The fluoropyrimidine 5-fluorouracil (5-FU) has remained the most extensively used
chemotherapeutic agent in the treatment of advanced colorectal cancer for more than
40 years. During this time, many 5-FU-based regimens have been developed, including
48-h infusion or continuous infusions of 5-FU that are considered by many to be the
safest and most effective.
Capecitabine (Xeloda®: F Hoffmann-La Roche, Basel, Switzerland) is an oral fluoropyrimidine
carbamate rationally designed to generate 5-FU preferentially in tumour tissue through
exploitation of higher intratumoral concentrations of thymidine phosphorylase (Miwa
et al, 1998; Schüller et al, 2000). Human pharmacokinetic studies have shown that
after oral administration, capecitabine is rapidly and almost completely absorbed
through the gastrointestinal wall, thus avoiding direct intestinal exposure to 5-FU
(Reigner et al, 2001). Capecitabine is then metabolised to 5-FU via a three-step enzymatic
cascade. The final stage of this conversion is mediated by thymidine phosphorylase,
an enzyme present at significantly increased concentrations in a wide range of tumour
types, including colorectal, breast and gastric cancers, compared with normal tissue
(Miwa et al, 1998). The tumour-preferential activation of capecitabine reduces systemic
exposure to 5-FU and potentially improves efficacy and safety (Schüller et al, 2000).
As an oral agent, capecitabine enables dosing that approximates to continuous infusion
5-FU with improved convenience. Conventional infused 5-FU regimens require central
venous access via a Port-a-Cath®, Hickman catheter or Groshong and the use of portable
pumps, causing considerable inconvenience to patients. In addition, the rate of complications
such as thrombosis and infection is reported to be as high as 20–60% with chronic
venous access devices (Hartkamp et al, 2000; Schwarz et al, 2000). These factors,
together with the known patient preference for oral chemotherapy (Liu et al, 1997;
Borner et al, 2002), generated the need for an oral agent such as capecitabine that
could achieve continuous exposure to 5-FU in a similar manner to infused regimens.
A randomised, phase II trial in patients with advanced colorectal cancer demonstrated
that capecitabine is well tolerated and has substantial antitumour activity (Van Cutsem
et al, 2000). Subsequently, two multicentre, open-label, phase III studies were conducted
to compare capecitabine with intravenous (i.v.) 5-FU/leucovorin (5-FU/LV; Mayo Clinic
regimen, the regulatory standard at the time), as first-line treatment for metastatic
colorectal cancer (mCRC)(Hoff et al, 2001; Van Cutsem et al, 2001a). One study was
conducted in Europe, Australia, Israel and Asia and the other was conducted in the
USA, Canada, Brazil and Mexico. Both studies used identical protocols and an integrated
analysis of all data was prospectively planned. The integrated analysis has provided
an opportunity to retrospectively assess the use of capecitabine in a large, well-characterised
population of patients with mCRC. Safety evaluation demonstrated that capecitabine
has an improved safety profile compared with 5-FU/LV, with a significantly lower incidence
of diarrhoea, stomatitis, nausea and alopecia. The lower incidence of Grade 3–4 neutropaenia
with capecitabine led to significantly less neutropaenic fever/sepsis and consequently
fewer hospitalisations (Cassidy et al, 2002). The improved safety profile of capecitabine
also results in better utilisation of medical resources, leading to a pharmacoeconomic
advantage for capecitabine over i.v. 5-FU. This was demonstrated in an analysis of
medical resource use in the European randomised trial (Twelves et al, 2001). The safety
data from the two trials have been reviewed extensively by Cassidy et al (2002). This
paper provides a detailed review of the efficacy analyses of the pooled data.
PATIENTS AND METHODS
Trial design
The two studies used identical protocols and conduct, with the primary objective of
establishing that oral capecitabine achieves a response rate at least equivalent to
i.v. 5-FU/LV in patients with previously untreated mCRC (α-level of 2.5% and an equivalence
margin of 10%). Secondary objectives were to compare additional efficacy parameters,
including time to disease progression (TTP), overall survival, duration of response
and time to first response, as well as safety and quality of life profiles and medical
resource utilisation during treatment.
All patients recruited to the trials had received no prior cytotoxic chemotherapy
for metastatic disease. Adjuvant or neo-adjuvant therapy completed at least 6 months
prior to enrolment was permitted.
Treatment
Patients were randomised to receive either oral capecitabine (1250 mg m−2 twice daily
for 14 days followed by a 7-day rest period) or 5-FU/LV administered according to
the Mayo Clinic regimen (LV 20 mg m−2 followed by 5-FU 425 mg m−2, administered as
an i.v. bolus on days 1–5 every 28 days) (Hoff et al, 2001; Van Cutsem et al, 2001a).
The standard capecitabine dose reduction scheme, described in detail elsewhere (Cassidy
et al, 2002), was used for management of adverse events. Patients were treated for
up to 48 weeks until disease progression or unacceptable toxicity. Treatment continuation
beyond 48 weeks was permitted in patients without progressive disease at the discretion
of the investigator (poststudy treatment phase).
Evaluation of efficacy
Tumour evaluations were made at baseline and then at 6-weekly intervals during study
treatment, based on standard World Health Organization (1979) criteria. In addition
to the investigator assessment, an Independent Review Committee (IRC), consisting
of a panel of radiologists who were blinded to study treatment, clinical condition
of the patient and investigator's assessment, evaluated tumour responses solely on
the basis of imaging.
RESULTS
Patient population
In total, 1207 patients were randomised to treatment with capecitabine (603 patients)
or 5-FU/LV (604 patients). All patients were included in the efficacy analysis. The
demographic and baseline characteristics of patients in the two groups were well balanced
(Table 1
Table 1
Demographics and baseline characteristics
>Capecitabine
5-FU/LV
(n=603)
(n=604)
Male/female (%)
60/40
61/39
Age (years): median (range)
64 (23–86)
63 (24–87)
KPS (%): mean (range)
89 (70–100)
89 (70–100)
Colon/rectal cancer (%)
70/30
71/29
Tumour differentiation (%)
Well differentiated
11
11
Moderately differentiated
62
63
Poorly differentiated
19
17
Undetermined/unknown
8
10
Number of metastatic sites (%)
1
25
22
2
24
21
⩾3
52
57
Metastatic sites (%)
Liver
77
77
Lung
33
33
Lymph nodes
33
35
Peritoneum
14
14
Prior adjuvant chemotherapy (%)
24
26
). As expected, in both treatment groups, the majority of patients had colon rather
than rectal cancer. The proportions of patients who had previously received adjuvant
chemotherapy were similar in the two groups and there was no significant difference
between the groups with respect to extent or sites of metastatic disease. In general,
there were no differences in the distribution of prognostic factors at baseline; although
significant differences in serum alkaline phosphatase concentrations favouring the
5-FU/LV group were observed in one study (Hoff et al, 2001), no significant differences
were apparent in the integrated data (Table 2
Table 2
Distribution of prognostic factors in the two treatment groups (mean values±s.d.)
Capecitabine (n=603)
5-FU/LV (n=604)
Wilcoxon test
Z
P-value
Alkaline phosphatasea (U/l)
142.9 (121.2)
135.5 (116.4)
−1.7
0.091
ASAT (IU)
21.5 (15.5)
20.7 (15.7)
−1.5
0.13
Haemoglobin (g/dl)
12.9 (1.9)
12.9 (1.9)
0.2
0.87
a
Normalised serum alkaline phosphatase.
ASAT=aspartate aminotransferase.
).
The median duration of treatment was 4.5 months in the capecitabine group and 4.6
months in the 5-FU/LV group. Safety data, including data on treatment interruption
and dose modification, are described in detail elsewhere (Cassidy et al, 2002).
Tumour responses
Results from the integrated analysis demonstrate a significantly superior overall
response rate with capecitabine compared with 5-FU/LV (26 vs 17%, P<0.0002; Table
3
Table 3
Investigator-assessed tumour response rates
Capecitabine
5-FU/LV
(n=603)
(n=604)
P-value
PR+CR (%)
25.7
16.7
<0.0002
95% CI
22.4–29.6
13.8–19.9
Stable disease (%)
48.3
52.2
95% CI
43.7−51.8
48.1−56.2
PR=partial response, CR=complete response.
). Notably, the superior efficacy of capecitabine was confirmed by the IRC-assessed
response rate (22 vs 13%, P<0.0001). Furthermore, analysis of the data according to
subpopulations defined by baseline characteristics consistently demonstrated superior
response rates for capecitabine compared with 5-FU/LV (P<0.05; Figure 1
Figure 1
Response rates by subpopulation.
). In both treatment arms, response rates decreased with increasing numbers of metastatic
sites, as would be expected. Of note, in patients who had previously received adjuvant
chemotherapy, the response rate with capecitabine was 21% (31 out of 147 patients)
compared with only 9% (14 out of 155) in patients treated with 5-FU/LV.
Response to treatment occurred at least as rapidly in patients treated with capecitabine
compared with patients who received 5-FU/LV (median time to response: 1.7 vs 2.4 months,
respectively). The median duration of response was also similar in the two treatment
groups (8.1 and 9.4 months in the capecitabine and 5-FU/LV groups, respectively).
Time to disease progression
TTP was equivalent in the two treatment groups (hazard ratio (HR) 0.997, 95% confidence
interval (CI) 0.885−1.123, log-rank P=0.95). The median TTP was 4.6 months (95% CI
4.3−5.3) with capecitabine and 4.7 months (95% CI 4.3−5.4) with 5-FU/LV (Figure 2
Figure 2
Time to disease progression.
). Subgroup analysis according to baseline characteristics, including cancer type
(rectal vs colon cancer), history of adjuvant chemotherapy and gender, demonstrated
no significant differences between the two treatment groups for TTP.
Regression analyses were undertaken to assess the impact of prognostic factors on
TTP for the entire population. Univariate Cox regression analyses including treatment
as a covariable were performed, and identified a number of factors associated with
reduced TTP. These included poor Karnofsky performance status (KPS; 70 vs 100%), liver
metastases, multiple metastatic sites and younger age, with prognostic significance
at a level of 15% (Table 4
Table 4
Results of univariate Cox regression analysis: TTP
Both treatment groups
Capecitabine group
Factor
HR
P-value
HR
P-value
Liver metastases (yes vs no)
1.37
0.0001
1.39
0.0016
Metastatic sites (>1 vs 1)
1.39
0.0001
1.55
0.0001
KPS
70 vs 100%
1.67
0.0009
1.61
0.0010
80 vs 100%
1.14
0.29
1.36
0.017
90 vs 100%
1.02
0.83
1.16
0.17
Previous adjuvant therapy (yes vs no)
1.00
0.96
0.92
0.39
Large (>10 patients) vs small (⩽10 patients) recruitment/treatment center
1.01
0.94
0.88
0.15
Age
0.99
0.045
0.99
0.0008
Gender
0.92
0.36
1.03
0.70
). Previous adjuvant treatment and gender did not appear to impact on disease progression.
A multivariate Cox regression analysis using backward elimination of factors, with
the first step including all factors identified in the univariate analyses, was then
performed to assess the impact of independent prognostic factors on the treatment
effect at a significance level of 5%. This analysis confirmed an increased risk of
progression with lower age, liver metastases, poor KPS (70 or 80% at baseline) and
multiple metastatic sites (Table 5
Table 5
Results of multivariate Cox regression analysis: TTP
Both treatment groups
Capecitabine group
Factor
HR
P-value
HR
P-value
Predominant metastatic site: liver
1.38
0.0001
1.46
0.0001
Metastatic sites (>1 vs 1)
1.42
0.0001
1.61
0.0001
KPS
70 vs 100%
1.55
0.0001
1.52
0.0018
80 vs 100%
NA
NA
1.32
0.018
Age
0.99
0.013
0.99
0.0001
NA=not available.
). Of note, the analyses confirmed that risk of disease progression was independent
of treatment, as indicated by the HR of 1.02 (95% CI 0.90–1.15; P=0.79).
Overall survival
Overall survival data, updated in June 2002 after 1147 events, confirm the integrated
analysis results reported by Twelves (2002). In patients receiving capecitabine, overall
survival was equivalent to that in patients treated with 5-FU/LV (HR 0.95, 95% CI
0.84−1.06, P=0.48). The median survival was 12.9 months (95% CI 11.8−14.0) in the
capecitabine group and 12.8 months (95% CI 11.7−14.0) in the 5-FU/LV group after 583
and 564 events, respectively (Figure 3
Figure 3
Overall survival: updated June 2002.
). Univariate analyses identified nine prognostic factors for survival with a significance
level of 15%. Multivariate Cox regression analysis confirmed that lower KPS (70 or
80 vs 100%), multiple metastatic sites and the presence of liver metastases were independent
prognostic indicators for poor survival (Table 6
Table 6
Results of multivariate Cox regression analysis: survival
Factor
HR
P-value
Treatment
0.99 (0.87–1.13)
0.90
Country Mexico
2.71
0.0002
Predominant metastatic site: liver
1.38
0.0001
KPS
70 vs 100%
2.34
0.0001
80 vs 100%
1.66
0.0001
Differentiation (well vs other)
0.77
0.016
Previous surgery
0.77
0.014
Number of metastatic sites
1.06
0.013
Metastatic sites (1 vs more)
1.29
0.013
Race ‘other’a
0.64
0.033
a
Oriental (n=8), Hispanic (n=23) and all races other than Caucasian and Black.
). Patients with well-differentiated tumours had a slightly reduced risk of death
compared with patients having less well-differentiated tumours. The data also suggest
that previous surgery may have a prognostic effect, but the number of patients who
did not have prior surgery was extremely small, as approximately 90% of patients had
received prior surgery. Similarly, multivariate Cox regression analysis suggested
that risk of death was markedly reduced in patients defined as race ‘other’ compared
with the rest of the population (HR=0.64). However, this subgroup, comprising multiple
ethnic groups (including Orientals and Hispanics), included only 35 patients in the
capecitabine arm and 34 patients in the 5-FU/LV arm, and thus the results are difficult
to interpret. Of note, the analyses confirmed that survival was independent of treatment.
In addition to the predefined prognostic factors, baseline serum alkaline phosphatase,
ASAT, serum albumin and haemoglobin were all confirmed as prognostic factors for survival
in a secondary analysis (Table 7
Table 7
Prognostic value of baseline factors: survival
Wald test
HR
P-value
Alkaline phosphatase(U/l)
a
1.003
0.0001
Treatment interaction
1.000
0.91
ASAT (IU)
1.017
0.0001
Treatment interaction
1.003
0.33
Albumin (g dl)
0.975
0.0001
Treatment interaction
0.958
0.0001
Haemoglobin (g dl)
0.870
0.0001
Treatment interaction
0.971
0.39
a
Normalised serum alkaline phosphatase.
).
Both irinotecan monotherapy (Cunningham et al, 1998; Rougier et al, 1998) and oxaliplatin
in combination with 5-FU/LV (André et al, 1999; Maindrault-Goebel et al, 1999) have
proven efficacy in patients with mCRC that has progressed during/following previous
5-FU-based therapy. Therefore, the impact of second-line chemotherapy on survival
in the capecitabine phase III trials was also evaluated. The results of this analysis
demonstrated that a similar number of patients in the capecitabine and 5-FU/LV groups
received second-line chemotherapy (55 and 56% of patients, respectively). However,
the choice of treatment was different for patients in the two treatment groups: among
patients receiving second-line therapy, those in the capecitabine group received second-line
5-FU-based treatment more frequently than patients in the 5-FU/LV arm (54 vs 35%,
P=0.00001, Table 8
Table 8
Second-line chemotherapy: incidence, timing and duration
Capecitabine
5-FU/LV
Second-line treatment
% of patients receiving second-line therapy (n=334)
Treatment starta
Duration (days)
% of patients receiving second-line therapy (n=340)
Treatment starta
Duration (days)
Irinotecan
29
192
66
41
185
60
Oxaliplatin
3
289
71
6
169
71
5-FU
54
168
59
35
194
64
a
Median days from randomisation to start of second-line chemotherapy.
) (Twelves, 2001). Consequently, second-line irinotecan therapy was administered to
a smaller proportion of those patients who received second-line treatment in the capecitabine
arm than in the 5-FU/LV arm (29 vs 41%, respectively, P<0.001) (Twelves, 2001). The
timing and duration of second-line treatment was similar in the two groups.
DISCUSSION
The common mode of action of 5-FU and oral fluoropyrimidines predicts similar efficacy
for these two approaches. For this reason, trials comparing oral fluoropyrimidines
and conventional i.v. 5-FU/LV regimens in the treatment of colorectal cancer generally
require demonstration of equivalent efficacy between the two agents. However, the
results of this integrated analysis demonstrated that as first-line therapy for mCRC,
capecitabine offers a superior response rate and equivalent time to progression and
survival compared with i.v. bolus 5-FU/LV. The efficacy of capecitabine therefore
compares favourably with that of other oral fluoropyrimidines evaluated in patients
with mCRC. Recently, two large, independent, phase III trials in a total of more than
1400 patients demonstrated that the dihydropyrimidine dehydrogenase inhibitor eniluracil
in combination with oral 5-FU is less effective than 5-FU/LV (Mayo Clinic regimen)
as first-line treatment for mCRC (Van Cutsem et al, 2001b; Schilsky et al, 2002).
Overall survival was significantly inferior with eniluracil/oral 5-FU vs 5-FU/LV in
one trial and TTP was significantly inferior with eniluracil/5-FU in the other. Similarly,
a large phase III trial in 816 patients failed to demonstrate equivalent efficacy
for UFT/LV and 5-FU/LV (Mayo Clinic regimen). In this study, the risk of disease progression
was increased by 22% in patients receiving the investigational therapy, UFT/LV (P=0.011,
HR 0.823, 95% CI 0.708–0.958) (Douillard et al, 2002; Schmoll, 2003). Whereas the
current analysis demonstrates superior response rates for capecitabine vs 5-FU/LV,
the overall response rates for UFT/LV and 5-FU/LV did not differ significantly between
treatment arms, with a trend to a lower response rate for UFT/LV. Capecitabine is
the only oral fluoropyrimidine that has demonstrated efficacy at least equivalent
to that of 5-FU/LV (Mayo Clinic regimen) as first-line therapy for colorectal cancer,
leading to its regulatory approval worldwide in this indication.
The superior response rate observed with capecitabine compared with 5-FU/LV was seen
consistently in all subpopulation analyses. Patients with poor prognostic indicators,
such as poor KPS and liver metastases, were more likely to respond if treated with
capecitabine than with 5-FU/LV. The superior response rate was particularly pronounced
in the subpopulation of patients who had previously received adjuvant 5-FU. However,
even among patients not previously exposed to fluoropyrimidines of any kind, the response
rate was superior for those receiving capecitabine.
A multivariate analysis of survival to evaluate the impact of prognostic factors confirmed
the primary analysis of survival, demonstrating that survival was independent of treatment
administered. Evaluation of the impact of second-line treatment on survival outcomes
demonstrated that poststudy treatment favoured the 5-FU/LV group, and therefore strengthens
the claim that capecitabine results in efficacy at least equivalent to that achieved
with 5-FU/LV.
An integrated analysis of safety data from the phase III trials has also demonstrated
that capecitabine has an improved safety profile compared with 5-FU/LV, with a significantly
(P<0.001) lower incidence of diarrhoea (47.7 vs 58.2%), stomatitis (24.3 vs 61.6%),
nausea (37.9 vs 47.6%) and alopecia (6.0 vs 20.6%) (Cassidy et al, 2002). The only
adverse event occurring significantly more frequently with capecitabine was hand-foot
syndrome (53.5 vs 6.2% with 5-FU/LV, P<0.001). This cutaneous side effect is readily
managed by treatment interruption and dose reduction and led to hospitalisation of
only two patients (both for <24 h). The lower incidence of Grade 3–4 neutropaenia
(2.3 vs 22.8%) with capecitabine compared with 5-FU/LV led to significantly (P<0.001)
less neutropaenic fever/sepsis (0.2 vs 3.4%) and consequently fewer hospitalisations
(Cassidy et al, 2002). Grade 4 adverse events were more common with 5-FU/LV than with
capecitabine (5.1 vs 3.0%, respectively; P=0.078), mostly comprising neutropaenia-related
complications and diarrhoea. The incidence of grade 3 or 4 treatment-related adverse
events during the first treatment cycle was significantly higher in patients receiving
5-FU/LV than in those receiving capecitabine (22.6 vs 9.1%, respectively; P<0.001).
The results of this integrated analysis therefore support the use of capecitabine
as first-line monotherapy for advanced colorectal cancer. As an effective oral agent,
capecitabine meets patients' needs for a convenient, oral treatment suitable for outpatient
therapy. In addition, analysis of medical resource use demonstrated that significantly
fewer patients required hospitalisation for treatment-related adverse events (11.6
vs 18.0%, P<0.005), and fewer physician visits were required for treatment administration
with capecitabine than with 5-FU/LV (4 vs 15 in a 12-week period).
Combination chemotherapy is becoming increasingly common in patients who can tolerate
intensive therapy. Two phase III studies have demonstrated that the addition of irinotecan
to bolus or infused 5-FU/LV provides a modest but statistically significant survival
benefit in the first-line treatment of patients with colorectal cancer (Douillard
et al, 2000; Saltz et al, 2000). However, there are certain patient subgroups for
whom first-line combination therapy may not be the most appropriate treatment strategy.
For example, in patients with poor performance status and elevated serum LDH, irinotecan/5-FU/LV
combination therapy did not appear to confer a survival benefit. In the subgroup of
patients who had previously received adjuvant therapy, overall survival was reduced
compared with the overall patient population (FDA Medical Officer Summary, 1999; Knight
et al, 2000). In a multivariate analysis of almost 4000 patients, Köhne et al (2002)
identified four clinical parameters (performance status, WBC count, alkaline phosphatase
concentration and number of involved tumour sites) enabling grouping of patients into
low-, medium- or high-risk categories. Assessment of risk for each patient potentially
facilitates decisions on whether more or less intensive treatments are most appropriate
for each individual. Recently published National Comprehensive Cancer Network (NCCN)
guidelines (National Comprehensive Cancer Network Clinical Practice Guidelines in
Oncology, 2003) recommend that in patients who cannot tolerate intensive combination
therapy, fluoropyrimidine monotherapy is the most appropriate treatment strategy.
In this context, capecitabine provides a highly active first-line treatment option.
The ECOG and EORTC are currently planning a study in poor-prognosis patients comparing
capecitabine monotherapy vs capecitabine/irinotecan combination therapy vs capecitabine/oxaliplatin
combination therapy. Results of this trial should provide insight into the optimisation
of treatment strategies for patients with a poor prognosis.
Another important consideration when comparing sequential vs combination therapy in
the first-line setting is the tolerability of the two approaches. The analyses of
the NCCTG 9741 and CALGB 89803 randomised phase III trials have raised concerns about
the safety of irinotecan in combination with bolus 5-FU/LV, with an unexpectedly high
number of early deaths leading to modification or closure of treatment arms combining
bolus 5-FU/LV regimens with irinotecan or oxaliplatin (Morton et al, 2001; Rothenberg
et al, 2001; Ratain, 2002).
Irinotecan/fluoropyrimidine therapy might be better tolerated when 5-FU/LV is administered
as a protracted infusion, and recent data from the NCCTG trial also suggest that combination
therapy with infused 5-FU/LV may provide efficacy advantages over those incorporating
a bolus regimen (Goldberg et al, 2004). Capecitabine, which approximates to continuous
infusion 5-FU and has an improved safety profile compared with bolus 5-FU, potentially
provides a better-tolerated combination partner for irinotecan. Recently results from
two trials evaluating first-line capecitabine plus irinotecan, (n=37 and 52) showed
response rates of 43 and 46% and median time to progression of 9.3 and 7.1 months,
respectively (Borner et al, 2003; Patt et al, 2003). Phase III evaluation of capecitabine/irinotecan
combination therapy is ongoing. Capecitabine is also in the early stages of evaluation
in combination with oral irinotecan, thus offering potential for all-oral combination
therapy for patients with colorectal cancer.
Similarly, clinical studies have demonstrated that oxaliplatin in combination with
infused 5-FU/LV is a highly effective first-line treatment for patients with advanced
colorectal cancer, resulting in superior response rates and TTP compared with 5-FU/LV
alone (de Gramont et al, 2000; Giacchetti et al, 2000). In preclinical models the
combination is more effective if 5-FU is administered as a continuous infusion. This
observation suggests that replacing cumbersome i.v. 5-FU infusions with oral capecitabine
may represent a more effective, more convenient oxaliplatin combination therapy than
current i.v. 5-FU-based regimens. Mature results of a phase II, multicentre trial
of capecitabine plus oxaliplatin in 96 patients has demonstrated an overall response
rate of 55%, with consistently high (>50%) response rates across all patient subgroups
studied (Van Cutsem et al, 2003). In this trial the median progression-free survival
was 7.7 months and median overall survival was 19.5 months. The regimen had a favourable
safety profile, with a low incidence of grade 3 or 4 treatment-related adverse events.
An extensive phase III programme is evaluating both capecitabine plus irinotecan and
capecitabine plus oxaliplatin with or without biological agents (bevacizumab) in first-line
and in the adjuvant setting.
In addition to combination with irinotecan and oxaliplatin for the treatment of advanced
colorectal cancer, capecitabine has been evaluated as a combination partner for radiotherapy
in the management of rectal cancer. Preclinical studies demonstrated that capecitabine
and radiotherapy have enhanced antitumour activity, which is most likely attributable
to the further upregulation of thymidine phosphorylase (the enzyme responsible for
the final conversion of capecitabine to 5-FU) in tumour cells following radiotherapy
(Sawada et al, 1999). More recently, a phase II study demonstrated that capecitabine/radiotherapy
combination treatment is feasible with promising activity (Dunst et al, 2003). Phase
II evaluation, particularly in the neo-adjuvant setting, is ongoing and a phase III
trial (NSABP R-04) will compare chemoradiation with capecitabine vs protracted infusion
5-FU. The addition of oxaliplatin or irinotecan to capecitabine could further improve
chemoradiation efficacy outcomes in the future, and phase I trials are ongoing.
Capecitabine is also an attractive agent for use in the adjuvant setting. A phase
III trial to evaluate capecitabine treatment for Dukes' C colon cancer completed patient
accrual in 2001 and the safety and efficacy results are eagerly awaited.
The results of this integrated efficacy analysis have confirmed the results of the
two individual trials, showing that capecitabine is a highly effective agent for the
first-line treatment of advanced colorectal cancer. As first-line therapy, capecitabine
results in superior response rate, is more convenient and has an improved safety profile
compared with 5-FU/LV. Phase I and II studies evaluating capecitabine in combination
regimens indicate that capecitabine is a very promising and suitable candidate to
replace 5-FU as the backbone of colorectal cancer chemotherapy. Phase III trials should
elucidate whether capecitabine may become the backbone of colorectal cancer combination
therapy, not only with irinotecan, oxaliplatin and radiotherapy but also with novel
agents such as EGFR inhibitors and anti-angiogenic agents.