Abstract
Background: Platinum-based chemotherapy is the first-line treatment for advanced urinary tract urothelial cancers. However, the optimal second-line treatment is unclear. Although tegafur-uracil is sometimes used for advanced urothelial cancer patients after the treatment failure of platinum-based chemotherapy, there is little evidence regarding its use as a second-line treatment. Patients and Methods: Advanced urothelial cancer patients previously treated with platinum-based chemotherapy were retrospectively analyzed. Overall survival (OS) was compared between patients with and without tegafur-uracil treatment. Results: Thirty-one patients (27 and 4 patients with and without tegafur-uracil treatment, respectively) were analyzed. OS from the last day of the final chemotherapy course was better in patients with tegafur-uracil treatment than in those without (p<0.001, 358 and 66.5 days of the median survival time, respectively). Conclusion: Tegafur-uracil may be a candidate for the secondary treatment of advanced urothelial cancer patients after the treatment failure of platinum-based chemotherapy.
Localized upper urinary tract urothelial cancer and localized muscle-invasive bladder cancer are usually treated with nephroureterectomy and cystectomy. However, the incidence of recurrence or metastasis is not rare and systemic chemotherapy is required for such patients, as well as those with inoperable advanced urinary tract urothelial cancer (1). Platinum-based chemotherapy is the first-line treatment for inoperable locally advanced or metastatic urinary tract urothelial cancer (lamUC). The methotrexate/vinblastine/doxorubicin/cisplatin (MVAC) protocol was used as the standard first-line treatment for patients with inoperable locally advanced or metastatic bladder cancer (2, 3). Because upper urinary tract cancer, including both renal pelvic cancer and ureteral cancer, is pathologically same as bladder cancer, chemotherapeutic protocols administered for bladder cancer have been widely applied. However, MVAC is associated with a high incidence of severe adverse events (sAEs). The gemcitabine/cisplatin (GC) protocol was developed as an alternative first-line treatment and was associated with a similar clinical efficacy and less sAEs than MVAC (4). Recently, dose-dense protocols for MVAC and GC were developed, which yielded better efficacy than conventional MVAC and GC. Of these, dose-dense GC was used as the standard first-line treatment because of its better tolerability than dose-dense MVAC (5).
In contrast to the well-characterized first-line treatments, the standard treatment for lamUC patients after the treatment failure of platinum-based chemotherapy remains unclear. Impaired renal function, poor performance status, advanced age and comorbidities in such patients result in limited trial feasibility; therefore, second-line treatment protocols with a 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 prodrug of 5-fluorouracil and used as a standard post-operative adjuvant treatment in early stage lung cancer (7, 8). Although there are no current reports regarding the efficacy of tegafur-uracil in lamUC, its efficacy in early-stage non-invasive bladder cancer has been reported (9-11). Therefore, tegafururacil is sometimes used to treat lamUC patients after the treatment failure of first-line platinum-based chemotherapy. However, there is little evidence to support its use as a second-line treatment. Therefore, the efficacy of tegafur-uracil was examined retrospectively in this study.
Patients and Methods
Study population. Patients with inoperable lamUC treated with platinum-based chemotherapy as the first-line treatment at the Kanazawa University Hospital between 2008 and 2013 were identified using patients' charts. All patients had histologically-confirmed urothelial carcinoma of the bladder, ureter or renal pelvis.
Definitions and outcomes. Cisplatin and carboplatin were the platinum agents used in the patients included in this study. The treatments used after the failure of first-line platinum-based chemotherapy were checked and patient's backgrounds, as well as overall survival (OS) from the last day of previous chemotherapy were compared between patients with and without tegafur-uracil treatment. Factors predictive of OS in lamUC patients with tegafururacil treatment were also investigated. The Seventh Edition of the TNM Classification of Malignant Tumors (Union for International Cancer Control) was used for TNM staging.
Statistical analyses. Statistical analyses were performed using the commercially available software Prism (GraphPad, San Diego, CA, USA) and SPSS (IBM, Armonk, NY, USA). Comparisons between the two groups were performed using unpaired two-sided t-tests and Fisher's exact tests. OS was estimated using the Kaplan–Meier method. Univariate analyses of differences among patient groups were performed using log rank tests. Multivariate analysis was performed to identify independent prognostic factors using Cox's proportional hazards regression and stepwise backward procedures. In all analyses, pp<0.05 was taken to indicate statistical significance.
Results
Patients' background. The number of patients with and without tegafur-uracil treatment after the treatment failure of platinum-based chemotherapy was 27 and 4, respectively. There were no differences in age, gender, primary tumor site, TNM stage and total number of courses of chemotherapy between the two groups. A variety of platinum-based chemotherapy protocols were administered other than MVAC and GC. Carboplatin was mainly administered in cisplatin-unfit patients with insufficient renal function. A couple of platinum-based chemotherapy protocols were administered for identical patients as the subsequent chemotherapy after the treatment failure of first-line chemotherapy (Table I).
Overall survival in patients with or without tegafur-uracil. The OS of lamUC patients with and without tegafur-uracil treatment was estimated. There was a significant difference between the two groups (pp<0.001); the median survival time of patients with and without tegafur-uracil treatment was 358 and 66.5 days, respectively (Figure 1).
Factors predictive of survival in patients treated with tegafur-uracil. To determine the factors that were indicative of better survival, univariate analysis was performed for six variables; age at diagnosis, sex, primary site, duration of chemotherapy, interval from the last day of previous chemotherapy to the first day of tegafur-uracil treatment and dose of tegafur-uracil. The occurrence of more than 30 days from the last day of the previous chemotherapy to the day of commencing tegafur-uracil and a dose of tegafur-uracil of 400 mg/day were significant factors for long survival (p=0.008 and p=0.002, respectively). Multivariate analysis revealed that a dose of 400 mg/day of tegafur-uracil was a significant factor for long survival with a hazard ratio of 4.7 (p=0.019, 95% confident interval 1.292–17.11) (Table II). The OS of lamUC patients with 400 mg/day and ≤300 mg/day tegafur-uracil treatment was estimated and the median survival time was 734 days and 209 days, respectively (Figure 2).
Discussion
Although platinum-based chemotherapy is used as the first-line treatment for lamUC, there is still no evidence to support a standard second-line treatment. Because the survival time of lamUC patients in whom platinum-based chemotherapy fails is extremely limited, it is urgent and necessary for patients, urologists and oncologists to develop an appropriate second-line treatment for lamUC. A randomized phase III trial of vinflunine after the treatment failure of platinum-based chemotherapy was performed recently in lamUC patients. Although there was no statistically significant difference in OS between vinflunine and the best supportive care group in intention to treat analysis at the first report in 2009, the subsequent long-term follow-up results of the study reported in 2013 demonstrated that vinflunine significantly prolonged OS compared with best supportive care in the eligible population (median survival time of 6.9 and 4.3 months, respectively) (12, 13). In the present study, the median survival time of patients with tegafur-uracil treatment was 12 months; surprisingly the median survival time of patients treated with 400 mg/day tegafur-uracil was 24 months. These data suggest that tegafur-uracil may be more beneficial than vinflunine. Moreover, a high incidence of grade 3 and 4 sAEs was reported in patients with vinflunine, whereas sAEs were rare in the present study. Consistent with this, a randomized phase III trial using tegafur-uracil and S-1 for locally advanced gastric cancer patients showed that the most frequent sAE during a 2-year treatment with tegafur-uracil alone group was neutropenia with an incidence of only 11% compared to 50% with vinflunine. The incidence of all other sAEs, including both haematological and non-haematological events, in the tegafur-uracil-alone group was <10% (14). Therefore, in the present study, most patients with tegafur-uracil treatment could be treated as outpatients. In addition, tegafur-uracil may be acceptable for older patients, as well as those with a relatively poor performance status. However, the results of these comparisons may not be correct because of differences in background between the present study and previous studies using vinflunine or other agents. Also, the possibility that tegafur-uracil was unintentionally administered to patients who were in a better systemic condition compared to those who did not receive tegafur-uracil should also be considered. As such, utmost care should be taken when comparing the present study with previous observations.
This study has some limitations. This was a retrospective study with a small sample size and all patients were Japanese. Therefore, evidence needs to be accumulated because the incidence of lamUC is relatively low. A prospective randomized controlled trial with a large-sized population is required to confirm our preliminary observations regarding the efficacy of tegafur-uracil in lamUC patients after the treatment failure of first-line platinum-based chemotherapy. Nevertheless, this is the first report to clarify the efficacy of tegafur-uracil; the data suggest that tegafur-uracil may be a candidate for the second-line treatment of lamUC patients after the treatment failure of platinum-based chemotherapy with little toxicity. The optimal dose of tegafur-uracil for the best response may be 400 mg/day.
- Received November 16, 2014.
- Revision received November 25, 2014.
- Accepted December 2, 2014.
- Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved