ABSTRACT: Phase II studies of single-agent docetaxel (Taxotere) yielded promising results in advanced or metastatic transitional cell carcinoma (TCC) of the urothelium. Antitumor responses have been demonstrated in previously treated and chemotherapy-naive TCC patients, as well as in a subgroup of patients with renal impairment unable to receive traditional cisplatin-based regimens. Investigations of docetaxel-containing doublet and triplet drug combinations in the first-line setting have been pursued. When combined with cisplatin in previously untreated patients, response rates of 52% to 60% have been achieved, with median overall survival of 8 to 13.6 months. Triplet drug combinations of the docetaxel/platinum base have been investigated, when the addition of an anthracycline (doxorubicin or epirubicin [Ellence]) or of gemcitabine (Gemzar) has proven feasible, and has resulted in favorable efficacy findings. Non-platinum-containing regimens such as docetaxel/gemcitabine are also being studied. Randomized phase III trials of a docetaxel-containing regimen in comparison with established regimens are ongoing, and additional studies are warranted to determine if overall long-term survival of TCC patients can be improved. [ONCOLOGY 16(Suppl 6):107-111, 2002]
Conventional chemotherapy for transitional cell carcinoma (TCC) traditionally includes cisplatin-based combination regimens. Cisplatin is considered the most effective drug for the treatment of metastatic urothelial cancer, with response rates of 12% to 40% when used as a single agent in the first-line setting. Improved response rates have been attained with multidrug combinations, the most established of which is MVAC (methotrexate, vinblastine, doxorubicin [Adriamycin], cisplatin). Two large phase III studies have demonstrated a survival benefit of the four-drug MVAC combination in comparison to single-agent cisplatin and to the three-drug CISCA combination of cyclophosphamide, doxorubicin, and cisplatin.[2,3]
Despite the high response rates achieved with the MVAC regimen, most patients relapse and die from their disease. Median survival time is only 9 to 12 months, and only 3% to 11% of patients achieve long-term survival. In the last several years, numerous changes to the established regimens have been attempted (eg, addition of hematopoietic growth factors, dose intensification), however, it does not appear that further improvements in therapy will arise from manipulation of existing regimens. Rather, advances are more likely to come from incorporation of newer agents such as docetaxel. Several phase II trials of docetaxel for treatment in TCC, as a single-agent (Table 1)[4-6] and in combination regimens, have been completed or are ongoing, and the results are discussed here.
Previously Treated TCC
No second-line chemotherapy has demonstrated a survival benefit for patients who relapse after treatment with a cisplatin-containing chemotherapy regimen, prompting the search for new active agents. McCaffrey and colleagues conducted a study of single-agent docetaxel in patients with advanced TCC who had failed to respond or relapsed on prior cisplatin-based chemotherapy. Patients were treated with docetaxel at 100 mg/m² administered as a 1-hour infusion every 21 days, and therapy continued until there was evidence of progressive disease or unacceptable toxicity. Colony-stimulating factors were not administered prophylactically, but were allowed if patients were hospitalized for neutropenic fever.
Patients were considered evaluable for efficacy and toxicity if they had received at least one dose of therapy. A total of 30 patients met these criteria and were considered assessable, having received a median of three courses of therapy (range: 1-11). There were four partial responses, for an overall response rate of 13.3%. Median duration of response was 4 months (range: 3-8 months), and the median time to achieve response was 7 weeks. Response was related to the interval between completion of prior therapy, with an interval of 6.5 months in nonresponders vs an interval of 31.5 months in responders. Median survival was 9 months (95% confidence interval [CI]: 6-12 months).
The most common toxicities were hematologic in nature, with grade 3/4 neutropenia in 83% and grade 3 anemia in 27% of patients. Nonhematologic toxicities were mild to moderate in severity, with no grade 4 events reported. Grade 3 mucositis was observed in two patients (7%), requiring dose adjustment.
Previously Untreated TCC
In previously untreated TCC patients, de Wit et al investigated single-agent docetaxel at 100 mg/m² every 3 weeks. If tumor regression was not demonstrated after two cycles of therapy, patients were offered cisplatin combination chemotherapy. A total of 29 patients who received at least two cycles of therapy were considered to be assessable for response. An overall response rate of 31% was demonstrated, with four complete responses and five partial responses. The median duration of response for complete and partial responders was 6 months.
The predominant toxicity was grade 3/4 neutropenia in 48% of patients; however, it was rapidly reversible. Grade 3/4 nonhematologic toxicities were notably uncommon. Grade 3 toxicities, reported in one patient each (3%), included nausea/vomiting, fatigue, edema, neurosensory toxicity, neuromotor toxicity, and diarrhea. Frequently occurring grade 1 and 2 toxicities included myalgia (11%), fatigue (15%), and neurosensory changes (15%). The authors concluded that single-agent docetaxel was active in this group of patients with extensive metastatic disease and proposed that further investigations in combination regimens be pursued.
Renally Impaired Patients
A significant number of patients with locally advanced or metastatic bladder cancer may present with or develop ureteral obstruction associated with impaired renal function, or patients may have impaired renal function due to coexisting illnesses. Several of the established chemotherapy agents (eg, cisplatin, methotrexate, and ifosfamide [Ifex]), are not ideal agents for administration to such patients because they are eliminated renally. In contrast, docetaxel is cleared primarily by the hepatic route.
Dimopoulos and colleagues therefore undertook an investigation of single-agent docetaxel for the treatment of patients with metastatic TCC and impaired renal function. Out of 65 previously untreated metastatic urothelial cancer patients referred for medical treatment, 11 patients (17%) had impaired renal function defined as serum creatinine of 1.6 mg/dL or more. This subgroup of patients had a median serum creatinine of 2.6 mg/dL (range: 1.8-11 mg/dL). Patients were treated with docetaxel at 100 mg/m² every 3 weeks for a total of six cycles, or until progressive disease. Prophylactic granulocyte colony-stimulating factor (G-CSF [Neupogen]), 5 µg/kg, was administered on days 5 to 14. For patients experiencing febrile neutropenia, the docetaxel dose was reduced by 25% on all subsequent cycles. Five of 11 patients (45%) achieved a partial response, and an additional three patients (27%) demonstrated stable disease. Median time to best response was 6 weeks (range: 6-9). Duration of response ranged from 5 to 22+ months. The median survival of all treated patients was 11 months.
Treatment was reasonably well tolerated, with grade 3/4 neutropenia in five patients (45%) and neutropenic fever in two patients (18%). The authors concluded that docetaxel can be safely and effectively administered to metastatic urothelial cancer patients with impaired renal function. Treatment with docetaxel allowed a substantial proportion of patients who otherwise would be ineligible for cisplatin-based therapy to achieve tumor control.
• Cisplatin/Docetaxel—The combination of docetaxel and cisplatin has shown activity for a number of tumor types, including ovarian, breast, head and neck, gastric, and non-small-cell lung cancers.[7-12] Historically, the best responses in the treatment of TCC have been attained with combination chemotherapy regimens that employ cisplatin. The different mechanisms of action, the lack of completely overlapping toxicities, and the high individual activity led to investigations of the docetaxel/cisplatin combination for TCC (Table 2).[13-17]
Sengelov and colleagues investigated a combination of docetaxel at 75 mg/m² and cisplatin at 75 mg/m² every 21 days. A total of 25 patients with locally advanced or metastatic TCC of the urothelial tract considered incurable with radiation or surgery were assessable for response and toxicity. Patients received a median of six courses of chemotherapy with administration of full doses of both drugs in 95 out of 155 (61%) courses administered. Six patients required dose reduction of docetaxel because of hematologic toxicities, and nine patients required dose reduction of cisplatin because of renal dysfunction. However, the overall delivered dose-intensity of each drug was 90% or above.
A total of 15 patients (60%) achieved a response, including seven complete responses and eight partial responses. An additional six patients had stable disease. The median duration of response was 10.3 months (range: 4-26.5 months) and median survival was 13.6 months (range: 1.5-26.5 months). Grade 3/4 toxicities included neutropenia (56%), nausea and vomiting (32%), and alopecia (44%). Other toxicities were grades 1 and 2 in severity and consisted of peripheral neuropathy (76%), mucositis (40%), and diarrhea (40%).
A similar investigation of the docetaxel/cisplatin combination was conducted by the Hellenic Cooperative Oncology Group in a multicenter phase II study. A total of 66 patients with advanced or metastatic TCC not amenable to radiation or surgery were enrolled in the study. Patients were treated on an outpatient basis with docetaxel at 75 mg/m² followed by cisplatin at 75 mg/m². Treatment was administered once every 3 weeks for six cycles. All patients received concomitant G-CSF from day 5 until resolution of neutropenia. An overall response rate of 52% was demonstrated, with 8 complete responses (12%) and 26 partial responses (40%). The median response duration was 8 months (range: 2-31 months), and the median overall survival was 8 months (range: 1-33 months). A logistic regression model was used to evaluate the effect of different variables on overall response. Findings demonstrated that an increased likelihood of response was seen in patients with an absence of lung metastases and weight loss.
Therapy was generally well tolerated, with predominantly hematologic toxicities. The incidence of grade 3/4 neutropenia was 33%, with 10 episodes of neutropenic fever. Grade 3/4 anemia was reported in 14% of patients. Nonhematologic toxicities were mild to moderate in severity and included grade 3 diarrhea (13%), nausea and vomiting (7%), stomatitis (3%), and neurotoxicity (3%). The investigators concluded that a randomized trial comparing the docetaxel/cisplatin combination to the MVAC regimen was warranted. A phase III trial has been initiated with over 200 patients enrolled.
The same regimen of docetaxel at 75 mg/m² and cisplatin at 75 mg/m², was tested by investigators from Spain. A total of 20 patients with locally advanced or metastatic urothelial cancer were enrolled, with 19 evaluable for response and all patients evaluable for toxicity. A median of four cycles (range: 1-6) of therapy was administered at 100% relative dose intensity. An overall response rate of 53% was reported, including four complete responses and six partial responses. The main toxicities were hematologic, with grade 3/4 neutropenia in seven patients (35%), and febrile neutropenia in three patients (15%). Grade 3 nonhematologic toxicities included asthenia (20%), nausea/vomiting (10%), and diarrhea or neurotoxicity in one patient each (5%).
• Docetaxel and Gemcitabine—Based upon the individual activity of docetaxel and gemcitabine and their combined synergistic effect in urothelial cancer, investigation of the use of docetaxel and gemcitabine in combination has been pursued with the potential to identify an active, non-cisplatin-containing regimen. Investigators at the University of California, Los Angeles, administered docetaxel at 80 mg/m² on day 1 and gemcitabine at 800 mg/m² on days 1, 8, and 15, with the cycle repeated every 21 days. A total of 14 patients with advanced TCC were enrolled and received a total of 64 cycles of therapy, with a median of five cycles.
Grade 4 neutropenia developed in eight patients, which necessitated a protocol amendment reducing the dose of docetaxel from 80 mg/m² to 60 mg/m². An overall response rate of 43% was reported in 14 patients, with two complete responses and four partial responses. Toxicities included grade 4 neutropenia (29%), grade 3 neutropenia (57%), grade 3 fatigue (7%), and grade 3 rash (7%). Accrual to the study continues to a total population of 30 patients.
Triplet Drug Regimens
• Docetaxel/cisplatin/epirubicin—The triplet drug combination of docetaxel, cisplatin, and epirubicin has been evaluated in a phase II trial for patients with advanced and metastatic TCC. A total of 32 patients were enrolled on the study. Prior adjuvant therapy was allowed if treatment was completed at least 6 months prior to study entry. All patients were required to have measurable disease at the time of study entry. Treatment consisted of epirubicin at 40 mg/m² administered by IV push, followed by docetaxel at 75 mg/m² as a 1-hour IV infusion, followed by cisplatin at 75 mg/m². Two of the 32 patients enrolled in the study received only one cycle of therapy and were not evaluable for response. The median number of cycles administered in the remaining 30 evaluable patients was five (range: 1-8).
An overall response rate of 67% was achieved, with 9 complete responses and 11 partial responses. The median survival for the entire group was 14.5 months (range: 3-24 months). When evaluated as a subgroup, five of seven patients (72%) with locally advanced disease responded to therapy, including one pathologic complete response and three clinical complete responses. For patients with metastatic disease, responses were demonstrated in all metastatic sites, including the liver and the lung.
Hematologic toxicities included World Health Organization (WHO) grade 3/4 neutropenia (53%), anemia (13%), and thrombocytopenia (9.4%). There were four episodes of febrile neutropenia requiring hospitalization; however, no major infections or treatment-related deaths occurred. Despite the use of hematopoietic growth factors for grade 3/4 neutropenia and/or febrile neutropenia, dose reduction due to neutropenia was required in 53% of patients, and 17% required two dose reductions. However, neutropenia recovered quickly, and there were no treatment delays because of myelosuppression. Grade 3/4 nausea and vomiting was reported in 16% of patients, and the remaining toxicities were mild to moderate in severity.
• Docetaxel/cisplatin/doxorubicin—Preliminary safety findings of the triplet drug combination of docetaxel, cisplatin, and doxorubicin for patients with advanced or metastatic urothelial cancer were presented in abstract form. Investigators administered doxorubicin at 30 mg/m² and docetaxel at 75 mg/m² on day 1 and cisplatin at 70 mg/m² on day 15, with cycles repeated once every 28 days. The regimen was feasible. Preliminary toxicity findings in 26 patients enrolled at the time of publication included febrile neutropenia in five patients (19%), grade 3 neutropenia in 23% of cycles, grade 3 nausea and vomiting in 3.5% of cycles, and grade 3 peripheral neuropathy in one patient (4%). Accrual to the study is ongoing.
• Docetaxel/gemcitabine/carboplatin—The triplet drug combination of docetaxel, gemcitabine, and carboplatin has been investigated in a phase I/II dose finding study at New York Presbyterian Hospital. Two groups of patients with urothelial carcinoma were enrolled on the study: chemotherapy-naive patients who were considered poor prognosis (group 1) and previously treated patients (group 2). Two dose levels were evaluated. Dose level 1 investigated docetaxel at 50 mg/m², carboplatin at an area under the concentration-time curve (AUC) of 5 (AUC 4 for group 2 patients) on day 1, and gemcitabine at 800 mg/m² on days 1 and 8, every 21 days. Dose level 2 investigated the same doses, but gemcitabine was administered on day 2 and repeated on day 8 or 15. At the time of publication, 13 patients were evaluable for response and 17 for toxicity. An overall response rate of 38% was demonstrated, with three complete responses including one patient with previously treated disease. Toxicities included grade 3/4 neutropenia (65%), grade 3 thrombocytopenia (29%) and febrile neutropenia (24%), grade 3/4 hyperglycemia (12%), grade 3 nausea/vomiting (12%), and grade 3 diarrhea (6%).
Docetaxel has demonstrated activity as a single agent in both previously treated and untreated patients with TCC of the urothelium. This activity is comparable to that seen with other agents frequently used in combination therapy, or to palliate patients as single agents. Specifically, docetaxel has provided meaningful antitumor control among select patients who cannot tolerate cisplatin-based therapy because of renal impairment, with an overall response rate of 45%. Single-agent docetaxel may be considered among those agents that can be used in the palliative management of patients with relapsed disease following prior platinum-containing chemotherapy.
Several studies have evaluated the combination of docetaxel and cisplatin, where mostly nonoverlapping toxicities result in a regimen with a manageable safety profile. Phase II study results of the doublet have demonstrated a high level of antitumor activity, with response rates ranging from 52% to 60% and meaningful median overall survival ranging from 8 to 13.6 months. The main toxicities were predominantly hematologic in nature and were manageable and predictable. The results of an ongoing phase III trial comparing docetaxel/cisplatin with the established MVAC regimen will serve to better define the role of the docetaxel/cisplatin regimen in the metastatic setting.
Studies investigating the docetaxel/gemcitabine-based combination have proven feasible and may provide a useful nonplatinum regimen for the treatment of TCC. The investigations of triplet drug regimens based upon the docetaxel/platinum combination have proven feasible and highly efficacious, with an overall response rate of 67%, including nine complete responses, and median survival of 14.5 months. Additional phase III trials of docetaxel-containing regimens for locally advanced and metastatic TCC are warranted.
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