S u p e r i o r S u r v i v a l W i t h C a p e c i t a b i n e P l u s D o c e t a x e l C o m b i n a t i o n T h e r a p y i n A n t h r a c y c l i n e - P r e t r e a t e d P a t i e n t s W i t h A d v a n c e d B r e a s t C a n c e r : P h a s e I I I T r i a l R e s u l t s
By Joyce O’Shaughnessy, David Miles, Svetislava Vukelja, Vladimir Moiseyenko, Jean-Pierre Ayoub, Guadalupe Cervantes,
Pierre Fumoleau, Stephen Jones, Wing-Yiu Lui, Louis Mauriac, Chris Twelves, Guy Van Hazel, Shailendra Verma,
Purpose: Docetaxel and capecitabine, a tumor-acti- compared with docetaxel. Gastrointestinal side effects vated oral fluoropyrimidine, show high single-agent and hand-foot syndrome were more common with com- efficacy in metastatic breast cancer (MBC) and synergy bination therapy, whereas myalgia, arthralgia, and neu- in preclinical studies. This international phase III trial tropenic fever/sepsis were more common with single- compared efficacy and tolerability of capecitabine/do- agent docetaxel. More grade 3 adverse events occurred cetaxel therapy with single-agent docetaxel in anthra- with combination therapy (71% v 49%, respectively), cycline-pretreated patients with MBC. whereas grade 4 events were slightly more common with Patients and Methods: Patients were randomized to docetaxel (31% v 25% with combination). 21-day cycles of oral capecitabine 1,250 mg/m2 twice Conclusion: The significantly superior TTP and sur- daily on days 1 to 14 plus docetaxel 75 mg/m2 on day vival achieved with the addition of capecitabine to 1 (n ؍ 255) or to docetaxel 100 mg/m2 on day 1 (n ؍ 256). docetaxel 75 mg/m2, with the manageable toxicity Results: Capecitabine/docetaxel resulted in signifi- profile, indicate that this combination provides clear cantly superior efficacy in time to disease progression benefits over single-agent docetaxel 100 mg/m2. Do- (TTP) (hazard ratio, 0.652; 95% confidence interval [CI], cetaxel/capecitabine therapy is an important treatment 0.545 to 0.780; P ؍ .0001; median, 6.1 v 4.2 months), option for women with anthracycline-pretreated MBC. overall survival (hazard ratio, 0.775; 95% CI, 0.634 to J Clin Oncol 20:2812-2823. 2002 by American 0.947; P ؍ .0126; median, 14.5 v 11.5 months), and Society of Clinical Oncology. objective tumor response rate (42% v 30%, P ؍ .006)
THE TREATMENT OF metastatic breast cancer, which presenting with metastatic breast cancer that has recurred
ultimately develops in 30% to 40% of all patients with
breast cancer in Western countries, is a considerable chal-
For patients in whom anthracyclines have failed, taxane-
lenge for oncologists. The shift in the use of anthracyclines
based therapy is a current standard of care. In a phase III
and taxanes to earlier in the course of disease, including the
study in this setting, single-agent docetaxel resulted in
adjuvant setting, has increased the likelihood of patients
significantly superior overall survival (11.4 v 8.7 months,P ϭ .0097) compared with a combination regimen ofmitomycin plus vinblastine.1 Patients receiving single-agentdocetaxel also achieved significantly superior time to dis-ease progression (4.4 v 2.5 months, P ϭ .001) and response
From the Baylor-Sammons Cancer Center, Dallas, and US Oncol-ogy, Houston, TX; Guy’s Hospital, London, United Kingdom; Petrov
rates (30% v 12%, P Ͻ .0001) compared with the mitomy-
Research Institute, St Petersburg, Russia; Hopital Notre Dame, Mon-
cin/vinblastine combination therapy. The efficacy of single-
treal, and Ottawa Regional Cancer Centre, Ottawa, Canada; Issste
agent docetaxel was also demonstrated in a further random-
Hospital, Mexico City, Mexico; Centre Rene Gauducheau Nantes-
ized trial in a similar patient population, where docetaxel
Atlantique, Saint Herblain, and Institut Bergonie´, Bordeaux, France;
was shown to be more effective than methotrexate plus
Taipei-Veterans General Hospital, Taiwan; Beatson Oncology Centre,Glasgow, and Western General Hospital, Edinburgh, Scotland; and
fluorouracil (5-FU), resulting in significantly superior re-
Perth Oncology, Perth, Western Australia.
sponse rates (42% v 21%, P Ͻ .001) and time to disease
Submitted September 7, 2001; accepted March 15, 2002.
progression (6.3 v 3.0 months, P Ͻ .001).2 There was no
This research was supported by F. Hoffmann-La Roche, Ltd, Nutley, NJ.
significant difference in overall survival between the two
Some authors have received more than $2,000 a year working in a
regimens (10.4 and 11.1 months, respectively, Pconsultant capacity or by performing contract work within the past 2years for either Roche, Nutley, NJ, or Aventis, Bridgewater, NJ (D.M.,
Despite attempts to improve further the efficacy of
S.Vukelja, P.F., and R.L.) or both (J.O., S.J., C.T., and G.V.H).
taxane-based therapy in patients with anthracycline-pre-
Address reprint requests to Joyce O’Shaughnessy, MD, Baylor-
treated metastatic breast cancer, including combination of a
Sammons Cancer Center and US Oncology, 3535 Worth St, 5th Floor,
taxane with other cytotoxic drugs, no cytotoxic regimen has
Dallas, TX 75246; email: joyce.o’shaughnessy@usoncology.com.
until now improved survival compared with single-agent
2002 by American Society of Clinical Oncology. 0732-183X/02/2012-2812/$20.00
docetaxel. Trastuzumab in combination with chemotherapy
Journal of Clinical Oncology, Vol 20, No 12 (June 15), 2002: pp 2812-2823
Downloaded from www.jco.org by Ma. Luisa TIAMBENG on August 1, 2005 .
Copyright 2002 by the American Society of Clinical Oncology. All rights reserved.
has demonstrated a survival benefit compared with chemo-
to be at least equivalent, a test for superiority of the combination
therapy alone in HER2-positive patients.3 This is, however,
regimen over single-agent docetaxel was to be applied. Additionalobjectives included comparison of the safety profiles and medical care
applicable only to the 20% to 25% of women with meta-
utilization in each treatment arm. In addition, changes in quality of life
static breast cancer whose tumors overexpress HER2. Thus
(QOL) were to be compared in selected centers (determined by the
the need for new treatments for patients whose tumors are
availability of validated European Organization for Research and
HER2-negative and for those whose disease is unresponsive
Treatment of Cancer [EORTC] questionnaire translations), and the
or resistant to anthracyclines has provided the impetus for
pharmacokinetics of capecitabine were to be investigated in 16 patientsrandomized to combination therapy.
exploration of novel combination regimens.
The oral fluoropyrimidine capecitabine (Xeloda; Hoff-
mann-La Roche, Nutley, NJ) was rationally designed to
To be eligible for the study, patients had to be female and aged Ն 18
generate 5-FU preferentially in tumor tissue and to mimic
years and have histologically or cytologically confirmed breast cancer
continuous-infusion 5-FU. This tumor selectivity is achieved
with unresectable locally advanced and/or metastatic disease. Patients
through exploitation of the significantly higher activity of
were required to have at least one bidimensionally measurable lesion
thymidine phosphorylase in many human tumor tissues com-
that had not been irradiated, with a minimum size in at least one
pared with healthy tissue.4,5 Clinical studies have shown that
diameter of Ն 20 mm for liver lesions and Ն 10 mm for lung, skin, andlymph node metastases. All patients were to have breast cancer that had
single-agent capecitabine is an active and tolerable treatment in
recurred after anthracycline treatment, defined as: (1) progression while
metastatic breast cancer that has progressed during or after
receiving anthracycline-based chemotherapy without experiencing any
anthracycline and taxane therapy, achieving response rates of
transient improvement; (2) no response after administration of four or
20% to 26% and a median survival in excess of 1 year.6,7
more cycles of anthracycline-based chemotherapy; (3) relapsing within
This activity in heavily pretreated patients provided the
2 years of completing (neo)adjuvant anthracycline-based chemother-apy; or (4) a brief objective response to anthracycline-based chemo-
rationale for investigating capecitabine earlier in the disease
therapy with subsequent progression while receiving the same therapy
course and in combination with other cytotoxic agents. In
or within 12 months after the last dose. All patients had to have a
addition, capecitabine is an attractive agent for incorpora-
Karnofsky performance score of Ն 70% and a life expectancy Ն 3
tion into combination regimens because of the low inci-
months, and they had to provide written, informed consent before any
dence of myelosuppression. Consequently, a number of
Patients were ineligible if they had previously received a docetaxel-
studies have investigated capecitabine in combination with
containing regimen in either the adjuvant or advanced disease setting
cytotoxic agents with differing mechanisms of action and
(prior paclitaxel was permitted, no minimum interval from prior
safety profiles.8-18 Preclinical studies in human cancer
paclitaxel exposure to study entry was specified), or if they had
xenograft models demonstrated that administration of do-
received three or more chemotherapy regimens for advanced/metastatic
cetaxel or paclitaxel results in further upregulation of
disease. Patients with prior radiotherapy to the axial skeleton within 4weeks of treatment start were excluded, as were those who had received
thymidine phosphorylase in tumor tissue.19 This finding has
hormonal therapy within 10 days of treatment start or chemotherapy
been confirmed in women with primary breast cancer who
within 4 weeks of treatment start. Patients with clinically significant
were treated with preoperative docetaxel.20 Co-administra-
cardiac disease, evidence of CNS metastases, known hypersensitivity
tion of capecitabine and either docetaxel or paclitaxel in
to 5-FU, or prior unanticipated, severe reactions to drugs formulated
xenograft models resulted in synergistic antitumor activity,
with polysorbate 80, eg, taxanes, or to fluoropyrimidines were alsoineligible. Women with a history of another malignancy (except basal
whereas taxanes in combination with either 5-FU or uracil
cell skin carcinoma and carcinoma-in-situ of the uterine cervix) within
plus tegafur demonstrated only additive efficacy.19
5 years of study entry were not eligible.
Based on a phase I study,11 a regimen of capecitabine
Other ineligibility criteria included hemoglobin less than 8.0 g/dL,
1,250 mg/m2 twice daily on days 1 to 14 in combination
neutrophil count less than 1.5 ϫ 109/L, platelet count less than 100 ϫ
with docetaxel 75 mg/m2 on day 1 every 3 weeks was
109/L, serum creatinine more than 1.5 times the upper normal limit, andALT, AST, and alkaline phosphatase more than five times the upper
selected for further clinical development. We report the
normal limit. Patients with serum bilirubin values above the upper
results of a randomized, international, phase III study
normal limit for more than one of three baseline values were also
comparing this combination regimen with single-agent do-
excluded, except for women with documented Gilbert’s syndrome who
had normal values for all liver enzymes.
The primary objective of the study was to demonstrate superior time
Patients were stratified according to whether or not they had received
to disease progression (or death in patients with no evidence of disease
prior paclitaxel therapy (no other stratification was performed) and
progression) with the capecitabine plus docetaxel combination regimen
were randomized by country to at least 6 weeks of treatment with one
compared with single-agent docetaxel. Secondary objectives included
of the following: oral capecitabine 1,250 mg/m2 twice daily on days 1
demonstration of a superior overall response rate and at least equivalent
to 14 followed by a 7-day rest period plus docetaxel 75 mg/m2
overall survival with the combination regimen. If survival was shown
administered as a 1-hour intravenous infusion on the first day of each
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Copyright 2002 by the American Society of Clinical Oncology. All rights reserved.
3-week cycle; or docetaxel 100 mg/m2 administered as a 1-hour
neutrophil counts less than 0.5 ϫ 109/L (grade 4) for more than 1 week
intravenous infusion on the first day of each 3-week cycle.
or febrile (Ն 38°C) neutropenia, the docetaxel dose was reduced from
In the combination arm, patients were still regarded as “on study
75 to 55 mg/m2. If the adverse event recurred at 55 mg/m2, docetaxel
therapy” if for any reason docetaxel treatment was discontinued before
disease progression and the patient continued to receive capecitabine
A similar dose modification scheme was used in patients receiving
alone. However, if capecitabine was discontinued before disease
single-agent docetaxel. Dose reduction was not required after the first
progression and the patient continued to receive single-agent docetaxel,
appearance of any grade 2 toxicity, although treatment was interrupted
the patient was considered to be receiving treatment “off study.”
until the toxicity had resolved to grade 0 or 1. Except for neutropenia/
Patients with mild hepatic impairment (ALT and/or AST between
granulocytopenia, treatment was interrupted and the dose was reduced
2.5 and five times the upper normal limit and alkaline phosphatase Յ
by 25% (to 75 mg/m2) in patients who experienced a second occurrence
2.5 times upper normal limit; or ALT and/or AST between 1.5 and five
of a given grade 2 toxicity or any grade 3 toxicity and by a further 25%
times the upper normal limit) who were randomized to single-agent
(to 55 mg/m2) in patients who experienced a third occurrence of a given
docetaxel received a reduced dose of 75 mg/m2. All patients received
grade 2 toxicity, a second occurrence of a given grade 3 toxicity, or any
docetaxel premedication (eg, dexamethasone) as per the treatment
grade 4 toxicity. Treatment was discontinued if, despite dose reduction,
center policy at the time the study was conducted. No premedication for
a given toxicity occurred for a fourth time at grade 2, a third time at
capecitabine was required. Capecitabine was administered orally twice
grade 3, or a second time at grade 4. In patients experiencing grade 3
daily, within 30 minutes of completion of a meal (breakfast, evening
or 4 neutropenia/granulocytopenia, docetaxel was readministered only
meal), approximately 12 hours apart. Tablets were to be swallowed
when the neutrophil count was Ն 1.5 ϫ 109. If patients experienced
with approximately 200 mL of water. Patients achieving a complete or
febrile (Ն 38°C) neutropenia or neutrophil counts less than 0.5 ϫ 109/L
partial response or stable disease after 6 weeks of therapy continued on
(grade 4) for more than 1 week, the docetaxel dose was reduced from
treatment until disease progression or development of unacceptable
100 to 75 mg/m2. If the adverse event recurred at 75 mg/m2, the dose was
toxicity. Patients with documented progressive disease were withdrawn
decreased from 75 to 50 mg/m2 or treatment was discontinued.
Screening assessment, including medical history, physical examina-
Treatment was continued at the same dose (without interruption or
tion, ECG, chest x-ray, bone scans, and tumor measurements, was
dose reduction) if patients experienced grade 1 toxicities or other
conducted within 2 weeks before treatment start. Further assessments
toxicities considered by the investigator unlikely to become serious or
conducted within 7 days before treatment start included vital signs,
life threatening (eg, alopecia). For all other treatment-related adverse
Karnofsky performance status, and laboratory tests (hematology, blood
events (except isolated neutropenia/granulocytopenia) with intensity of
grade 2 or higher, the dose modification scheme described below was
Tumor responses were assessed on the basis of World Health
implemented. Dose reduction was not required after the first appear-
Organization (WHO) criteria21 at 6-week intervals until week 48 and
ance of any grade 2 toxicity, although treatment was interrupted until
then at 12-week intervals until disease progression. Tumor response
the toxicity had resolved to grade 0 to 1, and symptomatic treatment
was also assessed in each patient within 2 weeks of discontinuing study
medication. The best overall response achieved was reported. Patients
In the combination arm, treatment with both agents was interrupted
with no tumor assessment after baseline were classified as nonre-
(for a maximum of 2 weeks) and the doses of both capecitabine and
sponders. In responding patients, the response had to be confirmed a
docetaxel were reduced by 25% in patients who experienced a second
minimum of 4 weeks after the first response had been recorded. Patients
occurrence of a given grade 2 toxicity or any grade 3 toxicity.
were classified as achieving stable disease if at the first tumor
Docetaxel therapy was discontinued if toxicities did not resolve to
assessment after study treatment administration there was neither
grade 0 or 1 within 2 weeks, but capecitabine could be resumed at 75%
disease progression nor a response that was later confirmed. Copies of
of the starting dose on resolution of the toxicity to grade 0 or 1. If
all x-rays and computed tomography scans were supplied for indepen-
patients experienced a third occurrence of a given grade 2 toxicity, a
dent review by a panel of radiologists, who were blinded to the study
second occurrence of a given grade 3 toxicity, or any grade 4 toxicity,
treatment, the clinical condition of the patient, and the investigator’s
the capecitabine dose was reduced by 50% and docetaxel was discon-
evaluation. For patients who achieved a partial or complete response,
tinued. Capecitabine was discontinued if, despite dose reduction, a
time to response was defined as the interval between randomization and
given toxicity occurred for a fourth time at grade 2, a third time at grade
the first recording of tumor response. Duration of response was
3, or a second time at grade 4. In patients in the combination arm who
assessed according to WHO criteria. For complete responders, duration
discontinued docetaxel therapy for adverse events, single-agent cape-
of response was defined as the interval between the first recording of a
citabine could be continued alone. If no grade 2, 3, or 4 toxicities
complete response and the time of disease progression or death. For
occurred with capecitabine alone, the dose could be escalated at each
partial responders, duration of response was measured from random-
subsequent cycle by 25%. If either docetaxel treatment delay or
ization. Patients whose disease did not progress were censored using
capecitabine treatment interruption was indicated, then treatment with
the date at which they were last known to have not progressed. Time to
both agents was delayed or interrupted. In patients experiencing grade
disease progression was defined as the time from randomization to the
3 or 4 neutropenia/granulocytopenia, capecitabine was not expected to
first recording of disease progression or the date of death in patients
worsen or prolong this adverse event, and therefore treatment was to be
with no evidence of disease progression.
continued throughout grade 3 or 4 neutropenic episodes. However,
Adverse events and medical care utilization were recorded through-
capecitabine was to be discontinued if any grade 2 clinical adverse
out the study and for 28 days after the last administration of study drug.
event coincided with the neutropenic phase and the patient was to be
Adverse events were graded according to National Cancer Institute of
hospitalized and closely monitored. Docetaxel was readministered only
Canada common toxicity criteria; hand-foot syndrome was graded 1 to
when the neutrophil count was Ն 1.5 ϫ 109. If patients experienced
3, as defined in previous capecitabine clinical studies.6,22
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Copyright 2002 by the American Society of Clinical Oncology. All rights reserved.
QOL was assessed using the EORTC QOL questionnaire C30
Table 1. Baseline Characteristics, All Randomized Patients
(version 2.0) and the breast cancer module QLQ-BR23 in centers where
questionnaires were available in appropriate, validated translations.
Patients completed questionnaires before administration of any treat-
ment on the first day of therapy, every 6 weeks at the start of each
treatment cycle (until week 48), and when going off study. In addition,
the first 16 patients allocated to the combination arm in six selected
centers were to provide blood samples for pharmacokinetic evaluation
The sample size was calculated using the Lachin approach.23 To
achieve 80% power, the study needed to include 454 assessable
patients, assuming a median time to disease progression for docetaxel
of 4.5 months and a minimal improved benefit with the addition of
capecitabine to docetaxel of at least 6 weeks. Therefore, the target
enrollment was 500 patients, allowing for 10% of patients to be lost to
follow-up. A population of 454 assessable patients gave approximately
90% power for assessment of overall response rate, a secondary
efficacy parameter, assuming a response rate of 45% with docetaxel
and an improvement with the addition of capecitabine of 15% (to 60%).
Patients were randomized by country using a block size of four via
a computer-assisted, touch-tone, central randomization service located
Abbreviations: KPS, Karnofsky performance status; ER, estrogen receptor;
in Houston, TX, and Brussels, Belgium. Previous treatment with
paclitaxel was the only variable used for stratification.
*Locally advanced disease status was retrospectively defined.
The efficacy analysis was based on the intent-to-treat population (all
randomized patients). Safety was assessed using the safety populationof all patients who received at least one dose of study medication andfor whom follow-up safety information was available. A two-sided
treatment arms, the most frequently involved metastatic
log-rank test (alpha ϭ 0.05) was used to test differences in time todisease progression. QOL data were scored according to standard
sites were the lymph nodes, liver, bone, and lung. The
EORTC procedures.24,25 The primary QOL analysis used the “last
treatment histories in the two groups were also similar
observation carried forward” approach to replace missing data. Patients
(Table 2). Approximately one third of patients in each
were excluded from the pharmacokinetic analysis if they vomited
treatment group had received prior endocrine therapy in the
within 2 hours after capecitabine intake on the two sampling days, if
adjuvant setting, and one half had received endocrine
blood samples could not be obtained, or if the time of drug adminis-tration and/or blood sampling was not clearly documented. Compliance
therapy in the metastatic setting. As defined by the protocol,
with capecitabine therapy was assessed by comparing the amount of
all patients had received previous anthracycline-based che-
motherapy. The most frequently administered anthracycline
Clinical cutoff for the study analysis was February 15, 2001. A
in both arms was doxorubicin, and the best response to
minimum follow-up of 15 months had been reached in all patients.
anthracycline treatment for metastatic disease was balanced
between the two groups. Best response to previous pacli-taxel therapy for metastatic disease was also balanced in the
two treatment arms. Approximately one third of patients in
In total, 511 patients were enrolled from 75 centers in 16
each group received study therapy as first-line treatment for
countries (Argentina, Australia, Brazil, Canada, France,
metastatic disease (35% in the combination arm and 31% in
Germany, Israel, Italy, Mexico, New Zealand, Norway, Russia,
the single-agent arm), and approximately two thirds re-
Spain, Taiwan, the United Kingdom, and the United States).
ceived study therapy as second- or third-line treatment (65%
Patients were randomized to either capecitabine 1,250 mg/m2
twice daily on days 1 to 14 plus docetaxel 75 mg/m2 (n ϭ 255)or to docetaxel 100 mg/m2 alone (n ϭ 256) every 3 weeks. The
median time from the primary diagnosis of breast cancer to
All efficacy data are reported using the intent-to-treat (all
randomization was 29 months (range, 3 to 302 months) for
randomized) patient population (n ϭ 255 in the combination
women in the combination arm and 28 months (range, 3 to 304
arm; n ϭ 256 in the docetaxel alone arm).
Capecitabine/docetaxel combination therapy resulted in
The baseline characteristics of patients were well bal-
significantly superior time to disease progression, the pri-
anced between the two treatment groups (Table 1). In both
mary end point, compared with single-agent docetaxel
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Copyright 2002 by the American Society of Clinical Oncology. All rights reserved.
Table 2. Treatment Histories, All Randomized Patients Fig 2. Overall survival.
The analysis of survival demonstrated that overall sur-
vival was superior in the combination arm, with a hazard
ratio of 0.775 (P ϭ .0126; 95% CI, 0.634 to 0.947). This
translates into a 23% reduction in risk of death in patients
receiving combination therapy compared with single-agent
docetaxel. Median survival was 14.5 months (95% CI, 12.3
to 16.3 months; 72% of events) with the combination
*Anthracyclines administered in both the neoadjuvant and adjuvant settings
regimen and 11.5 months (95% CI, 9.8 to 12.7 months; 79%
in 6% and 5% of the combination and single-agent arms, respectively, and in
of events) with single-agent docetaxel (Fig 2). The survival
all three settings in 0.4% of each treatment arm.
curves separated early and maintained a clear separation
†Defined in Patients and Methods under Patient Population.
over time. The 12-month survival rate was 57% (95% CI,
‡Excluding previous hormonal regimens for metastatic disease.
51% to 63%) in the combination arm and 47% (95% CI,
§Two patients received study therapy as fourth-line treatment.
41% to 53%) in the single-agent arm. Median censoringtimes were 23.2 months and 22.9 months, respectively.
(log-rank P ϭ .0001; hazard ratio, 0.652; 95% confidence
The combination regimen also demonstrated a signifi-
interval [CI], 0.545 to 0.780). The hazard ratio translates
cantly superior objective response rate, with 42% of patients
into a 35% decrease in risk of disease progression with the
in the combination arm achieving an objective tumor
addition of capecitabine to docetaxel therapy. Median time
response compared with 30% in the single-agent arm (P ϭ
to disease progression was 6.1 months (95% CI, 5.4 to 6.5
.006) (Table 3). The significantly superior response rates
months; 93% of events) in the combination arm and 4.2
observed in the investigator-assessed results were confirmed
months (95% CI, 3.4 to 4.5 months; 98% of events) with
(32% with combination therapy v 23% with docetaxel alone,
P ϭ .025) by the Independent Review Committee, membersof which had only radiologic studies for review and not
Table 3. Objective Tumor Response Rate (best response), Investigator Assessment
*Main reason for missing post-baseline data: early dropouts during the first
Fig 1. Time to disease progression.
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Copyright 2002 by the American Society of Clinical Oncology. All rights reserved.
Table 4. Number of Responders (confirmed responses) by Time Period Fig 3. Quality of life: global health status.
lesions measurable only on physical examinations. In allmajor subgroup analyses, including by age, anthracycline
quently in the combination arm (20%) than in the single-
resistance, extent of prior chemotherapy, predominant met-
agent arm (7%), and the use of poststudy capecitabine was
astatic site, and number of metastatic sites, the response rate
more common in the single-agent group (17%) than in the
in the combination arm was higher than in the single-agent
combination arm (3%). The majority of patients reported as
receiving poststudy docetaxel in the combination arm (36
Table 4 shows time to response in confirmed responders.
[73%] of 49 patients) represented patients in whom cape-
In all time periods there were at least as many responses in
citabine therapy was discontinued before disease progres-
the combination arm as in the single-agent arm, with the
sion but docetaxel was continued alone.
majority of all responses occurring in the first four treatmentcycles. The duration of response according to WHO criteria
in patients achieving either a partial or a complete responsewas similar in the two treatment groups. The median
A total of 454 patients from 15 countries completed QOL
duration of response was 7.3 months (95% CI, 6.9 to 8.4
questionnaires (224 in the combination arm and 230 in the
months) for the 106 responders in the combination arm and
single-agent arm). The EORTC QLQ-C30 Global Health
7.0 months (95% CI, 5.8 to 8.0 months) for the 76
Score was preselected as the primary parameter for statis-
responders in the single-agent arm. The percentage of
tical testing in the QOL analysis, with a comparison of the
patients without disease progression after 6 months was
treatment arms at day 127 prespecified in the protocol. No
41% in the combination arm (95% CI, 35% to 47%)
significant differences could be found. Figure 3 shows the
compared with 29% (95% CI, 23% to 34%) in the single-
QOL scores for the Global Health Score over time, demon-
agent docetaxel arm (P ϭ .04).
strating that scores were similar in the two treatment arms.
The time to disease progression data were supported by
There was a trend toward less deterioration of Global Health
the superior results of the time to treatment failure analysis,
Score in the combination arm over time. The impact of
a composite of safety and efficacy end points, in which
chemotherapy-induced side effects, as measured by the
withdrawals of patients because of progressive disease or
systemic therapy side effects symptom scale, was similar in
death, adverse events, treatment refusal, or loss to follow-up
were included as events. The median time to treatment failure
was 4.0 months (95% CI, 3.3 to 4.3 months; 96% of events) inthe combination arm and 2.8 months (95% CI, 2.4 to 3.5
The safety population (n ϭ 506) included 251 patients in
months; 98% of events) in the single-agent arm (P ϭ .0002).
the combination arm and 255 patients in the docetaxel arm,
The combination and single-agent docetaxel treatment
all of whom received at least one dose of study drug. The
groups were well balanced in terms of poststudy therapies
median duration of treatment was 3.8 months (range, 0.07 to
for breast cancer, including surgical intervention (7% v 4%,
14.7 months) with the combination regimen and 2.8 months
respectively), radiotherapy (30% in both groups), endocrine
(range, 0.03 to 12.2 months) with single-agent docetaxel.
therapy (30% v 27%), chemotherapy (70% v 63%), vinorel-
The median duration of docetaxel therapy during the study
bine (31% v 26%), anthracyclines (10% v 11%), 5-FU (20%
period in patients receiving combination therapy was also
v 23%), and treatment with trastuzumab (9% in both
2.8 months. Forty-five patients (18%) in the combination
groups). Poststudy docetaxel was administered more fre-
arm discontinued docetaxel therapy but continued to receive
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Copyright 2002 by the American Society of Clinical Oncology. All rights reserved.
Fig 4. Received versus planned dose of capecitabine and docetaxel in the combination arm. Fig 5. Incidence of grade 3 or 4 treatment-related adverse events over
capecitabine alone. The median duration of single-agent
Patients receiving the combination regimen experienced a
capecitabine in these patients was 3.2 months.
higher incidence of gastrointestinal adverse events and
The dose received in each cycle was recorded as a
hand-foot syndrome, a cutaneous condition affecting the
percentage of the planned dose, which was defined using the
palms and soles. This was typically treated by investigators
first dose in cycle 1, extrapolated to the end of the cycle in
in this trial with systemic vitamin preparations such as
which study treatment was discontinued. In the combination
vitamin B (pyridoxine) or locally with emollients. Patients
arm, the median delivered dose of capecitabine during the
receiving docetaxel alone experienced a higher incidence of
course of the study was 77% of the planned dose, and the
neutropenic fever, arthralgia, and pyrexia (Fig 6).
corresponding value for docetaxel was 87%. The delivered
The spectrum of grade 3 or 4 toxicities was similar to the
versus planned dose and interquartile range for capecitabine
profile for all grades and is shown in Table 5. Apart from
and docetaxel dosing in the combination and single-agent
neutropenic fever, grade 4 adverse events were rare in both
arms are depicted in Fig 4. In the single-agent docetaxel
treatment arms. The most common grade 3 treatment-
arm, the overall median delivered dose was 100% of the
related adverse events were hand-foot syndrome and stoma-
planned dose (interquartile range, 75% to 100%). The
titis in the combination arm and neutropenic fever and
median delivered versus planned dose was 100% up to week
neutropenia requiring medical intervention in the single-
27 and was 75% in weeks 28 to 30 (interquartile range, 75%
agent docetaxel arm. Approximately two thirds of patients
to 100%). No cases of clinically relevant noncompliance
(65%) in the combination arm required dose reduction of
capecitabine alone (4%), docetaxel alone (10%), or both
The incidence of treatment-related adverse events was
drugs (51%) for adverse events. In the single-agent do-
similar in the combination and single-agent arms (98% v94%, respectively). The percentage of patients experiencinggrade 3 treatment-related adverse events was higher in thecombination therapy group (71% v 49% in the single-agentdocetaxel arm); there was a slightly lower incidence ofgrade 4 treatment-related adverse events with combinationtherapy (25% v 31%). In both treatment groups, the overallincidence of grade 3 or 4 adverse events was highest in thefirst treatment cycle (38% in the combination group and40% in the single-agent group). The incidence of grade 3 or4 adverse events over time is shown in Fig 5. In the secondcycle, more patients experienced grade 3 or 4 adverse eventsin the combination arm (36% v 19% in the single-agentarm), primarily because of grade 3 hand-foot syndrome(combination arm: 2% in weeks 1 to 3 and 13% in weeks 4to 6). In all other cycles, the incidence of grade 3 or 4adverse events was similar in the two groups. Fig 6. Most common treatment-related clinical adverse events.
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Table 5. Summary of Treatment-Related Grade 3 or 4 Adverse Events
The impact of dose reduction on efficacy was assessed by
Occurring in > 5% of Patients
including the time to the first dose reduction as a time-
dependent covariate in a proportional hazards regression
model of time to disease progression. For the combination
therapy arm, this retrospective analysis did not show any
evidence that dose modification had a negative impact on
efficacy. The hazard ratio for patients with versus without
dose reductions in the combination arm was 0.84 for all
levels of dose reductions (representing a 16% reduction in
risk of disease progression in patients with v without dose
reduction) (Table 8). In the single-agent docetaxel group,
the hazard ratio was 0.99 for all level dose reductions.
However, an increased risk of disease progression was seen
*Requiring medical intervention (eg, antibiotic therapy, granulocyte colony-
in patients with a dose reduction to 50% of the starting dose
in those randomized to docetaxel alone (hazard ratio, 1.91). In addition, an analysis was performed for patients with
cetaxel group, 36% of patients required dose reduction. The
versus without capecitabine dose reduction for the second
median time to dose reduction was longer in the combina-
cycle. Single-agent docetaxel is included as a reference arm
tion therapy group, as shown in Table 6. Capecitabine
in the Kaplan-Meier plot shown in Fig 7.
treatment interruption in the combination arm was required
Premature withdrawal for adverse events or intercurrent
in 34% of cycles. The adverse events, either alone or in
illness was more common in the combination arm than in
combination, most frequently leading to capecitabine treat-
the docetaxel arm (26% v 20%, respectively). In both
ment interruption were hand-foot syndrome (11.1%), diar-
treatment arms, insufficient therapeutic response was the
rhea (8.5%), and stomatitis (4.6%). The median duration of
most common reason for treatment withdrawal, but this was
treatment interruption per cycle was 6 days (interquartile
less frequent in the combination arm than in the single-agent
range, 3 to 9 days). In the combination arm, 27% of 1,317
arm (43% v 60%, respectively). An exploratory subpopula-
docetaxel administrations were delayed compared with 20%
tion analysis in the combination arm according to age (Ͻ 60
of 1,373 docetaxel administrations in the single-agent arm. v Ն 60 years) demonstrated that during the first treatment
Dose reduction was effective in reducing the recurrence
cycle, 4% of patients younger than 60 years discontinued
of grade 3 or 4 treatment-related adverse events in both
treatment compared with 18% of patients Ն 60 years.
treatment arms, as shown in Table 7 and reflected in Fig 5.
Corresponding values during the first two treatment cycleswere 17% and 31%, respectively. Despite this high discon-tinuation rate, efficacy was maintained in the combination
Table 6. Summary of Dose Reductions
arm, as indicated by the hazard ratio for survival of 0.836 infavor of the combination in patients
The incidence of treatment-related hospitalizations was
similar in the two treatment arms (28% of patients in the
combination arm and 26% in the single-agent arm). The
most common cause of hospitalization in both treatment
groups was neutropenic fever (12% v 13%, respectively).
The number of treatment-related hospitalizations was also
similar in the two groups (95 v 91, respectively). In the
combination arm, gastrointestinal adverse events rarely led
to hospitalization, and only one patient in the combination
arm was hospitalized primarily because of hand-foot
The majority of deaths in both treatment arms was
considered by the investigators to be due to progressive
disease and unrelated to treatment. Deaths classified by the
investigators as probably, possibly, or remotely related to
study treatment, during or within 28 days of completing the
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Copyright 2002 by the American Society of Clinical Oncology. All rights reserved.
Table 7. Percentage of Patients With Treatment-Related Adverse Events With Cycles of the Starting Dose (100%) and After Dose Reductions to 75% or 50% of the Starting Dose
study, occurred in three patients (1.2%) in the combination
granulocytopenia during the first cycle compared with 71%
arm and one patient (0.4%) in the single-agent arm. In the
of patients in the docetaxel alone group.
combination arm, the causes of death were enterocolitis in
Grade 3 hyperbilirubinemia (1.5 to three times the upper
one patient, classified by the investigator as “probably”
normal limit) was more frequent with combination therapy
related to treatment, sepsis in one patient (possibly related to
than with single-agent docetaxel (6.8% v 2.0%, respective-
treatment), and pulmonary edema (probably related to
ly); the incidence of grade 4 bilirubin elevations (more than
treatment). In addition, one patient receiving combination
three times the upper normal limit) was similar in the two
therapy died from hepatic coma 29 days after the last dose
groups (2.0% v 1.6%, respectively). In patients receiving
of study drug; the investigator considered the death to be
combination therapy, hyperbilirubinemia was generally tran-
“possibly” related to docetaxel, with the adverse reaction
sient (in six of the 22 patients with bilirubin elevations a single
possibly potentiated by capecitabine. One patient receiving
occurrence was recorded with normal bilirubin values before
docetaxel alone died from neutropenic sepsis, probably
and afterward) and was rarely associated with grade 3 or 4
related to treatment. In total, five patients in the combination
elevations in transaminase concentrations (grade 3 or 4 eleva-
arm and nine patients in the single-agent arm died from any
tions in ALT and AST in only 1.6% and 2.8% of patients in the
cause (related and unrelated to treatment) within 60 days of
combination arm, respectively). Most cases of hyperbiliru-
initiation of treatment (2.0% v 3.5%, respectively).
binemia had no clinical repercussions.
Laboratory abnormalities led to premature withdrawal in
six patients in the combination arm (neutropenia, thrombo-
Grade 3 or 4 neutropenia/granulocytopenia was less
cytopenia, AST, and/or ALT each in one patient and
frequent in patients receiving the combination regimen than
hyperbilirubinemia in three patients) and four patients in the
in those treated with docetaxel alone (68% v 77%, respec-
docetaxel arm (elevated AST and/or ALT in two patients,
tively). Grade 4 neutropenia/granulocytopenia occurred in
hyperbilirubinemia in one patient, and multiple laboratory
49% of the combination arm compared with 66% of the
abnormalities in one patient). Grade 3 hyperglycemia oc-
single-agent docetaxel arm. Fifty-three percent of patients inthe combination arm experienced grade 3 or 4 neutropenia/
Table 8. Impact of Dose Reductions on Time to Disease Progression or Fig 7. Time to disease progression in patients with versus without capecitabine dose reduction for the second cycle.
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Copyright 2002 by the American Society of Clinical Oncology. All rights reserved.
curred in 13% of the combination arm and 7% of the
The side effect profile of capecitabine/docetaxel therapy
single-agent docetaxel arm. Grade 4 hyperglycemia was
is generally manageable and consistent with the known
observed in 1% of patients in both treatment arms.
toxicities of the individual agents. There was a higherincidence of gastrointestinal side effects and hand-foot
Pharmacokinetics and Pharmacodynamics
syndrome in patients receiving combination therapy than inthose receiving single-agent docetaxel; myalgia, arthralgia,
Only 12 of the planned 16 patients were recruited to the
and neutropenic fever were more common with single-agent
pharmacokinetic study of combined docetaxel/capecitabine,
docetaxel. The incidence of grade 4 adverse events was
of whom 11 were assessable on day 1 of cycle 1, with five
higher in the single-agent docetaxel arm, primarily because
assessable on day 1 of cycle 4. No major or clinically
of neutropenic fever, which reflects the higher incidence of
relevant pharmacokinetic differences in serum concentra-
grade 4 neutropenia. The aggregate incidence of grade 3
tions or clearance of docetaxel or capecitabine between the
adverse events was higher in the combination arm, predom-
first and fourth cycles were observed, although conclusions
inantly because of grade 3 hand-foot syndrome, which
were limited because of the small number of patients
peaked in cycle 2 (13% of patients at risk). Side effects
associated with the capecitabine/docetaxel combination
were manageable with appropriate medical intervention (eg,loperamide and rehydration for diarrhea, mouthwash and
This phase III study demonstrates that capecitabine/
fluconazole for stomatitis, and oral vitamin B preparations
docetaxel combination therapy is more effective than a
and emollients for hand-foot syndrome) and treatment
current standard treatment, single-agent docetaxel, and is
interruption and/or dose reductions when needed. It is
thus a significant development for patients with breast
important to note that the higher incidence of gastrointesti-
cancer whose disease has progressed after an anthracycline-
nal adverse events and hand-foot syndrome observed in
containing regimen. The addition of capecitabine to do-
patients receiving the combination regimen did not seem to
cetaxel 75 mg/m2 resulted in a significant improvement in
adversely affect QOL (Global Health Score), the mainte-
overall survival, time to disease progression, and response
nance of which is an important goal in palliative treatment.
rate compared with docetaxel 100 mg/m2 alone.
Furthermore, as measured by systemic therapy side effect
The addition of capecitabine to docetaxel resulted in a
scores, side effects were judged to be no more troublesome
23% reduction in risk of death compared with docetaxel,
in patients receiving combination therapy compared with
with an increase in median survival of 3 months. The
patients in the single-agent arm (data not shown).29 Given
survival benefit with capecitabine/docetaxel combination
the decreased tolerance of the combination regimen in
therapy was seen early in the course of treatment and
patients Ն 60 years, reflected in particular by the higher rate
persisted throughout the study. The survival difference can
of treatment discontinuation in the first and second cycles, a
clearly be attributed to the addition of capecitabine, as
25% reduction in the capecitabine starting dose (950 mg/m2
patients in the combination arm received a lower dose of
twice daily) should be considered. A similar dose reduction
docetaxel, and there was no excess death rate due to
might be considered appropriate for patients with compro-
administration of full-dose docetaxel. A high proportion of
mised performance status and/or comorbidities.
patients in both treatment groups received poststudy che-
The use of warfarin or coumarin as concomitant treat-
motherapy, and the incidence of poststudy chemotherapy
ment was permitted in the study. However, an interaction
administration was balanced between the two treatment
between capecitabine and coumarin has been observed, and
groups (70% v 63% with combination therapy and single-
the pharmacokinetics of coumarin are affected by capecit-
abine. Therefore, careful monitoring of coagulation param-
The efficacy of single-agent docetaxel was consistent
eters in patients receiving concomitant coumarin derivatives
with that reported in the phase III study by Nabholtz et al,1
(eg, warfarin, phenprocoumon) is essential.30
with the median survival of 11.5 months falling within the
The controversy over sequential versus combination
range of 9 to 12 months typically observed in anthracycline-
treatment has generated considerable interest in the oncol-
resistant patients.1,2,26-28 The objective response rate of 30%
ogy community. No combination chemotherapy has dem-
was also consistent with published data from phase III trials
onstrated a significant survival benefit compared with se-
investigating single-agent docetaxel in this setting.1 No
quential single-agent therapy. In a landmark, three-arm,
single agent or combination chemotherapy regimen has here-
phase III trial by Sledge et al,31 patients received doxoru-
tofore been demonstrated to provide superior overall survival
bicin followed at disease progression by paclitaxel, or
compared with docetaxel, a highly effective single agent.
paclitaxel followed at progression by doxorubicin, or doxo-
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Copyright 2002 by the American Society of Clinical Oncology. All rights reserved.
rubicin plus paclitaxel combination therapy as first-line
addressed in this trial. However, it is a question of signifi-
treatment for metastatic breast cancer. Efficacy was similar
in the two sequential arms, but response rate and time to
Until such data become available, capecitabine/docetaxel
treatment failure were significantly superior in the combi-
combination therapy is a valuable strategy based on the
nation arm. Nevertheless, these improvements in efficacy
superior efficacy seen in the present trial. In addition, it
did not translate into a significant survival benefit. Sequen-
should be taken into account that after failure of study
tial administration of single agents has been considered to
chemotherapy in the current trial, only 60% to 70% of
be a valid and acceptable standard of care.
patients received further cytotoxic therapy. Therefore, 30%
The present trial provides clear evidence that combina-
to 40% of patients did not have the opportunity to benefitfrom subsequent chemotherapy administered sequentially.
tion therapy offers a survival advantage compared with
Additional trials investigating weekly docetaxel and lower
single-agent therapy. However, the relative merits of se-
doses of capecitabine or docetaxel are ongoing or planned.
quential versus combination therapy with these two agents
The results of these trials should provide further insight into
were not addressed in the present trial. Of note, the use of
the optimal use of these agents in the management of breast
poststudy chemotherapy was high in both arms (70% in the
combination arm and 63% in the single-agent arm); 44
The significantly superior survival, including a 3-month
(27%) of 163 patients who received poststudy chemother-
improvement in median survival, achieved with combined
apy in the single-agent docetaxel arm received poststudy
docetaxel plus capecitabine and the manageable toxicity
capecitabine. The early separation of the survival curves
should establish this regimen as an important treatment
suggests that the combination therapy prevented early
option for patients with anthracycline-pretreated metastatic
deaths in a subset of patients, the majority of whom had
heavily pretreated disease and significant tumor burden in
this trial. Whether combination capecitabine/docetaxel willprovide superior benefit compared with sequential admin-
In addition to the investigators listed in the author list and in the
Appendix, we thank Markus Abt, Hans Ulrich Burger, Eileen Codner,
istration of the same agents (docetaxel followed by capecit-
Anne Digiacomo, Lucille Donatacci, Jan Fagerberg, Stefan Frings,
abine or capecitabine followed by docetaxel) in the treat-
Patricia Kalber, Bruno Osterwalder, Trilok Parekh, Peter Stoll, Stu
ment of metastatic breast cancer is not known and was not
Teller, and Alex Zukiwski for their assistance in this publication.
The appendix listing participating investigators is available online at www.jco.org.
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Anais do XIV Seminário Nacional Mulher e Literatura / V Seminário Internacional Mulher e Literatura ESCREVENDO E BORDANDO, A NAÇÃO E A BANDEIRA, AS PALAVRAS E OS ACTOS: SÍMBOLOS E PODER PELA PENA DE ADELAIDE CABETE E CAROLINA BEATRIZ ÂNGELO […] reclamaria todas as medidas que considero necessárias para modificar a situação deprimente em que se encontra a mulher: Seria meu cui
Rev Biomed 1998; 9:92-96. Helicobacter pylori : susceptibility Original Article to amoxycillin, erythromycin, tetracycline, ciprofloxacine, nitrofurantoin and metronidazole in Costa Rica. Eugenia M. Quintana-Guzmán1, María L. Arias-Echandi1, Pilar Salas-Chaves1, Henry Davidovich-Rose2,Karl Schosinsky-Neverman1. 1Facultad de Microbiología, Universidad de Costa Rica, 2Servicio d