A phase II study of gemcitabine and capecitabine in metastatic renal cancer

A report of Cancer and Leukemia Group B protocol 90008

Authors

  • Walter M. Stadler MD,

    Corresponding author
    1. Section of Hematology/Oncology, Department of Medicine, University of Chicago Medical Center, Chicago, Illinois
    • Section of Hematology/Oncology, Department of Medicine, University of Chicago, 5841 South Maryland Avenue, MC-2115, Chicago, IL 60637
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    • Fax: (773) 702-3163

  • Susan Halabi PhD,

    1. Cancer and Leukemia Group B Statistical Center, Durham, North Carolina
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  • Brian Rini MD,

    1. Department of Medicine, University of California at San Francisco, San Francisco, California
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  • Marc S. Ernstoff MD,

    1. Department of Medicine, Dartmouth Medical School-Norris Cotton Cancer Center, Lebanon, New Hampshire
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  • Enrique Davila MD,

    1. Mount Sinai Medical Center, Miami, Florida
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  • Joel Picus MD,

    1. Department of Medicine, Washington University School of Medicine, St. Louis, Missouri
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  • Robert Barrier MS,

    1. Cancer and Leukemia Group B Statistical Center, Durham, North Carolina
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  • Eric J. Small MD,

    1. Department of Medicine, University of California at San Francisco, San Francisco, California
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  • for Cancer and Leukemia Group B

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    • The following institutions participated in this study: CALGB Statistical Center, Durham, NC (Stephen George, PhD; supported by CA33601); Cancer Centers of the Carolinas, Greenville, SC (Jeffrey K. Giguere, MD; supported by CA29165); Christiana Care Health Services, Inc. Community Clinical Oncology Program (CCOP), Wilmington, DE (Stephen Grubbs, MD; supported by CA45418); Dartmouth Medical School-Norris Cotton Cancer Center, Lebanon, NH (Marc S. Ernstoff, MD; supported by CA04326); Georgetown University Medical Center, Washington, DC (Edward Gelmann, MD; supported by CA77597); Grand Rapids Clinical Oncology Program, Grand Rapids, MI (Kathleen J. Yost, MD); Kansas City CCOP, Kansas City, MO (Jorge C. Paradelo, MD); Mount Sinai Medical Center, Miami, FL (Rogerio Lilenbaum, MD; supported by CA45564); Northern Indiana Cancer Research Consortium CCOP, South Bend, IN (Rafat Ansari, MD; supported by CA86726); Rhode Island Hospital, Providence, RI (William Sikov, MD; supported by CA08025); Roswell Park Cancer Institute, Buffalo, NY (Ellis Levine, MD; supported by CA02599); Southeast Cancer Control Consortium Inc. CCOP, Goldsboro, NC (James N. Atkins, MD; supported by CA45808); State University of New York Upstate Medical University, Syracuse, NY (Stephen L. Graziano, MD; supported by CA21060); Syracuse Hematology-Oncology Association CCOP, Syracuse, NY (Jeffrey Kirshner, MD; supported by CA45389); University of California at San Diego, San Diego, CA (Stephen L. Seagren, MD; supported by CA11789); University of Chicago Medical Center, Chicago, IL (Gini Fleming, MD; supported by CA41287); University of Iowa, Iowa City, IA (Gerald Clamon, MD; supported by CA47642); University of Missouri/Ellis Fischel Cancer Center, Columbia, MO (Michael C. Perry, MD; supported by CA12046); University of Nebraska Medical Center, Omaha, NE (Anne Kessinger, MD; supported by CA77298); University of North Carolina at Chapel Hill, Chapel Hill, NC (Thomas C. Shea, MD; supported by CA47559); and Washington University School of Medicine, St. Louis, MO (Nancy Bartlett, MD; supported by CA77440).


  • The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute.

  • Presented in part at the Annual Meeting of the American Society of Clinical Oncology, New Orleans, Louisana, 2004.

Abstract

BACKGROUND

The objective of this study was to verify previous reports of activity with gemcitabine plus a fluoropyrimidine in patients with metastatic renal cell cancer in a multiinstitutional setting.

METHODS

Eligibility included a Zubrod performance status from 0 to 2, no prior gemcitabine or fluoropyrimidine therapy, and normal organ function. Patients received gemcitabine at a dose of 1000 mg/m2 on Days 1, 8, and 15 and capecitabine at a dose of 830 mg/m2 twice daily on Days 1 through 21 on a 28-day cycle with specified dose reductions for baseline renal insufficiency. The primary endpoint was the response rate, which was assessed every 8 weeks. The statistical plan tested the hypothesis that the response rate was 5% versus an alternative of 15%.

RESULTS

Sixty patients were enrolled, and 4 of those patients never started treatment. Of the 56 evaluable patients, 79% of patients underwent prior nephrectomy, 75% of patients received prior systemic therapy, and 75% of patients had clear cell histology. Risk stratification revealed that 34%, 43%, and 16% of patients were in Risk Groups 1, 2, and 3, respectively. Toxicity (graded according to the National Cancer Institute's Common Toxicity Criteria [version 2.0]) included Grade 3 or 4 neutropenia in 45% of patients, Grade 2 or greater fatigue in 32% of patients, Grade 2 or greater nausea in 29% of patients, Grade 2 or greater hand-foot reaction in 39% of patients, and Grade 2 or greater diarrhea in 22% of patients. Six patients responded (11%; 95% confidence interval, 4–22%), and the overall median survival was 14.5 months.

CONCLUSIONS

Gemcitabine plus capecitabine had modest activity in patients with metastatic renal cancer, although the degree of activity and its associated toxicity would not support further evaluation in a Phase III trial of unselected patients. More focused investigations to identify patients most likely to benefit or to enhance activity with additional agents would be reasonable. Cancer 2006. © 2006 American Cancer Society.

Metastatic renal cell cancer traditionally has been considered a disease that is refractory to most systemic therapies. To date, immunotherapy has formed the mainstay of systemic treatment approaches. Until recently, high-dose interleukin-2 (IL-2) was the only drug approved by the U.S. Food and Drug Administration- because it leads to occasional complete responses and apparent cures.1, 2 Unfortunately, only a minority of patients are eligible for high-dose IL-2 therapy and only 5% to 10% of those patients experience this maximum benefit. Outpatient interferon α leads to improvements in survival, but the absolute benefit is small, and the associated systemic toxicity of interferon has prompted many to conclude that such treatment has minimal clinical utility.3 The oral tyrosine kinase inhibitors sorafenib and sunitinib, which target the vascular endothelial growth factor receptor (VEGFR) and the platelet-derived growth factor receptor (PDGFR), are approved for use in patients with advanced renal cell carcinoma and are likely to supplant immunotherapy as first-line therapy for these patients.4, 5 Nevertheless, complete responses have been observed only rarely with these agents, and preliminary data suggest that the vast majority of patients eventually will progress. Thus, there is a continued need for newer approaches in the treatment of metastatic renal cancer.

Although renal cancer has been considered a disease that is resistant to traditional cytotoxic chemotherapy, several lines of evidence suggest that the pyrimidine analogs have clinical activity. Specifically, 5-flurouracil (5-FU) and its analogs reportedly led to objective responses in up to 20% of patients, and activity also was observed with gemcitabine and troxacitabine.6 Based on these observations, investigators at the University of Chicago embarked on a series of Phase I and II trials with gemcitabine and 5-FU combinations.7–11 The initial Phase II study in 41 patients revealed an objective response rate of 17%, and a retrospective review of 153 patients who were treated on 5 separate trials revealed an overall response rate of 11% and a suggestion of improved survival compared with a prognostic risk factor-matched historic cohort.12 Those results compared favorably with the results from a multiinstitutional trial of infusional 5-FU in which a response rate of only 5% was reported and in which the investigators concluded that nucleoside analog therapy in metastatic renal cancer had little clinical utility.13 Single-institution studies of the oral 5-FU analog capecitabine with gemcitabine also reportedly produced response rates similar to those reported with the gemcitabine/5-FU regimens.14, 15 Because the response rates from single-institution settings just barely are sufficient to justify a Phase III comparative trial, and because the toxicities in the single-institution trials were not insignificant, a multiinstitutional Phase II study of gemcitabine and capecitabine in patients with metastatic renal carcinoma was initiated in to determine whether a more definitive comparative trial was justified.

MATERIALS AND METHODS

Patients

Eligibility criteria for participation included histologically demonstrated metastatic or unresectable renal cell cancer; a Zubrod performance status of 0 to 2; no prior exposure to gemcitabine or fluoropyrimidines; measurable disease, which was defined according to standard Response Evaluation Criteria in Solid Tumors (RECIST); no significant cardiovascular disease, which was defined as no myocardial infarction in the 12 months prior to enrollment and no evidence of clinically significant heart failure, coronary artery disease, or arrythmias; no history of malabsorption; and lack of pregnancy or breast feeding. Patients also were required to have normal organ function, which was defined as granulocytes >1500/μL, platelets >100,000/μL, bilirubin <1.5 times the upper limit of normal, and an estimated creatinine clearance of >30 mL per minute. All patients provided written informed consent, and the protocol was approved by the Institutional Review Board of all participating centers.

Treatment

Patients who had an estimated creatinine clearance of >50 mL per minute according to the Cockcroft–Gault formula received gemcitabine at a dose of 1000 mg/m2 on Days 1, 8, and 15 and capecitabine at a dose of 830 mg/m2 twice daily on Days 1 through 21 of a 28-day cycle. Patients who had an estimated creatinine clearance of 30 to 50 mL per minute were started at a capecitabine dose of 622 mg/m2 twice daily. Specified dose reductions included the reduction of gemcitabine to 750 mg/m2 and 500 mg/m2 for myelosuppression or hepatotoxicity and the reduction of capecitabine to 622 mg/m2 and 415 mg/m2 for mucositis, diarrhea, hepatotoxicity, or hand-foot syndrome. These initial doses were based on a previously performed Phase I study.16 Patients who were unable to restart therapy within 3 weeks because of toxicities or who experienced Grade 3 toxicity despite a 2-level dose reduction of either gemcitabine or capecitabine were removed from the protocol. Otherwise, treatment was to continue until evidence of progressive disease or until the patient refused further treatment.

Data Collection and Safety Monitoring

Patients underwent computed tomography (CT) scans of the chest, abdomen, and pelvis at baseline and every 8 weeks thereafter. RECIST recommendations were used to categorize responses.17 Toxicity was monitored every 4 weeks, except for the complete blood count, which was obtained weekly, and was categorized according to the National Cancer Institute's Common Toxicity Criteria (version 2.0). Serious adverse events were reported to the Cancer and Leukemia Group B (CALGB) Central Office and the principal investigator according to CALGB policies. Patient registration and data collection were managed by the CALGB Statistical Center. Data quality was ensured by careful review of data by CALGB Statistical Center staff and by the study chairperson. Statistical analyses were performed by CALGB statisticians. In addition, participating sites were audited every 3 years, and 37% of the patients entered on this trial underwent an audit review.

Statistical Analysis

The primary study endpoint was the objective response rate.17 The original statistical plan specified that a total of 60 patients were to be enrolled to test the null hypothesis that the response rate was ≤5% versus the alternative hypothesis that the response rate was ≥15% assuming a Type I error rate of 0.07 and 86% power.18 Toxicity was an important secondary endpoint with a null hypothesis that the toxicity probability (Grade 4 or 5) was ≤0.10 versus the alternative hypothesis that toxicity probability was ≥0.30 with a Type I error rate of 0.04 and a power of 90%. Thus, serious toxicity in ≥14 patients at any time would lead to the conclusion that the regimen is not worthy of further study. Interim analysis to assess response and toxicity without suspension of accrual was to be performed after the first 25 enrolled patients underwent a response evaluation, and a decision rule required that ≥2 responders had be seen among those 25 patients. However, by the time these data became available, all 60 patients already had been accrued, and the study was closed.

Other secondary endpoints were progression-free survival and overall survival. Progression-free survival was defined as the interval between treatment initiation and the date of disease progression or death, whichever occurred first. Overall survival was defined as the interval between treatment initiation and the date of death. The 95% confidence interval (95% CI) for the objective response rate was computed based on the exact binomial distribution. Overall survival and progression-free survival distributions were estimated by using the Kaplan–Meier product-limit method.

RESULTS

The planned 60 patients were enrolled over 19 weeks (from December 2002 to April 2003) from 18 main member institutions. Three patients withdrew consent prior to receiving any treatment, and 1 patient died prior to starting treatment: This left 56 evaluable patients for the current analysis. Baseline patient characteristics are described in Table 1. This was a fairly typical metastatic renal cell cancer cohort with a median age of 63 years and a male predominance. Only 14% of patients had a performance status of 2, but 43% of patients had ≥3 metastatic sites of disease. Seventy-nine percent of patients had undergone a prior nephrectomy, and 75% of patients had received prior systemic therapy. Detailed histologic data were not collected as part of the original data collection; however, a retrospective review showed that 75% of patients had clear cell tumors, 5% of patients had papillary tumors, 2% of patients had chromophobe tumors, and 18% of patients had unclassified tumors or had no available data. Evaluation of histologic grade revealed the 25% of tumors were Grade 1 or 2, 39% of tumors were Grade 3 or 4, and, in 36% of tumors, grade was not reported. Risk stratification according to the Memorial Sloan-Kettering criteria was also performed retrospectively and revealed that 34% of patients were in Risk Group 1, 43% of patients were in Risk Group 2, and 16% of patients were in Risk Group 3, and 7% of patients not classifiable because of incomplete information.19

Table 1. Patient Characteristics (n = 56)
CharacteristicNo. of patientsPercent
  • *

    Patients may have received >1 prior therapy.

Median age (interquartile range), y62 (54–69)
Male:female ratio43/1377/23
Race/ethnicity
 White4885.7
 African American47.1
 Other47.1
Performance status
 02138
 12748
 2814
No. of metastatic disease sites
 11730
 21527
 ≥32443
Tumor histology
 Clear cell4275
 Papillary35
 Chromophobe12
 Not recorded or not available1018
Tumor Fuhrman grade
 Grade 1/21425
 Grade 3/42239
 Not recorded or not available2036
Prognostic risk group
 11934
 22443
 3916
 Incomplete information47
Prior therapy*
 Radiotherapy1730
 Systemic therapy4275
 Nephrectomy4479

Toxicities are noted in Table 2. Grade 3 or 4 neutropenia developed in 45% of patients, although only 1 episode of neutropenic fever was reported. Grade 3 or 4 fatigue was observed in only 7% of patients, but 32% of patients reported at least Grade 2 fatigue. Similarly, 29% of patients experienced at least Grade 2 nausea, 39% experienced at least Grade 2 hand-foot reaction, and 22% experienced at least Grade 2 diarrhea. Serious adverse events included a patient who developed an acute abdomen, which required bowel resection secondary to a mesenteric artery infarct. That patient subsequently died of a hemorrhagic cardiovascular accident while receiving warfarin. One patient each also experienced Grade 3 cardiac ischemia, thrombosis, and a gastrointestinal bleed. Two patients also experienced warfarin toxicity, most likely as a result of a drug interaction with capecitabine; 2 patients experienced Grade 3 elevated aspartate aminotransferase levels; and 3 patients experienced hyponatremia. It is noteworthy that 36% of patients discontinued therapy because of a documented adverse event, and an additional 21% of patients refused further therapy, although they had not met a protocol-defined endpoint.

Table 2. Treatment-Related Toxicity*: Worst Grade per Patient Possibly, Most Likely, or Definitively Related to Therapy
Treatment-related toxicityGrade 2 (Moderate)Grade 3 (Severe)Grade 4 (Life threatening)
No. of patients%No. of patients%No. of patients%
  • WBC indicates white blood cell count; NOS, not otherwise specified.

  • *

    Toxicity was graded according the National Cancer Institute's Common Toxicity Criteria (version 2.0).

  • There was 1 additional fatal hemorrhagic stroke.

Blood/bone marrow
 Hemoglobin173071312
 Leukocytes (total WBC)142561135
 Neutrophils/granulocytes7131832713
 Platelets6113512
Cardiovascular (general)
 Edema470000
 Cardiac-ischemia/infarction001200
 Thrombosis/embolism001200
 Phlebitis (superficial)120000
 Circulatory or cardiac, other001212
Coagulation
Prothrombin time elevated002400
Constitutional symptoms
 Fatigue14253512
 Weight loss120000
 Constitutional symptoms, other001200
Dermatology/skin
 Hand-foot skin reaction17305900
 Exfoliative dermatitis, NOS471200
 Alopecia240000
 Erythema multiforme120000
Gastrointestinal
 Nausea101861100
 Emesis7133500
 Anorexia8142400
 Stomatitis/pharyngitis8142400
 Diarrhea6115912
 Gastritis120000
 Dehydration242400
 Gastrointestinal, NOS001212
Hepatic
 Aspartate aminotransferase002400
 Alkaline phosphatase120000
 Infection      
 Febrile neutropenia001202
 Infection, NOS121200
Metabolic/laboratory
 Increased creatinine240000
 Hyperglycemia471200
 Hyponatremia003500
 Hypokalemia002400
 Hyperkalemia100000
Neurology
 Dizziness120000
 Hallucination, NOS001200
 Peripheral motor neuropathy120000
 Peripheral sensory neuropathy350000
 Anxiety240000
Pulmonary
 Dyspnea (shortness of breath)472400
 Hypoxia001200
Summary: Maximum toxicity8143664814

Objective responses according to by standard RECIST criteria were observed in 6 patients for an overall response rate of 11% and (95% CI, 4–22%). All responders had clear cell histology, 5 of 6 responders had Grade 3 or 4 disease, and 5 of 6 responders had undergone prior nephrectomy. There were no complete responses. With a median follow-up of 26 months in the surviving patients, 4 of 6 responders developed disease progression with a median 10.4-month response duration, and the median time to progression for the entire population was 5.6 months (95% CI, 3.5–8.3 months). The median survival was 14.5 months (95% CI, 8.8–19.9 months) (Fig. 1).

Figure 1.

This chart illustrates Kaplan–Meier survival.

DISCUSSION

The current multicenter Phase II study of gemcitabine and capecitabine confirmed previous single-institution observations regarding the efficacy of gemcitabine and 5-FU or capecitabine for the treatment of metastatic renal cell carcinoma.7–12, 15 The observed objective response rate of 11% compared favorably with multiinstitutional studies of single-agent 5-FU, was similar to the rate reported with immunotherapy, and even was higher than that reported with the newly approved tyrosine kinase inhibitor sorafenib.20 The median survival was encouraging and, once again, compared favorably with historic series of other cytotoxic therapies and the immature survival data from the sorafenib Phase III study.19–21 The duration of response also was encouragingly long, suggesting that there is a subset of patients who experience significant benefit.

Nevertheless, the 6 observed objective responses were only slightly greater than the numbers that were prespecified as necessary for further evaluation of the regimen. Likewise, toxicity was not inconsequential and, as may be expected from a multiinstitutional trial, was somewhat greater than that reported in the single-institutional trials. Serious toxicities, as defined by the National Cancer Institute Common Toxicity Criteria grading scale and by serious adverse events, were modest and similar to those reported with other cytotoxic therapy used in solid tumor oncology. The serious Grade 4 or 5 toxicity also was less than that prespecified as unacceptable. Nevertheless, persistent Grade 1 and 2 toxicities were problematic. Specifically, the relatively high incidences of fatigue, gastrointestinal toxicities, and hand-foot syndrome were deemed unacceptable by a large percentage of participating patients and their treating physicians. Thus, the high rate of treatment discontinuation and the modest response rate dampen enthusiasm for further development of gemcitabine and capecitibine in unselected patients with renal cancer at the dose and schedule reported here.

It should be noted, however, that the observed incidence of hand-foot syndrome and diarrhea with this regimen is not dissimilar from that reported with sorafenib, and asymptomatic myelosuppression also is common with sunitinib treatment.4, 20 Furthermore, the observed toxicities could be improved by adjustments of dose, schedule, or improved supportive care. In addition, there is no effective therapy for patients who fail on sorafenib and/or sunitinib therapy. Therefore, further evaluation of nucleoside analog therapy in patients with metastatic renal cancer may be a fruitful avenue of investigation if the population that benefits from this approach could be identified. For example, it has been suggested that patients who have poorly differentiated or sarcomatoid histology may benefit from gemcitabine-based chemotherapy.22 The current study was not informative in this regard, because data on subtype and grade were unavailable in 18% of patients and 36% of patients, respectively, and the number of responders was low. It also is possible, or perhaps even likely, that molecular criteria would be more useful for identifying a population that would benefit. Finally, whether pyrimidine nucleoside analogs enhances the activity of VEGF-targeted or VEGFR/PDGFR-targeted agents could be investigated. This especially is a potentially fruitful area of research given preclinical and emerging clinical data for potentiation of chemotherapy, including pyrimidine analogs, by VEGF pathway-directed agents.23, 24

In summary, the combination of gemcitabine and capecitabine cannot be recommended for general care or for further study in a Phase III setting in unselected patients with renal cell carcinoma. However, further efforts to develop this combination in patients with renal cell carcinoma with a focus on identifying the population most likely to benefit and/or on the value of additional agents to enhance the activity of this regimen would be reasonable.

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