Original Paper
Urologia Internationalis
Received: February 5, 2013 Accepted after revision: July 3, 2013 Published online: November 13, 2013
Urol Int 2014;92:180–185 DOI: 10.1159/000354149
Clinical Outcome of Paclitaxel and Carboplatin as Second-Line Chemotherapy for Advanced Urothelial Carcinoma Resistant to First-Line Therapy with Gemcitabine and Cisplatin Tomoaki Terakawa a Hideaki Miyake b Naoki Yokoyama a Akira Miyazaki a Hiroyuki Tanaka a Takaaki Inoue a Masato Fujisawa b a Division of Urology, Hyogo Cancer Center, Akashi, and b Division of Urology, Kobe University Graduate School of Medicine, Kobe, Japan
Key Words Urothelial carcinoma · Paclitaxel · Carboplatin · Second-line chemotherapy
Abstract Objective: The objective was to investigate the efficacy and tolerability of combined therapy with paclitaxel and carboplatin (TC) in patients with advanced urothelial carcinoma after the failure of first-line chemotherapy with gemcitabine and cisplatin (GC). Patients and Methods: This was a retrospective study including a total of 16 patients with advanced urothelial carcinoma who showed evidence of progressive and/or recurrent disease after first-line therapy with GC and subsequently received second-line chemotherapy consisting of paclitaxel (175 mg/m2) and carboplatin (area under the curve 5). TC therapy was repeated every 3 weeks and was continued until disease progression or intolerable toxicity was observed. Results: The baseline patient characteristics were rather favorable; only 3 of 16 patients had liver metastases and 7 patients had an Eastern Cooperative Oncology Group performance status of 0. Of these, response to TC therapy was achieved in 5 (31.3%), including 2 with complete and 3 with partial response. The median progressionfree and overall survival times in the 16 patients were 7.9
© 2013 S. Karger AG, Basel 0042–1138/13/0922–0180$38.00/0 E-Mail [email protected] www.karger.com/uin
and 17.3 months, respectively. Conclusions: TC therapy appeared to show modest activity with acceptable tolerability in patients refractory to GC therapy; therefore, TC chemotherapy might be considered as an alternative option as a second-line regimen for advanced urothelial carcinoma following GC therapy. © 2013 S. Karger AG, Basel
Introduction
Urothelial carcinoma is the fifth or sixth most common malignancy in Western industrialized countries [1]. Approximately 30 and 5% of patients with urothelial carcinoma present with muscle-invasive and metastatic disease, respectively, at presentation. In addition, despite adequate local therapy for patients with muscle-invasive disease by radical surgery, more than one-third of these patients ultimately develop metastatic disease [2]. Urothelial carcinoma has been regarded as a disease comparatively sensitive to chemotherapeutic agents; therefore, systemic chemotherapy remains the standard of care for patients with metastatic urothelial carcinoma [3]. Combination chemotherapy with methotrexate, vinblastine, doxorubicin and cisplatin (MVAC) has been the Tomoaki Terakawa Division of Urology Hyogo Cancer Center 13-70 Kitaouji-cho, Akashi 673-8558 (Japan) E-Mail daatera0804 @ yahoo.co.jp
standard first-line chemotherapy for metastatic urothelial carcinoma since this regimen was reported in 1985 [4]. In recent years, however, combination chemotherapy with gemcitabine and cisplatin (GC) has become more widely used as another first-line regimen, since GC therapy was shown to have equivalent efficacy and less toxicity than MVAC therapy in a randomized phase 3 trial including 405 patients with locally advanced or metastatic urothelial carcinoma [5]. To date, however, there has not been any standard regimen for patients with advanced urothelial carcinoma who failed cisplatin-based combination chemotherapy, such as MVAC or GC. Recently, several combination chemotherapies with novel active agents have been applied to advanced urothelial carcinoma resistant to the cisplatin-based regimen [3, 6–10]. Vinflunine in combination with best supportive care has demonstrated a 2-month survival advantage as second-line chemotherapy after failure of cisplatinbased regimens compared to best supportive care alone in a phase 3 trial [6]. In addition, several studies have investigated the combination chemotherapy of gemcitabine and paclitaxel (GP) [7–9]. Although the high response rate and prolonged survival of second-line GP chemotherapy were confirmed in a phase 2 study, prolonged treatment with this regimen could not show a survival superior to short-term treatment in a phase 3 trial. Among several combination therapies used as a second-line regimen, the combined chemotherapy with paclitaxel and carboplatin (TC) has been shown to have promising therapeutic activity against cisplatin-refractory urothelial carcinoma [11–13]; however, the efficacy of TC therapy as a second-line regimen was assessed in patients who had previously received MVAC therapy alone. Therefore, we assessed the utility and tolerability of TC therapy in a total of 16 patients with advanced urothelial carcinoma who had failed first-line chemotherapy with GC.
central nervous system, active infection, inadequately controlled diabetes, or those treated with chemotherapy other than GC prior to TC therapy were excluded. Informed consent to perform this study was obtained from all patients, and the study was approved by the research ethics committees of our institutions. The protocol was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice Guidelines. In this series, paclitaxel (175 mg/m2) and carboplatin (area under the curve 5) were injected intravenously on day 1, and dihydrocortisol (20 mg), ranitidine (50 mg) and diphenhydramine (50 mg) were given as premedication 30 min prior to the administration of paclitaxel. As a rule, this combined regimen was repeated every 3 weeks until disease progression or unacceptable adverse events occurred. Tumor measurements were generally performed by computed tomography before and every 2–3 courses after the initiation of TC therapy. Response and progression were assessed by the treating physician as well as the radiologist based on the Response Evaluation Criteria in Solid Tumors 1.0. Adverse events associated with TC therapy were assessed according to the National Cancer Institute – Common Toxicity Criteria (version 4.0). As for further treatment, in general, patients who experienced progression after the second-line TC chemotherapy received no further treatment except for best supportive care at our institution. All statistical analyses were performed using StatView 5.0 software (Abacus Concepts, Inc., Berkeley, Calif., USA). Progressionfree survival (PFS) and overall survival (OS) were determined by the Kaplan-Meier method.
Results
The data of 16 patients who underwent second-line treatment with TC therapy at our institution between April 2009 and January 2013 were retrospectively evaluated. Eligibility criteria for this retrospective analysis included histologically proven urothelial carcinoma that was not curable by surgery or radiation therapy, presence of measurable progressive and/or recurrent disease before the introduction of TC therapy, an Eastern Cooperative Oncology Group performance status of 0, 1 or 2, and adequate organ function defined by granulocyte count ≥1,500/mm3, platelet count ≥100,000/mm3, serum total bilirubin
Urologia Internationalis
Received: February 5, 2013 Accepted after revision: July 3, 2013 Published online: November 13, 2013
Urol Int 2014;92:180–185 DOI: 10.1159/000354149
Clinical Outcome of Paclitaxel and Carboplatin as Second-Line Chemotherapy for Advanced Urothelial Carcinoma Resistant to First-Line Therapy with Gemcitabine and Cisplatin Tomoaki Terakawa a Hideaki Miyake b Naoki Yokoyama a Akira Miyazaki a Hiroyuki Tanaka a Takaaki Inoue a Masato Fujisawa b a Division of Urology, Hyogo Cancer Center, Akashi, and b Division of Urology, Kobe University Graduate School of Medicine, Kobe, Japan
Key Words Urothelial carcinoma · Paclitaxel · Carboplatin · Second-line chemotherapy
Abstract Objective: The objective was to investigate the efficacy and tolerability of combined therapy with paclitaxel and carboplatin (TC) in patients with advanced urothelial carcinoma after the failure of first-line chemotherapy with gemcitabine and cisplatin (GC). Patients and Methods: This was a retrospective study including a total of 16 patients with advanced urothelial carcinoma who showed evidence of progressive and/or recurrent disease after first-line therapy with GC and subsequently received second-line chemotherapy consisting of paclitaxel (175 mg/m2) and carboplatin (area under the curve 5). TC therapy was repeated every 3 weeks and was continued until disease progression or intolerable toxicity was observed. Results: The baseline patient characteristics were rather favorable; only 3 of 16 patients had liver metastases and 7 patients had an Eastern Cooperative Oncology Group performance status of 0. Of these, response to TC therapy was achieved in 5 (31.3%), including 2 with complete and 3 with partial response. The median progressionfree and overall survival times in the 16 patients were 7.9
© 2013 S. Karger AG, Basel 0042–1138/13/0922–0180$38.00/0 E-Mail [email protected] www.karger.com/uin
and 17.3 months, respectively. Conclusions: TC therapy appeared to show modest activity with acceptable tolerability in patients refractory to GC therapy; therefore, TC chemotherapy might be considered as an alternative option as a second-line regimen for advanced urothelial carcinoma following GC therapy. © 2013 S. Karger AG, Basel
Introduction
Urothelial carcinoma is the fifth or sixth most common malignancy in Western industrialized countries [1]. Approximately 30 and 5% of patients with urothelial carcinoma present with muscle-invasive and metastatic disease, respectively, at presentation. In addition, despite adequate local therapy for patients with muscle-invasive disease by radical surgery, more than one-third of these patients ultimately develop metastatic disease [2]. Urothelial carcinoma has been regarded as a disease comparatively sensitive to chemotherapeutic agents; therefore, systemic chemotherapy remains the standard of care for patients with metastatic urothelial carcinoma [3]. Combination chemotherapy with methotrexate, vinblastine, doxorubicin and cisplatin (MVAC) has been the Tomoaki Terakawa Division of Urology Hyogo Cancer Center 13-70 Kitaouji-cho, Akashi 673-8558 (Japan) E-Mail daatera0804 @ yahoo.co.jp
standard first-line chemotherapy for metastatic urothelial carcinoma since this regimen was reported in 1985 [4]. In recent years, however, combination chemotherapy with gemcitabine and cisplatin (GC) has become more widely used as another first-line regimen, since GC therapy was shown to have equivalent efficacy and less toxicity than MVAC therapy in a randomized phase 3 trial including 405 patients with locally advanced or metastatic urothelial carcinoma [5]. To date, however, there has not been any standard regimen for patients with advanced urothelial carcinoma who failed cisplatin-based combination chemotherapy, such as MVAC or GC. Recently, several combination chemotherapies with novel active agents have been applied to advanced urothelial carcinoma resistant to the cisplatin-based regimen [3, 6–10]. Vinflunine in combination with best supportive care has demonstrated a 2-month survival advantage as second-line chemotherapy after failure of cisplatinbased regimens compared to best supportive care alone in a phase 3 trial [6]. In addition, several studies have investigated the combination chemotherapy of gemcitabine and paclitaxel (GP) [7–9]. Although the high response rate and prolonged survival of second-line GP chemotherapy were confirmed in a phase 2 study, prolonged treatment with this regimen could not show a survival superior to short-term treatment in a phase 3 trial. Among several combination therapies used as a second-line regimen, the combined chemotherapy with paclitaxel and carboplatin (TC) has been shown to have promising therapeutic activity against cisplatin-refractory urothelial carcinoma [11–13]; however, the efficacy of TC therapy as a second-line regimen was assessed in patients who had previously received MVAC therapy alone. Therefore, we assessed the utility and tolerability of TC therapy in a total of 16 patients with advanced urothelial carcinoma who had failed first-line chemotherapy with GC.
central nervous system, active infection, inadequately controlled diabetes, or those treated with chemotherapy other than GC prior to TC therapy were excluded. Informed consent to perform this study was obtained from all patients, and the study was approved by the research ethics committees of our institutions. The protocol was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice Guidelines. In this series, paclitaxel (175 mg/m2) and carboplatin (area under the curve 5) were injected intravenously on day 1, and dihydrocortisol (20 mg), ranitidine (50 mg) and diphenhydramine (50 mg) were given as premedication 30 min prior to the administration of paclitaxel. As a rule, this combined regimen was repeated every 3 weeks until disease progression or unacceptable adverse events occurred. Tumor measurements were generally performed by computed tomography before and every 2–3 courses after the initiation of TC therapy. Response and progression were assessed by the treating physician as well as the radiologist based on the Response Evaluation Criteria in Solid Tumors 1.0. Adverse events associated with TC therapy were assessed according to the National Cancer Institute – Common Toxicity Criteria (version 4.0). As for further treatment, in general, patients who experienced progression after the second-line TC chemotherapy received no further treatment except for best supportive care at our institution. All statistical analyses were performed using StatView 5.0 software (Abacus Concepts, Inc., Berkeley, Calif., USA). Progressionfree survival (PFS) and overall survival (OS) were determined by the Kaplan-Meier method.
Results
The data of 16 patients who underwent second-line treatment with TC therapy at our institution between April 2009 and January 2013 were retrospectively evaluated. Eligibility criteria for this retrospective analysis included histologically proven urothelial carcinoma that was not curable by surgery or radiation therapy, presence of measurable progressive and/or recurrent disease before the introduction of TC therapy, an Eastern Cooperative Oncology Group performance status of 0, 1 or 2, and adequate organ function defined by granulocyte count ≥1,500/mm3, platelet count ≥100,000/mm3, serum total bilirubin
