Randomized phase II trial of gemcitabine plus irinotecan or docetaxel in stage IIIB or stage IV NSCLC

C. M. Rocha Lima1,*, N. A. Rizvi2, C. Zhang3, J. E. Herndon, 2nd3, J. Crawford4, R. Govindan6, G. W. King6 and M. R. Green7

1 University of Miami and Sylvester Cancer Center, Miami, FL; 2 Memorial Sloan-Kettering Cancer Center, New York, NY; 3 CALGB Statistical Center, Durham, NC; 4 Duke University Medical Center, Durham, NC; 5 Washington University School of Medicine, St Louis, MO; 6 Cancer Centers of the Carolinas, Greenville, SC; 7 Medical University of South Carolina, Charleston, SC, USA

Received 24 July 2003; revised 27 October 2003; accepted 19 December 2003


    ABSTRACT
 Top
 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
Background:

To evaluate the activity and tolerability of gemcitabine plus irinotecan or docetaxel as first-line chemotherapy for advanced non-small cell lung cancer (NSCLC).

Patients and methods:

Eligible patients with chemotherapy-naïve stage IIIB or IV NSCLC were randomized to receive gemcitabine 1000 mg/m2 on days 1 and 8, plus either irinotecan 100 mg/m2 or docetaxel 40 mg/m2 on days 1 and 8. Treatment was administered every 3 weeks.

Results:

Of the 80 enrolled patients with stage IIIB or IV NSCLC, 78 were evaluable for activity and safety. Overall response rates, consisting of partial responses, were 12.8% [95% confidence interval (CI) 4% to 35%] for gemcitabine–irinotecan and 23.1% (95% CI 10% to 42%) for gemcitabine–docetaxel. Median overall survival was 7.95 months (95% CI 5.2–10.2) and 12.8 months (95% CI 7.9–17.1) for gemcitabine–irinotecan and gemcitabine–docetaxel, respectively. The corresponding estimated 1-year survivals were 23% and 51%, respectively. The 2-year survival rate in arm A (gemcitabine–irinotecan) is not currently estimable. The 2-year survival rate for arm B (gemcitabine–docetaxel) is 22% (95% CI 6% to 37%). Both combinations were well tolerated; the most common hematological toxicity was neutropenia, which occurred in 26% of patients in each treatment arm.

Conclusions:

These results suggest that gemcitabine plus docetaxel or irinotecan is well tolerated in patients with chemotherapy-naïve advanced NSCLC. The survival data with the combination gemcitabine–docetaxel are promising. Gemcitabine–docetaxel combination therapy may be particularly useful for patients who have experienced toxicities with a platinum regimen or in patients who may be more susceptible to platinum-related toxicity.

Key words: CALGB 39809, docetaxel, gemcitabine, irinotecan, non-small cell lung cancer


    Introduction
 Top
 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
Currently, platinum-based combination chemotherapy is regarded as the standard of care for unresectable stage IIIB or IV non-small cell lung cancer (NSCLC) [1], which accounts for ~70% of newly diagnosed NSCLC cases [2]. In a large meta-analysis by the NSCLC Collaborative Group published in 1995, cisplatin-containing therapy for advanced disease was shown to confer an absolute survival gain of 10% at 1 year and a modest 1.5-month improvement in median survival compared with best supportive care (BSC) alone [3].

The emergence of a new generation of chemotherapeutic agents (i.e. the taxanes, topoisomerase I inhibitors, vinorelbine and gemcitabine) with anticancer activity in NSCLC has generated interest in the development of novel platinum combinations. In addition, some of these new drugs have shown survival advantages as single agents compared with BSC alone [4, 5]. Randomized phase III trials demonstrated that the new platinum combinations result in improvement in survival compared with single-agent platinum [6, 7] and older platinum combinations [8]. Within this drug class, the newer platinum combinations have similar efficacy results [9]. Non-platinum doublets are an alternative for the development of new treatment approaches in NSCLC. For example, within the Cancer and Leukemia Group B (CALGB), a randomized phase II trial of ifosfamide–paclitaxel and ifosfamide–vinorelbine produced response rates of 34% and 30%, and 1-year survival rates of 36% and 37%, respectively [10]. Of note, however, is that these particular ifosfamide-containing regimens were not further pursued, primarily due to toxicity and cost issues.

Given the insufficient activity and considerable toxicity associated with cisplatin-based NSCLC regimens, the CALGB designed a randomized, non-comparative, phase II trial of gemcitabine plus docetaxel or irinotecan as first-line therapy for advanced disease. These particular non-platinum combinations were selected in light of the single-agent activity of gemcitabine [1113], docetaxel [1418] and irinotecan [1922] in patients with previously treated and chemotherapy-naïve NSCLC. In addition, phase I data supporting the feasibility and tolerability of these doublets when using nearly full doses of each agent are available [2325]. Preclinical evidence of a dose-dependent synergic interaction between gemcitabine and irinotecan in the SCOG human small cell lung cancer cell line lent further support to the inclusion of the gemcitabine–irinotecan arm [26, 27].


    Patients and methods
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 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
Patient eligibility
This multicenter, open-label, randomized trial was conducted at nine centers in the USA. Eligible patients were at least 18 years of age, with histologically or cytologically confirmed measurable stage IIIB or IV NSCLC. An Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 was required, as well as adequate bone marrow (granulocyte count ≥1500 cells/µl and platelet count ≥100 000/µl), renal function (serum creatinine level ≤1.5 mg/dl) and hepatic function [bilirubin ≤1.5 mg/dl, aspartate aminotransferase (AST) ≤2x the upper limit of normal (ULN), and alkaline phosphatase <2.5x the ULN if AST >1.5x the ULN]. Before study entry, at least 2 weeks must have elapsed since any prior radiation therapy, and patients who had received previous chemotherapy for NSCLC were not eligible to participate. Patients with known central nervous system (CNS) metastases were eligible, provided that at least 2 weeks had elapsed since completion of cranial radiation therapy.

The study was approved by Institutional Review Boards at each participating center and was conducted in compliance with Institutional Review Board regulations. All patients provided written informed consent. Patient registration and data collection were managed by the CALGB Statistical Center. Data quality was ensured by careful review of all data at the CALGB Statistical Center and by the study chairperson.

Treatment plan
A randomization scheme stratified by disease stage (i.e. IIIB, IV without CNS involvement, IV with CNS involvement, or recurrent/progressive disease after surgery and/or radiation therapy) was used to assign patients to one of two treatment arms: gemcitabine 1000 mg/m2 as a 30-min infusion on days 1 and 8, followed immediately by irinotecan 100 mg/m2 as a 90-min infusion on days 1 and 8 of each 21-day cycle (arm A); or gemcitabine 1000 mg/m2 as a 30-min infusion on days 1 and 8, followed immediately by docetaxel 40 mg/m2 as a 60-min infusion on days 1 and 8 of each 21-day cycle (arm B). In both study arms, treatment was administered on an outpatient basis.

Baseline evaluation prior to study entry included history and physical examination, performance status, tumor measurements, complete blood count with differential, platelet count, biochemical profile, chest X-ray, and radiographic imaging of chest and upper abdomen (including liver and adrenals) by computed tomography scan or magnetic resonance imaging (as clinically appropriate). Complete blood count was measured on days 1 and 8 of each cycle. Before each subsequent treatment cycle, patients underwent history and physical examination, toxicity assessment, complete blood count, platelet count, biochemical profile and chest X-ray (when clinically appropriate).

Patients in both treatment groups received a 5-HT3 receptor antagonist [either granisetron 2 mg orally (p.o.) or 1 mg intravenously (i.v.) or ondansetron 24 mg p.o. or 20 mg i.v.] prior to each treatment day. Patients who received docetaxel were also given dexamethasone 8 mg p.o. every 12 h, for a total of five doses, starting the night prior to docetaxel administration. Patients who received irinotecan were given dexamethasone 10 mg i.v. prior to treatment.

Appropriate dose modifications were made in each treatment arm based on toxicity observed with previously administered doses. Doses of all drugs were held for 1 week for patients with granulocyte counts <1500 cells/µl or platelet counts <100 000 cells/µl on day 1 of a given treatment cycle. Following recovery of granulocytes to ≥1500 cells/µl or platelets to ≥100 000 cells/µl, doses of all drugs were administered at 75% of the previous dose. On day 8 of the treatment cycle, granulocyte counts <1500 cells/µl or platelet counts <100 000 cells/µl necessitated a 25% dose reduction for subsequent cycles. Febrile neutropenia, sepsis or thrombocytopenia requiring platelet transfusion necessitated a 25% dose reduction of each drug for all subsequent cycles in both treatment groups. The use of filgrastim or sargramostim was discouraged, but was allowed until the resolution of febrile neutropenia or a septic episode in patients who had prognostic factors predictive of clinical deterioration [e.g. pneumonia, hypotension, multi-organ dysfunction (sepsis syndrome) or fungal infection]. The use of erythropoietin was permitted at the discretion of the treating physician.

If diarrhea was evident at the beginning of a new cycle, all drugs were to be reduced by 25% (if seven to nine additional stools/day versus pretreatment) or 50% (if ≥10 additional stools/day versus pretreatment) on day 1 of each subsequent cycle. On day 8 of treatment, if patients experienced four or more additional stools compared with pretreatment output, treatment was to be held and day 8 dose reductions (varied based on stool output) were to occur. Indications for a 25% dose reduction of both drugs included grade 3 stomatitis/esophagitis with either regimen, grade 2 hepatic dysfunction with gemcitabine–irinotecan or grade 3/4 edema with gemcitabine/docetaxel. In the gemcitabine–docetaxel arm, reducing the docetaxel dose by either 25% or 50% was indicated based on the degree of liver function test abnormality. For grade 2 skin toxicity with either regimen, the gemcitabine dose only was to be decreased by 25%. Adverse events that required removal from study included grade 3/4 pulmonary or skin toxicity, grade 4 hypersensitivity reaction (or a hypersensitivity reaction that recurred despite treatment), dose-limiting edema (i.e. failed to improve to grade ≤2 after dose reduction), grade ≥3 neurotoxicity, and grade ≥3 hepatic dysfunction lasting >3 weeks.

Tumor responses were assessed radiographically every two cycles. Complete response (CR) was defined as the disappearance of all disease, signs, symptoms and biochemical changes related to the tumor. Partial response (PR) was defined as a reduction of ≥50% (bidimensional disease) or ≥30% (unidimensional disease) in the sum of the longest diameters of all measured lesions, without the development of new lesions or enlargement of any existing lesion. Patients with stable disease demonstrated a <50% reduction or <25% increase (bidimensional disease), or <30% reduction or <20% increase (unidimensional disease), in the sum of the products of the longest diameters of all measured lesions compared with the size at study entry, and the appearance of no new lesions. Objective progression or relapse was evidenced by a bidimensional lesion that increased ≥25% or a unidimensional lesion that increased ≥30% from time of entry (or time of maximum regression in responders); the appearance of new areas of malignant disease; two-step deterioration in performance status; <10% weight loss; or increasing symptoms that did not constitute progression but warranted a new evaluation for extent of disease. Patients received a minimum of two treatment cycles unless there was clear evidence of progression after one treatment cycle. Patients with an objective response or stable disease were to continue treatment for at least six cycles, or for two cycles beyond best response, and then at the discretion of the investigator or until disease progression. Following treatment discontinuation or removal from the study, patients were observed every 3 months for 1 year, then every 6 months thereafter until disease progression or death.

Statistical analysis
The primary objective of this randomized phase II study was to evaluate the activity of two combination chemotherapy regimens. The study was not designed as a comparative study. Rather, for each treatment regimen, a single-stage study with an accrual goal of 36 patients was used to differentiate a response rate between 20% and 40%. For this design, the type I error [e.g. probability of concluding that the regimen is effective (≥40% response rate) when the true response rate is ≤20%] is 0.089. The type II error (e.g. probability of concluding that the response rate is ≤20% when the true response rate is ≥40%) is 0.090.

The secondary objectives of this study were to describe the overall and failure-free survival and duration of response of patients treated with each chemotherapy combination, and to evaluate the toxicity associated with each combination. For each of the two treatment groups, Kaplan–Meier curves were used to describe overall and failure-free survival, as well as duration of response. Survival was calculated from the date of randomization until death or last-known follow-up. Failure-free survival was calculated as the time between randomization and disease progression, death or last known follow-up. Duration of response was defined as the time between the initial documentation of response and subsequent failure (death or disease progression). The frequency of the occurrence of toxicities was tabulated by the most severe occurrence experienced by each individual patient. Statistical analyses were performed by CALGB statisticians.


    Results
 Top
 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
Patient characteristics
A total of 80 patients were enrolled between September 1999 and October 2000. Two ineligible patients were excluded from the efficacy and safety analyses; one patient had a performance status of 2 and one patient had received radiotherapy <2 weeks prior to study enrolment.

The two treatment groups were well balanced for performance status, disease stage, extent of involvement and histology (Table 1). Compared with the gemcitabine–docetaxel group, the gemcitabine–irinotecan group had a higher median age (63.2 versus 56.5 years) and a higher concentration of males (71.8% versus 46.1%). The majority of patients in both arms were >50 years old and had a performance status of 1, <5% weight loss in the prior 6 months and stage IV disease without CNS involvement.


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Table 1. Patient characteristics (n = 78)
 
Treatment administration
A median of four cycles was delivered in each arm. The dose intensity for all drugs and the percentage of planned total chemotherapy doses delivered were similar in both study arms (Table 2).


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Table 2. Dose intensitya per patient on cycles 1 and 2
 
Responses and survival
Objective response data for both groups are presented in Table 3. Five patients receiving gemcitabine–irinotecan and nine patients receiving gemcitabine–docetaxel had a PR, for an overall response rate of 12.8% [95% confidence interval (CI) 4% to 35%] for gemcitabine–irinotecan and 23.1% (95% CI 10% to 42%) for gemcitabine–docetaxel. No CRs occurred in either treatment group.


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Table 3. Objective response to treatment (n = 78)
 
To date, 35 of 39 patients who received gemcitabine–irinotecan (arm A) and 29 of 39 patients who received gemcitabine–docetaxel (arm B) have died, and an additional three patients in arm A and nine patients in arm B demonstrated disease progression. Two patients, one per treatment group, died while receiving therapy on protocol. One patient receiving gemcitabine–irinotecan had a cardiac arrest on cycle one, day 3, but it was unclear whether the death was treatment-related. One patient receiving gemcitabine–docetaxel died as a result of pulmonary emboli and sepsis on cycle one, day 14; the death was considered disease-related.

Median overall survival for patients receiving gemcitabine–irinotecan was 7.95 months (95% CI 5.2–10.2). For patients receiving gemcitabine–docetaxel, the median survival was 12.8 months (95% CI 7.9–17.1). The estimated 1-year survival was 23% in arm A and 51% in arm B (Figure 1). At the time of this report, 2-year survival was not estimable for arm A. The 2-year survival rate for arm B is 22% (95% CI 6% to 37%). The median follow-up for patients remaining alive was 20 months (range 10.4–32.9). Median failure-free survival was 3.5 months (95% CI 2.7–5.5) in arm A and 4.5 months (95% CI 2.5–6.7) in arm B. The estimated 1-year failure-free survival was 8% for arm A and 15% for arm B (Figure 2). Unfortunately, no second-line therapy data were captured in this trial.



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Figure 1. Overall survival.

 


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Figure 2. Failure-free survival.

 
Survival statistics derived from gender and histological subanalyses are shown in Table 4. Non-comparative analyses suggest that the longest median survivals and the highest 1-year survival rates were observed in the female and non-adenocarcinoma subsets of the gemcitabine–docetaxel group.


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Table 4. Survival statistics by gender and histology
 
Safety
Both combinations were well tolerated in this study population. Overall, 62% of patients in arm A and 61% of patients in arm B experienced at least one grade 3 or 4 toxicity (Table 5). The most common grade 3 or 4 hematological toxicity was neutropenia, which occurred in 26% of patients in each treatment arm. In arm A, two patients experienced febrile neutropenia and one patient developed an infection. No cases of febrile neutropenia or infection were reported in arm B. One patient in arm B required a platelet transfusion; one patient in arm A and three patients in arm B required red blood cell transfusions. The most common non-hematological toxicities included fatigue, nausea, vomiting and diarrhea. Only one patient discontinued treatment because of adverse events. This patient had grade 3 febrile neutropenia as the maximum toxicity, and the treating physician decided to take him off treatment. There was no significant association between pulmonary toxicities and prior chest radiotherapy. Unfortunately, pre-existing symptoms were not prospectively collected to make correlations with the reported toxicity from therapy.


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Table 5. Grade 3/4 toxicity (n = 78)
 

    Discussion
 Top
 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
In this randomized phase II trial, gemcitabine–irinotecan and gemcitabine–docetaxel were well tolerated as first-line chemotherapy for advanced NSCLC. The response rates for both non-platinum doublets were relatively modest (12.8% and 23.1% for gemcitabine–irinotecan and gemcitabine–docetaxel, respectively), and, in fact, were lower than those historically observed among advanced NSCLC patients with previously untreated disease and a good performance status. However, the 1- and 2-year survival rates of 51% and 22%, respectively, and the 12.8-month median survival for the gemcitabine–docetaxel group are encouraging. Since the initiation of this study, efficacy data for a number of non-randomized phase II trials of various gemcitabine–docetaxel schedules for chemotherapy-naïve, advanced NSCLC have become available, with response rates of 24–60% and median survival durations up to 13 months (Table 6) [2838]. The day 1 and 8 every 21 days gemcitabine–docetaxel schedule in the present study is particularly useful, as it retains dose intensity in most patients without granulocyte colony-stimulating factor support.


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Table 6. Response and survival rates in non-randomized phase II trials of docetaxel–gemcitabine as first-line therapy for advanced (stage IIIB or IV) NSCLC
 
The Greek Oncology Cooperative Group (GOCG) for Lung Cancer recently published the results of a large (n = 441) randomized trial that assessed 21-day cycles of docetaxel 100 mg/m2, day 8, plus gemcitabine 1100 mg/m2, days 1 and 8, versus docetaxel 100 mg/m2 plus cisplatin 80 mg/m2 as first-line chemotherapy for advanced NSCLC [39]. In the platinum-containing arm, docetaxel and cisplatin were given on days 1 and 2, respectively. Overall response rates to docetaxel–gemcitabine and docetaxel–cisplatin therapy were 33.3% and 34.6%, respectively, with median response durations of 7 months in each group. The two regimens were similar with respect to median time to progression (9 and 8 months, respectively), as well as median (9.8 and 10 months, respectively), 1-year (39% and 41%, respectively) and 2-year (8% in both groups) survival. Interestingly, docetaxel–gemcitabine was significantly more active than docetaxel–cisplatin among patients with adenocarcinomas. The response rates in patients with adenocarcinomas were 43.2% and 23.2%, respectively. Conversely, docetaxel–gemcitabine and docetaxel–cisplatin induced responses in 27.6% and 40.4%, respectively, in other types of NSCLC [39]. In the present study, gemcitabine–docetaxel seemed to be more effective in non-adenocarcinoma patients. Clearly, all these analyses must be evaluated with caution, given the minimal amounts of tumor tissue often available for classification. Of note, our histological subanalysis was not prospectively planned, which was also the case for the GOCG histological subanalysis.

Clinical trials studying the combination of irinotecan and gemcitabine for the treatment of advanced NSCLC have been less explored than the docetaxel–gemcitabine combination. Two phase I trials of the combination of gemcitabine and irinotecan in previously treated NSCLC have been reported [40, 41]. Nishio et al. [41] studied the combination with both gemcitabine and irinotecan given on days 1 and 15 every 4 weeks. The maximum tolerated dose was 1000 mg/m2 for gemcitabine and 150 mg/m2 for irinotecan. Diarrhea and neutropenia were the dose-limiting toxicities. A 29% response rate was reported. A multicenter randomized phase II trial from Greece studying single-agent irinotecan or the gemcitabine–irinotecan combination has recently been presented [42]. In this trial, previously treated NSCLC patients received either gemcitabine 1000 mg/m2 on days 1 and 8 and irinotecan 300 mg/m2 on day 8 every 3-week cycle, or single-agent irinotecan 300 mg/m2 once every 3 weeks. Despite a higher response rate of 21% for gemcitabine plus irinotecan versus 5.5% for irinotecan alone, the overall survival was similar in both groups (9 and 8 months, respectively).

The tolerability of the gemcitabine–docetaxel and gemcitabine–irinotecan schedules assessed in our study is noteworthy. The grade 3/4 toxicity profiles of the two regimens were quite comparable, with the exception of a higher incidence of fatigue with gemcitabine–docetaxel and higher incidences of both nausea and vomiting with gemcitabine–irinotecan. In the aforementioned GOGC for Lung Cancer trial, gemcitabine–docetaxel was more attractive than cisplatin–docetaxel from a toxicity standpoint, as it was associated with significantly less grade 3/4 neutropenia, grade 3 nausea/vomiting and grade 3/4 diarrhea [39]. There have been other reports of pulmonary toxicity among patients receiving gemcitabine, docetaxel or the combination of the two agents [35, 36, 4348]. During a phase I trial by Dunsford et al. [44], three of five patients treated with docetaxel 60 mg/m2 day 1 plus gemcitabine 1000 mg/m2 days 1 and 15 for metastatic transitional cell carcinoma developed pulmonary toxicity, evidenced by dyspnea alone (n = 1) or in conjunction with pulmonary infiltrates (n = 2). One of these cases was fatal. Although the investigators were not able to determine whether their findings reflected chance or an actual increased risk of gemcitabine–docetaxel-induced pulmonary toxicity, they recommended careful patient selection, close monitoring, and prompt discontinuation followed by a corticosteroid regimen in patients developing dyspnea or pulmonary infiltrates. More recently, two separate research groups each reported that non-fatal pneumonitis emerged in six patients receiving gemcitabine–docetaxel for advanced NSCLC [overall incidences of 12% (six of 49) and 19% (six of 32)], all 12 of whom responded to corticosteroids [35, 36]. While five of the cases in the Popa et al. [35] trial (which evaluated a regimen that was identical to ours) occurred in patients with a history of chest/mediastinal radiotherapy, no relationship between pneumonitis and prior radiation was evident in our trial or any other study [36].

The role of gemcitabine–docetaxel or gemcitabine and irinotecan in the management of advanced NSCLC cannot be established from our small, randomized phase II trial. Overall, despite accumulating evidence of activity and tolerability, non-platinum regimens are not yet positioned to replace platinum-based therapy in the first-line management of advanced NSCLC [49]. The efficacy results of gemcitabine and irinotecan were disappointing. Other investigators have not reported the same dismal experience with gemcitabine and irinotecan in NSCLC. The gemcitabine and docetaxel combination survival data are of interest. This combination may be particularly useful in patients who have experienced toxicities with a platinum or who may be more susceptible to platinum-related toxicity (e.g. patients with pre-existing renal disease, neurotoxicity or gastrointestinal complications). Further studies of gemcitabine–docetaxel alone and in combination with emerging molecular agents with therapeutic potential for advanced NSCLC should be considered.


    Acknowledgements
 
The research for CALGB 39809 was supported, in part, by grants from the National Cancer Institute (CA31946) to the Cancer and Leukemia Group B (Richard L. Schilsky, MD, Chairman). The contents of this manuscript are solely the responsibility of the authors, and do not necessarily represent the official views of the National Cancer Institute.

The following institutions participated in this study: CALGB Statistical Office, Durham, NC (Stephen George, PhD; supported by CA33601); Cancer Centers of the Carolinas, Greenville, SC (Jeffrey K. Giguere, MD; supported by CA29165); Duke University Medical Center, Durham, NC (Jeffrey Crawford, MD; supported by CA47577); Georgetown University Medical Center, Washington, DC (Edward Gelmann, MD; supported by CA77597); Medical University of South Carolina, Charleston, SC (Mark Green, MD; supported by CA03927); Southern Nevada Cancer Research Foundation CCOP, Las Vegas, NV (John Ellerton, MD; supported by CA35421); SUNY Upstate Medical University, Syracuse, NY (Stephen L. Graziano, MD; supported by CA21060); University of Tennessee Memphis, Memphis, TN (Harvey B. Niell, MD; supported by CA47555); University of California at San Diego, San Diego, CA (Stephen L. Seagren, MD; supported by CA11789); and Washington University School of Medicine, St Louis, MO (Nancy Bartlett, MD; supported by CA77440).


    FOOTNOTES
 
* Correspondence to: Dr C. M. S. Rocha Lima, University of Miami and Sylvester Cancer Center, 1475 NW 12th Avenue, (D8-4), Suite 3310, Miami, FL 33136, USA. Tel: +1-305-243-1086; Fax: +1-305-243-4905; E-mail: crocha{at}med.miami.edu Back


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 Patients and methods
 Results
 Discussion
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