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Journal of Clinical Oncology, Vol 22, No 11 (June 1), 2004: pp. 2084-2091
© 2004 American Society of Clinical Oncology.
DOI: 10.1200/JCO.2004.11.069
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XELOX (Capecitabine Plus Oxaliplatin): Active First-Line Therapy for Pa... http://jco.ascopubs.org/cgi/content/full/22/11/2084
ABSTRACT
TOP
PURPOSE: Capecitabine has demonstrated high efficacy as first-line treatment for
ABSTRACT
metastatic colorectal cancer (MCRC). Oxaliplatin shows synergy with fluorouracil
INTRODUCTION
(FU), with little toxicity overlap. The XELOX regimen (capecitabine plus oxaliplatin),
PATIENTS AND METHODS
established in a previous dose-finding study, should improve on infused oxaliplatin RESULTS
with FU and leucovorin (FOLFOX) regimens. The present studies further characterize DISCUSSION
efficacy and safety of the XELOX regimen. Authors' Disclosures of...
REFERENCES
PATIENTS AND METHODS: The antitumor activity of XELOX was investigated in a
colon cancer xenograft model. Patients with MCRC received first-line XELOX in
3-week treatment cycles: intravenous oxaliplatin 130 mg/m2 (day 1) followed by oral capecitabine 1,000 mg/m2 twice
daily (day 1, evening, to day 15, morning).
RESULTS: A preclinical study confirmed that capecitabine has supra-additive activity with oxaliplatin. In the clinical study,
53 of 96 patients (55%) achieved an objective response, and 30 (31%) experienced disease stabilization for 3 months
following treatment. After 24 months' minimum follow-up, median time to disease progression (TTP) and median overall
survival were 7.7 and 19.5 months, respectively. XELOX safety was predictable and similar to the FOLFOX4 regimen,
except that myelosuppression was uncommon with XELOX (grade 3 or 4 neutropenia, 7%). Most adverse events were
mild to moderate, the most common being acute sensory neuropathy (85%). Sixty-day, all-cause mortality was 2%.
CONCLUSION: XELOX is a highly effective first-line treatment for MCRC. Response rates, TTP, and overall survival are
similar to those observed with FU/leucovorin/oxaliplatin combinations. XELOX provides a more convenient regimen, likely
to be preferred by both patients and healthcare providers. Capecitabine has the potential to replace FU/LV in combination
with oxaliplatin for MCRC.
INTRODUCTION
TOP
Intravenous fluorouracil (FU) has been the mainstay of chemotherapy for
ABSTRACT
metastatic colorectal cancer (MCRC) for many years. Prolonged infusion of FU in
INTRODUCTION
combination with the biomodulator leucovorin (LV) has an improved safety and
efficacy profile compared with the bolus FU/LV,1-3 but the inconvenience and RESULTS
morbidity associated with long-term central venous access emphasized the need for DISCUSSION
alternative regimens. Capecitabine is an oral fluoropyrimidine that was rationally Authors' Disclosures of...
designed to generate FU preferentially at the tumor site, via a three-step enzymatic REFERENCES
process that exploits the significantly higher activity of thymidine phosphorylase
(TP) in tumors, compared with healthy tissue.4 Twice-daily dosing of oral capecitabine obviates the drawbacks of
prolonged infusions of FU. A prospective, integrated analysis of two large, randomized phase III trials in MCRC
demonstrated that capecitabine monotherapy achieves significantly higher tumor response rates compared with FU/LV
(Mayo Clinic regimen) (26% v 17%, P < .0002).5-7 Capecitabine also had an improved safety profile versus FU/LV (Mayo
Clinic regimen), causing significantly less diarrhea, stomatitis, nausea, alopecia, and neutropenia, leading to less
neutropenic fever/sepsis and associated hospitalizations.8 Hand-foot syndrome (HFS) occurred more frequently with
capecitabine than with FU/LV, but this cutaneous side effect is never life-threatening and rarely led to hospitalization. A
large phase III trial (n = 1,987) is also evaluating capecitabine as adjuvant treatment for patients with Dukes' C colon
cancer. A planned safety analysis, conducted 19 months following the enrollment of the last patient, has confirmed that
the improved safety profile of capecitabine versus intravenous (IV) FU/LV observed in the metastatic setting is mirrored
with adjuvant treatment.9 Capecitabine is therefore a highly active, more convenient, and better-tolerated alternative to
FU/LV in colorectal cancer therapy.
Infused FU/LV in combination with oxaliplatin, a third generation platinum analog, proved more effective than FU/LV alone
in the first- and second-line treatment of MCRC. Addition of oxaliplatin to FU/LV therapy significantly increased response
rates and time to disease progression (TTP) compared with FU/LV in the first-line treatment of colorectal cancer in three
randomized studies10-12 and as second-line therapy versus FU/LV.13 Recently, a large cooperative group trial (N9741)
showed significant improvements in response rate, TTP, and overall survival with oxaliplatin plus infused FU/LV versus
2 de 19 02/07/2009 12:54 a.m.

irinotecan plus bolus FU/LV.14
Despite the increased efficacy associated with infused FU/LV plus oxaliplatin, the administration schedules for the FU
component are inconvenient for both patients and healthcare professionals. These require two bolus injections plus two
22-hour infusions every 2 weeks,10 or 5 days of continuous infusion with chronomodulation equipment every 3 weeks,11
or weekly 24-hour infusion.12 Because capecitabine has already demonstrated its ability to replace FU/LV as a highly
effective and more convenient treatment for colorectal cancer, there is a strong rationale for investigating the efficacy and
safety of capecitabine in combination with oxaliplatin.
A phase I study showed that the combination of capecitabine with oxaliplatin (XELOX) is feasible and established the
recommended dose regimen as IV oxaliplatin 130 mg/m2 on day 1 followed by oral capecitabine 1,000 mg/m2 twice daily,
days 1 to 14, in a 3-week cycle.15 A xenograft study has also been performed to further elucidate the preclinical rationale
for the XELOX combination. In addition, the current international, phase II study was conducted to evaluate further the
efficacy and safety of this regimen as first-line therapy for patients with MCRC and thus determine the potential of
capecitabine to replace FU/LV as the standard combination partner for oxaliplatin.

Evaluation of Capecitabine Plus Oxaliplatin in a Human Cancer Xenograft TOP
Model ABSTRACT
The effect of capecitabine and oxaliplatin, alone and in combination, on tumor INTRODUCTION
growth and expression of TP in a human colon cancer xenograft model was PATIENTS AND METHODS
investigated. The human colon cancer xenograft model, CXF280, was provided by
RESULTS
DISCUSSION
H.H. Fiebig (Freiburg University, Freiburg, Germany). Tumor tissue from human
Authors' Disclosures of...
colon cancer CXF280 was inoculated subcutaneously into BALB/c nu/nu mice. Drugs
REFERENCES
were administered when tumor volume (1/2 x length x width x width) reached
approximately 0.3 to 0.5 cm3 . To evaluate the antitumor effect of capecitabine and oxaliplatin, tumor size and body
weight were measured twice a week. Capecitabine, dissolved in 40 mmol/L citrate buffer (pH 6.0) containing 5% gum
arabic, was administered orally for 14 consecutive days. Oxaliplatin in 5% glucose solution was given intravenously on day
1. Tumor TP was measured by enzyme-linked immunosorbent assay, with monoclonal antibodies specific for human TP as
described previously.16
Phase II Study Design

This was a large, open-label, phase II study, conducted at 13 centers in Europe, Israel, and North America. The primary
end point was overall response rate as assessed by the investigator. Secondary end points included independently
reviewed response rate, TTP, overall survival, 1-year survival, and safety. The study was performed in accordance with
the Helsinki declaration and its amendments, and ICH-GCP guidelines.17 All patients provided written, informed consent.
Patients
Patients aged 18 to 75 years with measurable, histologically confirmed metastatic or locally advanced colorectal cancer
were eligible for the study. Patients were required to be ambulatory and have a Karnofsky performance status of > 70%,
with a life expectancy of 3 months. Prior chemotherapy for advanced disease was not permitted, but adjuvant or
neoadjuvant chemotherapy was allowed, providing it was completed at least 6 months before start of study treatment.
Exclusion criteria included prior therapy with capecitabine, oxaliplatin, or irinotecan, history of previous malignancy within
5 years, clinically significant cardiac disease, evidence of CNS metastases, radiotherapy or surgery within 4 weeks before
treatment, neutropenia (< 1.5 /µL), thrombocytopenia (< 100/µL), severe renal function impairment (creatinine
clearance < 30 mL/min), or abnormal liver function. Pregnant or lactating women were excluded from the study; women
of childbearing potential and sexually active males were required to agree to practice appropriate and adequate
contraception.
Study Assessments
Prestudy screening assessments included a full medical history, vital signs and physical measurements, and hematologic
and blood chemistry tests. Tumor assessments were performed by computed tomography scan, x-ray, and/or magnetic
resonance imaging during screening, after the first three cycles of treatment, then after every two cycles of treatment
until disease progression or withdrawal from study medication. In patients whose disease had not progressed when
stopping treatment, tumor assessments were performed every 3 months until progression. In addition to investigator
3 de 19 02/07/2009 12:54 a.m.

assessment, tumor imagery was evaluated by an independent review committee (IRC), using x-ray, magnetic resonance
imaging, or computed tomography scans. Investigators and the IRC assessed the same scans. In addition, survival was
monitored at intervals of every 3 months in each patient leaving the study. Tumor response was assessed according to
WHO criteria18 and confirmed at least 4 weeks later by the same evaluation. TTP was defined as the interval between the
first dose of study treatment and the first recording of disease progression or death.
Adverse events, including neurosensory toxicity and HFS, were classified by National Cancer Institute Common Toxicity
Criteria version 2.
Treatment
Treatment comprised IV oxaliplatin 130 mg/m2 (diluted in a 5% glucose solution) day 1 then oral capecitabine 1,000
mg/m2 twice daily from the evening of day 1 to the morning of day 15, followed by a 7-day treatment-free interval, in a
3-week cycle. Pyridoxine prophylaxis or treatment for HFS was not permitted during this study, given that pyridoxine has
been reported to reduce the efficacy of cisplatin.19 The capecitabine starting dose was reduced to 75% of the standard
capecitabine starting dose in patients with moderate renal impairment (30 mL/min creatinine clearance < 50 mL/min).
The dose of capecitabine was adjusted for adverse events of grade 2 or higher intensity, according to the standard
scheme, described in detail by Blum et al.20 The dose of oxaliplatin was reduced for grade 3 vomiting, grade 3 or 4
thrombocytopenia, or grade 4 neutropenia, and for paresthesiae with pain or functional impairment > 7 days, or
paresthesiae with pain persistent between cycles. For paresthesiae with functional impairment persistent between cycles,
oxaliplatin was discontinued.
The planned number of treatment cycles was 11, but patients maintaining a response or stable disease after this time
could continue treatment at the discretion of the investigator. Patients could also continue capecitabine monotherapy after
discontinuation of oxaliplatin irrespective of the number of cycles already received.
Statistical Analysis
The efficacy analyses were based on the intent-to-treat population. The primary end point was overall confirmed response
rate, as assessed by the investigators. The 95% CI for response risk was calculated. According to the method of
Fleming,21 80 assessable patients were required to demonstrate a 40% overall response rate with a power of 90%. TTP
and survival were estimated by Kaplan-Meier analysis. Safety was analyzed in all patients who received at least one dose
of study medication.
Clinical cutoff for the study analysis was January 15, 2003. A minimum follow-up of 24 months had been reached in all
patients.
RESULTS
Capecitabine and Oxaliplatin in a Preclinical Xenograft Model TOP
In a human tumor xenograft model, the combination of capecitabine and oxaliplatin ABSTRACT
INTRODUCTION
inhibited the in vivo growth of CXF280 human colon cancer more effectively than
either agent alone, administered at their maximum-tolerated doses (Fig 1).
RESULTS
Toxicity in terms of weight loss did not appear to be additive in the capecitabine
DISCUSSION
plus oxaliplatin group. Furthermore, oxaliplatin upregulated TP expression in Authors' Disclosures of...
CXF280 tumor tissue (Fig 2). The high activity observed with capecitabine and REFERENCES
oxaliplatin may be due, therefore, to upregulation of TP. The fact that toxicity
(monitored by assessing body weight loss) was not enhanced with the XELOX combination may support the hypothesis
that TP upregulation is a tumor-specific phenomenon.
4 de 19 02/07/2009 12:54 a.m.

Fig 1. Inhibition of tumor growth (± standard deviation) by capecitabine,

oxaliplatin, and the combination in a human colon cancer xenograft model
CXF280. P < .05 versus both single agents. MTD, maximum tolerated dose.
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Fig 2. Oxaliplatin further upregulates thymidine phosphorylase in CXF280

human colon cancer xenografts (bars indicate standard deviation). P < .05
versus control (oxaliplatin). TP, thymidine phosphorylase.

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Patient Demographics
A total of 96 patients were recruited between July 2000 and March 2001, from 13 centers in seven countries (Belgium,
Canada, France, Germany, Israel, Italy, Spain, and the United Kingdom). The patient profile was typical of a first-line
MCRC trial population: approximately half of the patients (54%) had multiple metastases, with liver, lymph nodes, and
lung being the most frequent sites of metastases (Table 1). One enrolled patient initially diagnosed with a colorectal
cancer liver metastasis was subsequently found to have a hemangioma, rather than metastatic disease. The median time
from the primary diagnosis of colorectal cancer to inclusion was 2.9 months. Of the 27 patients (28%) who had received
prior adjuvant or neoadjuvant chemotherapy, 26 had received IV FU, and one had received oral tegafur/uracil. Eleven
patients (11%) had received prior radiotherapy.
View this table: Table 1. Patient Characteristics (N = 96)

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Treatment
A total of 39 patients (39%) completed the planned 11 cycles of either XELOX or capecitabine monotherapy, of whom 21
(22%) continued with either XELOX or capecitabine monotherapy after 11 cycles. A median of eight cycles of XELOX
combination therapy (range, one to 26 cycles) were administered, and patients received a median of two cycles of
capecitabine monotherapy after discontinuation of oxaliplatin (range, one to 39 cycles). Table 2 shows the numbers of
patients receiving XELOX or capecitabine monotherapy at each cycle.
View this table: Table 2. Patients Receiving XELOX or Capecitabine Monotherapy at Each Cycle
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Efficacy
All efficacy analyses were conducted on the intent-to-treat population, which comprised all patients enrolled—that is, none
of the enrolled patients withdrew before receiving treatment. All patients were followed up for a minimum of 24 months.
An objective response was observed in 53 patients (55%; 95% CI, 45% to 65%; Table 3), with complete response in two
patients (2%). All objective responses were confirmed at least 4 weeks after first observation. Disease stabilization was
achieved in a further 30 patients (31%; 95% CI, 22% to 42%). Notably, disease stabilization lasted longer than 3 months
from start of treatment in all of these patients.
View this table: Table 3. Tumor Response to Treatment (investigator-ITT Population)

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The response rate by IRC assessment was 45% (43 patients; 95% CI, 35% to 55%). Concordance between investigator
and IRC was high, with identical assessments in 63 of the 85 patients (74%) for whom an assessment by both investigator
and IRC was available. The majority of discrepancies were between patients classified as showing partial response or
stable disease.
Response rates were analyzed in patient subpopulations (Fig 3). XELOX achieved consistently high (> 50%) response rates
in all patient subpopulations studied.
Fig 3. Response rates among patient subgroups. KPS, Karnofsky

performance status.

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After a minimum follow-up of 24 months, the median TTP in the intent-to-treat population was 7.7 months (95% CI, 6.4%
to 8.6%; Fig 4). Median overall survival was 19.5 months (95% CI, 15.3% to 21.6%; Fig 5). The survival rate was 70% at
1 year and 30% at 2 years.
Fig 4. Time to disease progression (n = 96).

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Fig 5. Overall survival (n = 96).

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Poststudy Treatment
A total of 66 patients (69%) received second-line and 35 (36%) received third-line chemotherapy. The most common
second-line chemotherapy was irinotecan (48 patients; 50%), either as monotherapy or in combination with FU (Table 4).
Second-line capecitabine was given to 11 patients after disease progression (including four who received further XELOX).
Twelve patients (13%) received palliative radiotherapy, and five underwent surgery, including four patients who
underwent partial hepatic resection and one who underwent a partial liver and lung resection.
View this table: Table 4. Chemotherapy After Withdrawal From Study Treatment
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Safety
Safety was evaluated in all patients who received treatment (n = 96). Of the 59 patients withdrawing during the
treatment phase (the first 11 cycles), the majority (35 patients) withdrew because of disease progression (Table 5).
View this table: Table 5. Reasons for Withdrawal During the First 11 Cycles
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The most common (> 20%) treatment-related adverse events are shown in Figure 6. Sensory neuropathy, a frequent side
effect of oxaliplatin, was the most common treatment-related adverse event, occurring in 85% of patients. The majority
of neuropathy was mild to moderate, with only 17% experiencing cumulative neurotoxicity (grade 3 or 4). The majority of
treatment-related adverse events were mild to moderate in intensity. The most common grade 3 or 4 treatment-related
adverse events were sensory neuropathy (17%), diarrhea (16%), and nausea or vomiting (13%; Fig 7). Only five patients
(5%) experienced grade 4 treatment-related adverse events. HFS was experienced by 35 patients (36%), but at grade 3
intensity in only three patients (3%).
Fig 6. Most common (> 20%) treatment-related adverse events (all

grades).

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Fig 7. Most common ( 2%) treatment-related grade 3 or 4 adverse

events.

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Grade 3 elevations in laboratory parameters were rare, comprising neutropenia (7%), thrombocytopenia (4%), anemia
(1%), and hyperbilirubinemia (4%). Hyperbilirubinemia was an isolated laboratory abnormality and was not accompanied
by grade 3 or 4 elevations in alkaline phosphatase or liver transaminases. No grade 4 elevations in laboratory
abnormalities were observed.
XELOX demonstrated a similar favorable safety profile among the subgroups of patients aged 65 years or younger than
65 years. Stomatitis was the only treatment-related adverse event more common in patients at least 65 years old than
those younger than 65 years (34% v 17%, respectively), but no patients in either age group experienced grade 3 or 4
stomatitis. Overall, there was a similar incidence of grade 3 or 4 treatment-related adverse events in the two age groups
(64% of patients younger than 65 years and 59% of patients 65 years or older). Among the subgroups of patients at least
65 years old or younger than 65 years, there were no significant differences in the incidences of any grade 3 or 4
treatment-related adverse events, including peripheral sensory neuropathy (15 v 18%, respectively), diarrhea (14 v 18%,
respectively), nausea or vomiting (12 v 14%, respectively), neutropenia (6 v 5%), and HFS (6 v 0%, respectively).
Forty-eight patients (50%) received full doses of capecitabine and oxaliplatin throughout the study. Dose reduction was
required for capecitabine alone in 14 patients (15%), for oxaliplatin alone in 12 patients (13%), and for both agents in 22
patients (23%). The majority of dose reductions were by one level (reduction to 75% of starting dose of capecitabine
and/or 100 mg/m2 oxaliplatin). Only seven patients (7%) required a second level dose reduction, to 50% of starting dose
of capecitabine and/or 80 mg/m2 oxaliplatin. Adverse events most commonly leading to dose reduction were
myelosuppression and neurotoxicity. The incidence of dose reduction was similar in the subgroups of male and female
patients and those younger than 65 years or at least 65 years (data not shown).
Three deaths occurred during or within 28 days of withdrawal from study treatment during the planned 11 treatment
cycles, but only one of these was considered possibly related to treatment (pulmonary fibrosis, a rare but known side
effect of oxaliplatin, which occurred during cycle 8). The other two deaths were caused by colonic perforation and cardiac
arrest, both during cycle 1. Sixty-day all-cause mortality was therefore 2%.
DISCUSSION
TOP
The XELOX regimen is a rational combination treatment. The addition of oxaliplatin
ABSTRACT
to infused FU/LV chemotherapy results in higher response rates and TTP in both
INTRODUCTION
first- and second-line treatment of advanced colorectal cancer. Oral capecitabine
monotherapy has previously shown superior antitumor activity to bolus FU/LV RESULTS
(Mayo Clinic regimen) in this setting, with higher response rates (26% v 17%, P < DISCUSSION
.0002) and at least equivalent TTP and overall survival in two large randomized Authors' Disclosures of...
studies.5–7 REFERENCES
The high clinical activity of the XELOX combination may be explained in part by the preclinical data suggesting that
capecitabine and oxaliplatin have supra-additive activity in combination. Our studies show that the combination of
capecitabine and oxaliplatin inhibit the in vivo growth of CXF280 human colon cancer more effectively than either agent
8 de 19 02/07/2009 12:54 a.m.

alone. Furthermore, oxaliplatin upregulates TP, the key enzyme involved in tumor-specific generation of FU with
capecitabine, in CXF280 tumor tissues. Oxaliplatin-induced upregulation of TP could therefore result in supra-additive
activity with XELOX that may not occur with IV infused oxaliplatin with FU and leucovorin (FOLFOX) combinations.
This clinical study was undertaken to further evaluate the combination of XELOX as first-line therapy for MCRC. XELOX
achieved a high response rate of 55%, with an additional 31% of patients maintaining stable disease for at least 3 months.
Moreover, subgroup analysis showed that the response rate remained high (> 50%) irrespective of patient and disease
characteristics for all subgroups explored, which included those younger than 65 years or at least 65 years, and those with
Karnofsky performance status 80 or > 80, prior adjuvant therapy, and liver or lung metastases. These efficacy results
compare favorably with the randomized studies of FU/LV with or without oxaliplatin,10-12 which demonstrated significant
improvements for the combination (FOLFOX4) compared with FU/LV alone. XELOX achieves similar response rates and
progression-free and overall survival to all of the regimens combining protracted FU/LV infusion with oxaliplatin.
Capecitabine and oxaliplatin do not have overlapping key toxicities, and the combination was well tolerated even with the
long treatment duration. The safety profile of XELOX was similar to that of FU/LV plus oxaliplatin, with a lower incidence of
grade 3 or 4 neutropenia. Only three patients experienced grade 3 HFS. The low incidence of grade 3 HFS with XELOX
may be due to the 20% lower dose of Xeloda used in the XELOX trial compared with the monotherapy studies. However,
HFS is thought to be due to chronic daily exposure, and it is also possible that oxaliplatin-induced neurotoxicity may be
masking the symptoms of HFS. In addition, XELOX demonstrated a similar safety profile in patients younger than 65 years
or at least 65 years. Fifty percent of patients received the full doses of capecitabine and oxaliplatin throughout the study.
The median time to first dose reduction was identical for both agents (2.9 months). There was a similar incidence of dose
reduction in males and females younger than 65 years or at least 65 years.
The data therefore indicate that three-times-weekly XELOX is a highly effective regimen for the first-line treatment of
advanced colorectal cancer and that capecitabine has strong potential to replace FU/LV as the optimal combination partner
for oxaliplatin. The XELOX dose schedule of capecitabine 1,000 mg/m2 twice daily with oxaliplatin 130 mg/m2 had been
previously identified in a phase I dose-escalation study.15
Other regimens with capecitabine and oxaliplatin have been evaluated. Before completion of the dose-escalation study,
another phase II trial evaluated a higher dose of capecitabine, 1,250 mg/m2 twice daily (the recommended dose for
capecitabine monotherapy), in combination with oxaliplatin 130 mg/m2 in patients with pretreated and previously
untreated MCRC.22 While a response rate of 49% was obtained in patients receiving the combination as first-line therapy,
the incidence of grade 3 or 4 diarrhea was 33% in treatment-naïve patients and 50% in pretreated patients. Although the
authors recommend the full dose of both agents for treatment of patients with advanced CRC, more than 25% of the
chemotherapy-naïve population required a capecitabine dose reduction after the first cycle. A randomized, phase II trial
has evaluated two schedules of capecitabine plus oxaliplatin as first-line therapy in 89 patients with MCRC.23 Patients
were randomly assigned to receive a dose-intensified regimen (capecitabine 1,750 mg/m2 twice daily on days 1 to 7 and
14 to 21 plus oxaliplatin 85 mg/m2 on days 1 and 14, every 28 days) or XELOX as given in the present study (capecitabine
1,000 mg/m2 twice daily days 1 to 14 plus oxaliplatin 130 mg/m2 on day 1, every 21 days). No formal prospective
comparison of efficacy in the two treatment groups was planned and the study was not powered statistically for such a
comparison. Both regimens were active, achieving response rates of 55% and 42%, with median progression-free survival
of 10.5 and 6.0 months, respectively. However, in the absence of data from a prospective, randomized, phase III
comparison, no conclusions about the efficacy and safety of the dose-intensified regimen relative to XELOX can be drawn.
Another phase II study has evaluated a lower dose of capecitabine (750 mg/m2 twice daily) than used in the XELOX
regimen.24 This regimen achieved a response rate of only 34% in 35 patients treated. In summary, the dose of 1,000
mg/m2 capecitabine twice daily in combination with oxaliplatin, as used in the XELOX regimen, achieves high efficacy
while maintaining a good safety profile.
The XELOX regimen has demonstrated similar efficacy and safety to FOLFOX. Interestingly, the incidence of grade 3 or 4
neutropenia is lower with the XELOX regimen than with the FOLFOX4 regimen (7% v 42% to 47%), as is the incidence of
febrile neutropenia (0% v 1% to 4%).10,14 In addition, XELOX requires only one clinic visit per 3-week cycle for a 2-hour
infusion of oxaliplatin. This constitutes a marked advantage over regimens combining infused FU/LV and oxaliplatin in
terms of the impact on patients' daily lives and convenience for both patients and caregivers. With these regimens, FU/LV
is administered in two 22-hour infusions over 3 days every 2 weeks,10 a 5-day chronomodulated infusion every 3
weeks,11 or a weekly 24-hour infusion.12 In patients with MCRC, for whom treatment is essentially palliative, these
protracted infusion times represent a significant portion of the patient's remaining life span. In addition, patients are
exposed to the potential complications of central venous access. The simplified XELOX regimen is thus likely to have
9 de 19 02/07/2009 12:54 a.m.

important implications for patients' well-being and autonomy.
In summary, this study shows that XELOX is a highly effective therapy for patients with MCRC. Response rates, time to
progression, and overall survival compare favorably with previous studies of FU/LV/oxaliplatin, and the XELOX
combination offers substantially improved convenience and is less disruptive for patients. Capecitabine therefore could
replace FU/LV as the standard combination partner for oxaliplatin in this setting. Phase III evaluation of XELOX versus
FU/LV plus oxaliplatin in both the first- and second-line settings is ongoing, as is evaluation of the XELOX regimen as
adjuvant treatment for Dukes' C colon carcinoma. In addition, the XELOX regimen offers a novel, well-tolerated, and
active backbone for incorporation of innovative targeted agents such as the EGFR-directed drugs gefitinib, erlotinib, and
cetuximab, or the antiangiogenic monoclonal antibody bevacizumab.
Authors' Disclosures of Potential Conflicts of

Interest
TOP
The following authors or their immediate family members have indicated a financial
ABSTRACT
interest. No conflict exists for drugs or devices used in a study if they are not being
INTRODUCTION
evaluated as part of the investigation. Acted as a consultant within the last 2 years:
Jim Cassidy, Roche; Alberto Sobrero, Sanofi; Chris Twelves, Roche; Charles Butts, RESULTS
Roche. Performed contract work within the last 2 years: Eric Van Cutsem, Roche, DISCUSSION
Sanofi; Patrick Schöffski, Roche. Received more than $2,000 a year from a Authors' Disclosures of...
company for either of the last 2 years: Alberto Sobrero, Sanofi; Chris Twelves, REFERENCES
Roche.
Acknowledgment
We thank Stuart Teller, Jan Fagerberg, Stefan Frings, Eileen Codner, Peter Stoll, Patricia Kalber, Anne DiGiacomo, and
Pierre Ducournau; Sanofi-Synthelabo for providing oxaliplatin; and Dr H.H. Fiebig of Freiburg University, Germany, for the
CXF280 colon cancer line.
NOTES
Supported by F. Hoffmann-La Roche Ltd.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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j.cassidy@beatson.gla.ac.uk. PubMed Citation

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2 de 19 02/07/2009 12:54 a.m.

irinotecan plus bolus FU/LV.14

PATIENTS AND METHODS

Phase II Study Design

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4 de 19 02/07/2009 12:54 a.m.

Fig 1. Inhibition of tumor growth (± standard deviation) by capecitabine,

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Fig 2. Oxaliplatin further upregulates thymidine phosphorylase in CXF280

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View this table: Table 1. Patient Characteristics (N = 96)

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View this table: Table 3. Tumor Response to Treatment (investigator-ITT Population)

Fig 3. Response rates among patient subgroups. KPS, Karnofsky

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Fig 4. Time to disease progression (n = 96).

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Fig 5. Overall survival (n = 96).

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Fig 6. Most common (> 20%) treatment-related adverse events (all

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[in a new window]

Fig 7. Most common ( 2%) treatment-related grade 3 or 4 adverse

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important implications for patients' well-being and autonomy.

Authors' Disclosures of Potential Conflicts of

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17. ICH website. http://www.ich.org

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capecitabine: A phase II trial. Cancer100:531-537, 2004[CrossRef][Medline]

Submitted November 13, 2003; accepted March 8, 2003.

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