title: In vitro drug sensitivity predicts response and survival after individualized sensitivity-directed chemotherapy in metastatic melanoma: a multicenter phase II trial of the Dermatologic Cooperative Oncology Group.
abstract: OBJECTIVE
  In vitro sensitivity assays are promising tools to predict the individual outcome of different chemotherapy regimens. However, a direct association between in vitro and in vivo chemosensitivity has to be shown by clinical studies. This multicenter phase II trial was aimed to investigate the efficacy of a sensitivity-directed, first-line chemotherapy in metastasized melanoma patients, and to prove an association between in vitro sensitivity and therapy outcome.
  
  
  METHODS
  The primary study end point was objective response; secondary end points were safety, overall survival, and progression-free survival. Viable tumor cells obtained from metastatic lesions were tested for chemosensitivity to seven single drugs and five drug combinations using an ATP-based luminescence viability assay.
  
  
  RESULTS
  Out of 82 recruited patients (intention-to-treat), 57 received assay-directed chemotherapy and 53 were evaluable for all study end points (per protocol). The drug combinations used were gemcitabine+treosulfan, paclitaxel+cisplatin, paclitaxel+doxorubicin, and gemcitabine+cisplatin. The per protocol population could be divided into 22 (42%) chemosensitive and 31 (58%) chemoresistant patients by an arbitrary chemosensitivity index. Objective response was 36.4% in chemosensitive patients compared with 16.1% in chemoresistant patients (P=0.114); progression arrest (complete response+partial response+stable disease) was 59.1% versus 22.6% (P=0.01). Chemosensitive patients showed an increased overall survival of 14.6 months compared with 7.4 months in chemoresistant patients (P=0.041).
  
  
  CONCLUSIONS
  In vitro chemosensitivity testing may be worthy of further exploration to see if it could be a useful tool to predict the outcome of melanoma patients treated with a sensitivity-directed chemotherapy. Therefore, these preliminary results will be evaluated by a planned phase III trial using a randomized, standard-regimen controlled setting.
authors.affiliation: Skin Cancer Unit, German Cancer Research Center Heidelberg and Department of Dermatology, University Hospital of Mannheim, Mannheim, Germany. s.ugurel@dkfz.de
authors.forename: Selma
authors.initials: S
authors.lastname: Ugurel
authors.forename: Dirk
authors.initials: D
authors.lastname: Schadendorf
authors.forename: Claudia
authors.initials: C
authors.lastname: Pföhler
authors.forename: Karsten
authors.initials: K
authors.lastname: Neuber
authors.forename: Adina
authors.initials: A
authors.lastname: Thoelke
authors.forename: Jens
authors.initials: J
authors.lastname: Ulrich
authors.forename: Axel
authors.initials: A
authors.lastname: Hauschild
authors.forename: Konstanze
authors.initials: K
authors.lastname: Spieth
authors.forename: Martin
authors.initials: M
authors.lastname: Kaatz
authors.forename: Werner
authors.initials: W
authors.lastname: Rittgen
authors.forename: Stefan
authors.initials: S
authors.lastname: Delorme
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Tilgen
authors.forename: Uwe
authors.initials: U
authors.lastname: Reinhold
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000465:Algorithms; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D002066:Busulfan / Q000031:analogs & derivatives / Q000627:therapeutic use; D002945:Cisplatin / Q000627:therapeutic use; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000627:therapeutic use; D004317:Doxorubicin / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000502:physiology; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D005260:Female; D006801:Humans; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000401:mortality; D008875:Middle Aged; D017239:Paclitaxel / Q000627:therapeutic use; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016019:Survival Analysis; D016896:Treatment Outcome; D000093542:Gemcitabine
chemical_list: D003841:Deoxycytidine; D004317:Doxorubicin; C018404:treosulfan; D002066:Busulfan; D017239:Paclitaxel; D002945:Cisplatin; D000093542:Gemcitabine