Thymidylate synthase quantitation and in vitro chemosensitivity testing predicts responses and survival of patients with isolated nonresectable liver tumors receiving hepatic arterial infusion chemotherapy

Abstract

BACKGROUND Patients with isolated, nonresectable liver tumors may receive regional hepatic arterial infusion (HAI) chemotherapy with response rates of about 50%. The objective of this study was to investigate the value of thymidylate synthase (TS) determination in combination with in vitro chemosensitivity testing to predict the responses and survival of patients receiving HAI. METHODS TS mRNA expression was quantitated using a reverse transcription–polymerase chain reaction technique with β‐actin as the internal standard. In vitro chemosensitivity testing was performed with tumor cell suspensions using the human tumor colony‐forming assay (HTCA). RESULTS An analysis of the test combination in 24 consecutive patients revealed that 77% (10 of 13) of the sensitive and 9% (1 of 11) of the resistant patients had complete or partial clinical responses. Sensitive patients were 8.5‐fold more likely to respond (P = 0.0036) and displayed with 32 months (range, 5–75 months) a longer median survival than resistant patients with 17 months (range, 3–28 months, P = 0.003). Analysis of the Kaplan–Meier curves revealed that sensitive patients had a higher overall survival probability, as determined by the log rank test (P = 0.044). CONCLUSIONS These results suggest that the clinical outcomes of patients receiving HAI therapy may be predictable with TS quantitation and HTCA. It is possible, therefore, that this combination may be used in the future to select patients with liver tumors who will benefit from HAI before the start of regional chemotherapy. Cancer 2000;89:288–96. © 2000 American Cancer Society.

Are Colon and Rectal Cancer Two Different Tumor Entities? A Proposal to Abandon the Term Colorectal Cancer

“…Various prognostic molecular or enzymatic factors have been tested in CC, RC, and CRC in the spontaneous courses and in multimodal therapy aiming at personalized treatment. We and other groups [ 132 , 134 ] were the first to study the potential role of TS and DPD to individualize patient selection for adjuvant/neoadjuvant and for palliative treatment in CRC [ 62 , 150 , 151 ] and conducted the first prospective randomized trial for treatment of metastases [ 130 ] to introduce individualization to surgical oncology. Comparing the results from multimodal trials about molecular prognostic factors possibly used for treatment individualization reveal rather different results for CC and RC.…”

“…Treatment individualization may be possible in metastatic disease using fluropyrimide modulating protocols as well [ 130 , 150 , 151 , 152 ]. However, nobody so far distinguished the primary origin in metastatic CRC disease.…”

Thymidylate synthetase mRNA levels are increased in liver metastases of colorectal cancer patients resistant to fluoropyrimidine-based chemotherapy

“…Both preclinical and clinical data have suggested that TS expression may be useful for predicting clinical response of metastatic CRC patients to fluoropyrimidine based chemotherapy [15-17]. Several in vitro studies have demonstrated an increased level of TS expression in tumor cells resistant to fluoropyrimidines [18].…”

Patient-centered developments in colon- and rectal cancer with a multidisciplinary international team: From translational research to national guidelines

“…First, being cautious, we correlated the in vitro results with the individual clinical responses to HAI, and then we used the drugs effective in vitro to add to 5-FU + FA for HAI in vivo [ 40 , 41 ]. After we had seen that patients with low TS responded very well to HAI with 5-FU[ 27 , 42 ] and that drug selection with the HTCA was possible[ 40 ] we finally added TS determination to our prospective in vitro individualization trial. With this strategy we were able to show an impressive response rate of 77% and median survival time of 32 mo in in vitro sensitive patients vs 9%/17 mo of the in vitro resistant patients receiving the standard MFFM protocol (Table 1 )[ 42 ].…”