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, P consultant capacity or by performing contract work within the past 2 years 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’ until now improved survival compared with single-agent 2002 by American Society of Clinical Oncology.
docetaxel. Trastuzumab in combination with chemotherapy Journal of Clinical Oncology, Vol 20, No 12 (June 15), 2002: pp 2812-2823 Downloaded from 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 Downloaded from by Ma. Luisa TIAMBENG on August 1, 2005 . 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 Downloaded from by Ma. Luisa TIAMBENG on August 1, 2005 . 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 Downloaded from by Ma. Luisa TIAMBENG on August 1, 2005 . 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
*Main reason for missing post-baseline data: early dropouts during the first Fig 1. Time to disease progression.
Downloaded from by Ma. Luisa TIAMBENG on August 1, 2005 . 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 Downloaded from by Ma. Luisa TIAMBENG on August 1, 2005 . 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.
Downloaded from by Ma. Luisa TIAMBENG on August 1, 2005 . Copyright 2002 by the American Society of Clinical Oncology. All rights reserved. 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 Downloaded from by Ma. Luisa TIAMBENG on August 1, 2005 . 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.
Downloaded from by Ma. Luisa TIAMBENG on August 1, 2005 . 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- Downloaded from by Ma. Luisa TIAMBENG on August 1, 2005 . 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
1. Nabholtz J-M, Senn HJ, Bezwoda WR, et al: Prospective ran- 6. Blum JL, Jones SE, Buzdar AU, et al: Multicenter phase II study domized trial of docetaxel versus mitomycin plus vinblastine in of capecitabine in paclitaxel-refractory metastatic breast cancer. J Clin patients with metastatic breast cancer progressing despite previous anthracycline-containing chemotherapy. J Clin Oncol 17:1413-1424, 7. Blum JL, Dieras V, Lo Russo PM, et al: Multicenter, phase II study of capecitabine in taxane-pretreated metastatic breast carcinoma.
2. Sjo¨stro¨m J, Blomqvist C, Mourisden H, et al: Docetaxel com- pared with sequential methotrexate and 5-fluorouracil in patients with 8. Khoury P, Villalona-Calero M, Blum J, et al: Phase I study of advanced breast cancer after anthracycline failure: A randomised phase capecitabine in combination with paclitaxel in patients with previously III study with crossover on progression by the Scandinavian Breast treated metastatic breast cancer. Proc Am Soc Clin Oncol 17:206a,1998 (abstr 1800) 9. Pe´rez-Manga G, Batista N, Constenla M, et al: Efficacy and 3. Slamon DJ, Leyland-Jones B, Shak S, et al: Use of chemotherapy safety profile of capecitabine (Xeloda) in combination with paclitaxel plus a monoclonal antibody against HER2 for metastatic breast cancer (P) in patients with locally advanced or metastatic breast cancer: that overexpresses HER2. N Engl J Med 344:783-792, 2001 Preliminary results of a phase II study. Breast Cancer Res Treat 64:124, 4. Miwa M, Ura M, Nishida M, et al: Design of a novel oral fluoropyrimidine carbamate, capecitabine, which generates 5-fluorou- 10. Villalona-Calero MA, Weiss GR, Burris HA, et al: Phase I and racil selectively in tumours by enzymes concentrated in human liver pharmacokinetic study of the oral fluoropyrimidine capecitabine in and cancer tissue. Eur J Cancer 34:1274-1281, 1998 combination with paclitaxel in patients with advanced solid malignan- 5. Schu¨ller J, Cassidy J, Dumont E, et al: Preferential activation of capecitabine in tumor following oral administration in colorectal cancer 11. Pronk L, Vasey PA, Sparreboom A, et al: A phase I and patients. Cancer Chemother Pharmacol 34:293-296, 2000 pharmacokinetic study of the combination of capecitabine and do- Downloaded from by Ma. Luisa TIAMBENG on August 1, 2005 . Copyright 2002 by the American Society of Clinical Oncology. All rights reserved. cetaxel in patients with advanced solid tumours. Br J Cancer 83:22-29, chemotherapy in advanced breast cancer patients. Oncol Rep 7:945- 12. Tonkin K, Scarfe A, Koski S, et al: Preliminary results of a 21. World Health Organization Handbook for Reporting Results of phase I/II study of weekly docetaxel (Taxotere) combined with inter- Cancer Treatment. Geneva, Switzerland, World Health Organization, mittent capecitabine (Xeloda) for patients with anthracycline pre- treated metastatic breast cancer. Proc Am Soc Clin Oncol 20:67b, 2001 22. Van Cutsem E, Findlay M, Osterwalder B, et al: Capecitabine, an oral fluoropyrimidine carbamate with substantial activity in ad- 13. Meza LA, Amin B, Horsey M, et al: A phase II study of vanced colorectal cancer: Results of a randomized phase II study. J Clin capecitabine in combination with paclitaxel as first or second line therapy in patients with metastatic breast cancer (MBC). Proc Am Soc 23. Lachin JM: Introduction to sample size determination and power for clinical trials. Controlled Clin Trials 2:93-113, 1981 14. Venturini M, Del Mastro L, Merlano M, et al: Dose-finding 24. Osoba D, Rodrigues G, Myles J, et al: Interpreting the signifi- study of capecitabine in combination with docetaxel and epirubicin in cance of changes in health-related quality-of-life scores. J Clin Oncol16:139-144, 1998 prior untreated advanced breast cancer patients. Proc Am Soc Clin 25. King T: The interpretation of scores from the EORTC quality of life questionnaire QLQ-C30. Qual Life Res 5:555-567, 1996 15. Venturini M, Del Mastro L, Durando A, et al: TEX (Taxotere, 26. Brodowicz T, Koestler WJ, Tomek S, et al: Monotherapy with epirubicin and Xeloda) regimen as first line chemotherapy in advanced docetaxel in second- or third-line treatment of anthracycline-resistant breast cancer: A multicenter phase II study. Proc Am Soc Clin Oncol metastatic breast cancer. Anticancer Drugs 11:149-153, 2000 27. Bonneterre J, Spielman M, Guastalla J-P, et al: Efficacy and 16. Nole` F, Catania C, Mandala` M, et al: Phase I study of safety of docetaxel (Taxotere™) in heavily pretreated advanced breast vinorelbine (V) and capecitabine (C) in advanced breast cancer (ABC).
cancer patients: The French compassionate use programme experience.
Breast Cancer Res Treat 64:125, 2000 (abstr 539) 17. Welt A, Borquez D, Oberhoff C, et al: Phase I study of 28. Valero V, Holmes FA, Walters RS, et al: Phase II trial of capecitabine and vinorelbine in pretreated patients with metastatic docetaxel: A new, highly effective antineoplastic agent in the manage- breast cancer. Proc Am Soc Clin Oncol 20:58b, 2001 (abstr 1979) ment of patients with anthracycline-resistant metastatic breast cancer.
18. Bonnefoi H, Biganzoli L, Mauriac L, et al: An EORTC-IDBBC phase I study of cyclophosphamide (C) and epirubicin (E) in combi- 29. Twelves C, Fumoleau P, Jones SE, et al: Adding Xeloda nation with capecitabine (X) (CEX) as primary treatment of locally (capecitabine) to Taxotere (docetaxel) significantly improves survival advanced/inflammatory (LA/I) or large operable (LO) breast cancer without compromising quality of life in patients with metastatic breast (BC). Proc Am Soc Clin Oncol 20:13b, 2001 (abstr 1800) cancer. Poster presented at San Antonio Breast Cancer Meeting, San 19. Sawada N, Ishikawa T, Fukase Y, et al: Induction of thymidine Antonio, TX, December 12, 2001 (poster no. 542) phosphorylase activity and enhancement of capecitabine efficacy by 30. Capecitabine prescribing information. Nutley, NJ, F. Hoff- Taxol/Taxotere in human cancer xenografts. Clin Cancer Res 4:1013- 31. Sledge GW Jr, Neuberg D, Ingle J, et al: Phase III trial of 20. Kurosumi M, Tabei T, Suemasu K, et al: Enhancement of doxorubicin (A) vs. paclitaxel (T) vs. doxorubicin ϩ paclitaxel (A ϩ T) immunohistochemical reactivity for thymidine phosphorylase in breast as first-line therapy for metastatic breast cancer (MBC): An Intergroup carcinoma cells after administration of docetaxel as a neoadjuvant trial. Proc Am Soc Clin Oncol 16:1a, 1997 (abstr 2) Downloaded from by Ma. Luisa TIAMBENG on August 1, 2005 . Copyright 2002 by the American Society of Clinical Oncology. All rights reserved.


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

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