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Phase III Study Comparing a Semimonthly With a Monthly Regimen of Fluorouracil and Leucovorin As Adjuvant Treatment for Stage II and III Colon Cancer Patients: Final Results of GERCOR C96.1

Thierry André, Emmanuel Quinaux, Christophe Louvet, Philippe Colin, Erik Gamelin, Olivier Bouche, Emmanuel Achille, Pascal Piedbois, Nicole Tubiana-Mathieu, Arnaud Boutan-Laroze, Michel Flesch, Gérard Lledo, Yves Raoul, Isabelle Debrix, Marc Buyse, Aimery de Gramont

From the Hôpital Tenon, Assistance Public Hôpitaux de Paris and CancerEst; Hôpital Saint-Antoine, Assistance Public Hôpitaux de Paris and CancerEst; GERCOR, Paris; Clinique Courlancy, Reims; Centre Hospitalier Universitaire de Reims, Reims; Centre Paul Papin, Angers; Clinique Claude Bernard, Metz; Hôpital Henri Mondor, Assistance Public Hôpitaux de Paris, Creteil; Astra-Zeneca, Rueil-Malmaison; Centre Hospitalier Universitaire de Limoges, Limoges; Centre Hospitalier d'Argenteuil, Argenteuil; Hôpital Devron, Dijon; Clinique St Jean, Lyon; Clinique St Vincent, St Grégoire, France; and the International Drug Development Institute, Ottignies Louvain-La-Neuve, Belgium

Address reprint requests to Thierry André, MD, Service d'Oncologie Médicale, Hôpital Tenon, 4, rue de la Chine, F-75970 Paris Cedex 20, France; e-mail: thierry.andre{at}tnn.aphp.fr

	ABSTRACT

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Purpose: This randomized, 2 x 2 factorial study compared a semimonthly regimen (fluorouracil [FU] and leucovorin [LV] semi-monthly is LV5FU2) with a monthly regimen of FU and LV (mFU/LV) as well as 24 weeks versus 36 weeks of each regimen as adjuvant treatment of stage II and III colon cancer.

Patients and Methods: LV5FU2 was administered semimonthly for 2 days as racemate (dl) or levogyre (l-; 200 or 100 mg/m²) as a 2-hour infusion, followed by 400 mg/m² FU bolus and a 600-mg/m² FU 22-hour continuous infusion. FU and LV were administered monthly (mFU/LV) for 5 days as dl- or l-LV 15-minute infusion, followed by a 400 mg/m² FU 15-minute infusion. The primary end point was disease-free survival (DFS).

Results: Between September 1996 and November 1999, 905 patients with stage II (43%) and III (57%) colon cancer were enrolled. The median follow-up was 6 years. There was no statistically significant difference between mFU/LV and LV5FU2 in terms of DFS (150 v 148 events; hazard ratio [HR],1.01; 95% CI, 0.806 to 1.269; P = .94) and overall survival (OS; 104 v 103 events; HR,1.02; 95% CI, 0.77 to 1.34; P = .91). No statistical difference was observed between 24 or 36 weeks of chemotherapy. Median survival from metastatic relapse was 24 months. The survival of patients with metastatic relapse (n = 243) was significantly longer for patients with a longer time from random assignment to relapse (< 1, 1 to 2, 2 years; log-rank test for trend P, .0497).

Conclusion: DFS and OS were not statistically different between treatment groups and treatment durations. These data confirm the value of LV5FU2 as control arm in the Multicenter International Study of Oxaliplatin/5FU-LV in the Adjuvant Treatment of Colon Cancer and Pan-European Trials in Adjuvant Colon Cancer studies.

	INTRODUCTION

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Colorectal carcinoma is the most common gastrointestinal malignancy, and each year worldwide 500,000 people die of the disease and nearly 1 million patients are newly diagnosed. As many as 40% to 50% of patients who undergo potentially curative surgery alone will ultimately relapse and die of metastatic disease.¹ Over the past years, considerable progresses have been made in the treatment of patients with colon cancer. The use of optimized, leucovorin (LV)-modulated fluorouracil (FU) regimens have increased the median survival of patients with metastatic (stage IV) colon cancer from barely 6 months without treatment to more than 12 months.² The use of continuous infusion allowed the administration of high doses of LV and FU, leading to enhanced efficacy with acceptable toxicity.³ The addition of new chemotherapeutic agents (eg, oxaliplatin, irinotecan) to these regimens has further extended median survival to approximately 20 months.^4-6

The purpose of adjuvant chemotherapy is to reduce the risk of recurrence of the cancer either locally or with distant metastases, which could be due to remaining nondetectable tumor cells after surgery. The Intergroup trial (INT-0035) was the first large-scale study to demonstrate a significant effect of adjuvant treatment in stage III colon cancer patients with FU plus levamisole given for 1 year.⁷ The efficacy of FU bolus and LV became the standard chemotherapy for stage III colon cancer in 1996.^8,9 Available clinical trial data do not support the routine use of adjuvant chemotherapy for all stage II patients, but suggest that it should be considered, in case of high-risk patients.¹⁰

Concerning the duration of adjuvant chemotherapy, the INT-0089 study showed that 6 months of FU plus LV (Roswell Park schedule or North Central Cancer Treatment Group and Mayo Clinic regimen) were equivalent in term of OS to 12 months of FU plus levamisole.⁹ The North Central Cancer Treatment Group and National Cancer Institute of Canada Clinical Trials Group study showed that 6 months of combined FU and LV were equivalent to 12 months of combined FU, LV, and levamisole.¹¹ Based on these results, a semimonthly regimen of FU and LV (LV5FU2) was selected as the control arm of the Multicenter International Study of Oxaliplatin/5FU-LV in the Adjuvant Treatment of Colon Cancer (MOSAIC) study, which showed a significant advantage in terms of disease-free survival (DFS) at 3 years for oxaliplatin, FU, and LV (FOLFOX4).¹² In 2004, adjuvant chemotherapy with FU modulated by LV combined with oxaliplatin (FOLFOX4) became an accepted standard of care for patients with stage III colon cancer (MOSAIC study).¹²

This study was undertaken to compare the therapeutic ratio, efficacy, and toxicity of a monthly schedule of a15-minute infusion of FU plus high-dose LV for 5 consecutive days with LV5FU2, given for different durations (24 v 36 weeks) in the adjuvant setting, after resection of stage II and III colon or high rectum cancer.

In 2003, we reported the early results of this study (C96-1), which failed to show, after a median follow-up of 41 months, a statistically significant difference in DFS or overall survival (OS) between LV5FU2 and monthly mFU/LV or between treatment durations.¹³ These early results also showed LV5FU2 to be less toxic than mFU/LV.^13,14 Herein, we report the final DFS and OS results of the C96-1 study with a median follow-up of 6 years. We also carry out prognostic factor analyses and further analyses of patients with metastatic relapses.

	PATIENTS AND METHODS

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Our methods have been described previously.^14,15 Patients with stage II or III colon or high rectum (Gastrointestinal Tumor Study Group 1975) cancer were randomly assigned to two adjuvant chemotherapy regimens (LV5FU2 or mFU/LV) and two treatment durations (24 or 36 weeks) using a 2 x 2 factorial design. A dynamic minimization procedure was used to stratify patients according to institution, cancer stage (II or III), number of affected nodes for stage III cancer ( 4 or > 4), adjacent organs invasion, and time between surgery and random assignment (< 20, 20 to 35, or 36 to 49 days).

Chemotherapy Administration Schedules
Patients assigned to the LV5FU2 group received racemate (dl-)LV 200 mg/m² (or levogyre [l-]LV 100 mg/m², according to drug availability in each institution) as a 2-hour infusion, followed by bolus FU 400 mg/m² and a 22-hour infusion of FU 600 mg/m² for 2 consecutive days every 14 days. The use of implantable ports and disposable or electronic pumps allowed chemotherapy to be administered on an outpatient basis. Patients in this group received 12 or 18 cycles of treatment depending on whether they were randomly assigned to the 24- or the 36-week treatment group. Patients could be treated in the 7 days after random assignment. Patients in the mFU/LV group received an infusion of dl-LV 200 mg/m² (or l-LV 100 mg/m²) for 15 minutes, followed by a 15-minute bolus FU 400 mg/m² for 5 consecutive days every 28 days. In this study, we chose mFU/LV as the reference arm. mFU/LV differs from the monthly Mayo Clinic regimen by a higher dose of LV (200 v 20 mg/m²), a different period of administration (15 minutes v bolus), and a slightly lower dose per day of FU (400 v 425 mg/m²). In the case of grade 2 toxicity, FU was administered over 60 minutes; for toxicities greater than 2, FU was given over 60 minutes and the dose decreased to 300 mg/m². Appropriate adjustment in dosage was made according to toxicity.

Follow-Up Procedures
Before random assignment, every 6 months for 5 years, and then annually, patients were assessed for: medical history, physical examination, renal and liver function tests, complete blood cell count, carcinoembryonic antigen (CEA), chest x-ray, abdominal ultrasound or computerized tomography scan. Colonoscopy was performed within 6 months of the end of chemotherapy, and repeated every 3 years if the previous colonoscopy was normal, or every year if the previous colonoscopy showed polyps with polypectomy. The protocol was reviewed and approved by the ethics review committee of Saint-Antoine Hospital (Paris, France). All patients provided written informed consent before inclusion in the trial.

Statistical Methodology
DFS was assessed by recording colorectal cancer relapse, second colorectal cancer, or death. Two-sided statistical tests were performed on the DFS (primary efficacy criterion), OS, and toxicities. Survival curves were estimated by the Kaplan-Meier method. Patients lost to follow-up were censored at the last documented visit. The differences in DFS and in OS were evaluated using a log-rank test, or an unadjusted proportional hazards regression model to assess hazard ratios and their 95% CIs. Proportional hazards regression models of DFS and OS were used to identify significant prognostic covariates. Treatment effect was estimated using a proportional hazard regression model after adjustment for all significant prognostic factors.

	RESULTS

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A total of 905 patients with stage II (43%) and III (57%) cancer were randomly assigned in this study between July 1996 and November 1999. Four patients (0.4%) were ineligible but were nevertheless included in the analyses performed as intent to treat (two patients with metastatic disease at inclusion in the LV5FU2 arm, one patient with metastatic disease at inclusion in the mFU/LV arm, and one patient with low rectum cancer in the mFU/LV arm). All patients entered onto the study could potentially be followed for more than 5 years after random assignment and, at the time of the final analysis, the median follow-up time was 6.06 years in the mFU/LV group and 6.03 years in the LV5FU2 group. As described in our earlier report,^14,15 the clinical and pathologic characteristics of our patients were well-balanced among the study arm.

Cancer Recurrence and DFS
Table 1 summarizes patient status at 6 years median follow-up. For the whole population, 246 patients relapsed with distant metastasis, 10 presented local relapse alone, five had second colon or rectal cancer alone, and 37 died without relapse, for a total of 298 events, evenly distributed between the LV5FU2 and mFU/LV arms (148 and 150 events, respectively). Figure A1 (online only) shows the DFS curves for both regimens. There was no significant difference between the LV5FU2 and mFU/LV regimens (DFS at 6 years, 66% and 65%, respectively; hazard ratio [HR], 1.01; 95% CI, 0.81 to 1.27; P = .74). Similar results were obtained when data were analyzed for treatment duration (Fig A2, online only): 151 events were observed in the 24-week group versus 147 events in the 36-week group (HR, 0.97; 95% CI, 0.77 to 1.22; P = .63).

View larger version (12K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Overall survival according to treatment. mFU/LV, monthly fluorouracil and leucovorin; LV5FU2, semimonthly fluorouracil and leucovorin.

View larger version (14K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Survival after metastatic relapse according to the time to relapse (Rel).

View larger version (12K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig A3. Overall survival according to treatment duration.

Among patients with stage II, in term of DFS, 74 events were recorded, equally distributed between the LV5FU2 and mFU/LV groups with 37 events and a DFS at 6 years of 80% in both arms (HR, 1.02; 95% CI, 0.64 to 1.60). In term of OS, 21 and 24 deaths occurred in LV5FU2 and mFU/LV with an OS at 6 years of 88% and 89%, respectively (HR, 0.89; 95% CI, 0.50 to 1.60).

Among patients with stage III, in term of DFS, 224 events were recorded, 111 and 113 in the LV5FU2 and mFU/LV arms and a DFS at 6 years of 54% and 55%, respectively (HR, 1.01; 95% CI, 0.78 to 1.31). In term of OS, 78 and 79 deaths occurred with an OS at 6 years of 67% and 69%, respectively (HR, 1.02; 95% CI, 0.75 to 1.40).

Prognostic Variables
Table 3 presents the prognostic impact of patient and tumor-related factors on recurrence and death. In univariate analyses, stage, adhesion, or invasion to adjacent organ, regional peritoneum involvement (a tumor nodule resected in the pericolorectal adiposite tissue of a primary carcinoma without histological evidence of residual lymph node), obstruction, histologic differentiation, and type of stage II (high v low risk) were all significant prognostic factors for both DFS and OS. Other factors such as age, sex, and time interval between surgery and treatment, localization, and perforation were not found to be statistically significant either for DFS or for OS. These univariate analyses were confirmed in a multivariate proportional hazards regression model in which stage, adhesion, or invasion to adjacent organ, regional peritoneum involvement, obstruction, and poor histologic differentiation all remained statistically significant (Table 4). After adjustment for these factors, there was still no significant difference between LV5FU2 and mFU/LV in terms of either DFS (HR, 1.05; 95% CI, 0.84 to 1.32; P = .66) or OS (HR, 1.06; 95% CI, 0.81 to 1.39; P = .69).

	DISCUSSION

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With a median follow-up of 6 years, this study did not demonstrate any efficacy difference between LV5FU2 and mFU/LV. Even though the study was not designed as an equivalence study, the point estimate of the DFS and OS hazard ratios are close to 1, and the limits of the 95% DFS CI (0.81 to 1.27) suggest that the HRs of the two regimens do not differ by more than 20% to 25%, and can therefore be considered approximately equivalent in terms of efficacy, despite major differences in toxicity.^13,14 Three other studies^15-17 comparing an infusional FU schedule with or without LV to the Mayo Clinic regimen did not demonstrate any significant difference in terms of DFS or OS. Two of these studies compared FU delivered by protracted infusion (PVI 5FU) .^15,16 The third one, the Pan-European Trials in Adjuvant Colon Cancer (PETACC-2) study randomly assigned 1,601 patients with stage III colon cancer to 6 months of LV5FU2 or two other FU continuous infusion schedule (Spanish Cooperative Group for Gastrointestinal Tumor Therapy = FU 3 g/m² weekly or Arbeitsgemeinschaft fur Internistische Onkologie = LV 500 mg/m² and FU 2.6 g/m² weekly for 6 weeks with 2 weeks rest) and the Mayo Clinic regimen.¹⁷ Similar to our own previously published safety results, ^13,14 infusional FU schedules with or without LV were less toxic as compared with the Mayo regimen (Table A2). In PETACC-2, the LV5FU2 regimen appeared to be the best tolerated infusional regimen.¹⁷ The major drawback of continuous infusion with FU is the need for an implantable port with its associated adverse effects.

This study evaluated also duration of chemotherapy (24 v 36 weeks), and failed to demonstrate a significant improvement in patient DFS or OS when chemotherapy was given for 36 weeks as compared with 24 weeks. In the literature, 6 months of adjuvant chemotherapy with FU and LV were also shown to be equivalent to 12 months of the same chemotherapy¹¹ and 6 months of FU plus LV with or without levamisole was shown to be equivalent to 1 year of FU plus levamisole.^8,9 All these results indicate that an increase in the duration of chemotherapy with FU and LV beyond 6 months (24 weeks) is not associated with better efficacy.

Updated analyses of this trial produced some interesting results. The time between surgery and randomization was not a prognostic factor in this study where this parameter was a stratification criterion. In univariate and multivariate prognostic analyses (Tables 3 and 4), high risk stage II disease, as defined in the MOSAIC study^10,18,19 (invasion and/or adhesion to adjacent organ, obstruction, perforation, poor histological differentiation, number of examined nodes fewer than 10) was shown to be the most potent prognostic factor for relapse or death. Obstruction, in and of itself, was also an independent prognostic factor for the whole population.

We analyzed the OS of patients with metastatic relapses. The median time between metastatic relapse and death was 24 months, which is much longer than the reported 14.2 months observed in the Adjuvant Colon Cancer End Points (ACCENT) meta-analysis.²⁰ One possible explanation is that most patients with metastatic relapse in our study had surgery of their metastasis with a curative intent and/or were treated with a combination of oxaliplatin or CPT11 with FU and LV (Table 2), which has been shown to contribute to increase the median OS for metastatic disease.^4-6 In ACCENT, a majority of adjuvant studies had been carried out before the approval of oxaliplatin and irinotecan.²⁰ This study (C96-1) was the most recent one to be included in ACCENT.²⁰ A median OS of 24 months was close to the OS observed for patients with an initial diagnosis of metastatic disease, which reflects the progress in the management of metastatic colorectal cancer based a multidisciplinary approach (surgery of metastasis, use of oxaliplatin and irinotecan). The high proportion of patients with surgery for metastatic relapses (38%) underscores the importance of an intense follow-up for patients at risk of a relapse.²¹ The time from metastatic relapse to death was longer for patients with a late metastatic relapse. This observation suggests that for future studies in first-line metastatic colorectal cancer, patients should be stratified according to time from initial diagnosis to metastasis.

One of the decisive advantages of LV5FU2 is that this regimen can be safely combined with other cytotoxic agents in colorectal cancer, such as oxaliplatin or CPT11. Combination of LV5FU2 with oxaliplatin or CPT11 in metastatic disease had a more favorable safety profile while extending both progression-free survival^4,6,22 and OS.^6,22 These results validate the choice of LV5FU2 as the control group of trials testing the addition of oxaliplatin (MOSAIC)¹² or irinotecan (PETACC-3)²³ to adjuvant chemotherapy for patients with stage II and III colon cancer.

	Appendix

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We thank the following investigators for their participation: P. Agranat (Aulnay sous Bois), D. Auby (Libourne), D. Avenin (Paris), P. Ayela (Lourdes), C. Bachmeyer (Creil), J.C. Barbare (Compiègne), E. Bartheme (Metz), K. Beerblock (Paris), A. Bellaiche Miccio (Ermont), D. Belpomme (Paris), L. Benoist (Annecy), C. Berger (Avignon), P. Bergerault (Vannes), V. Blin-Avedian (Gueret), A. Botton (Pontoise), J.M. Boudet (Paris), B. Brun (Paris), F. Burki (Saint-Jean), J. Cady (Paris), P.E. Cailleux (Tours), L. Cals (Toulon), L. Cany (Périgueux), E. Carola (Senlis), S. Catan (Paris), G. Champault (Bondy), L. Chauvenet (Paris), M.C. Clavero-Fabri (Bris sous Forges), I. Cojean-Zelek (Paris), Y. Coscas (Boulogne), I. Cumin (Lorient), F. Cvitkovic (Saint-Cloud), P. Dalivoust (Marseille), J. Dauba (Calais), P. Debourdeau (Clamart), B. Demuynck (Bagnolet), J. Doll (Le Chesnay), E. Dorval (Tours), B. Dreyfus (Poitiers), J.L. Duval (Toulon), F. Economides (Dunkerque), P. Euvrard (Venissieux), J. Ezenfis (Paris), J.P. Fauchart (Charleville-Mezières), R. Favre (Marseille), D. Faysse (Lyon), L. Fenoll (St-Doulchard), J. Fournet (Grenoble), F. Fruge (Poitiers), G. Ganem (Le Mans), L. Gasnault (Dunkerque), J.L. Gaudin (Lyon), B. Gayet (Paris), P. Geoffroy (Epernay), P. Gomez (Rouen), S. Greget (La Réunion), L. Hannoun (Paris), M. Hebbar (Lille), F. Hedelius (Saint-Priest), F. Hennebelle (Gien), S. Houry (Paris), E. Jonveaux (Charleville-Mezières), A. Kanoui (Sarcelles), M. Kohn (Epinay sur Seine), H. Lacroix (Nantes), B. Landi (Paris), P. Lapleige (Blois), A. Laugros (Freyming-Merlebach), G. Lledo (Lyon), B. Leduc (Brive), A. Lerol (Eaubonne), E. Leroy-Terquem (Meulan), G. Letanche (Givors), J.P. Lotz (Paris), M. Maigre (Saumur), E. Malaurie (Créteil), J. Mandet (Mareuil les Meaux), P. Marti (Pau), C. Maurel (Vannes), M.P. Meurisse (Libourne), L. Mignot (Suresnes), P. Mital (Arras), S. Moreau (Paris), F. Morvan (Pontoise), M. Mousseau (Grenoble), T. Muron (Saint-Etienne), S. Nahon (Montfermeil), A. Naouri (Macon), S. Nasca (Reims), M. Noirclerc (Mulhouse), P. Nouyrigat (Hyères), S. Oudard (Paris), J.F. Paitel (La Rochelle), R. Parc (Paris), A. Pasturaud (Le Port Marly), D. Pezet (Clermont-Ferrand), D. Pillon (Bourg en Bresse), C. Platini (Thionville), J.F. Pollet (Marseille), Y. Raoul (Saint-Grégoire), J.L. Ratoanina (La Martinique), Y. Rinaldi (Marseille), M.L. Rouhier (Saumur), C. Rozec (Paris), F. Selle (Paris), C. Stampsli (Laval), F. Talarmin (Metz), A. Thiellet (Meudon la Forêt), E. Tirret (Paris), J. Toumieux (Chateauroux), C. Tournigand (Paris), E. Vaillant (Vienne), J.M. Vannetzel (Neuilly), C. Varette (Quincy sous Senart), C. Vilain (Montargis), S. Walter (Metz), and J.L. Wendling (Toulon).

View larger version (12K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig A1. Disease-free survival according to treatment. mFU/LV, monthly fluorouracil and leucovorin; LV5FU2, fluorouracil and leucovorin semimonthly.

View larger version (12K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig A2. Disease-free survival according to treatment duration.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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

Employment or Leadership Position: Pascal Piedbois, Astra Zeneca (U) Consultant or Advisory Role: None Stock Ownership: None Honoraria: Thierry André, Baxter; Aimery de Gramont, Baxter Research Funding: None Expert Testimony: None Other Remuneration: None

	AUTHOR CONTRIBUTIONS

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

 
Conception and design: Thierry André, Philippe Colin, Marc Buyse, Aimery de Gramont

Administrative support: Thierry André

Provision of study materials or patients: Thierry André, Philippe Colin, Erick Gamelin, Olivier Bouche, Emmanuel Achille, Pascal Piedbois, Nicole Tubiana-Mathieu, Arnaud Boutan-Laroze, Michel Flesch, Gérard Lledo, Yves Raoul, Aimery de Gramont

Collection and assembly of data: Thierry André, Christophe P. Louvet, Isabelle Debrix

Data analysis and interpretation: Thierry André, Emmanuel M. Quinaux, Christophe Louvet, Marc Buyse

Manuscript writing: Thierry André, Emmanuel Quinaux, Christophe Louvet, Pascal Piedbois, Isabelle Debrix, Marc Buyse, Aimery de Gramont

Final approval of manuscript: Thierry André, Emmanuel Quinaux, Christophe Louvet, Philippe Colin, Erick Gamelin, Olivier Bouche, Emmanuel Achille, Pascal Piedbois, Nicole Tubiana-Mathieu, Arnaud Boutan-Laroze, Flesch Michel, Gérard Lledo, Yves Raoul, Isabelle Debrix, Marc Buyse, Aimery de Gramont

	NOTES

 
Supported by grants from the Association Pour la Recherche en Cancérologie (APREC) and from Wyeth (Lederle and Puteaux, France) and Baxter (Maurepas, France).

Presented in part at the 41st Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 13-17, 2005.

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

	REFERENCES

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Submitted April 19, 2007; accepted May 30, 2007.

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