A longterm follow-up study of thymidylate synthase as a predictor for survival of patients with liver tumours receiving hepatic arterial infusion chemotherapy.
OBJECTIVE
Thymidylate synthase (TS) is a key-enzyme for DNA synthesis and targeted by fluoropyrimidines (FPs). High TS ratios are associated with resistance to systemic FP-based chemotherapy. The aim of this study was to report the influence of TS ratios on primary tumour response to FP-based HAI and long-term follow-up of patients with isolated non-resectable liver tumours in part from a previously published study.


METHODS
Fifty-one consecutive patients with liver tumours receiving HAI with available tumour tissue for TS quantitation were studied between 1991 and 2001. Liver metastases were from colorectal origin in 41 patients and other primary sites in 6 patients. Four patients had primary liver cancers. Tumour tissue was obtained at laparotomy for the intraarterial infusion device implantation. TS mRNA quantitation was performed by RT-PCR using beta-actin as internal standard.


RESULTS
The median TS ratio was 2.2 with high variation among tumours ranging from 0.1 to 27. Twenty-two out of 51 patients responded to HAI. The median TS ratio of the responders was 1.6 and more than two-fold lower than the ratio of the non-responders with 3.3 (p < 0.01). In the subgroup with TS<or=3.0, 18 out of 29 patients responded. In the subgroup with TS>3.0 only four out of 22 patients responded. No patients with very high TS ratios >or=4.5 ( n = 13) responded to HAI. Median survival was 20 months (range: 3-109). Patients with TS-ratios <or=3.0 showed, with 55%, a higher 2-year survival rate than patients with TS-ratios >3.0 with 27%.


CONCLUSIONS
TS seems to be a predictive and prognostic factor for patients with isolated non-resectable liver tumours receiving FP-based HAI. Patients with very high TS ratios do not seem to benefit from FP-based HAI.
Hillenbrand
A
A
Department of Visceral and Transplantation Surgery, University of Ulm, Steinhoevelstrasse 9, 89075 Ulm, Germany.
Formentini
A
A
Staib
L
L
Sander
S
S
Salonga
D
D
Danenberg
K
K
Danenberg
P
P
Kornmann
M
M
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015251:Epirubicin / Q000008:administration & dosage; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D005500:Follow-Up Studies; D006801:Humans; D007261:Infusions, Intra-Arterial; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D016019:Survival Analysis; D013940:Thymidylate Synthase / Q000378:metabolism*; D016896:Treatment Outcome
D015251:Epirubicin; D013940:Thymidylate Synthase; D005472:Fluorouracil