Intratumorale Thymidylatsynthasespiegel können ein längeres tumorfreies Überleben unter adjuvanter 5-Fluorouraciltherapie bei Patienten mit kolorektalen Karzinomen vorhersagen

Abstract

Patients with stage II and III colorectal cancer may receive adjuvant 5-fluorouracil (5- FU) after Ro resection of their primary tumor. In spite of this adjuvant treatment 30 – 40% of the patients develop local or distant recurrences. Owing to the fact that 30% of the patients will never develop a recurrence, even without adjuvant therapy, only 30% really profit from the adjuvant treatment. Presently it is not possible to identify responded and non-responders. However, several in vitro and in vivo studies have shown that high intratumoral thymidylate synthase (TS) levels are associated with 5-FU resistance. TS is a key enzyme of DNA synthesis and is irreversibly blocked by the active metabolite of 5-FU. The aim of this retrospective study was to investigate the value of intratumoral TS quantitation as a predictive marker for disease-free survival and recurrence in patients with colorectal cancer receiving adjuvant 5-FU chemotherapy. Therefore, we investigated patients from two adjuvant prospective-randomized multicenter studies (FOGT 1 — colon cancer, FOGT 2 — rectal cancer). Independently of the study arm, all patients received weekly 5-FU (450 mg/m2 i.v. in 90 min) in combination with levamisol (3x50 mg/day for 3 days every 14 days) until postoperative week 52. Patient monitoring was independent of this data evaluation. TS mRNA quantitation was performed from paraffin-embedded primary tumor sections using polymerase chain reaction after RNA isolation and reverse transcription. TS quantitation was successfully performed in 194 patients. Based on other studies (Salonga et al. 2000), patients were stratified according to their high (n = 88) and low (n = 106) TS level. Patients with high and low TS did not show a difference in recurrence rate, with 36 and 35%, respectively. The median diseasefree survival of patients with low TS (38 of 106) was 644 days (389 – 770 days). In contrast, the median disease-free survival of patients with high TS (31 of 88) was only 364 days. Patients with low TS levels had a 1.8-fold longer disease-free survival than patients with high TS (p = 0.0156 log-rank test). We conclude from the results of this retrospective study that patients with low TS profit more from adjuvant 5-FU chemotherapy than patients with high TS levels. In order to improve adjuvant treatment of colorectal cancer, in the future, patients with low TS should receive low dose 5-FU and leucovorin, whereas patients with high TS should receive other 5-FU regimens or other agents for adjuvant treatment.