Phase I trial of intraperitoneal iododeoxyuridine with and without intravenous high-dose folinic acid in the treatment of advanced malignancies primarily confined to the peritoneal cavity: flow cytometric and pharmacokinetic analysis.
In this Phase I study, the maximally tolerated doses (MTDs) of i.p. iododeoxyuridine (IdUrd) alone and in combination with i.v. calcium leucovorin (LV) were determined. The pharmacokinetics and pharmacological advantage of IdUrd were evaluated, and flow cytometric analysis allowed examination of the extent of incorporation of IdUrd into tumor cells with and without the addition of i.v. LV. Thirty-nine patients with advanced neoplasms primarily confined to the peritoneal space were enrolled in a dose-escalation trial using 4-h dwells of IdUrd administered i.p. daily for 4 days with and without an i.v. infusion of LV 500 mg/m2/day for 4.5 days. Twenty-three patients received single-agent therapy, and 13 patients received i.p. IdUrd in combination with i.v. LV. The MTD of single-agent IdUrd administered on this schedule was 4125 mg/m2/day for 4 days; and that of the IdUrd in combination was 3438 mg/m2/day. Dose-limiting toxicities were myelosuppression and stomatitis. During the period of the dwell, the peritoneal AUC (area under the curve) of IdUrd exceeded the plasma AUC of IdUrd by one or two orders of magnitude in all patients at all doses tested; there was a possible effect of LV on peritoneal AUC. The geometric mean pharmacological advantage (AUCperitoneal/ AUCplasma) was 181 at 625 mg/m2/day and 90 at 4538 mg/m2/day. Flow cytometric analysis suggests saturation of IdUrd measured in DNA at the 2500-3125 mg/m2 dose level, without an increase after the addition of LV. Twelve patients received 4-12 courses of therapy. One patient with recurrent ovarian cancer who received 16 courses of therapy experienced complete resolution of her ascites, near normalization of CA-125 levels, and improved quality of life; two patients with high-risk tumors receiving "adjuvant" therapy are disease-free at 3 and 6 years after treatment; other patients experienced transient clearing of ascites. The recommended Phase II dose of i.p. IdUrd using a 4-h dwell daily for 4 days is 3750 mg/m2/day alone or 3125 mg/m2/day in combination with continuous i.v. LV at 500 mg/m2/day for 4.5 days. Although flow cytometric data suggest that DNA incorporation of IdUrd is not affected by the addition of LV, the cytotoxicity of the combination regimen may be increased due to LV-enhanced, IdUrd-related inhibition of thymidylate synthase. For this reason, we recommend that efficacy studies of the combination continue in parallel with studies of IdUrd alone.
Morgan
R J
RJ
Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, California 91010, USA.
Newman
E M
EM
Doroshow
J H
JH
McGonigle
K
K
Margolin
K
K
Raschko
J
J
Chow
W
W
Somlo
G
G
Leong
L
L
Tetef
M
M
Shibata
S
S
Hamasaki
V
V
Carroll
M
M
Vasilev
S
S
Akman
S
S
Coluzzi
P
P
Wagman
L
L
Longmate
J
J
Paz
B
B
Yen
Y
Y
Klevecz
R
R
D000328:Adult; D000368:Aged; D000931:Antidotes / Q000008:administration & dosage*; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D018394:CA-125 Antigen / Q000097:blood; D004273:DNA, Neoplasm / Q000378:metabolism; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000097:blood / Q000188:drug therapy; D006801:Humans; D007065:Idoxuridine / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D002955:Leucovorin / Q000008:administration & dosage*; D008297:Male; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000097:blood / Q000188:drug therapy; D010190:Pancreatic Neoplasms / Q000097:blood / Q000188:drug therapy; D010534:Peritoneal Neoplasms / Q000097:blood / Q000188:drug therapy*
D000931:Antidotes; D000964:Antimetabolites, Antineoplastic; D018394:CA-125 Antigen; D004273:DNA, Neoplasm; D007065:Idoxuridine; D002955:Leucovorin