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© 2002 American Society for Clinical Oncology Superior Survival With Capecitabine Plus Docetaxel Combination Therapy in Anthracycline-Pretreated Patients With Advanced Breast Cancer: Phase III Trial ResultsByFrom the Baylor-Sammons Cancer Center, Dallas, and US Oncology, Houston, TX; Guy’s Hospital, London, United Kingdom; Petrov Research Institute, St Petersburg, Russia; Hopital Notre Dame, Montreal, and Ottawa Regional Cancer Centre, Ottawa, Canada; Issste Hospital, Mexico City, Mexico; Centre Rene Gauducheau Nantes-Atlantique, Saint Herblain, and Institut Bergonié, Bordeaux, France; Taipei-Veterans General Hospital, Taiwan; Beatson Oncology Centre, Glasgow, and Western General Hospital, Edinburgh, Scotland; and Perth Oncology, Perth, Western Australia. Address reprint requests to Joyce O’Shaughnessy, MD, Baylor-Sammons Cancer Center and US Oncology, 3535 Worth St, 5th Floor, Dallas, TX 75246; email: joyce.o'shaughnessy{at}usoncology.com
PURPOSE: Docetaxel and capecitabine, a tumor-activated oral fluoropyrimidine, show high single-agent efficacy in metastatic breast cancer (MBC) and synergy in preclinical studies. This international phase III trial compared efficacy and tolerability of capecitabine/docetaxel therapy with single-agent docetaxel in anthracycline-pretreated patients with MBC. PATIENTS AND METHODS: Patients were randomized to 21-day cycles of oral capecitabine 1,250 mg/m2 twice daily on days 1 to 14 plus docetaxel 75 mg/m2 on day 1 (n = 255) or to docetaxel 100 mg/m2 on day 1 (n = 256). RESULTS: Capecitabine/docetaxel resulted in significantly superior efficacy in time to disease progression (TTP) (hazard ratio, 0.652; 95% confidence interval [CI], 0.545 to 0.780; P = .0001; median, 6.1 v 4.2 months), overall survival (hazard ratio, 0.775; 95% CI, 0.634 to 0.947; P = .0126; median, 14.5 v 11.5 months), and objective tumor response rate (42% v 30%, P = .006) compared with docetaxel. Gastrointestinal side effects and hand-foot syndrome were more common with combination therapy, whereas myalgia, arthralgia, and neutropenic fever/sepsis were more common with single-agent docetaxel. More grade 3 adverse events occurred with combination therapy (71% v 49%, respectively), whereas grade 4 events were slightly more common with docetaxel (31% v 25% with combination). CONCLUSION: The significantly superior TTP and survival achieved with the addition of capecitabine to docetaxel 75 mg/m2, with the manageable toxicity profile, indicate that this combination provides clear benefits over single-agent docetaxel 100 mg/m2. Docetaxel/capecitabine therapy is an important treatment option for women with anthracycline-pretreated MBC.
THE TREATMENT of metastatic breast cancer, which ultimately develops in 30% to 40% of all patients with breast cancer in Western countries, is a considerable challenge for oncologists. The shift in the use of anthracyclines and taxanes to earlier in the course of disease, including the adjuvant setting, has increased the likelihood of patients presenting with metastatic breast cancer that has recurred after treatment with these agents. For patients in whom anthracyclines have failed, taxane-based therapy is a current standard of care. In a phase III study in this setting, single-agent docetaxel resulted in significantly superior overall survival (11.4 v 8.7 months, P = .0097) compared with a combination regimen of mitomycin plus vinblastine.1 Patients receiving single-agent docetaxel also achieved significantly superior time to disease progression (4.4 v 2.5 months, P = .001) and response rates (30% v 12%, P < .0001) compared with the mitomycin/vinblastine combination therapy. The efficacy of single-agent docetaxel was also demonstrated in a further randomized trial in a similar patient population, where docetaxel was shown to be more effective than methotrexate plus fluorouracil (5-FU), resulting in significantly superior response rates (42% v 21%, P < .001) and time to disease progression (6.3 v 3.0 months, P < .001).2 There was no significant difference in overall survival between the two regimens (10.4 and 11.1 months, respectively, P = .79). Despite attempts to improve further the efficacy of taxane-based therapy in patients with anthracycline-pretreated metastatic breast cancer, including combination of a taxane with other cytotoxic drugs, no cytotoxic regimen has until now improved survival compared with single-agent docetaxel. Trastuzumab in combination with chemotherapy has demonstrated a survival benefit compared with chemotherapy alone in HER2-positive patients.3 This is, however, applicable only to the 20% to 25% of women with metastatic breast cancer whose tumors overexpress HER2. Thus the need for new treatments for patients whose tumors are HER2-negative and for those whose disease is unresponsive or resistant to anthracyclines has provided the impetus for exploration of novel combination regimens. The oral fluoropyrimidine capecitabine (Xeloda; Hoffmann-La Roche, Nutley, NJ) was rationally designed to generate 5-FU preferentially in tumor tissue and to mimic continuous-infusion 5-FU. This tumor selectivity is achieved through exploitation of the significantly higher activity of thymidine phosphorylase in many human tumor tissues compared with healthy tissue.4,5 Clinical studies have shown that single-agent capecitabine is an active and tolerable treatment in metastatic breast cancer that has progressed during or after anthracycline and taxane therapy, achieving response rates of 20% to 26% and a median survival in excess of 1 year.6,7 This activity in heavily pretreated patients provided the rationale for investigating capecitabine earlier in the disease course and in combination with other cytotoxic agents. In addition, capecitabine is an attractive agent for incorporation into combination regimens because of the low incidence of myelosuppression. Consequently, a number of studies have investigated capecitabine in combination with cytotoxic agents with differing mechanisms of action and safety profiles.8-18 Preclinical studies in human cancer xenograft models demonstrated that administration of docetaxel or paclitaxel results in further upregulation of thymidine phosphorylase in tumor tissue.19 This finding has been confirmed in women with primary breast cancer who were treated with preoperative docetaxel.20 Co-administration of capecitabine and either docetaxel or paclitaxel in xenograft models resulted in synergistic antitumor activity, whereas taxanes in combination with either 5-FU or uracil plus tegafur demonstrated only additive efficacy.19 Based on a phase I study,11 a regimen of capecitabine 1,250 mg/m2 twice daily on days 1 to 14 in combination with docetaxel 75 mg/m2 on day 1 every 3 weeks was selected for further clinical development. We report the results of a randomized, international, phase III study comparing this combination regimen with single-agent docetaxel 100 mg/m2.
The primary objective of the study was to demonstrate superior time to disease progression (or death in patients with no evidence of disease progression) with the capecitabine plus docetaxel combination regimen compared with single-agent docetaxel. Secondary objectives included demonstration of a superior overall response rate and at least equivalent overall survival with the combination regimen. If survival was shown to be at least equivalent, a test for superiority of the combination regimen over single-agent docetaxel was to be applied. Additional objectives included comparison of the safety profiles and medical care utilization in each treatment arm. In addition, changes in quality of life (QOL) were to be compared in selected centers (determined by the availability of validated European Organization for Research and Treatment of Cancer [EORTC] questionnaire translations), and the pharmacokinetics of capecitabine were to be investigated in 16 patients randomized to combination therapy.
Patient Population Patients were ineligible if they had previously received a docetaxel-containing regimen in either the adjuvant or advanced disease setting (prior paclitaxel was permitted, no minimum interval from prior paclitaxel exposure to study entry was specified), or if they had received three or more chemotherapy regimens for advanced/metastatic disease. Patients with prior radiotherapy to the axial skeleton within 4 weeks of treatment start were excluded, as were those who had received hormonal therapy within 10 days of treatment start or chemotherapy within 4 weeks of treatment start. Patients with clinically significant cardiac disease, evidence of CNS metastases, known hypersensitivity to 5-FU, or prior unanticipated, severe reactions to drugs formulated with polysorbate 80, eg, taxanes, or to fluoropyrimidines were also ineligible. Women with a history of another malignancy (except basal cell skin carcinoma and carcinoma-in-situ of the uterine cervix) within 5 years of study entry were not eligible. Other ineligibility criteria included hemoglobin less than 8.0 g/dL, neutrophil count less than 1.5 x 109/L, platelet count less than 100 x 109/L, serum creatinine more than 1.5 times the upper normal limit, and ALT, AST, and alkaline phosphatase more than five times the upper normal limit. Patients with serum bilirubin values above the upper normal limit for more than one of three baseline values were also excluded, except for women with documented Gilbert’s syndrome who had normal values for all liver enzymes.
Study Treatment In the combination arm, patients were still regarded as "on study therapy" if for any reason docetaxel treatment was discontinued before disease progression and the patient continued to receive capecitabine alone. However, if capecitabine was discontinued before disease progression and the patient continued to receive single-agent docetaxel, the patient was considered to be receiving treatment "off study."
Patients with mild hepatic impairment (ALT and/or AST between 2.5 and five times the upper normal limit and alkaline phosphatase
Dose Modification
In the combination arm, treatment with both agents was interrupted (for a maximum of 2 weeks) and the doses of both capecitabine and docetaxel were reduced by 25% in patients who experienced a second occurrence of a given grade 2 toxicity or any grade 3 toxicity. Docetaxel therapy was discontinued if toxicities did not resolve to grade 0 or 1 within 2 weeks, but capecitabine could be resumed at 75% of the starting dose on resolution of the toxicity to grade 0 or 1. If patients experienced a third occurrence of a given grade 2 toxicity, a second occurrence of a given grade 3 toxicity, or any grade 4 toxicity, the capecitabine dose was reduced by 50% and docetaxel was discontinued. Capecitabine was discontinued if, despite dose reduction, a given toxicity occurred for a fourth time at grade 2, a third time at grade 3, or a second time at grade 4. In patients in the combination arm who discontinued docetaxel therapy for adverse events, single-agent capecitabine could be continued alone. If no grade 2, 3, or 4 toxicities occurred with capecitabine alone, the dose could be escalated at each subsequent cycle by 25%. If either docetaxel treatment delay or capecitabine treatment interruption was indicated, then treatment with both agents was delayed or interrupted. In patients experiencing grade 3 or 4 neutropenia/granulocytopenia, capecitabine was not expected to worsen or prolong this adverse event, and therefore treatment was to be continued throughout grade 3 or 4 neutropenic episodes. However, capecitabine was to be discontinued if any grade 2 clinical adverse event coincided with the neutropenic phase and the patient was to be hospitalized and closely monitored. Docetaxel was readministered only when the neutrophil count was
A similar dose modification scheme was used in patients receiving single-agent docetaxel. Dose reduction was not required after the first appearance of any grade 2 toxicity, although treatment was interrupted until the toxicity had resolved to grade 0 or 1. Except for neutropenia/granulocytopenia, treatment was interrupted and the dose was reduced by 25% (to 75 mg/m2) in patients who experienced a second occurrence of a given grade 2 toxicity or any grade 3 toxicity and by a further 25% (to 55 mg/m2) in patients who experienced a third occurrence of a given grade 2 toxicity, a second occurrence of a given grade 3 toxicity, or any grade 4 toxicity. Treatment was discontinued if, despite dose reduction, a given toxicity occurred for a fourth time at grade 2, a third time at grade 3, or a second time at grade 4. In patients experiencing grade 3 or 4 neutropenia/granulocytopenia, docetaxel was readministered only when the neutrophil count was
Study Assessments Tumor responses were assessed on the basis of World Health Organization (WHO) criteria21 at 6-week intervals until week 48 and then at 12-week intervals until disease progression. Tumor response was also assessed in each patient within 2 weeks of discontinuing study medication. The best overall response achieved was reported. Patients with no tumor assessment after baseline were classified as nonresponders. In responding patients, the response had to be confirmed a minimum of 4 weeks after the first response had been recorded. Patients were classified as achieving stable disease if at the first tumor assessment after study treatment administration there was neither disease progression nor a response that was later confirmed. Copies of all x-rays and computed tomography scans were supplied for independent review by a panel of radiologists, who were blinded to the study treatment, the clinical condition of the patient, and the investigator’s evaluation. For patients who achieved a partial or complete response, time to response was defined as the interval between randomization and the first recording of tumor response. Duration of response was assessed according to WHO criteria. For complete responders, duration of response was defined as the interval between the first recording of a complete response and the time of disease progression or death. For partial responders, duration of response was measured from randomization. Patients whose disease did not progress were censored using the date at which they were last known to have not progressed. Time to disease progression was defined as the time from randomization to the first recording of disease progression or the date of death in patients with no evidence of disease progression. Adverse events and medical care utilization were recorded throughout the study and for 28 days after the last administration of study drug. Adverse events were graded according to National Cancer Institute of Canada common toxicity criteria; hand-foot syndrome was graded 1 to 3, as defined in previous capecitabine clinical studies.6,22 QOL was assessed using the EORTC QOL questionnaire C30 (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 treatment 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 on days 14 and 77.
Statistical Analysis Patients were randomized by country using a block size of four via a computer-assisted, touch-tone, central randomization service located in Houston, TX, and Brussels, Belgium. Previous treatment with paclitaxel was the only variable used for stratification. The efficacy analysis was based on the intent-to-treat population (all randomized patients). Safety was assessed using the safety population of all patients who received at least one dose of study medication and for whom follow-up safety information was available. A two-sided log-rank test (alpha = 0.05) was used to test differences in time to disease progression. QOL data were scored according to standard EORTC procedures.24,25 The primary QOL analysis used the "last observation carried forward" approach to replace missing data. Patients were excluded from the pharmacokinetic analysis if they vomited within 2 hours after capecitabine intake on the two sampling days, if blood samples could not be obtained, or if the time of drug administration and/or blood sampling was not clearly documented. Compliance with capecitabine therapy was assessed by comparing the amount of dispensed and returned medication. Clinical cutoff for the study analysis was February 15, 2001. A minimum follow-up of 15 months had been reached in all patients.
Patient Population In total, 511 patients were enrolled from 75 centers in 16 countries (Argentina, Australia, Brazil, Canada, France, Germany, Israel, Italy, Mexico, New Zealand, Norway, Russia, Spain, Taiwan, the United Kingdom, and the United States). Patients were randomized to either capecitabine 1,250 mg/m2 twice daily on days 1 to 14 plus docetaxel 75 mg/m2 (n = 255) or to docetaxel 100 mg/m2 alone (n = 256) every 3 weeks. The median time from the primary diagnosis of breast cancer to randomization was 29 months (range, 3 to 302 months) for women in the combination arm and 28 months (range, 3 to 304 months) in the single-agent arm. The baseline characteristics of patients were well balanced between the two treatment groups (Table 1). In both treatment arms, the most frequently involved metastatic sites were the lymph nodes, liver, bone, and lung. The treatment histories in the two groups were also similar (Table 2). Approximately one third of patients in each treatment group had received prior endocrine therapy in the adjuvant setting, and one half had received endocrine therapy in the metastatic setting. As defined by the protocol, all patients had received previous anthracycline-based chemotherapy. The most frequently administered anthracycline in both arms was doxorubicin, and the best response to anthracycline treatment for metastatic disease was balanced between the two groups. Best response to previous paclitaxel therapy for metastatic disease was also balanced in the two treatment arms. Approximately one third of patients in each group received study therapy as first-line treatment for metastatic disease (35% in the combination arm and 31% in the single-agent arm), and approximately two thirds received study therapy as second- or third-line treatment (65% and 68%, respectively).
Efficacy All efficacy data are reported using the intent-to-treat (all randomized) patient population (n = 255 in the combination arm; n = 256 in the docetaxel alone arm). Capecitabine/docetaxel combination therapy resulted in significantly superior time to disease progression, the primary end point, compared with single-agent docetaxel (log-rank P = .0001; hazard ratio, 0.652; 95% confidence interval [CI], 0.545 to 0.780). The hazard ratio translates into a 35% decrease in risk of disease progression with the addition of capecitabine to docetaxel therapy. Median time to disease progression was 6.1 months (95% CI, 5.4 to 6.5 months; 93% of events) in the combination arm and 4.2 months (95% CI, 3.4 to 4.5 months; 98% of events) with docetaxel alone (Fig 1).
The analysis of survival demonstrated that overall survival was superior in the combination arm, with a hazard ratio of 0.775 (P = .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 regimen and 11.5 months (95% CI, 9.8 to 12.7 months; 79% of events) with single-agent docetaxel (Fig 2). The survival curves separated early and maintained a clear separation over time. The 12-month survival rate was 57% (95% CI, 51% to 63%) in the combination arm and 47% (95% CI, 41% to 53%) in the single-agent arm. Median censoring times were 23.2 months and 22.9 months, respectively.
The combination regimen also demonstrated a significantly superior objective response rate, with 42% of patients in the combination arm achieving an objective tumor response compared with 30% in the single-agent arm (P = .006) (Table 3). The significantly superior response rates observed in the investigator-assessed results were confirmed (32% with combination therapy v 23% with docetaxel alone, P = .025) by the Independent Review Committee, members of which had only radiologic studies for review and not lesions measurable only on physical examinations. In all major subgroup analyses, including by age, anthracycline resistance, extent of prior chemotherapy, predominant metastatic site, and number of metastatic sites, the response rate in the combination arm was higher than in the single-agent docetaxel arm.
Table 4 shows time to response in confirmed responders. In all time periods there were at least as many responses in the combination arm as in the single-agent arm, with the majority of all responses occurring in the first four treatment cycles. The duration of response according to WHO criteria in patients achieving either a partial or a complete response was similar in the two treatment groups. The median duration of response was 7.3 months (95% CI, 6.9 to 8.4 months) for the 106 responders in the combination arm and 7.0 months (95% CI, 5.8 to 8.0 months) for the 76 responders in the single-agent arm. The percentage of patients without disease progression after 6 months was 41% in the combination arm (95% CI, 35% to 47%) compared with 29% (95% CI, 23% to 34%) in the single-agent docetaxel arm (P = .04).
The time to disease progression data were supported by the superior results of the time to treatment failure analysis, a composite of safety and efficacy end points, in which withdrawals of patients because of progressive disease or 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) in the combination arm and 2.8 months (95% CI, 2.4 to 3.5 months; 98% of events) in the single-agent arm (P = .0002). The combination and single-agent docetaxel treatment groups were well balanced in terms of poststudy therapies for breast cancer, including surgical intervention (7% v 4%, respectively), radiotherapy (30% in both groups), endocrine therapy (30% v 27%), chemotherapy (70% v 63%), vinorelbine (31% v 26%), anthracyclines (10% v 11%), 5-FU (20% v 23%), and treatment with trastuzumab (9% in both groups). Poststudy docetaxel was administered more frequently in the combination arm (20%) than in the single-agent arm (7%), and the use of poststudy capecitabine was more common in the single-agent group (17%) than in the combination arm (3%). The majority of patients reported as receiving poststudy docetaxel in the combination arm (36 [73%] of 49 patients) represented patients in whom capecitabine therapy was discontinued before disease progression but docetaxel was continued alone.
QOL
Safety The safety population (n = 506) included 251 patients in the combination arm and 255 patients in the docetaxel arm, all of whom received at least one dose of study drug. The median duration of treatment was 3.8 months (range, 0.07 to 14.7 months) with the combination regimen and 2.8 months (range, 0.03 to 12.2 months) with single-agent docetaxel. The median duration of docetaxel therapy during the study period in patients receiving combination therapy was also 2.8 months. Forty-five patients (18%) in the combination arm discontinued docetaxel therapy but continued to receive capecitabine alone. The median duration of single-agent capecitabine in these patients was 3.2 months. The dose received in each cycle was recorded as a percentage of the planned dose, which was defined using the first dose in cycle 1, extrapolated to the end of the cycle in which study treatment was discontinued. In the combination arm, the median delivered dose of capecitabine during the course of the study was 77% of the planned dose, and the corresponding value for docetaxel was 87%. The delivered versus planned dose and interquartile range for capecitabine and docetaxel dosing in the combination and single-agent arms are depicted in Fig 4. In the single-agent docetaxel arm, the overall median delivered dose was 100% of the planned dose (interquartile range, 75% to 100%). The median delivered versus planned dose was 100% up to week 27 and was 75% in weeks 28 to 30 (interquartile range, 75% to 100%). No cases of clinically relevant noncompliance were detected.
The incidence of treatment-related adverse events was similar in the combination and single-agent arms (98% v 94%, respectively). The percentage of patients experiencing grade 3 treatment-related adverse events was higher in the combination therapy group (71% v 49% in the single-agent docetaxel arm); there was a slightly lower incidence of grade 4 treatment-related adverse events with combination therapy (25% v 31%). In both treatment groups, the overall incidence of grade 3 or 4 adverse events was highest in the first treatment cycle (38% in the combination group and 40% in the single-agent group). The incidence of grade 3 or 4 adverse events over time is shown in Fig 5. In the second cycle, more patients experienced grade 3 or 4 adverse events in the combination arm (36% v 19% in the single-agent arm), primarily because of grade 3 hand-foot syndrome (combination arm: 2% in weeks 1 to 3 and 13% in weeks 4 to 6). In all other cycles, the incidence of grade 3 or 4 adverse events was similar in the two groups.
Patients receiving the combination regimen experienced a higher incidence of gastrointestinal adverse events and hand-foot syndrome, a cutaneous condition affecting the palms and soles. This was typically treated by investigators in this trial with systemic vitamin preparations such as vitamin B6 (pyridoxine) or locally with emollients. Patients receiving docetaxel alone experienced a higher incidence of neutropenic fever, arthralgia, and pyrexia (Fig 6).
The spectrum of grade 3 or 4 toxicities was similar to the profile for all grades and is shown in Table 5. Apart from neutropenic fever, grade 4 adverse events were rare in both treatment arms. The most common grade 3 treatment-related adverse events were hand-foot syndrome and stomatitis in the combination arm and neutropenic fever and neutropenia requiring medical intervention in the single-agent docetaxel arm. Approximately two thirds of patients (65%) in the combination arm required dose reduction of capecitabine alone (4%), docetaxel alone (10%), or both drugs (51%) for adverse events. In the single-agent docetaxel group, 36% of patients required dose reduction. The median time to dose reduction was longer in the combination therapy group, as shown in Table 6. Capecitabine treatment interruption in the combination arm was required in 34% of cycles. The adverse events, either alone or in combination, most frequently leading to capecitabine treatment interruption were hand-foot syndrome (11.1%), diarrhea (8.5%), and stomatitis (4.6%). The median duration of treatment interruption per cycle was 6 days (interquartile range, 3 to 9 days). In the combination arm, 27% of 1,317 docetaxel administrations were delayed compared with 20% of 1,373 docetaxel administrations in the single-agent arm.
Dose reduction was effective in reducing the recurrence of grade 3 or 4 treatment-related adverse events in both treatment arms, as shown in Table 7 and reflected in Fig 5. The impact of dose reduction on efficacy was assessed by 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 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 versus without capecitabine dose reduction for the second cycle. Single-agent docetaxel is included as a reference arm in the Kaplan-Meier plot shown in Fig 7.
Premature withdrawal for adverse events or intercurrent illness was more common in the combination arm than in the docetaxel arm (26% v 20%, respectively). In both treatment arms, insufficient therapeutic response was the most common reason for treatment withdrawal, but this was less frequent in the combination arm than in the single-agent arm (43% v 60%, respectively). An exploratory subpopulation analysis in the combination arm according to age (< 60 v  60 years) demonstrated that during the first treatment cycle, 4% of patients younger than 60 years discontinued treatment compared with 18% of patients 60 years. Corresponding values during the first two treatment cycles were 17% and 31%, respectively. Despite this high discontinuation rate, efficacy was maintained in the combination arm, as indicated by the hazard ratio for survival of 0.836 in favor of the combination in patients 60 years. 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 syndrome. 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 study, occurred in three patients (1.2%) in the combination arm and one patient (0.4%) in the single-agent arm. In the combination arm, the causes of death were enterocolitis in one patient, classified by the investigator as "probably" related to treatment, sepsis in one patient (possibly related to treatment), and pulmonary edema (probably related to treatment). In addition, one patient receiving combination therapy died from hepatic coma 29 days after the last dose of study drug; the investigator considered the death to be "possibly" related to docetaxel, with the adverse reaction possibly potentiated by capecitabine. One patient receiving docetaxel alone died from neutropenic sepsis, probably related to treatment. In total, five patients in the combination arm and nine patients in the single-agent arm died from any cause (related and unrelated to treatment) within 60 days of initiation of treatment (2.0% v 3.5%, respectively).
Laboratory Abnormalities Grade 3 hyperbilirubinemia (1.5 to three times the upper normal limit) was more frequent with combination therapy than with single-agent docetaxel (6.8% v 2.0%, respectively); the incidence of grade 4 bilirubin elevations (more than three times the upper normal limit) was similar in the two groups (2.0% v 1.6%, respectively). In patients receiving combination therapy, hyperbilirubinemia was generally transient (in six of the 22 patients with bilirubin elevations a single occurrence was recorded with normal bilirubin values before and afterward) and was rarely associated with grade 3 or 4 elevations in transaminase concentrations (grade 3 or 4 elevations in ALT and AST in only 1.6% and 2.8% of patients in the combination arm, respectively). Most cases of hyperbilirubinemia had no clinical repercussions. Laboratory abnormalities led to premature withdrawal in six patients in the combination arm (neutropenia, thrombocytopenia, AST, and/or ALT each in one patient and hyperbilirubinemia in three patients) and four patients in the docetaxel arm (elevated AST and/or ALT in two patients, hyperbilirubinemia in one patient, and multiple laboratory abnormalities in one patient). Grade 3 hyperglycemia occurred in 13% of the combination arm and 7% of the single-agent docetaxel arm. Grade 4 hyperglycemia was observed in 1% of patients in both treatment arms.
Pharmacokinetics and Pharmacodynamics
This phase III study demonstrates that capecitabine/docetaxel combination therapy is more effective than a current standard treatment, single-agent docetaxel, and is thus a significant development for patients with breast cancer whose disease has progressed after an anthracycline-containing regimen. The addition of capecitabine to docetaxel 75 mg/m2 resulted in a significant improvement in overall survival, time to disease progression, and response rate compared with docetaxel 100 mg/m2 alone. The addition of capecitabine to docetaxel resulted in a 23% reduction in risk of death compared with docetaxel, with an increase in median survival of 3 months. The survival benefit with capecitabine/docetaxel combination therapy was seen early in the course of treatment and persisted throughout the study. The survival difference can clearly be attributed to the addition of capecitabine, as patients in the combination arm received a lower dose of docetaxel, and there was no excess death rate due to administration of full-dose docetaxel. A high proportion of patients in both treatment groups received poststudy chemotherapy, and the incidence of poststudy chemotherapy administration was balanced between the two treatment groups (70% v 63% with combination therapy and single-agent docetaxel, respectively). The efficacy of single-agent docetaxel was consistent with that reported in the phase III study by Nabholtz et al,1 with the median survival of 11.5 months falling within the range of 9 to 12 months typically observed in anthracycline-resistant patients.1,2,26-28 The objective response rate of 30% was also consistent with published data from phase III trials investigating single-agent docetaxel in this setting.1 No single agent or combination chemotherapy regimen has heretofore been demonstrated to provide superior overall survival compared with docetaxel, a highly effective single agent.
The side effect profile of capecitabine/docetaxel therapy is generally manageable and consistent with the known toxicities of the individual agents. There was a higher incidence of gastrointestinal side effects and hand-foot syndrome in patients receiving combination therapy than in those receiving single-agent docetaxel; myalgia, arthralgia, and neutropenic fever were more common with single-agent docetaxel. The incidence of grade 4 adverse events was higher in the single-agent docetaxel arm, primarily because of neutropenic fever, which reflects the higher incidence of grade 4 neutropenia. The aggregate incidence of grade 3 adverse events was higher in the combination arm, predominantly because of grade 3 hand-foot syndrome, which 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 fluconazole for stomatitis, and oral vitamin B6 preparations and emollients for hand-foot syndrome) and treatment interruption and/or dose reductions when needed. It is important to note that the higher incidence of gastrointestinal adverse events and hand-foot syndrome observed in patients receiving the combination regimen did not seem to adversely affect QOL (Global Health Score), the maintenance of which is an important goal in palliative treatment. Furthermore, as measured by systemic therapy side effect scores, side effects were judged to be no more troublesome in patients receiving combination therapy compared with patients in the single-agent arm (data not shown).29 Given the decreased tolerance of the combination regimen in patients The use of warfarin or coumarin as concomitant treatment was permitted in the study. However, an interaction between capecitabine and coumarin has been observed, and the pharmacokinetics of coumarin are affected by capecitabine. Therefore, careful monitoring of coagulation parameters in patients receiving concomitant coumarin derivatives (eg, warfarin, phenprocoumon) is essential.30 The controversy over sequential versus combination treatment has generated considerable interest in the oncology community. No combination chemotherapy has demonstrated a significant survival benefit compared with sequential single-agent therapy. In a landmark, three-arm, phase III trial by Sledge et al,31 patients received doxorubicin followed at disease progression by paclitaxel, or paclitaxel followed at progression by doxorubicin, or doxorubicin plus paclitaxel combination therapy as first-line treatment for metastatic breast cancer. Efficacy was similar in the two sequential arms, but response rate and time to treatment failure were significantly superior in the combination arm. Nevertheless, these improvements in efficacy did not translate into a significant survival benefit. Sequential administration of single agents has been considered to be a valid and acceptable standard of care. The present trial provides clear evidence that combination therapy offers a survival advantage compared with single-agent therapy. However, the relative merits of sequential versus combination therapy with these two agents were not addressed in the present trial. Of note, the use of poststudy chemotherapy was high in both arms (70% in the combination arm and 63% in the single-agent arm); 44 (27%) of 163 patients who received poststudy chemotherapy in the single-agent docetaxel arm received poststudy capecitabine. The early separation of the survival curves suggests that the combination therapy prevented early 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 will provide superior benefit compared with sequential administration of the same agents (docetaxel followed by capecitabine or capecitabine followed by docetaxel) in the treatment of metastatic breast cancer is not known and was not addressed in this trial. However, it is a question of significant scientific interest. Until such data become available, capecitabine/docetaxel combination therapy is a valuable strategy based on the superior efficacy seen in the present trial. In addition, it should be taken into account that after failure of study chemotherapy in the current trial, only 60% to 70% of patients received further cytotoxic therapy. Therefore, 30% to 40% of patients did not have the opportunity to benefit from subsequent chemotherapy administered sequentially. Additional trials investigating weekly docetaxel and lower doses of capecitabine or docetaxel are ongoing or planned. The results of these trials should provide further insight into the optimal use of these agents in the management of breast cancer patients. The significantly superior survival, including a 3-month improvement in median survival, achieved with combined docetaxel plus capecitabine and the manageable toxicity should establish this regimen as an important treatment option for patients with anthracycline-pretreated metastatic breast cancer.
APPENDIX Brazil: M.J. Froimtchuk, MD, Rio de Janeiro; and J.L. Pedrini, MD, Porto Alegre. Canada: B. Walley, MD, Saskatoon; B. Colwell, MD, Halifax; P.E. Goss, MD, Toronto; S-C. Tang, MD, St John’s; T.A. Vandenberg, MD, London; L. Yelle, MD, Montreal; A.M. Oza, MD, Toronto; J. Robert, MD, Quebec City; and E. Tomiak, MD, Ottawa. Germany: R.H. Mertelsmann, MD, Freiberg; and K. Possinger, MD, Berlin. Spain: J-A. Moreno-Nogueira, MD, Seville; A. Lluch Hernandez, MD, Valencia; and M. Martin, MD, Madrid. France: F.L. Turpin, MD, Saint Cloud; D. Maraninchi, MD, Marseille; and T. Bachelot, MD, Lyon. United Kingdom: D.C. Talbot, MD, Oxford; J. Mansi, MD, London; S. O’Reilly, MD, Merseyside; K.J. O’Byrne, MD, Leicester; and A. Makris, MD, Northwood. Italy: R. Rosso, MD, Genova; P.F. Conte, MD, Pisa; A. Villa, MD, Milan; G. Comella, MD, Naples; M. Tonato, MD, Perugia; and A. Santoro, MD, Rozzano. Israel: M.J. Inbar, MD, Tel Aviv; S. Rizel, MD, Tel Hashomer; R. Catane, MD, Jerusalem; D.B. Geffen, MD, Beer Sheva; B. Uzieli, MD, Jerusalem; G. Fried, MD, Haifa; and I. Ben-Shahar, MD, Nahariya. Mexico: J.E. Gonzalez, MD, Monterrey; J.A. Silva, MD, Mexico City; and C. Chan Navarro, MD, Guadalajara. Norway: B. Erikstein, MD, and E.A. Wist, MD, Oslo. New Zealand: M.P.N. Findlay, MD, Wellington; and V.J. Harvey, MD, Auckland. Argentina: R.D. Chacon, MD, and E. Mickiewicz, MD, Buenos Aires. Taiwan: T-Y. Chao, MD, and A.L. Cheng, MD, Taipei. Russia: M. Lichinitser, MD, V. Gorbunova, MD, and A.A. Borisov, MD, Moscow. United States: P.R. Kaywin, MD, Miami, FL; M.R. Modiano, MD, Tucson, AZ; W.G. Harker, MD, Salt Lake City, UT; E. Tai, MD, Sunnyvale, CA; J.F. Kroener, MD, La Jolla, CA; K-Y. Yeung, MD, Clinton, MD; M.R. Moore, MD, Decatur, GA; and W.D. Henner, MD, Portland, OR.
This research was supported by F. Hoffmann-La Roche, Ltd, Nutley, NJ. In addition to the investigators listed in the author list and in the Appendix, we thank Markus Abt, Hans Ulrich Burger, Eileen Codner, Anne Digiacomo, Lucille Donatacci, Jan Fagerberg, Stefan Frings, Patricia Kalber, Bruno Osterwalder, Trilok Parekh, Peter Stoll, Stu Teller, and Alex Zukiwski for their assistance in this publication.
Some authors have received more than $2,000 a year working in a consultant capacity or by performing contract work within the past 2 years for either Roche, Nutley, NJ, or Aventis, Bridgewater, NJ (D.M., S.Vukelja, P.F., and R.L.) or both (J.O., S.J., C.T., and G.V.H).
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ABSTRACT
INTRODUCTION
2.5 times upper normal limit; or ALT and/or AST between 1.5 and five times the upper normal limit) who were randomized to single-agent docetaxel received a reduced dose of 75 mg/m2. All patients received docetaxel premedication (eg, dexamethasone) as per the treatment center policy at the time the study was conducted. No premedication for capecitabine was required. Capecitabine was administered orally twice daily, within 30 minutes of completion of a meal (breakfast, evening meal), approximately 12 hours apart. Tablets were to be swallowed with approximately 200 mL of water. Patients achieving a complete or partial response or stable disease after 6 weeks of therapy continued on treatment until disease progression or development of unacceptable toxicity. Patients with documented progressive disease were withdrawn from the study. 
