Phase I trial of intraperitoneal gemcitabine in the treatment of advanced malignancies primarily confined to the peritoneal cavity.
OBJECTIVE
To determine the maximally tolerated dose, toxicity, and pharmacokinetics of i.p. gemcitabine.


METHODS
Patients had peritoneal carcinomatosis. Gemcitabine (40, 80, 120, or 160 mg/m(2)) was administered into the peritoneal cavity in 2 L of warmed saline on days 1, 4, 8, and 12 of a 28-day cycle.


RESULTS
Thirty patients received 63 (median, 2; range, 0-6) courses. Tumors included ovary (14), uterus (2), colon (6), pancreas (3), and others (5). Dose-limiting toxicity included nausea, vomiting, diarrhea, dyspnea, fatal respiratory failure, and grade 3 elevation of alanine aminotransferase in three patients. Hematologic toxicity and pain were </=grade 2. Three patients had decreased or resolved ascites. Of 19 patients evaluable for response, 10 had stable disease (median, 3.5 courses) and 9 had progressive disease. The median peak peritoneal concentration was 1,116-fold (range, 456-1,886) higher than the peak plasma level. Plasma and peritoneal levels were undetectable within 8 to 12 h. At 120 mg/m(2), the median peritoneal area under the concentration versus time curve (AUC) was 82,612 ng/mL x h (range, 53,296-199,830) and the plasma AUC was 231 ng/mL x h (range, 47.6-259.5). The mean peritoneal advantage (AUC(peritoneal)/AUC(plasma)) was 847 (range, 356-1,385).


CONCLUSIONS
I.p. administration of gemcitabine is tolerated within the tested dosage range. Technical problems with the Porta-Cath device and i.p. therapy per se may have been exacerbated by the enrollment of many patients with a variety of advanced i.p. diseases. Given the significant increase in local dose intensity and the documented activity of this drug, this agent may be an excellent candidate for i.p. therapy in optimally debulked ovarian cancer, either alone or in combination.
Morgan
Robert J
RJ
Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, California, USA. rmorgan@coh.org
Synold
Timothy W
TW
Xi
Bixin
B
Lim
Dean
D
Shibata
Stephen
S
Margolin
Kim
K
Schwarz
Roderich E
RE
Leong
Lucille
L
Somlo
George
G
Twardowski
Przemyslaw
P
Yen
Yun
Y
Chow
Warren
W
Tetef
Merry
M
Lin
Paul
P
Paz
Benjamin
B
Koczywas
Mariana
M
Wagman
Lawrence
L
Chu
David
D
Frankel
Paul
P
Stalter
Susan
S
Doroshow
James H
JH
D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007263:Infusions, Parenteral; D008297:Male; D008875:Middle Aged; D010534:Peritoneal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000093542:Gemcitabine
D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; D000093542:Gemcitabine