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JOURNAL OF CLINICAL ONCOLOGY

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R E P O R T

Randomized Phase III Study of Capecitabine Plus Oxaliplatin Compared With Fluorouracil/Folinic Acid Plus Oxaliplatin As First-Line Therapy for Metastatic Colorectal Cancer
Jim Cassidy, Stephen Clarke, Eduardo Daz-Rubio, Werner Scheithauer, Arie Figer, Ralph Wong, Sheryl Koski, Mikhail Lichinitser, Tsai-Shen Yang, Fernando Rivera, Felix Couture, Florin Sirzen, and Leonard Saltz
From the Beatson Oncology Centre, Glasgow, United Kingdom; University of Sydney and Sydney Cancer Centre, Sydney, Australia; Hospital Clnico San Carlos, Madrid; Hospital Marques De Valdecilla, Santander, Spain; Vienna University Medical School, Vienna, Austria; Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Cancer Care Manitoba, St Boniface General Hospital, Winnipeg, Manitoba; Cross Cancer Institute, Edmonton, Alberta; CHUQ LHotel-Dieu De Quebec, Quebec, Canada; Russian Cancer Research Center, Moscow, Russian Federation; Chang-Gung Memorial Hospital, Taipei, Taiwan; F. Hoffmann-La Roche, Basel, Switzerland; and the Memorial Sloan Kettering Cancer Center, New York, NY. Submitted October 30, 2007; accepted December 19, 2007. Supported by Roche. Presented in part at the 31st European Society of Medical Oncology Congress, Istanbul, Turkey, September 29October 3, 2006; the American Society of Clinical Oncology Gastrointestinal Cancers Symposium, Orlando, FL, January 19-21, 2007; and the 43rd Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, June 1-5, 2007. Authors disclosures of potential conicts of interest and author contributions are found at the end of this article. Corresponding author: Jim Cassidy, MD, Glasgow University, Garscube Estate, Switchback Rd, Glasgow, Scotland, G61 1BD; e-mail: j.cassidy@ beatson.gla.ac.uk. 2008 by American Society of Clinical Oncology 0732-183X/08/2612-2006/$20.00 DOI: 10.1200/JCO.2007.14.9898

Purpose To evaluate whether capecitabine plus oxaliplatin (XELOX) is noninferior to uorouracil. folinic acid, and oxaliplatin (FOLFOX-4) as rst-line therapy in metastatic colorectal cancer (MCRC). Patients and Methods The initial design of this trial was a randomized, two-arm, noninferiority, phase III comparison of XELOX versus FOLFOX-4. After patient accrual had begun, the trial design was amended in 2003 after bevacizumab phase III data became available. The resulting 2 2 factorial design randomly assigned patients to XELOX versus FOLFOX-4, and then to also receive either bevacizumab or placebo. We report here the results of the analysis of the XELOX versus FOLFOX-4 arms. The analysis of bevacizumab versus placebo with oxaliplatin-based chemotherapy is reported separately. The prespecied primary end point for the noninferiority analysis was progressionfree survival. Results The intent-to-treat population comprised 634 patients from the original two-arm portion of the study, plus an additional 1,400 patients after the start of the amended 2 2 design, for a total of 2,034 patients. The median PFS was 8.0 months in the pooled XELOX-containing arms versus 8.5 months in the FOLFOX-4 containing arms (hazard ratio [HR], 1.04; 97.5% CI, 0.93 to 1.16). The median overall survival was 19.8 months with XELOX versus 19.6 months with FOLFOX-4 (HR, 0.99; 97.5% CI, 0.88 to 1.12). FOLFOX-4 was associated with more grade 3/4 neutropenia/ granulocytopenia and febrile neutropenia than XELOX, and XELOX with more grade 3 diarrhea and grade 3 hand-foot syndrome than FOLFOX-4. Conclusion XELOX is noninferior to FOLFOX-4 as a rst-line treatment for MCRC, and may be considered as a routine treatment option for appropriate patients. J Clin Oncol 26:2006-2012. 2008 by American Society of Clinical Oncology

INTRODUCTION

FOLFOX-4, a bi-weekly schedule of bolus and infusional uorouracil (FU)/folinic acid (FA) plus oxaliplatin (Eloxatin; Sano-Aventis, Bridgewater, NJ), is a widely used regimen for rst-line treatment of metastatic colorectal cancer (MCRC).1 Capecitabine (Xeloda; Hoffmann-La Roche Inc, Nutley, NJ) is an oral uoropyrimidine with similar efcacy to bolus FU/FA as rst-line treatment for MCRC2-4 and as adjuvant therapy for stage III colon cancer.5 Capecitabine has been tested in combination with oxaliplatin in a variety of different schedules.6-8 XELOX, which consists of a 21-day intermittent schedule of capecitabine combined with a 3-weekly dose of ox-

aliplatin, has shown an overall response rate (ORR) of 55% and median overall survival (OS) of 19.5 months in a large phase II study.6 Based on these phase II results, we started a two-arm, randomized, noninferiority, phase III study (XELOX-1; NO16966A) comparing XELOX with FOLFOX-4 in the rst-line treatment of MCRC. After the pivotal phase III data for bevacizumab became available,9 the protocol was amended to a randomized, 2 2 factorial design with two coprimary objectives. The primary end point was progression-free survival (PFS). The rst coprimary objective, which is the focus of this report, was to evaluate the noninferiority of XELOX with or without bevacizumab versus FOLFOX-4

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XELOX v FOLFOX-4 in First-Line Colorectal Cancer

with or without bevacizumab. The second coprimary objective was to evaluate for the superiority of bevacizumab versus placebo when combined with oxaliplatin-based chemotherapy (ie, XELOX or FOLFOX-4), and will be presented as a separate paper.10
PATIENTS AND METHODS
Study Design NO16966 commenced as a two-arm, open-label, randomized phase III comparison of XELOX versus FOLFOX-4. The protocol was amended to a placebo-controlled, double-blind (for bevacizumab), randomized, 2 2 factorial design, and bevacizumab or placebo were added to both treatment groups. The study was performed in accordance with the Declaration of Helsinki and Good Clinical Practice Guidelines. Written informed consent was obtained from all patients participating in the study. Approval of the protocol was obtained from an independent ethics committee or institutional review board of each site. Patient Population Patients age 18 years with histologically conrmed colorectal cancer, unresectable metastatic disease (one or more unidimensionally measurable lesions), an Eastern Cooperative Oncology Group (ECOG) performance status of 1 and a life expectancy of longer than 3 months were eligible. No prior systemic therapy for metastatic disease or prior oxaliplatin or bevacizumab were allowed. Radiation therapy or surgery for metastatic disease was permitted if completed at least 4 weeks before randomization and if untreated measurable disease remained. Patients were required to have adequate hematologic/clotting, hepatic, and renal function. Pregnant or breast-feeding women were excluded. Other key exclusion criteria were: clinically signicant cardiovascular disease; clinically detectable ascites; use of full-dose anticoagulants or thrombolytics; known CNS metastases; serious nonhealing wound, ulcer or bone fracture; known bleeding diathesis or coagulopathy; and proteinuria 500 mg/24 hours. Treatment Plan Patients were assigned to treatment using an interactive voice response system. Randomization was stratied by region, ECOG performance status, liver as a metastatic site, number of metastatic sites (organs), and alkaline phosphatase level. XELOX consisted of a 2-hour intravenous infusion of oxaliplatin 130 mg/m2 on day 1 plus oral capecitabine 1,000 mg/m2 twice daily for 2 weeks in a 3-week cycle. The rst dose of capecitabine was given in the evening of day 1 and the last dose on the morning of day 15. The FOLFOX-4 regimen has been previously described.1 After amendment of the study protocol, bevacizumab or placebo was added at 7.5 mg/kg every third week to XELOX, and at 5 mg/kg every second week to FOLFOX-4. Bevacizumab or placebo was given as a 30to 90-minute intravenous infusion on day 1 of each cycle before oxaliplatin. Treatment was continued until disease progression (PD) or for 48 weeks (ie, up to 16 cycles of XELOX or 24 cycles of FOLFOX-4), whichever came rst (study treatment phase). Patients who completed the 48-week treatment phase without PD were eligible to continue treatment until PD in a poststudy treatment phase. Patients whose tumor became operable, and for whom resection was performed, were allowed to enter the poststudy treatment phase. If one of the regimen components was discontinued, treatment could be continued with the remaining components as follows: capecitabine or FU/ FA bevacizumab/placebo could be given after discontinuing oxaliplatin; XELOX, FOLFOX-4, capecitabine, or FU/FA could be given after discontinuing bevacizumab/placebo; bevacizumab/placebo could be given after discontinuing XELOX, FOLFOX-4, capecitabine or FU/FA; or patients were not permitted to continue on oxaliplatin with or without bevacizumab/placebo. Assessments Medical history, physical examination, chest x-ray, ECG, and carcinoembryonic antigen measurement were performed within 21 days before starting treatment. Assessments of vital signs, ECOG performance status, height,
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weight, and routine blood analysis (hematology and chemistry) were performed within 7 days of starting treatment. During treatment, physical examination, hematology, and biochemistry analyses were repeated on day 1 of every treatment cycle. Tumor assessments (computed tomography scan, magnetic resonance imaging) were made within 28 days before starting study treatment and repeated after every two XELOX cycles and every three FOLFOX-4 cycles (ie, every sixth week in both arms and at the end of treatment). Response Evaluation Criteria in Solid Tumors guidelines11 were used to dene all responses. Conrmation of response was required after a minimum of 4 weeks. Tumor responses were assessed by investigators and also by an independent response review committee. After completion of study treatment, patients were followed every 3 months until PD and/or death. Patients were evaluated for adverse events during therapy and until 28 days after the last study drug dose. Adverse events were graded according to National Cancer Institute Common Toxicity Criteria, version 3. Statistical Analysis The intent-to-treat (ITT) patient population included all patients who underwent randomization and signed the informed consent form. The eligible patient population (EPP) was the ITT population minus patients who did not receive at least one dose of study drug, and those patients who violated major protocol inclusion/exclusion criteria. As requested by regulatory authorities, the primary analysis of noninferiority was conducted in this EPP population. All patients receiving at least one dose of study drug were included in the safety analysis. As a rst step, the analysis of pooled XELOX-containing compared with pooled FOLFOX-4 containing arms was performed. If positive, an interaction test was performed on PFS to check for any interaction between the different treatment components (FOLFOX-4, XELOX, bevacizumab, nonbevacizumab). Independent of the interaction test, a clinical assessment of treatment effect was also performed. An interaction could be ruled out if the statistical interaction test was not signicant and the clinical assessment revealed no clinically relevant difference. If an interaction was ruled out, the pooled analysis remained the primary analysis. If an interaction could not be ruled out, then results in the bevacizumab and nonbevacizumab treatment subgroups would have had to be considered. PFS, the primary study end point, was dened as the time from the date of randomization to the rst documentation of disease progression by the investigators, or death from any cause. In order to retain an experiment-wise two-sided type I error of 5%, the noninferiority test for PFS was studied with a two-sided signicance level of 2.5% (the remaining 2.5% were used for the superiority testing). Noninferiority was concluded if the upper limit of the 97.5% CI of the hazard ratio (HR) was 1.23. The noninferiority margin of 1.23 corresponds to retention of at least 50% of the benet that oxaliplatin plus FU/FA has shown over FU/FA alone in the rst-line treatment of MCRC. To conrm the robustness of the primary analysis, Cox models including key demographic and baseline characteristics (ie, sex, age, race, use of adjuvant therapy), and stratication variables were performed on PFS. For the further assessment of noninferiority, a preplanned exploratory analysis of XELOX and bevacizumab versus FOLFOX-4 and bevacizumab and a post hoc exploratory analysis of the XELOX versus FOLFOX-4 arms in the two-arm part of the study were also performed. The secondary efcacy end points were OS, ORR, duration of response, and time to treatment failure. For ORR, noninferiority of pooled XELOX versus pooled FOLFOX-4 arms was concluded if the lower limit of the twosided 97.5% CI for the odds ratio was higher than 0.66. The remaining secondary efcacy analyses were considered descriptive only. PFS, OS, and time to treatment failure were analyzed using Cox models and presented as Kaplan-Meier estimates with HR and 97.5% CIs. Overall response was assessed by logistic regression, and presented with 97.5% CIs. Duration of overall response was presented as Kaplan-Meier estimates with 97.5% CIs. The analysis of NO16966 was event driven. The nal analysis was to be done when 1,200 PFS events had occurred in the EPP, this approach ensuring 90% power at an level of 2.5. All the results presented, except OS, are based
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on the main clinical cutoff date (January 31, 2006). In order to provide the most up-to-date results for OS, data presented are based on a more recent clinical cutoff date (January 31, 2007).

RESULTS

Patient Population Between July 2003 and May 2004, 634 patients were randomly assigned in the two-arm portion of the study. Between February 2004 and February 2005, an additional 1,401 patients were randomly assigned in the 2 2 factorial part of the study. One patient, who was randomly assigned twice, was excluded from the FOLFOX-4bevacizumab arm (and not treated) for not providing informed consent, but was later included and treated at another center in the XELOX and placebo arm. Overall, 2,034 patients made up the ITT population from the following regions: Europe (n 1,048); Canada (n 343); Oceania (n 188); United States (n 178); central/eastern Asia (n 163); South America (n 65); and South Africa (n 49). The EPP population comprised a total of 1,904 patients (Fig 1). The safety population comprised 1,304 patients in the nonbevacizumab-treated groups and 694 patients in the bevacizumab-treated groups. Baseline demographic and clinical characteristics were well balanced between treatment arms (Table 1). Efcacy The cutoff dates were January 31, 2006, for PFS and January 31, 2007, for OS. The median follow-up times at the respective cutoff dates were 17.7 and 29.7 months.

Both a clinically relevant and statistically signicant (P .7025) treatment interaction was ruled out. Therefore, the pooled analysis of all patients treated with XELOX (ie, XELOX, XELOX and placebo, and XELOX and bevacizumab) versus FOLFOX-4 (ie, FOLFOX-4, FOLFOX-4 and placebo, FOLFOX-4 and bevacizumab) was the primary analysis of noninferiority. The median PFS (ITT analysis) was 8.0 months in the pooled XELOX-containing arms versus 8.5 months in the FOLFOX-4 containing arms (HR, 1.04; 97.5% CI, 0.93 to 1.16), the upper limit of the 97.5% CI being below the predened noninferiority margin of 1.23 (Fig 2). Similar results were observed in the EPP with a median PFS of 7.9 months in the pooled XELOX-containing arms versus 8.5 months in the FOLFOX-4 containing arms (HR, 1.05; 97.5% CI, 0.94 to 1.18). The two exploratory analyses were further supportive of the main study ndings. Median PFS with XELOX and bevacizumab was 9.3 months versus 9.4 months with FOLFOX-4 and bevacizumab (HR, 1.01; 97.5% CI, 0.83 to 1.23; ITT). In the two-arm part of the study, the median PFS with XELOX was 7.3 months versus 7.7 months with FOLFOX-4 (HR, 0.96; 97.5% CI, 0.80 to 1.16; ITT). The noninferiority results for PFS were further supported by subgroup analyses dened by demographic and baseline characteristics and stratication variables (Fig 3). The HRs for PFS in the ITT population were similar across the different subgroups. Response Rates and Overall Survival ORR for the two regimens, as assessed both by investigators (XELOX 47% v FOLFOX 48%) and the independent response review committee (37% in each arm), were essentially the same (Table 2).

Initial 2-arm design

Protocol amendment

Revised 2x2 factorial design

Allocation

Randomized (n = 634)

Randomized (n = 1401)

ITT Analysis

Allocated to XELOX (n = 317) Included in ITT (n = 317)

Allocated to FOLFOX-4 (n = 317) Included in ITT (n = 317)

Allocated to XELOX + placebo (n = 350) Included in ITT (n = 350)

Allocated to XELOX + bevacizumab (n = 350) Included in ITT (n = 350)

Allocated to FOLFOX-4 + placebo (n = 351) Included in ITT (n = 351)

Allocated to FOLFOX-4 + bevacizumab (n = 350) Included in ITT (n = 349) Did not receive treatment No informed consent(n = 1)

Included in EPP population (n = 303)

Included in EPP population (n = 294) Excluded (n = 23) No measurable lesion (n = 15) Prior treatment for advanced disease (n = 3) Did not receive 1 dose of study treatment (n = 4) MCRC not histologically confirmed (n = 1) Evidence of CNS disease (n = 1) Received prior oxaliplatin (n = 1)

Included in EPP population (n = 327) Excluded (n = 23) No measurable lesion (n = 9) Prior treatment for advanced disease (n = 6) Did not receive 1 dose of study treatment (n = 7) Severe renal impairment (n = 1)

Included in EPP population (n = 337) Excluded (n = 13) No measurable lesion (n = 8) Prior treatment for advanced disease (n = 2) Did not receive 1 dose of study treatment (n = 1) MCRC not histologically confirmed (n = 1) Evidence of CNS disease (n = 1)

Included in EPP population (n = 326) Excluded (n = 25) No measurable lesion (n = 11) Prior treatment for advanced disease (n = 4) Did not receive 1 dose of study treatment (n = 9) MCRC not histologically confirmed (n = 1) Evidence of CNS disease (n = 1) Positive pregnancy test (n = 1)

Included in EPP population (n = 317) Excluded (n = 33) No measurable lesion (n =13) Prior treatment for advanced disease (n = 7) Did not receive 1 dose of study treatment (n =15) MCRC not histologically confirmed (n = 2) No informed consent (n = 1)

Fig 1. CONSORT diagram. XELOX, capacitabine and oxaliplatin; FOLFOX-4, infused uorouracil, folinic acid, and oxaliplatin; ITT, intent-to-treat; EPP, eligible patient population; MCRC, metastatic colorectal cancer. 2008
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EPP Analysis

Excluded (n = 14) No measurable lesion (n = 7) Prior treatment for advanced disease (n = 6) Did not receive 1 dose of study treatment (n = 1)

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XELOX v FOLFOX-4 in First-Line Colorectal Cancer

Table 1. Baseline Patient Characteristics (intent-to-treat population) FOLFOX-4 Characteristic No. of patients Sex Male Female Age, years Median Range ECOG performance status 0 1 2 Primary tumor site Colorectal Colon Rectal Stage at rst diagnosis Local regional Metastatic No. of metastatic sites 0 1 2 3 4 Alkaline phosphatase Abnormal Normal Prior adjuvant therapy No Yes Median time from start of adjuvant therapy to randomization, days No. 317 204 113 62 24-83 163 154 0 17 200 100 144 173 1 118 121 47 30 135 182 234 83 613.0 51 49 0 5 63 32 45 55 1 37 38 15 10 43 57 74 26 211 138 0 25 232 94 141 210 1 142 122 65 21 147 201 266 85 913.0 64 36 % FOLFOX-4 Placebo No. 351 186 165 60 26-83 60 40 0 7 66 27 40 60 1 41 35 19 6 42 58 76 24 198 147 0 28 223 98 128 221 1 150 132 44 22 146 199 261 88 813.0 53 47 % FOLFOX-4 Bevacizumab No. 349 205 144 60 19-82 57 43 0 8 64 28 37 63 1 43 38 13 6 42 58 75 25 160 157 0 30 204 83 133 184 0 127 106 55 29 132 183 229 88 687.0 59 41 % XELOX No. 317 194 123 61 24-84 50 50 0 9 64 26 42 58 0 40 33 17 9 42 58 72 28 207 143 0 30 233 87 138 212 0 155 112 58 25 149 200 259 91 843.0 61 39 % XELOX Placebo No. 350 205 145 61 18-83 59 41 0 9 67 25 39 61 0 44 32 17 7 43 57 74 26 207 142 1 32 236 82 122 228 0 134 121 64 31 156 191 274 76 752.5 59 41 % XELOX Bevacizumab No. 350 213 137 61 18-86 59 41 1 9 67 23 35 65 0 38 35 18 9 45 55 78 22 61 39 %

Abbreviations: ECOG, Eastern Cooperative Oncology Group; FOLFOX-4, infused uorouracil, folinic acid, and oxaliplatin; XELOX, capecitabine and oxaliplatin.

The median OS in the ITT population was 19.8 months in the pooled XELOX arms and 19.6 months in the pooled FOLFOX-4 arms, with a corresponding HR of 0.99 (97.5% CI, 0.88 to 1.12; Fig 4). The HR of XELOX and bevacizumab versus FOLFOX-4 and bevacizumab was

0.99 (97.5% CI, 0.80 to 1.23; online-only Fig A1) and in the two-arm part of the study the HR of XELOX versus FOLFOX-4 was 0.90 (97.5% CI, 0.74 to 1.10). The details of OS and other descriptive secondary end points are presented in Table 2. Second-Line Therapy There were no major imbalances between the treatment groups with respect to the use of second-line therapy: XELOX-containing arms, 51%, and FOLFOX-4 containing arms, 53%. The most common agents used were: irinotecan (41% with FOLFOX-4 v 39% with XELOX); FU (29% v 25%); capecitabine (12% v 7%); cetuximab (11% v 9%); and bevacizumab (5% v 6%). Safety The median dose intensities (ratio of dose received to dose planned) of FU, capecitabine, oxaliplatin, and bevacizumab were 0.89 in all treatment arms. The median number of cycles administered was 10 in the FOLFOX-4/FOLFOX-4 and placebo groups (range, one to 24), 12 in the FOLFOX-4-bevacizumab group (range, one to 25), seven in the XELOX/XELOX and placebo groups (range, one to 16), and eight in the XELOX and bevacizumab group (range, one to 17).
2008 by American Society of Clinical Oncology

1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 5

Proportion of Patients

FOLFOX-4/FOLFOX-4+placebo/FOLFOX-4+bevacizumab n = 1017; 826 events XELOX/XELOX+placebo/XELOX+bevacizumab n = 1017; 813 events HR = 1.04 [97.5% CI: 0.931.16] (ITT) HR = 1.05 [97.5% CI: 0.941.18] (EPP) Upper limit below < 1.23 (non-inferiority margin)

8.0

8.5

10

15

20

25

30

Time (months)
Fig 2. Progression-free survival (intent-to-treat population [ITT]). FOLFOX-4, infused uorouracil, folinic acid, and oxaliplatin; XELOX, capacitabine and oxaliplatin; EPP, eligible patient population; HR, hazard ratio. www.jco.org

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n ITT population ECOG PS 0 2034

Table 2. Analysis of Efcacy (intent-to-treat population) FOLFOX-4/FOLFOX-4 Placebo/FOLFOX-4 Bevacizumab 1,017 8.5 1.04 0.93 to 1.16 XELOX/XELOX Placebo/XELOX Bevacizumab 1,017 8.0

End Point 1146 881 826 1205 ECOG PS 1 1 metastatic site No. of patients Primary Median progression-free survival, months Hazard ratio 97.5% CI Secondary Overall response rate, % Investigator assessed Odds ratio 97.5% CI IRC assessed Odds ratio 97.5% CI Median overall survival, months Hazard ratio 97.5% CI Median time to treatment failure, months Hazard ratio 97.5% CI Median duration of response, months Hazard ratio 97.5% CI

2 metastatic sites
Abnormal alkaline phosphatase Normal alkaline phosphatase Liver metastases No Yes Female Male

865 1156 483 1151 827 1207 1294 740

48 0.94 0.77 to 1.15 37 1.00 0.81 to 1.23 19.6 0.99 0.88 to 1.12 6.3 1.08 0.97 to 1.20 7.6 1.00 0.85 to 1.18

47

37

19.8

< 65 years 65 years

5.9

No prior adjuvant chemotherapy 1523 Prior adjuvant chemotherapy Asian or Pacific Islander White 511 215 1759 0.2 0.4 0.6 1 2 3 4 56

7.5

Risk Ratio and 95% CI Fig 3. Subgroup analysis of progression-free survival (PFS) according to baseline demographic and stratication variables (intent-to-treat [ITT] population). n, number of patients; ECOG, Eastern Cooperative Oncology Group.

Abbreviations: FOLFOX-4, uorouracil, folinic acid, and oxaliplatin; IRC, independent response review committee; XELOX, capecitabine and oxaliplatin. Non-inferiority was concluded if the upper limit of the 97.5% CI was 1.23. Non-inferiority was concluded if the lower limit of the 97.5% CI was 0.66. Cut-off date of January 31, 2007. Safety population.

For the assessment of safety of XELOX versus FOLFOX-4, patients in the pooled XELOX/XELOX and placebo and pooled FOLFOX-4/FOLFOX-4 and placebo arms were compared. For the assessment of safety with addition of bevacizumab, patients in XELOX and bevacizumab and FOLFOX-4 and bevacizumab arms were compared. A summary of adverse events associated with XELOX versus FOLFOX-4 by National Cancer Institute Common Toxicity Criteria grade is presented in Table 3. While the overall rates of grade 3/4 adverse events were fairly similar with both FOLFOX-4 and XELOX, grade 4 adverse events were more common with FOLFOX-4 (25% and 12%, respectively), this difference being predominantly due to grade 4 neutropenia. The rates of some individual adverse events also differed between the two regimens. Whereas FOLFOX-4 was associated with more grade 3/4 neutropenia/granulocytopenia (44% v 7%), febrile neutropenia (4.8% v 0.9%), and grade 3/4 venous thromboembolic events (6.3% v 3.8%) than XELOX, XELOX was associated with more grade 3 diarrhea (19% v 11%) and grade 3 hand-foot syndrome (6% v 1%). As would be expected, rates of grade 3/4 neurosensory toxicity were similar with both regimens (approximately 17%). Grade 3/4 cardiac disorders were reported in nine FOLFOX-4 recipients (1.4%) and six XELOX recipients (0.9%).
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2008 by American Society of Clinical Oncology

The addition of bevacizumab did not alter the similarities and differences in safety prole between XELOX and FOLFOX-4 (onlineonly Table A1). The tolerability prole of XELOX and FOLFOX-4 in the United States versus all patients is shown in online-only Table A2. Treatment was discontinued due to adverse events in 161 patients (25%) treated with FOLFOX-4, 170 patients (26%) treated with XELOX, 104 patients (30%) treated with FOLFOX-4-bevacizumab,

FOLFOX-4/FOLFOX-4+placebo/FOLFOX-4+bevacizumab n = 1017; 695 events

1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 5 10

Proportion of Patients

XELOX/XELOX+placebo/XELOX+bevacizumab n = 1017; 692 events HR = 0.99 [97.5% CI: 0.881.12] (ITT) HR = 1.00 [97.5% CI: 0.881.13] (EPP)

19.6 19.8

15

20

25

30

35

40

Time (months)
Fig 4. Overall survival (intent-to-treat population [ITT]). FOLFOX-4, infused uorouracil folinic acid, and oxaliplatin; XELOX, capacitabine and oxaliplatin; EPP, eligible patient population; HR, hazard ratio.
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XELOX v FOLFOX-4 in First-Line Colorectal Cancer

Table 3. Most Frequent (

20% of patients) Adverse Events (treatment-related and unrelated) NCI-CTC Grade

FOLFOX-4/FOLFOX-4 1 Adverse Event All events Nausea Diarrhea Neutropenia Fatigue Vomiting Paresthesia Stomatitis Anorexia Hand-foot syndrome Constipation Pyrexia Abdominal pain Thrombocytopenia Peripheral neuropathy Asthenia No. 627 258 179 18 131 141 165 162 103 45 114 119 81 36 74 49 % 97 40 28 3 20 22 25 25 16 7 18 18 12 6 11 8 No. 576 123 141 79 110 85 54 67 59 13 50 45 66 92 33 59 2 % 89 19 22 12 17 13 8 10 9 2 8 7 10 14 5 9

Placebo (n 3 No. 454 33 70 173 49 28 25 13 17 8 15 9 24 20 23 22 % 70 5 11 27 8 4 4 2 3 1 2 1 4 3 4 3

649) 4 No. 161 0 3 106 2 0 0 0 0 0 0 1 2 0 1 % 25 0 1 16 1 0 0 0 0 0 0 1 1 0 1 No. 615 224 171 16 108 143 137 102 108 105 97 82 75 23 73 38 1 % 94 34 26 2 16 22 21 16 16 16 15 13 11 4 11 6

XELOX/XELOX 2 No. 572 153 126 118 107 103 74 30 56 53 45 33 63 78 30 58 % 87 23 19 18 16 16 11 5 9 8 7 5 10 12 5 9

Placebo (n 3 No. 449 30 123 39 33 34 31 8 16 40 9 6 36 39 24 26 %

655) 4 No. 81 0 9 6 1 0 0 0 0 0 0 0 7 0 2 % 12 0 1 1 1 0 0 0 0 0 0 0 1 0 1

69 5 19 6 5 5 5 1 2 6 1 1 5 6 4 4

Abbreviations: FOLFOX-4, infused uorouracil, folinic acid, and oxaliplatin; NCI-CTC, National Cancer Institute Common Toxicity Criteria; XELOX, capecitabine and oxaliplatin.

and 109 patients (31%) treated with XELOX and bevacizumab. The most common reasons for treatment discontinuation were neurosensory toxicity and diarrhea. Treatment-related mortality up to 28 days after the last treatment dose was documented in 11 patients (1.7%) treated with FOLFOX-4, 14 patients (2.1%) treated with XELOX, six patients (1.8%) treated with FOLFOX-4 and bevacizumab, and eight patients (2.3%) treated with XELOX and bevacizumab. The respective 60-day all-cause mortality rates were 2.3% (n 15), 3.4% (n 22), 1.5% (n 5), and 2.5% (n 9).
DISCUSSION

This large multinational randomized phase III trial demonstrates that XELOX is noninferior to FOLFOX-4 in terms of PFS, OS, and ORR in the rst-line treatment of patients with MCRC. With approximately 1,000 patients in each pooled treatment arm, the NO16966 trial is the largest conducted to date to address this question. The overall nding of noninferiority was also supported by exploratory analyses conducted in the XELOX and bevacizumab versus FOLFOX-4 and bevacizumab subgroups and the original XELOX versus FOLFOX-4 arms. Collectively, these analyses show that the ndings of the main analysis are robust. Previously, the efcacy and safety of capecitabine as single-agent therapy was established based on comparisons with bolus regimens of FU/FA.2-5 However, in current clinical practice, infusional regimens of FU/FA are often preferred because they confer some benets in terms of toxicity and efcacy. This trial compared a capecitabinebased regimen with a regimen that included a bolus and continuous infusion of FU, and demonstrated that the efcacy of these two treatment options in this combination therapy context is similar.
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The efcacy of capecitabine and oxaliplatin combinations has been tested in three other smaller phase III trials in the rst-line setting12-14 and in one trial in the second-line setting.15 While the XELOX regimen was used in two rst-line trials,12,14 a modied capecitabine and oxaliplatin regimen (CAPOX) was used in the third rst-line trial.13 FOLFOX-6 was used as the comparator regimen in one trial,12 while two trials used other infusional FU and oxaliplatin with (FUFOX) or without FA (FUOX) regimens. Ducreux et al12 showed noninferiority of XELOX versus FOLFOX-6 in terms of response rate (42 v 46%). Median TTP (9.1 v 9.7 months) and overall survival (19.5 v 18.8 months) were also similar in the two groups. Daz-Rubio et al14 reported equivalent efcacy with XELOX and FUOX, with a median TTP of 8.9 months with XELOX and 9.5 months with FUOX. In contrast, in the trial by Porschen et al,13 the median PFS was 7.1 months with the nonstandard CAPOX regimen and 8.0 months with FUFOX (HR, 1.17; 95% CI, 0.96 to 1.43; P .117); the upper 95% CI exceeded the prospectively dened interval for noninferiority (1.29). However, the study by Porschen et al13 was underpowered, and it is possible that an imbalance in restaging intervals in this trial, particularly during the rst 20 weeks, may have biased the results in favor of FUFOX. Finally, Rothenberg et al15 showed that XELOX is noninferior to FOLFOX-4 in terms of PFS in the secondline treatment of MCRC. Safety data from this trial suggest that while the prole of adverse events associated with both the XELOX and FOLFOX-4 regimens are similar, there are differences in the rates at which these occur. The XELOX regimen was associated with more grade 3 diarrhea, whereas FOLFOX-4 was associated with more grade 3/4 neutropenia/granulocytopenia and febrile neutropenia. The FOLFOX-4 regimen involves two 22-hour infusions of FU every 14 days, which require catheter placement and regular visits to
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Cassidy et al

the clinic. The FOLFOX-4 regimen was selected as the comparator in this study for regulatory reasons but is still widely used globally. Although modied FOLFOX regimens (such as mFOLFOX-6) have replaced FOLFOX-4 in some countries and although these do afford some greater convenience in terms of one 2-day infusion instead of two 22-hour infusions, the XELOX regimen requires still fewer planned ofce visits, with oxaliplatin administered every 21 days and capecitabine taken orally. Of note, there was a slight increase in grade 3/4 thromboembolic events with FOLFOX-4, some of which may have been attributable to catheter use. In conclusion, XELOX is noninferior to FOLFOX-4, and may be considered as a standard treatment in the rst-line treatment of MCRC.

Employment or Leadership Position: Florin Sirzen, Roche (C) Consultant or Advisory Role: Jim Cassidy, Roche (C); Stephen Clarke, Roche (C); Eduardo Daz-Rubio, Roche (C), Sano-aventis (C); Arie Figer, Roche (C); Ralph Wong, Roche (C), Sano-aventis (C) Stock Ownership: None Honoraria: Jim Cassidy, Roche; Stephen Clarke, Roche; Eduardo Daz-Rubio, Roche, Sano-aventis; Werner Scheithauer, Roche, Sano-aventis; Arie Figer, Roche; Fernando Rivera, Roche; Felix Couture, Roche Research Funding: Jim Cassidy, Roche; Eduardo Daz-Rubio, Roche, Sano-aventis; Werner Scheithauer, Roche, Sano-aventis; Arie Figer, Roche; Fernando Rivera, Roche; Leonard Saltz, Roche, Genentech Expert Testimony: None Other Remuneration: None

AUTHOR CONTRIBUTIONS
Conception and design: Jim Cassidy, Florin Sirzen Administrative support: Florin Sirzen Provision of study materials or patients: Jim Cassidy, Stephen Clarke, Eduardo Daz-Rubio, Werner Scheithauer, Arie Figer, Ralph Wong, Sheryl Koski, Mikhail Lichinitser, Tsai-Shen Yang, Fernando Rivera, Felix Couture, Leonard Saltz Collection and assembly of data: Werner Scheithauer, Arie Figer, Fernando Rivera, Florin Sirzen Data analysis and interpretation: Jim Cassidy, Florin Sirzen Manuscript writing: Jim Cassidy, Stephen Clarke, Eduardo Daz-Rubio, Florin Sirzen Final approval of manuscript: Jim Cassidy, Eduardo Daz-Rubio, Werner Scheithauer, Arie Figer, Ralph Wong, Sheryl Koski, Mikhail Lichinitser, Tsai-Shen Yang, Fernando Rivera, Felix Couture, Florin Sirzen, Leonard Saltz
Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205-216, 2000 12. Ducreux M, Bennouna J, Hebbar M, et al: Efcacy and safety ndings from a randomized phase III study of capecitabine (X) oxaliplatin (O) (XELOX) vs. infusional 5- FU/LV O (FOLFOX-6) for metastatic colorectal cancer (MCRC). J Clin Oncol 25:170s, 2007 (suppl; abstr 4029) 13. Porschen R, Arkenau H-T, Kubicka S, et al: Capecitabine plus oxaliplatin compared with uorouracil and leucovorin plus oxaliplatin: A randomized comparison in metastatic colorectal cancer a nal report of the AIO Colorectal Study Group. J Clin Oncol 25:4217-4223, 2007 14. Daz-Rubio E, Tabernero J, Gomez-Espana A, et al: Phase III study of capecitabine plus oxaliplatin versus continuous infusion uorouracil plus oxaliplatin as rst-line therapy in metastatic colorectal cancer: Final report of the Spanish Cooperative Group for the Treatment of Digestive Tumors trial. J Clin Oncol 25:4224-4230, 2007 15. Rothenberg ML, Navarro M, Butts C, et al: Phase III trial of capecitabine oxaliplatin (XELOX) vs. 5-uorouracil (5-FU), leucovorin (LV), and oxalind platin (FOLFOX4) as 2 -line treatment for patients with metastatic colorectal cancer (MCRC). J Clin Oncol 25:171s, 2007 (abstr 4031)

AUTHORS DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Although all authors completed the disclosure declaration, the following author(s) indicated a nancial 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 ASCOs conict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conicts of Interest section in Information for Contributors.

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1. de Gramont A, Figer A, Seymour M, et al: Leucovorin and uorouracil with or without oxaliplatin as rst-line treatment in advanced colorectal cancer. J Clin Oncol 18:2938-2947, 2000 2. Van Cutsem E, Twelves C, Cassidy J, et al: Oral capecitabine compared with intravenous uorouracil plus leucovorin in patients with metastatic colorectal cancer: Results of a large phase III study. J Clin Oncol 19:4097-4106, 2001 3. Van Cutsem E, Hoff PM, Harper P, et al: Oral capecitabine vs intravenous 5-uorouracil and leucovorin: Integrated efcacy data and novel analyses from two large, randomized, phase III trials. Br J Cancer 90:1190-1197, 2004 4. Hoff PM, Ansari R, Batist G, et al: Comparison of oral capecitabine versus intravenous uorouracil plus leucovorin as rst-line treatment in 605 patients with metastatic colorectal cancer: Results of a randomized phase III study. J Clin Oncol 19:2282-2292, 2001 5. Twelves C, Wong A, Nowacki MP, et al: Capecitabine as adjuvant treatment for stage III colon cancer. N Engl J Med 352:2696-2704, 2005 6. Cassidy J, Tabernero J, Twelves C, et al: XELOX (capecitabine plus oxaliplatin): Active rst-

line therapy for patients with metastatic colorectal cancer. J Clin Oncol 22:2084-2091, 2004 7. Grothey A, Jordan K, Kellner O, et al: Capecitabine plus irinotecan (CAPIRI) vs capecitabine plus oxaliplatin (CAPOX) as rst-line therapy of advanced colorectal cancer (ACRC): Updated results of a randomized phase II trial. Eur J Cancer 1:S90, 2003 (suppl; abstr 295) 8. Scheithauer W, Kornek GV, Raderer M, et al: Randomized multicenter phase II trial of two different schedules of capecitabine plus oxaliplatin as rst-line treatment in advanced colorectal cancer. J Clin Oncol 21:1307-1312, 2003 9. Hurwitz H, Fehrenbacher L, Novotny W, et al: Bevacizumab plus irinotecan, uorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335-2342, 2004 10. Saltz L, Clarke S, Daz-Rubio E, et al: Efcacy and safety of bevacizumab in combination with oxaliplatin-based chemotherapy as rst-line therapy in metastatic colorectal cancer: A randomized phase III study. J Clin Oncol doi:10.1200/JCO.2007.14.9930 11. Therasse P, Arbuck SG, Eisenhauer EA, et al: New guidelines to evaluate the response to treatment in solid tumors: European Organisation for Research and Treatment of Cancer, National Cancer

Acknowledgment The Acknowledgment is included in the full-text version of this article, available online at www.jco.org. It is not included in the PDF version (via Adobe Reader). Appendix The Appendix is included in the full-text version of this article, available online at www.jco.org. It is not included in the PDF version (via Adobe Reader).

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