Response prediction in hepatic artery infusion with fluoropyrimidines using cell culture and thymidylate synthase quantitation

K. H. Link, M. Kornmann, H. J. Lenz, U. Butzer, J. Pillasch, F. Safi, F. Gansauge, K. D. Danenberg, P. V. Danenberg, H. G. Beger

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Since non-responders to chemotherapy should be withheld from therapy, while treatment should be administered to all responders, our aim was to predict individual response (CR + PR) and resistance (NC + PD) of patients with isolated non resectable liver metastases treated regionally with fluoropyrimidines via an intraarterial (i.a.) access device using the combination of the human tumor colony-forming assay (HTCA) and the quantitation of thymidylate synthase gene expression (TSGE). This treatment and selection strategy might save unnecessary toxicity and resources and increase response rates in the treated group. Biopsies of 15 patients (pts) with liver metastases of colorectal cancer (CRC) and 1 pt with liver metastases of an unknown primary tumor were tested in the HTCA for 5- fluorouracil (FU)/folinic acid (FA) sensitivity and/or were quantitated for TSGE. The HTCA was performed in soft agar culture with continuous 5-FU/FA exposure, the TSGE by using the polymerase chain reaction with β-actin expression as an internal standard. Nine pts received 5-FU/FA via ports and 7 pts 5-fluoro-2'-deoxyuridine (FUDR) via totally implantable pumps. Response was evaluated after 2 or 3 therapy cycles according to WHO criteria. One out of 16 pts achieved a CR and 5/16 PR (CR + PR: 6/16, 37.5%), while 6/16 pts showed NC and 4/16 PD. In 9 pts the combination of the HTCA and TSGE was used for correlative clinical response prediction, while in 7 pts only TSGE data were available, since no HTCA result could be obtained. If in vitro resistance was defined as TSGE > 8 x 10-3 and reduction of colony growth < 50% in the HTCA, all pts classified in vitro resistant (6/16) showed clinical resistance (NC + PD) to fluoropyrimidine treatment. There was no pt resistant in vitro, who responded clinically. With the definition of in vitro sensitivity as TSGE ≤ 8 x 10-3 and reduction of colony growth ≥ 50% in the HTCA 6/10 in vitro sensitive pts showed clinical response (1 CR, 5 PR) and 4/10 did not respond (2 NC, 2 PD). Using the test combination 100% (6/6, test sensitivity) of the responders and 60% (6/10, test specificity) of the non-responders were predicted correctly. In vitro sensitivity corresponded in 60% (6/10) with clinical outcome, in vitro resistance in 100% (6/6). In view of these results, the HTCA and TSGE in combination might be valuable in vitro techniques for prediction of clinical resistance and response to fluoropyrimidines administered regionally to the liver.

Original languageEnglish
Pages (from-to)115-121
Number of pages7
JournalRegional Cancer Treatment
Issue number3-4
Publication statusPublished - 1995
Externally publishedYes


  • 5-fluorouracil (FU)
  • Chemosensitivity
  • Colorectal liver metastases
  • Human tumor colony-forming assay (HTCA)
  • Thymidylate synthase gene expression (TSGE)

ASJC Scopus subject areas

  • Oncology
  • Pharmacology


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