Abstract
Cong Xue1,*, Xin An1,*, Ye Cao2, Tanhuan Chen1, Wei Yang 1, Yingfei Deng1, Hui Han3, Xiaoyu Teng1, Fangjian Zhou3, Yanxia Shi1
1Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, People’s Republic of China
2Department of GCP, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, People’s Republic of China
3Department of Urology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, People’s Republic of China
*These authors contributed equally to this work
Correspondence to:
Yanxia Shi, email: [email protected]
Fangjian Zhou, email: [email protected]
Keywords: capecitabine, docetaxel, second-line, chemotherapy, urothelial cancer
Received: December 14, 2015 Accepted: July 29, 2016 Published: August 26, 2016
ABSTRACT
Purpose: The purpose of this study was to evaluate the effectiveness and toxicity of capecitabine (C) chemotherapy regimen with or without (w/o) docetaxel (D) in patients with advanced urothelial carcinoma (UC).
Results: Clinical benefit rate were similar in two arms (C arm vs DC arm: 38.9% vs 45.5%, p = 0.411). There were two cases achieved partial response in DC arm. In C arm, the median PFS was 3.0 months (95% CI 2.5–3.5 months) and median OS was 11.3 months (95% CI 8.6–14.1 months). In DC arm, the median PFS was 2.2 months (95% CI 1.7–2.7 months) and median OS was 18 months (95% CI 6.8–29.9 months). Adverse events were mostly acceptable, including myelosuppession, hand-foot syndrome and mucositis. Anemia and leukopenia was found more in the DC arm than in the C arm.
Materials and Methods: This is a one-center, observational, retrospective study. From April 2009 to March 2015, a total of 29 patients with metastatic UC were included in the study. Survivals, response rates and toxicities were collected retrospectively.
Conclusions: The result showed the activity and toxicity of C w/o D. As DC treatment did not reveal better outcome, C or D single-agent might be an option in platinum-failed patients with advanced urothelial carcinoma. Further clinical trials are warranted.
INTRODUCTION
Urothelial cancer (UC) is a common cancer in men in China [1]. The prognosis of patients with advanced UC is quite poor, with median overall survival (OS) of 10–15 months [2–4]. The standard first-line treatment for metastatic UC is cisplatin combined with gemcitabine, for which response rate is about 50%, with a median progression-free survival (PFS) of 7–8 months. Dose- dense MVAC is also a standard regimen with similar response rate and more toxicity [3]. Once the disease progress the response rate (RR) of palliative regimen is usually less than 20%, while remaining survival of the patient is quite short (usually 6–9 months) [5].
Till now there are no standard palliative regimens for patients who failed platinum-based therapy. The optional second-line agents include taxanes (docetaxel and paclitaxel) [6, 7], pemetrexed [8–10], vinflunine [11, 12] and so on. Single-agent regimen is preferred for palliative chemotherapy. Although higher RR is attained in combination therapy, the high RR seldom translate into an improvement in survivals (especially OS) [5]. The toxicity is even greater and intolerable in pretreated patients. Therefore, it is essential to find an ideal second-line therapy for metastatic UC.
Capecitabine (C), an orally bioavailable 5-fluorouracil (FU) prodrug, is widely used in solid tumors for its wide-spectrum efficacy, mild toxicity and oral convenience [13–15]. The combination of 5-FU and other chemotherapy agents had been assessed in metastatic UC. Most regimens were active and tolerable [16–20]. Capecitabine is an optional radiosensitizing agent which given during concurrent radiation as well [21]. However little is known about using capecitabine in advanced UC, including single-agent or combination therapy.
We conducted a retrospective study to investigate the clinical efficacy and toxicity of capecitabine in advanced UC. As docetaxel (D) is a commonly used second-line agent in metastatic UC [6], moreover docetaxel and capecitabine (DC) is a proved effective and tolerable regimen in metastatic breast cancer [13], the DC combination regimen is seldom reported in UC. Therefore, we also reviewed and analyzed the data of DC therapy. To our knowledge, no study has evaluated the clinical usage of capecitabine with or without (w/o) docetaxel in advanced UC. Thus, the primary objective of this retrospective observational study was to evaluate the efficacy and toxicity profile of capecitabine w/o docetaxel chemotherapy regimen, in order to provide another treatment choice of patients with advanced UC.
RESULTS
A total of 29 patients were included in the study. All were with good performance status (ECOG 0-1). Eighteen patients were in the C arm and 11 patients were in the DC arm. Their characteristics are listed in Table 1. In the whole group, most patients were men. More male Patients in the C arm were found than those in the DC arm (p = 0.033). Other characteristics were balanced between two arms. 20.7% (n = 6) had liver metastases and 51.7% (n = 15) had visceral metastases (lung, liver, or brain). Prior gemcitabine and platinum exposure were recorded in 24 patients, including 21 for the first-line, and 3 for the adjuvant chemotherapy. Five patients who received DC or C as first line therapy were chemotherapy-naïve. Twenty-two patients had transitional-cell carcinomas (TCC). The other histologies included adenocarcinoma (n = 3), signet ring cell carcinoma (n = 1), and poorly differentiated carcinoma (n = 3).
Table 1: Baseline patients characteristics
Characteristic | C arm (n = 18) | DC arm (n= 11) | p | ||
|---|---|---|---|---|---|
No. | % | No. | % | ||
Age, years | |||||
Median | 53.5 | 59 | |||
Range | 31–82 | 28–70 | |||
Sex | 0.033 | ||||
Male | 17 | 94.4 | 7 | 63.6 | |
Female | 1 | 5.6 | 4 | 36.4 | |
Histology | 0.558 | ||||
TCC | 13 | 72.2 | 9 | 81.8 | |
Others | 5 | 27.8 | 2 | 18.2 | |
ECOG | 0.577 | ||||
0 | 11 | 61.1 | 5 | 45.5 | |
1 | 7 | 38.9 | 6 | 54.5 | |
Time from prior therapy | 0.853 | ||||
≤ 3 months | 10 | 5 | 45.5 | ||
> 3 months | 8 | 6 | 54.5 | ||
Visceral metastases | 0.812 | ||||
Yes | 9 | 50 | 6 | 54.5 | |
No | 9 | 50 | 5 | 45.5. | |
Liver metastases | 0.494 | ||||
Yes | 3 | 16.7 | 3 | 27.3 | |
No | 15 | 83.3 | 8 | 72.7 | |
Primary invasive tumor site | 0.293 | ||||
Bladder | 10 | 55.6 | 7 | 63.6 | |
Renal and upper urinary tract | 5 | 27.8 | 5* | 36.4 | |
Urachus | 3 | 16.7 | / | / | 0.976 |
Line of therapy | |||||
First line | 5 | 27.8 | 3 | 27.2 | |
Second line | 13 | 72.2 | 8 | 72.8 | |
Prior gemcitabine and platinum exposure | 0.364 | ||||
Yes | 14 | 77.8 | 10 | 90.9 | |
Adjuvant GP | 1 | 5.6 | 2 | 18.2 | |
First line GP | 13 | 72.2 | 8 | 72.7 | |
No | 4 | 22.2 | 1 | 9.1 | |
Prior nephrectomy | 0.229 | ||||
Yes | 3 | 16.7 | 4 | 36.4 | |
No | 15 | 83.3 | 7 | 63.6 | |
*One patient was diagnosed with bladder and pelvic ureteral carcinoma. TCC, Transitional-cell carcinoma.
Median follow-up time was 6.53 months (range, 1.3 to 41.2 months). At the time of analysis, 27 patients had progressed, 13 patients had died. The median maintenance period of capecitabine was 59 days. The median number of docetaxel regimens administered was 2 (range, 2–4).
Statistically significant difference of clinical benefit rate (CBR) was not found between patients in C arm (7/18, 38.9%) and those in DC arm (5/11, 45.5%, p = 0.411). Partial response (PR) was achieved in two patients in DC arm (2/11, 18.2%). None of patients in C arm achieved PR.
When capecitabine was administrated alone, the median PFS was 3.0 months (95% CI 2.5–3.5 months) and median OS was 11.3 months (95% CI 8.6–14.1 months). When in DC combination the median PFS was 2.2 months (95% CI 1.7–2.7 months) and median OS was 18 months (95% CI 6.8–29.9 months). The differences of PFS and OS between two arms were similar and had no statistical significance (PFS, p = 0.810; OS, p = 0.771).
Subgroup analysis showed that the prognosis of patients with non-TCC was significantly poorer than those with TCC. PFS of TCC was 4.8 months (95% CI 0.9–8.7 months) while non-TCC was 1.8 months (95% CI 1.6–2.1 months, p = 0.003). OS of TCC was 11.3 months (95%CI 3.9–18.7 months), significantly longer than that of non-TCC, 4.1 months (95% CI 1.4–6.7 months, p = 0.004).
Dose reduction of capecitabine was required in five patients for the following reasons: hand-foot syndrome (HFS, two, one in C arm and one in DC arm), mucositis (two in C arm), and leukopenia (one in DC arm). One patient in the C arm required treatment discontinuation because of thrombopenia. Dose reduction of docetaxel was required in one patient for edema. Two patients required treatment discontinuation because of edema (n = 1) and leukopenia (n = 1).
The most common adverse events (AEs) are listed in Table 2. All of them were consistent with the known toxicity of capecitabine and docetaxel. The most commonly reported AE was anemia. And this event happened more in the DC arm than in the C arm (81.2% vs 22.2%, p = 0.002). Other reported AEs included leukopenia, mucositis, thrombocytopenia and hand-foot syndrome. Among them, leukopenia happened more in the DC arm than in the C arm as well (63.6% vs 11.1%, p = 0.003). The frequencies of other AEs were similar between two arms. Most of these AEs were mild. The most common grade 3 or worse AEs was leukopenia (n = 2) and thrombocytopenia (n = 1). Both happened in the DC arm. But the differences between two arms were not statistically significant.
Table 2: Adverse events
Adverse event | C arm (n = 18) | DC arm (n =11) | ||||||
|---|---|---|---|---|---|---|---|---|
Grade | ||||||||
Any | 3 or 4 | Any | 3 or 4 | |||||
No. | % | No. | % | No. | % | No. | % | |
Anemia | 4 | 22.2 | – | – | 9 | 81.2 | – | – |
Leukopenia | 2 | 11.1 | – | – | 7 | 63.6 | 2 | 18.2 |
Mucositis | 2 | 11.1 | – | – | 3 | 27.3 | – | – |
Thrombocytopenia | 1 | 5.6 | – | – | 1 | 9.9 | 1 | 9.9 |
Hand-foot skin reaction | 1 | 5.6 | – | – | 3 | 16.7 | – | – |
Anorexia | 2 | 11.1 | – | – | 2 | 18.2 | – | – |
Edema | – | – | – | – | 2 | 18.2 | – | – |
Fatigue | 1 | 5.6 | – | – | 1 | 9.9 | – | – |
Diarrhea | – | – | – | – | 1 | 9.9 | – | – |
ALT elevation | 1 | 5.6 | – | – | – | – | – | – |
ALT: alanine aminotransferase.
We tried to evaluate the association of following factors with OS, like hemoglobin, albumin, time from prior therapy, liver metastasis, neutrophil, lymphocyte, platelet counts and performance status by Cox regression model. These factors were formerly found to be associated with OS [22–24]. However all factors were not associated with OS in univariate analysis (all p > 0.05). So we did not perform multivariate analysis afterwards.
DISCUSSION
The efficacy and toxicity of patients treated with capecitabine w/o docetaxel for advanced UC was reported for the first time. The major limitations of this study are the retrospective nature and, limited sample size and immature survival data. Further randomized trials are warranted.
Results of a phase II study showed that a RR of 15% and median PFS of 1.9 months of continuously infused 5-FU in metastatic UC, indicating the prolonged 5-FU administration might be a useful regimens for these patients [16]. Capecitabine converts into 5-FU via thymidine phosphorylase (TP) in the tumor. Previous study showed that the expression of TP was generally high in UC, indicating the potential usage of capecitabine in UC [25]. In our study the PFS of 3.0 months of capecitabine single agent was similar to former studies [10]. Although there was no major response (CR or PR) in the population with single agent, the survivals were not shorter than those with combination treatment, indicating single-agent might be an eligible choice in the second-line setting.
Former in vitro studies found that taxanes greatly increased the TP level in tumors, the combination of taxanes and capecitabine made synergic effect [26]. Therefore, we assumed that docetaxel might be a good companion for capecitabine in advanced UC.
Docetaxel is commonly used in platinum-resistant advanced UC, for which single-arm phase II trials reported RR of 13.3% and median OS of 9 months [6]. Previous clinical trials indicated docetaxel combined with oxaliplatin [27], gemcitabine [28, 29] or ifosfamide and cisplatin regimen [30] were mostly tolerable and moderately active (RR 27–47%) for advanced UC after failure of platinum-based therapy. Although in our study the ORR of DC (18.2%) was lower, the CBR and survivals were not inferior to prior results [3]. Patients with stable disease (SD) also benefitted from the treatment. We tried to evaluate the association of some factors with OS, like albumin. But we failed even in univariate analysis due to the limited sample size and immature OS data.
Our study showed that the AEs of capecitabine w/o docetaxel included anemia, leukopenia, mucositis, thrombocytopenia and HFS. Most were tolerable [6, 13]. Anemia and leukopenia were reported more in the DC arm than in the C arm, but the frequencies were not higher than former studies [13]. Severe leukopenia happened more in the DC arm than the C arm. But it was also manageable. No treatment-related death was observed in this study.
Recently Raggi et al. performed a meta-analysis to study the impact of single-agent compared with doublet chemotherapy as second-line therapy of advanced UC [31]. It showed that doublet regimen improved ORR and PFS significantly, while OS was not prolonged. And the toxicity was similar. When analyzing the regimens including taxanes (paclitaxel or docetaxel), only ORR advantage existed in the doublet therapy. Neither improvement of PFS nor OS was found. The authors recommend the clinical usage of single taxanes in the second-line setting. Another meta-analysis had different results. Sonpavde et al. found patients of combination chemotherapy showed improved OS compared with patients of single-agent chemotherapy as salvage therapy for advanced UC. The main limitation was that single and combination cohorts were derived from separate trials and not directly compared in prospective trials. Patients could receive combination chemotherapy might have better performance status [32]. According to our results, we had the same opinions on the usage of single-agent palliative chemotherapy. In some selected patients combination therapy might be an option.
There is a growing interest in targeted therapies in UC. However the results were not satisfied. For instance, even if epidermal growth factor receptor (EGFR) was overexpressed in the majority of UC, the response rates and survivals were disappointing in unselected population receiving gemcitabine and platinum regimen plus gefitinib [33, 34]. The application of bevacizumab in metastatic cases was proved marginally effective while inducing cardiovascular toxicity and treatment-related death [35, 36]. Overexpression or amplification in human epidermal growth factor receptor 2 (HER2) is variable in different population (20–50% of tumors) [37–39]. Two phase II studies containing trastuzumab and chemotherapy in metastatic patients revealed inconsistent results [40, 41]. Recently numerous genomic alterations are identified in UC, for example TP53, PI3K and FGFR3 [42, 43]. Related inhibitors are being studied as well. Immunotherapy is now the key focus of studies. CTLA-4 inhibitor, PD-1 inhibitors and PD-L1 inhibitors have shown compelling activities in advanced UC [44–46]. PD-L1 inhibitor atezolizumab (MPDL3280a) showed certain activity in patients with metastatic UC after failure of platinum –based chemotherapy. The RR for all patients was 15%. The activity was durable in responders. Patients with increased percentage of PD-L1-positive immune cells reached higher RR. Atezolizumab was safe and well tolerated in the patient population [47]. Due to the moderate efficacy of conventional chemotherapy, targeted therapy and immunotherapy may be the critical methods to improve the outcomes of patients with metastatic UC.
In conclusion, the retrospective study revealed that capecitabine w/o docetaxel was tolerable and might be an optional palliative treatment for metastatic UC. Although ORR was higher in the DC arm, the CBR, PFS and OS were not outstanding compared to the C single-drug regimen. Single-agent palliative treatment as docetaxel or capecitabine might be optional in pretreated patients with metastatic UC. Further randomized trials are warranted to validate the efficacy of capecitabine w/o docetaxel in metastatic UC.
MATERIALS AND METHODS
Study population
This study is a one-institution, observational, retrospective study that includes patients diagnosed with UC treated with capecitabine w/o docetaxel at Sun Yat-Sen University Cancer Center. Patients were treated with capecitabine w/o docetaxel as first-line or second-line therapy, between April 2009 and March 2015. Using our center-based database, all patients who received capecitabine between 2009 and 2015 and diagnosed of UC were identified (n = 49). Twelve patients were excluded because they received capecitabine for adjuvant chemotherapy. Seven patients without follow-up were excluded. One patient was excluded because he received capecitabine with oxaliplatin. Overall 29 patients were included in the analysis. If recurrence or metastasis occurred within 1 year after adjuvant chemotherapy, the regimen (capecitabine w/o docetaxel) was also defined as second-line therapy. Because no patient identification data was collected, and it was a retrospective descriptive study, moreover we did not have any interventions afterwards, so specific written or verbal informed consent was not provided to the participators.
Treatments
All Patients were treated at a dose of capecitabine 1000mg/m2 given orally twice daily on days 1–14 every 3 weeks, among them 11 patients received docetaxel 75mg/m2 iv on day 1 every 3 weeks concurrently. The institutional ethics review board approved this study to review medical records including basic characteristics, prior therapy, capecitabine w/o docetaxel courses, efficacy, AEs, disease progression and death events.
Tumor response was evaluated by computed tomography (CT) or magnetic resonance imaging (MRI) every 2 cycles while in treatment period, according to RECIST 1.0. After progression, patients were followed up every 3 months until death. PFS was defined as the duration from the date of treatment began to the date of disease progression or last follow-up. OS was defined as the duration from the date of treatment began to the date of death from any cause or last follow-up. AEs were identified and recorded retrospectively. Severity of AEs was evaluated following Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
Statistical analysis
The primary objective of this retrospective observational study was the CBR of capecitabine w/o docetaxel, including the percentage of complete response (CR), PR and SD. The secondary endpoints included AEs, PFS, and OS. PFS and OS were estimated using Kaplan–Meier methods and compared using the log-rank tests. Differences across treatment arms regarding all categorical variables were examined with a χ2 test. Analyses were carried out using the statistical software package SPSS 16.0(SPSS, Chicago, IL). All statistical tests were two-sided, and a p-value < 0.05 was considered as statistically significant.
CONFLICTS OF INTEREST
The authors declare that they have no conflicts of interest.
GRANT SUPPORT
This study was supported by the Chinese National Natural Science Foundation project (Grant No. 30500610) and Science and technology project of Guangdong Province (Grant No. 2013B021800062 and 2012B061700082).
REFERENCES
1. GLOBALCAN2012: http://globocan.iarc.fr/Pages/fact_sheets_population.aspx. Nov 16 2015.
2. Ardavanis A, Tryfonopoulos D, Alexopoulos A, Kandylis C, Lainakis G, Rigatos G. Gemcitabine and docetaxel as first-line treatment for advanced urothelial carcinoma: a phase II study. Br J Cancer. 2005; 92:645–650.
3. Von der Maase H, Hansen SW, Roberts JT, Dogliotti L, Oliver T, Moore MJ, Bodrogi I, Albers P, Knuth A, Lippert CM, Kerbrat P, Sanchez Rovira P, Wersall P, et al. Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol. 2000; 18:3068–3077.
4. Neri B, Vannini L, Giordano C, Grifoni R, Pantaleo P, Baldazzi V, Crisci A, Lapini A, Raugei A, Carini M. Gemcitabine plus docetaxel as first-line biweekly therapy in locally advanced and/or metastatic urothelial carcinoma: a phase II study. Anticancer Drugs. 2007; 18:1207–1211.
5. Gallagher DJ, Milowsky MI, Bajorin DF. Advanced bladder cancer: status of first-line chemotherapy and the search for active agents in the second-line setting. Cancer. 2008; 113:1284–1293.
6. McCaffrey JA, Hilton S, Mazumdar M, Sadan S, Kelly WK, Scher HI, Bajorin DF. Phase II trial of docetaxel in patients with advanced or metastatic transitional-cell carcinoma. J Clin Oncol. 1997; 15:1853–1857.
7. Vaughn DJ, Broome CM, Hussain M, Gutheil JC, Markowitz AB. Phase II trial of weekly paclitaxel in patients with previously treated advanced urothelial cancer. J Clin Oncol. 2002; 20:937–940.
8. Sweeney CJ, Roth BJ, Kabbinavar FF, Vaughn DJ, Arning M, Curiel RE, Obasaju CK, Wang Y, Nicol SJ, Kaufman DS. Phase II study of pemetrexed for second-line treatment of transitional cell cancer of the urothelium. J Clin Oncol. 2006; 24:3451–3457.
9. Galsky MD, Mironov S, Iasonos A, Scattergood J, Boyle MG, Bajorin DF. Phase II trial of pemetrexed as second-line therapy in patients with metastatic urothelial carcinoma. Invest New Drugs. 2007; 25:265–270.
10. Bambury RM, Benjamin DJ, Chaim JL, Zabor EC, Sullivan J, Garcia-Grossman IR, Regazzi AM, Ostrovnaya I, Apollo A, Xiao H, Voss MH, Iyer G, Bajorin DF, et al. The safety and efficacy of single-agent pemetrexed in platinum-resistant advanced urothelial carcinoma: a large single-institution experience. Oncologist. 2015; 20:508–515.
11. Culine S, Theodore C, De Santis M, Bui B, Demkow T, Lorenz J, Rolland F, Delgado FM, Longerey B, James N. A phase II study of vinflunine in bladder cancer patients progressing after first-line platinum-containing regimen. Br J Cancer. 2006; 94:1395–1401.
12. Guglieri-Lopez B, Perez-Pitarch A, Porta-Oltra B, Ferriols-Lisart F, Climente-Marti M, Alos-Alminana M. Effectiveness, toxicity, and economic evaluation of vinflunine for the treatment of patients with transitional cell carcinoma in the Spanish outpatient setting. Anticancer Drugs. 2015; 26:860–865.
13. Mavroudis D, Papakotoulas P, Ardavanis A, Syrigos K, Kakolyris S, Ziras N, Kouroussis C, Malamos N, Polyzos A, Christophyllakis C, Kentepozidis N, Georgoulias V. Breast Cancer Investigators of the Hellenic Oncology Research Group: Randomized phase III trial comparing docetaxel plus epirubicin versus docetaxel plus capecitabine as first-line treatment in women with advanced breast cancer. Ann Oncol. 2010; 21:48–54.
14. Glynne-Jones R, Sebag-Montefiore D, Maughan TS, Falk SJ, McDonald AC. A phase I dose escalation study of continuous oral capecitabine in combination with oxaliplatin and pelvic radiation (XELOX-RT) in patients with locally advanced rectal cancer. Ann Oncol. 2006; 17:50–56.
15. Hong YS, Song SY, Lee SI, Chung HC, Choi SH, Noh SH, Park JN, Han JY, Kang JH, Lee KS, Cho JY. A phase II trial of capecitabine in previously untreated patients with advanced and/or metastatic gastric cancer. Ann Oncol. 2004; 15:1344–1347.
16. Highley MS, Griffiths GO, Uscinska BM, Huddart RA, Barber JB, Parmar MK, Harper PG. A phase II trial of continuous 5-fluorouracil in recurrent or metastatic transitional cell carcinoma of the urinary tract. Clin Oncol (R Coll Radiol). 2009; 21:394–400.
17. Bhattacharyya M, Powles T, Mutsvangwa K, Wilson P, Oliver T, Shamash J. A phase II study of mitomycin, fluorouracil, folinic acid, and irinotecan (MFI) for the treatment of transitional cell carcinoma of the bladder. Urol Oncol. 2013; 31:878–882.
18. Lin CC, Hsu CH, Huang CY, Cheng AL, Chen J, Vogelzang NJ, Pu YS. Weekly cisplatin plus infusional high-dose 5-fluorouracil and leucovorin (P-HDFL) for metastatic urothelial carcinoma: an effective regimen with low toxicity. Cancer. 2006; 106:1269–1275.
19. Lin CC, Hsu CH, Huang CY, Cheng AL, Vogelzang NJ, Pu YS. Phase II trial of weekly paclitaxel, cisplatin plus infusional high dose 5-fluorouracil and leucovorin for metastatic urothelial carcinoma. J Urol. 2007; 177:84–89; discussion 89.
20. Mitin T, Hunt D, Shipley WU, Kaufman DS, Uzzo R, Wu CL, Buyyounouski MK, Sandler H, Zietman AL. Transurethral surgery and twice-daily radiation plus paclitaxel-cisplatin or fluorouracil-cisplatin with selective bladder preservation and adjuvant chemotherapy for patients with muscle invasive bladder cancer (RTOG 0233): a randomised multicentre phase 2 trial. Lancet Oncol. 2013; 14:863–872.
21. Patel B, Forman J, Fontana J, Frazier A, Pontes E, Vaishampayan U. A single institution experience with concurrent capecitabine and radiation therapy in weak and/or elderly patients with urothelial cancer. Int J Radiat Oncol Biol Phys. 2005; 62:1332–1338.
22. Sonpavde G, Pond GR, Rosenberg JE, Bajorin DF, Choueiri TK, Necchi A, Di Lorenzo G, Bellmunt J. Improved 5-Factor Prognostic Classification of Patients Receiving Salvage Systemic Therapy for Advanced Urothelial Carcinoma. J Urol. 2016; 195:277–282.
23. Bellmunt J, Choueiri TK, Fougeray R, Schutz FA, Salhi Y, Winquist E, Culine S, von der Maase H, Vaughn DJ, Rosenberg JE. Prognostic factors in patients with advanced transitional cell carcinoma of the urothelial tract experiencing treatment failure with platinum-containing regimens. J Clin Oncol. 2010; 28:1850–1855.
24. Sonpavde G, Pond GR, Fougeray R, Choueiri TK, Qu AQ, Vaughn DJ, Niegisch G, Albers P, James ND, Wong YN, Ko YJ, Sridhar SS, Galsky MD, et al. Time from prior chemotherapy enhances prognostic risk grouping in the second-line setting of advanced urothelial carcinoma: a retrospective analysis of pooled, prospective phase 2 trials. Eur Urol. 2013; 63:717–723.
25. Kamoshida S, Shiogama K, Shimomura R, Inada K, Sakurai Y, Ochiai M, Matuoka H, Maeda K, Tsutsumi Y. Immunohistochemical demonstration of fluoropyrimidine-metabolizing enzymes in various types of cancer. Oncol Rep. 2005; 14:1223–1230.
26. Sawada N, Ishikawa T, Fukase Y, Nishida M, Yoshikubo T, Ishitsuka H. Induction of thymidine phosphorylase activity and enhancement of capecitabine efficacy by taxol/taxotere in human cancer xenografts. Clin Cancer Res. 1998; 4:1013–1019.
27. Srinivas S, Harshman LC. A phase II study of docetaxel and oxaliplatin for second-line treatment of urothelial carcinoma. Chemotherapy. 2009; 55:321–326.
28. Gitlitz BJ, Baker C, Chapman Y, Allen HJ, Bosserman LD, Patel R, Sanchez JD, Shapiro RM, Figlin RA. A phase II study of gemcitabine and docetaxel therapy in patients with advanced urothelial carcinoma. Cancer. 2003; 98:1863–1869.
29. Naiki T, Kawai N, Hashimoto Y, Okamura T, Ando R, Yasui T, Okada A, Etani T, Tozawa K, Kohri K. Gemcitabine and docetaxel, an effective second-line chemotherapy for lung metastasis of urothelial carcinoma. Int J Clin Oncol. 2014; 19:516–522.
30. Kakutani S, Fukuhara H, Taguchi S, Nagata M, Niimi A, Hattori M, Miyazaki H, Fujimura T, Nakagawa T, Kume H, Igawa Y, Homma Y. Combination of docetaxel, ifosfamide and cisplatin (DIP) as a potential salvage chemotherapy for metastatic urothelial carcinoma. Jpn J Clin Oncol. 2015; 45:281–285.
31. Raggi D, Miceli R, Sonpavde G, Giannatempo P, Mariani L, Galsky MD, Bellmunt J, Necchi A. Second-line single-agent versus doublet chemotherapy as salvage therapy for metastatic urothelial cancer: a systematic review and meta-analysis. Ann Oncol. 2016; 27:49–61.
32. Sonpavde G, Pond GR, Choueiri TK, Mullane S, Niegisch G, Albers P, Necchi A, Di Lorenzo G, Buonerba C, Rozzi A, Matsumoto K, LeeJL, Kitamura H, et al. Single-agent Taxane Versus Taxane-containing Combination Chemotherapy as Salvage Therapy for Advanced Urothelial Carcinoma. Eur Urol. 2016; 69:634–641.
33. Philips GK, Halabi S, Sanford BL, Bajorin D, Small EJ. A phase II trial of cisplatin (C), gemcitabine (G) and gefitinib for advanced urothelial tract carcinoma: results of Cancer and Leukemia Group B (CALGB) 90102. Ann Oncol. 2009; 20:1074–1079.
34. Miller K, Morant R, Stenzl A, Zuna I, Wirth M. A Phase II Study of the Central European Society of Anticancer-Drug Research (CESAR) Group: Results of an Open-Label Study of Gemcitabine plus Cisplatin with or without Concomitant or Sequential Gefitinib in Patients with Advanced or Metastatic Transitional Cell Carcinoma of the Urothelium. Urol Int. 2016; 96:5–13.
35. Balar AV, Apolo AB, Ostrovnaya I, Mironov S, Iasonos A, Trout A, Regazzi AM, Garcia-Grossman IR, Gallagher DJ, Milowsky MI, Bajorin DF. Phase II study of gemcitabine, carboplatin, and bevacizumab in patients with advanced unresectable or metastatic urothelial cancer. J Clin Oncol. 2013; 31:724–730.
36. Hahn NM, Stadler WM, Zon RT, Waterhouse D, Picus J, Nattam S, Johnson CS, Perkins SM, Waddell MJ, Sweeney CJ. Phase II trial of cisplatin, gemcitabine, and bevacizumab as first-line therapy for metastatic urothelial carcinoma: Hoosier Oncology Group GU 04-75. J Clin Oncol. 2011; 29:1525–1530.
37. Jimenez RE, Hussain M, Bianco FJ, Jr, Vaishampayan U, Tabazcka P, Sakr WA, Pontes JE, Wood DP, Jr, Grignon DJ. Her-2/neu overexpression in muscle-invasive urothelial carcinoma of the bladder: prognostic significance and comparative analysis in primary and metastatic tumors. Clin Cancer Res. 2001; 7:2440–2447.
38. Kruger S, Weitsch G, Buttner H, Matthiensen A, Bohmer T, Marquardt T, Sayk F, Feller AC, Bohle A. Overexpression of c-erbB-2 oncoprotein in muscle-invasive bladder carcinoma: relationship with gene amplification, clinicopathological parameters and prognostic outcome. Int J Oncol. 2002; 21:981–987.
39. Chow NH, Chan SH, Tzai TS, Ho CL, Liu HS. Expression profiles of ErbB family receptors and prognosis in primary transitional cell carcinoma of the urinary bladder. Clin Cancer Res. 2001; 7:1957–1962.
40. Hussain MH, MacVicar GR, Petrylak DP, Dunn RL, Vaishampayan U, Lara PN, Jr., Chatta GS, Nanus DM, Glode LM, Trump DL, Chen H, Smith DC. National Cancer Institute: Trastuzumab, paclitaxel, carboplatin, and gemcitabine in advanced human epidermal growth factor receptor-2/neu-positive urothelial carcinoma: results of a multicenter phase II National Cancer Institute trial. J Clin Oncol. 2007; 25:2218–2224.
41. Oudard S, Culine S, Vano Y, Goldwasser F, Theodore C, Nguyen T, Voog E, Banu E, Vieillefond A, Priou F, Deplanque G, Gravis G, Ravaud A, et al. Multicentre randomised phase II trial of gemcitabine+platinum, with or without trastuzumab, in advanced or metastatic urothelial carcinoma overexpressing Her2. Eur J Cancer. 2015; 51:45–54.
42. Iyer G, Al-Ahmadie H, Schultz N, Hanrahan AJ, Ostrovnaya I, Balar AV, Kim PH, Lin O, Weinhold N, Sander C, Zabor EC, Janakiraman M, Garcia-Grossman IR, et al. Prevalence and co-occurrence of actionable genomic alterations in high-grade bladder cancer. J Clin Oncol. 2013; 31:3133–3140.
43. Network. CGAR: Comprehensive molecular characterization of urothelial bladder carcinoma. Nature. 2014; 507:315–322.
44. Carthon BC, Wolchok JD, Yuan J, Kamat A, Ng Tang DS, Sun J, Ku G, Troncoso P, Logothetis CJ, Allison JP, Sharma P. Preoperative CTLA-4 blockade: tolerability and immune monitoring in the setting of a presurgical clinical trial. Clin Cancer Res. 2010; 16:2861–2871.
45. NCT02256436. Cg: A study of pembrolizumab (MK-3475) versus paclitaxel, docetaxel, or vinflunine for participants with advanced urothelial cancer (MK-3475–045/ KEYNOTE-045).
46. NCT02108652. Cg: A study of MPDL3280A in patients with locally advanced or metastatic urothelial bladder cancer [IMvigor210].
47. Rosenberg JE, Hoffman-Censits J, Powles T, van der Heijden MS, Balar AV, Necchi A, Dawson N, O'Donnell PH, Balmanoukian A, Loriot Y, Srinivas S, Retz MM, Grivas P, et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet. 387:1909–1920.
