CONDUCT OF THE TRIAL
The trial opened on September 15, 2001. The first per-protocol analysis, in November 2006, after the enrollment of 600 patients, revealed 16 recurrences, distant metastases, or death from any cause in the standard-chemotherapy group and 24 in the capecitabine group. At the time, the hazard ratio for disease recurrence in the standard-chemotherapy group as compared with the capecitabine group was 0.53. In view of the small number of events, however, this hazard ratio was uncertain. Still, the Bayesian probability of a hazard ratio of less than 0.8046 was 96%, which exceeded the limit of 80% that was based on the predictive probability that after additional follow-up, the results would clearly favor futility. The data and safety monitoring board permanently closed the trial on December 29, 2006, after a total enrollment of 633 patients. We performed all statistical analyses of data available as of May 2008. The median follow-up was 2.4 years, and the maximum follow-up was 5.6 years.
Randomization was suspended during the 10-week period when the protocol was amended for capecitabine toxicity. The 19 patients enrolled during this period were all assigned to standard chemotherapy. Analyses including and excluding these patients showed no substantive differences (data not shown). All patients were included in this analysis.
Of the 633 enrolled patients, 326 were randomly assigned to standard chemotherapy (133 chose CMF, 184 chose doxorubicin plus cyclophosphamide, and 9 withdrew before choosing a regimen) and 307 were randomly assigned to capecitabine; 13 patients (9 in the standard-chemotherapy group and 4 in the capecitabine group) never received the assigned therapy. lists the characteristics of the patients. The two groups were balanced except for a slight imbalance in tumor size (P=0.04). Approximately two thirds of the patients were 70 years of age or older, and about 5% were 80 years of age or older. Most had an excellent performance status (i.e., they were ambulatory and without symptoms), 11% were black, two thirds had hormone-receptor–positive tumors, 10% had HER2-positive tumors, and 70% had positive lymph nodes; about half the tumors were more than 2 cm in diameter. The protocol was amended in 2006 to recommend trastuzumab therapy for patients with HER2-positive tumors; 8 of the 10 patients with HER2-positive disease who were subsequently enrolled received trastuzumab.
Baseline Characteristics of the Patients.*
shows the rates of relapse-free survival, relapse, overall survival, and death, as well as the causes of death. At a median follow-up of 2.4 years, the rates of both relapse and death in the capecitabine group were nearly twice those in the standard-chemotherapy group. The most common cause of death in the capecitabine group was breast cancer (in 18 of 38 patients [47%]), whereas in the standard-chemotherapy group the most common causes of death were other cancer or cardiovascular disease (in 12 of 24 patients [50%]). shows the results of the multivariate analysis. The treatment group was significantly predictive of relapse-free survival, even after adjusting for tumor size, the number of positive lymph nodes, and hormone-receptor status. In this model, based on 622 patients, of whom 16% had disease recurrence, the hazard ratio for recurrence in the capecitabine group was twice that in the standard-chemotherapy group (hazard ratio, 2.09; P<0.001). In addition, a larger tumor, a larger number of positive nodes, and a negative hormone-receptor status were associated with a significantly higher risk of relapse (P=0.05, P=0.004, and P<0.001 for the three comparisons, respectively). shows the Kaplan–Meier plot of relapse-free survival according to treatment group, without adjustment for other clinical variables.
Outcomes at a Median Follow-up of 2.4 Years.*
Results of Multivariate Analysis of Relapse-free and Overall Survival among 622 Patients.*
Kaplan–Meier Estimates of Relapse-free and Overall Survival According to Treatment Group
also shows results of the multivariate model of overall survival. After adjustment for standard covariates, patients assigned to capecitabine had a risk of death that was nearly twice that for patients who were assigned to standard chemotherapy (hazard ratio, 1.85; P = 0.02). As compared with smaller tumors and hormone-receptor–positive tumors, larger tumors and hormone-receptor–negative tumors were associated with significantly shorter survival (P = 0.02 and P<0.001, respectively). shows a Kaplan–Meier plot of overall survival according to treatment group. Estimates of relapse-free survival and overall survival at 3 years indicate the advantage of standard chemotherapy, as compared with capecitabine (relapse-free survival, 85% vs. 68%; overall survival, 91% vs. 86%). We have not directly compared doxorubicin plus cyclophosphamide with CMF because these regimens were not randomly assigned. However, the comparisons of capecitabine with doxorubicin plus cyclophosphamide or CMF are qualitatively the same (data not shown).
shows the comparison of the benefits of capecitabine with those of standard chemotherapy in women with hormone-receptor–positive tumors and in those with hormone-receptor-negative tumors. The interaction between treatment and hormone-receptor status in this post hoc analysis was significant for both relapse-free survival and overall survival. Among patients with hormone-receptor–negative tumors who received capecitabine, the risk of relapse was more than quadrupled (hazard ratio, 4.39; 95% confidence interval [CI], 2.9 to 6.7; P<0.001), and the risk of death was more than tripled (hazard ratio, 3.76; 95% CI, 2.23 to 6.34; P<0.001), as compared with patients in all other study groups combined. There was no significant interaction between treatment group and relapse-free survival or overall survival for patients with hormone-receptor–positive tumors.
shows the incidence of grade 3, 4, and 5 adverse events that were possibly, probably, or definitely related to treatment. There were two drug-related deaths in the capecitabine group. Of the patients who received CMF, 70% had at least one grade 3 or grade 4 adverse event, as compared with 60% of patients who received doxorubicin plus cyclophosphamide and 34% of patients who received capecitabine. Among patients who received CMF or doxorubicin plus cyclophosphamide, 52% and 54%, respectively, had hematologic grade 3 or grade 4 toxic effects, but only 2% of the capecitabine group had such toxic effects. A nonhematologic grade 3 or grade 4 adverse event occurredin 41% of patients who received CMF, 25% of those who received doxorubicin plus cyclophosphamide, and 33% of those who received capecitabine. Two patients receiving doxorubicin plus cyclophosphamide required red-cell transfusions. Congestive heart failure developed in one patient receiving CMF and in none of the patients receiving doxorubicin plus cyclophosphamide; myelodysplasia developed in one patient receiving capecitabine. A total of 62% of the patients in the CMF group, 92% of the patients in the doxorubicin-cyclophosphamide group, and 80% of the patients in the capecitabine group received all planned cycles of treatment.
Grade 3, 4, or 5 Adverse Events.*
In a preplanned substudy, capecitabine adherence was assessed in 161 patients using pill bottles with microelectronic monitoring. Adherence was defined as the number of doses taken divided by the number of doses planned. Compliance was defined as receipt of 80% or more of planned doses. Of these patients, 76% took more than 80% of the planned doses and 14% took 60 to 79% of the planned doses. The clinical characteristics of these patients were similar to those of the patients in the entire capecitabine population. Age was not related to adherence.22