Originally published as JCO Early Release 10.1200/JCO.2006.09.2684 on June 4 2007

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Phase III Study of Capecitabine Plus Oxaliplatin Compared With Fluorouracil and Leucovorin Plus Oxaliplatin in Metastatic Colorectal Cancer: A Final Report of the AIO Colorectal Study Group

Rainer Porschen, Hendrik-Tobias Arkenau, Stephan Kubicka, Richard Greil, Thomas Seufferlein, Werner Freier, Albrecht Kretzschmar, Ullrich Graeven, Axel Grothey, Axel Hinke, Wolff Schmiegel, Hans-Joachim Schmoll

From the Hospital Bremen East; Medical School Hanover; University of Salzburg; University Clinic Ulm; Private Oncology Clinic Hildesheim; Robert-Rössle-Clinic; Helios Clinic; Charité Berlin Buch; Hospital Maria Hilf Moenchengladbach; Research Institute WISP Langenfeld; Ruhr-University Bochum; and Martin-Luther-University Halle, Germany; and the Mayo Clinic Rochester, Rochester, MN

Address reprint requests to Rainer Porschen, MD, PhD, Director, Clinic of Internal Medicine, Hospital Bremen East, Zuericher Stasse 40, D-28325 Bremen, Germany; e-mail: rainer.porschen{at}klinikum-bremen-ost.de

	ABSTRACT

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Purpose To compare the use of capecitabine plus oxaliplatin (CAPOX) with infusional fluorouracil (FU)/folinic acid plus oxaliplatin (FUFOX) as first-line therapy for patients with metastatic colorectal cancer (MCRC).

Patients and Methods A total of 474 patients with MCRC received either CAPOX (capecitabine 1,000 mg/m² bid, days 1 to 14 plus oxaliplatin 70 mg/m² days 1 and 8, repeated every 22 days) ) or FUFOX (oxaliplatin 50 mg/m² followed by leucovorin 500 mg/m² plus FU 2,000 mg/m² as a 22-hour infusion days 1, 8, 15, and 22, repeated every 36 days). The primary end point was progression-free survival (PFS). Secondary end points were response rate (RR), overall survival (OS), time to treatment failure, and toxicity. The study was designed to determine noninferiority for the CAPOX regimen.

Results Median PFS was 7.1 months in the CAPOX arm and 8.0 months in the FUFOX arm (hazard ratio [HR], 1.17; 95% CI, 0.96 to 1.43; P = .117). Median OS was 16.8 months (CAPOX) and 18.8 months (FUFOX; HR, 1.12; 95% CI, 0.92 to 1.38; P = .26). Overall RRs were 48% for CAPOX (95% CI, 41% to 54%) and 54% for FUFOX (95% CI, 47% to 60%). Both regimens were generally well tolerated, although there was a significantly higher incidence of grade 2/3 hand-foot syndrome (HFS) in the CAPOX arm (P = .028).

Conclusion CAPOX resulted in a slightly inferior efficacy than FUFOX. With respect to PFS, the best estimate of the HR of 1.17 was within the prespecified equivalence range. However, a relevant inferiority cannot be excluded. Both regimens were generally well tolerated but there was a significantly higher rate of grade 2/3 HFS in the CAPOX arm.

	INTRODUCTION

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For more than four decades, fluorouracil (FU), and later in combination with folinic acid (FA), has been the mainstay of palliative therapy for metastatic colorectal cancer (MCRC).^1,2 The combination of infusional FU/FA with either oxaliplatin or irinotecan improved efficacy, and both regimens currently are used as standard therapies in chemotherapy-naive patients with MCRC.^3-6

Capecitabine is an oral FU prodrug achieving tumor-selective activation via a triple enzymatic cascade.⁷ Capecitabine has shown comparable efficacy and less toxicity (neutropenic fever/sepsis, GI toxicity, and alopecia) compared with bolus FU/FA (Mayo Clinic) as first-line treatment for patients with MCRC.^8,9 In phase II studies the combination of capecitabine and oxaliplatin (CAPOX) showed promising efficacy with manageable toxicity.^10-12

We therefore performed this phase III study to evaluate the efficacy and toxicity of CAPOX compared with infusional FU/FA plus oxaliplatin (FUFOX).

	PATIENTS AND METHODS

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This phase III trial of the Arbeitsgemeinschaft Internistische Onkologie was performed according to the Helsinki declaration (International Conference on Harmonisation Technical Requirements for the Registration of Pharmaceuticals for Human Use Good Clinical Practice guidelines) and was approved by the ethical committee of the State of Bremen, Germany.

Patients
Eligible criteria were age older than 18 years, Eastern Cooperative Oncology Group performance status (ECOG PS) 2 with life expectancy of more than 3 months, histologically confirmed colorectal cancer, adjuvant/neoadjuvant treatment completed more than 6 months previously, and measurable tumor parameters according to the Response Evaluation Criteria in Solid Tumors.¹³

Main exclusion criteria were prior treatment for MCRC, previous malignancy within 5 years (except for basal cell skin cancer or in situ carcinoma of the cervix), CNS metastasis, heart disease grade New York Heart Association classification III/IV, myocardial infarction within 6 months, renal impairment (creatinine clearance < 30 mL/min), abnormal liver function tests (serum bilirubin > 1.5x upper normal limit, ALT and AST > 2.5x upper normal limit), WBC count < 3,000/µL, or platelets < 100,000/µL. Pregnant or lactating women were also excluded. Women of childbearing potential and sexually active males were required to practice appropriate contraception.

Random Assignment and Stratification
After screening was conducted to establish eligibility, computer-based randomization was performed centrally by fax. Stratification was performed according to ECOG PS (0 to 1 v 2), WBC count (< 8,000 v 8,000/µL), alkaline phosphatase (AP; < 300 v 300 U/L), and number of metastatic sites (one v > one site).

Study Assessments
Prestudy screening included full medical examination, vital signs, CBC, and blood biochemistry tests. Tumor assessments were performed by computed tomography scan or magnetic resonance imaging, x-ray, and ultrasound. During therapy, tumor assessments were repeated after three cycles of CAPOX and two cycles of FUFOX. Response was evaluated according to the Response Evaluation Criteria in Solid Tumors. Follow-up for disease progression and survival monitoring were performed every 3 months after the end of treatment. Toxicity was evaluated according to National Cancer Institute Common Toxicity Criteria, version 2.¹⁴ Oxaliplatin-related peripheral neuropathy was graded on a scale from 1 to 4 according to Wasserman et al.¹⁵ Twenty percent of all patients were monitored thoroughly through an external review committee.

Chemotherapy Schedules
FUFOX consisted of oxaliplatin 50 mg/m² administered as a 2-hour infusion, followed by leucovorin 500 mg/m² administered as a 2-hour infusion, and FU 2,000 mg/m² administered intravenously as a 22-hour infusion on days 1, 8, 15, and 22. CAPOX consisted of capecitabine 1,000 mg/m² administered bid from days 1 to 14 and oxaliplatin 70 mg/m² administered intravenously on days 1 and 8, Table 1. In both arms chemotherapy started within 28 days after random assignment and was administered until progression of disease or severe toxicity.

Statistical Analysis
The study was designed to show noninferiority of the capecitabine-based arm with respect to the primary end point of progression-free survival (PFS), defined as the interval between random assignment and the first recording of disease progression or death. Secondary end points were response rates (RR), overall survival (OS), toxicity, and time to treatment failure (TTF). The efficacy analysis was based on the intent-to-treat population.

The sample size estimation was based on the following model: assuming equal efficacy of both arms, a hypothetical inferiority of CAPOX in median PFS of 2 months or more (7 v 9 months, corresponding to a hazard ratio [HR] of 1.29 or an absolute difference of 9% in the PFS rate after 9 months) had to be excluded with a 95% CI and a power of 80%.

The Kaplan-Meier method has been used to estimate survival curves (PFS/OS), and TTF, defined as the time between random assignment and either premature treatment termination due to toxicity or the patient's request to withdraw. The log-rank test was used to compare the curves.¹⁶ The Cox regression model was applied for HR estimation and for multivariate analysis of prognostic factors for PFS and OS survival, using a backward selection approach.¹⁷ Fisher's exact test and the ² test for trend were used to compare proportions of RR or toxicity grades. All P values presented are two-sided. The cutoff date for the present analysis was the January 31, 2007.

	RESULTS

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Patient Characteristics
From August 2002 to August 2004, 476 patients were randomly assigned at 68 institutions in Germany and one institution in Austria (CAPOX, 242 patients; FUFOX, 234 patients). Two patients were ineligible: one because of double randomization and one because of neuroendocrine tumor histology (Fig 1). Patient and tumor characteristics were well balanced between the arms with respect to stratification factors and baseline characteristics (Table 2). Both arms were dominated by males (CAPOX, 62%; FUFOX, 64%). The median age was 65 years. Adjuvant chemotherapy/radiotherapy was administered to 32%/15% of patients in the CAPOX arm and 29%/13% of patients in the FUFOX arm, respectively. In both arms, the majority of patients had an ECOG PS of 0 to 1. About half of the patients had multiple sites of metastases (CAPOX, 51%; FUFOX, 51%). Surgery of the primary colorectal cancer was performed in 93% of patients (CAPOX, 92%; FUFOX, 95%).

View larger version (35K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Consolidated Standards of Reporting Trials diagram. CAPOX, capecitabine plus oxaliplatin; FUFOX, infusional fluorouracil and folinic acid plus oxaliplatin.

The most common hematologic and nonhematologic toxicities are shown in Appendix Figure A1 (online only). In both arms, grade 3/4 hematologic toxicities were infrequent and manageable. The most frequent nonhematologic grade 3/4 toxicity was neuropathy (27% in the FUFOX arm and 25% in the CAPOX arm). Other grade 3/4 toxicities such as nausea, vomiting, and diarrhea were similar in both arms, whereas grade 2/3 hand-foot syndrome (HFS) occurred more often in the CAPOX arm (10% v 4%; P = .028; Fig 2).

View larger version (17K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Most common grade 3/4 clinical adverse events. CAPOX, capecitabine plus oxaliplatin; FUFOX, infusional fluorouracil and folinic acid plus oxaliplatin. (*) P = .028.

The oxaliplatin dose-intensity (SD) was 94.2% (± 24.8%) in the CAPOX arm and 95% (± 38.3%) in the FUFOX arm. The calculated mean (SD) dose per cycle for FU was 7,127.2 mg (± 1,237.2) and for capecitabine 26,801.5 mg (± 3,232.2).

Reasons for discontinuation of treatment in the CAPOX and FUFOX regimens were as follows: tumor progression (46% v 37%), death as a result of tumor (7% v 5%), death as a result of other causes (2% v 2%), severe adverse events (21% v 24%), patient refusal (8% v 14%), protocol violation (1% v 3%), and other reasons (14% v 14%).

Objective Tumor Responses and PFS
After a median follow-up time of 17.3 months in both arms, 395 patients showed signs of tumor progression. Objective tumor RRs were as follows: CAPOX, 48% (95% CI, 41% to 54%; complete response, 2%; partial response, 46%; stable disease, 28%) and FUFOX, 54% (95% CI, 47% to 60%; complete response, 6%; partial response, 48%; stable disease, 23%; P = .7). Secondary surgery (liver metastasectomy) was performed in four patients in the CAPOX arm and in 10 patients in the FUFOX arm.

Median PFS was 7.6 months (CAPOX, 7.1 months; FUFOX, 8.0 months; HR, 1.17; 95% CI, 0.96 to 1.43; P = .117; Fig 3). The multivariate analysis revealed three independent prognostic factors for impaired PFS: metastatic sites more than one, higher WBC count, and increased AP levels. In the final model, the HR for the treatment effect did not change distinctly.

View larger version (17K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 3. Progression-free survival. CAPOX, capecitabine plus oxaliplatin; FUFOX, infusional fluorouracil and folinic acid plus oxaliplatin.

OS
Currently, 370 deaths of 470 assessable patients have been reported (79%). To date, median OS was 17.3 months (CAPOX, 16.8 months; FUFOX, 18.8 months; HR, 1.12; 95% CI, 0.92 to 1.38; P = .26; Fig 4). Independent prognostic factors for improved OS in the multivariate analysis were age younger than 70 years, PS 0 to 1, WBC less than 8,000/µL, and AP levels less than 300 U/L.

View larger version (18K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 4. Overall survival. CAPOX, capecitabine plus oxaliplatin; FUFOX, infusional fluorouracil and folinic acid plus oxaliplatin.

Second-Line Therapy
In both the CAPOX and FUFOX arms, 66% of patients received second-line treatment. Most of the patients received irinotecan-based chemotherapy in the second-line treatment (81% in both CAPOX and FUFOX arms). Additional treatments included reintroduction with oxaliplatin (CAPOX, 13%; FUFOX, 21%), cetuximab (CAPOX, 22%; FUFOX, 21%), or mitomycin (CAPOX, 9%; FUFOX, 9%). On subsequent treatment lines, patients in the CAPOX arm changed to FU (43%) and 29% continued with capecitabine. In the FUFOX arm, 56% continued with FU and 30% received capecitabine. In total, 56% patients of the entire study population received all three drugs: fluoropyrimidine, oxaliplatin, and irinotecan (CAPOX, 57%; FUFOX, 55%).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
We performed this phase III study to evaluate the efficacy and toxicity of CAPOX compared with FUFOX. Both regimens were chosen based on the experience of two German Arbeitsgemeinschaft Internistische Onkologie studies in patients with MCRC. A phase III study showed that the weekly FUFOX regimen was superior to bolus FU/FA, and a phase II trial demonstrated high activity of CAPOX.^10,18

The toxicity analysis demonstrated that both regimens had comparable safety profiles with manageable adverse effects. The main nonhematologic grade 3/4 toxicity was neuropathy, followed by GI adverse effects, such as diarrhea, nausea, and vomiting. The main grade 3/4 hematologic toxicity was neutropenia, accounting for 7% of all patients in both arms. Only HFS grade 2/3 was significantly higher in the CAPOX arm (P = .028). These results were in accordance with other studies.

The Spanish Cooperative Group for the Treatment of Digestive Tumors (TTD) trial compared the capecitabine and oxaliplatin (XELOX) regimen with the TTD schedule in patients with newly diagnosed MCRC.¹⁹ In this trial paresthesia was most prominent, followed by GI adverse effects such as diarrhea; similar to our trial, HFS was significantly higher in the XELOX arm. Two additional trials compared XELOX with either infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX) 4 or FOLFOX6 resulting in a similar toxicity profile as our study, although patients less often experienced grade 3/4 neurotoxicity, whereas neutropenia was more frequent^20,21 (Table 3).

Comparing our results with other studies was helpful, and indeed there were signs that capecitabine plus oxaliplatin was less effective compared with infusional FU/leucovorin/oxaliplatin.

The phase II trial, TREE-1, randomly assigned 147 patients comparing three different fluoropyrimidine/oxaliplatin-based regimens. In this trial, the RR, TTF, and PFS for CAPOX were inferior to modified FOLFOX (29% v 39%; 4.4 v 6.4 months; and 5.9 v 8.7 months, respectively).²²

Furthermore, a difference of 4.7% in RR in favor for FOLFOX6 compared with XELOX has been observed in another study. The primary end point of this study including 306 patients was best response rate of the population treated per protocol, as assessed by an independent review committee. The upper limit of the 95% CI was 14.4% and was just below the noninferiority margin of 15%. For the intent-to-treat population, the upper limit of the 95% CI was 16.2%, and was above the noninferiority margin.²³

More strikingly, the results of the Spanish TTD group were nearly identical to our results with respect to the primary end point. Although not statistically significant, there was a trend of noninferiority for their primary end point, time to tumor progression (FUOX, 9.5 months v XELOX, 8.9 months; P = .154). Similar to our analysis, the HR of 1.18 was within the predefined range (upper margin for noninferiority, 1.27) but the CI clearly breached the HR of 1.27 (95% CI, 0.9 to 1.5).¹⁹

In contrast to the above results were the data of an international study investigating the role of XELOX ± bevacizumab versus FOLFOX ± bevacizumab. This trial started as a two-arm study comparing XELOX versus FOLFOX4 (634 patients) and was amended to a 2 x 2 study by adding placebo or the monoclonal antibody bevacizumab (1,401 patients). This study met its primary end point, PFS, demonstrating noninferiority for the XELOX regimen. The addition of bevacizumab to XELOX resulted in a significant increase in PFS compared with XELOX alone, whereas the addition of bevacizumab to FOLFOX4 did not show a benefit.²⁰

Nearly 70% of our patients received a second-line therapy. Most patients received an irinotecan-based chemotherapy (81% CAPOX v 82% FUFOX). Similar numbers of treatment lines and drugs such as cetuximab and mitomycin were administered, demonstrating that patients in both arms received comparable and state-of-the-art treatments. In total, 56% patients of our population received all three drugs: fluoropyrimidine, oxaliplatin, and irinotecan. According to a survival model developed by Grothey et al,^24,25 our patients followed closely the median OS curve calculated for this model. This model showed a longer OS for patients receiving three drugs (fluoropyrimidine, oxaliplatin, and irinotecan) compared with patients with only one or two drugs.

In our study patients were stratified according to a prognostic score, including ECOG PS, AP, sites of metastasis, and WBC count.²⁶ The results showed that nearly all markers (AP > 300 U/L, > one site of metastasis, and WBC > 8,000 µ/L) were significant negative prognostic factors for PFS, except ECOG PS more than 2 (probably due to the small number of patients in this group). These factors could be used to stratify groups in additional clinical trials using oxaliplatin-based regimens.

In this study the combination of capecitabine plus oxaliplatin resulted in slightly inferior efficacy compared with FUFOX. With respect to PFS, the best estimate of the HR of 1.17 was within the prespecified equivalence range. However, a relevant inferiority cannot be excluded by the upper margin of the CI. Both regimens were generally well tolerated but there was a significantly higher rate of grade 2/3 HFS in the CAPOX arm.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment: N/A Consultant: N/A Stock: N/A Honoraria: Rainer Porschen, Roche; Stefan Kubicka, Roche; Albrecht Kretzschmar, Roche; Ullrich Graeven, Roche, Sanofi-aventis; Axel Grothey, Roche, Sanofi-aventis; Hans-Joachim Schmoll, Roche, Sanofi-aventis Research Funds: Rainer Porschen, Roche, Sanofi-Aventis Testimony: N/A Other: Rainer Porschen, Roche

	AUTHOR CONTRIBUTIONS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Conception and design: Rainer Porschen, Hendrik-Tobias Arkenau, Ullrich Graeven, Axel Grothey, Axel Hinke, Wolff Schmiegel, Hans-Joachim Schmoll

Administrative support: Rainer Porschen, Hendrik-Tobias Arkenau, Axel Hinke

Provision of study materials or patients: Rainer Porschen, Hendrik-Tobias Arkenau, Stefan Kubicka, Richard Greil, Thomas Seufferlein, Werner Freier, Albrecht Kretzschmar, Ullrich Graeven, Wolff Schmiegel, Hans-Joachim Schmoll

Collection and assembly of data: Rainer Porschen, Hendrik-Tobias Arkenau

Data analysis and interpretation: Rainer Porschen, Hendrik-Tobias Arkenau, Axel Hinke, Hans-Joachim Schmoll

Manuscript writing: Rainer Porschen, Hendrik-Tobias Arkenau, Axel Hinke, Hans-Joachim Schmoll

Final approval of manuscript: Rainer Porschen, Hendrik-Tobias Arkenau, Stefan Kubicka, Thomas Seufferlein, Werner Freier, Albrecht Kretzschmar, Ullrich Graeven, Axel Grothey, Axel Hinke, Wolff Schmiegel, Hans-Joachim Schmoll

	Appendix

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The following investigators participated in the study: Aachen (Tummes); Ansbach (Hahn); Aschersleben (Deist); Augsburg (Heinrich); Aurich (Langer); Bad Homburg (Rohwedder); Bad Soden (Seipelt); Berlin (Zuchold, Reichardt, Kretzschmar); Bietigheim-Bissingen (Dietrich); Bochum (Andre, Ansorge, Behringer, Schmiegel); Bonn (Fronshoff, Ko); Bremen (Arkenau, Doering, Porschen); Bremerhaven (Ahlf); Dernbach (Hoffknecht); Dortmund (Hagen); Duisburg (Selbach, Petrasch); Eschweiler (Fuchs); Flensburg (Hartwigsen); Frankfurt (Trojan); Geilenkirchen (Schardt, Zeidler); Goch (Runde); Göttingen (Hilden); Greven (Nischik); Grevenbroich (Prangischvili); Hagen (Lindemann, Zinngrebe); Halle (Arnold, Behrens, Steudel, Schmoll); Hamburg (Lipp); Hannover (Kubicka, Greten); Hildesheim (Freier); Homburg (Lubomierski); Jena (Eigendorff); Karlsruhe (Ebenezer); Koblenz (Hermesdorf); Kronach (Stauch); Leer (Köchling); Leipzig (Abelius); Lemgo (Constantin); Lüneburg (Heinkele); Magdeburg (Kröning); Mainz (Höhler, Möhler); Marburg (Balser); Mönchengladbach (Koch, Graeven); Münster (Bremer, Wehmeyer); Nordhausen (Keppler, Parchim, Hesse); Recklinghausen (Heer); Riedlingen (Pernice); Rinteln (Krause); Rotenburg (Schlichting); Rüsselsheim (Fried-Proell); Saarbrücken (Jacobs, Preiβ); Salzburg (Greil, Hausmaninger); Salzwedel (Roth); Siegen (Gaska); Stuttgart (Hiller); Troisdorf (Forstbauer); Ulm (Seufferlein, Hahn, Adler); Unna (Steinmeister); Vechta (Diers); Velbert (Nusch); Weiden (Weiβ); Weiβenfels (Bornschein); Werningerode (Wilhelm); Wuppertal (Papavasiliou).

View larger version (21K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig A1. Most common clinical adverse events (all grades). CAPOX, capecitabine plus oxaliplatin; FUFOX, infusional fluorouracil and folinic acid plus oxaliplatin.

View larger version (16K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig A2. Time to treatment failure. CAPOX, capecitabine plus oxaliplatin; FUFOX, infusional fluorouracil and folinic acid plus oxaliplatin.

	ACKNOWLEDGMENTS

 
We thank Birgit Petershagen, Sascha Neugebauer, and Christina Englisch-Fritz, MD, for collecting and analyzing the data. We are indebted to all of the surgeons, oncologists, gastroenterologists, and research support staff in the participating centers listed in the Appendix.

	NOTES

 
published online ahead of print at www.jco.org on June 4, 2007.

Supported by research grants received from Hoffmann-La Roche, Germany, and Sanofi-aventis, Germany.

Presented in part at the 41st Annual Meeting of the American Society of Clinical Oncology, May 13-17, 2005, Orlando, FL, and the Gastrointestinal Cancer Meeting of the American Society of Clinical Oncology, January 26-28, 2006, San Francisco, CA.

R.P. and H.T.A. contributed equally to this study.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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Submitted November 7, 2006; accepted March 21, 2007.

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