title: A prospective blinded study of the predictive value of an extreme drug resistance assay in patients receiving CPT-11 for recurrent glioma.
abstract: This adjunct to a prospective phase II blinded study of 48 patients with recurrent malignant glioma evaluated the predictive reliability of an extreme drug resistance (EDR) to identify clinical resistance to irinotecan (CPT-11), using fresh tumor biopsies obtained from recurrent patients immediately prior to their first dose of CPT-11 therapy. In vitro tumor response to SN38 (bioactive species of CPT-11 used in the EDR assay) determined prior to treatment was correlated with objective response, time to tumor progression (TTP) and survival following the administration of CPT-11. SN38 activity was tested in 19 of 29 tumors, with 15 of 18 assay results evaluable for correlation with clinical outcomes. In vitro drug resistance was classified as either extreme, intermediate (IDR), or low (LDR). TTP and survival were estimated by the Kaplan-Meier method, and compared using the Mantel-Haenszel log-rank and Fisher's exact test statistics. In vitro tumor response was bifurcated into either EDR (n = 4) or IDR/LDR (n = 11) categories for comparison with outcomes. Results correlated significantly with both TTP and survival. Median TTP for IDR/LDR cases was 3 months versus 6 weeks for EDR cases (log-rank test; p = 0.0288, hazards ratio = 3.06). A 13-week median survival for EDR cases was significantly shorter compared to 38 weeks for IDR/LDR cases (p = 0.029). Further, 100-day survival favored the IDR/LDR cases (Fisher's exact test; p = 0.008). At last follow-up, two of three survivors were patients who had tumors IDR/LDR to SN38. These prospective data support the notion that patients should avoid agents to which their tumor demonstrates EDR.
authors.affiliation: Oncotech, Inc., Tustin, CA 92780, USA.
authors.forename: Ricardo J
authors.initials: RJ
authors.lastname: Parker
authors.forename: John P
authors.initials: JP
authors.lastname: Fruehauf
authors.forename: Rita
authors.initials: R
authors.lastname: Mehta
authors.forename: Emese
authors.initials: E
authors.lastname: Filka
authors.forename: Timothy
authors.initials: T
authors.lastname: Cloughesy
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000401:mortality; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D005260:Female; D005910:Glioma / Q000188:drug therapy* / Q000401:mortality; D006801:Humans; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*; D011237:Predictive Value of Tests; D011446:Prospective Studies; D012680:Sensitivity and Specificity; D015996:Survival Rate; D059004:Topoisomerase I Inhibitors; D016896:Treatment Outcome
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D059004:Topoisomerase I Inhibitors; D000077146:Irinotecan; D002166:Camptothecin