Japanese Journal of Clinical Oncology 30:547-552 (2000)
© 2000 Foundation for Promotion of Cancer Research
Single Agent Paclitaxel as a First-line Therapy in Advanced Urothelial Carcinoma: Its Efficacy and Safety in Patients Even With Pretreatment Renal Insufficiency
1Division of Medical Oncology, Department of Medicine and 4Division of Urology, Department of Surgery, Taipei Veterans General Hospital, 2National Yang-Ming University, School of Medicine and 3Division of Hematology/Oncology, Department of Medicine, Mackay Memorial Hospital – Taipei, Taipei, Taiwan
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Background: Cisplatin-based chemotherapy is the mainstay of the treatment for advanced urothelial cancer, but patients with renal insufficiency before therapy are usually contraindicated to receiving platinum-based chemotherapy. Paclitaxel is one of the most promising agents against advanced urothelial carcinoma in recent trials and it can be easily tolerated even in patients with compromised renal function. We conducted a study in order to evaluate the efficacy and safety of paclitaxel as a first-line therapy in advanced urothelial carcinoma patients.
Methods: Thirteen advanced chemo-naive urothelial carcinoma patients with a median age of 71 years were studied, seven of them demonstrating renal insufficiency (pretreatment serum creatinine 
1.5 mg/dl). All 13 patients received a minimum of two cycles of paclitaxel 175 mg/m2, delivered by intravenous infusion for 3 h every 3 weeks.
Results: Four of the 13 patients responded to treatment, a response rate of 30.8%, with two of these achieving complete remission and two showing partial responses. The median overall survival period of all 13 patients was nine months (95% CI: 6.51–11.49) and our study revealed a statistical tendency in the difference of median overall survival time between responders and non-responders (13 months versus 7.5 months, log-rank p = 0.038), although the number of cases was limited. The differences in response rate and median overall survival time, comparing patients with renal insufficiency and those with normal renal function, were not significant. Treatment-related toxicity was mild, with only two (15.4%) patients suffering from grade 3–4 leukopenia. No treatment-related mortality was noted.
Conclusions: Single-agent paclitaxel can be used as a first-line therapy in advanced urothelial carcinoma patients, and is especially suitable for those with pretreatment renal insufficiency, since the antitumor activity is significant while toxicity is well tolerated.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Advanced urothelial carcinoma is a relatively chemosensitive neoplasm and cisplatin-based combination chemotherapy has become the standard treatment for this disease, with reported response rates of 39–70% (1,2). The major toxicities of cisplatin-based chemotherapy are myelosuppression, nausea, vomiting and nephrotoxicity, which limit its usage to patients with normal renal function and adequate performance status (3). Vaughn (1999) proposed that up to 25% of patients with urothelial cancer have pretreatment serum creatinine concentrations
1.6 mg/dl (3), but cisplatin-based chemotherapy is usually contraindicated in these patients because of their pretreatment renal insufficiency. Finding a novel and effective agent for the treatment of this subgroup of patients is important for clinical practice. Recent studies have shown that paclitaxel offers significant antitumor activity for the treatment of advanced urothelial carcinoma, used either as a single agent (4–6) or in combination with other drugs (7–9). In a review of the literature, only one report advises that paclitaxel may be used as a second-line therapy in urothelial cancer patients with renal insufficiency (5), while no reports suggest paclitaxel as a first-line therapy for elderly advanced urothelial cancer patients with renal insufficiency before therapy. We therefore decided to assess the efficacy and safety of single-agent paclitaxel as a first-line therapy in advanced urothelial-carcinoma patients regardless of their renal function status.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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From October 1996 to May 1999, 13 histologically documented locally advanced or metastatic urothelial carcinoma patients (10 males and three females), either with pretreatment renal insufficiency (pretreatment serum creatinine
1.5mg/dl) or not, were enrolled in this study. Ten of them had unresectable primary tumor only, one had neck lymph node metastases and two had bony metastases. The patients’ characteristics are presented in Table 1.
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Inclusion Criteria
Eligibility criteria included age between 18 and 80 years, dimensionally measurable locally advanced or metastatic disease, adequate hepatic function (serum total bilirubin level
2.0 mg/dl, serum aspartate transaminase level 2 times the upper limit of normal), adequate bone marrow reserve (absolute neutrophils count 1200/µl, platelet count 100 000/µl). Patients should not have received prior chemotherapy or immunotherapy and previous radiotherapy must have been finished for at least 2 months. Major surgery must have been at least 4 weeks prior to the beginning of treatment and all patients were required to have life expectancies of at least 2 months. All patients provided written, informed consent before entry.
Exclusion Criteria
Exclusion criteria included age <18 or >80 years, previous treatment of the current disease with cytotoxic chemotherapy or immunotherapy, inadequate hematological function (as defined by absolute neutrophils count <1200/µl or platelet count <100 000/µl before therapy), inadequate hepatic function (as defined by serum total bilirubin level >2.0 mg/dl or serum aspartate transaminase level >2 times the upper limit of normal), second malignancy with the exception of in situ cervical cancer or adequately treated basal cell or squamous cell carcinoma of the skin, history of concurrent cardiac disease such as severe heart failure, uncontrolled atrial or ventricular arrhythmia, recent myocardial infarction; pre-existing sensory or motor neuropathy >grade 1 according to the WHO criteria, active infection or other serious underlying medical problems that would impair the ability of the patient to receive protocol treatment, pregnancy and breast feeding and the patient’s refusal of further treatment at any time during the study.
Therapy
All patients were hospitalized for treatment. An intravenous infusion of paclitaxel 175 mg/m2 was administered for 3 h every 3 weeks and dexamethasone and antihistamine were given before paclitaxel infusion for anaphylaxis prophylaxis, while prophylactic hematopoietic growth factor support was not used routinely. The treatment was continued until intolerable toxicity developed or objective evidence of disease progression was noted. At least two cycles of chemotherapy were administered to all patients.
Definition of Response
Complete remission (CR) was defined as the complete disappearance of all clinically detectable disease for at least 4 weeks, measured by image studies and physical examination. Partial response (PR) was defined as a >50% decrease in tumor mass for at least 4 weeks, as determined by cross-sectional area from a two-dimensional image study. Stable disease (SD) was defined as a reduction in tumor mass of <50% or an increase of <25% for at least 4 weeks, as measured by cross-sectional area from two-dimensional strategies. If any new lesions were detected or the tumor mass increased by >25%, progressive disease (PD) was defined. Because it is difficult to measure bone metastases, a separate set of response criteria were used for lytic or blastic bone lesions. Complete remission required complete disappearance of all lesions as measured by X-ray, bone scan, computerized tomographic (CT) scan or MRI for at least 1 month. Partial response required a decrease in size of lytic lesions as measured by X-ray, bone scan, CT scan or MRI or a decreased uptake of blastic bone lesions as measured by bone scan for at least 1 month. In the 10 patients with unresectable primary tumor only, the treatment responses were evaluated by two-dimensional image study as mentioned above and in the one patient with neck lymphadenopathy the response was evaluated by the size of the neck lymph nodes. In the other three patients with both bony metastases and locally advanced primary tumor, responses were evaluated by a separate criterion for bony metastases as mentioned above and two-dimensional image study for primary tumors. Time to progression was measured from the time of therapy initiation to the time that progressive disease was documented. Overall survival time was measured from the initiation of therapy to the last clinical visit or death.
Evaluation and Follow-up
All patients received an evaluation which included recording of detailed history and physical examination, tumor mapping (chest X-ray or CT scan for intrathoracic lesions, ultrasound or CT scan for intra-abdominal lesions), complete blood count and serum biochemistry workup. All patients were asked to visit out-patient clinics 1 week after chemotherapy to check complete blood count and serum biochemistry, where necessary. Chest X-ray and abdominal CT scan were performed after every two cycles for evaluation of treatment response. Adverse effects were assessed according to ECOG criteria.
Statistical Methods
A survival curve was plotted for median survival times using the Kaplan–Meier method. A value of p < 0.05 was considered statistically significant. A log-rank test was used for the analysis of overall survival and a Pearson chi-squared test or a Fisher’s exact test was used for analyzing the relationship of treatment response between normal renal function (NRF) and renal insufficiency (RI) patients.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Thirteen patients were enrolled in this study with a median age of 71 years. Two of them were classified CR (15.4%), two PR (15.4%), one SD (7.7%) and eight PD (61.5%). The overall response rate was 30.8%. The patients’ clinical profiles, cycles of therapy, responses to treatment and overall and progression-free survival times are shown in Table 2.
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Treatment-related toxicities were graded according to ECOG toxicity criteria. The major toxicity was myelosuppression: seven patients (53.9%) developed leukopenia after chemotherapy, with two (15.4%) determined grade 3–4. Only one patient (7.7%) received hematopoietic growth factor support after chemotherapy because of grade 4 leukopenia with infection, recovering uneventfully. Six patients (46.2%) developed anemia, with one (7.7%) classified grade 3. Grade 3 thrombocytopenia was revealed in one patient (7.7%). Nausea/vomiting, stomatitis and diarrhea were rare with gradings of
2. One patient developed grade 1 cardiotoxicity (sinus bradycardia) during paclitaxel infusion and recovered after chemotherapy was completed. Two patients (15.4%) developed grade 2 peripheral neuropathy after chemotherapy; three patients (23.1%) presented with infection during the post-chemotherapy neutropenic stage and all recovered well. No treatment-related mortality occurred during this study. Treatment-related toxicities are presented in Table 3. The major toxicities for NRF patients and for those with RI were similar: one (16.7%) NRF and one (14.3%) RI patient developed grade 3–4 leukopenia; one (16.7%) NRF and two (28.6%) RI patients contracted febrile neutropenia; one (16.7%) NRF and one (14.3%) RI patient developed complications involving peripheral neuropathy.
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After a median 8-month follow-up (range 1.5–33 months), four of the 13 patients had survived. The Kaplan–Meier estimate for median overall survival duration was 9 months (95% CI: 6.51–11.49; Fig. 1). The projected 1-year survival rate was 29.8%. The median overall survival time for the nine non-responders was 7.5 months and for the remaining four responders 13 months (p = 0.0386, log-rank). The median overall-survival time for the seven RI patients was 9 months and for the remaining six patients 8 months (p = 0.7682, log-rank). The correlation between response and pretreatment renal function status was not statistically significant (p = 1.000, Fisher’s exact test).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Since 1985, when Harker et al. (10) and Sternberg et al. (11) reported that the combination of cisplatin, methotrexate and vinblastine, with doxorubicin (the M-VAC regimen) or without doxorubicin (the CMV regimen), produced significant activity against metastatic urothelial carcinoma, cisplatin-based chemotherapy has become the mainstay of treatment in advanced urothelial carcinoma. However, the nephrotoxicity of cisplatin limits its use to patients with normal renal function, as up to 25% of patients with advanced urothelial cancer have pretreatment serum creatinine concentrations
1.6 mg/dl (3). A significant number of patients with locally advanced or metastatic urothelial cancer develop urogenital tract obstruction resulting in renal impairment (12). Other patients may have impaired renal function due to co-existing medical illness unrelated to the malignancy. Trials that have evaluated M-VAC reported a high degree of toxicity, mainly neutropenic fever or sepsis (16–25% of patients) and grade 3–4 mucositis (13–17%) (13). However, if left untreated, the median overall survival time of patients with advanced urothelial cancer without treatment rarely exceeded 3–6 months (8), so it is necessary to find a novel chemotherapeutic drug for patients unsuitable for receiving cisplatin-based chemotherapy. Paclitaxel has been one of the most promising of the new agents in recent trials, demonstrating significant activity against human bladder cancer cell lines (14). It is not nephrotoxic and can be easily tolerated by patients with varying degrees of renal insufficiency (4–9), making it very suitable for patients with compromised renal function before anti-cancer therapy. In 1996, Dreicer et al. studied nine cases of advanced urothelial cancer treated with various doses of paclitaxel, six of them exhibiting renal insufficiency, with a median serum creatinine concentration of 2.25 mg/dl (5). The toxicity was deemed acceptable and four of nine patients developed an objective response.
In our study, we enrolled 13 patients with advanced urothelial carcinoma. The median age was 71 years. Seven of the 13 patients demonstrated impaired renal function (serum creatinine 1.5 mg/dl). In 1994, Dreicer’s group reported that a higher dosage of paclitaxel such as 250 mg/m2 routinely needs hematopoietic growth factor support (4) and subsequently reported that using paclitaxel 175 mg/m2 in previously treated urothelial-carcinoma patients was relatively safe even without routine growth factor support (5). We therefore chose paclitaxel 175 mg/m2 as the treatment dosage in our study. After paclitaxel treatment, the overall response rate was 30.8%, which is not inferior to those with other single chemotherapeutic agents in advanced urothelial carcinoma (4–6,15–17). Two of the four responding patients achieved complete remission after paclitaxel therapy, one patient’s remission lasting for 3 months and the other’s 10 months. The median overall survival period was 9 months, comparable to previous studies (4–11). The median overall survival time for the four responders was 13 months and that of the nine non-responders 7.5 months. There is a trend that the difference in survival time between responders and non-responders is significant (p = 0.0386, log-rank), despite the limited number of cases. Although the dosage of paclitaxel in our study (175 mg/m2) is lower than that in other reports (4,6,7), the comparable response rate confirms significant single-agent activity against urothelial cancer. The treatment-related toxicity for paclitaxel in our study was mild. The major toxicity was myelosuppression: seven (53.9%) patients developed leukopenia after chemotherapy, but only two (15.4%) were assessed above grade 3. The other treatment-related toxicities noted, such as cardiovascular and neurological manifestations, were mild (grade 2). No treatment mortality was noted in this study.
Seven of our 13 patients revealed renal insufficiency before treatment (pretreatment serum creatinine level 1.5 mg/dl). The response rate for RI patients was 28.57%, similar to the response rate for patients with normal renal function (33.33%), while the relationship between response and renal-function status was statistically insignificant (p = 1.00, Fisher’s exact test). Further, a comparison of the median overall survival time for RI patients and NRF patients did not reveal a significant difference (9 and 8 months; p = 0.7682, log-rank). The toxicity profiles for these two groups are similar: one (16.7%) NRF and one (14.3%) RI patient developed grade 3–4 leukopenia; one (16.7%) NRF and two (28.6%) RI patients contracted febrile neutropenia; one (16.7%) NRF and one (14.3%) RI patient developed complications involving peripheral neuropathy. Although this small-scale trial cannot confirm the efficacy and safety in either RI or NRF urothelial carcinoma patients, it suggests that using palitaxel 175 mg/m2 as a first-line therapy in advanced urothelial carcionmas is effective and relatively safe regardless of the renal function status.
In conclusion, paclitaxel 175 mg/m2 delivered by intravenous infusion for 3 h every 3 weeks is an effective first-line therapy for advanced urothelial carcinoma patients, and is especially suitable for those with pretreatment renal insufficiency. The toxicity is mild and well tolerated and hematopoietic growth factor support is not necessary. Further large prospective randomized clinical trials are needed to confirm and establish the efficacy of this novel first-line therapy.
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FOOTNOTES |
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+ For reprints and all correspondence: Po-Min Chen, Division of Medical Oncology, Department of Medicine, Taipei Veterans General Hospital, No. 201, Sec. 2, Shih-Pai Road, Taipei 112, Taiwan. E-mail: pmchen@vghtpe.gov.tw
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REFERENCES |
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1 Sternberg CN, Yagoda A, Scher HI, Watson RC, Geller N, Herr HW, et al. Methotrexate, vinblastine, doxorubicin and cisplatin for advanced transitional cell carcinoma of the urothelium. Efficacy and patterns of response and relapse. Cancer 1989;64:2448–58.[Web of Science][Medline]
2 Loehrer PJ Sr, Einhorn LH, Elson PJ, Crawford ED, Kuebler P, Tannock I, et al. A randomized comparison of cisplatin alone or in combination with methotrexate, vinblastine and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study. J Clin Oncol 1992;10:1066–73.[Abstract]
3 Vaughn DJ. Review and outlook for the role of paclitaxel in urothelial carcinoma. Semin Oncol 1999;26(Suppl 2):117–22.
4 Roth BJ, Dreicer R, Einhorn LH, Neuberg D, Johnson DH, Smith JL, et al. Significant activity of paclitaxel in advanced transitional-cell carcinoma of the urothelium: a phase II trial of the Eastern Cooperative Oncology Group. J Clin Oncol 1994;12:2264–70.
5 Dreicer R, Gustin DM, See WA, Williams RD. Paclitaxel in advanced urothelial carcinoma: its role in patients with renal insufficiency and as salvage therapy. J Urol 1996;156:1606–8.[Web of Science][Medline]
6 Papamichael D, Gallagher CJ, Oliver RTD, Johnson PW, Waxman J. Phase II study of paclitaxel in pretreated patients with locally advanced/metastatic cancer of the bladder and ureter. Br J Cancer 1997;75:606–7.[Web of Science][Medline]
7 Redman BG, Smith DC, Flaherty L, Du W, Hussian M. Phase II trial of paclitaxel and carboplatin in the treatment of advanced urothelial carcinoma. J Clin Oncol 1998;16:1844–8.[Abstract]
8 Zielinski CC, Schnack B, Grbovic M, Brodowicz T, Wiltschke C, Steger G, et al. Paclitaxel and carboplatin in patients with metastatic urothelial cancer: result of a phase II trial. Br J Cancer 1998;78:370–4.[Web of Science][Medline]
9 Pycha A, Grbovic M, Posch B, Schnack B, Haitel A, Heinz-Peer G, et al. Paclitaxel and carboplatin in patients with metastatic transitional cell cancer of the urinary tract. Urology 1999;53:510–5.[Web of Science][Medline]
10 Harker WG, Meyers FJ, Freiha FS, Palmer JM, Shortliffe LD, Hannigan JF, et al. Cisplatin, methotrexate and vinblastine (CMV): an effective chemotherapy regimen for metastatic transitional cell carcinoma of urinary tract. A Northern California Oncology Group Study. J Clin Oncol 1985;3:1463–70.
11 Sternberg CN, Yagoda A, Scher HI, Watson RC, Ahmed T, Weiselberg LR, et al. Preliminary results of M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin) for transitional cell carcinoma of the urothelium. J Urol 1985;133:403–7.[Web of Science][Medline]
12 Leibovitch I, Ben-Chaim J, Ramon J, Madjar I, Engelberg IS, Glodwasser B. The significance of ureteral obstruction in invasive transitional cell carcinoma of the urinary bladder. J Surg Oncol 1993;52:31–5.[Web of Science][Medline]
13 Saxman SB, Propert KJ, Einhorn LH, Crawford ED, Tannock I, Raghavan D, et al. Long-term follow-up of a phase III intergroup study of cisplatin alone or in combination with methotrexate, vinblastine and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study. J Clin Oncol 1997;15:2564–9.
14 Rangel C, Niell H, Miller A, Cox C. Taxol and taxotere in bladder cancer: in vitro activity and urine stability. Cancer Chemother Pharmacol 1994;33:460–4.[Web of Science][Medline]
15 Moore MJ, Tannock IF, Ernst DS, Huan S, Murry N. Gemcitabine: a promising new agent in the treatment of advanced urothelial cancer. J Clin Oncol 1997;15:3341–5.
16 de Wit R, Kruit WH, Stoter G, de Boer M, Kerger J, Verweij J. Docetaxol (Taxotere): an active agent in metastatic urothelial cancer: result of a phase II study in non-chemotherapy-pretreated patients. Br J Cancer 1998;78:1342–5.[Web of Science][Medline]
17 Dimopoulos MA, Deliveliotis C, Moulopoulos LA, Papadimitriou C, Mitropoulos D, Anagnostopoulos A, et al. Treatment of patients with metastatic urothelial carcinoma and impaired renal function with single-agent docetaxel. Urology 1998;52:56–60.[Web of Science][Medline]
Received July 13, 2000; accepted September 12, 2000.
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