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Gemcitabine Plus Capecitabine Compared With Gemcitabine Alone in Advanced Pancreatic Cancer: A Randomized, Multicenter, Phase III Trial of the Swiss Group for Clinical Cancer Research and the Central European Cooperative Oncology Group

Richard Herrmann, György Bodoky, Thomas Ruhstaller, Bengt Glimelius, Emilio Bajetta, Johannes Schüller, Piercarlo Saletti, Jean Bauer, Arie Figer, Bernhard Pestalozzi, Claus-Henning Köhne, Walter Mingrone, Salomon M. Stemmer, Karin Tàmas, Gabriela V. Kornek, Dieter Koeberle, Susanne Cina, Jürg Bernhard, Daniel Dietrich, Werner Scheithauer

From the University Hospital, Basel; Kantonsspital, St Gallen; Ospedale Regionale, Lugano; Centre Hospitalier Universitaire Vaudoise, Lausanne; Universitätsspital, Zurich; Kantonsspital, Aarau; Swiss Group for Clinical Cancer Research Coordinating Center, Bern, Switzerland; Szt László Hospital, Budapest, Hungary; University of Uppsala, Uppsala, Sweden; Istituto Nazionale per lo studio e la Cura dei Tumori, Milan, Italy; Krankenanstalt Rudolfstiftung, Wien; University of Vienna Medical School, Vienna, Austria; Sourasky Medical Center, Tel Aviv; Rabin Medical Center, Petach Tikva, Israel; and the Universitätsklinikum, Dresden, Germany

Address reprint requests to Richard Herrmann, MD, Division of Oncology, Department of Internal Medicine, University Hospital of Basel, Petersgraben 4, CH-4031 Basel, Switzerland; e-mail: herrmannr{at}uhbs.ch

	ABSTRACT

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

 
Purpose This phase III trial compared the efficacy and safety of gemcitabine (Gem) plus capecitabine (GemCap) versus single-agent Gem in advanced/metastatic pancreatic cancer.

Patients and Methods Patients were randomly assigned to receive GemCap (oral capecitabine 650 mg/m² twice daily on days 1 to 14 plus Gem 1,000 mg/m² by 30-minute infusion on days 1 and 8 every 3 weeks) or Gem (1,000 mg/m² by 30-minute infusion weekly for 7 weeks, followed by a 1-week break, and then weekly for 3 weeks every 4 weeks). Patients were stratified according to center, Karnofsky performance score (KPS), presence of pain, and disease extent.

Results A total of 319 patients were enrolled between June 2001 and June 2004. Median overall survival (OS) time, the primary end point, was 8.4 and 7.2 months in the GemCap and Gem arms, respectively (P = .234). Post hoc analysis in patients with good KPS (score of 90 to 100) showed a significant prolongation of median OS time in the GemCap arm compared with the Gem arm (10.1 v 7.4 months, respectively; P = .014). The overall frequency of grade 3 or 4 adverse events was similar in each arm. Neutropenia was the most frequent grade 3 or 4 adverse event in both arms.

Conclusion GemCap failed to improve OS at a statistically significant level compared with standard Gem treatment. The safety of GemCap and Gem was similar. In the subgroup of patients with good performance status, median OS was improved significantly. GemCap is a practical regimen that may be considered as an alternative to single-agent Gem for the treatment of advanced/metastatic pancreatic cancer patients with a good performance status.

	INTRODUCTION

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Pancreatic cancer is responsible for approximately 5% of cancer-related deaths in industrialized societies.¹ Recent estimates indicate that approximately 32,000 new cases and deaths are expected to occur in the United States during 2005.² Prognosis remains poor; the 1- and 5-year survival rates are 23% and approximately 4%, respectively, for all stages combined.²

Single-agent gemcitabine (Gem) is a standard therapy for advanced/metastatic pancreatic cancer, improving overall survival (OS) slightly and offering a significant clinical benefit compared with fluorouracil (FU).³ However, overall response rates (ORRs) remain low.^3,4 In recent years, various agents (eg, cisplatin, oxaliplatin, docetaxel) have been investigated in combination with Gem in phase I and II trials.^5-7 Phase III trials of Gem plus FU compared with single-agent Gem in patients with advanced disease have shown no significant increase in median OS.^8,9 In another phase III trial,¹⁰ combination of Gem and oxaliplatin, compared with single-agent Gem, resulted in an improved ORR (27% v 17%, respectively; P = .04) and median progression-free survival (PFS) time (5.8 v 3.7 months, respectively; P = .04). However, Gem plus oxaliplatin failed to improve OS in a recently presented Eastern Cooperative Oncology Group trial.¹¹

Capecitabine is an oral fluoropyrimidine^12,13 that is currently approved for the treatment of colorectal cancer and breast cancer. The improved tolerability and similar efficacy of capecitabine compared with intravenous FU/leucovorin and the convenience of oral administration make capecitabine an attractive treatment option in various other cancers (for review, see Walko and Lindley¹⁴). Capecitabine demonstrates single-agent activity in advanced pancreatic cancer,¹⁵ with ORR in a range similar to that of single-agent Gem.³

Gem and capecitabine are both nucleoside analogs that act mechanistically by inhibiting different targets^14,16 and show synergistic antitumor activity when combined in human xenograft models.¹⁷ Capecitabine and Gem have nonoverlapping toxicity; dose-limiting toxicities for Gem include myelosuppression, hepatic transaminase increases, and flu-like symptoms,¹⁸ whereas dose-limiting toxicities for capecitabine are predominantly GI events and hand-foot syndrome.¹⁴ The combination of capecitabine and Gem (GemCap) has shown promising clinical activity in phase I and II clinical studies in advanced pancreatic cancer patients.^19-22

The GemCap regimen used in the current trial was selected on the basis of the maximum-tolerated dose for the combination determined in a phase I and II trial.¹⁹ The objective of this phase III trial was to compare the efficacy and safety of the GemCap combination with Gem alone in the treatment of patients with locally advanced or metastatic pancreatic cancer.

	PATIENTS AND METHODS

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

 
Trial Design
This randomized, stratified, multicenter, phase III trial was conducted at 30 centers in eight countries. The trial was sponsored by the Swiss Group for Clinical Cancer Research, and the Central European Cooperative Oncology Group played a supportive role in Austria.

The primary trial end point was OS. Secondary end points were PFS, ORR, safety, and quality of life (which will be reported elsewhere). Informed consent was obtained from all patients, and ethical committee approval was received by all participating centers. The trial was conducted in accordance with the Declaration of Helsinki and its subsequent amendments and according to Good Clinical Practice guidelines.

Patients
Patients were eligible if they met the following criteria: histologic/cytologic proof of primary inoperable/metastatic pancreatic adenocarcinoma; age more than 18 years; Karnofsky performance score (KPS) 60; no prior chemotherapy; and adequate bone marrow reserve (WBC count 3.5 x 10⁹/L, platelets 100 x 10⁹/L, and hemoglobin 10.0 g/dL). Adjuvant treatment with FU plus radiotherapy was allowed if therapy had been administered more than 12 months before trial inclusion.

Exclusion criteria included the following: known CNS metastases; history of other primary malignancy within 5 years, except for adequately treated cervical carcinoma in situ or basal cell skin carcinoma; insufficient liver function (bilirubin, AST/ALT/alkaline phosphatase > 5x normal); creatinine clearance less than 30 mL/min (calculated according to Cockcroft-Gault formula); active infection; breast feeding/pregnancy; reproductive potential without using effective contraception; serious concomitant systemic disorder incompatible with the trial in the investigator's judgment; known hypersensitivity or anticipated severe reaction to fluoropyrimidines; concomitant treatment with sorivudine or related analogs; grade 2 nausea or grade 1 vomiting (despite adequate treatment); and any medical condition that could interfere with taking oral medication and/or GI absorption (eg, partial small bowel obstruction; however, patients with prior Whipple procedure or duodenal bypasses were allowed).

Drug Administration
Before random assignment, patients were stratified by KPS (90 to 100 v 60 to 80), disease extent (locally advanced v metastatic), presence or absence of pain requiring medication, and enrolling center. Patients who were randomly assigned to the GemCap combination received oral capecitabine 650 mg/m² twice daily at approximately 12-hour intervals on days 1 to 14 every 3 weeks and Gem 1,000 mg/m² intravenously over 30 minutes on days 1 and 8 every 3 weeks. Patients who were randomly assigned to single-agent Gem received Gem 1,000 mg/m² intravenously over 30 minutes weekly for 7 weeks, followed by a 1-week break, and then weekly for 3 weeks every 4 weeks. Capecitabine (Xeloda; F. Hoffmann-La Roche AG, Basel, Switzerland) was supplied as film-coated tablets in two dose strengths (150 and 500 mg); the closest practical dose (by rounding up or down) calculated on body-surface area based on a combination of tablets was taken within 30 minutes after the end of a meal with approximately 200 mL of water (not fruit juice). Gem (Gemzar; Eli Lilly & Co, Indianapolis, IN) was supplied as sterile lyophilized powder in vials containing either 200 or 1,000 mg; the powder was reconstituted in sterile normal saline. In both treatment arms, ondansetron 8 mg or equivalent was administered orally as premedication on the day of Gem administration. In addition, one dose of corticosteroids (eg, prednisone 50 mg or dexamethasone 8 mg) could be administered to prevent flu-like symptoms. Treatment was continued until disease progression or for a maximum of 24 weeks, except in the case of unacceptable toxicity. Treatment could be resumed later at the discretion of the investigator.

Assessments
Pretreatment baseline evaluation included complete medical history, physical examination, vital signs (including weight, pulse, and blood pressure), ECG, chest radiography, documentation of KPS, and routine laboratory tests. Treatment visits occurred weekly for the first 7 weeks, and subsequently, they occurred for administration of Gem. Laboratory tests were performed at regular intervals during treatment, usually coinciding with the administration of Gem. Adverse events were monitored continuously during treatment and for 4 weeks after last drug administration. All adverse reactions were assessed according to National Cancer Institute Common Toxicity Criteria (version 2.0).

Response evaluation was performed at the start of weeks 7, 17, and 25 and every 9 weeks thereafter until disease progression using contrast computed tomography scan; response was defined according to Response Evaluation Criteria in Solid Tumors.²³ Objective responses (complete or partial) were supposed to be confirmed after a minimum of 4 weeks.

Adverse Events and Dose Modification Guidelines
Grade 3 or 4 hematologic adverse events necessitated delay or interruption of treatment until they resolved to grade 0 or 1, and the dose of Gem was to be subsequently reduced by 25% at the discretion of the investigator. No dose modification was required for anemia because it was managed by RBC transfusion. Grade 2 to 4 nonhematologic adverse events necessitated delay or interruption of treatment as summarized in Appendix Table A1 (online only). Treatment cycles could be delayed up to 3 weeks. Supportive and/or prophylactic care for symptoms could be administered as needed (eg, hematopoietic growth factors for symptomatic neutropenia, but not given prophylactically; loperamide for diarrhea; and metoclopramide or 5-hydroxytryptamine-3 antagonist for nausea and vomiting).

Statistics
The primary end point hypothesis used for sample size estimation was that the GemCap combination would increase the median OS time by 2 months (from 5 to 7 months) compared with single-agent Gem. Two interim analyses and one final analysis were planned for the primary end point using the two-sided log-rank test (overall type I error probability of 5% and power of 80%). If an interim analysis showed a significant difference between arms, the decision to stop the trial would be made. The O'Brien and Fleming²⁴ stopping boundary was applied, and the resulting maximum required number of events (deaths) was 284. Three hundred eligible patients (150 in each arm) were planned to be included in this trial. The two interim analyses were performed after observing approximately 95 (one third) and 190 (two thirds) events. The corresponding significance levels of the three analyses were P = .00044, .01305, and .04569.

Intent-to-treat analysis was applied to the analysis of all end points. For analyses of toxicity end points, only patients who had received trial treatment, regardless of eligibility, were included. Survival probabilities of time-to-event type end points were estimated using the Kaplan-Meier method and compared between arms using the log-rank test. Medians and their associated 95% CIs were calculated. Cox regression was performed to explore the effects of stratification factors and treatment on survival probabilities. Proportional hazards assumption was checked. Contingency tables were analyzed by Fisher's exact test. CIs for response rates were calculated using the Clopper-Pearson method.

	RESULTS

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Patients
A total of 319 patients were randomly assigned between June 2001 and June 2004. Baseline patient and disease characteristics were similar in both arms (Table 1). The flow of patients during the trial is summarized in Figure 1. Of the patients initially enrolled, all were assessable for OS and PFS, 315 were assessable for safety, and 303 with measurable lesions were assessable for response. Safety data are not available for one patient in the GemCap arm (wrong diagnosis) and three patients in the Gem arm (one early tumor death, one serious adverse event before first study drug, and one screening failure); none of these patients received any study drug.

View larger version (52K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Study population. Gem, gemcitabine; GemCap, gemcitabine plus capecitabine; SAE, serious adverse event.

View larger version (12K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Kaplan-Meier overall survival curves. Gem, gemcitabine; GemCap, gemcitabine plus capecitabine.

View larger version (13K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 3. Kaplan-Meier overall survival curves in patients with good Karnofsky performance score (score of 90 to 100). Gem, gemcitabine; GemCap, gemcitabine plus capecitabine.

The median dose-intensity for capecitabine was 94%; 43% of the patients received 90% of the prescribed dose, and 26% of patients received 80% of the prescribed dose. The median dose-intensity for Gem was 97% and 95% in the GemCap and Gem arms, respectively; 28% and 33% of the patients received 90% and 13% and 15% of the patients received 80% of the prescribed dose of Gem in the GemCap and Gem arms, respectively. Full treatment (24 weeks) was completed in 53 (33%) of 159 patients receiving GemCap and 44 (28%) of 157 patients receiving Gem.

Second-line chemotherapy was administered to 89 and 90 patients in the GemCap and Gem arms, respectively. The selection was up to the individual investigator, and a variety of different drugs was used. Capecitabine alone or in combination with other agents was administered to 16 patients in the Gem arm.

Safety
The majority of treatment-related adverse events were grade 1 or 2 in severity in each arm. The overall frequency of grade 3 or 4 hematologic adverse events was similar in each arm (Table 4), as was the frequency of hematologic adverse events. Neutropenia was the most frequent grade 3 or 4 hematologic adverse event in each arm. Grade 3 or 4 nonhematologic adverse events were infrequent. Grade 3 or 4 diarrhea was the most common nonhematologic adverse event.

	DISCUSSION

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There was no statistically significant difference between the GemCap and Gem treatment arms with respect to primary (OS) and secondary (PFS and ORR) efficacy end points in this trial. However, post hoc analysis of patients with a good KPS (score of 90 to 100) showed that median OS time was statistically significantly longer in the GemCap arm compared with the Gem arm (10.1 v 7.4 months, respectively; P = .014). We consider this median survival gain of 2.7 months or 36% in patients receiving GemCap compared with patients receiving Gem alone to be clinically significant for patients with a good performance status. The observed significant increase in PFS seems to support this finding. If confirmed, these results would suggest that these patients should be studied separately in future trials.

The results of our phase III trial confirm the promising clinical activity of the combination of GemCap demonstrated in previous phase I/II and phase II studies.^19-22 The median OS time of 7.2 months in patients receiving single-agent Gem in our trial was longer than we had initially anticipated. We had expected the median OS time to be approximately 5 months, as had been reported at the time of planning this trial.^3,8 However, more recently published trials with single-agent Gem have reported median OS times in a range of 6 to 8 months.^9,10,20,25 We suspect that the OS prolongation during single-agent Gem therapy over recent years may reflect a general improvement in the standard of cancer care and a better selection of patients.

GemCap was well tolerated and a relatively easy regimen to administer compared with single-agent Gem, which is reflected in the high median dose-intensity of greater than 90% for all agents used. There was no significant difference between the treatment arms with respect to the frequency of overall or specific grade 3 or 4 adverse events. Neutropenia was the primary grade 3 or 4 treatment-related adverse event. There was a marginal increase in grade 3 or 4 nonhematologic adverse events, such as nausea and diarrhea, in the GemCap arm, but the frequency of these events remained low.

In previous phase II trials of GemCap, the median OS time was 8 to 9.5 months, and the ORR was 17% to 19%. Although the median OS time (8.4 months) was remarkably similar in our trial, the ORR was somewhat lower (10%). Nevertheless, median response duration was 7.3 months (95% CI, 6.3 to 8.1 months) in the GemCap arm compared with 5.9 months (95% CI, 4.0 to 8.2 months) in the Gem arm. Furthermore, interim data have been reported for a large United Kingdom (UK) phase III trial comparing GemCap with single-agent Gem for the treatment of advanced pancreatic cancer.²⁵ Median OS time was significantly superior with GemCap compared with Gem (7.4 v 6 months, respectively; P = .014), as was ORR (14% v 7%, respectively; P = .001). The 1-year survival rates in the UK trial were 26% and 19%, respectively. These results were similar to those in our trial but obtained with a larger number of patients. As in our trial, there was little difference between the treatment arms with respect to the frequency of grade 3 or 4 adverse events, although grade 3/4 neutropenia (36% for GemCap v 26% for Gem) and thrombocytopenia (11% for GemCap v 6% for Gem) tended to be more frequent with GemCap. It should be noted that the capecitabine dose in the UK trial was higher than in ours (approximately 44% higher dose-intensity), as was the dose of Gem in the GemCap arm (approximately 12% higher). The dose of Gem in the single-agent Gem arm of each trial was identical.

There was an excess of early deaths in the GemCap arm in our trial, which may have contributed to obscuring a potential difference in median OS between the treatments. These early deaths all occurred in the poor performance subgroup (KPS 80) and were primarily related to disease progression (10 deaths in the GemCap arm and five deaths in the Gem arm). Additional explanations for our trial failing to meet its primary end point may be a rather low absolute and high relative dose-intensity of capecitabine as demonstrated by its low toxicity and the smaller sample size compared with the UK trial.

There is considerable debate over the current standard of care in advanced pancreatic cancer. Apart from the UK GemCap trial,²⁵ other phase III studies have shown no significant OS advantage for Gem plus FU,^8,9 irinotecan,²⁶ pemetrexed,²⁷ cisplatin,²⁸ cisplatin/epirubicn/FU,²⁹ or oxaliplatin^10,11 compared with Gem alone. A pooled retrospective analysis revealed that Gem plus platinum, compared with single-agent Gem, increased median OS time (8.3 v 6.7 months, respectively; P = .031) and PFS (5.5 v 3.5 months, respectively; P = .003).³⁰ Conversely, another recent pooled analysis of 3,682 patients enrolled onto 12 phase III trials showed no significant differences for OS comparing Gem/platinum or Gem/fluoropyrimidine combinations to single-agent Gem.³¹ The only other agent to have shown a survival benefit when added to Gem is erlotinib.³² In conclusion, the results of this and other studies indicate that the combination of GemCap may be considered a valuable alternative to Gem alone for the treatment of patients with advanced/metastatic pancreatic cancer who have a good performance status.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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

 
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: Bengt Glimelius, Roche, Sanofi-Aventis; Jean Bauer, Eli Lilly; Arie Figer, Roche Stock: N/A Honoraria: Richard Herrmann, Roche Pharma Switzerland; Arie Figer, Roche; Gabriela V. Kornek, Roche; Werner Scheithauer, Roche Research Funds: Bengt Glimelius, Funds, Merck, Sanofi-Aventis; Emilio Bajetta, Funds, Roche S.p.A.; Arie Figer, Funds, Roche, Swiss Group for Clinical Cancer Research; Werner Scheithauer, Funds, Eli Lilly Testimony: Arie Figer, Roche Other: N/A

	AUTHOR CONTRIBUTIONS

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

 
Conception and design: Richard Herrmann, Thomas Ruhstaller, Piercarlo Saletti, Bernhard Pestalozzi, Jürg Bernhard, Werner Scheithauer

Administrative support: Richard Herrmann, Bernhard Pestalozzi, Susanne Cina, Werner Scheithauer

Provision of study materials or patients: Richard Herrmann, György Bodoky, Thomas Ruhstaller, Bengt Glimelius, Emilio Bajetta, Johannes Schüller, Piercarlo Saletti, Jean Bauer, Arie Figer, Bernhard Pestalozzi, Claus-Henning Köhne, Walter Mingrone, Salomon M. Stemmer, Karin Tamas, Gabriela V. Kornek, Dieter Koeberle, Werner Scheithauer

Collection and assembly of data: Richard Herrmann, György Bodoky, Thomas Ruhstaller, Piercarlo Saletti, Arie Figer, Bernhard Pestalozzi, Karin Tamas, Gabriela V. Kornek, Susanne Cina, Werner Scheithauer

Data analysis and interpretation: Richard Herrmann, Bernhard Pestalozzi, Daniel Dietrich

Manuscript writing: Richard Herrmann, Bernhard Pestalozzi, Claus-Henning Köhne, Daniel Dietrich

Final approval of manuscript: Richard Herrmann, György Bodoky, Thomas Ruhstaller, Bengt Glimelius, Emilio Bajetta, Johannes Schüller, Piercarlo Saletti, Jean Bauer, Arie Figer, Bernhard Pestalozzi, Claus-Henning Köhne, Walter Mingrone, Salomon M. Stemmer, Karin Tamas, Gabriela V. Kornek, Dieter Koeberle, Jürg Bernhard, Daniel Dietrich, Werner Scheithauer

Other: Jürg Bernhard

	Appendix

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

 
The following centers and investigators participated in this trial: Switzerland: Aarau (C. Caspar, W. Mingrone), Basel (R. Herrmann, L. Jost, A. Lohri, C. Ludwig), Berne (M. Borner, D. Rauch), Chur (F. Egli), Geneva (A. Roth), Lausanne (J. Bauer, R. Popescu), St. Gallen (D. Köberle, R. Morant, T. Ruhstaller), Ticino (M. Bonomo, P. Saletti, C. Sessa), and Zurich (H. Adam, L. Widmer, B. Pestalozzi); Austria: Feldkirch (A. Lang) and Vienna (W. Scheithauer, J. Schüller); Finland: Oulo (T. Turpeenniemi-Hujanen), Tampere (P. Kellokompu-Lehtinen), and Turku (S. Pyrhönen); Germany: Dresden (C.H. Köhne, G. Kornek); Hungary: Budapest (G. Bodoky, K. Tamas); Israel: Petach Tikva (S. Stemmer) and Tel-Aviv (A. Figer, M. Inbar); Italy: Milano (E. Bajetta) and Napoli (P. Comella); and Sweden: Uppsala (B. Glimelius).

View larger version (12K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig A1. Kaplan-Meier overall survival curves for patients with poor Karnofsky performance score (score of 60 to 80). Gem, gemcitabine; GemCap, gemcitabine plus capecitabine.

View larger version (11K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig A2. Kaplan-Meier progression-free survival curves. Gem, gemcitabine; GemCap, gemcitabine plus capecitabine.

	ACKNOWLEDGMENTS

 
We thank Stefan Frings and other colleagues at Roche for their assistance in the conduct of this trial.

	NOTES

 
Supported by F. Hoffmann-La Roche AG, Eli Lilly Switzerland, and the Swiss federal government.

Presented in part at the 41st Annual Meeting of the American Society of Clinical Oncology, May 13-17, 2005, Orlando, FL, and the 13th Annual European Cancer Congress, October 31-November 3, 2005, Paris, France.

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

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Submitted September 11, 2006; accepted December 4, 2006.

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