Substitution of anti-androgens and tegafur-uracil combination therapy for castration-resistant prostate cancer: Results of a multi-center randomized phase II study

Abstract

We conducted this study to determine whether substitution with anti-androgen (SOA) and tegafur-uracil (a pro‑drug of 5-FU) combination therapy is more effective than SOA alone after relapse from initial hormonal therapy. Patients who were histologically confirmed and relapsed after initial hormonal therapy were included. All patients were randomly allocated into two groups: SOA alone (group A) or SOA combined with tegafur-uracil (group B). The mRNA expression of four enzymes, including thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), orotate phospho-ribosyltransferase (OPRT) and thymidine phosphorylase (TP), in prostate cancer cells was analyzed by quantitative reverse-transcription polymerase chain reaction. Fifty-two patients were enrolled in this study. The median age was 77 (range: 47-92) years. The PSA response rate in group B (61.5%) tended to be higher compared to that in group A (34.6%) (p=0.095). Group B (median: 15.9 months) had a significantly longer time to PSA progression (TTP) compared to group A (6.4 months) (p=0.014). In patients with a lower TS expression or a higher OPRT expression, group B demonstrated a higher PSA response rate compared to group A (p=0.019 and p=0.041, respectively). In addition, in the patients with a lower TS expression, group B demonstrated a significantly longer TTP compared to group A (p=0.018). There were no severe adverse events in either treatment group. After relapse from initial hormonal therapy, SOA combined with tegafur-uracil is effective and well tolerated. The TS mRNA expression level may be a predictive factor for this combination therapy.

Efficacy and Safety of Neoadjuvant Luteinizing Hormone-Releasing Hormone Antagonist and Tegafur-Uracil Chemohormonal Therapy for High-Risk Prostate Cancer

“…In this study, we reported that neoadjuvant LHRH antagonist and UFT combination therapy for high-risk PCa was similar to the BCR of low- and intermediate-risk PCa in patients who underwent RARP. Selecting UFT as a neoadjuvant treatment for high-risk PCa was based on the results of subsequent clinical studies [ 22 , 23 , 24 ]. Takahashi et al [ 22 ] conducted a multicenter prospective randomized phase II trial to evaluate the efficacy and safety of ADT + UFT versus ADT alone for CRPC.…”

“…Tegafur-uracil (UFT) is an oral cytotoxic prodrug of 5-fluorouracil (5-FU) that contains tegafur and uracil in a 1:4 molar ratio [ 22 , 23 ]. Tegafur is metabolized in the liver to 5-FU, and uracil prevents 5-FU degeneration [ 22 ]. Adjuvant chemotherapy with UFT has been demonstrated to be effective against several types of cancer [ 22 ].…”

“…Tegafur is metabolized in the liver to 5-FU, and uracil prevents 5-FU degeneration [ 22 ]. Adjuvant chemotherapy with UFT has been demonstrated to be effective against several types of cancer [ 22 ]. Uracil competitively inhibits 5-FU metabolism and prevents its rapid degradation, resulting in tumor-selective prolonged 5-FU activity [ 23 ].…”

“…Uracil competitively inhibits 5-FU metabolism and prevents its rapid degradation, resulting in tumor-selective prolonged 5-FU activity [ 23 ]. The efficacy and safety of UFT-containing regimens have been reported for various malignant neoplasms, including lung, breast, gastric, and castration-resistant PCa (CRPC) [ 22 , 23 , 24 ]. The usefulness of UFT for treating CRPC has been demonstrated in late-line administration and combination with other anticancer agents [ 22 , 23 , 24 ].…”

“…The efficacy and safety of UFT-containing regimens have been reported for various malignant neoplasms, including lung, breast, gastric, and castration-resistant PCa (CRPC) [ 22 , 23 , 24 ]. The usefulness of UFT for treating CRPC has been demonstrated in late-line administration and combination with other anticancer agents [ 22 , 23 , 24 ]. Therefore, we focused on the UFT that is easy to administer and effective for CRPC.…”