Phase I trial of intraperitoneal gemcitabine in the treatment of advanced malignancies primarily confined to the peritoneal cavity

Robert J. Morgan, Timothy W. Synold, Bixin Xi, Dean Lim, Stephen Shibata, Kim Margolin, Roderich E. Schwarz, Lucille Leong, George Somlo, Przemyslaw Twardowski, Yun Yen, Warren Chow, Merry Tetef, Paul Lin, Benjamin Paz, Mariana Koczywas, Lawrence Wagman, David Chu, Paul Frankel, Susan Stalter & 1 others James H. Doroshow

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Purpose: To determine the maximally tolerated dose, toxicity, and pharmacokinetics of i.p. gemcitabine. Experimental Design: Patients had peritoneal carcinomatosis. Gemcitabine (40, 80, 120, or 160 mg/m2) 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/m2, 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 (AUCperitoneal/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.

Original languageEnglish (US)
Pages (from-to)1232-1237
Number of pages6
JournalClinical Cancer Research
Volume13
Issue number4
DOIs
StatePublished - Feb 15 2007

Fingerprint

gemcitabine
Peritoneal Cavity
Area Under Curve
Neoplasms
Therapeutics
Maximum Tolerated Dose
Alanine Transaminase
Ascites
Respiratory Insufficiency
Dyspnea
Ovarian Neoplasms
Nausea
Uterus
Vomiting
Pancreas
Ovary
Diarrhea
Colon
Research Design
Pharmacokinetics

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Phase I trial of intraperitoneal gemcitabine in the treatment of advanced malignancies primarily confined to the peritoneal cavity. / Morgan, Robert J.; Synold, Timothy W.; Xi, Bixin; Lim, Dean; Shibata, Stephen; Margolin, Kim; Schwarz, Roderich E.; Leong, Lucille; Somlo, George; Twardowski, Przemyslaw; Yen, Yun; Chow, Warren; Tetef, Merry; Lin, Paul; Paz, Benjamin; Koczywas, Mariana; Wagman, Lawrence; Chu, David; Frankel, Paul; Stalter, Susan; Doroshow, James H.

In: Clinical Cancer Research, Vol. 13, No. 4, 15.02.2007, p. 1232-1237.

Research output: Contribution to journalArticle

Morgan, RJ, Synold, TW, Xi, B, Lim, D, Shibata, S, Margolin, K, Schwarz, RE, Leong, L, Somlo, G, Twardowski, P, Yen, Y, Chow, W, Tetef, M, Lin, P, Paz, B, Koczywas, M, Wagman, L, Chu, D, Frankel, P, Stalter, S & Doroshow, JH 2007, 'Phase I trial of intraperitoneal gemcitabine in the treatment of advanced malignancies primarily confined to the peritoneal cavity', Clinical Cancer Research, vol. 13, no. 4, pp. 1232-1237. https://doi.org/10.1158/1078-0432.CCR-06-1735
Morgan, Robert J. ; Synold, Timothy W. ; Xi, Bixin ; Lim, Dean ; Shibata, Stephen ; Margolin, Kim ; Schwarz, Roderich E. ; Leong, Lucille ; Somlo, George ; Twardowski, Przemyslaw ; Yen, Yun ; Chow, Warren ; Tetef, Merry ; Lin, Paul ; Paz, Benjamin ; Koczywas, Mariana ; Wagman, Lawrence ; Chu, David ; Frankel, Paul ; Stalter, Susan ; Doroshow, James H. / Phase I trial of intraperitoneal gemcitabine in the treatment of advanced malignancies primarily confined to the peritoneal cavity. In: Clinical Cancer Research. 2007 ; Vol. 13, No. 4. pp. 1232-1237.
@article{2ff5d388c1664aab857e44538a48da9a,
title = "Phase I trial of intraperitoneal gemcitabine in the treatment of advanced malignancies primarily confined to the peritoneal cavity",
abstract = "Purpose: To determine the maximally tolerated dose, toxicity, and pharmacokinetics of i.p. gemcitabine. Experimental Design: Patients had peritoneal carcinomatosis. Gemcitabine (40, 80, 120, or 160 mg/m2) 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/m2, 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 (AUCperitoneal/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.",
author = "Morgan, {Robert J.} and Synold, {Timothy W.} and Bixin Xi and Dean Lim and Stephen Shibata and Kim Margolin and Schwarz, {Roderich E.} and Lucille Leong and George Somlo and Przemyslaw Twardowski and Yun Yen and Warren Chow and Merry Tetef and Paul Lin and Benjamin Paz and Mariana Koczywas and Lawrence Wagman and David Chu and Paul Frankel and Susan Stalter and Doroshow, {James H.}",
year = "2007",
month = "2",
day = "15",
doi = "10.1158/1078-0432.CCR-06-1735",
language = "English (US)",
volume = "13",
pages = "1232--1237",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "4",

}

TY - JOUR

T1 - Phase I trial of intraperitoneal gemcitabine in the treatment of advanced malignancies primarily confined to the peritoneal cavity

AU - Morgan, Robert J.

AU - Synold, Timothy W.

AU - Xi, Bixin

AU - Lim, Dean

AU - Shibata, Stephen

AU - Margolin, Kim

AU - Schwarz, Roderich E.

AU - Leong, Lucille

AU - Somlo, George

AU - Twardowski, Przemyslaw

AU - Yen, Yun

AU - Chow, Warren

AU - Tetef, Merry

AU - Lin, Paul

AU - Paz, Benjamin

AU - Koczywas, Mariana

AU - Wagman, Lawrence

AU - Chu, David

AU - Frankel, Paul

AU - Stalter, Susan

AU - Doroshow, James H.

PY - 2007/2/15

Y1 - 2007/2/15

N2 - Purpose: To determine the maximally tolerated dose, toxicity, and pharmacokinetics of i.p. gemcitabine. Experimental Design: Patients had peritoneal carcinomatosis. Gemcitabine (40, 80, 120, or 160 mg/m2) 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/m2, 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 (AUCperitoneal/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.

AB - Purpose: To determine the maximally tolerated dose, toxicity, and pharmacokinetics of i.p. gemcitabine. Experimental Design: Patients had peritoneal carcinomatosis. Gemcitabine (40, 80, 120, or 160 mg/m2) 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/m2, 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 (AUCperitoneal/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.

UR - http://www.scopus.com/inward/record.url?scp=33947328024&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33947328024&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-06-1735

DO - 10.1158/1078-0432.CCR-06-1735

M3 - Article

VL - 13

SP - 1232

EP - 1237

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 4

ER -