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.
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.
Ugurel
Selma
S
Skin Cancer Unit, German Cancer Research Center Heidelberg and Department of Dermatology, University Hospital of Mannheim, Mannheim, Germany. s.ugurel@dkfz.de
Schadendorf
Dirk
D
Pföhler
Claudia
C
Neuber
Karsten
K
Thoelke
Adina
A
Ulrich
Jens
J
Hauschild
Axel
A
Spieth
Konstanze
K
Kaatz
Martin
M
Rittgen
Werner
W
Delorme
Stefan
S
Tilgen
Wolfgang
W
Reinhold
Uwe
U
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
D003841:Deoxycytidine; D004317:Doxorubicin; C018404:treosulfan; D002066:Busulfan; D017239:Paclitaxel; D002945:Cisplatin; D000093542:Gemcitabine