Originally published as JCO Early Release 10.1200/JCO.2006.09.8467 on June 4 2007

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Phase III Study of Capecitabine Plus Oxaliplatin Compared With Continuous-Infusion Fluorouracil Plus Oxaliplatin As First-Line Therapy in Metastatic Colorectal Cancer: Final Report of the Spanish Cooperative Group for the Treatment of Digestive Tumors Trial

Eduardo Díaz-Rubio, Jose Tabernero, Auxiliadora Gómez-España, Bartomeu Massutí, Javier Sastre, Manuel Chaves, Alberto Abad, Alfredo Carrato, Bernardo Queralt, Juan José Reina, Joan Maurel, Encarnación González-Flores, Jorge Aparicio, Fernando Rivera, Ferrán Losa, Enrique Aranda

From the Department of Medical Oncology, Hospital Clinico Universitario San Carlos, Madrid; Hospital Vall d’Hebrón, University Barcelona; Hospital Clinic; Hospital Hospitalet, Barcelona; Hospital Reina Sofia, Córdoba; Hospital General, Alicante; Hospital Virgen Rocio, Sevilla; Hospital Germans Trias i Pujol, Badalona; Hospital Universitario Elche, Alicante; ICO, Girona; Hospital J. Ramón Jimenez, Huelva; Hospital Virgen de las Nieves, Granada; Hospital la Fe, Valencia; and the Hospital Marqués Valdecilla, Santander, Spain

Address reprint requests to Eduardo Díaz-Rubio, PhD, Servicio de Oncologia Medica, Hospital Clínico San Carlos, 28040 Madrid, Spain; e-mail: ediazrubio.hcsc{at}salud.madrid.org

	ABSTRACT

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Purpose The aim of this phase III trial was to compare the efficacy and safety of capecitabine plus oxaliplatin (XELOX) versus Spanish-based continuous-infusion high-dose fluorouracil (FU) plus oxaliplatin (FUOX) regimens as first-line therapy for metastatic colorectal cancer (MCRC).

Patients and Methods A total of 348 patients were randomly assigned to receive XELOX (oral capecitabine 1,000 mg/m² bid for 14 days plus oxaliplatin 130 mg/m² on day 1 every 3 weeks) or FUOX (continuous-infusion FU 2,250 mg/m² during 48 hours on days 1, 8, 15, 22, 29, and 36 plus oxaliplatin 85 mg/m² on days 1, 15, and 29 every 6 weeks).

Results There were no significant differences in efficacy between XELOX and FUOX arms, which showed, respectively, median time to tumor progression (TTP; 8.9 v 9.5 months; P = .153); median overall survival (18.1 v 20.8 months; P = .145); and confirmed response rate (RR; 37% v 46%; P = .539). The safety profile of the two regimens was similar, although there were lower rates of grade 3/4 diarrhea (14% v 24%) and grade 1/2 stomatitis (28% v 43%), and higher rates of grade 1/2 hyperbilirubinemia (37% v 21%) and grade 1/2 hand-foot syndrome (14% v 5%) with XELOX versus FUOX, respectively.

Conclusion This randomized study shows a similar TTP of XELOX compared with FUOX in the first-line treatment of MCRC, although there was a trend for slightly lower RR and survival. XELOX can be considered as an alternative to FUOX.

	INTRODUCTION

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Oxaliplatin has been combined successfully with both bolus and infusional regimens of fluorouracil and leucovorin (FU/LV) to achieve significant improvements in efficacy in first-line metastatic colorectal cancer (MCRC) treatment^1-3 and in the adjuvant setting^4,5 when compared with FU/LV alone.

Capecitabine is an oral fluoropyrimidine that generates FU preferentially in tumor tissue by exploiting the increased expression of the enzyme thymidine phosphorylase in tumors.^6,7 Data from phase III trials show that capecitabine can replace bolus FU/LV as first-line therapy for MCRC^8-10 and in the adjuvant setting,¹¹ with the added benefits of improved safety and convenience.^12,13 Capecitabine has also been combined successfully with oxaliplatin (XELOX) to produce an effective first-line regimen for MCRC as demonstrated in phase II studies.^14-16

We therefore considered it appropriate to compare the efficacy and safety of XELOX with the Spanish Cooperative Group for the Treatment of Digestive Tumors (TTD) regimen, which uses weekly high-dose FU in continuous infusion (CIV) plus oxaliplatin (FUOX), without LV,^17-19 in a phase III trial in the first-line treatment of MCRC.

	PATIENTS AND METHODS

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Study Design
This study was a multicenter, randomized, open-label, phase III trial designed to compare the efficacy and safety of XELOX and FUOX in the first-line treatment of MCRC. Local ethics committee approval was obtained before enrollment of any patient into the study, which was performed in accordance with the Declaration of Helsinki and its subsequent amendments as well as Good Clinical Practice Guidelines. Signed informed consent was obtained from all patients before study entry.

Patient Population
Outpatients age 18 years with histologically confirmed MCRC, a Karnofsky performance status 70%, and a life expectancy more than 3 months were enrolled. All patients had to have at least one measurable lesion according to Response Evaluation Criteria in Solid Tumors Group criteria.²⁰ Adjuvant chemotherapy (fluoropyrimidine with or without LV), if administered, should have been completed more than 1 year before study entry.

Patients had to have adequate hematologic (hemoglobin 10 mg%, neutrophil count 1.5 x 10⁹/L, and platelets 100 x 10⁹/L), hepatic (serum bilirubin < 2.0x upper normal limit [UNL]; AST and ALT values 2.5x UNL in the absence of hepatic metastases or 5x UNL in the presence of hepatic metastases; and alkaline phosphatase 2.5x ULN or 5x ULN in case of hepatic or bone metastases), and renal function (creatinine clearance 1.5x ULN). Pregnant or breast-feeding women were excluded. Other exclusion criteria were clinically significant cardiac disease or myocardial infarction within the last 12 months; severe renal failure (creatinine clearance < 30 mL/min); lack of physical integrity of the upper GI tract; peripheral neuropathy; history of other malignancy except cured basal cell carcinoma or in situ cervical carcinoma; or CNS metastases.

Treatment Plan
Patients were randomly assigned to either XELOX (3-week cycle) or FUOX (6-week cycle) using a centrally generated computer randomization code. XELOX consisted of oral capecitabine 1,000 mg/m² bid for 14 days plus oxaliplatin 130 mg/m² on day 1 every 3 weeks. FUOX consisted of FU 2,250 mg/m² diluted in saline administered by CIV during 48 hours on days 1, 8, 15, 22, 29, and 36, plus oxaliplatin 85 mg/m² on days 1, 15, and 29 every 6 weeks. Oxaliplatin was administered as a 120-minute intravenous infusion in 5% dextrose. Administration of antiemetics before oxaliplatin infusion depended on the investigator's judgment, although 5-hydroxytryptamine-3 antagonists were recommended. Patients were scheduled to receive a total of 12 cycles of XELOX and six cycles of FUOX (36 weeks in each group) or until disease progression, intolerable adverse events, or patient refusal to continue treatment. Patients with stable disease could continue to receive treatment after this period according to the judgment of the investigator. Patients could also continue capecitabine or FU single-agent therapy after discontinuation of oxaliplatin because of toxicity.

Patients were evaluated for adverse events before oxaliplatin administration and graded according to National Cancer Institute Common Toxicity Criteria version 2.0.²¹ Hand-foot syndrome was classified into three grades using a previously described system.²² Paresthesia was classified into four grades (1, dysesthesia with exposure to cold; 2, paresthesia; 3, paresthesia with pain; 4, paresthesia with functional deterioration).

Dose modifications to initial therapy were as described previously in the original XELOX¹⁴ and FUOX¹⁹ reports.

Assessments
Medical history, physical examination, routine blood analysis (hematology and biochemistry), and a pregnancy test for women of child-bearing age were performed within 1 week, and carcinoembryonic antigen and ECG measurements were performed within 3 weeks of entry. Imaging studies (including chest x-ray, computed tomography scans, and other examinations, as indicated) were performed within 4 weeks of study entry and were repeated every 12 weeks during treatment.

Response Evaluation Criteria in Solid Tumors Group guidelines²⁰ were used to define all responses after patients received at least 9 weeks of therapy as follows: complete response, partial response, stable disease, or progressive disease. Disease control was defined as the sum of patients achieving a complete response, partial response, or stable disease. Confirmation of all responses was required after 4 weeks. The response was assessed only by the investigators.

Statistical Analysis
The primary statistical analysis of efficacy was the comparison of time to tumor progression (TTP) between groups in the per-protocol population. To determine sample size, we used the results of a previously published trial of FUOX¹⁹ in the first-line therapy of MCRC,¹⁹ which showed a median TTP of approximately 7.0 months. We considered a noninferiority hypothesis when the median TTP in the XELOX arm was not lower than 5.5 months. These values corresponded to a hazard ratio less than 1.27. The sample size estimated for noninferiority with an = .05 and an 80% power was 165 patients in each treatment arm. Assuming a 5% loss of patients to follow-up, the total number of patients to be enrolled needed to be 348 (174 patients in each arm).

Comparison of baseline clinical and demographic characteristics between the treatment groups was made using Fisher's exact, t, or ² test depending on the distribution of the variables. An = .05 was used for all comparisons.

TTP was the primary end point of the study. Secondary end points were safety, response rate, time to treatment failure (TTF), overall survival (OS), and duration of response. TTP, TTF, OS, and duration of response were determined using the Kaplan-Meier method to provide the median value and 95% CIs. Treatment groups were compared using the log-rank test, and the Cox regression model was used to calculate the hazard ratio and to explore the relationship between survival and other variables.

Response rates were compared using ² statistics. Comparison of adverse events between the groups was performed using Fisher's exact test. The cutoff date for the analysis was June 15, 2006.

	RESULTS

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Patient Characteristics
From April 2002 to August 2004, 348 patients (intent-to-treat population) were enrolled at 29 Spanish centers and were randomly assigned to treatment: 174 to XELOX and 174 to FUOX. Six patients (three in each treatment arm) did not initiate study treatment, leaving 342 patients who constituted the per-protocol population (171 in each treatment arm; Appendix Fig A1, online only). Baseline demographic and clinical characteristics were well balanced between treatment arms (Table 1). However, significantly more patients in the XELOX arm (26%) than in the FUOX arm (16%) had received previous adjuvant chemotherapy (P = .032), which consisted of fluoropyrimidine therapy with or without LV.

View larger version (13K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Time to disease progression (TTP). FUOX, fluorouracil plus oxaliplatin; XELOX, capecitabine plus oxaliplatin; HR, hazard ratio.

View larger version (16K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Overall survival. FUOX, fluorouracil plus oxaliplatin; XELOX, capecitabine plus oxaliplatin; HR, hazard ratio.

Forty-five (27%) patients in each treatment arm discontinued treatment because of adverse events. The main reasons for the discontinuations with XELOX and FUOX, respectively, included neurologic toxicity (14 and 17 patients), oxaliplatin intolerance (two and three patients: allergic reactions, pharyngolaryngeal dysesthesias or gastrointestinal disorders), hematotoxicity (four and four patients), diarrhea (two and two patients), asthenia (zero and two patients), hepatic toxicity (zero and three patients), and cerebrovascular events (three and one patient).

Deaths were considered possibly related to treatment in four patients (one patient receiving XELOX and three patients receiving FUOX). Causes of death in these patients were febrile neutropenia, stomatitis, and thrombocytopenia in the patient receiving XELOX; pneumonia (n = 2) and septic shock (n = 1) in the three patients receiving FUOX. The 60-day mortality rates were 2% (n = 3) with XELOX and 3% (n = 5) with FUOX.

	DISCUSSION

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This study provides a piece of evidence that XELOX is an active and safe regimen for the treatment of patients with MCRC in the first-line setting. The efficacy of XELOX was not inferior to that of a CIV FUOX regimen, and both regimens showed a favorable safety profile. Regarding the primary end point of the trial, there was no a statistically significant difference in median TTP between the treatment arms. More importantly, the median TTPs in the two arms of this study were consistent with those observed in other studies of patients treated with regulatory agency–approved oxaliplatin combination chemotherapy schedules in the first-line setting.^1,23 TTP is a shorter-term end point compared with OS, and provides convincing evidence to allow a more accurate treatment comparison because the effect of second and successive treatment lines is not considered. There were no significant differences in the secondary efficacy end points of the study between the two treatment arms. However, the response rate and the median OS figures were somewhat lower in the XELOX arm than in the FUOX arm. Although patients were randomly assigned to study treatment, patients allocated to the XELOX arm were more likely to have received previous adjuvant chemotherapy than those in the FUOX arm (26% v 16%; P = .032). It is arguable that this imbalance may have created a bias toward a less favorable outcome in the XELOX group; nevertheless, the analysis of TTP (whether patients received adjuvant treatment or not) did not show any statistically significant difference (P = .527). Finally there were no differences in the opportunity to receive second-line chemotherapy in both arms (57.9% of the patients receiving XELOX and 58.5% of the patients receiving FUOX), or in the opportunity to undergo surgery for liver metastasis. As expected, a longer OS was observed in both arms in those patients that underwent an R0 surgery.

The findings of this study are consistent with previous phase II data with the XELOX regimen in the first-line treatment of MCRC. Objective response rates in trials using the same dose and schedule as those used in this trial ranged from 39% to 55%, with median TTP of 6 to 8 months, and median OS of 20 months.^14-16 Data for the FUOX arm were consistent with those obtained by our group in the previous phase II trial (TTP, 7.3 months).¹⁹ Furthermore, the efficacy results demonstrated with either XELOX or FUOX in the present study are consistent with phase III trials of different FU/LV regimens (CIV, chronomodulated, or bolus) in combination with oxaliplatin. In these studies, objective response rates ranged from 44% to 53%, median PFS ranged from 8 to 9 months, and median OS ranged from 16 to 21 months.^1,2,23,24 Kubicka et al²⁵ have recently reported a large, randomized, phase III comparison of the capecitabine plus oxaliplatin regimen (a modified XELOX regimen) and CIV FU/LV plus oxaliplatin in first-line treatment of MCRC. Efficacy results (response rate, median PFS, and median OS) were also similar with both capecitabine plus oxaliplatin and CIV FU/LV plus oxaliplatin.

In addition, the safety profile of both the XELOX and FUOX regimens was favorable. The most common and significant adverse event in both treatment arms was oxaliplatin-induced neurotoxicity, with grade 3/4 peripheral neuropathy occurring in approximately 16% to 18% of patients. Many other of the most common adverse events occurred at similar rates with both XELOX and FUOX (ie, asthenia, nausea, vomiting, and neutropenia), although there were some differences between treatments. FUOX was associated with significantly more grade 3/4 diarrhea and grade 1/2 mucositis, whereas XELOX was associated with significantly more grade 1/2 hyperbilirubinemia and hand-foot syndrome—both mild toxicities related to the use of capecitabine.

The XELOX regimen offers unique advantages over the infusional FUOX regimen with respect to its simplicity and convenience. The FUOX regimen has to be administered weekly during 48 hours using a portable infusion pump. Oxaliplatin is administered as a 2-hour infusion once every 2 weeks. Administration of the FUOX regimen is time consuming, inconvenient, and uncomfortable for the patients, who are required to make regular hospital visits. With XELOX, capecitabine is administered orally for the first 14 days and oxaliplatin is administered on the first day of each 3-week cycle. Oxaliplatin administration can be timed to coincide with the routine review of the patient for monitoring of clinical status and treatment-related toxicity. This substantially reduces both travel time and the amount of time spent at the hospital for treatment.

Other ongoing studies are evaluating the efficacy and safety profile of XELOX compared with other CIV FU/LV plus oxaliplatin regimens. The preliminary results of the NO16966 study have demonstrated that the XELOX regimen is equivalent to the CIV FU/LV plus oxaliplatin regimen in terms of efficacy and safety profile.²⁶

Our study has several limitations. First, the margin set for establishing noninferiority might be considered too high. However, when establishing this margin, we are defining the largest difference that is clinically acceptable. We believe that a difference of less than 1.5 months in TTP is not clinically significant in patients with MCRC. Second, our comparison arm consisted of a regimen of FU plus oxaliplatin that is used in the Spanish setting. Therefore, our results could not be generalized to other FU plus oxaliplatin regimens.

In conclusion, this randomized study shows a similar TTP of XELOX compared with FUOX in the first-line treatment of MCRC, although there was a trend for slightly lower response rate and survival. Both regimens showed a similar toxicity profile. However, the requirement for only one hospital visit every 3 weeks makes XELOX a simpler and more convenient regimen; therefore, XELOX is a useful alternative to FUOX for the first-line treatment of MCRC.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment: N/A Consultant: Eduardo Díaz-Rubio, Sanofi-aventis, Roche; Jose Tabernero, Sanofi-aventis, Roche; Alfredo Carrato, Sanofi-aventis, Roche; Enrique Aranda, Sanofi-aventis, Roche Stock: N/A Honoraria: N/A Research Funds: N/A Testimony: N/A Other: N/A

	AUTHOR CONTRIBUTIONS

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Conception and design: Eduardo Díaz-Rubio, Enrique Aranda

Provision of study materials or patients: Eduardo Díaz-Rubio, Jose Tabernero, Auxiliadora Gómez-España, Bartomeu Massutí, Javier Sastre, Manuel Chaves, Alberto Abad, Alfredo Carrato, Bernardo Queralt, Juan José Reina, Joan Maurel, Encarnación González-Flores, Jorge Aparicio, Fernando Rivera, Ferrán Losa, Enrique Aranda

Collection and assembly of data: Eduardo Díaz-Rubio, Jose Tabernero, Auxiliadora Gómez-España, Bartomeu Massutí, Javier Sastre, Manuel Chaves, Alberto Abad, Alfredo Carrato, Bernardo Queralt, Juan José Reina, Joan Maurel, Encarnación González-Flores, Jorge Aparicio, Fernando Rivera, Ferrán Losa, Enrique Aranda

Data analysis and interpretation: Eduardo Díaz-Rubio, Enrique Aranda

Manuscript writing: Eduardo Díaz-Rubio, Jose Tabernero

Final approval of manuscript: Eduardo Díaz-Rubio, Jose Tabernero, Auxiliadora Gómez-España, Bartomeu Massutí, Javier Sastre, Manuel Chaves, Alberto Abad, Alfredo Carrato, Bernardo Queralt, Juan José Reina, Joan Maurel, Encarnación González-Flores, Jorge Aparicio, Fernando Rivera, Ferrán Losa, Enrique Aranda

	Appendix

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The investigators listed below cared for the patients in this study: Aranda E. and Gómez-España A. (Hospital Reina Sofia, Córdoba); Massuti B. (Hospital General, Alicante); Diaz-Rubio E. and Sastre J. (Hospital Clínico Universitario San Carlos, Madrid); Tabernero J. and Casado E. (Vall d' Hebrón University Hospital, Barcelona); Chaves M. (Hospital Virgen del Rocio, Sevilla); Abad A. (Hospital Germans Trias i Pujol, Badalona); Carrato A. and Gallego J. (Hospital Universitario, Elche); Queralt B. (Instituto Catalán de Oncología, Girona); Reina J.J. (Hospital Juan Ramón Jimenez); Maurel J. (Hospital Clínico, Barcelona); González-Flores E. (Hospital Virgen de las Nieves, Granada); Aparicio J. (Hospital La Fe, Valencia); Rivera F. (Hospital Marqués de Valdecilla, Santander); Losa F. (Hospital de Hospitalet); Garcia T. (Hospital Morales Meseguer); Sánchez Rovira P. (Hospital general, Jaén), Maestu I. (Hospital Virgen de los Lirios), Busquier I. (Hospital Provincial, Castellón); Alfaro J. (Consorci Sanitari Terrasa); Muñoz M. (Hospital Virgen de la Luz); Jimenez E. (Hospital General, Jerez); Centelles M. (Hospital Sagrat Cor, Barcelona); Checa T. (Instituto Oncológico Corachán, Barcelona); Valero P. (Clínica Sagrado Corazón); Mel R. (Complexo Hospitalario Xeral Calde, Lugo); Bueso P. (Hospital de Barbastro, Huesca); Cardona T. (Hospital de Mataró); Alés J.E. (Hospital Ruber Internacional, Madrid); Guash I. (Centro Hospitalario Manresa). Centers for Statistics and Data Management (Biometrica): Oscar Salamanca and Juan Luis Sanz. Spanish Cooperative Group for the Treatment of Digestive Tumors (TTD): Inmaculada Ruiz de Mena.

View larger version (26K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig A1. Consort flowchart. ITT, intent to treat; XELOX, capecitabine plus oxaliplatin; FUOX, fluorouracil plus oxaliplatin.

	ACKNOWLEDGMENTS

 
We thank Drs Abad, Ales, Alfaro, Aparicio, Aranda, Bueso, Busquier, Cardona, Carrato, Casado, Centelles, Chaves, Checa, Diaz-Rubio, Gallego, Garcia, Gómez-España, González-Flores, Guash, Jiménez, Losa, Maestu, Massuti, Maurel, Mel, Muñoz, Queralt, Reina, Rivera, Sánchez Rovira, Sastre, Tabernero, and Valero. We also thank the participating physicians for their cooperation and support.

	NOTES

 
published online ahead of print at www.jco.org on June 4, 2007.

Supported by the Treatment of Digestive Tumors (TTD), Madrid, Spain, and by Roche and Sanofi-Aventis.

Presented in part at the 41st Annual Meeting of the American Society of Clinical Oncology, May 13-17, 2005, Orlando, FL; the 42nd Annual Meeting of the American Society of Clinical Oncology, June 2-6, 2005, Atlanta, GA; and the Annual Meeting of the European Society for Medical Oncology, Istanbul, Turkey, September 29-October 3, 2006.

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

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26. Cassidy J, Clarke S, Diaz-Rubio E, et al: First efficacy and safety results from XELOX-1/NO16966, a randomised 2x2 factorial phase III trial of XELOX vs. FOLFOX4 + bevacizumab or placebo in first-line metastatic colorectal cancer (MCRC). Ann Oncol 17:LBA3, 2006 (suppl 9)

Submitted November 11, 2006; accepted January 16, 2007.

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Related Editorial

• Should Capecitabine Replace Infusional Fluorouracil and Leucovorin When Combined With Oxaliplatin in Metastatic Colorectal Cancer?
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