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Multicenter Phase II Trial of Chemoradiation With Oxaliplatin for Rectal Cancer

Claus Rödel, Torsten Liersch, Robert Michael Hermann, Dirk Arnold, Thomas Reese, Matthias Hipp, Alois Fürst, Nimrod Schwella, Michael Bieker, Gunter Hellmich, Hermann Ewald, Jörg Haier, Florian Lordick, Michael Flentje, Heiko Sülberg, Werner Hohenberger, Rolf Sauer

From the Departments of Radiation Therapy and Surgery, University of Erlangen-Nürnberg, Erlangen; Departments of General Surgery and Radiation Oncology and Radiotherapy, University of Göttingen, Göttingen; Departments of Haematology and Oncology and Radiotherapy, Martin Luther University Halle-Wittenberg, Halle-Wittenberg; Department of Radiotherapy, University of Regensburg; Department of Surgery, Caritas-Hospital St Josef, Regensburg; Departments of Haematology, Oncology, and Immunology and Radiotherapy, Philipps-University Hospital, Marburg; Department of General and Abdominal Surgery, Dresden-Friedrichstadt Hospital, and Teaching Hospital of Technical University Dresden, Dresden; Department of General Surgery and Thoracic Surgery, University Hospital of Schleswig-Holstein, Kiel; Department of General Surgery, University Hospital Münster, Münster; Third Department of Internal Medicine (Hematology/Medical Oncology), Klinikum Rechts der Isar, Technical University of Munich, Munich; Department of Radiation Oncology, University of Würzburg, Würzburg; and WiSP Research Institute, Langenfeld, Germany

Address reprint requests to Claus Rödel, MD, Department of Radiotherapy, University of Erlangen, Universitätsstr 27, 91054 Erlangen, Germany; e-mail: claus.roedel{at}strahlen.med.uni-erlangen.de

	ABSTRACT

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Purpose To evaluate the activity and safety of preoperative radiotherapy (RT) and concurrent capecitabine and oxaliplatin (XELOX-RT) plus four cycles of adjuvant XELOX in patients with rectal cancer.

Patients and Methods One hundred ten patients with T3/T4 or N+ rectal cancer were entered onto the trial in 11 investigator sites and received preoperative RT (50.4 Gy in 28 fractions). Capecitabine was administered concurrently at 1,650 mg/m² on days 1 to 14 and 22 to 35, and oxaliplatin was administered at 50 mg/m² on days 1, 8, 22, and 29. Surgery was scheduled 4 to 6 weeks after completion of XELOX-RT. Four cycles of adjuvant XELOX (capecitabine 1,000 mg/m² bid on days 1 to 14; oxaliplatin 130 mg/m² on day 1) were administered. The main end points were activity as assessed by the pathologic complete response (pCR) rate and the feasibility of postoperative XELOX chemotherapy.

Results After XELOX-RT, 103 of 104 eligible patients underwent surgery; pCR was achieved in 17 patients (16%), one patient had ypT0N1 disease, and 53 patients showed tumor regression of more than 50% of the tumor mass. R0 resections were achieved in 95% of patients, and sphincter preservation was accomplished in 77%. Full-dose preoperative XELOX-RT was administered in 96%. Grade 3 or 4 diarrhea occurred in 12% of patients. Postoperative complication occurred in 43% of patients. Sixty percent of patients received all four cycles of adjuvant XELOX, with sensory neuropathy (18%) and diarrhea (12%) being the main grade 3 or 4 toxicities.

Conclusion Preoperative XELOX-RT plus four cycles of adjuvant XELOX is an active and feasible treatment. This regimen is proposed for phase III evaluation comparing standard fluorouracil-based treatment with XELOX- based multimodality treatment.

	INTRODUCTION

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Fluorouracil (FU) -based chemoradiotherapy (CRT) improved survival for locally advanced rectal cancer when used in the postoperative setting.^1,2 A phase III trial of our group demonstrated that preoperative FU CRT plus four cycles of postoperative FU chemotherapy is superior to standard postoperative treatment in terms of local control and acute and long-term toxicity.³ Two recent phase III trials from the European Organisation for Research and Treatment of Cancer (EORTC), EORTC 22921, and the Fédération Francophone de Cancérologie Digestive (FFCD), FFCD 9293, have confirmed the advantages of preoperative FU CRT over radiotherapy (RT) alone with respect to local control rates, but in none of these phase III trials was survival significantly improved.^4,5 Thus, with optimized local treatment, including preoperative FU CRT and total mesorectal excision, local relapse rates have now been reduced to 5% to 10%; however, distant metastases still occur in 25% to 30% of patients. Evidently, any further improvement will require the integration of more effective systemic therapy into the multimodality concept.

Although attempts to improve the efficacy of FU-based CRT by incorporation of semustine or FU modulation through folinic acid or levamisole have failed to demonstrate any significant benefit, continuous infusion of FU during RT has been shown to be superior to bolus FU regarding disease-free and overall survival.^6-8 Capecitabine is an oral fluoropyrimidine that imitates the pharmacokinetics of continuous FU infusion and is preferentially converted to the active metabolite within tumor cells by exploiting the higher activity of the enzyme thymidine phosphorylase in tumor tissue compared with normal tissue.⁹ This tumor-selective activation of capecitabine is improved further when combined with RT, which upregulates thymidine phosphorylase in tumor cells but not in healthy tissue.¹⁰ Oxaliplatin, one of the most active single agents in the treatment of colorectal cancer, is also a reasonable candidate for combined-modality programs because of its relative lack of acute dose-limiting adverse effects when added to RT and FU/capecitabine. Recent preclinical studies have demonstrated oxaliplatin to be a potent radiosensitizing agent.^11,12 Moreover, results from two recent studies have shown that the addition of oxaliplatin to FU/leucovorin improves disease-free survival of patients with stage II and III colon cancer.^13,14

The aim of this multicenter phase II trial was to confirm the activity and safety of our recently published single-center neoadjuvant capecitabine and oxaliplatin (XELOX) -RT protocol in a multi-institutional setting with 110 patients included at 11 investigator sites.¹⁵ Moreover, because the cumulative doses of these drugs applied during preoperative CRT are substantially lower than in adjuvant colon cancer trials, the safety and feasibility of four additional adjuvant cycles of XELOX were tested. The overall aim was to establish a regimen of preoperative XELOX-RT followed by surgery plus adjuvant chemotherapy with XELOX that could be proposed for phase III evaluation versus standard FU CRT plus adjuvant FU.

	PATIENTS AND METHODS

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This study was approved by the ethics committee of the University of Erlangen (Nr. 3085) and by all local review boards of the participating institutions. Each patient gave written informed consent before being accrued.

Eligibility Criteria
Eligibility criteria included histopathologically confirmed rectal adenocarcinoma with the inferior margin within 16 cm from anal verge as assessed by rigid rectoscopy. The tumor had to have evidence of T3 or T4 disease and/or positive perirectal lymph nodes by endorectal ultrasound, multisclice computed tomography (CT), or magnetic resonance imaging of the pelvis. Further inclusion criteria were Eastern Cooperative Oncology Group performance status 2 and adequate hematologic, liver, and renal function (neutrophils 1.5 x 10⁹/L, platelet count 100 x 10⁹/L, creatinine clearance > 50 mL/min, total bilirubin concentration < 2x the upper normal limit, and liver transaminase or alkaline phosphatase concentrations < 3x the upper normal limit). Patients were excluded for metastatic disease, prior RT to the pelvic region or previous chemotherapy, and other cancers. Patients suffering from the following conditions were also ineligible: inflammatory bowel disease, malabsorption syndrome, previous history of cardiac arrhythmia or coronary heart disease, peripheral neuropathy, and psychiatric disorders or psychological disabilities thought to adversely affect treatment compliance. Pregnant or lactating patients and women with childbearing potential who lacked effective contraception were excluded. No upper age limit was defined.

Pretreatment Evaluation
Pretreatment evaluation included a complete history and physical examination, biopsy, digital rectal examination, rigid rectoscopy, colonoscopy, endorectal ultrasound, CT or magnetic resonance imaging of the pelvis, abdominal CT, and chest x-ray. Complete laboratory tests included a full blood count, blood electrolytes, creatinine, urea, liver transaminases, alkaline phosphatase, and total bilirubin. Cardiac function was investigated both by an ECG and an echocardiogram.

Treatment
Neoadjuvant CRT (XELOX-RT). RT was delivered with x-ray by a linear accelerator with minimum of 6 MV through a three- or four-field box technique to the primary tumor and mesorectal, presacral, and internal iliac lymph nodes up to the level of the bottom of the fifth lumbar vertebra. Irradiation techniques and treatment volumes have been described in detail elsewhere.¹⁵ All patients received a total dose of 50.4 Gy, with daily fractions of 1.8 Gy on 5 days per week. During preoperative treatment, capecitabine was delivered orally at a fixed dose of 825 mg/m² twice daily on days 1 to 14 and 22 to 35 of RT. The first daily dose was administered approximately 2 hours before RT, with the second dose administered 12 hours later. Oxaliplatin was administered as a 2-hour infusion on days 1, 8, 22, and 29 at a dose of 50 mg/m²/d, as previously established in our single-center phase I/II study.¹⁵

Patients were monitored weekly regarding history, clinical examination, blood count, and biochemistry including liver function. We did not modify the RT schedule for grade 2 toxicities unless the severity worsened. The doses of capecitabine and oxaliplatin were adjusted for adverse events according to a standard scheme, which is described in detail by Rödel et al.¹⁵

Adjuvant chemotherapy (XELOX). Four to 6 weeks after surgery, patients received another 12 weeks of capecitabine at a dose of 2,000 mg/m²/d for 14 days, every 21 days. Oxaliplatin was administered on day 1 of each of four cycles at a dose of 130 mg/m²/d. The indication to apply postoperative chemotherapy was based on pretreatment staging results (ie, patients with downstaging to International Union Against Cancer [UICC] stage 0 or I after preoperative CRT were also eligible for postoperative chemotherapy). The following recommendations for chemotherapy dose reductions were applied: in case of grade 2 toxicity according to National Cancer Institute Common Toxicity Criteria,¹⁶ capecitabine was interrupted, and appropriate symptomatic treatment was administered. When the toxicity resolved to grade 0 or 1, treatment was continued at 75% of the original dose in case of the first appearance of the respective toxicity and at 50% of the starting dose in case of the second appearance. The dose of oxaliplatin was reduced for grade 3 vomiting, grade 3 or 4 thrombocytopenia or neutropenia, and for paresthesia with pain or functional impairment of more than 7 days in duration. For paresthesia with functional impairment persistent between cycles, oxaliplatin was discontinued.

Surgery and Pathology
Four to 6 weeks after completion of XELOX-RT, total mesorectal excision was performed according to a standardized technique. Assessment of the intended surgical procedure (ie, whether sphincter preservation was deemed possible or not) was performed by the treating surgeon before start of treatment. If adjacent organs were involved intraoperatively, surgery was extended to partial or total resection of adjacent pelvic organs.

The extent of residual tumor in the resected specimen was classified according to the TNM staging system of the American Joint Committee on Cancer (AJCC)/UICC, using the prescript "y" to indicate that the tumor has been treated before surgical resection.¹⁷ Residual tumor mass, fibrotic changes, and irradiation vasculopathy after preoperative XELOX-RT were semiquantitatively evaluated according to a 5-point rectal cancer regression grading established by Dworak et al¹⁸ and evaluated for its prognostic impact by our group previously.¹⁹ A pathologic complete response (pCR) was defined as the absence of viable tumor cells in the primary tumor and in the lymph nodes (ypT0N0).

Study Design
The primary end point of this phase II study was the pCR rate after neoadjuvant XELOX-RT. Current standard preoperative FU CRT yields pCR rates in the range of 5% to 10%.^3-5 Using a single-stage design according to Fleming,²⁰ a pCR rate of 15% was considered to qualify the experimental treatment for further testing. A pCR rate of 7.5% was ruled out as futile. With a sample size of 96 patients, the risk of erroneously claiming sufficient activity despite a true pCR rate of 7.5% (type I error) amounted to 5%, with a type II error probability of mistakenly rejecting XELOX-RT in case of truly promising activity set to 20%, corresponding to a power of 80%. The planned patient number was increased to 110 to allow for drop-outs. Secondary end points included toxicity and compliance with the regimen, R0 resection rates, rates of sphincter-sparing surgery, tumor regression grades, pathologic downstaging, and 1-month surgical complications.

	RESULTS

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A total of 110 patients were enrolled between April 2004 and March 2005. Figure 1 shows the progress of all patients during the trial. Six patients were ineligible; Table 1 lists the baseline characteristics of the remaining 104 patients.

View larger version (33K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Trial progress. CRT, chemoradiotherapy.

Compliance With the Regimen and Toxicity
Neoadjuvant CRT. RT was applied as prescribed in 95 (91%) of 104 patients. Unplanned treatment interruptions of more than 2 days as a result of toxicity occurred in five patients (5%; all completed full-dose RT). In four patients (4%), RT was discontinued as a result of diarrhea (n = 2), ileus (n = 1), and genitourinary toxicity (n = 1) after 19.8, 34.2, and 41.4 Gy (2x), respectively. The mean relative dose-intensity of both capecitabine and oxaliplatin during neoadjuvant CRT was 100% and 95% to 96% for the first and second cycles, respectively (Fig 2).

View larger version (19K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Mean relative dose-intensities of capecitabine (Cape) and oxaliplatin (Ox) during neoadjuvant chemoradiotherapy (CRT) and four cycles of adjuvant chemotherapy. The circles (Cape) and triangles (Ox) plot the dose-intensity relative to the prescribed dose for every individual patient. The bars represent the mean relative dose-intensity for all patients. (*) One patient died before surgery, and two patients with no information after surgery were excluded; 28 patients not receiving adjuvant chemotherapy (see Fig 1) were plotted at 0%.

Adjuvant chemotherapy. Of the 103 resected patients, 73 (71%) commenced adjuvant chemotherapy after a median interval of 5.3 weeks (range, 3.1 to 19.1 weeks), and 28 patients (27%) did not receive any postoperative chemotherapy, mainly because of postoperative complications (n = 14, 50%) or patient refusal (n = 6, 21%; Fig 1). A total of 61 patients (60%) received all four adjuvant chemotherapy cycles. The protocol-specified duration of four cycles (14 days of treatment, 7 days of rest) was 84 days; the median and mean (± standard deviation) duration for the 61 patients who completed all four cycles was 84 days and 86 days (± 7.5 days), respectively. Sixty-five patients (64%) received at least three cycles, and 68 patients (67%) received at least two cycles (with or without dose reduction). With appropriate dose reduction as a result of treatment-induced toxicity and including the 28 patients with complete omission of adjuvant chemotherapy, the mean relative dose-intensity of capecitabine and oxaliplatin, as calculated for the entire cohort of 101 patients (two patients with no information were excluded), decreased to 53% and 52% in the last cycle, respectively (Fig 2). If expressed by the number of patients who received at least 75% of the prescribed cumulative doses of chemotherapy, the relative dose-intensities were 50% (51 of 101 patients) for capecitabine and 53% (54 of 101 patients) for oxaliplatin.

Toxicity. Table 4 lists the incidence of acute toxicity during neoadjuvant CRT and adjuvant chemotherapy. Two deaths occurred; one death occurred shortly after completion of preoperative CRT as a result of septicemia and tumor progression in a female patient with a large tumor extending to the bladder and uterus, and the other death occurred in a male patient who died from cardiac arrest after the first adjuvant chemotherapy cycle with no prior signs or symptoms of cardiac toxicity. Diarrhea was the most common severe toxicity during neoadjuvant CRT, with 12 patients (12%) suffering from grade 3 or 4 diarrhea. In the adjuvant setting, grade 3 sensory neuropathy (18%) and diarrhea (12%) were the predominant grade 3 or 4 toxicities.

	DISCUSSION

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The following three different schedules for incorporating XELOX into preoperative CRT have been published so far (Table 5): (1) synchronous oxaliplatin, capecitabine, RT, and elective surgery (SOCRATES)^21,22; (2) RT, oxaliplatin, and capecitabine (RadiOxCape)²³ and capecitabine, oxaliplatin, RT, and excision (CORE)²⁴; and (3) our XELOX-RT regimen. The cumulative doses of capecitabine, oxaliplatin, and RT with these three different regimens were as follows: (1) 42,900 mg/m², 260 mg/m², and 45 Gy; (2) 41,250 mg/m², 250 mg/m², and 45 Gy, and (3) 46,200 mg/m², 200 mg/m², and 50.4 Gy, respectively. All three XELOX-RT schedules seem to be equally active and tolerable and may now be tested in larger phase III trials.

The most important results of this second part of our study are that 60% of the entire cohort of 103 operated patients completed all four XELOX cycles (with or without dose reduction), that 50% and 53% of patients received at least 75% of the prescribed doses of capecitabine and oxaliplatin, respectively, and that 27% of patients, for different reasons, did not receive any adjuvant chemotherapy. The CORE study reported similar figures with 30 (35%) of 85 patients not receiving any adjuvant XELOX and with a further 12 (14%) of 85 patients who stopped adjuvant chemotherapy prematurely.²⁴ It is evident that preoperative CRT, surgical complications, and the fact that a substantial part of patients will have pCR or yUICC stage I and II tumors as a result of downstaging effects or initial clinical staging error compromise the possibility and willingness of patients to tolerate postoperative chemotherapy. However, this is true not only for patients treated with more active protocols, such as XELOX-RT, but also for patients treated with standard FU CRT. In three recent, large, phase III trials of preoperative FU CRT plus postoperative FU chemotherapy (EORTC 22921, FFCD 9293, and our German trial), a total of 25%, 23%, and 20% of patients, respectively, did not start postoperative chemotherapy.^3-5

Currently, there are three different approaches to address this problem in the management of rectal cancer. The first one is to completely omit postoperative chemotherapy or leave the decision to apply adjuvant chemotherapy to the individual physician or participating center, as was done in most phase II trials of preoperative CRT with new drugs, but also in phase III studies that primarily address local end points (National Surgical Adjuvant Breast and Bowel Project R-04 in the United States and Actions Concertées dans les Cancers Colorectaux et Digestifs 12/0405 in France). The second approach is to apply neoadjuvant chemotherapy before preoperative CRT rather than adjuvant chemotherapy.^25-27 This strategy avoids the problems of postoperative chemotherapy but is associated with its own caveats, such as selection of radioresistant clones, possibly reduced compliance to CRT, and substantial delay of definitive surgery.²⁸ The third approach is the one currently adopted by most groups (E5204 Intergroup Trial in the United States and Pan-European Trials in Adjuvant Colon Cancer 6 in Europe) that have designed phase III comparisons of standard FU versus more intense CRT protocols. These trials stick to the concept of preoperative CRT plus adjuvant chemotherapy and simply accept that a certain percentage of patients will not receive protocol-conformal postoperative chemotherapy. A fourth approach, which has not yet been tested in prospective phase III clinical studies, would be to tailor postoperative treatment according to risk factors or response parameters, such as tumor regression, circumferential resection margin invasion, and, probably most important, nodal status (ypN0 v ypN1/2).^19,29,30

	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 Leadership: N/A Consultant: Dirk Arnold, Hoffmann-La Roche AG, Sanofi-Aventis; Florian Lordick, Hoffmann- La Roche AG, Sanofi-Aventis GmbH; Michael Flentje, Sanofi-Aventis GmbH Stock: N/A Honoraria: Claus Rödel, Hoffmann-La Roche AG, Sanofi-Aventis GmbH; Florian Lordick, Hoffmann-La Roche AG, Sanofi-Aventis GmbH Research Funds: Claus Rödel, Hoffmann- La Roche AG, Sanofi-Aventis GmbH; Florian Lordick, Sanofi-Aventis GmbH Testimony: N/A Other: N/A

	AUTHOR CONTRIBUTIONS

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Conception and design: Claus Rödel, Torsten Liersch, Dirk Arnold, Michael Flentje, Heiko Sülberg, Werner Hohenberger, Rolf Sauer

Administrative support: Claus Rödel, Gunter Hellmich

Provision of study materials or patients: Claus Rödel, Torsten Liersch, Robert Michael Hermann, Dirk Arnold, Thomas Reese, Matthias Hipp, Alois Fürst, Nimrod Schwella, Michael Bieker, Gunter Hellmich, Hermann Ewald, Jörg Haier, Florian Lordick, Michael Flentje, Werner Hohenberger, Rolf Sauer

Collection and assembly of data: Claus Rödel, Torsten Liersch, Robert Michael Hermann, Dirk Arnold, Thomas Reese, Matthias Hipp, Alois Fürst, Nimrod Schwella, Michael Bieker, Gunter Hellmich, Hermann Ewald, Jörg Haier, Florian Lordick, Michael Flentje, Heiko Sülberg, Werner Hohenberger, Rolf Sauer

Data analysis and interpretation: Claus Rödel, Torsten Liersch, Robert Michael Hermann, Dirk Arnold, Thomas Reese, Matthias Hipp, Alois Fürst, Nimrod Schwella, Michael Bieker, Gunter Hellmich, Hermann Ewald, Jörg Haier, Florian Lordick, Michael Flentje, Heiko Sülberg, Werner Hohenberger, Rolf Sauer

Manuscript writing: Claus Rödel, Torsten Liersch, Robert Michael Hermann, Dirk Arnold, Thomas Reese, Matthias Hipp, Alois Fürst, Nimrod Schwella, Michael Bieker, Gunter Hellmich, Hermann Ewald, Jörg Haier, Florian Lordick, Michael Flentje, Heiko Sülberg, Werner Hohenberger, Rolf Sauer

Final approval of manuscript: Claus Rödel, Torsten Liersch, Robert Michael Hermann, Dirk Arnold, Thomas Reese, Matthias Hipp, Alois Fürst, Nimrod Schwella, Michael Bieker, Gunter Hellmich, Hermann Ewald, Jörg Haier, Florian Lordick, Michael Flentje, Heiko Sülberg, Werner Hohenberger, Rolf Sauer

	Appendix

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Other members of the German Rectal Cancer Study Group who participated in this study are as follows: B. Bittorf, T. Papadopoulos, V. Schellerer (Universitätsklinikum Erlangen); K. Becker, H. Höfler, M. Molls, J.-R. Nährig, J. Nekarda, R. Rosenberg, J.-R. Siewert, F. Zimmermann (Klinikum rechts der Isar der TU München); D. Bartsch, R. Engenhart-Cabillic, B. Gerdes, R. Moll, A. Neubauer, M. Rothmund, P. Vacha (Klinikum der Philipps-Universität Marburg); H. Becker, L. Füzesi, B. Gunawan, C.F. Hess, C. Heuermann, H. Rothe, H. Schmidberger (Universitätsklinikum Göttingen); N. Christen, G. Haroske, B. von Nessen, S. Petersen, J. Schorcht, A. Schuster, E. Zschuppe (Städt. Klinikum Dresden-Friedrichstadt); H. Dralle, J. Dunst, S. Hauptmann, U. Krause, H.J. Schmoll, T. Sutter (Martin-Luther-Universität Halle-Wittenberg); B. Feyerabend, B. Kimmig, G. Klöppel, B. Kremer, B. Sipos, A. Solterbeck, U. Solterbeck, J. Tepel (Universitätsklinikum Schleswig-Holstein, Campus Kiel); G. Beckmann, H. Lührs, D. Meyer, P. Reimer, M. Sailer, W. Scheppach, A. Thiede (Universitätsklinikum Würzburg); W. Böcker, P. Gassmann, N. Senninger, N. Willich (Westfälische Wilhelms-Universität Münster); A. Agha, F. Bataille, A. Hartmann, F. Hofstädter, I. Ieselnieks, O. Kölbl, C. Schäfer (Universitätsklinikum Regensburg).

	NOTES

 
Supported by a grant from Hoffmann- La Roche AG, Grenzach-Wyhlen, Germany, and Sanofi-Aventis Pharma GmbH, Berlin, Germany.

Presented in part at the 2006 Gastrointestinal Cancers Symposium, January 26-28, 2006, San Francisco, CA.

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

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Submitted July 25, 2006; accepted October 5, 2006.

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