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© 2000 American Society for Clinical Oncology Phase I Evaluation of Sequential Doxorubicin Gemcitabine Then Ifosfamide Paclitaxel Cisplatin for Patients With Unresectable or Metastatic Transitional-Cell Carcinoma of the Urothelial TractFrom the Genitourinary Oncology Service, Division of Solid Tumor Oncology, Department of Medicine; Department of Radiology; the Division of Epidemiology and Biostatistics; and Division of Urology, Department of Surgery, Memorial Sloan-Kettering Cancer Center; and Department of Medicine, Joan and Sanford Weill Medical College of Cornell University, New York, NY. Address reprint requests to Dean F. Bajorin, MD, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021.
PURPOSE: This phase I trial sought to evaluate the toxicity of and determine the maximum-tolerated dose (MTD) for the two-drug regimen doxorubicin and gemcitabine (AG) followed by the three-drug regimen of ifosfamide, paclitaxel, and cisplatin (ITP) in patients with unresectable or metastatic transitional-cell carcinoma. PATIENTS AND METHODS: Patients received AG every other week for six cycles followed by ITP every 3 weeks for four cycles. Five AG dose levels were investigated, up to doxorubicin 50 mg/m2 and gemcitabine 2,000 mg/m2, to determine the MTD of the regimen. The dose and schedule of ITP were constant: ifosfamide 1,500 mg/m2 (days 1 to 3); paclitaxel 200 mg/m2 (day 1); and cisplatin 70 mg/m2 (day 1). Granulocyte colony-stimulating factor was given between all cycles of therapy. RESULTS: Fifteen patients enrolled onto this phase I trial. AG was well tolerated at all dose levels, with no grade 3 or 4 myelosuppression. Toxicity experienced with ITP included grade 3 and 4 granulocytopenia in four patients and grade 3 nausea/vomiting in three patients. No grade 3 and 4 neurotoxicity was observed. Eight of 14 assessable patients experienced a major response to AG, including five of six patients treated at the two highest AG dose levels. After completion of AG-ITP, nine of 14 assessable patients had a major response (three complete responses and six partial responses). CONCLUSION: AG is a well-tolerated and active regimen. Sequential chemotherapy with AG-ITP is also well tolerated, and phase II investigation at the highest dose level is ongoing.
TRANSITIONAL-CELL carcinoma (TCC) of the bladder is a chemotherapeutically responsive neoplasm. One of the principles of developing effective treatment programs is to combine agents with independent activity and nonoverlapping toxicities so that each component can be administered in adequate doses. With cisplatin-based combination chemotherapy regimens, overall response proportions (complete response [CR] plus partial response [PR]) of 50% to 75% were observed.1-4 Although the optimal combination has not been defined, data from two large randomized trials support the use of the methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC) combination as standard therapy.5,6 The first trial compared M-VAC with cisplatin and demonstrated a significant advantage in overall response proportion (39% v 12%, respectively) and survival (12.5 months v 8.2 months, respectively) for the M-VAC arm. The second trial compared M-VAC with cisplatin, doxorubicin, and cyclophosphamide and also showed a response and survival advantage for M-VAC.6 Despite these results, the median survival for patients treated with M-VAC is only 11 to 13 months, and long-term survival is seen in a small proportion of patients.7 Thus, the vast majority of patients relapse and succumb to recurrent disease, underlining the need for more effective therapy. The focus of current investigation has been on the identification of new drugs with single-agent activity and their incorporation into novel combinations. Several new drugs have been identified as active in TCC, including the taxanes, gemcitabine, and ifosfamide. In a phase II study performed by the Eastern Cooperative Oncology Group, 42% of patients responded to paclitaxel at 250 mg/m2 by 24-hour continuous infusion; the CR proportion was 27%.8 Ifosfamide, the oxazaphosphorine analog of cyclophosphamide, is active in patients with both TCC and squamous cell carcinoma histologies.9-11 A 20% response proportion was noted among 56 patients in a trial of ifosfamide as second-line therapy for metastatic TCC.11 Gemcitabine, a deoxycytidine analog with structural similarities to cytarabine, has been shown to have first- and second-line activity in TCC, with response proportions approximating 25%.12-15 A large number of phase I and II trials have evaluated these agents in two- and three-drug combination regimens.16-24 Promising response proportions and median survival data have been reported. We recently reported the results of a three-drug regimen of ifosfamide, paclitaxel, and cisplatin (ITP), with recombinant human granulocyte colony-stimulating factor (rhG-CSF) support, in 44 patients with previously untreated urothelial cancer, with treatment intervals of 4 weeks (29 patients) and 3 weeks (15 patients).23,24 Thirty of 44 assessable patients (68%; 95% confidence interval, 52% to 81%) demonstrated a major response (10 CRs and 20 PRs), with durations of response ranging from 9 to 35 months. At a median follow-up of 21 months, eleven patients (25%) remain disease-free, and the median survival is 18 months. Heterogeneity in the intrinsic sensitivity of tumor cells to chemotherapy represents the most important cause of resistance to and, ultimately, failure of treatment for disseminated malignancy. The problem of resistance to treatment has commonly been addressed by the simultaneous use of multiple chemotherapeutic agents. This approach exploits the probability that a cell resistant to one drug is sensitive to others. For this approach to be maximally successful, however, each drug in the combination must be delivered at a sufficiently high dose level to destroy sensitive cells. Overlapping toxicity, especially myelosuppression, is a major factor limiting dose-intensity when multiple drugs are used simultaneously. An alternate approach to improving outcomes in cancer chemotherapy trials is to deliver sequential, rather than simultaneous, chemotherapy to facilitate the delivery of a higher dose-intensity of therapy. Theoretical models suggest that sequential administration of chemotherapy, rather than simultaneous administration of all agents, might be better at targeting different cell populations in a tumor.25,26 Preclinical models and recent clinical trial results suggest promise to this approach.27-29 Additionally, the use of two- or three-agent combinations given sequentially in high doses offers a potential means to overcome some of the toxicity associated with simultaneous administration of all agents. To explore the hypothesis that sequential chemotherapy might improve the outcome in patients with metastatic TCC and to build on our favorable experience with the ITP combination, we sought to study sequenced therapy consisting of doxorubicin and gemcitabine (AG) followed by ITP. Because little data existed for the AG combination, a phase I investigation was conducted to determine the maximum-tolerated dose (MTD) of the AG combination and assess the tolerability of AG-ITP. This report details the results of phase I examination of the AG-ITP sequence.
Patient Population To be eligible for this study, all patients were required to have pathologic confirmation of unresectable or metastatic TCC of the urothelial tract. Metastatic lesions were required to be bidimensionally measurable. Examination under anesthesia, cystoscopy, and needle biopsies of pelvic nodes (when indicated) were performed to assess and stage patients with unresectable primary bladder tumors. All patients were required to be a minimum of 18 years old and to have a minimum Karnofsky performance status (KPS) of 60%. Other eligibility criteria included: neutrophil count  1,500 cells/µL; platelet count 150,000 cells/µL; serum creatinine  1.5 mg/dL or creatinine clearance 60 mL/min/1.73m2; bilirubin 1.5 times normal; and AST less than two times normal. Normal cardiac function, as judged by chest radiography, ECG, and nuclear medicine gated cardiac scan, was required. Patients who had evidence of New York Heart Association functional class III or IV heart disease or severe arrhythmias, including first-, second-, or third-degree heart block, were excluded. Patients were not eligible if they had received any prior systemic chemotherapy or irradiation within 3 weeks of the start of protocol therapy. Patients with evidence of another active cancer were excluded. The Institutional Review Board of Memorial Sloan-Kettering Cancer Center approved the protocol; written informed consent was obtained from all patients before entry onto the study.
Treatment Plan Patients initially received six cycles of AG repeated every 2 weeks. The plan of the phase I investigation was to first maximize the dose of gemcitabine to 2,000 mg/m2 and then, if well tolerated, maximize the dose of doxorubicin to 50 mg/m2. On day 1 of each 2-week cycle, patients received doxorubicin by intravenous (IV) push plus gemcitabine by IV infusion at 10mg/m2/min at one of five planed dose levels (Table 1). Patients were instructed in the administration of rhG-CSF and self-administered 5 µg/kg/d by subcutaneous injection on days 3 to 11 of each cycle.
Delays and dose attenuations were prescribed for specific toxicities. If on the scheduled day of chemotherapy administration, the absolute neutrophil count (ANC) was less than 1,000 cells/µL or the platelet count was less than 100,000/µL, AG therapy was delayed for 1 week. If blood counts remained unsatisfactory after two 1-week delays, the patient was removed from protocol. Irrespective of the number of cycles of AG administered, ITP therapy was to commence 12 weeks after the first cycle of AG. Therefore, it was possible for patients requiring dose delays to receive fewer than six cycles of AG before crossover to ITP at week 13 of protocol therapy. The dosage of gemcitabine was to be reduced by 20% if a patient developed neutropenic fever (ANC below 1,000/µL at the time of a documented temperature of 38°C or greater) or a documented bacteremia. If a patient developed bilirubin greater than 1.5 times normal or transaminases greater than three times normal and drug toxicity was suspected, therapy was to be withheld for 2 weeks until toxicity was grade 2 or less, and the subsequent gemcitabine dosage was to be reduced by 20%. Doxorubicin was to be discontinued if congestive heart failure or persistent arrhythmia occurred. Gemcitabine was to be discontinued if pulmonary toxicity occurred. After completion of AG chemotherapy, ITP chemotherapy was administered for four cycles every 21 days, either inpatient or outpatient. Paclitaxel, 200 mg/m2 by 3-hour infusion, followed by cisplatin 70 mg/m2 and then ifosfamide 1,500 mg/m2 were given IV on day 1; ifosfamide was repeated on days 2 and 3. Mesna prophylaxis at 300 mg/m2 IV was given 30 minutes before and 4 and 8 hours after ifosfamide. Substitution of oral mesna at 600 mg/m2 was allowed for the 4- and 8-hour IV doses. To reduce the potential for acute allergic reactions after paclitaxel, patients received premedication with oral dexamethasone 20 mg at 14 hours and 7 hours, plus diphenhydramine hydrochloride 50 mg and cimetidine 300 mg both IV at 1 hour. Hydration with 5% dextrose/.5 normal saline with potassium chloride 20 mEq per liter was infused at 150 to 250 mL/h (minimum 2 L per day) and continued until the patient completed chemotherapy and was able to take adequate liquids orally. Patients self-administered rhG-CSF 5 µg/kg subcutaneously daily from days 6 to 17 of each cycle. Complete blood counts were performed twice weekly. If the WBC exceeded 10,000/µL for 2 days, then G-CSF was discontinued. Delays and dose attenuations were made for specific toxicities. If on the scheduled day of chemotherapy administration the ANC was less than 1,000 cells/µL or the platelet count was less than 100,000/µL, ITP therapy was to be delayed by 1-week intervals. Patients who developed grade 3 or 4 neurotoxicity were to be removed from study. Grade 3 or 4 mucositis, neutropenia complicated by fever (ANC < 1,000 cells/µL with temperature > 100.5°F), culture-documented infection, or grade 4 thrombocytopenia necessitated dose reduction by 25% of both ifosfamide and paclitaxel doses to 1,125 mg/m2 and 150 mg/m2, respectively. Uncomplicated grade 3 or 4 neutropenia did not require dose adjustment. Patients who developed grade 3 or 4 renal insufficiency (creatinine > three times normal) that was not related to obstructive uropathy were to have treatment withheld until recovery of renal function. Cisplatin was to be recommenced in divided doses over 2 days, with 12.5 gm mannitol before each cisplatin dose. Cisplatin and ifosfamide were to be discontinued in patients with persistent grade 3 or greater toxicity. Adjunctive surgery after completion of protocol therapy included cystectomy for patients with responding locally advanced bladder tumors and resection of responding metastatic disease in resectable solitary nodal or pulmonary sites.
Dose Escalation
Response Criteria
Patient Characteristics and Chemotherapy Delivery Between October 1997 and July 1998, 15 patients were enrolled onto the phase I portion of this trial (Table 2). Patients had generally favorable performance status, with a median KPS of 90%. Ten of 15 patients had visceral metastatic disease. A previous analysis by our group demonstrated the negative impact of KPS < 80 or visceral metastases on survival of patients treated with M-VAC chemotherapy.31 A profound difference in survival of patients with 0, 1, or 2 prognostic factors was noted. Five patients (33%) had zero risk factors, nine (60%) had one risk factor, and one (7%) had two risk factors.
Most patients were able to receive AG-ITP chemotherapy as planned or with only minor deviations. Of the 15 patients enrolled onto the phase I portion of this trial, nine patients received six cycles of AG and four cycles of ITP chemotherapy at full doses and on schedule. Two patients received six cycles of AG, but required minor deviations from planned ITP therapy. One patient who had grade 3 neuro-cortical toxicity during the first cycle of ITP had ifosfamide omitted from the final three cycles of therapy, and one patient with grade 3 nausea and vomiting after three cycles of ITP received only paclitaxel for the final cycle of therapy. Four patients did not complete planned therapy. One patient at dose level III withdrew consent after two cycles of AG and was lost to follow-up. One patient at dose level I developed grade 4 pulmonary toxicity after the third cycle of AG (see below). This patient received two further cycles of doxorubicin alone before crossover to ITP. After one cycle of ITP, his condition deteriorated, and he was removed from the study. Two patients, including one each at dose levels II and III, developed progressive disease after four and three cycles of AG, respectively, and were unable to continue therapy.
Toxicity Assessment
The toxicity associated with the ITP regimen as initial chemotherapy has been previously described.23,24 In this phase I study, toxicity was largely hematologic (Tables 3 and 4), including grade 4 neutropenia in three patients, grade 3 neutropenia in one patient, grade 3 thrombocytopenia in two patients, and grade 3 anemia in five patients. There was one episode of uncomplicated neutropenic fever. Nonhematologic toxicity included three patients with grade 3 nausea/vomiting, one with grade 3 neuro-cortical toxicity attributed to ifosfamide, and one patient with grade 3 fatigue. The majority of patients had grade 1 or 2 fatigue.
Response Assessment Response assessment after the AG portion of therapy was available for 14 patients (Table 4). One patient treated at dose level 3 who withdrew consent after two cycles of AG was not assessable for response. Response assessment after AG therapy included one patient with complete regression of tumor (treated at dose level 4) and seven patients with greater than 50% regression. Three patients developed progressive disease while receiving AG, including one each at dose levels 1,2, and 3. Response assessment for the six patients treated at AG dose levels 4 and 5 included one complete regression and five partial regressions. Response assessment after completion of AG-ITP was available for 14 patients (Table 4). Nine major responses were observed, including three CRs and six PRs. Two patients had stabilization of disease (nonresponders), and three patients progressed on AG-ITP. As described above, these three patients had progressive disease after AG and received zero (two patients) or one (one patient) cycle of ITP. Among six patients treated at the two highest AG dose levels, there were three CRs and three PRs.
This phase I study demonstrates the feasibility of sequential doxorubicin (50 mg/m2, day 1) and gemcitabine (2000 mg/m2, day 1) every 2 weeks for six cycles, followed by ifosfamide (1,500 mg/m2, days 1 to 3), paclitaxel (200 mg/m2, day 1), and cisplatin (70 mg/m2, day 1) every 3 weeks for four cycles. The AG regimen was well tolerated at all dose levels, with no grade 3 or 4 neutropenia or thrombocytopenia. Grade 3 and 4 nonhematologic toxicity was limited to one episode of grade 3 fatigue and one episode of possible grade 4 pulmonary toxicity. The hematologic toxicity observed with ITP in sequential therapy was similar to our previous experience.23,24 Three patients (20%) developed grade 4 neutropenia, and one episode of neutropenic fever was noted. Nonhematologic toxicity from ITP was tolerable, but emesis seemed more prevalent in this trial than in our previous experience with ITP. Three episodes of grade 3 emesis (20%) were seen in the current trial compared with no grade 3 emesis among 44 patients previously treated at our institution with the ITP regimen. No patients developed grade 3 or 4 neurotoxicity, perhaps because AG is not neurotoxic and only four cycles of ITP were administered. In our previous experience, most patients developing grade 3 and 4 neurotoxicity received more than four cycles of ITP.23 It is likely that the intensity of the sequential AG-ITP regimen contributed to the substantial number of patients who developed grade 3 anemia (six of 15, 40%) and required blood transfusion. Based on this observation, we are now administering prophylactic erythropoietin to all patients on the phase II trial if their hemoglobin falls below 10 g/dL. An actual MTD was not achieved in this phase I trial because the phase I portion of the trial was to be terminated if level 5 doses were achieved. Because the patients treated at the highest dose level (gemcitabine 2,000 mg/m2 and doxorubicin 50 mg/m2) did not experience severe toxicity, it is possible that higher doses are achievable. However, based on the dose response phenomenon of doxorubicin in breast cancer, it is unlikely that further increments in doxorubicin will result in greater clinical activity. Although higher levels of gemcitabine are also possible, the maximal dose of 2,000 mg/m2 every other week was felt to be a reasonable goal of the trial. It seems that the AG regimen and the AG-ITP sequence are active in the treatment of metastatic or unresectable TCC. Eight of 14 assessable patients treated with AG demonstrated at least 50% reduction of tumor, including five of six patients treated at the two highest dose levels. Similarly, nine of 14 patients had a major response after completion of protocol therapy, including three CRs and six PRs. The major response proportion, as well as the durability of response, cannot be adequately determined in the phase I study, so a phase II study is ongoing. The high degree of activity of the AG combination was surprising, and several explanations exist. Firstly, a dose-response phenomenon for doxorubicin in TCC may exist. In a review of the single-agent activity of doxorubicin in advanced disease, an increasing response proportion was noted for doxorubicin between dose-intensities of 12.5 mg/m2/wk and 25 mg/m2/wk.34 The latter dose level was a primary end point of the phase I portion of the current investigation. Similarly, the prolonged infusion of gemcitabine may have contributed to the antitumor activity. Plunkett et al35 have reported that intracellular gemcitabine triphosphate levels are maximized when the drug is administered at an infusion rate of 10 mg/m2/min, the infusion rate chosen for this trial. Lastly, although synergism between gemcitabine and doxorubicin is possible, this has not been supported by preclinical data. In conclusion, the AG regimen, given on alternating weeks with growth factor support, can be administered safely at doses of 50 mg/m2 and 2,000 mg/m2. Not only is this regimen well tolerated, but substantial activity is observed in patients with advanced TCC, both when given alone and as a component of sequenced therapy with ITP. Phase II investigation in patients with metastatic or unresectable TCC continues at these doses to determine the response proportion and evaluate response durability of this novel chemotherapy approach.
Supported by Eli Lilly & Company, Inc, Indianapolis, IN, and Bristol-Myers Squibb, Inc, Princeton, NJ.
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
