Phase I evaluation of sequential doxorubicin gemcitabine then ifosfamide paclitaxel cisplatin for patients with unresectable or metastatic transitional-cell carcinoma of the urothelial tract.
OBJECTIVE
This phase I trial sought to evaluate the toxicity of and determine the maximum-tolerated dose (MTD) for the two-drug regimen doxorubicin and gemcitabine (AG) followed by the three-drug regimen of ifosfamide, paclitaxel, and cisplatin (ITP) in patients with unresectable or metastatic transitional-cell carcinoma.


METHODS
Patients received AG every other week for six cycles followed by ITP every 3 weeks for four cycles. Five AG dose levels were investigated, up to doxorubicin 50 mg/m(2) and gemcitabine 2, 000 mg/m(2), to determine the MTD of the regimen. The dose and schedule of ITP were constant: ifosfamide 1,500 mg/m(2) (days 1 to 3); paclitaxel 200 mg/m(2) (day 1); and cisplatin 70 mg/m(2) (day 1). Granulocyte colony-stimulating factor was given between all cycles of therapy.


RESULTS
Fifteen patients enrolled onto this phase I trial. AG was well tolerated at all dose levels, with no grade 3 or 4 myelosuppression. Toxicity experienced with ITP included grade 3 and 4 granulocytopenia in four patients and grade 3 nausea/vomiting in three patients. No grade 3 and 4 neurotoxicity was observed. Eight of 14 assessable patients experienced a major response to AG, including five of six patients treated at the two highest AG dose levels. After completion of AG-ITP, nine of 14 assessable patients had a major response (three complete responses and six partial responses).


CONCLUSIONS
AG is a well-tolerated and active regimen. Sequential chemotherapy with AG-ITP is also well tolerated, and phase II investigation at the highest dose level is ongoing.
Dodd
P M
PM
Genitourinary Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, New York, New York, USA.
McCaffrey
J A
JA
Hilton
S
S
Mazumdar
M
M
Herr
H
H
Kelly
W K
WK
Icasiano
E
E
Boyle
M G
MG
Bajorin
D F
DF
D000368:Aged; D000380:Agranulocytosis / Q000139:chemically induced; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000009:adverse effects; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000009:adverse effects; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage* / Q000009:adverse effects; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001854:Bone Marrow Cells / Q000187:drug effects; D002295:Carcinoma, Transitional Cell / Q000188:drug therapy* / Q000556:secondary; D002945:Cisplatin / Q000008:administration & dosage* / Q000009:adverse effects; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D004317:Doxorubicin / Q000008:administration & dosage* / Q000009:adverse effects; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000627:therapeutic use; D006801:Humans; D007069:Ifosfamide / Q000008:administration & dosage* / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D017239:Paclitaxel / Q000008:administration & dosage* / Q000009:adverse effects; D012074:Remission Induction; D014571:Urologic Neoplasms / Q000188:drug therapy*; D014839:Vomiting / Q000139:chemically induced; D000093542:Gemcitabine
D000903:Antibiotics, Antineoplastic; D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D018906:Antineoplastic Agents, Alkylating; D000972:Antineoplastic Agents, Phytogenic; D003841:Deoxycytidine; D016179:Granulocyte Colony-Stimulating Factor; D004317:Doxorubicin; D017239:Paclitaxel; D002945:Cisplatin; D007069:Ifosfamide; D000093542:Gemcitabine