Japanese Journal of Clinical Oncology Advance Access published online on April 23, 2007
Japanese Journal of Clinical Oncology, doi:10.1093/jjco/hym011
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© 2007 Foundation for Promotion of Cancer Research
Efficacy and Safety of Gemcitabine Monotherapy in Patients with Transitional Cell Carcinoma after Cisplatin-Containing Therapy: A Japanese Experience
1 Department of Urology, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Ibaraki
2 Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka
3 Department of Urology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka
4 Department of Urology, Kyoto Prefectural University of Medicine, Kyoto
5 Eli Lilly Japan K.K., Kobe, Japan
For reprints and all correspondence: Hideyuki Akaza, Department of Urology, Institute of Clinical Medicine, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba-city, Ibaraki, 305-0006, Japan. E-mail: akazah{at}md.tsukuba.ac.jp
Received September 30, 2006; accepted November 8, 2006
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Abstract |
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 TOP Abstract INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementAPPENDIXReferences |
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Background: In Japan, the standard chemotherapy for advanced transitional cell carcinoma (TCC) of the urothelium is MVAC (methotrexate, vinblastine, adriamycin, cisplatin). However, a second-line therapy is still required for patients with recurrent TCC who discontinued MVAC because of toxicity or have MVAC refractory tumors.
Methods: We evaluated gemcitabine monotherapy in patients with advanced TCC who were previously treated with a platinum-based regimen. Gemcitabine (1000 mg/m2) was given once a week for three consecutive weeks followed by a week of rest. This cycle was repeated at least three times, or until disease progression or intolerable adverse events were observed.
Results: Of the 46 patients entered into this study, 44 received gemcitabine. Performance status (PS) at study entry was: PS 0 (30 patients), PS 1 (12 patients) and PS 2 (2 patients). Stages III/IV were observed in 1/9 patients; the other 34 patients had relapsed after surgery. All 44 patients had been previously treated with a platinum-based regimen. The overall response rate was 25%, 1-year survival rate 52.3%, median survival time 12.6 months and median progression free survival 3.1 months. The major grade 3/4 hematological toxicity was neutropenia (47.7%), and the major grade 3/4 non-hematological toxicity was anorexia (9.1%). All adverse drug reactions seen in the study were manageable.
Conclusion: Gemcitabine monotherapy is a sufficiently active and well-tolerated therapy for patients who have previously undergone chemotherapy with a platinum-based regimen.
Key Words: gemcitabine • bladder cancer • second-line chemotherapy • transitional cell carcinoma • cisplatin resistance
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INTRODUCTION |
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Transitional cell carcinoma (TCC) of the urothelium develops in the urinary tract epithelium, which covers the proximal side of the bladder, renal pelvis and ureter. More than 90% of TCC is bladder cancer; the renal pelvis and ureter are involved in the remaining 10% (1). Systemic chemotherapy is available for patients with advanced TCC who are inoperable or have metastasis (2). Patients with advanced renal pelvic or ureteral cancer are usually treated by the same chemotherapy regimen used for bladder cancer (1, 3).
In addition to MVAC (methotrexate, vinblastine, adriamycin, cisplatin), GC (gemcitabine and cisplatin) combination therapy has been used as one option for first-line therapy in patients with advanced TCC. Both have high overall response rates, although GC was shown to have less toxicity than MVAC (4–6). Second-line therapies for TCC advanced patients have also been investigated with single agents and combination therapies (7). In these studies gemcitabine monotherapy was shown to have a higher response rate than other monotherapies such as taxane and ifosfamide in patients who had previously been treated with platinum-based regimens, including MVAC.
In Japan, gemcitabine has not been approved by MHLW (Ministry of Health, Labor and Welfare) for treatment of TCC, and MVAC therapy remains the most common regimen for chemonaive TCC patients. However, gemcitabine monotherapy has received MHLW approval for non-small cell lung cancer, pancreatic cancer and biliary tract cancer. Good efficacy and tolerability were seen in all of the studies leading up to these approvals, and given the promising results from an overseas study of gemcitabine monotherapy in TCC patients previously treated with platinum (7, 9), it is expected that gemcitabine monotherapy will continue to show good efficacy and tolerability for these types of patients in Japan. Therefore a phase II study was planned to examine the efficacy and safety profile of gemcitabine monotherapy on advanced and recurrent TCC as a second-line therapy following treatment with a platinum-based regimen.
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PATIENTS AND METHODS |
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A multi-center open-label phase II study was carried out at 16 institutions. Subjects were patients with histologically or cytologically confirmed TCC of the urothelium. All patients had advanced or metastatic disease which showed evidence of recurrence or progression following treatment with a first-line platinum-based regimen. Patients had to have at least one measurable lesion diagnosed with computed tomography (CT) or magnetic resonance imaging (MRI). An ECOG performance status of 0–2, estimated life expectancy of at least 3 months and age between 20 and 74 years were also required. Patients with an irradiated lesion of interest, or with lesions that recurred in a previously irradiated area were excluded. Full informed consent was obtained from all patients. The study was approved by the Institutional Review Board (IRB) of each institution.
All patients were registered using the centralized registration method. Prior to registration, prospective subjects were screened in two steps. Tumors were first measured three weeks before registration using CT or MRI; a chest X-ray was also taken at this time. Next, within one week of registration the following lab tests were performed: Hb (
9.5 g/dL), WBC (4000/mm3), ANC (2000/mm3), PLT (100 000/mm3), AST/ALT (
2.5 times normal), total bilirubin (1.5 mg/dL), serum creatinine (1.5 mg/dL). Performance status (0–2), weight and pregnancy (negative) were also determined at this time.
Gemcitabine (1000 mg/m2) was administered intravenously (30 min) over a 28-day period (1 cycle): 3 consecutive weeks of treatment (administration: days 1, 8, 15) followed by a week of rest. This cycle was repeated at least three times, or until disease progression or an intolerable adverse event was observed. Prior to each cycle the patient had to meet the following hematology criteria: WBC (3000/mm3), ANC (1500/mm3), PLT (100 000/mm3). Criteria for administration within a cycle (days 8, 15) were: WBC (2000/mm3), ANC (1000/mm3), PLT (70 000/mm3). Dose reduction (not lower than 800 mg/m2) for a given cycle was allowed if any of the following adverse events were observed in the preceding cycle: neutropenia (<1000/mm3: 4 days or longer), leukopenia (<2000/mm3: 4 days or longer), thrombocytopenia (<20 000/mm3). No other chemotherapy, immunotherapy, hormonal cancer therapy, or experimental medications were allowed while a patient was on study.
The primary endpoint was overall response rate. Secondary endpoints included duration of response, progression free survival and survival. Tumors were assessed at each cycle, between day 22 and the start of the next cycle, using the same method as that at baseline. Following the final administration, tumor assessment was performed every 4 weeks until progressive disease (PD) or post-treatment with another regimen. All assessments of efficacy were made in accordance with the General Rules for Clinical and Pathological Studies on Bladder Cancer (3rd edn, 2001) and the General Rules for Clinical and Pathological Studies on Renal Pelvic and Ureteral Cancer (2nd edn, 2002) by the Japanese Urological Association and the Japanese Society of Pathology. The responses for all patients were confirmed by extramural reviewers. Survival distribution and progression free survival were estimated using the Kaplan–Meier method.
Safety was assessed using the type, frequency and severity (grade) of adverse events. All assessments were made according to NCI-CTC version 2.0 (National Cancer Institute-Common Toxicity Criteria.
Based on previous study results in TCC patients who had undergone chemotherapy, the expected response rate was set at 20% and the threshold response rate at 5%. Under these assumptions the sample size needed to be at least 32 to demonstrate the true response rate exceeded the threshold response rate at a one-sided significant level of 5% with a power of 80%. However, to maximize safety information the minimum sample size was set at 40.
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RESULTS |
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This study was conducted from January 2004 to June 2005. Of the 46 patients who entered this study, 44 were administered gemcitabine and two were excluded before the first administration. The background characteristics of the patients administered the study drug are shown in Table 1; information on clinical stage and both primary and metastatic lesions is also summarized in Table 1. The two excluded patients were found to be ineligible because one did not meet the study criteria for first-line prior chemotherapy and the other suddenly worsened before first administration of the study drug.
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There were 32 males and 12 females with a median age of 65 (range: 35–74) administered at least one cycle of the study drug, all of whom had advanced or metastatic disease that had recurred or progressed after receiving a first-line platinum-based regimen. Stage III was observed in one patient, Stage IV in nine patients, and the remaining 34 patients had relapsed following surgery. Primary lesions were located at the bladder (20 patients: 45.5%) and renal pelvis–ureter (24 patients: 54.5%). Major metastatic lesions were observed in the lymph nodes (20 patients: 45.5%), lung (17 patients: 38.6%), bone (9: 20.5%) and liver (6: 13.6%). The performance status (PS) of all patients at study entry ranged from 0 to 2: PS 0 (30 patients: 68.2%), PS 1 (12 patients: 27.3%), PS 2 (2 patients: 4.5%). Prior first-line chemotherapy included MVAC (35 patients: 79.5%), MVAC plus other medication (4 patients: 9.1%), MEC (methotrexate, epirubicin, cisplatin/4 patients: 9.1%), and methotrexate/etoposide/cisplatin (1 patient: 2.3%).
The overall response rate and the response rates for affected organs (bladder, renal pelvis–ureter) for all patients are shown in Table 2. A total of 11 patients achieved PR for an overall response rate of 25% (95% CI, 13.2–40.3%): 5 (25%) patients for bladder and 6 (25%) patients for renal pelvis–ureter. Median progression free survival was 3.1 months (95% CI, 2.0–4.1 months) and median duration of response 7.5 months (95% CI, 4.5–10.3 months). The median survival time was 12.6 months (95% CI, 7.9–14.4 months) and the 1 year survival rate 52.3% (Fig. 1). The median survival times for bladder and renal pelvis–ureter were 11.5 and 13.1 months, respectively.
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The main hematological toxicities are shown in Table 3. The most common severe (Grade 3/4) toxicity was neutropenia (22 patients: 50.0%). G-CSF administration was required for five of these patients, but these events were well managed, and all 22 patients recovered satisfactorily. Other severe toxicities were less frequently observed. Severe (Grade 3/4) non-hematological toxicities (Table 4) were also not frequent, the most common being anorexia (4 patients: 9.1%). All adverse drug reactions seen in the study were manageable and there were no related deaths.
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The median of cycles completed was three (range: 1–21). The dose intensity for the 548 total doses in the study was 653.3 mg/week. Doses were reduced (800 mg/m2) for two (0.4%) administrations, once for each of two patients (increased alanine aminotransferase; and acute pyelonephritis, rash, malaise). Only three patients were discontinued for safety reasons and two of these were for gemcitabine related adverse events.
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DISCUSSION |
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Gemcitabine is a promising drug for patients with advanced/recurrent TCC, both as a first line therapy combined with platinum and as a second line drug after platinum therapy failure (8).
The purpose of this study was to investigate the efficacy and safety profile of gemcitabine single agent as a second line therapy for patients with advanced/metastatic TCC. Previously Lorusso et al. conducted a phase II study for TCC second line patients with gemcitabine 1250 mg/m2 on a 4 week schedule (9). In our study the overall response rate was 25%, comparable to the 22.6% (7/31) response rate observed in the Lorusso study. While we obtained a more favorable MST (12.6 months versus 9.3 months), both were phase II studies with a small number of patients, so the MST of these two studies might in fact be similar. Some phase II comparative studies of the single agents docetaxel, paclitaxel (weekly) and ifosfamide were also conducted as a second-line therapy in advanced TCC patients. The overall response rates of docetaxel, paclitaxel (weekly) and ifosfamide were all found to be lower than single agent gemcitabine: 13%, 10% and 20% respectively (10–12). This was especially true for taxane monotherapy where study results did not suggest any satisfactory efficacy in TCC second line patients who had mostly MVAC refractory TCCs (7, 11). Therefore, it appears that gemcitabine is effective in controlling disease progression and prolonging patient life, even in cases of recurrent or progressive disease following first-line platinum-based combination therapy.
The platinum combination therapies MVAC and MEC are widely used in Japan for advanced TCC patients (13). Although these platinum combination regimens have high response rates, significant problems remain. Toxicities in MVAC are often considerable including myelosuppression, sepsis, mucositis, nephrotoxicity, peripheral neuropathy, and a toxic death rate of 3–4% (14, 15). Prolongation of survival is also seldom observed, and progression or recurrence of TCC often occurs after a short progression-free period in MVAC therapy (16). More importantly, the adverse drug reactions related to MVAC are difficult to manage clinically because they are symptomatic, irreversible or require intensive treatment. This has made it necessary to pursue a more tolerable alternative therapy for MVAC.
A significant step forward was made in 1999 when another first-line therapy for TCC became available. This novel GC combination therapy showed similar efficacy in patients with bladder cancer, but more importantly its toxicity profile was clearly superior to MVAC (4). Because of its clear safety advantage and comparable efficacy, GC is now widely used as one of the standard first-line therapies for metastatic TCC patients in the USA and Europe (17–19).
Gemcitabine has fewer related severe adverse events than other cytotoxic drugs, the only significant DLT for gemcitabine being myelosuppression. Hematological toxicities that occurred in our study were expected and no unusual trends were observed. The only notable Grade 3/4 toxicity was neutropenia (50.0%: 22/44). Grade 3/4 hematological and non-hematological toxicities such as leucopenia and nausea/vomiting were observed but were not frequent. All of the events were easily managed. Importantly, there were few adverse events specific to this study. Most of the adverse events related to gemcitabine were reported in other diseases such as non-small lung cancer, pancreatic cancer and biliary tract cancer (20–23). Gemcitabine has also been widely studied in combination with other cytotoxic drugs, especially with cisplatin for patients with advanced non-small cell lung cancer (24). Here the major known adverse events were neutropenia, thrombocytopenia and nausea/vomiting (25–27). These were basically the as same as those seen in GC therapy for chemonaive patients with advanced TCC.
In conclusion, gemcitabine single agent shows good efficacy and safety as a second-line therapy for Japanese patients with advanced/recurrent TCC which is considered to be refractory to MVAC therapy.
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Conflict of interest statement |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementAPPENDIXReferences |
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None declared.
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APPENDIX |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementAPPENDIXReferences |
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The Japanese Gemcitabine Study Group
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References |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementAPPENDIXReferences |
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