A phase II trial of weekly intravenous gemcitabine and cisplatin with continuous infusion fluorouracil in patients with metastatic renal cell carcinoma

C. M. George1,+, N. J. Vogelzang1,2,3, B. I. Rini1, F. J. Geoffroy4, P. Kollipara5 and W. M. Stadler1,2,3

1Section of Hematology/Oncology, Department of Medicine; 2Section of Urology, Department of Surgery; 3Cancer Research Center, University of Chicago; 4Methodist Medical Center, Peoria, IL; 5Fort Wayne Medical Oncology/Hematology Inc, Fort Wayne, IN, USA

Received 9 April 2001; revised 25 June 2001; accepted 17 August 2001.


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background

We reported previously that the combination of gemcitabine and continuous infusion fluorouracil (5-FU) has activity in renal cell carcinoma [1]. Based upon in vitro synergy of gemcitabine/cisplatin and 5-FU/cisplatin, we hypothesized that the addition of cisplatin could improve the objective response rate of gemcitabine and 5-FU with manageable toxicity.

Patients and methods

Twenty-one patients with metastatic renal cell carcinoma (RCC) and a Cancer and Leukemia Group B performance status of 0 to 2 were enrolled. Ten had received prior systemic therapy. Treatment consisted of gemcitabine 600 mg/m2 and cisplatin 20 mg/m2 on days 1, 8 and 15 of each 28-day cycle. Continuous infusion 5-FU was given from day 1 to day 21.

Results

No complete responses and one partial response were observed for an objective response rate of 5% (95% confidence interval 0% to 24%). Two minor responses (25% to 50% regression) were also observed. The median overall survival was 10 months with 35% of patients surviving at 1 year. Grade 3–4 myelosuppression (mostly thrombocytopenia) occurred in nine (43%) patients. Nausea/vomiting and neuropathy were dose-limiting in an additional five patients. Only 51% of treatment cycles were delivered on time and without dose reduction.

Conclusions

The addition of cisplatin to gemcitabine and 5-FU did not improve the objective response rate of gemcitabine and 5-FU alone and added to the toxicity. Due to the cumulative toxicity, further trials with this cisplatin-containing regimen in RCC are not indicated.

Key words: cisplatin, fluorouracil, gemcitabine, phase II, renal cell carcinoma


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
In the year 2001, there will be ~31 000 new cases of kidney cancer in the USA; the vast majority of these will be renal cell carcinoma (RCC) [2]. Approximately 30% to 50% of these cases will be metastatic or unresectable at diagnosis [3]. Immunotherapy with interferon-{alpha} (IFN-{alpha}) and/or interleukin 2 (IL-2) can produce objective radiologic responses in 0% to 30% of patients [4]. There is no standard treatment for RCC patients who are unresponsive or intolerant of cytokine-based therapy [5].

The regimen of weekly gemcitabine and continuous infusion 5-FU has proven tolerable in phase I studies [6]. We reported previously an objective response rate of 17% using weekly gemcitabine and continuous infusion 5-FU in 41 patients with metastatic RCC. The regimen was well tolerated; fatigue and grade 2 myelosuppression were the most common toxicities reported [1]. Further off-protocol experience with this regimen has confirmed this modest activity in metastatic RCC.

Cisplatin has not been carefully studied in RCC, although older data suggest minimal, if any, activity [7]. However, the doublets of cisplatin/5-FU and cisplatin/gemcitabine have been studied extensively in cancers of the cervix [8], esophagus [9], head and neck [10,11], lung [12], and urothelium [13] with some suggestion of synergy between cisplatin and both 5-FU and gemcitabine. At low doses, cisplatin can be administered weekly with minimal myelosuppression. We thus hypothesized that the three-drug combination of 5-FU, gemcit-abine, and cisplatin would increase the objective response rate seen with gemcitabine and 5-FU without significantly increasing its toxicity.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
All procedures were reviewed by and were in accordance with the ethical standards of the University of Chicago Institutional Review Board.

Patient eligibility
Patients with histologically confirmed unresectable or metastatic RCC were eligible. All patients had to have a Cancer and Leukemia Group B (CALGB) performance status of <=2. Prior treatment with cisplatin, 5-FU, 5'-deoxy-5-fluorouridine (FUDR), uracil + tegafur (UFT), capecitabine or gemcitabine was exclusionary. Patients in whom central nervous system (CNS) metastases had been adequately treated were eligible. Patients with significant coronary artery disease or a myocardial infarction within 6 months of study entry, lactating women, and patients unable to give informed consent due to medical or psychiatric conditions were also excluded.

Study design
This was a phase II, multi-institutional study conducted at six hospitals within the National Cancer Institute (NCI)-funded University of Chicago phase II consortium. The treatment consisted of outpatient gemcitabine at 600 mg/m2 over 30 min and cisplatin at 20 mg/m2 over 1 to 2 h on days 1, 8 and 15. 5-FU was given by continuous intravenous infusion via a permanent catheter at 150 mg·m2/day on days 1 to 21. No treatment was given on days 22 to 28. One 4-week treatment period constituted one cycle. Disease re-evaluation took place after every two cycles using the same radiological tests performed at baseline.

At least two cycles of treatment were administered unless the patient met withdrawal criteria or had progressive disease. Patients experiencing grade 3 or 4 toxicity attributable to therapy and not to the underlying disease had further treatment withheld until such toxicity improved to grade <=2. Patients in whom grade 3 or 4 toxicity persisted longer than 4 weeks were removed from the study. Cycles interrupted for toxicity were not resumed; patients began the next cycle as scheduled or when toxicity had improved to grade <=2, whichever was longer.

Response assessment
A complete response was defined as complete disappearance of all evidence of disease. A partial response was defined as >=50% decrease from baseline in the sum of the products of perpendicular diameters of all measurable lesions lasting at least 4 weeks. Progressive disease was defined as either a 25% increase or an increase of 10 cm2 in the sum of the products of measurable lesions over the smallest sum observed, or the appearance of any new lesion or reappearance of any lesion that had disappeared. Stable disease was that which did not meet the criteria for complete response, partial response, or disease progression.

Statistical considerations
The purpose of this phase II study was to assess the overall objective response rate of gemcitabine, 5-FU and cisplatin in a population of patients with metastatic RCC. Patients were accrued using a two-stage phase II design [14] to test the null hypothesis that the response rate is <5%. Twenty-one patients were enrolled in the first stage; if <=1 response was observed, no further patients would be accrued. The probability of accepting the drug combination if the true response rate was <5% is 0.05, and the probability of accepting the drug combination if the true response rate was 20% is 0.90.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patient demographics
Twenty-one patients were treated from May 1999 to May 2000. Table 1 lists patient characteristics. Two patients were not evaluable for response. One patient had initiated treatment when it was learned that all sites of disease had been irradiated previously. The second patient suffered a cerebral vascular accident (CVA) during cycle 2 of therapy. During the ensuing hospitalization, he suffered a pulmonary embolus and died from complications 3 weeks later. The treating physicians felt the death was not due to progressive disease. Both patients are included in the intention-to-treat analysis of objective response and in the toxicity assessment.


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Table 1. Patient characteristics
 
Response to treatment
Table 2 shows the response to study treatment. Of the 21 total patients, there were no complete responses and one partial response, for an objective response rate of 5% [95% confi dence interval (CI) 0% to 24%]. Ten patients experienced disease stabilization, four for 24 or more weeks (24, 32, 41 and 52 weeks). The patient who partially responded was a 51-year-old man with recurrent disease in the hilar and mediastinal lymph nodes 4 months after nephrectomy for a localized clear-cell renal carcinoma. The lesions had progressed during previous treatment with IFN-{alpha} and IL-2. Following two cycles of study treatment, his computed tomography (CT) scan revealed near resolution of the lesions. He received two more cycles of chemotherapy; repeat CT imaging demonstrated a durable response that lasted for a total of 7 months before disease progression.


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Table 2. Best response to therapy
 
In addition, two minor responses (25% to 50% decrease in tumor size) were also observed. These responses were defined post hoc because of the long period of disease stability (41 and 52 weeks). One patient had well differentiated, clear-cell carcinoma and the other had granular, non-clear-cell type. One patient experienced durable improvement in disease-related pain. These minor responses are not included in the calculation of objective response rate.

Toxicity
Hematological and non-hematological toxicities are listed in Table 3. Hematological toxicity was moderate with one case of grade 4 neutropenia and one neutropenic fever. One third of patients experienced grade 3 thrombocytopenia.


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Table 3. Adverse events
 
Thromboembolic events occurred in two patients: one patient was treated for a lower extremity deep vein thrombosis 6 months after starting treatment. Therapy was not interrupted. A second patient suffered a CVA during cycle 2 and a pulmonary embolus during the ensuing admission. The source of embolic disease was not discovered.

Renal toxicity was not prominent. One patient who enrolled with a baseline creatinine of 1.1 mg/dl received multiple cycles of therapy complicated by myelosuppression and a slow rise in creatinine. During his tenth and final cycle, his creatinine was 3.0 mg/dl. During cycle 10, the patient was hospitalized with pneumonia, ultimately complicated by acute renal failure, hypertension, and lower extremity edema.

Twenty-four percent of patients experienced grade <=2 sensory neuropathy. One patient experienced grade 3 sensory neuropathy after nine cycles of therapy. Four patients experienced grade 2 neuropathy; in two cases, this level of toxicity prompted the discontinuation of study treatment. Both patients had demonstrated a long period of stable disease (11 and 12 cycles) and further treatment was not felt to be in either patient’s best interest.

Nine patients came off study due to toxicity (Table 4). The treatment limiting toxicities were myelosuppression (two patients), nausea and vomiting (two patients), neuropathy (three patients), acute renal failure (one patient), fatigue (one patient) and thromboembolic events (one patient). In two cases, the patients found toxicity intolerable (nausea and fatigue, respectively) despite a common toxicity criteria (CTC) grade of <2.


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Table 4. Termination of study treatment due to toxicity
 
Out of 89 cycles of chemotherapy given, 45 (51%) were delivered on the scheduled days without dose reduction. Six patients (29%) received all treatment at full dose without interruptions or reductions. Myelosuppression caused or contributed to the majority of treatment modifications [31 out of 44 cycles (70%)]. Other factors included nausea and vomiting (six cycles); fatigue (two); neuropathy (one); acute sinusitis (one); pneumonia (one); and acute CVA (one). Two patients developed clinically apparent disease progression mid-cycle.


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Given the resistance of renal cell carcinoma to systemic treatment with biologic or cytotoxic agents, new approaches that build on active regimens are warranted. We demonstrated previously a 17% objective response rate with gemcitabine and continuous infusion 5-FU in RCC patients. We thus hypothesized, based on in vitro synergistic effects of cisplatin and gemcitabine, that the addition of low-dose cisplatin would improve response rates without significantly increased toxicity.

The present trial noted one objective response out of 21 treated patients. By the stopping rules established in the protocol, the chance of falsely rejecting the null hypothesis (that the true response rate of the treatment is <5%) was not sufficiently probable to justify enrolment of additional patients. Given the 95% CI of the objective response rate (0% to 24%), the alternative hypothesis that the treatment’s true response rate is >20% is neither rejected nor accepted. The efficacy observed in this trial is within the range of the 17% response rate observed previously with gemcitabine and 5-FU [1].

The addition of cisplatin to the gemcitabine–5-FU doublet increased toxicity compared with published reports of gemcitabine and 5-FU alone. In a similar group of patients, Rini et al. noted 4% grade 3/4 thrombocytopenia compared with 33% in the present trial [1]. Likewise, grade >=2 fatigue and grade >=2 nausea/vomiting were reported in 29% and 14% of patients treated with gemcitabine–5-FU alone, compared with 52% and 34% in the present trial. Mucositis rates were similar in the two trials.

The combination of gemcitabine, cisplatin and 5-FU has not been studied extensively. Oettle et al. treated esophageal cancer patients with gemcitabine 1000 mg/m2, 5-FU 750 mg/m2 over 24 h, folinic acid 200 mg/m2, and cisplatin at escalating doses every week for 4 weeks out of six. At a cisplatin dose of 30 mg/m2 the major toxicities were leukopenia and thrombocytopenia [15]. Harris and colleagues conducted a phase I study of gemcitabine, cisplatin and 5-FU with sequential radiation therapy. Two cycles of chemotherapy where given prior to combined 5-FU and twice-daily radiation. The maximum tolerated doses of chemotherapy were gemcitabine 175 mg·m2/day on days 1 to 5, cisplatin 20 mg/m2 on days 1 to 5, and 5-FU 600 mg/m2 by continuous infusion on days 1 to 5 with granulocyte colony stimulating factor (GCSF) support during each 4-week cycle. Dose limiting toxicities were hematological [16]. Both studies are consistent with our observation that myelosuppression is the dominant toxicity.

Although myelosuppression contributed to 70% of dose and schedule modifications, it accounted for only two out of nine treatment failures in the current trial. Among the patients who could not tolerate further treatment despite dose reductions and supportive care, nausea, vomiting and neuropathy were most commonly encountered.

In summary, the combination gemcitabine, cisplatin and continuous infusion 5-FU is feasible, but myelosuppression is common. Cumulative toxicity (neuropathy) and refractory low-grade fatigue and nausea are problematic in patients treated for prolonged periods. This study demonstrates a 5% objective response rate and provides no evidence that gemcitabine–5-FU–cisplatin is superior in efficacy to gemcitabine–5-FU in renal cell cancer patients. Given the broad application of the doublets gemcitabine/cisplatin and 5-FU–cisplatin, the described three-drug regimen should be investigated in other tumor types.


    Acknowledgements
 
The authors gratefully acknowledge the University of Chicago Protocol and Data Management Office, Dr Everett Vokes, Dr Keith Shulman, Dr Daniel Shevrin, Dr David Taber, Dr Gregory Masters, Dr David Sciortino, Dr Christopher Ryan, Dr Todd Zimmerman, Dr Apurva Desai, and all the physicians, nurses, and data managers involved in carrying out this study. The authors further acknowledge the Kidney Cancer Association and especially the patients and their families for their participation and support of this research. The work was supported in part by the University of Chicago Phase II contract (grant number N01CM07003), the University of Chicago Cancer Center Support Grant (CA14599), the Stulberg Award from the Kidney Cancer Association (WMS), and the Fred C. Buffett Professorship (to NJV).


    Footnotes
 
+ Correspondence to: University of Chicago Medical Center, Department of Medicine, Section of Hematology/Oncology, 5841 S. Maryland Avenue, MC 2115, Chicago, IL 60637-1470, USA. Tel: +1-773-834-4028; Fax: +1-773-702-0963; E-mail: cgeorge@medicine.bsd.uchicago.edu Back


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
1. Rini BI, Vogelzang NJ, Dumas MC et al. Phase II trial of weekly intravenous gemcitabine with continuous infusion fluorouracil in patients with metastatic renal cell cancer. J Clin Oncol 2000; 18: 2419–2426.[Abstract/Free Full Text]

2. Greenlee R, Hill-Harmon M, Murray T et al. Cancer statistics. CA Cancer J Clin 2001; 51: 15–36.[Abstract/Free Full Text]

3. Chow W, Devesa S, Joseph J et al. Epidemiology of renal cell carcinoma. In Vogelzang NJ, Scardino PT, Shipley WU, Coffey DS (eds): Comprehensive Textbook of Genitourinary Oncology, 2nd edition. Philadelphia, PA: Lippincott Williams and Wilkins 2000; 1010–1110.

4. Sadler WM, Kuzel T, Dumas M et al. Multicenter phase II trial of interleukin-2, interferon-{alpha}, and 13-cisretinoic acid in patients with metastatic renal-cell carcinoma. J Clin Oncol 1998; 16: 1820–1825.[Abstract]

5. Motzer RJ, Russo P. Systemic therapy for renal cell carcinoma. J Urol 2000; 163: 408–417.[ISI][Medline]

6. Bertucci D. Phase I trial of continuous infusion 5-fluorouracil (5-FU) and weekly gemcitabine (dFdC): updated results. Proc Am Soc Clin Oncol 1999; 18: 203a.

7. Rossof AH, Talley RW, Stephens R et al. Phase II evaluation of cis-dichlorodiammineplatinum(II) in advanced malignancies of the genitourinary and gynecologic organs: a Southwest Oncology Group Study. Cancer Treat Rep 1979; 63: 1557–1564.[ISI][Medline]

8. Morris M, Eifel PJ, Lu J et al. Pelvic radiation with concurrent radiotherapy compared with pelvic and para-aortic radiation for high-risk cervical cancer. N Engl J Med 1999; 340: 1137–1143.[Abstract/Free Full Text]

9. Lizuka T, Kakegawa T, Ide H. et al. Phase II study of CDDP + 5-FU for squamous esophageal carcinoma: JEOG Co-operative Study Results. Proc Clin Oncol 1999; 10:157 (Abstr).

10. Jacobs C, Lyman G, Velez-Garcia E et al. A phase III randomized study comparing cisplatin and fluorouracil as single agents and in combination for advanced squamous-cell carcinoma of the head and neck. J Clin Oncol 1992; 10: 257–263.[Abstract]

11. Forastiere AA, Metch B, Schuller DE et al. Randomized comparison of cisplatin plus fluorouracil and carboplatin plus fluorouracil versus methotrexate in advanced squamous-cell carcinoma of the head and neck: a Southwest Oncology Group study. J Clin Oncol 1992; 10: 1245–1251.[Abstract]

12. Sandler AB, Nemunaitis J, Denham C et al. Phase III trial of gemcitabine plus cisplatin versus cisplatin alone in patients with locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol 2000; 18: 122–130.[Abstract/Free Full Text]

13. Von der Masse J, Hansen SW, Roberts JT et al. Gemcitabine and cisplatin versus methtrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol 2000; 17: 3068–3077.

14. Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials 1989; 10: 1–10.[ISI][Medline]

15. Oettle H, Arnold D, Stroszczynski C et al. Phase I trial of gemcitabine (GEM), cisplatin (CDDP) and 5-fluorouracil [24 h] (FU) with folinic acid (FA) in patients with advanced esophageal cancer. Proc Am Soc Clin Oncol 2000; (Abstr 887).

16. Harris W, Landry J, Staley C et al. A phase I study of gemcitabine, cisplatin and 5-fluorouracil (GPF) with radiation for patients with advanced GI malignancies. Proc Am Soc Clin Oncol 2000; (Abstr 1205).





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