Ninety-six-hour paclitaxel infusion after progression during short taxane exposure: A phase II pharmacokinetic and pharmacodynamic study in metastatic breast cancer Journal Article


Authors: Seidman, A. D.; Hochhauser, D.; Gollub, M.; Edelman, B.; Yao, T. J.; Hudis, C. A.; Francis, P.; Fennelly, D.; Gilewski, T. A.; Moynahan, M. E.; Currie, V.; Baselga, J.; Tong, W.; O'Donaghue, M.; Salvaggio, R.; Auguste, L.; Spriggs, D.; Norton, L.
Article Title: Ninety-six-hour paclitaxel infusion after progression during short taxane exposure: A phase II pharmacokinetic and pharmacodynamic study in metastatic breast cancer
Abstract: Purpose: A phase II trial of paclitaxel infused over 96 hours in patients with metastatic breast cancer with demonstrated disease progression (PD) during short-infusion taxone treatment was performed to evaluate schedule-dependent activity with prolonged drug exposure. The tolerability of this strategy and its pharmacokinetic profile and pharmacodynamic correlates were also investigated. Patients and Methods: Paclitaxel was administered to 26 patients with metastatic breast cancer at 120 to 140 mg/m2 intravenously over 96 hours. Twenty-three patients had demonstrated PD while receiving prior 3-hour paclitaxel, two during 1-hour docetaxel, and one during infusions of docetaxel and then paclitaxel. Twenty-one patients (81%) had no prior response to the short taxane infusion (primary resistance) and five (19%) had prior partial responses (PRs) of brief duration before PD (secondary resistance). Plasma paclitaxel concentrations were assessed at 24, 48, 72, and 96 hours. Results: After delivery of 195 cycles, seven of 26 assessable patients (26.9%; 95% confidence interval, 11.6% to 47.8%) had major objective responses, with a median response duration of 6 months (range, 1 to 13). The predominant toxicities were neutropenia (76% grade ≥ 3) and stomatitis (15% grade ≥ 3). Despite omission of premeditations, no significant hypersensitivity reactions occurred. The median steady-state paclitaxel concentration (Css) in 23 assessable patients was 0.047 μmol/L (range, .023 to .176). Patients who experienced grade 4 neutropenia had significantly decreased paclitaxel clearance and higher Css than those with grade 1 to 3 neutropenia (P < .05). Pretreatment elevation of hepatic transaminases was associated with delayed clearance (P < .01) and increased myelo-suppression and mucosal toxicity. Conclusion: Paclitaxel demonstrates activity against metastatic breast cancer when administered over 96 hours to patients with disease that recently had progressed during short taxane exposure. Delayed paclitaxel clearance and consequent increased toxicity occured in patients with hepatic dysfunction. The activity observed supports preclinical data that suggest variability in efficacy and resistance patterns to paclitaxel based on duration of exposure. © 1996 by American Society of Clinical Oncology.
Keywords: adult; clinical article; human tissue; aged; middle aged; human cell; histopathology; neutropenia; drug efficacy; paclitaxel; metastasis; breast cancer; antineoplastic agents, phytogenic; breast neoplasms; docetaxel; taxoids; taxane derivative; recombinant granulocyte colony stimulating factor; infusions, intravenous; granulocytopenia; intravenous drug administration; dose time effect relation; bridged compounds; long term exposure; cremophor; subcutaneous drug administration; humans; human; female; priority journal; article
Journal Title: Journal of Clinical Oncology
Volume: 14
Issue: 6
ISSN: 0732-183X
Publisher: American Society of Clinical Oncology  
Date Published: 1996-06-01
Start Page: 1877
End Page: 1884
Language: English
DOI: 10.1200/jco.1996.14.6.1877
PUBMED: 8656256
PROVIDER: scopus
DOI/URL:
Notes: Article -- Export Date: 22 November 2017 -- Source: Scopus
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MSK Authors
  1. William Ping-Yiu Tong
    122 Tong
  2. Andrew D Seidman
    244 Seidman
  3. Clifford Hudis
    840 Hudis
  4. Larry Norton
    562 Norton
  5. Marc J Gollub
    105 Gollub
  6. Tzy-Jyun Yao
    42 Yao
  7. David R Spriggs
    312 Spriggs
  8. Violante Currie
    30 Currie
  9. Jose T Baselga
    395 Baselga