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with or without bevacizumab. The second coprimary objective was weight, and routine blood analysis (hematology and chemistry) were per-
to evaluate for the superiority of bevacizumab versus placebo when formed within 7 days of starting treatment. During treatment, physical exam-
combined with oxaliplatin-based chemotherapy (ie, XELOX ination, hematology, and biochemistry analyses were repeated on day 1 of
every treatment cycle.
or FOLFOX-4), and will be presented as a separate paper.10
Tumor assessments (computed tomography scan, magnetic reso-
nance imaging) were made within 28 days before starting study treat-
ment and repeated after every two XELOX cycles and every three
PATIENTS AND METHODS
FOLFOX-4 cycles (ie, every sixth week in both arms and at the end of
treatment). Response Evaluation Criteria in Solid Tumors guidelines11
Study Design were used to define all responses. Confirmation of response was re-
NO16966 commenced as a two-arm, open-label, randomized phase III quired after a minimum of 4 weeks. Tumor responses were assessed by
comparison of XELOX versus FOLFOX-4. The protocol was amended to a investigators and also by an independent response review committee.
placebo-controlled, double-blind (for bevacizumab), randomized, 2 ⫻ 2 fac- After completion of study treatment, patients were followed every 3
torial design, and bevacizumab or placebo were added to both treat- months until PD and/or death.
ment groups. Patients were evaluated for adverse events during therapy and until 28
The study was performed in accordance with the Declaration of Helsinki days after the last study drug dose. Adverse events were graded according to
and Good Clinical Practice Guidelines. Written informed consent was ob- National Cancer Institute Common Toxicity Criteria, version 3.
tained from all patients participating in the study. Approval of the protocol was
obtained from an independent ethics committee or institutional review board Statistical Analysis
of each site. The intent-to-treat (ITT) patient population included all patients who
underwent randomization and signed the informed consent form. The eligible
Patient Population patient population (EPP) was the ITT population minus patients who did not
Patients age ⱖ 18 years with histologically confirmed colorectal cancer, receive at least one dose of study drug, and those patients who violated major
unresectable metastatic disease (one or more unidimensionally measurable protocol inclusion/exclusion criteria. As requested by regulatory authorities,
lesions), an Eastern Cooperative Oncology Group (ECOG) performance sta- the primary analysis of noninferiority was conducted in this EPP population.
tus of ⱕ 1 and a life expectancy of longer than 3 months were eligible. No prior All patients receiving at least one dose of study drug were included in the
systemic therapy for metastatic disease or prior oxaliplatin or bevacizumab safety analysis.
were allowed. Radiation therapy or surgery for metastatic disease was permit- As a first step, the analysis of pooled XELOX-containing compared with
ted if completed at least 4 weeks before randomization and if untreated mea- pooled FOLFOX-4 – containing arms was performed. If positive, an interac-
surable disease remained. Patients were required to have adequate tion test was performed on PFS to check for any interaction between the
hematologic/clotting, hepatic, and renal function. Pregnant or breast-feeding different treatment components (FOLFOX-4, XELOX, bevacizumab, nonbe-
women were excluded. Other key exclusion criteria were: clinically significant vacizumab). Independent of the interaction test, a clinical assessment of treat-
cardiovascular disease; clinically detectable ascites; use of full-dose anticoagu- ment effect was also performed. An interaction could be ruled out if the
lants or thrombolytics; known CNS metastases; serious nonhealing wound, statistical interaction test was not significant and the clinical assessment re-
ulcer or bone fracture; known bleeding diathesis or coagulopathy; and pro- vealed no clinically relevant difference. If an interaction was ruled out, the
teinuria ⱖ 500 mg/24 hours. pooled analysis remained the primary analysis. If an interaction could not be
ruled out, then results in the bevacizumab and nonbevacizumab treatment
Treatment Plan
subgroups would have had to be considered.
Patients were assigned to treatment using an interactive voice response
PFS, the primary study end point, was defined as the time from the date
system. Randomization was stratified by region, ECOG performance status,
of randomization to the first documentation of disease progression by the
liver as a metastatic site, number of metastatic sites (organs), and alkaline
investigators, or death from any cause. In order to retain an experiment-wise
phosphatase level.
two-sided type I error of 5%, the noninferiority test for PFS was studied with a
XELOX consisted of a 2-hour intravenous infusion of oxaliplatin 130
two-sided significance level of 2.5% (the remaining 2.5% were used for the
mg/m2 on day 1 plus oral capecitabine 1,000 mg/m2 twice daily for 2 weeks in
superiority testing). Noninferiority was concluded if the upper limit of the
a 3-week cycle. The first dose of capecitabine was given in the evening of day 1
97.5% CI of the hazard ratio (HR) was ⱕ 1.23. The noninferiority margin of
and the last dose on the morning of day 15. The FOLFOX-4 regimen has been
1.23 corresponds to retention of at least 50% of the benefit that oxaliplatin plus
previously described.1 After amendment of the study protocol, bevacizumab
FU/FA has shown over FU/FA alone in the first-line treatment of MCRC. To
or placebo was added at 7.5 mg/kg every third week to XELOX, and at 5 mg/kg
confirm the robustness of the primary analysis, Cox models including key
every second week to FOLFOX-4. Bevacizumab or placebo was given as a 30-
demographic and baseline characteristics (ie, sex, age, race, use of adjuvant
to 90-minute intravenous infusion on day 1 of each cycle before oxaliplatin.
therapy), and stratification variables were performed on PFS.
Treatment was continued until disease progression (PD) or for 48 weeks
For the further assessment of noninferiority, a preplanned exploratory
(ie, up to 16 cycles of XELOX or 24 cycles of FOLFOX-4), whichever came first
analysis of XELOX and bevacizumab versus FOLFOX-4 and bevacizumab and
(study treatment phase). Patients who completed the 48-week treatment phase
a post hoc exploratory analysis of the XELOX versus FOLFOX-4 arms in the
without PD were eligible to continue treatment until PD in a poststudy treat-
two-arm part of the study were also performed.
ment phase. Patients whose tumor became operable, and for whom resection
The secondary efficacy end points were OS, ORR, duration of response,
was performed, were allowed to enter the poststudy treatment phase.
and time to treatment failure. For ORR, noninferiority of pooled XELOX
If one of the regimen components was discontinued, treatment could be
versus pooled FOLFOX-4 arms was concluded if the lower limit of the two-
continued with the remaining components as follows: capecitabine or FU/
sided 97.5% CI for the odds ratio was higher than 0.66. The remaining second-
FA ⫾ bevacizumab/placebo could be given after discontinuing oxaliplatin;
ary efficacy analyses were considered descriptive only.
XELOX, FOLFOX-4, capecitabine, or FU/FA could be given after discontinu-
PFS, OS, and time to treatment failure were analyzed using Cox models
ing bevacizumab/placebo; bevacizumab/placebo could be given after discon-
and presented as Kaplan-Meier estimates with HR and 97.5% CIs. Overall
tinuing XELOX, FOLFOX-4, capecitabine or FU/FA; or patients were not
response was assessed by logistic regression, and presented with 97.5% CIs.
permitted to continue on oxaliplatin with or without bevacizumab/placebo.
Duration of overall response was presented as Kaplan-Meier estimates with
Assessments 97.5% CIs.
Medical history, physical examination, chest x-ray, ECG, and carcino- The analysis of NO16966 was event driven. The final analysis was to be
embryonic antigen measurement were performed within 21 days before start- done when 1,200 PFS events had occurred in the EPP, this approach ensuring
ing treatment. Assessments of vital signs, ECOG performance status, height, 90% power at an ␣ level of 2.5. All the results presented, except OS, are based
on the main clinical cutoff date (January 31, 2006). In order to provide the Both a clinically relevant and statistically significant (P ⫽ .7025)
most up-to-date results for OS, data presented are based on a more recent treatment interaction was ruled out. Therefore, the pooled analysis of
clinical cutoff date (January 31, 2007). all patients treated with XELOX (ie, XELOX, XELOX and placebo,
and XELOX and bevacizumab) versus FOLFOX-4 (ie, FOLFOX-4,
RESULTS FOLFOX-4 and placebo, FOLFOX-4 and bevacizumab) was the pri-
mary analysis of noninferiority.
Patient Population The median PFS (ITT analysis) was 8.0 months in the pooled
Between July 2003 and May 2004, 634 patients were randomly XELOX-containing arms versus 8.5 months in the FOLFOX-4 –
assigned in the two-arm portion of the study. Between February 2004 containing arms (HR, 1.04; 97.5% CI, 0.93 to 1.16), the upper limit of
and February 2005, an additional 1,401 patients were randomly as- the 97.5% CI being below the predefined noninferiority margin of
signed in the 2 ⫻ 2 factorial part of the study. One patient, who was 1.23 (Fig 2). Similar results were observed in the EPP with a median
randomly assigned twice, was excluded from the FOLFOX-4- PFS of 7.9 months in the pooled XELOX-containing arms versus 8.5
bevacizumab arm (and not treated) for not providing informed con- months in the FOLFOX-4 – containing arms (HR, 1.05; 97.5% CI,
sent, but was later included and treated at another center in the 0.94 to 1.18).
XELOX and placebo arm. The two exploratory analyses were further supportive of the main
Overall, 2,034 patients made up the ITT population from the study findings. Median PFS with XELOX and bevacizumab was 9.3
following regions: Europe (n ⫽ 1,048); Canada (n ⫽ 343); Oceania months versus 9.4 months with FOLFOX-4 and bevacizumab (HR,
(n ⫽ 188); United States (n ⫽ 178); central/eastern Asia (n ⫽ 163); 1.01; 97.5% CI, 0.83 to 1.23; ITT). In the two-arm part of the study, the
South America (n ⫽ 65); and South Africa (n ⫽ 49). The EPP popu- median PFS with XELOX was 7.3 months versus 7.7 months with
lation comprised a total of 1,904 patients (Fig 1). The safety popula- FOLFOX-4 (HR, 0.96; 97.5% CI, 0.80 to 1.16; ITT).
tion comprised 1,304 patients in the nonbevacizumab-treated groups The noninferiority results for PFS were further supported by
and 694 patients in the bevacizumab-treated groups. Baseline demo- subgroup analyses defined by demographic and baseline characteris-
graphic and clinical characteristics were well balanced between treat- tics and stratification variables (Fig 3). The HRs for PFS in the ITT
ment arms (Table 1). population were similar across the different subgroups.
Allocated to XELOX Allocated to FOLFOX-4 Allocated to XELOX + Allocated to XELOX + Allocated to FOLFOX-4 + Allocated to FOLFOX-4 +
(n = 317) (n = 317) placebo (n = 350) bevacizumab (n = 350) placebo (n = 351) bevacizumab (n = 350)
Included in ITT (n = 317) Included in ITT (n = 317) Included in ITT (n = 350) Included in ITT (n = 350) Included in ITT (n = 351) Included in ITT (n = 349)
Did not receive treatment
No informed consent(n = 1)
Included in EPP population Included in EPP population Included in EPP population Included in EPP population Included in EPP population Included in EPP population
(n = 303) (n = 294) (n = 327) (n = 337) (n = 326) (n = 317)
Excluded (n = 14) Excluded (n = 23) Excluded (n = 23) Excluded (n = 13) Excluded (n = 25) Excluded (n = 33)
EPP Analysis
No measurable lesion (n = 7) No measurable lesion (n = 15) No measurable lesion (n = 9) No measurable lesion (n = 8) No measurable lesion (n = 11) No measurable lesion
Prior treatment for Prior treatment for advanced Prior treatment for advanced Prior treatment for Prior treatment for advanced (n =13)
advanced disease (n = 6) disease (n = 3) disease (n = 6) advanced disease (n = 2) disease (n = 4) Prior treatment for advanced
Did not receive ≥ 1 dose of Did not receive ≥ 1 dose of Did not receive ≥ 1 dose of Did not receive ≥ 1 dose of Did not receive ≥ 1 dose of disease (n = 7)
study treatment (n = 1) study treatment (n = 4) study treatment (n = 7) study treatment (n = 1) study treatment (n = 9) Did not receive ≥ 1 dose of
MCRC not histologically Severe renal impairment MCRC not histologically MCRC not histologically study treatment (n =15)
confirmed (n = 1) (n = 1) confirmed (n = 1) confirmed (n = 1) MCRC not histologically
Evidence of CNS disease Evidence of CNS disease Evidence of CNS disease confirmed (n = 2)
(n = 1) (n = 1) (n = 1) No informed consent (n = 1)
Received prior oxaliplatin Positive pregnancy test (n = 1)
(n = 1)
Fig 1. CONSORT diagram. XELOX, capacitabine and oxaliplatin; FOLFOX-4, infused fluorouracil, folinic acid, and oxaliplatin; ITT, intent-to-treat; EPP, eligible patient
population; MCRC, metastatic colorectal cancer.
Abbreviations: ECOG, Eastern Cooperative Oncology Group; FOLFOX-4, infused fluorouracil, folinic acid, and oxaliplatin; XELOX, capecitabine and oxaliplatin.
The median OS in the ITT population was 19.8 months in the pooled 0.99 (97.5% CI, 0.80 to 1.23; online-only Fig A1) and in the two-arm
XELOX arms and 19.6 months in the pooled FOLFOX-4 arms, with a part of the study the HR of XELOX versus FOLFOX-4 was 0.90 (97.5%
corresponding HR of 0.99 (97.5% CI, 0.88 to 1.12; Fig 4). The HR of CI, 0.74 to 1.10). The details of OS and other descriptive secondary end
XELOX and bevacizumab versus FOLFOX-4 and bevacizumab was points are presented in Table 2.
Second-Line Therapy
FOLFOX-4/FOLFOX-4+placebo/FOLFOX-4+bevacizumab
There were no major imbalances between the treatment groups
1.0
n = 1017; 826 events with respect to the use of second-line therapy: XELOX-containing
XELOX/XELOX+placebo/XELOX+bevacizumab
Proportion of Patients
0.9 n = 1017; 813 events arms, 51%, and FOLFOX-4 – containing arms, 53%. The most com-
0.8 mon agents used were: irinotecan (41% with FOLFOX-4 v 39% with
HR = 1.04 [97.5% CI: 0.93–1.16] (ITT)
0.7 HR = 1.05 [97.5% CI: 0.94–1.18] (EPP)
0.6
XELOX); FU (29% v 25%); capecitabine (12% v 7%); cetuximab
Upper limit below < 1.23 (non-inferiority margin)
0.5 (11% v 9%); and bevacizumab (5% v 6%).
0.4
0.3
0.2
Safety
0.1 8.0 8.5
The median dose intensities (ratio of dose received to dose
planned) of FU, capecitabine, oxaliplatin, and bevacizumab were ⱖ
0 5 10 15 20 25 30
0.89 in all treatment arms. The median number of cycles administered
Time (months) 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),
Fig 2. Progression-free survival (intent-to-treat population [ITT]). FOLFOX-4,
infused fluorouracil, folinic acid, and oxaliplatin; XELOX, capacitabine and oxali- seven in the XELOX/XELOX and placebo groups (range, one to 16),
platin; EPP, eligible patient population; HR, hazard ratio. and eight in the XELOX and bevacizumab group (range, one to 17).
grade 4 adverse events were more common with FOLFOX-4 (25% 0.9 n = 1017; 692 events
and 12%, respectively), this difference being predominantly due to 0.8
HR = 0.99 [97.5% CI: 0.88–1.12] (ITT)
0.7 HR = 1.00 [97.5% CI: 0.88–1.13] (EPP)
grade 4 neutropenia. 0.6
The rates of some individual adverse events also differed between 0.5
the two regimens. Whereas FOLFOX-4 was associated with more 0.4
0.3
grade 3/4 neutropenia/granulocytopenia (44% v 7%), febrile neutro- 0.2
penia (4.8% v 0.9%), and grade 3/4 venous thromboembolic events 0.1 19.6 19.8
(6.3% v 3.8%) than XELOX, XELOX was associated with more grade
0 5 10 15 20 25 30 35 40
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 Time (months)
similar with both regimens (approximately 17%). Grade 3/4 cardiac
Fig 4. Overall survival (intent-to-treat population [ITT]). FOLFOX-4, infused
disorders were reported in nine FOLFOX-4 recipients (1.4%) and six fluorouracil folinic acid, and oxaliplatin; XELOX, capacitabine and oxaliplatin; EPP,
XELOX recipients (0.9%). eligible patient population; HR, hazard ratio.
Table 3. Most Frequent (⬎ 20% of patients) Adverse Events (treatment-related and unrelated)
NCI-CTC Grade
1 2 3 4 1 2 3 4
Adverse Event No. % No. % No. % No. % No. % No. % No. % No. %
All events 627 97 576 89 454 70 161 25 615 94 572 87 449 69 81 12
Nausea 258 40 123 19 33 5 0 0 224 34 153 23 30 5 0 0
Diarrhea 179 28 141 22 70 11 3 ⬍1 171 26 126 19 123 19 9 1
Neutropenia 18 3 79 12 173 27 106 16 16 2 118 18 39 6 6 ⬍1
Fatigue 131 20 110 17 49 8 2 ⬍1 108 16 107 16 33 5 1 ⬍1
Vomiting 141 22 85 13 28 4 0 0 143 22 103 16 34 5 0 0
Paresthesia 165 25 54 8 25 4 0 0 137 21 74 11 31 5 0 0
Stomatitis 162 25 67 10 13 2 0 0 102 16 30 5 8 1 0 0
Anorexia 103 16 59 9 17 3 0 0 108 16 56 9 16 2 0 0
Hand-foot syndrome 45 7 13 2 8 1 — — 105 16 53 8 40 6 — —
Constipation 114 18 50 8 15 2 0 0 97 15 45 7 9 1 0 0
Pyrexia 119 18 45 7 9 1 0 0 82 13 33 5 6 ⬍1 0 0
Abdominal pain 81 12 66 10 24 4 1 ⬍1 75 11 63 10 36 5 0 0
Thrombocytopenia 36 6 92 14 20 3 2 ⬍1 23 4 78 12 39 6 7 ⬍1
Peripheral neuropathy 74 11 33 5 23 4 0 0 73 11 30 5 24 4 0 0
Asthenia 49 8 59 9 22 3 1 ⬍1 38 6 58 9 26 4 2 ⬍1
Abbreviations: FOLFOX-4, infused fluorouracil, 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 The efficacy of capecitabine and oxaliplatin combinations has
most common reasons for treatment discontinuation were neurosen- been tested in three other smaller phase III trials in the first-line
sory toxicity and diarrhea. setting12-14 and in one trial in the second-line setting.15 While the
Treatment-related mortality up to 28 days after the last treat- XELOX regimen was used in two first-line trials,12,14 a modified cape-
ment dose was documented in 11 patients (1.7%) treated with citabine and oxaliplatin regimen (CAPOX) was used in the third
FOLFOX-4, 14 patients (2.1%) treated with XELOX, six patients first-line trial.13 FOLFOX-6 was used as the comparator regimen in
(1.8%) treated with FOLFOX-4 and bevacizumab, and eight patients one trial,12 while two trials used other infusional FU and oxaliplatin
(2.3%) treated with XELOX and bevacizumab. The respective 60-day with (FUFOX) or without FA (FUOX) regimens. Ducreux et al12
all-cause mortality rates were 2.3% (n ⫽ 15), 3.4% (n ⫽ 22), 1.5% showed noninferiority of XELOX versus FOLFOX-6 in terms of re-
(n ⫽ 5), and 2.5% (n ⫽ 9). sponse 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.
DISCUSSION Dı́az-Rubio et al14 reported equivalent efficacy 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
This large multinational randomized phase III trial demonstrates that
XELOX is noninferior to FOLFOX-4 in terms of PFS, OS, and ORR in median PFS was 7.1 months with the nonstandard CAPOX regimen
the first-line treatment of patients with MCRC. With approximately and 8.0 months with FUFOX (HR, 1.17; 95% CI, 0.96 to 1.43; P ⫽
1,000 patients in each pooled treatment arm, the NO16966 trial is the .117); the upper 95% CI exceeded the prospectively defined interval
largest conducted to date to address this question. The overall finding for noninferiority (1.29). However, the study by Porschen et al13 was
of noninferiority was also supported by exploratory analyses con- underpowered, and it is possible that an imbalance in restaging inter-
ducted in the XELOX and bevacizumab versus FOLFOX-4 and bev- vals in this trial, particularly during the first 20 weeks, may have biased
acizumab subgroups and the original XELOX versus FOLFOX-4 the results in favor of FUFOX. Finally, Rothenberg et al15 showed that
arms. Collectively, these analyses show that the findings of the main XELOX is noninferior to FOLFOX-4 in terms of PFS in the second-
analysis are robust. line treatment of MCRC.
Previously, the efficacy and safety of capecitabine as single-agent Safety data from this trial suggest that while the profile of adverse
therapy was established based on comparisons with bolus regimens of events associated with both the XELOX and FOLFOX-4 regimens are
FU/FA.2-5 However, in current clinical practice, infusional regimens similar, there are differences in the rates at which these occur. The
of FU/FA are often preferred because they confer some benefits in XELOX regimen was associated with more grade 3 diarrhea, whereas
terms of toxicity and efficacy. This trial compared a capecitabine- FOLFOX-4 was associated with more grade 3/4 neutropenia/granulo-
based regimen with a regimen that included a bolus and continuous cytopenia and febrile neutropenia.
infusion of FU, and demonstrated that the efficacy of these two treat- The FOLFOX-4 regimen involves two 22-hour infusions of FU
ment options in this combination therapy context is similar. every 14 days, which require catheter placement and regular visits to
the clinic. The FOLFOX-4 regimen was selected as the comparator in Employment or Leadership Position: Florin Sirzén, Roche (C)
this study for regulatory reasons but is still widely used globally. Al- Consultant or Advisory Role: Jim Cassidy, Roche (C); Stephen Clarke,
though modified FOLFOX regimens (such as mFOLFOX-6) have Roche (C); Eduardo Dı́az-Rubio, Roche (C), Sanofi-aventis (C); Arie
Figer, Roche (C); Ralph Wong, Roche (C), Sanofi-aventis (C) Stock
replaced FOLFOX-4 in some countries and although these do afford Ownership: None Honoraria: Jim Cassidy, Roche; Stephen Clarke,
some greater convenience in terms of one 2-day infusion instead of Roche; Eduardo Dı́az-Rubio, Roche, Sanofi-aventis; Werner Scheithauer,
two 22-hour infusions, the XELOX regimen requires still fewer Roche, Sanofi-aventis; Arie Figer, Roche; Fernando Rivera, Roche; Felix
planned office visits, with oxaliplatin administered every 21 days and Couture, Roche Research Funding: Jim Cassidy, Roche; Eduardo
capecitabine taken orally. Of note, there was a slight increase in grade Dı́az-Rubio, Roche, Sanofi-aventis; Werner Scheithauer, Roche,
3/4 thromboembolic events with FOLFOX-4, some of which may Sanofi-aventis; Arie Figer, Roche; Fernando Rivera, Roche; Leonard Saltz,
Roche, Genentech Expert Testimony: None Other Remuneration: None
have been attributable to catheter use.
In conclusion, XELOX is noninferior to FOLFOX-4, and may be
considered as a standard treatment in the first-line treatment AUTHOR CONTRIBUTIONS
of MCRC.
Conception and design: Jim Cassidy, Florin Sirzén
Administrative support: Florin Sirzén
Provision of study materials or patients: Jim Cassidy, Stephen Clarke,
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS Eduardo Dı́az-Rubio, Werner Scheithauer, Arie Figer, Ralph Wong,
OF INTEREST
Sheryl Koski, Mikhail Lichinitser, Tsai-Shen Yang, Fernando Rivera,
Felix Couture, Leonard Saltz
Although all authors completed the disclosure declaration, the following Collection and assembly of data: Werner Scheithauer, Arie Figer,
author(s) indicated a financial or other interest that is relevant to the subject Fernando Rivera, Florin Sirzén
matter under consideration in this article. Certain relationships marked Data analysis and interpretation: Jim Cassidy, Florin Sirzén
with a “U” are those for which no compensation was received; those Manuscript writing: Jim Cassidy, Stephen Clarke, Eduardo Dı́az-Rubio,
relationships marked with a “C” were compensated. For a detailed Florin Sirzén
description of the disclosure categories, or for more information about Final approval of manuscript: Jim Cassidy, Eduardo Dı́az-Rubio,
ASCO’s conflict of interest policy, please refer to the Author Disclosure Werner Scheithauer, Arie Figer, Ralph Wong, Sheryl Koski, Mikhail
Declaration and the Disclosures of Potential Conflicts of Interest section in Lichinitser, Tsai-Shen Yang, Fernando Rivera, Felix Couture, Florin
Information for Contributors. Sirzén, Leonard Saltz
line therapy for patients with metastatic colorectal Institute of the United States, National Cancer Insti-
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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
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Appendix
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(via Adobe® Reader®).