title: Prospective evaluation of an in vitro radiation resistance assay in locally advanced cancer of the uterine cervix: a Southwest Oncology Group Study.
abstract: OBJECTIVE
  To investigate the feasibility of performing a fresh-tissue, in vitro radiation resistance assay (IVRRA) in a cooperative group setting and to assess the association of IVRRA results with clinical outcomes.
  
  
  METHODS
  Women with Stages IIB-IVA carcinoma of the uterine cervix without obvious para-aortic lymphadenopathy on imaging were eligible. Primary tumor biopsies were shipped to a central testing facility where agar-based cell suspensions were exposed to 300 cGy of RT ± cisplatin and cultured for 5 days. ³H-thymidine incorporation was used to determine percent cell inhibition (PCI) of test specimen compared to that of the untreated control. Tumors were considered to exhibit extreme radiation resistance (ERR), intermediate radiation resistance (IRR) or low radiation resistance (LRR) based on a standard data set from 39 previously studied specimens. Standardized doses of external beam radiation and intracavitary brachytherapy, when feasible, in addition to platinum-based chemotherapy were mandated. Progression-free survival (PFS) was the primary endpoint. Clinical response and overall survival (OS) were secondary endpoints. Clinical investigators were blinded to assay data and vice versa.
  
  
  RESULTS
  Thirty-six patients were enrolled, but analysis was limited to 17 patients whose specimens were adequate for IVRRA. The median follow-up time among patients still alive at last contact was 40 months (range: 0-56 months). There was no association between IVRRA and response. In the Cox model, IRR/ERR tumors showed worse PFS [HR = 11.2 (95% CI 1.3-96, p = 0.03)] and worse OS [HR=11.7 (95% CI 1.4-99.6, p = 0.03)] compared to LRR tumors when IVRRA was performed with RT alone, but there were no associations between IVRRA and PFS or OS when cisplatin was added to the IVRRA.
  
  
  CONCLUSIONS
  IVRRA (RT alone) results correlated with PFS and OS in this prospective trial, but follow-up trials are indicated to address feasibility and to confirm results in an expanded cohort. If confirmed, IVRRA could potentially direct molecular identification of novel targeted therapeutic approaches which might counteract radiation resistance.
authors.affiliation: Chao Family Comprehensive Cancer Center, University of California-Irvine Medical Center, Orange, CA 92868, USA.
authors.forename: Leslie M
authors.initials: LM
authors.lastname: Randall
authors.forename: Bradley J
authors.initials: BJ
authors.lastname: Monk
authors.forename: James
authors.initials: J
authors.lastname: Moon
authors.forename: Ricardo
authors.initials: R
authors.lastname: Parker
authors.forename: Muthana
authors.initials: M
authors.lastname: Al-Ghazi
authors.forename: Sharon
authors.initials: S
authors.lastname: Wilczynski
authors.forename: John P
authors.initials: JP
authors.lastname: Fruehauf
authors.forename: Maurie
authors.initials: M
authors.lastname: Markman
authors.forename: Robert A
authors.initials: RA
authors.lastname: Burger
mesh_terms: D001706:Biopsy; D002945:Cisplatin / Q000627:therapeutic use; D003131:Combined Modality Therapy; D018572:Disease-Free Survival; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D009367:Neoplasm Staging; D016016:Proportional Hazards Models; D011446:Prospective Studies; D011836:Radiation Tolerance; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000528:radiation effects; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000532:radiotherapy*
chemical_list: D002945:Cisplatin