title: Phase I/IIa study of sequential chemotherapy regimen of bendamustine/irinotecan followed by etoposide/carboplatin in untreated patients with extensive disease small cell lung cancer (EDSCLC).
abstract: OBJECTIVE
  The sequence bendamustine (B) + Irinotecan (I) followed by etoposide (E) + carboplatin (C) was hypothesized to increase progression-free survival (PFS) and overall survival (OS) in untreated extensive-disease small cell lung cancer (EDSCLC) patients compared to historical controls by exploiting mitotic catastrophe. Absent expression of ERCC-1 and expression of topoisomerases were hypothesized to be predictive for PFS and OS.
  
  
  METHODS
  This was a phase I/IIa trial in 30 patients to determine the maximum tolerated dose (MTD) of B + I and the PFS of B + I E + C with secondary end points including overall response rate (ORR) and OS. Biomarkers measured by immunohistochemistry (IHC) obtained from diagnostic specimens were correlated with outcome.
  
  
  RESULTS
  The MTD of B + I was not reached. During treatment with B + I, there were two grade 5 toxicities from neutropenic sepsis and metabolic encephalopathy. Other toxicities included fatigue, nausea/vomiting, diarrhea, and weight loss. For the sequence, the PFS and OS were 6.0 months and 10 months, respectively. The ORR for B + I and the sequence were 82% and 83%, respectively. Topoisomerase-2 expression was predictive for TTP and OS, but absent ERCC-1 expression was not, contrary to our hypothesis.
  
  
  CONCLUSIONS
  B + I is an active regimen in EDSCLC. Toxicities included two grade 5 events but were otherwise manageable. The novel sequence B + I E + C increased PFS and OS compared to historical controls. Correlative studies are conflicting regarding the mechanism of action of this novel sequence.
authors.affiliation: Alabama Oncology, Shelby County, AL, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Allendorf
authors.affiliation: Georgia Cancer Specialists/Northside Hospital Cancer Institute, Atlanta, GA, USA.
authors.forename: Rodolfo E
authors.initials: RE
authors.lastname: Bordoni
authors.affiliation: Comprehensive Cancer Center, Wake Forest Baptist Medical Center, Winston-Salem, NC, 27157, USA.
authors.forename: Stefan C
authors.initials: SC
authors.lastname: Grant
authors.affiliation: Division of Hematology/Oncology, Comprehensive Cancer Center, University of Alabama at Birmingham, 1824 6th Avenue South, WTI 210B, Birmingham, AL, 35294-3300, USA.
authors.forename: Mansoor N
authors.initials: MN
authors.lastname: Saleh
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Vishnu B
authors.initials: VB
authors.lastname: Reddy
authors.affiliation: Clinical Studies Unit, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Mary L
authors.initials: ML
authors.lastname: Jerome
authors.affiliation: Clinical Trials Network Office, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Pamela M
authors.initials: PM
authors.lastname: Dixon
authors.affiliation: Clinical Studies Unit, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Deborah K
authors.initials: DK
authors.lastname: Miley
authors.affiliation: Department of Medicine, Division of Preventive Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Karan P
authors.initials: KP
authors.lastname: Singh
authors.affiliation: Division of Hematology/Oncology, Comprehensive Cancer Center, University of Alabama at Birmingham, 1824 6th Avenue South, WTI 210B, Birmingham, AL, 35294-3300, USA. pacorobertuab@cs.com.
authors.forename: Francisco
authors.initials: F
authors.lastname: Robert
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000069461:Bendamustine Hydrochloride / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000172:deficiency / Q000235:genetics; D001928:Brain Diseases, Metabolic / Q000209:etiology; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D016190:Carboplatin / Q000008:administration & dosage / Q000009:adverse effects; D018288:Carcinoma, Small Cell / Q000188:drug therapy* / Q000235:genetics; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004720:Endonucleases / Q000172:deficiency / Q000235:genetics; D005047:Etoposide / Q000008:administration & dosage / Q000009:adverse effects; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D005767:Gastrointestinal Diseases / Q000139:chemically induced; D006402:Hematologic Diseases / Q000139:chemically induced; D006801:Humans; D000077146:Irinotecan; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D008938:Mitosis / Q000187:drug effects; D009102:Multiple Organ Failure / Q000209:etiology; D011014:Pneumonia / Q000139:chemically induced; D016896:Treatment Outcome; D015431:Weight Loss / Q000187:drug effects
chemical_list: D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D005047:Etoposide; D000077146:Irinotecan; D000069461:Bendamustine Hydrochloride; D016190:Carboplatin; C071447:ERCC1 protein, human; D004720:Endonucleases; D002166:Camptothecin
keywords: Biomarkers; Chemotherapy; Extensive small cell lung cancer; Lung cancer