Journal of Clinical Oncology, Vol 24, No 31 (November 1), 2006: pp. 4991-4997
© 2006 American Society of Clinical Oncology.
DOI: 10.1200/JCO.2006.06.8429
Phase III Study of Docetaxel and Cisplatin Plus Fluorouracil Compared With Cisplatin and Fluorouracil As First-Line Therapy for Advanced Gastric Cancer: A Report of the V325 Study Group
Eric Van Cutsem,
Vladimir M. Moiseyenko,
Sergei Tjulandin,
Alejandro Majlis,
Manuel Constenla,
Corrado Boni,
Adriano Rodrigues,
Miguel Fodor,
Yee Chao,
Edouard Voznyi,
Marie-Laure Risse,
Jaffer A. Ajani
From the University Hospital Gasthuisberg, Leuven, Belgium; N.N. Petrov Research Institute of Oncology, St Petersburg; N.N. Blokhin Cancer Research Center; Russian Scientific Centre of Radiology, Moscow, Russia; Fundación Arturo López Pérez; Hospital Clinico Universidad de Chile, Santiago, Chile; C.H. de Pontevedra, Pontevedra, Spain; Arcispedale Santa Maria Nuova, Reggio Emilia, Italy; Hospitais da Universidade de Coimbra, Coimbra, Portugal; Taipei Veterans General Hospital, Taipei, Taiwan; sanofi aventis, Antony, France; and The University of Texas M.D. Anderson Cancer Center, Houston, TX
Address reprint requests to Jaffer A. Ajani, MD, Department of Gastrointestinal Medical Oncology, University of Texas M.D. Anderson Cancer Center, Mail Stop 4261, 1515 Holcombe Blvd, Houston, TX 77030; e-mail: jajani{at}mdanderson.org
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ABSTRACT
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Purpose In the randomized, multinational phase II/III trial (V325) of untreated advanced gastric cancer patients, the phase II part selected docetaxel, cisplatin, and fluorouracil (DCF) over docetaxel and cisplatin for comparison against cisplatin and fluorouracil (CF; reference regimen) in the phase III part.
Patients and Methods Advanced gastric cancer patients were randomly assigned to docetaxel 75 mg/m2 and cisplatin 75 mg/m2 (day 1) plus fluorouracil 750 mg/m2/d (days 1 to 5) every 3 weeks or cisplatin 100 mg/m2 (day 1) plus fluorouracil 1,000 mg/m2/d (days 1 to 5) every 4 weeks. The primary end point was time-to-progression (TTP).
Results In 445 randomly assigned and treated patients (DCF = 221; CF = 224), TTP was longer with DCF versus CF (32% risk reduction; log-rank P < .001). Overall survival was longer with DCF versus CF (23% risk reduction; log-rank P = .02). Two-year survival rate was 18% with DCF and 9% with CF. Overall response rate was higher with DCF ( 2 P = .01). Grade 3 to 4 treatment-related adverse events occurred in 69% (DCF) v 59% (CF) of patients. Frequent grade 3 to 4 toxicities for DCF v CF were: neutropenia (82% v 57%), stomatitis (21% v 27%), diarrhea (19% v 8%), lethargy (19% v 14%). Complicated neutropenia was more frequent with DCF than CF (29% v 12%).
Conclusion Adding docetaxel to CF significantly improved TTP, survival, and response rate in gastric cancer patients, but resulted in some increase in toxicity. Incorporation of docetaxel, as in DCF or with other active drug(s), is a new therapy option for patients with untreated advanced gastric cancer.
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INTRODUCTION
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Gastric cancer is the second most common cause of cancer death worldwide.1 Advanced gastric cancer patients have a poor prognosis with a median survival time, if untreated, of 3 to 5 months.2-4 There has been little progress in the therapy for patients with advanced disease; only a few large randomized phase III trials have been conducted in the past decade.5-9 Patient selection (localized v metastatic; gastric v esophageal; potentially resectable v unresectable), trial methodology (with regard to stratification, principal end points, statistical methods, and expectations), and data monitoring have varied greatly among trials.6-9 The results have been mostly unsatisfactory and, therefore, an acceptable standard regimen has not emerged. Clearly, new active regimens are needed to improve the outcome for gastric cancer patients.
Docetaxel has shown activity against gastric cancer as monotherapy10-15 and in combination with other agents.16-19 To investigate whether adding docetaxel to a reference regimen of cisplatin and fluorouracil (CF) could improve patient outcomes (time-to-progression [TTP], overall survival [OS], quality of life, and response rate for palliation), a multinational, multi-institutional, open-label, randomized phase II/III study, V325, was designed. The phase II randomized part of the V325 study examined which of two docetaxel-containing combinations should be investigated in the phase III part: 155 patients received either docetaxel, cisplatin, and fluorouracil (DCF) or docetaxel and cisplatin (DC) and, based on overall response rate and safety data, the independent data monitoring committee selected DCF for comparison in the phase III part of the trial versus CF.20 The primary end point of the phase III part was TTP; OS was one of the secondary end points. Herein we discuss the final efficacy and safety analyses of the phase III part of V325 involving the 445 patients randomly assigned to this phase III part.
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PATIENTS AND METHODS
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Patient Characteristics
Major inclusion criteria were: age 18 years or older; histologically proven gastric or esophagogastric junction adenocarcinoma; measurable and/or assessable metastatic disease according to WHO criteria,21 or locally recurrent disease associated with one or more measurable lymph nodes; Karnofsky performance status higher than 70; no prior palliative chemotherapy; 6 weeks or longer from prior radiotherapy and 3 weeks or longer from surgery; adequate hepatic, renal, and hematologic function. Major exclusion criteria were concurrent cancer, neuropathy, brain, or leptomeningeal involvement, uncontrolled significant comorbid conditions, or if patient could not comprehend the purpose of the study and could not comply with its requirements. The protocol was approved by the institutional review board at each center. Patients provided written informed consent. An independent data monitoring committee evaluated safety throughout the V325 study period.
Stratification and Treatment
Random assignment was centralized and stratified for center, liver metastases, prior gastrectomy, measurable versus assessable cancer, and weight loss during the past 3 months ( 5% v > 5%). Patients were randomly assigned (1:1) to either docetaxel (Taxotere; sanofi-aventis, Paris, France) 75 mg/m2 (1-hour intravenous infusion) plus cisplatin 75 mg/m2 (1- to 3-hour intravenous infusion) on day 1, followed by fluorouracil 750 mg/m2/d (continuous intravenous infusion) for 5 days (DCF) every 3 weeks or cisplatin 100 mg/m2 on day 1 followed by fluorouracil 1,000 mg/m2/d for 5 days (CF) every 4 weeks. Dose modification criteria were predefined. All patients received appropriate hydration and premedications as previously reported.20 Treatment continued until disease progression, unacceptable toxicity, death, or consent withdrawal.
Evaluation and Outcomes
Before random assignment, a complete medical history and physical examination were undertaken, including CBC, blood chemistries, and tumor assessments. Tumor measurements were undertaken every 8 weeks until progression in both arms to avoid bias in TTP calculations. All radiologic assessments were reviewed by an external response review committee and were assessed by WHO criteria.21 TTP was measured from the day of random assignment to first evidence of progression or death occurring within 12 weeks of the last assessable tumor assessment. Survival was defined from the date of random assignment to death from any cause. Toxicities were graded according to the National Cancer Institute of Canada Common Toxicity Criteria, version 1.0.
Quality of life was assessed at the same intervals as tumor assessments and data were collected every 3 months after disease progression, using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ) -C30, version 3.22 Time to 5% definitive deterioration in global health status assessed by QLQ-C30 was the primary quality of life parameter; time to definitive worsening of Karnofsky performance status by one or more categories was the primary clinical benefit end point.
Statistical Analysis
The primary objective was to demonstrate superiority in TTP for DCF over CF, using an unstratified log-rank test with a two-sided 5% significance level, from 4 months (CF) to 6 months (DCF), corresponding to a hazard ratio (HR) of 1.5 with a 95% power, requiring at least 325 events with 230 patients per arm. The major secondary objective was to demonstrate superiority in OS for DCF over CF, using the unstratified log-rank test with a two-sided 5% significance level, from 8 months to 12 months, corresponding to a HR of 1.5, and requiring at least 325 events. The Kaplan-Meier method was used to calculate TTP and OS. Overall response rates were compared using a 2 test. A HR more than 1 showed the efficacy benefit to be in favor of DCF.
TTP and OS were calculated on the predefined full analysis population (all randomly assigned and treated patients). Patients were considered assessable for response if they received two or more chemotherapy cycles (except for early progression). Safety analyses included all treated patients and involved the analysis of treatment-emergent adverse events (ie, those occurring or worsening during the treatment period), including events possibly or probably related to study medication and those regardless of causality.
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RESULTS
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Patients
A total of 457 patients (DCF = 227; CF = 230) were randomly assigned from 72 centers in 16 countries between November 1999 and January 2003; 445 patients (DCF = 221; CF = 224) received the allocated combination and, thus, comprised the full analysis population and were analyzed for efficacy and safety. Both treatment groups were well balanced for baseline characteristics (Table 1). At baseline, 84% of patients had clinical signs and symptoms with 27% being severe (grade 3 or 4 by National Cancer Institute of Canada Common Toxicity Criteria, version 1.0). Fifty-seven percent of patients had 5% or greater weight loss 3 months before registration.
Chemotherapy
In total, 1,186 cycles of DCF and 906 cycles of CF were administered, with a median of six cycles with DCF (range, 1 to 16) and four with CF (range, 1 to 12; Table 2). The median time between random assignment and first intravenous infusion was similar between both arms: 1 day (0 to11) in the DCF arm and 1 day (0 to 11) in the CF arm. The median duration of therapy was 19 weeks with DCF (range, 3 to 56 weeks) and 16 with CF (range, 4 to 50 weeks). The median actual dose intensities of fluorouracil and cisplatin were similar in both arms. Cycle delays occurred in 141 patients (64%) for DCF and 95 patients (42%) for CF. Dose reductions occurred in 91 patients with DCF (41%) and 81 patients with CF (36%). In both arms, the fluorouracil dose was most commonly reduced. Gastrointestinal toxicities were the most common adverse events leading to dose reduction in DCF and CF. The most common adverse event leading to cycle delay was lethargy for DCF and neutropenia for CF. The main reason for therapy discontinuation was progressive disease in both groups, although this was less frequent with DCF than CF (30% v 44%), followed by adverse events (27% v 25%), consent withdrawal (22% v 12%), and death (10% v 9%; Table 2). The median number of chemotherapy cycles for patients withdrawing consent was six for DCF and five for CF. Based on the number of patients treated at an individual cycle, the percentage of patients within each cycle who discontinued due to consent withdrawal was similar between the treatment arms. The percentage of patients with grade 3 to 4 adverse events at the last cycle before consent withdrawal was similar between both arms (46% in the DCF arm and 42% in the CF arm).
Efficacy: Primary End Point (TTP)
At a median follow-up of 13.6 months, 341 (77%) of 445 patients had progressive cancer. The median TTP was significantly longer for DCF versus CF (5.6 months; 95% CI, 4.9 to 5.9; v 3.7 months; 95% CI, 3.4 to 4.5; HR, 1.47; 95% CI, 1.19 to 1.82; log-rank P < .001; risk reduction 32%; Fig 1A). Of note, 32% and 41% of patients received further chemotherapy in the DCF and CF arms, respectively.
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Fig 1. (A) Kaplan-Meier estimates of (A) time to progression and (B) overall survival among chemotherapy-naïve advanced gastric cancer patients treated with docetaxel, cisplatin, and fluorouracil (DCF) or cisplatin and fluorouracil (CF; full analysis population).
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Efficacy: Secondary End Point (OS)
At a median follow-up time of 23.4 months, 162 patients (73%) on DCF and 172 patients (77%) on CF had died. The median OS was significantly longer for DCF versus CF (9.2 months; 95% CI, 8.4 to 10.6; v 8.6 months; 95% CI, 7.2 to 9.5; HR, 1.29; 95% CI, 1.0 to 1.6; log-rank P = .02; risk reduction 23%; Fig 1B). The fraction of patients alive at 1 year was 40% for DCF and 32% for CF and at 2 years was 18% for DCF and 9% for CF.
Efficacy: Secondary End Point (Overall Response Rate)
The overall confirmed response rate was significantly higher with DCF (37%) than CF (25%; P = .01; Table 3). Prolonged duration of response ( 9 months from the onset of the response) was noted in 21 patients with DCF and 8 patients with CF.
Safety: Secondary End Point
All patients on DCF experienced at least one treatment-emergent adverse event (irrespective of relationship to treatment), as did all but three patients on CF. However, related grade 3 or 4 treatment-emergent adverse events occurred in 69% of patients on DCF and 59% of patients on CF. Main related treatment-emergent adverse events are summarized in Table 4.
Grade 3 to 4 neutropenia was more frequent with DCF, as was complicated neutropenia (febrile neutropenia or neutropenic infection: 29% with DCF and 12% with CF). In the DCF arm, complicated neutropenia was 27% without and 12% with the use of secondary granulocyte colony-stimulating factor prophylaxis. In patients age 65 years or older, grade 3 to 4 infection (related to treatment) was more frequent with DCF (20%) than CF (9%). The number of deaths occurring within 30 days of the last infusion was 23 (10%) with DCF and 19 (8%) with CF. The main cause of toxic deaths was infection in both arms (7 of 8 in DCF; 8 of 12 in CF); this occurred mainly in cycle one of DCF treatment.
Quality of Life and Clinical Benefit
The time to 5% deterioration of global health status (QLQ-C30) was significantly longer for DCF than CF (HR 1.44; 95% CI, 1.08 to 1.93; log-rank P = .01). Furthermore, the time to definitive worsening of Karnofsky performance status was significantly longer for DCF than CF (log-rank P = .009; HR 1.38; 95% CI, 1.08 to 1.76).
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Fig 2. The CONSORT diagram depicting the trajectory of the trial. *Due to adverse event (n = 8), death (n = 6), consent withdrawn (n = 2), lost to follow-up (n = 1).  Due to adverse event (n = 9), death (n = 7), consent withdrawn (n = 4), progression at D4 cycle 1 (n = 1).  One patient in this group was also ineligible because of early withdrawal due to consent being withdrawn.  Two patients in this group were also ineligible because of early withdrawals due to adverse event (n = 1) and consent being withdrawn (n = 1). DCF, docetaxel, cisplatin, and fluorouracil; CF, cisplatin and fluorouracil; TTP, time-to-progression; FAP, full analysis population; SP, safety population.
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DISCUSSION
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The V325 phase III study in patients with advanced gastric cancer showed that adding docetaxel to CF significantly improved TTP, survival, and overall response rate compared with CF, although with an expected increase in toxicities. These efficacy results with DCF are particularly important given that a new drug has not been approved for the treatment of advanced gastric cancer in the last 20 years and, of the few randomized trials performed, nearly all have been disappointing5-9 (mostly due to poor efficacy). The strategy of combining a new active agent with the reference regimen and comparing it to that regimen has been successfully used in numerous phase III trials in pancreatic cancer and colon cancer,23-29 but has been rarely employed for advanced gastric cancer, in part because of a lack of a globally accepted reference treatment. However, cisplatin-based combinations (particularly CF) have been accepted as one of the references against which new regimens may be compared. The V325 study compared docetaxel in combination with CF versus CF alone. Consequently, this trial provides a clear understanding of the impact on efficacy and safety of adding docetaxel to CF.
Compared with recent randomized phase III trials in advanced gastric cancer,5-7 the V325 study population had a very poor prognosis: 97% of patients had metastatic cancer, 81% had two or more organs involved, 84% were symptomatic at baseline, and 57% had more than 5% weight loss. Furthermore, patients were excluded if they could potentially undergo tumor resection after a response. This contrasts with previous studies where 13% to 40% of included patients had locally advanced disease that was potentially resectable after tumor response.6,7,30 In the V325 study, patients were stratified for five factors and the study had 95% power to detect differences in TTP or OS. Overall response rates, as well as the dates of progression, were reviewed and confirmed by the external response review committee, while the independent data monitoring committee continuously monitored the study. V325 is the first global phase III randomized study conducted by investigators from 72 institutions in 16 countries. Thus, V325 was a highly monitored trial that aspired to avoid methodologic deficiencies.
The median administered dose intensity of cisplatin and fluorouracil was the same for the DCF and CF arms. Furthermore, the V325 results with CF appear consistent with those previously published, in particular, the study by Dank and colleagues.8 Therefore, we could evaluate the impact of adding docetaxel to CF on efficacy and safety. Treatment with DCF reduced the risk of disease progression by 32% (log-rank P < .001) and reduced the risk of death by 23% (log-rank P = .02) compared with CF. Although the curves came near each other at the median survival point, considerable benefit was observed in the late observation period with the 2-year survival rate of 18% for DCF and 9% for CF. A 2-year survival rate exceeding 11% has only been observed in one other trial, a multicenter randomized trial in which 40% of the patients had locally advanced disease and half of the locally advanced patients with response underwent secondary surgery.5
Treatment with DCF resulted in a higher frequency of complicated neutropenia than CF, emphasizing the need for vigilant patient selection, education, monitoring, and active management. As most treatment-related fatal infections (the main cause of treatment-related deaths) occurred at cycle one and were concomitant with grade 3 to 4 neutropenia, primary prophylactic granulocyte colony-stimulating factor should be strongly considered in the management of these patients. Interestingly, the higher incidence of toxicity seen with DCF did not appear to impact quality of life and clinical benefit, which were significantly favorable in the DCF arm and may have been due to higher antitumor activity of DCF.
DCF should be considered as one of the reference regimens. But the quest to find more active combinations must continue. To make considerable improvements in the coveted end points (particularly, OS), the addition of targeted agents to active chemotherapy will be required. Such efforts could lead to a prolongation of TTP beyond 6 months and OS beyond 12 months, more consistently. The addition of another cytotoxic to established combinations is not likely to be well tolerated or efficacious. In order to make rapid progress in this field, it would be important to focus on meticulously designed phase III trials with a large sample size (at least 600) that are asking superiority questions (with enough statistical power to clearly discern OS differences), using rigorous trial methodology, and comparing a chemotherapy combination (for example, DCF) with a novel biochemotherapy combination that has a favorable safely profile and promising efficacy profile. In addition, correlative research with studies of patient genetics and tumor biology should become an integral part of such trials and could speed up the urgently needed progress and understanding of this disease.
In conclusion, the final results of the V325 study demonstrate that the addition of docetaxel to CF, a reference regimen, resulted in significantly improved TTP (primary end point), OS, and overall response rate (secondary end points), with global health status (quality of life) and Karnofsky performance status (clinical benefit) preserved for a longer time. Addition of docetaxel, as in DCF or with other active drug(s), is a new option for therapy for untreated gastric carcinoma.
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Appendix
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Funded by sanofi-aventis. The following sanofi-aventis personnel are acknowledged: A. Ardouin (Study Data Manager); A. Blattmann (International Clinical Trial Manager); M. Kopreski (Pharmacovigilance); C. Marabotti (Statistician); P. O'Grady (Editorial), I. Rasolofirina (Data Manager); S. Thompson (Statistician); N. Yateman (Statistician).
We thank the following investigators and institutions for their participation in this study: A. Anelli (Hospital AC Camargo, São Paolo, Brazil); P. Arbeloa (Centro ATACA, San Cristobal, Venezuela); C. Azevedo (Instituto Portugues de Oncologia, Porto, Portugal); L. Baez (Veterans' Administration Medical Center, Puerto Rico, United States); K. Bakri (Fear Valley Health System Medical Oncology/Cancer Center, Fayetteville, NC, United States); C. Barone (Universita Cattolica del Sacro Coure, Rome, Italy); S. Barroso (Hospital Distrital de Beja, Beja, Portugal); A. B. Benson III (Northwestern University Medical Center, Chicago, IL, United States); S. Cabral Filho (Pça Hugo Werneck Ambulatorio de Oncologia Clinica, Belo Horizonte, Brazil); J. S. Chen (Chang Gung Memorial Hospital Kweishen, Taoyuan, Taiwan); M. Clemens (Mutterhaus der Borromäerinnen, Trier, Germany); P. F. Conte (Universita degli Studi di Modena e Reggio Emilia Policlinico, Modena, Italy); P. Crilley (MCP-Hahnermann University, Philadelphia, PA, United States); J. De Grève (Centre of Oncology, Bruxelles, Belgium); F. Di Costanzo (U.O. di Chemioterapia e Terapia, Terni, Italy); J. Feldmann (Gulf Coast Oncology, Mobile, AL, United States); F. Fontes (Instituto Portugues de Oncologia de Coimbra, Coimbra, Portugal); E. Goker (Ege University, Izmir, Turkey); M. Gonzalez Baron (Hospital Universitario La Paz, Madrid, Spain); C. Gravalos (Hospital Universitario, Madrid, Spain); F. A. Greco (The Sarah Cannon Cancer Center, Nashville, TN, United States); D. Haller (Penn Cancer Center, Philadelphia, PA, United States); A. Hatfield (Carle Clinic Association/Carle Cancer Center, Urbana, IL, United States); W. J. Heim (Hematology and Oncology Associates of Northeastern PA, Dunmore, PA, United States); G. R. Justice (Pacific Coast Hematology/Oncology Medical Group Inc., Fountain Valley, CA, United States); D. P. Kelsen (Memorial Sloan-Kettering Cancer Center, NY, United States); R. J. Kirschling (St Luke's Speciality Clinic, Duluth, MN, United States); C. H. Koehne (Carl-Gustav-Carus der TU Dresden, Dresden, Germany); H. Kroening (Am Hasselbachplatz, Magdeburg, Germany); R. C. Lilenbaum (Mount Sinai Comprehensive Cancer Center, Miami Beach, FL, United States); A. Malzyner (Clinica de Oncologia Medica, Sao Paulo, Brazil); R. de W. Marsh (University of Florida, Gainesville, FL, United States); J. I. Martinez (Clinical San Rafael Carrera, Bogota, Colombia); J. Mauricio (Instituto Portuges de Oncologia, Porto, Portugal); J. McCann (Baystate Medical Center, Springfield, MA, United States); D. Mecarocci (U.O. di Chemioterapia e Terapia, Terni, Italy); E. P. Mitchell (Kimmel Cancer Center, Philadelphia, PA, United States); G. Morgan (Centro Medico de Occidente, Guadalajara, Mexico); C. Narvaez (Hospital Departamental de Pasto Carrera, Pasto, Colombia); P. Nunez (Padre Machado El Cementerio, Caracas, Venezuela); G. Olivares (Centro Medico Nacional Hospital de Oncologia, Mexico City, Mexico); L. Olivatto (INCA, Rio de Janeiro, Brazil); F. Olivella (National Cancer Institute Carrera, Bogota, Colombia); C. Ortiz (Hospital San Ignacio Carrera, Bogota, Colombia); H. Ozer (MCP-Hahnermann University, Philadelphia, PA, United States); L. Pandit (Pacific Coast Hematology/Oncology Medical Group Inc., Fountain Valley, CA, United States); F. Pasini (Medica Ospedale Civile Maggiore, Verona, Italy); J. Picus (Washington University School of Medicine, St Louis, MI, United States); F. L. Pimentel (Hospital de Sao Sebastiao, Santa Maria, Portugal); P. Pizao (Cidade Universitaria Zeferino Vaz, Campinas, Brazil); C. A. Presant (California Cancer Medical Center, West Covina, CA, United States); K. Rowland (Carle Clinic Association/Carle Cancer Center, Urbana, IL, United States); R. Sagarra (Cidade Universitaria Zeferino Vaz, Campinas, Brazil); J. F. Salas (Hospital Essalud Guillermo Almenara I, Lima, Peru); T. Salek (National Cancer Institute, Bratislava, Slovak Republic); L. Santos Matos (Hospital de pulido Valente, Lisbon, Portugal); J. Sastre (Hospital Clinico Universitario San Carlos, Madrid, Spain); A. P. Scholnik (Breslin Cancer Center, Lansing, MI, United States); D. C. Scullin Jr (Consultants in Blood Disorders and Cancer, Louisville, KY, United States); V. Silingardi (Universita degli Studi di Modena e Reggio Emilia Policlinico, Modena, Italy); G. Tekuzman (Hacettepe University, Ankara, Turkey); J. P. Thomas (University of Wisconsin, Madison, WI, United States); M. Tonato (Divisione di Oncologia Medica, Perugia, Italy); C. S. Vallejos (Instituto De Enfermedades Neoplasicas "Eduardo Caceres Grazinai," Lima, Peru); J. L. Van Laethem (Hôpital Erasme, Bruxelles, Belgium); I. Vochyanova (Oncology Institute St Elisabeth, Bratislava, Slovak Republic); U. Yilmaz (Eylül University, Izmir, Turkey).
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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.
| Authors |
Employment |
Leadership |
Consultant |
Stock |
Honoraria |
Research Funds |
Testimony |
Other |
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| Eric Van Cutsem |
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sanofi-aventis |
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| Vladimir M. Moiseyenko |
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sanofi-aventis |
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| Sergei Tjulandin |
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sanofi-aventis |
sanofi-aventis |
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| Alejandro Majlis |
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sanofi-aventis |
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| Manuel Constenla |
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sanofi-aventis |
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| Corrado Boni |
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sanofi-aventis |
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| Adriano Rodrigues |
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sanofi-aventis |
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| Yee Chao |
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sanofi-aventis |
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| Edouard Voznyi |
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sanofi-aventis |
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| Marie-Laure Risse |
sanofi-aventis |
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sanofi-aventis |
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| Jaffer A. Ajani |
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sanofi-aventis |
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sanofi-aventis |
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Author Contributions
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| Conception and design: Eric Van Cutsem, Jaffer A. Ajani
Administrative support: Marie-Laure Risse
Provision of study materials or patients: Eric Van Cutsem, Vladimir M. Moiseyenko, Sergei Tjulandin, Alejandro Majlis, Manuel Constenla, Corrado Boni, Adriano Rodrigues, Miguel Fodor, Yee Chao, Edouard Voznyi, Jaffer A. Ajani
Collection and assembly of data: Marie-Laure Risse
Data analysis and interpretation: Eric Van Cutsem, Marie-Laure Risse, Jaffer A. Ajani
Manuscript writing: Eric Van Cutsem, Vladimir M. Moiseyenko, Sergei Tjulandin, Alejandro Majlis, Manuel Constenla, Corrado Boni, Adriano Rodrigues, Miguel Fodor, Yee Chao, Edouard Voznyi, Marie-Laure Risse, Jaffer A. Ajani
Final approval of manuscript: Jaffer A. Ajani
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ACKNOWLEDGMENTS
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This study was funded by sanofi-aventis. Numerous individuals from many institutions participated to complete this study. The representative authors are grateful for everyone's effort.
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NOTES
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Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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REFERENCES
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Submitted March 29, 2006;
accepted July 25, 2006.
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TOP
ABSTRACT
INTRODUCTION
