Dose-intensification of MVAC with recombinant granulocyte colony-stimulating factor as initial therapy in advanced urothelial cancer.
OBJECTIVE
This study was undertaken to define an escalated dose schedule of methotrexate, vinblastine, doxorubicin, and cisplatin (E-MVAC) with hematopoietic growth-factor support, to define the ability to deliver E-MVAC with recombinant human granulocyte colony-stimulating factor (rhG-CSF) on 21- and 14-day schedules, and to assess the ability of rhG-CSF to maintain dose-intensity over four cycles of chemotherapy.


METHODS
Twenty-three patients with transitional-cell carcinoma of the urothelium received E-MVAC in a phase I investigation. Patients were treated on an every-21-day (n = 19) or every-14-day schedule of administration (n = 4), with rhG-CSF support. Delivered dose-intensity was calculated at the completion of four cycles of therapy relative to the planned administration of conventional MVAC (relative dose-intensity [RDI]). Peripheral-blood progenitor cell kinetics in these patients were studied prospectively.


RESULTS
Overall, the delivered RDI was 33% higher than the previously reported delivered dose-intensity of MVAC without hematopoietic support (140% for doxorubicin, 51% for cisplatin). Dose-intensity was well maintained through three cycles of therapy, after which leukopenia and thrombocytopenia became dose-limiting. Sixty-nine percent of patients with measurable disease responded, four (25%) with complete remissions. In five patients treated beyond the maximally tolerated dose (MTD), a 50- to 200-fold increase in G-CSF, granulocyte-macrophage CSF (GM-CSF), and interleukin-3 (IL-3)-responsive peripheral-blood progenitor cells over baseline was observed after 9 days of rhG-CSF administration.


CONCLUSIONS
These findings demonstrate the feasibility and limitations of dose intensification of M-VAC with rhG-CSF. While the overall impact of the increased drug administration can only be assessed in randomized comparisons, the results of the present trial suggest that escalations of the components of the four-drug regimen are unlikely to improve significantly the outcome for patients with advanced urothelial tract tumors.
Seidman
A D
AD
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021.
Scher
H I
HI
Gabrilove
J L
JL
Bajorin
D F
DF
Motzer
R J
RJ
O'Dell
M
M
Curley
T
T
Dershaw
D D
DD
Quinlivan
S
S
Tao
Y
Y
D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D002295:Carcinoma, Transitional Cell / Q000188:drug therapy*; D002945:Cisplatin / Q000008:administration & dosage; D004317:Doxorubicin / Q000008:administration & dosage; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage; D008875:Middle Aged; D011994:Recombinant Proteins / Q000627:therapeutic use; D016896:Treatment Outcome; D014571:Urologic Neoplasms / Q000188:drug therapy*; D014747:Vinblastine / Q000008:administration & dosage
D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; D014747:Vinblastine; D004317:Doxorubicin; D002945:Cisplatin; D008727:Methotrexate