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Phase III Trial in Metastatic Gastroesophageal Adenocarcinoma with Fluorouracil, Leucovorin Plus Either Oxaliplatin or Cisplatin: A Study of the Arbeitsgemeinschaft Internistische Onkologie

Salah-Eddin Al-Batran, Joerg Thomas Hartmann, Stephan Probst, Harald Schmalenberg, Stephan Hollerbach, Ralf Hofheinz, Volker Rethwisch, Gernot Seipelt, Nils Homann, Gerhard Wilhelm, Gunter Schuch, Jan Stoehlmacher, Hans Günter Derigs, Susanna Hegewisch-Becker, Johannes Grossmann, Claudia Pauligk, Akin Atmaca, Carsten Bokemeyer, Alexander Knuth, Elke Jäger

From the Department of Hematology and Oncology, Krankenhaus Nordwest, Frankfurt; Department of Medical Oncology, Hematology, Immunology, Rheumatology and Pulmology South West Cancer Center, Eberhard-Karls-University, Tuebingen; Department of Hematology and Oncology, Städtische Kliniken, Bielefeld; Department of Internal Medicine, Universitätsklinikum, Jena; Division of Gastroenterology, Department of Medicine, Allgemeines Krankenhaus, Celle; III. Department of Medicine, Universitätsklinikum Mannheim, Mannheim; Department of Hematology and Oncology, Katholisches Krankenhaus, Hagen; Gemeinschaftspraxis für Hämatologie und Internistische Onkologie, Bad Soden; Department of Medicine I, University of Lübeck, Lübeck; Department of Hematology and Oncology, Harz Klinikum Wernigerode; Department of Oncology and Hematology, Section of Pneumology, Universitätskrankenhaus Eppendorf and Onkologische Schwerpunktpraxis Eppendorf, Hamburg; Department of Internal Medicine I, Universitätsklinikum Carl Gustav Carus, Dresden; III. Department of Medicine, Johannes Gutenberg University, Mainz; Department of Medicine, Ev. Krankenhaus Bethesda, Mönchengladbach, Germany; and Department of Oncology, Universitätsspital, Zürich, Switzerland

Corresponding author: Salah-Eddin Al-Batran, MD, Krankenhaus Nordwest, Steinbacher Hohl 2-26, 60488 Frankfurt am Main, Germany; e-mail: albatran{at}aol.com

	ABSTRACT

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Purpose This study was designed to compare fluorouracil, leucovorin, and oxaliplatin with fluorouracil, leucovorin, and cisplatin in patients with advanced gastric cancer.

Patients and Methods Patients with previously untreated advanced adenocarcinoma of the stomach or esophagogastric junction were randomly assigned to receive either fluorouracil 2,600 mg/m² via 24-hour infusion, leucovorin 200 mg/m², and oxaliplatin 85 mg/m² (FLO) every 2 weeks or fluorouracil 2,000 mg/m² via 24-hour infusion, leucovorin 200 mg/m² weekly, and cisplatin 50 mg/m² every 2 weeks (FLP). The primary end point was progression-free survival (PFS).

Results Two hundred twenty patients (median age, 64 years; metastatic, 94%) were randomly assigned. FLO was associated with significantly less (any grade) anemia (54% v 72%), nausea (53% v 70%), vomiting (31% v 52%), alopecia (22% v 39%), fatigue (19% v 34%), renal toxicity (11% v 34%), thromboembolic events (0.9% v 7.8%), and serious adverse events related to the treatment (9% v 19%). FLP was associated with significantly less peripheral neuropathy (22% v 63%). There was a trend toward improved median PFS with FLO versus FLP (5.8 v 3.9 months, respectively; P = .077) and no significant difference in median overall survival (10.7 v 8.8 months, respectively). However, in patients older than 65 years (n = 94), treatment with FLO resulted in significantly superior response rates (41.3% v 16.7%; P = .012), time to treatment failure (5.4 v 2.3 months; P < .001), and PFS (6.0 v 3.1 month; P = .029) and an improved OS (13.9 v 7.2 months) as compared with FLP, respectively.

Conclusion FLO reduced toxicity as compared with FLP. In older adult patients, FLO also seemed to be associated with improved efficacy.

	INTRODUCTION

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Systemic chemotherapy is widely accepted as palliative treatment for patients with advanced gastric cancer, leading to objective responses, improvement of quality of life, and survival time.¹ On the basis of favorable response rates, fluorouracil (FU)- and cisplatin-containing combinations were considered to represent one of the standard therapies for patients with advanced gastric cancer, even though randomized trials failed to show an improvement over the previous regimens in terms of survival.²

Overall, the results of FU combined with cisplatin in unselected patient populations have been unsatisfactory so far, with response rates in the 25% range and progression-free survival (PFS) and overall survival (OS) ranging from 3 to 4 and 6 to 8 months, respectively.^3-5 Cisplatin-based combinations were also associated with considerable toxicity in patients with advanced disease, for whom tolerability and quality of life may represent a critical issue. The most widely used cisplatin-based regimen for the treatment of gastric cancer in Germany is FU, leucovorin, and cisplatin (FLP),^6-8 which contains cumulative doses of cisplatin and FU that are comparable to those used within the classical cisplatin and FU regimen (CF; cisplatin 100 mg/m², day 1; FU 1,000 mg/m², days 1 through 5; every 29 days) regimen.

Oxaliplatin, a third-generation platinum compound, proved to be effective in colorectal cancer and has a favorable toxicity profile as compared with cisplatin. Encouraging results were observed with oxaliplatin in combination with FU in numerous phase II studies for advanced gastric cancer, with response rates and PFS ranging from 38% to 55% and 5 to 7 months, respectively.^9-15 FU, leucovorin, and oxaliplatin (FLO) does not contain bolus FU and is, therefore, associated with less neutropenia as compared with FOLOFX-4 and FOLFOX-6 (grade 3 or 4 neutropenia, 5%¹⁰ v 36%¹¹ and 38%,⁹ respectively). FLO has shown promising activity and a favorable toxicity profile in a recent phase II study for patients with advanced gastric cancer.¹⁰ Here, we report the results of a randomized, multicenter study, comparing FLO with FLP chemotherapy in patients with advanced gastric cancer or adenocarcinoma of the esophagogastric junction (EGJ).

	PATIENTS AND METHODS

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Patient Eligibility
Patients with histologically confirmed locally advanced or metastatic adenocarcinoma of the stomach or EGJ were eligible. Further criteria were as follows: no prior palliative chemotherapy, age more than 18 years, Eastern Cooperative Oncology Group performance status 2, sufficient bone marrow function, creatinine clearance more than 50 mL/min, no concurrent uncontrolled medical illness, and no other current or previous malignancy within the past 5 years (with the exception of squamous cell carcinoma of the skin treated by surgery). Patients were excluded from the study if they had peripheral neuropathy of National Cancer Institute grade 2 at baseline; brain metastases; inflammatory bowel disease; coronary heart disease; cardiac insufficiency (New York Heart Association classification of heart disease class II through IV); known hypersensitivity to FU, leucovorin, oxaliplatin, or cisplatin; or were pregnant or breast-feeding. Women of child-bearing potential were advised to take adequate precautions to prevent pregnancy. Participants gave written informed consent before they entered the study, which was approved by the ethics committees of the participating institutions.

Treatment
Patients were stratified by center and randomly assigned to either FLO or FLP. Patients in the FLO arm received oxaliplatin 85 mg/m² and leucovorin 200 mg/m², each as a 2-hour intravenous infusion, followed by FU 2,600 mg/m² as a 24-hour continuous infusion every 2 weeks.¹⁰ Patients in the FLP arm received cisplatin 50 mg/m² as a 2-hour infusion every 2 weeks combined with leucovorin 200 mg/m² as a 2-hour infusion and FU 2,000 mg/m² as a 24-hour infusion every week for 6 weeks followed by a 2-week rest.^6-8 Antiemetic prophylaxis was given according to local protocols. While receiving cisplatin, patients were hydrated with up to 3,000 mL of normal saline. The prophylactic use of growth factors was not permitted. Treatment in both arms was continued until disease progression, unacceptable toxicity, patient's refusal, or physician's decision. The dose of FU was reduced by 20% for diarrhea or mucositis exceeding National Cancer Institute Common Toxicity Criteria (NCI-CTC) grade 2. FU and cisplatin were reduced by 20% for NCI-CTC grade 4 neutropenia or thrombocytopenia. Cisplatin was discontinued for NCI-CTC grade 2 or worse renal toxicity. Oxaliplatin dose modifications were performed as described previously.⁹

Toxicity Assessment
Toxicities were graded according to NCI-CTC version 2. Peripheral sensitive neuropathy was graded according to an oxaliplatin-specific scale as described previously.¹⁶

Evaluation of Efficacy Outcomes
Responses were classified according to WHO criteria. Computed tomography or magnetic resonance imaging scans of target areas were performed before the start of the treatment and were repeated every 6 weeks in both arms. Patients who discontinued the study were evaluated every 2 months. PFS was measured from the date of random assignment until disease progression or death of any cause. Time to treatment failure (TTF) was measured from the date of random assignment until disease progression, death of any cause, or treatment discontinuation owing to toxicity. OS was measured from date of random assignment until death of any cause.

Statistical Analysis
The primary end point was to demonstrate superiority of FLO over FLP in terms of PFS. Based on a planned sample size of 218 patients, the trial was designed to have an 80% power to detect an improvement in median PFS from 3.5 to 5.0 months (one-sided log-rank test; significance level = .05). Secondary end points were toxicity (P for trend test), response rates (Fishers' exact test), TTF (log-rank test), and OS (log-rank test). Survival data were calculated using the Kaplan-Meier method on the intent-to-treat (ITT) population, which was predefined as all randomly assigned patients with adenocarcinoma of the stomach or EGJ (efficacy population). The safety analysis included all patients who received chemotherapy (safety population). A preplanned interim analysis of toxicity and response was conducted after 80 patients were included in the study.

	RESULTS

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Patients
Between June 2003 and January 2006, a total of 220 patients (FLO, 112 patients; FLP, 108 patients) were recruited from 31 centers in Germany and one center in Switzerland. Two patients had ineligible disease (pancreatic neuroendocrine tumor and squamous cell carcinoma of the esophagus) and were excluded from the efficacy population. Six patients, all in the FLP arm, never received the study treatment because of death (one patient), rapid disease progression with deterioration of general health status (three patients), or renal failure (one patient) before treatment was initiated, or receiving a non–protocol-based treatment (one patient). These patients were excluded from the safety population. Therefore, 218 patients (FLO, 112 patients; FLP, 106 patients) were eligible for the efficacy analysis on an ITT basis, and 214 patients (FLO, 112 patients; FLP, 102 patients) were eligible for the safety analysis (Fig 1).

View larger version (20K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. CONSORT diagram. Abbreviations: FLO, fluorouracil; leucovorin, and oxaliplatin; FLP, fluorouracil, leucovorin, and cisplatin; ITT, intent to treat. *Because of death (one patient), rapid disease progression with deterioration of general health status (three patients) or renal failure (one patient) before treatment was initiated, or receiving a non–protocol-based treatment (one patient). Patients had ineligible disease (pancreatic neuroendocrine tumor and squamous cell carcinoma of the esophagus in one patient each).

Overall, 214 patients were assessable for toxicity (Table 2). The treatment was generally well tolerated, and the incidence of grade 3 to 4 toxicities was relatively low in the two treatment arms. There were no remarkable differences in the incidence of neutropenia, thrombocytopenia, or infections between the treatment arms. However, significantly fewer patients experienced anemia, leukopenia, and other nonhematologic toxicities after treatment with FLO as compared with FLP. In particular, there were significantly lower rates of NCI-CTC grades 1 to 4 nausea, vomiting, alopecia, fatigue, thromboembolic events, and renal toxicity with FLO as compared with FLP. NCI-CTC grade 1 to 4 peripheral neuropathy and elevations of the serum AST or ALT were significantly more frequent with FLO. Serious adverse events considered at least possibly related to the treatment were observed in 9% of patients treated with FLO and in 19% of patients treated with FLP (P = .03).

Efficacy
The median follow-up time for surviving patients was 14 months. One hundred ninety-nine patients (91.3%) had experienced progressive disease and 166 patients (76.1%) had died. The median PFS, which was the primary end point, was 5.8 months (95% CI, 4.5 to 6.6 months) with FLO and 3.9 months (95% CI, 3.1 to 4.8 months) with FLP (one-sided P = .0765; two-sided P = .153). The 6-month PFS rate was 44% (95% CI, 34.8% to 53.2%) and 31% (95% CI, 22.2% to 39.8%) with FLO and FLP, respectively (P = .024). A post hoc subgroup analysis was undertaken in patients older than 65 years (n = 94). For these patients, the median PFS was 6.0 months (95% CI, 4.5 to 9.5 months) with FLO and 3.1 months (95% CI, 2.1 to 4.4 months) with FLP. This difference was statistically significant (P = .029). FLO also significantly improved TTF in the group of older adult patients (5.4 v 2.3 months; P < .001).

The study was not powered to detect differences in OS and there was no statistically significant difference in the median OS between the two groups (FLO, 10.7 months, 95% CI, 8.5 to 13.9 months; FLP, 8.8 months, 95% CI, 7.7 to 12.0 months). The 1- and 2-year survival rates were 45% (95% CI, 35.8% to 54.2%) and 14% (95% CI, 7.6% to 20.4%) with FLO and 40% (95% CI, 30.7% to 49.3%) and 16% (95% CI, 9.0% to 23.0%) with FLP. In the group of older patients, median OS was 13.9 months (95% CI, 10.5 to 16.1 months) with FLO and 7.2 months (95% CI, 6.0 to 10.9 months) with FLP (log-rank test, P = .081; Wilcoxon test, P = .02). TTF, PFS, and survival results are shown in Fig 2.

View larger version (17K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Kaplan-Meier curves for (A) time to treatment failure (TTF), (B) progression-free survival (PFS), and (C) overall survival (OS) assessed in the entire population and (D) TTF, (E) PFS, and (F) OS in the subset of patients older than 65 years. Patients were treated with fluorouracil, leucovorin, and oxaliplatin (FLO) or fluorouracil, leucovorin, and cisplatin (FLP). In the group of patients younger than 65 years, no significant differences were evident between the two treatment arms. The distribution of important prognostic factors (eg, Eastern Cooperative Oncology Group performance status, locally advanced disease) and patients' baseline characteristics between arms in the group of older adult patients was similar to that in the entire and young population (data not shown). *One-sided log rank test as used for the sample size determination; all other statistical tests are two-sided. Wilcoxon, P = .02.

	DISCUSSION

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This randomized phase III trial involving 220 patients confirmed the efficacy of FU/oxaliplatin for the treatment of advanced gastric cancer observed in multiple previous phase II trials.^9-12 For instance, in a phase II study of FLO (n = 41),¹⁰ median PFS and OS were 5.6 and 9.6 months, respectively. In the current study, median PFS and OS with FLO are similar (5.8 and 10.7 months, respectively). Furthermore, the response rates with FLO were similar in the two studies (phase II study, 43%; present study, 35%). It is important to note that the results with FLP as a control arm also seem consistent with those recently published with the classical CF regimen in phase III trials, and in particular, the V325 study⁴ and the study presented by Dank et al⁵ at the 2005 Annual Meeting of the American Society of Clinical Oncology. When phase II trials are considered, FLP achieved higher response rates (eg, 46%),⁸ but median OS and the corresponding 1-year survival rate did not differ remarkably from those observed with FLP in the present study (9.7 months and 45.3% v 8.8 months and 40%, respectively).

The rates and types of adverse events observed in our study with FLO and FLP were consistent with those previously reported for each of the regimens.^8,10 In the present study, although both regimens generally had an acceptable toxicity profile, FLO was associated with improved tolerability and significantly fewer cumulative adverse events. The incidences of six clinically important toxicities, including anemia, nausea, vomiting, alopecia, fatigue, and renal toxicity, were significantly lower with FLO compared with FLP, as was the incidence of serious adverse events related to the treatment. Although observed in a small proportion of patients, thromboembolic events were also less common with FLO as compared with FLP (0.9% v 7.8%, respectively). This finding may be important because most of the events observed were grade 3 or 4. In addition, it seems consistent with observations known from the REAL-2 study, in which thromboembolic events occurred in 8.2% versus 15.9% of patients receiving an oxaliplatin-based versus a cisplatin-based treatment, respectively (P = .0003).¹⁷ As expected, cumulative sensory neuropathy represented the main toxicity of FLO (any grade, 62.5%; grade 3, 14.3%). This rate is somewhat lower than the rate of neuropathy usually observed in patients receiving FOLFOX for colorectal cancer (grade 3 or 4 in the range of 20% to 30%), but remains clinically significant. Notably, FU was administered weekly in the FLP regimen and every other week in the FLO regimen. This may have contributed to the differences observed in toxicity profiles.

Concerning the primary end point of the study, we noted a trend toward increased median PFS with FLO versus FLP (5.8 months v 3.9 months, respectively; P = .077). Interestingly, the subgroup analysis revealed that this trend was largely attributable to a favorable activity of FLO in the older adult patients. In patients older than 65 years, treatment with the FLO regimen resulted in a significantly superior response rate (41.3% v 16.7%; P = .012), TTF (5.4 v 2.3 months; P < .001), and PFS (6.0 v 3.1 month; P = .029). These differences also seemed to translate into a superior survival time with FLO as compared with FLP (13.9 v 7.2 months, respectively).

Thus FLO has elicited beneficial effects predominantly in older adult patients. One may speculate that this patient group was more vulnerable to the higher toxicity of FLP. Older adult patients treated with FLP discontinued treatment much earlier for toxicity or patient request (after 1.7 v 3.3 months) and had a strikingly shorter treatment duration (2.1 v 5.2 months; P = .0015) and TTF (2.3 v 5.4 months; P < .001) as compared with patients treated with FLO. This point should be considered within the limitations of a subgroup analysis. However, it supports recent publications indicating that FOLFOX is a tolerable and safe treatment option in older adult patients.^18,19 The results also may underline the need to design and conduct trials for gastric cancer targeted specifically at older adult patients.

Our study was designed to detect differences in PFS only, using a one-sided log-rank test. Therefore, it is possible that some of the nonsignificant results may reflect the limited statistical power of the study rather than the absence of superiority. Future studies in this field should also focus on superiority questions but should have adequate power to detect differences in all outcomes, including OS.

Oxaliplatin in combination with epirubicin and FU or epirubicin and capecitabine was also investigated in the REAL-2 study.¹⁷ The trial involved 1,000 patients with advanced gastric cancer who were randomly assigned to receive one of four combinations, including epirubicin, cisplatin, and FU as a control arm. The study demonstrated the noninferiority of oxaliplatin versus cisplatin, with overall survival at 1 year as the primary end point. In contrast to the REAL-2 trial, our trial aimed at investigating whether an oxaliplatin-containing regimen improves PFS as compared with a similar regimen containing cisplatin. The primary end point was not met, but the results show clear consistency with the hypothesis that oxaliplatin is at least as effective as cisplatin in the treatment of patients with advanced gastric cancer. In addition to their supportive value, our results also complement the recent works, providing a basis for the use of oxaliplatin within an anthracycline-free doublet. This is important, because patients who are not considered optimal candidates for a cisplatin-based treatment are, in most cases, less likely to tolerate an intense triplet combination.

Finally, the important question is how this phase III trial fits in the evolving field of chemotherapy for gastric cancer. The number of available chemotherapy regimens against metastatic gastric cancer is rapidly growing. As a result, oncologists may be increasingly shifting their practice toward a more individualized treatment strategy. Given the results of our study, FLO may particularly represent a useful treatment option for older adult patients and generally for patients who are considered by their treating physicians not to be capable of tolerating a more intensive triplet or cisplatin-containing combination. FLO may also represent a less toxic backbone for triple combinations (eg, those containing docetaxel).⁴ Notably, the costs of oxaliplatin in Europe have decreased by up to 85% as a result of patent expiries. This may enhance the first-line use of oxaliplatin in further groups of patients in the future. The results reported with FLO may be improved within sequential treatment strategies or by the addition of a third active drug to the combination.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. 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 or Leadership Position: None Consultant or Advisory Role: Salah-Eddin Al-Batran, Sanofi-aventis (C) Stock Ownership: None Honoraria: Salah-Eddin Al-Batran, Sanofi-aventis Research Funding: Salah-Eddin Al-Batran, Sanofi-aventis Expert Testimony: None Other Remuneration: None

	AUTHOR CONTRIBUTIONS

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

 
Conception and design: Salah-Eddin Al-Batran, Elke Jäger

Administrative support: Salah-Eddin Al-Batran, Claudia Pauligk

Provision of study materials or patients: Salah-Eddin Al-Batran, Joerg T. Hartmann, Stephan Probst, Harald Schmalenberg, Stephan Hollerbach, Ralf Hofheinz, Volker Rethwisch, Gernot Seipelt, Nils Homann, Gerhard Wilhelm, Gunter Schuch, Jan Stoehlmacher, Hans G. Derigs, Susanna Hegewisch-Becker, Johannes Grossmann, Claudia Pauligk, Akin Atmaca, Carsten Bokemeyer, Alexander Knuth, Elke Jäger

Collection and assembly of data: Salah-Eddin Al-Batran, Claudia Pauligk

Data analysis and interpretation: Salah-Eddin Al-Batran, Claudia Pauligk

Manuscript writing: Salah-Eddin Al-Batran, Claudia Pauligk

Final approval of manuscript: Salah-Eddin Al-Batran, Joerg T. Hartmann, Stephan Probst, Harald Schmalenberg, Stephan Hollerbach, Ralf Hofheinz, Volker Rethwisch, Gernot Seipelt, Nils Homann, Gerhard Wilhelm, Gunter Schuch, Jan Stoehlmacher, Hans G. Derigs, Susanna Hegewisch-Becker, Johannes Grossmann, Claudia Pauligk, Akin Atmaca, Carsten Bokemeyer, Alexander Knuth, Elke Jäger

	Appendix

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Participating institutions and investigators include the following:

Krankenhaus Nordwest, Frankfurt, Germany (Salah-Eddin Al-Batran, MD; Elke Jäger, MD; Akin Atmaca, MD; Claudia Pauligk, PhD); Städtische Kliniken, Bielefeld, Germany (Stephan Probst, MD, Martin Görner, MD); Eberhard-Karls-University, Tuebingen, Germany (Jörg Thomas Hartmann, MD); Universitätsklinikum, Jena, Germany (Harald Schmalenberg, MD, Klaus Höffken, MD); Allgemeines Krankenhaus, Celle, Germany (Stephan Hollerbach, MD, Catherine Hollerbach, MD); Universitätsklinikum Mannheim, Germany (Ralf Hofheinz, MD); Katholisches Krankenhaus, Hagen, Germany (Volker Rethwisch, MD, Hartmut Eimermacher, MD); Geimeinschaftspraxis für Hämatologie und Internistische Onkologie, Bad Soden, Germany (Gernot Seipelt, MD); University of Lübeck, Germany (Nils Homann, MD, Thomas Wagner, MD); Harz Klinikum Wernigerode, Germany (Gerhard Wilhelm, MD); Universitätskrankenhaus Eppendorf, Hamburg, Germany (Jan Stoehlmacher, MD; Gunter Schuch, MD; Carsten Bokemeyer, MD); Städtische Kliniken Frankurt Höchst, Germany (Hans Günter Derigs, MD; Thomas Flohr, MD); Onkologische Schwerpunktpraxis Eppendorf, Hamburg, Germany (Susanna Hegewisch-Becker, MD); Universitätsklinik Frankfurt, Germany (Mathias Rummel, MD; Paris Mitrou, MD); Ev. Krankenhaus Bethesda, Mönchengladbach, Germany (Johannes Grossmann, MD; Swen-Holger Quasdorff, MD); Universitätsspital, Zürich, Switzerland (Alexander Knuth, MD); Hospital zum Heiligen Geist, Frankfurt, Germany (Klaus Genth, MD, Michael Fach, MD, Dorothea Schwemer, MD); Krankenhaus Bad Cannstatt, Stuttgart, Germany (Markus Fritz, MD; Tilo Andus, MD); Onkologische Schwerpunktpraxis, Magdeburg, Germany (Hendrik Kröning, MD); Klinikum Darmstadt, Germany (Arne Brecht, MD, Dieter Fritze, MD); Praxis für Hämatologie und Onkologie, Darmstadt, Germany (Georgi Kojouharoff, MD); Gemeinschaftspraxis für Innere Medizin, Jena, Germany (Sabine Hahnfeld, MD); Praxisgemeinschaft für Hämatologie und Onkologie, Berlin, Germany (Herbert Lebahn, MD; Fritz Maiwirth, MD); Kreiskrankenhaus, Schotten, Germany (Martin Graubner, MD); Klinikum Offenbach, Germany (Thomas Stiegler, MD); Klinikum Offenbach, Germany (Wolfgang Blau, MD); Franziskushospital, Bielefeld, Germany (Hans J. Weh, MD); GPR Klinikum, Rüsselsheim, Germany (Siegbert Rossol, MD); Gemeinschaftspraxis Hämatologie und internistische Onkologie, Ansbach, Germany (Markus Hahn, MD); Johanniter-Krankenhaus, Bonn, Germany (Yon Ko, MD, Thomas Neuhaus, MD); Onkologische Schwerpunktpraxis, Kronach, Germany (Martina Stauch, MD); Kath. Klinikum St. Vincenz-Hospital, Mainz, Germany (Wolfgang Dippold, MD).

	ACKNOWLEDGMENTS

 
We thank Antje Neumann and Cornelia Frisch for their help in the study coordination. We thank Karin Scheffler (MCA, Berlin, Germany) and Renate Saouchi (Clinical Study Service, Munich, Germany) for study monitoring. We thank Axel Hinke, MD (Wissenschaftlicher Service Pharma GmbH, Langenfeld, Germany) and Michael Scholz (Trium Analysis Online GmbH) for the statistical analysis. We thank Mark Sievert, MD, Alf Riehl, MD, and Rosemarie Kuhl, MD (Sanofi-Aventis, Berlin, Germany) for the excellent collaboration.

	NOTES

 
A preliminary analysis of the study was presented as a Late Breaking Abstract (LBA4016) at the 42nd Annual Meeting of the American Society of Clinical Oncology, June 2-6, 2006 Atlanta, GA.

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

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Submitted August 10, 2007; accepted October 22, 2007.

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