Background: Patients (pts) with UICC stage IIb and III colon and stage II and III rectal cancer (CRC) may receive adjuvant chemotherapy with 5-fluorouracil (5-FU) and levamisol. Despite the treatment 30-40% of the patients develop local or distant tumor recurrence. Thymidylate synthase (TS) is a key enzyme in DNA synthesis and targeted by 5-FU, whereas dihydropyrimidine dehydrogenase (DPD) is the key enzyme for the inactivation and catabolism of 5-FU. High intratumoral levels of both enzymes have been associated with 5-FU resistance in advanced colorectal cancer (CRC). Aim: To investigate the value of TS and DPD as a predictive marker for disease-free survival (DFS) in pts with CRC receiving adjuvant 5-FU chemotherapy.
Methods: So far, primary tumor tissue of 348 pts with CRC, which were entered from 1992 to 1999 in our randomized adjuvant trials of colon and rectal cancer (5-FU/levamisol vs. 5-FU/levamisol with folinic acid vs. 5-FU/levamisol with interferon-g), respectively, was used for this retrospective analysis. TS and DPD mRNA quantitation was performed using an reverse transcription polymerase chain reaction technique with b-actin as internal standard.
Results: Neither TS or DPD predicted tumor recurrence nor survival in all 348 pts. However, in the subgroup of pts with tumor recurrence (130/348 = 37%) TS alone predicted DFS. Thus, pts with low TS levels (n = 84) had a median DFS of 19.4 months (range: 3.0-55.7 months) and pts with high TS levels (n = 46) of 11.7 months (range: 1.7-53.1 months; (p < 0.0001). There was also a trend for longer median DFS in pts with low DPD levels, however the difference was statistically not significant.
Conclusion: TS can predict the time to tumor recurrence in pts with CRC receiving adjuvant 5-FU treatment. It is possible that future adjuvant treatment of CRC is performed according to individual TS mRNA levels. Pts with low TS may receive adjuvant 5-FU according to current protocols, whereas pts with high TS may receive other 5-FU regimens or other agents for adjuvant chemotherapy.
