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Phase II Trial of Gemcitabine Plus Cisplatin in Patients With Metastatic Urothelial Cancer

From the Massachusetts General Hospital and Dana-Farber Cancer Institute, Boston, MA; University of Southern California–Norris Comprehensive Cancer Center, Los Angeles, CA; Johns Hopkins University, Baltimore, MD; Roswell Park Cancer Institute, Buffalo, NY; Vanderbilt University School of Medicine, Nashville, TN; Cancer Institute of New Jersey, New Brunswick, NJ; University of Chicago and Northwestern University Medical School, Chicago, IL; and Eli Lilly and Company, Indianapolis, IN.

Address reprint requests to Donald Kaufman, MD, Massachusetts General Hospital, 1 Hawthorne Place, Room 107, Boston, MA 02114.

	ABSTRACT

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PURPOSE: To assess the activity and toxicity of the combination of gemcitabine and cisplatin in the treatment of chemotherapy-naive patients with metastatic urothelial cancer.

PATIENTS AND METHODS: Forty-six patients with measurable stage IV carcinoma of the urothelium were enrolled onto this trial. Gemcitabine 1,000 mg/m² was administered intravenously for 30 to 60 minutes on days 1, 8, and 15 of each 28-day cycle. Cisplatin was administered after gemcitabine on day 1 of each cycle. The first 11 patients received an initial cisplatin dose of 100 mg/m². Due to the hematologic toxicity observed in several of these patients, the dose was reduced to 75 mg/m² in the remaining 35 patients. Patients were treated with six cycles, unless disease progression or severe toxicity necessitated earlier discontinuation.

RESULTS: Ten of the 46 patients achieved a complete response and nine showed a partial response. The overall response rate was 41%. The median time to treatment failure was 5.5 months. The median survival was 14.3 months, and the 1-year survival probability was 54%. Most of the toxicities were hematologic and, in general, easily manageable.

CONCLUSION: Gemcitabine plus cisplatin is active in the treatment of metastatic urothelial cancer in chemotherapy-naive patients and has an acceptable clinical safety profile. Studies are under way to further define the place of gemcitabine in combination with other chemotherapeutic agents in the treatment of metastatic urothelial cancer.

	INTRODUCTION

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TRANSITIONAL CELL cancer (TCC) of the urothelium is a relatively common tumor, ranked as the 10th leading cause of cancer death in 1999.¹ Systemic chemotherapy is a standard treatment option for patients who present with advanced disease or have disease progression after initial local treatment. Cisplatin has been studied extensively, and it has shown considerable activity in the treatment of metastatic urothelial cancer. The combination of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) is one of the most widely used regimens, with reported response rates of 35% to 70%.^2,3 However, this treatment is associated with significant toxicity, and the median survival of treated patients does not much exceed 12 to 13 months.^4-7 Additionally, long-term follow-up has shown that only 3.7% of patients treated with MVAC are alive at 6 years.⁸ Thus, there is substantial room for further therapeutic refinements to control toxicity and enhance efficacy for patients with advanced urothelial cancer.

Gemcitabine has been studied considerably as a single agent for the treatment of bladder cancer. Phase I and II studies of gemcitabine in the treatment of advanced or metastatic bladder cancer have yielded response rates of 23% to 28%.^9-12 Responses have been observed in the liver, lung, bone, and lymph nodes. These data demonstrate that gemcitabine monotherapy is promising for patients with metastatic TCC, including those previously treated with MVAC chemotherapy. In addition, the toxicity profile of single-agent gemcitabine in patients with metastatic TCC was modest and similar to that seen in patients with other tumor types, specifically, non–small-cell lung cancer (NSCLC).¹³

A synergistic effect between gemcitabine and cisplatin has been demonstrated in human ovarian cancer cell lines, human xenografts (head and neck squamous cell carcinoma), and a murine colon carcinoma cell line.^14,15 In vivo data have also shown an advantage of combined administration of gemcitabine and cisplatin. The combination has been extensively studied in patients with locally advanced or metastatic NSCLC. Data from phase II studies demonstrate enhanced response rates with gemcitabine and cisplatin in combination, compared with gemcitabine monotherapy (38% to 54% for combination therapy v 21% for single-agent gemcitabine).¹⁶ In addition, survival was longer in the combination trials than in single-agent gemcitabine studies.¹³ Gemcitabine plus cisplatin was associated with the toxicities predicted with a cisplatin-based regimen, namely nausea, vomiting, and myelosuppression (primarily neutropenia, but occasionally thrombocytopenia).¹⁷

These data, compiled mostly from studies of patients with NSCLC, indicate that gemcitabine in combination with cisplatin is more effective than either agent alone and has an acceptable toxicity profile. Although it is difficult to apply the results of one tumor type to another, the data from NSCLC studies, as well as the preliminary data regarding single-agent gemcitabine in bladder cancer, suggest that the combination of gemcitabine and cisplatin should be evaluated in patients with metastatic TCC.

	PATIENTS AND METHODS

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Patients
Patient eligibility criteria included histologically or cytologically confirmed stage IV TCC of the urothelial tract. Prior adjuvant or neoadjuvant therapy, if administered at least 16 weeks before enrollment, was allowed, but prior chemotherapy for metastatic disease was an exclusion criterion. Prior radiation therapy, completed at least 3 weeks before enrollment, was permitted as long as the irradiated area was not the only source of measurable disease. All patients were required to have a Karnofsky performance status of 60 to 100 and clinically measurable disease, and to provide written informed consent. Organ function criteria included an absolute granulocyte count of greater than 1.8 x 10⁹/L, a platelet count of greater than 100 x 10⁹/L, a hemoglobin level of greater than 9 gm/dL, calculated creatinine clearance of 60 mL/min, a bilirubin level of less than 2 mg/dL, and transaminase levels of less than 2.5 times normal. Patients with pure adenocarcinoma or squamous carcinoma were excluded from study. Additional exclusion criteria were significant hearing problems, pregnancy, severe congestive heart failure, and prior malignancy within 5 years.

Dosage and Administration
Gemcitabine 1,000 mg/m² was administered intravenously for 30 to 60 minutes on days 1, 8, and 15 of each 28-day cycle. Cisplatin was initially administered at a dose of 100 mg/m² on day 1 of each cycle, but severe hematologic toxicities among the first 11 patients prompted a protocol amendment to reduce the dose to 75 mg/m² in subsequent patients (see Results). Protocol-specified dose reductions included a 50% decrease in gemcitabine for an absolute granulocyte count of 0.5 to 0.99 x 10⁹/L or a platelet count of 50 to 74 x 10⁹/L on treatment day 8 or 15. The day-8 or -15 gemcitabine doses were held for an absolute granulocyte count of less than 0.5 x 10⁹/L or a platelet count of less than 50 x 10⁹/L. Subsequent cycles began only when toxicity had resolved to grade 1 or less. Significant hematologic toxicity (defined as neutropenic fever, grade 4 thrombocytopenia, or thrombocytopenia with bleeding) in the prior cycle prompted a dose reduction in both cisplatin and gemcitabine on the subsequent cycle. Only the cisplatin dose was adjusted for significant renal toxicity. Patients remained in the study until six cycles of therapy were administered, disease progression was noted, or excess toxicity was experienced, as judged by the investigator or the patient. All toxicity grading was by World Health Organization (WHO) criteria.

Assessment
Disease reevaluation was performed every two cycles using standard WHO criteria. Complete response (CR) was defined as the absence of all known disease for at least 4 weeks, and partial response (PR) was defined as a minimum 50% decrease in the sum of the orthogonal measurements of all tumor lesions for at least 4 weeks. Progressive disease was defined as a 25% increase in at least one measurable lesion, or the appearance of new lesions. All tumor responses were evaluated by an independent radiologist. Patients were followed for survival and disease progression every 3 months until death or loss to follow-up.

Statistical Methods
Patient enrollment followed a two-stage sequential design. If fewer than six of the initial 20 qualified patients responded, further accrual was to be halted. If six or more responses were observed, 40 qualified patients were to be enrolled. With this procedure, there was a 62% chance of terminating enrollment early at the end of the first stage if the true response rate was as low as 25% and a 2% chance of stopping early if the true response rate was as high as 50%. If enrollment continued through the end of the second stage, the procedure allowed a sufficiently accurate estimate of the tumor response rate. The width of the interval varied according to the actual observed response rate, but a response rate of 50% (20 of 40 patients) was expected to produce a 95% confidence interval (CI) of 34% to 66%.

The primary efficacy analysis included a maximum likelihood estimation of tumor response rate, including a 95% CI calculated using the normal approximation of the binomial distribution. The secondary efficacy analyses included the Kaplan-Meier estimation of overall survival, time to progressive disease, time to treatment failure, duration of response, and time to objective response. The change from baseline of weight and performance status was evaluated, and Functional Assessment of Cancer Therapy–General subscale and total scores were summarized at each cycle. Overall survival time, time to progressive disease, and time to treatment failure were analyzed using Cox’s proportional hazards model, and responses were analyzed using logistic regression. All patients who qualified for the safety analysis underwent the evaluation, which included summaries of the number of blood transfusions required, adverse event rates, laboratory changes, and the WHO toxicity grades for laboratory and nonlaboratory parameters.

	RESULTS

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Patient Characteristics
Fifty-one patients were entered onto the study, but five never received drug therapy, four did not meet the protocol entry criteria, and one withdrew before dosing for personal reasons. Of the 46 enrolled patients, eight (17%) were female and 38 (83%) were male; most were white. Patient age ranged from 37 to 80 years (median age, 61 years). Table 1 provides a summary of patient characteristics at baseline. Thirty patients (65.2%) had localized disease (limited to the bladder and/or lymph nodes only), and the remaining 16 (34.8%) had visceral disease. Forty patients (87%) had a performance status 80 at study entry. Although Karnofsky performance status, weight change, and Functional Assessment of Cancer Therapy–General scores were mandated by the protocol, no definitive conclusions could be made regarding the effect of chemotherapy on these variables because of incomplete and highly variable data, confounded by dropouts and changes in disease status. Nine patients (20%) had received prior systemic adjuvant or neoadjuvant chemotherapy (MVAC, seven patients; cisplatin, methotrexate, and vinblastine, two patients), and seven (15%) had undergone prior radiotherapy.

The first 11 patients treated on study received a cisplatin dose of 100 mg/m². However, because of hematologic toxicity, the initial cisplatin dose was reduced to 75 mg/m² (Table 2 and below). Of the first 11 patients, 100% had grade 3 or 4 neutropenia and 73% had grade 3 or 4 thrombocytopenia. The corresponding rates in the patients treated with a dose of 75 mg/m² were 63% and 60%. For the patients treated with cisplatin 75 mg/m², 34 of 164 cisplatin doses were reduced and 64 of 487 gemcitabine doses were reduced. One cisplatin dose and 82 gemcitabine doses were omitted.

The estimated median time to treatment failure was 5.5 months (95% CI, 4.5 to 6.5 months). An insufficient number of responders precluded analysis of the duration of response. Of the 19 patients with response, three responded after one cycle of therapy, 15 after two cycles, and one after completing six cycles of therapy. The Kaplan-Meier estimate of the median overall survival was 14.3 months (95% CI, 9.7 to 21.3 months) and the 1-year survival probability was 54% (Figs 1 and 2).

View larger version (8K): [in this window] [in a new window]   Fig 1. Kaplan-Meier estimate of overall survival.

View larger version (8K): [in this window] [in a new window]   Fig 2. Kaplan-Meier estimate of the 1-year survival probability.

Adverse Events
Table 2 lists the common toxicities observed during this study. As expected, grade 3 and 4 toxicities were primarily hematologic and, as noted earlier, were worse in patients treated with cisplatin 100 mg/m² than in those treated with 75 mg/m². Low-grade fever was reported in five of the 16 patients with grade 4 neutropenia, but no one was hospitalized for this event. Although grade 4 thrombocytopenia was observed in 13 patients, grade 4 hematuria or hemorrhage was reported in only one patient, and only 12 patients received platelet transfusions. Twenty-six patients (57%) received RBC transfusions for supportive care. One patient had a grade 3 increase in blood urea nitrogen without grade 3 creatinine, and another had grade 3 gastrointestinal hemorrhage at the time the platelet count was 9 x 10⁹/L (which had been 131 x 10⁹/L a week earlier). The investigator graded these events as only possibly related to the study drugs. Other grade 3 toxicities included one observation each of diarrhea and pulmonary toxicity and two incidences of grade 3 neuro-hearing toxicity. Study treatment was discontinued in four patients because of adverse events. One patient had a myocardial infarction and one demonstrated an increase in creatinine (from 1.2 to 2.4 mg/dL during the first cycle), both of which resulted in hospitalization. The two remaining patients had an increase in blood urea nitrogen and edema (thought to be drug related), which led to study treatment discontinuation. One patient died on study of an accidental injury (suspected suicide), considered to be unrelated to study drug administration. Overall, 26 patients had a serious adverse event. Of these events, 17 were considered by the investigator to have had some relationship to the study drug. None of the related serious adverse events occurred in more than 9% of patients.

	DISCUSSION

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MVAC became the standard of care for patients with metastatic TCC on the basis of randomized studies demonstrating a survival advantage compared with single-agent cisplatin, as well as the combination of cyclophosphamide, doxorubicin, and cisplatin.^3,18 However, long-term follow-up of patients on these trials revealed that the majority have recurrent disease, and only 5%, usually those with regional disease only, can be expected to be cured of their malignancy. Furthermore, the significant toxicities of MVAC, including myelosuppression, renal toxicity, neural toxicity, ototoxicity, and mucositis, limit broad application of this regimen. Thus, a number of novel agents have been investigated to determine their activity in this disease. The leading candidates emerging from these investigations are gemcitabine and paclitaxel.⁶

We and others have demonstrated a 20% to 30% response rate for gemcitabine monotherapy, with an equivalent response in previously treated as well as chemotherapy-naive patients.^9-12 Furthermore, CRs in patients with metastasis to the liver, which is typically resistant to standard chemotherapy, are particularly encouraging.¹¹ Given the known activity of cisplatin in metastatic TCC, and the preclinical data of synergism between gemcitabine and cisplatin, a combination chemotherapy regimen with these two agents seemed reasonable for patients with metastatic TCC. In this study, we demonstrated that this combination achieves an overall response rate of 41% (48% for patients receiving at least two cycles of therapy) and that approximately half of these responses were complete. We note that no combination chemotherapy regimen has consistently resulted in a greater than 25% CR rate. Furthermore, median survival was 14.3 months, which is particularly encouraging in light of the 12.5-month median survival observed in the multi-institutional study of MVAC.³

As with other studies of chemotherapy in this patient population, patients with locoregional disease had a higher response rate, as did those without prior neoadjuvant or adjuvant chemotherapy. Interestingly, of the nine patients with prior adjuvant chemotherapy, the only one who responded had received prior MVAC more than 12 months before study entry. This observation may need to be considered during further studies that examine initial chemotherapy regimens for patients with metastatic TCC.

Although the toxicity of this regimen was not insignificant, it was tolerable, with only four of 46 patients discontinuing therapy because of adverse events. It is noteworthy that a cisplatin dose of 100 mg/m² was too toxic. This observation was perhaps somewhat surprising, given that an acceptable toxicity of this dose was reported for the gemcitabine/cisplatin combination in patients with metastatic lung cancer.¹⁶ Whether these differences are due to patient selection, differences in toxicity reporting, or the frequent subclinical renal insufficiency in patients with metastatic bladder cancer remains unclear. Pulmonary toxicity has been extensively documented in several phase II trials, and cisplatin has been widely shown to be associated with cardiac and vascular toxicity. Although myocardial infarction is not a common drug toxicity for either drug, it has been reported with cisplatin. Perhaps more importantly, it should not be entirely unexpected in the elderly, cigarette-smoking men who comprised the majority of our study population.

Gemcitabine has been studied in combination with other anticancer drugs, in addition to cisplatin, in the treatment of metastatic bladder cancer. One phase II trial combining gemcitabine with carboplatin yielded a response rate of 68%,¹⁹ and another which added paclitaxel to the combination of gemcitabine and carboplatin reported a response rate of 58%.²⁰ The combination of paclitaxel and gemcitabine has demonstrated an overall response rate of 60% in a combined patient population of previously treated and untreated patients. This response rate increased to 80% when only chemotherapy-naive patients were considered.²¹ Similar data have also been reported by Moore et al,²² who noted 16 responders (including six CRs) among 28 patients treated with the equivalent regimen.

This was a phase II trial and, therefore, by definition, noncomparative. Nevertheless, it is our impression that gemcitabine/cisplatin is less toxic than MVAC. This hypothesis has been addressed in a completed phase III trial of 420 patients, comparing MVAC and gemcitabine/cisplatin in the treatment of metastatic bladder cancer. In summary, this phase II trial demonstrates that the combination of gemcitabine and cisplatin is highly active in patients with metastatic TCC and has an acceptable toxicity profile. The results of the phase III trial will help determine whether this combination offers an advantage over standard MVAC.

	ACKNOWLEDGMENTS

 
We thank Connie Tapley and Patti Rae for assistance with data collection and Sulu Gawande, Leigh Ann Perkinson, Teri Michelini, Debasish Roychowdhury; and Mary Ellen Ciampi for assistance with manuscript preparation and review.

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Submitted September 3, 1999; accepted January 5, 2000.

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This Article Abstract Full Text (PDF) Erratum (v18,p2644) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kaufman, D. Articles by Stadler, W. Search for Related Content PubMed PubMed Citation Articles by Kaufman, D. Articles by Stadler, W.