authors.forename: A
authors.initials: A
authors.lastname: Maiorino
authors.forename: L
authors.initials: L
authors.lastname: Brancaccio
authors.forename: R
authors.initials: R
authors.lastname: Cioffi
authors.forename: A
authors.initials: A
authors.lastname: Lombardi
authors.forename: P
authors.initials: P
authors.lastname: Carnicelli
authors.forename: V
authors.initials: V
authors.lastname: Tinessa
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D002945:Cisplatin / Q000008:administration & dosage; D018450:Disease Progression; D015251:Epirubicin / Q000008:administration & dosage; D005260:Female; D006801:Humans; D007191:Indazoles / Q000008:administration & dosage; D008175:Lung Neoplasms / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D016019:Survival Analysis; D014751:Vindesine / Q000008:administration & dosage
chemical_list: D007191:Indazoles; D015251:Epirubicin; D002945:Cisplatin; D014751:Vindesine; C016371:lonidamine