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Do Patients With Advanced Urothelial Carcinoma Benefit From Weekly Paclitaxel Chemotherapy? A GETUG Phase II Study
Original Contribution
Do Patients With Advanced Urothelial Carcinoma Benefit From Weekly Paclitaxel Chemotherapy? A GETUG Phase II Study Florence Joly,1 Nadine Houédé,2 Sabine Noal,1 Christine Chevreau,3 Frank Priou,4 Paule Chinet-Charrot,5 Frédéric Rolland,6 Aude Fléchon,7 Michel Henry-Amar,1 Stéphane Culine8 1
Centre François Baclesse, Caen, France Institut Bergonié, Bordeaux, France 3 Institut Claudius Rigaud, Toulouse, France 4 CH 85925 La Roche-sur-Yon, France 5 Centre Henri Becquerel, Rouen, France 6 Centre René Gauducheau, Nantes, France 7 Centre Léon Bérard, 69373 Lyon, France 8 Centre Val d’Aurelle, 34298 Montpellier, France The Genito-Urinary Group (GETUG) of the French Federation of Cancer Centers (FNCLCC) 2
Abstract Background: There is no standard second-line chemotherapy for patients who relapse with advanced urothelial carcinoma. A GETUG phase II clinical trial was designed to evaluate the response rate and the palliative clinical benefit of weekly paclitaxel. Patients and Methods: Paclitaxel (80 mg/m2, 1 hour) was administered on day 1, 8, and 15 (28-day course) to 45 patients. The primary endpoint was disease control rate (objective response and stable disease). Response rate was evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) criteria; quality of life (QOL) assessment used FACT-B1 and FACT-Taxane questionnaires. Results: Characteristics of the patients were: M/F, 36/9; mean age, 64 years; performance status (PS) 0-1, 82%; metastatic disease, 93%; gemcitabine/platinum first-line chemotherapy, 89%; median number of cycles, 2. Grade 3/4 toxicity was uncommon. The disease control rate was 47%. One patient achieved a complete response, 3 a partial response (objective response, 9%) and 17 (38%) a stable disease. Median time to progression or death were 3 and 7 months. Among the 21 patients with controlled disease, 10% displayed QOL improvement, and 14% decreased their analgesic consumption. Conclusion: Weekly paclitaxel is associated with limited objective response but a high rate of stabilization; QOL assessment indicates that a small group of patients might experience a clinical benefit.
Clinical Genitourinary Cancer, Vol. 7, No. 2, E28-E33, 2009
Introduction Keywords: Metastasis, Palliative therapy, Relapse, Urothelial cancer DOI: 10.3816/CGC.2009.n.018 Submitted: May 27, 2008; Revised: Jul 11, 2008; Accepted: Jul 31, 2008 Address for correspondence: Florence Joly, MD, PhD, Département d’oncologie Médicale, Centre François, Baclesse, 3, Avenue Général Harris, 14076 Caen cedex 05, France Fax: 33-231-455-097; e-mail: [email protected] This article might include the discussion of investigational and/or unlabeled uses of drugs and/or devices that might not be approved by the FDA. Electronic forwarding or copying is a violation of US and international copyright laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by CIG Media Group, LP, ISSN #1558-7673, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA. www.copyright.com 978-750-8400.
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Despite the effectiveness of chemotherapy, the treatment of metastatic urothelial cancer remains palliative and most patients will relapse. First-line cisplatin-based combinations are associated with clinical remission in 50% of patients with advanced urothelial carcinoma.1 Recently, gemcitabine and cisplatin have been shown to provide a disease control rate and survival benefit similar to that of standard MVAC (methotrexate/vinblastine/doxorubicin/ cisplatin) but less toxicity.2 There is no established standard chemotherapy for use in patients failing platinum-based regimens.3 However, a proportion of them are fit enough to be considered for second-line chemotherapy. In this situation, the goal of salvage therapy is to improve quality of life (QOL) rather than to increase survival rate. Therefore, active agents, with a favorable toxicity profile and that might induce clinical benefit, remain of interest. Single-agent paclitaxel is active in urothelial cancer; it is associated with a 42% response rate in patients with no previous therapy.4 In first-line treatment, in combination with platinum compounds, its overall response rate ranges from 35% to 65%.4,5 A majority of clinical experiences with paclitaxel have been obtained using a 3-week dosing schedule. Weekly administration of paclitaxel appears to minimize bone marrow suppression and other toxicities associated with standard paclitaxel 3-weekly administration without decreas-
August 2009
ing its efficacy.6 Few data are available on the activity of weekly paclitaxel administration in urothelial cancer after first-line chemotherapy including gemcitabine and cisplatin regimens and no study evaluated the clinical benefit of this treatment.4 We conducted a French multicenter phase II trial to evaluate the response rate, clinical benefit, and effect on QOL of a second-line chemotherapy with weekly paclitaxel.
Patients and Methods Patients Patients were eligible if they had urothelial carcinoma of the bladder, or urothelial tract, with a progressive measurable disease after previous line of chemotherapy for advanced disease (neoadjuvant, adjuvant, or metastatic therapy), life expectancy ≥ 3 months, World Health Organization (WHO) performance status of 0-2, normal baseline hematologic parameters, serum bilirubin level ≤ 1.5 normal limits (NL), and transaminases and alkalines phosphatases < 2.5 NL. Patients with brain metastasis or with grade ≥ 2 neuropathy were not eligible. They could have received taxanes in a 3-week schedule in first-line regimen. The study protocol was approved by the ethics committee and all patients provided written informed consent.
Treatment Plan Paclitaxel 80 mg/m2 was administered intravenously over 1 hour, on days 1, 8, and 15, of a 28-day course, for a maximum of 6 cycles. This schedule (day 1, day 8, day 15) was chosen to allow a rest of 1 week for the patients. Premedication with dexamethasone, dexchlorpheniramine, and ranitidine was given intravenously 30 minutes before the infusion of paclitaxel. On days 1, 8, and 15, full dose was given if the granulocytes were ≥ 1.5 × 109/L, platelets ≥ 100 × 106/L and there was no grade 3/4 nonhematologic toxicity. If granulocytes were ≤ 1.5 × 109/L, or platelets were ≤ 100 × 106/L for more than 7 days, or if the patient developed febrile neutropenia, platelets were ≤ 50 × 106/L or platelet transfusion was required, paclitaxel dose was reduced to 70 mg/m2. Treatment was stopped for patients presenting with persistent grade 3/4 nonhematologic toxicity, with the exception of nausea and vomiting.
Outcome Evaluation Before study entry and before each injection of paclitaxel, all patients underwent physical examination with evaluation of WHO performance status and weight performed, and had blood samples. All radiologically measurable disease was assessed every 2 cycles (every 8 weeks) with confirmation at least 4 weeks after the initial determination of the response. Toxicities were evaluated according to National Cancer Institute (NCI) toxicity criteria guidelines. Quality of life was assessed by the Functional Assessment of Cancer Therapy (FACT-G) with the bladder module (FACT-B1) and the taxane module (FACT-Taxane)7-9 before each cycle and every 3 months during follow-up. Tumor response was analyzed using Response Evaluation Criteria in Solid Tumors (RECIST). Palliative clinical benefit was defined as follows: objective response or stable disease and a 5-point absolute positive change of their score based on standard distribution of one of the QOL dimensions, without negative change of scores of the
Table 1 Patient Characteristics (n = 45) Characteristic Sex (M/F) Mean Age, Years (Range)
No. of Patients (%) 36/9 64 (47-79)
WHO Performance Status 0-1
37 (82)
2
8 (18)
Site of First Tumor Bladder
38 (84)
Other
7 (12)
Histology Transitional-cell carcinoma
43 (96)
Transitional carcinoma in situ
1 (2)
Unknown
1 (2)
Site of Relapse Locoregional Distant metastases
3 (7) 42 (93)
No. of Metastatic Sites 1
14 (33)
2
15 (36)
≥3
13 (31)
Metastatic Sites Nodes
23 (55)
Pulmonary
22 (52)
Liver
16 (38)
Bone
14 (33)
Soft tissue
2 (5)
Cerebral
1 (2)
Others
8 (19)
Previous Treatment Surgery
39 (87)
Irradiation
16 (36)
Chemotherapy
45 (100)
Adjuvant
32 (71)
Palliative
13 (29)
G-C Regimen*
40 (89)
*Gemcitabine/platinum regimen. Abbreviation: WHO = World Helath Organization
other dimensions, or an objective response or stable disease with a 25% or more decrease of their analgesic consumption with no increase in their analgesic score (using a 3-level score: 0 = none, l = minor non-opioid analgesic, 2 = mild narcotic, 3 = strong narcotic), or an objective response or stable disease with a 25% or more decrease in their analgesic score with no increase in analgesic consumption. These criteria had to be maintained at least on 2 consecutive evaluations at an interval of at least 4 weeks. Change of QOL with time was illustrated using median score of either dimension at each assessment.
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Palliative Chemotherapy by Paclitaxel in Advanced Urothelial Carcinoma trolled diseases, we carried on the second step. If 21 or more controlled diseases were observed at the second step, the disease control rate was > 30%. After the first 25 evaluable patients, 12 controlled diseases were observed, and 25 other patients were enrolled. Duration of response was calculated from the date of the best response assessment to the date of disease progression. Time to progression (from the date of enrollment to the date of disease progression) and overall survival (from the date of the enrollment to the date of death or the date of last follow-up) were estimated according to the Kaplan-Meier method. Ninety-five percent confidence interval (CI) of survival rate was estimated using the Rothman and Boice method.11 The STATA statistical software (STATA Corp, College Station, TX) was used to analyze data. Data were stored using a specific data management program (PIGAS) developed at the Institut Gustave Roussy.12 Data were updated on July 1, 2004.
Table 2 Toxicity (n = 44) Adverse Event
Grade 3 (%)
Grade 4 (%)
Nausea
1 (2)
0
Vomiting
1 (2)
0
Infection
2 (4)
0
Dyspnea
2 (4)
0
Peripheral Neuropathy
1 (2)
0
Confusion
1 (2)
0
Depression
0
1 (2)
Asthenia
6 (14)
0
Pain
17 (39)
0
Neutropenia
1 (2)
2 (4)
Anemia
3 (7)
2 (4)
Transaminases
1 (2)
0
Alkaline Phosphatases
1 (2)
0
Creatinemia
2 (4)
1 (2)
Results Patient Characteristics
From July 2002 to August 2003, 50 patients were enrolled. The patients’ characteristics are shown in Table 1. At the time of the analysis, 5 of them were not evaluable (2 were included but never Grades 3/4 (%) received the treatment, 1 had a renal adenocarcinoma and 2 refused 16/45 (36) Clinical Complications treatment after inclusion). Thirty-seven of the 45 evaluable patients 9/45 (20) Biological Complications (82%) had good performance status (0-1) and 42 (93%) had meta9/45 (20) Other Complications static disease. Twenty-six patients (58%) had visceral sites of metastatic disease. Twenty-eight of the 42 metastatic patients presented with metastases at 2 sites or more. Twenty-eight patients had initial Statistical Methods radical surgery of whom 60% (17 patients) had complete response, To be evaluable, patients had to have received at least 1 injection. and 7 patients had transurethral resection of the bladder of whom Analysis was conducted on an intention-to-treat basis. The primary none had responded. Sixteen patients (36%) received previous raendpoint was the disease control rate (complete, partial response, diation therapy. All patients had received first-line adjuvant chemoand stable disease). A 2-step plan was defined using the Fleming therapy (32 patients, 71%) or chemotherapy for metastatic disease model.10 Assuming an expected disease control rate (objective re(13 patients, 29%) of whom 2 for relapse occurring after surgery. It sponse rate and stable disease) p0 = 30% (p1 = 50%, α = 5% and a included gemcitabine and platinum regimens in 89% of cases and 1-sided test) and a fixed total number of 50 patients to be enrolled, MVAC (methotrexate/vinblastine/doxorubicin/cisplatin) for the the trial would be stopped after 25 patients were included if the others. Two patients also received paclitaxel associated with cisplatin number of controlled diseases was ≤ 7 leading to disease control for 4 cycles in 1 patient, associated with cisplatin and gemcitabine rate < 30%, or if the number of disease control was ≥ 14 leading for 6 cycles in the other (the association being allowed according to to disease control rate > 30%. If there were between 8 and 13 conprotocol). Sixty-two percent of the patients had an objective response after the first line Table 3 Response to Chemotherapy of chemotherapy (adjuvant, neoadjuvant, or for metastatic disease) including 22 complete Objective Response Response Measure responses and 6 partial responses. The median Stabilization Progression Complete Partial time since previous treatment was 5 months (range, 1-44 months), 6 months if adjuvant Number of Patients (N = 45) 1 (2%) 3 (7%) 17 (38%) 24 (53%) initial chemotherapy and 4 months if metaWHO PS 0/1 (n = 37) 1 3 14 19 static initial chemotherapy. PS 2
(n = 8)
Weight loss > 5 kg
0
0
3
5
0
0
4
1
Therapy Delivery and Toxicity
(n = 28)
1
1
11
15
Liver
(n = 16)
0
2
4
10
Nodes
(n = 14)
0
0
6
8
Bone
(n = 23)
1
2
10
10
A total of 150 cycles of paclitaxel were delivered with a median of 2 (range, 1-6 cycles) per patient. The reason for treatment stop was progression in 62% (28 of 45); toxicity, 13% (6 of 45: 2 flushes, 1 allergy, 1 neurologic toxicity, 1 decline of the global health status, 1 unknown); death, 11%; protocol end of treat-
> 2 Metastases Metastatic Site
Abbreviations: WHO PS = World Health Organization performance status
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Florence Joly et al ment after 6 or 7 cycles, 9% (4 of 45); others, 2% (1 thrombosis). Most of the patients (22 of 45) received 1 or 2 cycles occurring because of disease progression (15 of 22) or death (4 of 22). Three of these 4 deaths occurred before the end of the first cycle. The median dose of paclitaxel delivered per cycle was 239 mg/m2. The median cycle duration was 28 days (range, 25-34 days). Chemotherapy was well tolerated (Table 2). Grade 3 and 4 hematologic toxicity was uncommon. Two patients developed febrile neutropenia without complication. Grade 1/2 peripheral neuropathy was the most frequent nonhematologic toxicity. Treatment was discontinued because of toxicity in only 1 patient.
Figure 1 Change of Quality of Life Dimension Scores With Time (n = 35) FACT-B1 and FACT-Taxanes Scores 120
FB1TS FGTS FB1TOI TAXS BICS PWB SWB EWB FWB
100 80 60 40
Disease Control Rate and Survival At the time of the final analysis, among the 45 assessable patients, 21 patients had disease controlled according to our definition, leading to a disease control rate of 47% (95% CI, 32%-62%; Table 3). Among the 21 patients, 1 had a complete response, 3 a partial response (overall objective response rate: 9%; 95% CI, 2%-21%), and 17 a stable disease (38%, 95% CI, 24%-53%). Of these 21 patients with objective response or a stable disease, 86% (18 patients) had a good performance status (0 or 1); 71% (15 patients) received previously adjuvant or neoadjuvant chemotherapy. Response rate and overall survival did not differ whether patients initially presented with or without metastatic disease. In contrast, patients who responded (complete or partial response) to first-line chemotherapy had better disease control rate with paclitaxel than the other patients: corresponding figures were 55% in complete responders, 67% in partial responders, 29% in patients with stable disease, and 30% in patients who failed. The patient who achieved a complete response had bone and node metastasis. Two of the 3 patients with partial response had liver metastasis, and the other had node metastases. All of them had a delay more than 6 months from the first-line chemotherapy and they did not experience weight loss. Response duration was 2 months for the patient with complete response and 2, 4, and 5 months for the patients with partial response and between 2-6 months for patients with stable disease. Median time to progression was 96 days (range, 7-226 days). The 1-year overall survival rate was 22% (95% CI, 9%-39%) and the median overall survival 208 days (range, 11-549 days). It was 263 days (range, 200-334 days) in the 4 patients with objective response and 226 days (range, 62-549 days) in the 17 patients with disease stabilization.
Palliative Clinical Benefit Analgesic consumption could be assessed in 36 patients. Eleven percent (4 of 36) of patients decreased their analgesic consumption and 67% (24 of 36) had a stable consumption. Quality of life assessment could be evaluated in 35 patients. There was no decrease in the scores of the different QOL domains during the chemotherapy (Figure 1). Paclitaxel did not induce toxicity with negative effect on QOL based on taxane subscales of the FACT-Taxane module. Seventeen percent (6 of 35) of patients expressed improvement of their QOL at least in one domain (with absolute change of scores ≥ +5 points). Among the 21 patients with objective response or stabilization, 10% (2 of 21) displayed QOL improvement and 14% (3 of 21) decreased their analgesic consumption. According to our
20
0
1
2
3
4
5
6
7
8
2
Evaluation at Cycle No. 35
27
No. of Assessments 18 15 11
Abbreviations: BICS = bladder cancer subscale; EWB = emotional well being; FB1TS = Fact-B1 total score; FB1TOI = Fact-B1 outcome index; FGTS = Fact-G total score; FWB = functional well being; PWB = physical well being; SWB = social well being; TAXS = taxane subscale
definition, 24% (5 of 21) of patients with a disease control had a palliative clinical benefit.
Discussion After initial chemotherapy for advanced urothelial cancer, few agents are efficient and there is no standard of treatment.13 The response rate of most of the cytotoxic agents ranged between 0%-29%.14,15 There is a need for well-tolerated agents suitable for palliative therapy. Single-agent paclitaxel has shown to be active as first-line treatment and it has been recommended by the National Comprehensive Cancer Network (NCCN) guidelines as second-line treatment option in patients who relapse.4,16 Weekly paclitaxel is associated with an improvement safety profile when compared with standard 3-weekly paclitaxel and therefore it represents a good salvage therapy option.17,18 In our experience, weekly paclitaxel is well tolerated with no major toxicity. As it was chemotherapy with a palliative goal, our primary endpoint was disease control rate that included objective response rate and stable disease. Thirty-eight percent of the patients have stable disease. This study shows that paclitaxel leads to more than 30% of disease control. However, few objective responses were observed and duration of the response was short. With 9% of objective response rate, our study confirms the results reported by Vaughn et al among the same group of patients, who used the same administration schedule and observed 10% of overall response.19 The type of first-line chemotherapy regimen seems to have no influence on the efficacy of second-line weekly paclitaxel. In our study, most patients (89%) had received gemcitabine and platinum as a first-line regimen in contrast with only 6% in the Vaughn study (in which MVAC was the main regimen administered). Weekly paclitaxel is associated with an objective response rate lower than that observed with other second-line che-
Clinical Genitourinary Cancer August 2009ÊUÊE31
Palliative Chemotherapy by Paclitaxel in Advanced Urothelial Carcinoma motherapies such as ifosfamide or gemcitabine after the MVAC regimen20,21 or more recently with vinflunine after platinum-containing regimens.16 Such limited objective efficacy with paclitaxel could in part be explained by the development of resistance to paclitaxel involving multidrug resistance (MDR-1) phenotype.22 Combinations of paclitaxel and other drugs could induce higher response rates but their effect on survival is uncertain and they are often associated with limiting toxicity.23-25 Albers et al have reported that previous treatment intent (ie, adjuvant or neoadjuvant chemotherapy or chemotherapy given for metastatic disease) and performance status are important factors to predict response to second-line chemotherapy.26 Our results do not confirm these findings because no significant relationships are observed between response to second-line paclitaxel and initial metastatic disease. Patients with advanced urothelial cancer who early relapse after first-line chemotherapy are usually fragile with poor performance status, severe comorbidity, and large disease extension and do not benefit from second-line chemotherapy. Similar to the Vaughn study, most patients in our study had multiple visceral metastases that represent an independent poor prognostic factor for survival. Also, the time between first-line treatment and relapse was very short, indicating the aggressiveness of the disease.3 Is it appropriate to propose second-line treatment to patients who fail after first-line chemotherapy? Many patients who relapse generally are not good candidates to be included in new treatment approach trials. In routine practice, we probably need to improve the selection of candidates who might benefit from chemotherapy. New imaging technologies such as magnetic resonance imaging could help to quickly predict the response to chemotherapy after 1 or 2 cycles.27 In our study, there was 47% disease control. Seventeen (38%) patients had their disease stabilized for 2-6 months, duration similar to that observed in patients with objective response. Patients who achieved a response were those who had good performance status. In this situation, the goal is palliation and classic “objective response rate” might not be the best endpoint.4,24,28 Stabilization of the disease with improvement of symptoms (mainly pain) and QOL is probably a more feasible and realistic goal. Globally more than 50% of the patients achieved a benefit with control of pain or no decline of their QOL. Using our strict definition of palliative clinical response, 24% of patients could benefit from chemotherapy in contrast to the limited objective response rate observed. Our study is the first one reporting an evaluation of symptom control and QOL in patients who have relapsed with urothelial cancer. Nowadays, assessment of QOL and symptom controls is better codified with use of validated questionnaires and simple definition of symptom control; they should always be included in trials when the objective is palliation.29 In this context, information issued from data are particularly important in decision-making or simply in informing patients who request treatment.30
Conclusion Weekly paclitaxel is associated with a limited objective response rate in patients with advanced urothelial cancer who relapse after first-line chemotherapy. However, a small group of patients might experience a clinical benefit from this chemotherapy. There is still
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hope for the development of new more efficient second-line protocols with safe profiles to be proposed to patients having failed first-line chemotherapy. The main endpoint being palliation, more attention should be given to clinical palliative benefit rather than response rate or survival.
Disclosures The authors report no relevant conflicts of interest.
References 1. Culine S. The present and future of combination chemotherapy in bladder cancer. Semin Oncol 2002; 29:32-9. 2. von der Maase H, Sengelov L, Roberts JT, et al. Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. J Clin Oncol 2005; 23:4602-8. 3. Bajorin DF, Dodd PM, Mazumdar M, et al. Long-term survival in metastatic transitional-cell carcinoma and prognostic factors predicting outcome of therapy. J Clin Oncol 1999; 17:3173-81. 4. Bajorin DF. Paclitaxel in the treatment of advanced urothelial cancer. Oncology (Williston Park) 2000; 14:43-52, 57. 5. Raghavan D. Progress in the chemotherapy of metastatic cancer of the urinary tract. Cancer 2003; 97:2050-5. 6. Seidman AD, Hudis CA, Albanell J, et al. Dose-dense therapy with weekly 1-hour paclitaxel infusions in the treatment of metastatic breast cancer. J Clin Oncol 1998; 16:3353-61. 7. Cella D, Peterman A, Hudgens S, et al. Measuring the side effects of taxane therapy in oncology: the functional assesment of cancer therapy-taxane (FACTtaxane). Cancer 2003; 98:822-31. 8. Cella DF, Tulsky DS, Gray G, et al. The Functional Assessment of Cancer Therapy scale: development and validation of the general measure. J Clin Oncol 1993; 11:570-9. 9. Conroy T, Mercier M, Bonneterre J, et al. French version of FACT-G: validation and comparison with other cancer-specific instruments. Eur J Cancer 2004; 40:2243-52. 10. Fleming TR. One-sample multiple testing procedure for phase II clinical trials. Biometrics 1982; 38:143-51. 11. Rothman KJ, Boice JD, Jr. Epidemiologic Analysis With a Programmable Calculator. Boston, MA: Epidemiology Resources; 1982. 12. Wartelle M, Kramar A, Jan P, et al. “PIGAS”: An interactive statistical database management system, in Hammond R, McCarthy JL (eds): Proceedings of the Second International Workshop on Statistical Database Management. Springfield, VA, National Technical Information Service, Departement of Commerce. 1983 1983. 13. De Santis M, Bachner M. New developments in first- and second-line chemotherapy for transitional cell, squamous cell and adenocarcinoma of the bladder. Curr Opin Urol 2007; 17:363-8. 14. Culine S, Theodore C, De Santis M, et al. A phase II study of vinflunine in bladder cancer patients progressing after first-line platinum-containing regimen. Br J Cancer 2006; 94:1395-401. 15. Rosenberg JE, Carroll PR, Small EJ. Update on chemotherapy for advanced bladder cancer. J Urol 2005; 174:14-20. 16. Scher H, Bahnson R, Cohen S, et al. NCCN urothelial cancer practice guidelines. National Comprehensive Cancer Network. Oncology (Williston Park) 1998; 12:225-71. 17. Marchetti P, Urien S, Cappellini GA, et al. Weekly administration of paclitaxel: theoretical and clinical basis. Crit Rev Oncol Hematol 2002; 44(suppl):S3-13. 18. Markman M. Management of toxicities associated with the administration of taxanes. Expert Opin Drug Saf 2003; 2:141-6. 19. Vaughn DJ, Broome CM, Hussain M, et al. Phase II trial of weekly paclitaxel in patients with previously treated advanced urothelial cancer. J Clin Oncol 2002; 20:937-40. 20. Moore MJ, Tannock IF, Ernst DS, et al. Gemcitabine: a promising new agent in the treatment of advanced urothelial cancer. J Clin Oncol 1997; 15:3441-5. 21. Witte RS, Elson P, Bono B, et al. Eastern Cooperative Oncology Group phase II trial of ifosfamide in the treatment of previously treated advanced urothelial carcinoma. J Clin Oncol 1997; 15:589-93. 22. Raghavan D, Huben R. Management of bladder cancer. Curr Probl Cancer 1995; 19:1-64. 23. Li J, Juliar B, Yiannoutsos C, et al. Weekly paclitaxel and gemcitabine in advanced transitional-cell carcinoma of the urothelium: a phase II Hoosier Oncology Group study. J Clin Oncol 2005; 23:1185-91. 24. Sternberg CN. Second-line treatment of advanced transitional cell carcinoma of the urothelial tract. Curr Opin Urol 2001; 11:523-9. 25. Sternberg CN, Calabro F, Pizzocaro G, et al. Chemotherapy with an every-2-week regimen of gemcitabine and paclitaxel in patients with transitional cell carcinoma who have received prior cisplatin-based therapy. Cancer 2001; 92:2993-8. 26. Albers P, Siener R, Hartlein M, et al. Gemcitabine monotherapy as second-line treatment in cisplatin-refractory transitional cell carcinoma - prognostic factors for
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Florence Joly et al response and improvement of quality of life. Onkologie 2002; 25:47-52. 27. Schrier BP, Peters M, Barentsz JO, et al. Evaluation of chemotherapy with magnetic resonance imaging in patients with regionally metastatic or unresectable bladder cancer. Eur Urol 2006; 49:698-703. 28. Fields-Jones S, Koletsky A, Wilding G, et al. Improvements in clinical benefit with vinorelbine in the treatment of hormone-refractory prostate cancer: a phase
II trial. Ann Oncol 1999; 10:1307-10. 29. Joly F, Vardy J, Pintilie M, et al. Quality of life and/or symptom control in randomized clinical trials for patients with advanced cancer. Ann Oncol 2007; 18:1935-42. 30. Koopmans PP. Clinical endpoints in trials of drugs for cancer: time for a rethink? BMJ 2002; 324:1389-91.
Clinical Genitourinary Cancer August 2009ÊUÊE33
Do Patients With Advanced Urothelial Carcinoma Benefit From Weekly Paclitaxel Chemotherapy? A GETUG Phase II Study Florence Joly,1 Nadine Houédé,2 Sabine Noal,1 Christine Chevreau,3 Frank Priou,4 Paule Chinet-Charrot,5 Frédéric Rolland,6 Aude Fléchon,7 Michel Henry-Amar,1 Stéphane Culine8 1
Centre François Baclesse, Caen, France Institut Bergonié, Bordeaux, France 3 Institut Claudius Rigaud, Toulouse, France 4 CH 85925 La Roche-sur-Yon, France 5 Centre Henri Becquerel, Rouen, France 6 Centre René Gauducheau, Nantes, France 7 Centre Léon Bérard, 69373 Lyon, France 8 Centre Val d’Aurelle, 34298 Montpellier, France The Genito-Urinary Group (GETUG) of the French Federation of Cancer Centers (FNCLCC) 2
Abstract Background: There is no standard second-line chemotherapy for patients who relapse with advanced urothelial carcinoma. A GETUG phase II clinical trial was designed to evaluate the response rate and the palliative clinical benefit of weekly paclitaxel. Patients and Methods: Paclitaxel (80 mg/m2, 1 hour) was administered on day 1, 8, and 15 (28-day course) to 45 patients. The primary endpoint was disease control rate (objective response and stable disease). Response rate was evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) criteria; quality of life (QOL) assessment used FACT-B1 and FACT-Taxane questionnaires. Results: Characteristics of the patients were: M/F, 36/9; mean age, 64 years; performance status (PS) 0-1, 82%; metastatic disease, 93%; gemcitabine/platinum first-line chemotherapy, 89%; median number of cycles, 2. Grade 3/4 toxicity was uncommon. The disease control rate was 47%. One patient achieved a complete response, 3 a partial response (objective response, 9%) and 17 (38%) a stable disease. Median time to progression or death were 3 and 7 months. Among the 21 patients with controlled disease, 10% displayed QOL improvement, and 14% decreased their analgesic consumption. Conclusion: Weekly paclitaxel is associated with limited objective response but a high rate of stabilization; QOL assessment indicates that a small group of patients might experience a clinical benefit.
Clinical Genitourinary Cancer, Vol. 7, No. 2, E28-E33, 2009
Introduction Keywords: Metastasis, Palliative therapy, Relapse, Urothelial cancer DOI: 10.3816/CGC.2009.n.018 Submitted: May 27, 2008; Revised: Jul 11, 2008; Accepted: Jul 31, 2008 Address for correspondence: Florence Joly, MD, PhD, Département d’oncologie Médicale, Centre François, Baclesse, 3, Avenue Général Harris, 14076 Caen cedex 05, France Fax: 33-231-455-097; e-mail: [email protected] This article might include the discussion of investigational and/or unlabeled uses of drugs and/or devices that might not be approved by the FDA. Electronic forwarding or copying is a violation of US and international copyright laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by CIG Media Group, LP, ISSN #1558-7673, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA. www.copyright.com 978-750-8400.
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Despite the effectiveness of chemotherapy, the treatment of metastatic urothelial cancer remains palliative and most patients will relapse. First-line cisplatin-based combinations are associated with clinical remission in 50% of patients with advanced urothelial carcinoma.1 Recently, gemcitabine and cisplatin have been shown to provide a disease control rate and survival benefit similar to that of standard MVAC (methotrexate/vinblastine/doxorubicin/ cisplatin) but less toxicity.2 There is no established standard chemotherapy for use in patients failing platinum-based regimens.3 However, a proportion of them are fit enough to be considered for second-line chemotherapy. In this situation, the goal of salvage therapy is to improve quality of life (QOL) rather than to increase survival rate. Therefore, active agents, with a favorable toxicity profile and that might induce clinical benefit, remain of interest. Single-agent paclitaxel is active in urothelial cancer; it is associated with a 42% response rate in patients with no previous therapy.4 In first-line treatment, in combination with platinum compounds, its overall response rate ranges from 35% to 65%.4,5 A majority of clinical experiences with paclitaxel have been obtained using a 3-week dosing schedule. Weekly administration of paclitaxel appears to minimize bone marrow suppression and other toxicities associated with standard paclitaxel 3-weekly administration without decreas-
August 2009
ing its efficacy.6 Few data are available on the activity of weekly paclitaxel administration in urothelial cancer after first-line chemotherapy including gemcitabine and cisplatin regimens and no study evaluated the clinical benefit of this treatment.4 We conducted a French multicenter phase II trial to evaluate the response rate, clinical benefit, and effect on QOL of a second-line chemotherapy with weekly paclitaxel.
Patients and Methods Patients Patients were eligible if they had urothelial carcinoma of the bladder, or urothelial tract, with a progressive measurable disease after previous line of chemotherapy for advanced disease (neoadjuvant, adjuvant, or metastatic therapy), life expectancy ≥ 3 months, World Health Organization (WHO) performance status of 0-2, normal baseline hematologic parameters, serum bilirubin level ≤ 1.5 normal limits (NL), and transaminases and alkalines phosphatases < 2.5 NL. Patients with brain metastasis or with grade ≥ 2 neuropathy were not eligible. They could have received taxanes in a 3-week schedule in first-line regimen. The study protocol was approved by the ethics committee and all patients provided written informed consent.
Treatment Plan Paclitaxel 80 mg/m2 was administered intravenously over 1 hour, on days 1, 8, and 15, of a 28-day course, for a maximum of 6 cycles. This schedule (day 1, day 8, day 15) was chosen to allow a rest of 1 week for the patients. Premedication with dexamethasone, dexchlorpheniramine, and ranitidine was given intravenously 30 minutes before the infusion of paclitaxel. On days 1, 8, and 15, full dose was given if the granulocytes were ≥ 1.5 × 109/L, platelets ≥ 100 × 106/L and there was no grade 3/4 nonhematologic toxicity. If granulocytes were ≤ 1.5 × 109/L, or platelets were ≤ 100 × 106/L for more than 7 days, or if the patient developed febrile neutropenia, platelets were ≤ 50 × 106/L or platelet transfusion was required, paclitaxel dose was reduced to 70 mg/m2. Treatment was stopped for patients presenting with persistent grade 3/4 nonhematologic toxicity, with the exception of nausea and vomiting.
Outcome Evaluation Before study entry and before each injection of paclitaxel, all patients underwent physical examination with evaluation of WHO performance status and weight performed, and had blood samples. All radiologically measurable disease was assessed every 2 cycles (every 8 weeks) with confirmation at least 4 weeks after the initial determination of the response. Toxicities were evaluated according to National Cancer Institute (NCI) toxicity criteria guidelines. Quality of life was assessed by the Functional Assessment of Cancer Therapy (FACT-G) with the bladder module (FACT-B1) and the taxane module (FACT-Taxane)7-9 before each cycle and every 3 months during follow-up. Tumor response was analyzed using Response Evaluation Criteria in Solid Tumors (RECIST). Palliative clinical benefit was defined as follows: objective response or stable disease and a 5-point absolute positive change of their score based on standard distribution of one of the QOL dimensions, without negative change of scores of the
Table 1 Patient Characteristics (n = 45) Characteristic Sex (M/F) Mean Age, Years (Range)
No. of Patients (%) 36/9 64 (47-79)
WHO Performance Status 0-1
37 (82)
2
8 (18)
Site of First Tumor Bladder
38 (84)
Other
7 (12)
Histology Transitional-cell carcinoma
43 (96)
Transitional carcinoma in situ
1 (2)
Unknown
1 (2)
Site of Relapse Locoregional Distant metastases
3 (7) 42 (93)
No. of Metastatic Sites 1
14 (33)
2
15 (36)
≥3
13 (31)
Metastatic Sites Nodes
23 (55)
Pulmonary
22 (52)
Liver
16 (38)
Bone
14 (33)
Soft tissue
2 (5)
Cerebral
1 (2)
Others
8 (19)
Previous Treatment Surgery
39 (87)
Irradiation
16 (36)
Chemotherapy
45 (100)
Adjuvant
32 (71)
Palliative
13 (29)
G-C Regimen*
40 (89)
*Gemcitabine/platinum regimen. Abbreviation: WHO = World Helath Organization
other dimensions, or an objective response or stable disease with a 25% or more decrease of their analgesic consumption with no increase in their analgesic score (using a 3-level score: 0 = none, l = minor non-opioid analgesic, 2 = mild narcotic, 3 = strong narcotic), or an objective response or stable disease with a 25% or more decrease in their analgesic score with no increase in analgesic consumption. These criteria had to be maintained at least on 2 consecutive evaluations at an interval of at least 4 weeks. Change of QOL with time was illustrated using median score of either dimension at each assessment.
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Palliative Chemotherapy by Paclitaxel in Advanced Urothelial Carcinoma trolled diseases, we carried on the second step. If 21 or more controlled diseases were observed at the second step, the disease control rate was > 30%. After the first 25 evaluable patients, 12 controlled diseases were observed, and 25 other patients were enrolled. Duration of response was calculated from the date of the best response assessment to the date of disease progression. Time to progression (from the date of enrollment to the date of disease progression) and overall survival (from the date of the enrollment to the date of death or the date of last follow-up) were estimated according to the Kaplan-Meier method. Ninety-five percent confidence interval (CI) of survival rate was estimated using the Rothman and Boice method.11 The STATA statistical software (STATA Corp, College Station, TX) was used to analyze data. Data were stored using a specific data management program (PIGAS) developed at the Institut Gustave Roussy.12 Data were updated on July 1, 2004.
Table 2 Toxicity (n = 44) Adverse Event
Grade 3 (%)
Grade 4 (%)
Nausea
1 (2)
0
Vomiting
1 (2)
0
Infection
2 (4)
0
Dyspnea
2 (4)
0
Peripheral Neuropathy
1 (2)
0
Confusion
1 (2)
0
Depression
0
1 (2)
Asthenia
6 (14)
0
Pain
17 (39)
0
Neutropenia
1 (2)
2 (4)
Anemia
3 (7)
2 (4)
Transaminases
1 (2)
0
Alkaline Phosphatases
1 (2)
0
Creatinemia
2 (4)
1 (2)
Results Patient Characteristics
From July 2002 to August 2003, 50 patients were enrolled. The patients’ characteristics are shown in Table 1. At the time of the analysis, 5 of them were not evaluable (2 were included but never Grades 3/4 (%) received the treatment, 1 had a renal adenocarcinoma and 2 refused 16/45 (36) Clinical Complications treatment after inclusion). Thirty-seven of the 45 evaluable patients 9/45 (20) Biological Complications (82%) had good performance status (0-1) and 42 (93%) had meta9/45 (20) Other Complications static disease. Twenty-six patients (58%) had visceral sites of metastatic disease. Twenty-eight of the 42 metastatic patients presented with metastases at 2 sites or more. Twenty-eight patients had initial Statistical Methods radical surgery of whom 60% (17 patients) had complete response, To be evaluable, patients had to have received at least 1 injection. and 7 patients had transurethral resection of the bladder of whom Analysis was conducted on an intention-to-treat basis. The primary none had responded. Sixteen patients (36%) received previous raendpoint was the disease control rate (complete, partial response, diation therapy. All patients had received first-line adjuvant chemoand stable disease). A 2-step plan was defined using the Fleming therapy (32 patients, 71%) or chemotherapy for metastatic disease model.10 Assuming an expected disease control rate (objective re(13 patients, 29%) of whom 2 for relapse occurring after surgery. It sponse rate and stable disease) p0 = 30% (p1 = 50%, α = 5% and a included gemcitabine and platinum regimens in 89% of cases and 1-sided test) and a fixed total number of 50 patients to be enrolled, MVAC (methotrexate/vinblastine/doxorubicin/cisplatin) for the the trial would be stopped after 25 patients were included if the others. Two patients also received paclitaxel associated with cisplatin number of controlled diseases was ≤ 7 leading to disease control for 4 cycles in 1 patient, associated with cisplatin and gemcitabine rate < 30%, or if the number of disease control was ≥ 14 leading for 6 cycles in the other (the association being allowed according to to disease control rate > 30%. If there were between 8 and 13 conprotocol). Sixty-two percent of the patients had an objective response after the first line Table 3 Response to Chemotherapy of chemotherapy (adjuvant, neoadjuvant, or for metastatic disease) including 22 complete Objective Response Response Measure responses and 6 partial responses. The median Stabilization Progression Complete Partial time since previous treatment was 5 months (range, 1-44 months), 6 months if adjuvant Number of Patients (N = 45) 1 (2%) 3 (7%) 17 (38%) 24 (53%) initial chemotherapy and 4 months if metaWHO PS 0/1 (n = 37) 1 3 14 19 static initial chemotherapy. PS 2
(n = 8)
Weight loss > 5 kg
0
0
3
5
0
0
4
1
Therapy Delivery and Toxicity
(n = 28)
1
1
11
15
Liver
(n = 16)
0
2
4
10
Nodes
(n = 14)
0
0
6
8
Bone
(n = 23)
1
2
10
10
A total of 150 cycles of paclitaxel were delivered with a median of 2 (range, 1-6 cycles) per patient. The reason for treatment stop was progression in 62% (28 of 45); toxicity, 13% (6 of 45: 2 flushes, 1 allergy, 1 neurologic toxicity, 1 decline of the global health status, 1 unknown); death, 11%; protocol end of treat-
> 2 Metastases Metastatic Site
Abbreviations: WHO PS = World Health Organization performance status
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Florence Joly et al ment after 6 or 7 cycles, 9% (4 of 45); others, 2% (1 thrombosis). Most of the patients (22 of 45) received 1 or 2 cycles occurring because of disease progression (15 of 22) or death (4 of 22). Three of these 4 deaths occurred before the end of the first cycle. The median dose of paclitaxel delivered per cycle was 239 mg/m2. The median cycle duration was 28 days (range, 25-34 days). Chemotherapy was well tolerated (Table 2). Grade 3 and 4 hematologic toxicity was uncommon. Two patients developed febrile neutropenia without complication. Grade 1/2 peripheral neuropathy was the most frequent nonhematologic toxicity. Treatment was discontinued because of toxicity in only 1 patient.
Figure 1 Change of Quality of Life Dimension Scores With Time (n = 35) FACT-B1 and FACT-Taxanes Scores 120
FB1TS FGTS FB1TOI TAXS BICS PWB SWB EWB FWB
100 80 60 40
Disease Control Rate and Survival At the time of the final analysis, among the 45 assessable patients, 21 patients had disease controlled according to our definition, leading to a disease control rate of 47% (95% CI, 32%-62%; Table 3). Among the 21 patients, 1 had a complete response, 3 a partial response (overall objective response rate: 9%; 95% CI, 2%-21%), and 17 a stable disease (38%, 95% CI, 24%-53%). Of these 21 patients with objective response or a stable disease, 86% (18 patients) had a good performance status (0 or 1); 71% (15 patients) received previously adjuvant or neoadjuvant chemotherapy. Response rate and overall survival did not differ whether patients initially presented with or without metastatic disease. In contrast, patients who responded (complete or partial response) to first-line chemotherapy had better disease control rate with paclitaxel than the other patients: corresponding figures were 55% in complete responders, 67% in partial responders, 29% in patients with stable disease, and 30% in patients who failed. The patient who achieved a complete response had bone and node metastasis. Two of the 3 patients with partial response had liver metastasis, and the other had node metastases. All of them had a delay more than 6 months from the first-line chemotherapy and they did not experience weight loss. Response duration was 2 months for the patient with complete response and 2, 4, and 5 months for the patients with partial response and between 2-6 months for patients with stable disease. Median time to progression was 96 days (range, 7-226 days). The 1-year overall survival rate was 22% (95% CI, 9%-39%) and the median overall survival 208 days (range, 11-549 days). It was 263 days (range, 200-334 days) in the 4 patients with objective response and 226 days (range, 62-549 days) in the 17 patients with disease stabilization.
Palliative Clinical Benefit Analgesic consumption could be assessed in 36 patients. Eleven percent (4 of 36) of patients decreased their analgesic consumption and 67% (24 of 36) had a stable consumption. Quality of life assessment could be evaluated in 35 patients. There was no decrease in the scores of the different QOL domains during the chemotherapy (Figure 1). Paclitaxel did not induce toxicity with negative effect on QOL based on taxane subscales of the FACT-Taxane module. Seventeen percent (6 of 35) of patients expressed improvement of their QOL at least in one domain (with absolute change of scores ≥ +5 points). Among the 21 patients with objective response or stabilization, 10% (2 of 21) displayed QOL improvement and 14% (3 of 21) decreased their analgesic consumption. According to our
20
0
1
2
3
4
5
6
7
8
2
Evaluation at Cycle No. 35
27
No. of Assessments 18 15 11
Abbreviations: BICS = bladder cancer subscale; EWB = emotional well being; FB1TS = Fact-B1 total score; FB1TOI = Fact-B1 outcome index; FGTS = Fact-G total score; FWB = functional well being; PWB = physical well being; SWB = social well being; TAXS = taxane subscale
definition, 24% (5 of 21) of patients with a disease control had a palliative clinical benefit.
Discussion After initial chemotherapy for advanced urothelial cancer, few agents are efficient and there is no standard of treatment.13 The response rate of most of the cytotoxic agents ranged between 0%-29%.14,15 There is a need for well-tolerated agents suitable for palliative therapy. Single-agent paclitaxel has shown to be active as first-line treatment and it has been recommended by the National Comprehensive Cancer Network (NCCN) guidelines as second-line treatment option in patients who relapse.4,16 Weekly paclitaxel is associated with an improvement safety profile when compared with standard 3-weekly paclitaxel and therefore it represents a good salvage therapy option.17,18 In our experience, weekly paclitaxel is well tolerated with no major toxicity. As it was chemotherapy with a palliative goal, our primary endpoint was disease control rate that included objective response rate and stable disease. Thirty-eight percent of the patients have stable disease. This study shows that paclitaxel leads to more than 30% of disease control. However, few objective responses were observed and duration of the response was short. With 9% of objective response rate, our study confirms the results reported by Vaughn et al among the same group of patients, who used the same administration schedule and observed 10% of overall response.19 The type of first-line chemotherapy regimen seems to have no influence on the efficacy of second-line weekly paclitaxel. In our study, most patients (89%) had received gemcitabine and platinum as a first-line regimen in contrast with only 6% in the Vaughn study (in which MVAC was the main regimen administered). Weekly paclitaxel is associated with an objective response rate lower than that observed with other second-line che-
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Palliative Chemotherapy by Paclitaxel in Advanced Urothelial Carcinoma motherapies such as ifosfamide or gemcitabine after the MVAC regimen20,21 or more recently with vinflunine after platinum-containing regimens.16 Such limited objective efficacy with paclitaxel could in part be explained by the development of resistance to paclitaxel involving multidrug resistance (MDR-1) phenotype.22 Combinations of paclitaxel and other drugs could induce higher response rates but their effect on survival is uncertain and they are often associated with limiting toxicity.23-25 Albers et al have reported that previous treatment intent (ie, adjuvant or neoadjuvant chemotherapy or chemotherapy given for metastatic disease) and performance status are important factors to predict response to second-line chemotherapy.26 Our results do not confirm these findings because no significant relationships are observed between response to second-line paclitaxel and initial metastatic disease. Patients with advanced urothelial cancer who early relapse after first-line chemotherapy are usually fragile with poor performance status, severe comorbidity, and large disease extension and do not benefit from second-line chemotherapy. Similar to the Vaughn study, most patients in our study had multiple visceral metastases that represent an independent poor prognostic factor for survival. Also, the time between first-line treatment and relapse was very short, indicating the aggressiveness of the disease.3 Is it appropriate to propose second-line treatment to patients who fail after first-line chemotherapy? Many patients who relapse generally are not good candidates to be included in new treatment approach trials. In routine practice, we probably need to improve the selection of candidates who might benefit from chemotherapy. New imaging technologies such as magnetic resonance imaging could help to quickly predict the response to chemotherapy after 1 or 2 cycles.27 In our study, there was 47% disease control. Seventeen (38%) patients had their disease stabilized for 2-6 months, duration similar to that observed in patients with objective response. Patients who achieved a response were those who had good performance status. In this situation, the goal is palliation and classic “objective response rate” might not be the best endpoint.4,24,28 Stabilization of the disease with improvement of symptoms (mainly pain) and QOL is probably a more feasible and realistic goal. Globally more than 50% of the patients achieved a benefit with control of pain or no decline of their QOL. Using our strict definition of palliative clinical response, 24% of patients could benefit from chemotherapy in contrast to the limited objective response rate observed. Our study is the first one reporting an evaluation of symptom control and QOL in patients who have relapsed with urothelial cancer. Nowadays, assessment of QOL and symptom controls is better codified with use of validated questionnaires and simple definition of symptom control; they should always be included in trials when the objective is palliation.29 In this context, information issued from data are particularly important in decision-making or simply in informing patients who request treatment.30
Conclusion Weekly paclitaxel is associated with a limited objective response rate in patients with advanced urothelial cancer who relapse after first-line chemotherapy. However, a small group of patients might experience a clinical benefit from this chemotherapy. There is still
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hope for the development of new more efficient second-line protocols with safe profiles to be proposed to patients having failed first-line chemotherapy. The main endpoint being palliation, more attention should be given to clinical palliative benefit rather than response rate or survival.
Disclosures The authors report no relevant conflicts of interest.
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Florence Joly et al response and improvement of quality of life. Onkologie 2002; 25:47-52. 27. Schrier BP, Peters M, Barentsz JO, et al. Evaluation of chemotherapy with magnetic resonance imaging in patients with regionally metastatic or unresectable bladder cancer. Eur Urol 2006; 49:698-703. 28. Fields-Jones S, Koletsky A, Wilding G, et al. Improvements in clinical benefit with vinorelbine in the treatment of hormone-refractory prostate cancer: a phase
II trial. Ann Oncol 1999; 10:1307-10. 29. Joly F, Vardy J, Pintilie M, et al. Quality of life and/or symptom control in randomized clinical trials for patients with advanced cancer. Ann Oncol 2007; 18:1935-42. 30. Koopmans PP. Clinical endpoints in trials of drugs for cancer: time for a rethink? BMJ 2002; 324:1389-91.
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