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ANTICANCER RESEARCH 35: 1603-1606 (2015)

Efficacy of Tegafur-Uracil in Advanced Urothelial Cancer Patients after the Treatment Failure of Platinum-based

AERKEN MAOLAKE1, KOUJI IZUMI1, RIE TAKAHASHI2, SHINGO ITAI2, KAZUAKI MACHIOKA1, HIROSHI YAEGASHI1, TAKAHIRO NOHARA1, YASUHIDE KITAGAWA1, YOSHIFUMI KADONO1, HIROYUKI KONAKA1, ATSUSHI MIZOKAMI1 and MIKIO NAMIKI1

1Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, Ishikawa, Japan; 2Department of Hospital Pharmacy, Kanazawa University Hospital, Ishikawa, Japan

Abstract. Background: Platinum-based chemotherapy is the Platinum-based chemotherapy is the first-line treatment for first-line treatment for advanced urinary tract urothelial inoperable locally advanced or metastatic urinary tract cancers. However, the optimal second-line treatment is unclear. urothelial cancer (lamUC). The // Although tegafur-uracil is sometimes used for advanced / (MVAC) protocol was used as the urothelial cancer patients after the treatment failure of standard first-line treatment for patients with inoperable platinum-based chemotherapy, there is little evidence regarding locally advanced or metastatic bladder cancer (2, 3). its use as a second-line treatment. Patients and Methods: Because upper urinary tract cancer, including both renal Advanced urothelial cancer patients previously treated with pelvic cancer and ureteral cancer, is pathologically same as platinum-based chemotherapy were retrospectively analyzed. bladder cancer, chemotherapeutic protocols administered for Overall survival (OS) was compared between patients with and bladder cancer have been widely applied. However, MVAC without tegafur-uracil treatment. Results: Thirty-one patients is associated with a high incidence of severe adverse events (27 and 4 patients with and without tegafur-uracil treatment, (sAEs). The /cisplatin (GC) protocol was respectively) were analyzed. OS from the last day of the final developed as an alternative first-line treatment and was chemotherapy course was better in patients with tegafur-uracil associated with a similar clinical efficacy and less sAEs than treatment than in those without (p<0.001, 358 and 66.5 days of MVAC (4). Recently, dose-dense protocols for MVAC and the median survival time, respectively). Conclusion: Tegafur- GC were developed, which yielded better efficacy than uracil may be a candidate for the secondary treatment of conventional MVAC and GC. Of these, dose-dense GC was advanced urothelial cancer patients after the treatment failure used as the standard first-line treatment because of its better of platinum-based chemotherapy. tolerability than dose-dense MVAC (5). In contrast to the well-characterized first-line treatments, the Localized upper urinary tract urothelial cancer and localized standard treatment for lamUC patients after the treatment muscle-invasive bladder cancer are usually treated with failure of platinum-based chemotherapy remains unclear. nephroureterectomy and cystectomy. However, the incidence Impaired renal function, poor performance status, advanced of recurrence or metastasis is not rare and systemic age and comorbidities in such patients result in limited trial chemotherapy is required for such patients, as well as those feasibility; therefore, second-line treatment protocols with a with inoperable advanced urinary tract urothelial cancer (1). low incidence of sAEs for lamUC after the treatment failure of first-line platinum-based chemotherapy need to be developed (6). Tegafur-uracil, an oral anti-tumour agent with less toxicity than intravenous chemotherapy agents, is the pro- Correspondence to: Kouji Izumi, MD, Ph.D., Kanazawa University drug of 5- and used as a standard post-operative Graduate School of Medical Science, Department of Integrative adjuvant treatment in early stage (7, 8). Although Cancer Therapy and Urology, 13-1 Takaramachi Kanazawa, Ishikawa, 920-8640 Japan. Tel: +81 762652393, Fax: +81 there are no current reports regarding the efficacy of tegafur- 762226726, e-mail: [email protected] uracil in lamUC, its efficacy in early-stage non-invasive bladder cancer has been reported (9-11). Therefore, tegafur- Key Words: Urothelial carcinoma, tegafur-uracil, chemotherapy. uracil is sometimes used to treat lamUC patients after the

0250-7005/2015 $2.00+.40 1603 ANTICANCER RESEARCH 35: 1603-1606 (2015) treatment failure of first-line platinum-based chemotherapy. Table I. Patients’ background. However, there is little evidence to support its use as a second- line treatment. Therefore, the efficacy of tegafur-uracil was TU(−) TU(+) p-Value examined retrospectively in this study. n427 Median age (range), year 66 (65-79) 74 (54-84) 0.327 Patients and Methods Gender M 2 17 0.630 Study population. Patients with inoperable lamUC treated with F210 platinum-based chemotherapy as the first-line treatment at the Primary site Kanazawa University Hospital between 2008 and 2013 were UUT 1 16 0.304 identified using patients’ charts. All patients had histologically- B311 confirmed urothelial carcinoma of the bladder, ureter or renal pelvis. T ≤2 1 7 1.00 Definitions and outcomes. Cisplatin and were the ≥3 3 16 platinum agents used in the patients included in this study. The resected 0 4 treatments used after the failure of first-line platinum-based N chemotherapy were checked and patient’s backgrounds, as well as 0 0 12 0.139 overall survival (OS) from the last day of previous chemotherapy ≥1 4 15 were compared between patients with and without tegafur-uracil M treatment. Factors predictive of OS in lamUC patients with tegafur- 0 1 6 1.00 uracil treatment were also investigated. The Seventh Edition of the 1321 TNM Classification of Malignant Tumors (Union for International Median course No. (range) 4 (2-6) 3 (1-8) 0.484 Cancer Control) was used for TNM staging. CTx protocol GC 3 6 Statistical analyses. Statistical analyses were performed using the MVAC 0 6 commercially available software Prism (GraphPad, San Diego, GCar 1 8 CA, USA) and SPSS (IBM, Armonk, NY, USA). Comparisons GC + MVAC 0 3 between the two groups were performed using unpaired two-sided GC + GCar + MVAC 0 1 t-tests and Fisher’s exact tests. OS was estimated using the MVAC + PCG 0 2 Kaplan–Meier method. Univariate analyses of differences among Wk Car 0 1 patient groups were performed using log rank tests. Multivariate analysis was performed to identify independent prognostic factors TU, Tegafur uracil; M, male; F, female; UUT, upper urinary tract; B, using Cox’s proportional hazards regression and stepwise bladder; CTx, chemotherapy; GC, gemcitabine + cisplatin; MVAC, backward procedures. In all analyses, p<0.05 was taken to indicate methotrexate + vinblastine + doxorubicin + cisplatin; GCar, gemcitabine statistical significance. + carboplatin; PCG, + cisplatin + gemcitabine; Wk Car, weekly carboplatin. Five weeks of Wk Car was counted as one course. Results Patients’ background. The number of patients with and without tegafur-uracil treatment after the treatment failure of Factors predictive of survival in patients treated with platinum-based chemotherapy was 27 and 4, respectively. tegafur-uracil. To determine the factors that were indicative There were no differences in age, gender, primary tumor site, of better survival, univariate analysis was performed for six TNM stage and total number of courses of chemotherapy variables; age at diagnosis, sex, primary site, duration of between the two groups. A variety of platinum-based chemotherapy, interval from the last day of previous chemotherapy protocols were administered other than MVAC chemotherapy to the first day of tegafur-uracil treatment and and GC. Carboplatin was mainly administered in cisplatin- dose of tegafur-uracil. The occurrence of more than 30 days unfit patients with insufficient renal function. A couple of from the last day of the previous chemotherapy to the day platinum-based chemotherapy protocols were administered for of commencing tegafur-uracil and a dose of tegafur-uracil identical patients as the subsequent chemotherapy after the of 400 mg/day were significant factors for long survival treatment failure of first-line chemotherapy (Table I). (p=0.008 and p=0.002, respectively). Multivariate analysis revealed that a dose of 400 mg/day of tegafur-uracil was a Overall survival in patients with or without tegafur-uracil. The significant factor for long survival with a hazard ratio of 4.7 OS of lamUC patients with and without tegafur-uracil (p=0.019, 95% confident interval 1.292–17.11) (Table II). treatment was estimated. There was a significant difference The OS of lamUC patients with 400 mg/day and between the two groups (p<0.001); the median survival time ≤300 mg/day tegafur-uracil treatment was estimated and the of patients with and without tegafur-uracil treatment was 358 median survival time was 734 days and 209 days, and 66.5 days, respectively (Figure 1). respectively (Figure 2).

1604 Maolake et al: Tegafur-Uracil for Advanced Urothelial Cancer

Figure 1. The overall survival of locally advanced or metastatic urinary Figure 2. The overall survival of locally advanced or metastatic urinary tract urothelial cancer patients with or without tegafur-uracil (TU) tract urothelial cancer patients treated with 400 mg/day or ≤300 mg/day treatment after treatment failure of platinum-based chemotherapy was of tegafur-uracil was estimated using the Kaplan–Meier method estimated using the Kaplan-Meier method (p<0.001). (p=0.002).

Table II. Univariate and multivariate analyses of the clinical variables and overall survival.

HR (95%CI) p-Value

Univariate analysis Age at diagnosis, <75 vs. ≥75 years 0.724 (0.281-1.86) 0.451 Gender, F vs. M 0.628 (0.240-1.64) 0.343 Primary site, B vs. UUT 1.65 (0.625-4.33) 0.314 Duration of CTx, ≤90 vs. >90 days 0.870 (0.342-2.21) 0.770 Interval from CTx to TU, ≤30 vs. >30 days 4.34 (1.47-12.8) 0.008 Dose of TU, ≤300 vs. 400 mg/day 4.45 (1.72-11.5) 0.002 Multivariate analysis Interval from CTx to TU, ≤30 vs. >30 days 2.75 (0.910-8.33) 0.073 Dose of TU, ≤300 vs. 400 mg/day 4.70 (1.29-17.1) 0.019

HR, Hazard ratio; CI, confidence interval. All other abbreviations are the same as those used in Table I.

Discussion in 2013 demonstrated that significantly prolonged OS compared with best supportive care in the eligible Although platinum-based chemotherapy is used as the first- population (median survival time of 6.9 and 4.3 months, line treatment for lamUC, there is still no evidence to support respectively) (12, 13). In the present study, the median survival a standard second-line treatment. Because the survival time of time of patients with tegafur-uracil treatment was 12 months; lamUC patients in whom platinum-based chemotherapy fails surprisingly the median survival time of patients treated with is extremely limited, it is urgent and necessary for patients, 400 mg/day tegafur-uracil was 24 months. These data suggest urologists and oncologists to develop an appropriate second- that tegafur-uracil may be more beneficial than vinflunine. line treatment for lamUC. A randomized phase III trial of Moreover, a high incidence of grade 3 and 4 sAEs was vinflunine after the treatment failure of platinum-based reported in patients with vinflunine, whereas sAEs were rare chemotherapy was performed recently in lamUC patients. in the present study. Consistent with this, a randomized phase Although there was no statistically significant difference in OS III trial using tegafur-uracil and S-1 for locally advanced between vinflunine and the best supportive care group in gastric cancer patients showed that the most frequent sAE intention to treat analysis at the first report in 2009, the during a 2-year treatment with tegafur-uracil alone group was subsequent long-term follow-up results of the study reported neutropenia with an incidence of only 11% compared to 50%

1605 ANTICANCER RESEARCH 35: 1603-1606 (2015) with vinflunine. The incidence of all other sAEs, including Fountzilas G and Dimopoulos MA: Prospective, open-label, both haematological and non-haematological events, in the randomized, phase III study of two dose-dense regimens MVAC tegafur-uracil-alone group was <10% (14). Therefore, in the versus gemcitabine/cisplatin in patients with inoperable, metastatic or relapsed urothelial cancer: a Hellenic Cooperative Oncology present study, most patients with tegafur-uracil treatment could Group study (HE 16/03). Ann Oncol 24: 1011-1017, 2013. be treated as outpatients. In addition, tegafur-uracil may be 6 Bellmunt J, Choueiri TK, Schutz FA and Rosenberg JE: acceptable for older patients, as well as those with a relatively Randomized phase III trials of second-line chemotherapy in poor performance status. However, the results of these patients with advanced bladder cancer: progress and pitfalls. Ann comparisons may not be correct because of differences in Oncol 22: 245-247, 2011. background between the present study and previous studies 7 Hamada C, Tanaka F, Ohta M, Fujimura S, Kodama K, Imaizumi using vinflunine or other agents. Also, the possibility that M and Wada H: Meta-analysis of postoperative adjuvant tegafur-uracil was unintentionally administered to patients who chemotherapy with tegafur-uracil in non-small-cell lung cancer. J Clin Oncol 23: 4999-5006, 2005. were in a better systemic condition compared to those who did 8 Hamada C, Tsuboi M, Ohta M, Fujimura S, Kodama K, Imaizumi not receive tegafur-uracil should also be considered. As such, M and Wada H: Effect of postoperative adjuvant chemotherapy with utmost care should be taken when comparing the present study tegafur-uracil on survival in patients with stage IA non-small cell with previous observations. lung cancer: an exploratory analysis from a meta-analysis of six This study has some limitations. This was a retrospective randomized controlled trials. J Thorac Oncol 4: 1511-1516, 2009. study with a small sample size and all patients were Japanese. 9 Uchibayashi T, Kunimi K, Yamamoto H and Koshida K: Adjuvant Therefore, evidence needs to be accumulated because the therapy with 5-fluoro-1-(2-tetrahydrofuryl)-2,4 (1H,3H)- pyrimidinedione (UFT) and Bestatin in patients with transitional incidence of lamUC is relatively low. A prospective randomized cell carcinoma of the bladder – comparison between UFT therapy controlled trial with a large-sized population is required to alone and UFT therapy in combination with Bestatin. Int J Clin confirm our preliminary observations regarding the efficacy of Pharmacol Ther 33: 465-468, 1995. tegafur-uracil in lamUC patients after the treatment failure of 10 Kubota Y, Hosaka M, Fukushima S and Kondo I: Prophylactic oral first-line platinum-based chemotherapy. Nevertheless, this is the UFT therapy for superficial bladder cancer. Cancer 71: 1842-1845, first report to clarify the efficacy of tegafur-uracil; the data 1993. suggest that tegafur-uracil may be a candidate for the second- 11 Hirao Y, Okajima E, Ozono S, Samma S, Sasaki K, Hiramatsu T, line treatment of lamUC patients after the treatment failure of Babaya K, Watanabe S and Maruyama Y: A prospective randomized study of prophylaxis of tumor recurrence following platinum-based chemotherapy with little toxicity. The optimal transurethral resection of superficial bladder cancer – intravesical dose of tegafur-uracil for the best response may be 400 mg/day. thio-TEPA versus oral UFT. Cancer Chemother Pharmacol 30 Suppl: S26-30, 1992. 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