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© 2001 American Society for Clinical Oncology Combination Paclitaxel, Carboplatin, and Gemcitabine Is an Active Treatment for Advanced Urothelial CancerFrom the Division of Hematology and Oncology, Barbara Ann Karmanos Cancer Institute and Wayne State University, Detroit; and Division of Hematology and Oncology, University of Michigan Cancer Center, Ann Arbor, MI. Address reprint requests to Maha Hussain, MD, 5 Hudson, Harper Hospital, 3990 John R, Detroit, MI 48201; email: hussainm@ karmanos.org.
PURPOSE: To determine the efficacy and toxicity of the drug combination of carboplatin, paclitaxel, and gemcitabine in patients with advanced urothelial carcinoma. PATIENTS AND METHODS: Patients eligible included those with advanced urothelial malignancy of any histology, no previous chemotherapy for metastatic disease, Southwest Oncology Group performance status of 2 or less, serum creatinine levels of 2 mg/dL or less, and adequate bone marrow and hepatic function. Treatment consisted of paclitaxel 200 mg/m2, carboplatin (target area under the curve = 5) on day 1, and gemcitabine 800 mg/m2 on days 1 and 8, repeated every 21 days. RESULTS: Forty-nine patients (44 men and five women) were enrolled; the patients’ median age was 63 years, and their median creatinine clearance was 78 mL/min (range, 26 to 165 mL/min). Forty-three patients had transitional cell carcinoma, and six had squamous cell carcinoma or mixed histology. Ten patients had metastases to lymph nodes only, six had locally advanced disease, four had locally recurrent disease, 24 patients had visceral metastases, and five had soft tissue metastases. Twenty-one patients had disease in one site, 16 in two sites, and 12 in three sites. A total of 272 cycles were administered (median, six cycles; range, 1 to 15 cycles). Major toxicities were grade 3 and 4 neutropenia in 17 and 19 patients, respectively; grade 3 and 4 thrombocytopenia in 15 and six patients, respectively; grade 3 and 4 anemia in 10 and two patients, respectively; grade 3 neuropathy in four patients; and diarrhea in two patients. The incidence of febrile neutropenia was 1.4%; no patients died of drug toxicity. Forty-seven of the 49 patients were assessable for response. Fifteen (32%) patients experienced a complete response, and 17 (36%) patients experienced a partial response (32 of 47 patients, 68%; 95% confidence interval, 56.27 to 82.86). Responses were seen in all sites, including 15 (68%) of 22 patients with visceral metastases. The median survival was 14.7 months, with a 1-year survival of 59%. CONCLUSION: Combination paclitaxel, carboplatin, and gemcitabine is active; an encouraging number of patients with advanced urothelial carcinoma treated with this regimen experienced complete remission.
SYSTEMIC CHEMOTHERAPY is the primary treatment modality for patients with advanced urothelial cancer. The chemosensitivity of this disease is demonstrated by the presence of several agents with variable levels of activity ranging from 10% to 40%.1 Historically, cisplatin has been considered the most active single agent, and several cisplatin-based combinations are associated with higher total and complete response rates than those reported for cisplatin. Of the cisplatin-based combinations, methotrexate, vinblastine, doxorubicin and cisplatin (MVAC) has proven its superiority relative to cisplatin in an intergroup trial and to cisplatin, doxorubicin, and cyclophosphamide in another randomized trial.2,3 As a result, MVAC has been accepted as a standard treatment for metastatic bladder cancer, with patients treated with this regimen experiencing a median survival of approximately 12 months. Randomized trials, particularly the intergroup study of MVAC versus cisplatin, has also confirmed the toxicity of the combination regimen, which include drug-related deaths, sepsis, severe myelosuppression, mucositis, and renal impairment. These toxicities are especially relevant in patients with advanced urothelial cancer, a cancer in which the majority of the patients are older and usually have significant comorbid conditions. Long-term follow-up also indicates that the curative potential with MVAC is small, with less than 5% of patients alive at 5 years.4 Variable degrees of nephrotoxicity, nausea and vomiting are observed frequently in the patients treated with cisplatin. Although these toxicities can be minimized with the use of proper hydration and current antiemetics, patients with urothelial cancers often present with renal impairment and are more susceptible to the nephrotoxic effects of cisplatin. As a result, analogs of the agent have been studied. Carboplatin was developed with the intent of providing similar efficacy to cisplatin with less renal toxicity. Single-agent carboplatin has yielded response rates of 8% to 18%, with the higher response rates reported in previously untreated patients.5 Carboplatin seldom causes renal impairment and has an established formula (Calvert formula) that allows for the accurate dosing of the drug on the basis of renal function.6 The latter, coupled with its ease of administration, has made this agent an attractive alternative to cisplatin. In the 1990s, paclitaxel emerged as one of the most active agents in urothelial cancers, with overall and complete response rates of 42% and 27%, respectively.7 The combination of carboplatin and paclitaxel has been widely investigated.8-12 This combination provided the opportunity for a short outpatient schedule with a low toxicity profile and the ability to treat a larger group of patients who otherwise would not be candidates for cisplatin-based therapy. We reported our experience with 35 assessable patients treated with paclitaxel (200 mg/m2) and carboplatin (area under the curve [AUC] = 5) on day 1 of a 21-day cycle.12 The overall and complete response rates were 51.5% and 20%, respectively, and the median survival was 9.5 months. Responses occurred in visceral disease locations, sites that are typically less responsive to conventional chemotherapy. However, except for a more favorable toxicity profile and a simpler administration schedule, this combination is not likely to represent a major therapeutic advance over MVAC. Gemcitabine, a fluoropyrimidine that is structurally similar to cytarabine, is another active agent with response rates ranging from 24% to 28% in patients with advanced bladder cancer.13,14 On the basis of the single-agent activity of gemcitabine and the efficacy of the paclitaxel-carboplatin regimen, we designed a phase II trial evaluating the efficacy of the combination of paclitaxel, carboplatin, and gemcitabine in patients with advanced urothelial cancer.
Eligible patients had a diagnosis of locally advanced, recurrent, or metastatic urothelial carcinoma not curable by surgery or radiation therapy. To be included in the study, patients had to have bidimensionally measurable or assessable disease that had not been previously irradiated. If disease had been irradiated, the presence of disease outside the irradiated fields was required. A performance status of 0 to 2 by Southwest Oncology Group criteria, a serum creatinine level of 2.0 mg/dL or less or creatinine clearance 40 mL/min or more, granulocyte count 1,500/mm3 or more, platelet 100,000/mm3 or more, and total bilirubin 1.5 mg/dL or less were also required. Patients had to have recovered from any effects of major surgery, and at least 4 weeks should have elapsed since completion of radiation therapy. No previous systemic chemotherapy for metastatic disease was allowed; however, patients may have received adjuvant chemotherapy if completed at least 6 months before beginning protocol therapy. No previous malignancy was allowed, except for adequately treated nonmelanoma skin cancer, in situ cervical cancer, or other cancers for which the patient had been disease-free for a minimum of 2 years. Prestudy laboratory assessment required for determination of eligibility (including x-rays, scans, or physical examination used for tumor measurement) were performed no more than 28 days before registration. All patients were aware of the investigational nature of this study and signed a written informed consent in accordance with institutional Human Investigation Committee guidelines.
Definitions
Treatment Plan
equation
Paclitaxel infusion preceded carboplatin, and gemcitabine was infused after the carboplatin infusion on day 1. All patients were premedicated 30 minutes before paclitaxel administration with 20 mg dexamethasone given as an intravenous (IV) injection, 50 mg diphenhydramine IV, and ranitidine at a dose of 50 mg IV or famotidine 20 mg IV. Antiemetic therapy was administered at the discretion of the treating physician. Gemcitabine dose was escalated to the +1 dose level (1,000 mg/m2) while holding the doses for the other two drugs at the starting dose level (Table 1) if the nadir absolute granulocyte count (AGC) count was 1,000 cell/mm3 or more and the platelet count was 100,000/mm3 or more. Starting dose level (level 0) was maintained for AGC 500/mm3 or more and a platelet count of 50,000/mm3 or more. For AGC less than 500/mm3 and/or platelets less than 50,000/mm3, the dose was reduced by one dose level for the next cycle (-1 dose level: paclitaxel 175 mg/m2, carboplatin AUC of 3.75, gemcitabine 800 mg/m2 days 1 and 8). If AGC nadir was less than 500/mm3 or if the platelet nadir was less than 50,000/mm3 after a reduction to dose level -1, then subsequent cycles were started at dose level -2 (paclitaxel 135 mg/m2, carboplatin AUC of 2.5, gemcitabine 800 mg/m2 days 1 and 8). Day 8 gemcitabine treatment was given only if the AGC was 1,000/mm3 or more and the platelet count was more than 100,000/mm3. Dose modifications for nonhematologic toxicities, excluding alopecia, nausea, and vomiting were as follows: for grade 3 or 4 toxicities, therapy was delayed until recovery to grade 1 or less, and dose was reduced by one dose level for subsequent cycles. Once reduced, the dose could not be escalated back. Toxicity was evaluated weekly. Standard solid tumor criteria were used for response determination, and the latter was performed every three courses (every 9 weeks).
End Points and Statistical Design Treatment response rates are reported along with their 95% confidence intervals (CIs). Overall survival duration was measured from the time of treatment initiation to the death of the patient. The Kaplan-Meier product-limit method was used to generate actuarial survival curves. All statistical analyses were performed by SAS software version 6.12 (SAS, Cary, NC).
Forty-nine patients were enrolled between November 1997 and April 2000 at the Barbara Ann Karmanos Cancer Institute and the University of Michigan Comprehensive Cancer Center. Forty-four patients were men and five were women; 41 were white and eight were African-American. The median age of the patients was 63 years (range, 33 to 82 years). Forty-four patients had a Southwest Oncology Group performance status of 0 to 1 (24 and 20, respectively), and five patients had a performance status of 2. Table 2 outlines the patient characteristics. The majority of patients had recurrent or metastatic disease (43 of 49 patients; 88%), with 29 (59%) of 49 patients having metastases in viscera or soft tissue. Twenty-one patients had previous definitive surgery; one patient had radiation alone; two patients had surgery plus radiotherapy; two had surgery, radiotherapy, and chemotherapy (fluorouracil + cisplatin) for squamous cell carcinoma; and four had surgery and either adjuvant or neoadjuvant chemotherapy (three patients received MVAC and one patient received carboplatin and paclitaxel). Nineteen patients had no previous therapy for invasive disease; eight of 19 patients had undergone intravesical therapy previously.
Table 3 outlines the treatment summary. Of the 49 patients, 46 completed treatment as planned. Three patients did not complete treatment as planned. One died before receiving any chemotherapy (this patient was excluded from response and toxicity analyses); one patient refused treatment after the first course for personal reasons (this patient was included for toxicity but excluded from response), and the third developed an acute hypersensitivity reaction within the first few moments of paclitaxel infusion and was removed from the protocol (this patient was included in toxicity and response analyses). A total of 272 cycles were administered. Gemcitabine dose was escalated in two patients without a change in the starting doses for the other two drugs.
Overall, therapy was well tolerated. The most common toxicity was myelosuppression, with neutropenia as the major side effect. However, with 272 courses of therapy delivered, there were only four episodes of febrile neutropenia (1.4%). Although the protocol did not prohibit the use of growth factors, only two patients received limited courses of granulocyte colony-stimulating factor. There were no treatment-related deaths. Included in grade 3 infections are urinary tract–, upper respiratory–, and IV-port–related infections. Other less frequent high-grade toxicities included grade 3 nausea (two patients), grade 3 myalgia, anorexia, dehydration, skin rash, and hypersensitivity reaction (one patient each) ( Table 4). The patient who developed the hypersensitivity reaction was the only patient removed from the study because of drug toxicity. One of the two patients with dyspnea developed bilateral pulmonary infiltrates and severe hypoxia. Bronchoscopy and biopsy revealed no evidence of infection or cancer. This episode was attributed to gemcitabine-induced pulmonary toxicity, and the patient was later treated with carboplatin and paclitaxel. The pulmonary symptoms responded to corticosteroid therapy.
Response A total of 47 patients were assessable for response. Fifteen patients responded completely to therapy and 17 responded partially to therapy, for an overall response rate of 68% (95% CI, 56.27 to 82.86). Responses were seen in all disease sites. The response rates in the patients with visceral, soft tissue, and locally recurrent disease were similar (66.7%; 95% CI, 49.8 to 83.54). The response rates by disease site are outlined in Table 5. Three patients had stable disease. Neither of the two patients with pure squamous cell carcinoma responded to treatment. Two patients with locally advanced disease had surgically proven complete pathologic responses.
Survival Figures 1 and 2 illustrate the overall survival and survival on the basis of disease status. The median survival for the entire population was 14.7 months, with a 1-year survival of 58.5% and a 2-year survival of 24.3% (Fig 1). The patients with visceral metastases had a worse outcome than those without; however, the difference was not statistically significant (Fig 2). The median survival time for patients with visceral disease was 14.3 months versus 19.5 months for those without visceral metastases. The median survival for patients with locally advanced disease has not been reached.
Despite its chemosensitivity, advanced urothelial carcinoma continues to be a fatal disease. Progress in chemotherapy development in the last decade has yielded two active agents, paclitaxel and gemcitabine, with favorable toxicity profiles and potential synergistic interaction with platinum, thus leading first to the development of taxane-based and gemcitabine-based doublets ( Table 6).12,15-20 The good toxicity profile and interesting level of activity provided the basis for two phase III trials that compared MVAC to the combination of paclitaxel and carboplatin in an Eastern Cooperative Oncology Group ongoing trial and to cisplatin plus gemcitabine in a European trial.23 Although gemcitabine plus cisplatin seemed to be better tolerated (as reflected by a decreased incidence of neutropenic fever and toxic deaths in the cisplatin-gemcitabine arm of the study), unfortunately, the complete response rate and survival with this combination was not superior to that of MVAC,23 thus representing limited progress in the treatment of this disease.
Improvements in supportive care measures and the frequent use of imaging has probably contributed to the recently observed slight improvement in the survival of patients with urothelial carcinoma. However, the significant role of prognostic characteristics of the patients must also be emphasized. The presence of visceral metastases and poor performance status (Karnofsky scale  80%) have been constant independent predictors of poor outcome with cisplatin-based (mostly MVAC) therapy.24 It is conceivable, however, that better-tolerated and more effective therapy may minimize the adverse impact of these factors. We and others sought to enhance treatment efficacy by developing regimens incorporating three active agents to build on the paclitaxel- or gemcitabine-based doublets21,22 (Table 6). Despite a high percentage of patients with poor risk factors and high tumor burden, our response rate of 68% and complete response rate of 32% seems to compare favorably with the rates reported in the other trials (Table 6). Similarly, the high response rate and the favorable median survival in patients with visceral disease reflect the promising level of activity of this combination. The pathologic complete remission achieved in two patients who underwent radical cystectomy is also encouraging. All of this was achieved with an overall favorable toxicity profile. Table 6 summarizes recent phase II clinical trials incorporating gemcitabine, paclitaxel, or both. Comparison of outcome between these trials is limited by their nonrandomized nature; however, several observations could be made. First, there seems to be a trend toward higher overall and complete response rates and median survivals with the triplet-based therapies in general; second, the median survival time of patients on a regimen of paclitaxel plus cisplatin and carboplatin regimens seem comparable; and third, gemcitabine-cisplatin combinations seem to be associated with higher median survival. The latter, however, may be a consequence of the lower percentage of patients with visceral disease included in some of these trials. With a median of six courses, therapy in our study was well tolerated, with only one patient removed because of toxicity (an allergic reaction). This is important to highlight because despite the preponderance of good performance status, several treated patients were not good candidates for cisplatin-based therapy because of old age and comorbidities. Myelosuppression was the most common toxicity. The incidence of grade 4 neutropenia and thrombocytopenia were 39% and 13%, respectively, but there were few episodes of febrile neutropenia (1.4%) and no deaths due to drug toxicity. The use of growth factor therapy was not generally necessary. Considering the duration of therapy, the incidence of high-grade cumulative toxicities such as asthenia and neurotoxicity was low. With the progress made to date in the systemic therapy of advanced urothelial cancer, it should be possible and timely to address several issues in future randomized trials. The main focus should be on improving complete response rates with the hope of improving survival, with a secondary aim of reducing morbidity from a predominantly palliative therapy. These goals raise several major questions for future investigations: the role of novel agents singly and in combination; the role of platinum (cisplatin v carboplatin, or neither), and the choice of combination regimens. The substitution of carboplatin for cisplatin is a controversial issue—a controversy fueled by the lack of definitive randomized trials. Two small randomized trials attempted to address this issue25,26; however, both are flawed by study design limitations. Results from both trials indicated superior response rates and survival in favor of the cisplatin-based therapy. The first trial compared methotrexate, vinblastine, epirubicin, and cisplatin with methotrexate, vinblastine, epirubicin, and carboplatin, with 29 and 28 patients in each treatment arm, respectively.25 In addition to the small sample size, the carboplatin dose was calculated on the basis of a relatively low AUC of 3.76. The second small trial compared carboplatin (AUC = 5), methotrexate, and vinblastine (23 patients) with MVAC (24 patients).26 In addition to the small sample size, the imbalance between the study’s arms significantly limit the interpretation of outcome. A more recent report by Bellmunt et al22 described the results of a phase I-II trial that used paclitaxel, cisplatin, and gemcitabine (Table 6). This combination was active, with an overall response rate in the 58 assessable patients of 77.5% and a complete response rate of 27.6%; however, unlike our study, 61% (37 of 61) of patients in this trial had either locally advanced or pelvic nodal disease, and only 34% (21 of 61) of patients had visceral disease. The median survival was reported only for the first 15 patients from the phase I component of the study, which was 24 months. Major toxicities in patients treated on the phase II dose were high-grade (3 and 4) neutropenia (55%) (growth factor support was used regularly in several patients in both phase I and II of the trial because it was deemed necessary for safety) and thrombocytopenia (22%). The incidence of febrile neutropenia was 4.8%, and one patient died of drug toxicity. In addition, high-grade nausea and vomiting occurred in nine of 49 patients. The results of our study indicate that this carboplatin-based combination has a high response rate and results in median survival, even in patients with poor prognostic criteria. Furthermore, the convenient schedule and the favorable toxicity profile make this outpatient regimen widely applicable. This regimen is a potential alternative to cisplatin-based chemotherapy in the treatment of urothelial carcinoma and warrants further investigation in a randomized setting or in earlier stages of urothelial malignancy.
Supported in part by National Institutes of Health, grant nos. P30-CA22453-20 and 5-P30-CA46592-06, and by Lilly Oncology.
Presented in part at the Thirty-Sixth Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, May 20-23, 2000.
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Saxman SB, Propert KJ, Einhorn LH, 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 15: 2564-2569, 1997 5. Waxman J, Barton C: Carboplatin-based chemotherapy for bladder cancer. Cancer Treat Rev 19: 21-25, 1993 6. Calvert AH, Newell DR, Gumbrell LA, et al: Carboplatin dosage: Prospective evaluation of a simple formula based on renal function. J Clin Oncol 7: 1748-1756, 1989[Abstract]
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Vaughn DJ, Malkowicz SB, Zoltick B, et al: Paclitaxel plus carboplatin in advanced carcinoma of the urothelial: An active and tolerable outpatient regimen. J Clin Oncol 16: 255-260, 1998 10. Zielinski CC, Schnack B, Grbovic M, et al: Paclitaxel and carboplatin in patients with metastatic urothelial cancer: Results of a phase II trial. Br J Cancer 78: 370-374, 1998[Medline] 11. Droz JP, Mottet N, Prapotich D, et al: Phase II study of Taxol and carboplatin in patients with advanced transitional cell carcinoma of the urothelium: Preliminary results. Proc Am Soc Clin Oncol 17: 316a, 1998 (abstr 1219) 12. Redman BG, Smith DC, Flaherty L, et al: Phase II trial of paclitaxel and carboplatin in the treatment of advanced urothelial carcinoma. J Clin Oncol 16: 1844-1848, 1998[Abstract]
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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 17: 3173-3181, 1999 25. Petriolli R, Frediani B, Manganelli , et al: Comparison between a cisplatin-containing regimen and a carboplatin-containing regimen for recurrent or metastatic bladder cancer patients. Cancer 77: 344-351, 1996[Medline] 26. Bellmunt J, Ribas A, Eres N, et al: Carboplatin-based versus cisplatin based chemotherapy in the treatment of surgically incurable advanced bladder carcinoma. Cancer 80: 1966-1972, 1997[Medline] Submitted November 30, 2000; accepted February 7, 2001. This article has been cited by other articles:
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
