Adjuvant Trastuzumab Duration for HER-2-Positive Breast Cancer
Adjuvant Trastuzumab Duration for HER-2-Positive Breast Cancer
Between June 2004 and May 2012, 493 patients were assessed for eligibility, of whom 481 (98%) were eligible for the study. Seven patients did not meet all the eligibility criteria and five patients withdrew their consent. Therefore, 481 patients were centrally randomized to receive either 12-month (n = 241 patients) or 6-month (n = 240 patients) trastuzumab treatment (Figure 1; CONSORT diagram of the study). The two patient groups were well-balanced regarding their prognostic characteristics ( Table 1 ). The only difference was the slightly older median age of women in the 6-month treatment group (56 versus 54 years, P = 0.008). Approximately 21% of the patients had node-negative disease, while 14% had more than 10 infiltrated axillary nodes. The tumor expressed ER, PR, or both in roughly 67% of patients and was negative for both in 33%.
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Figure 1.
CONSORT diagram of the trial.
The proportion of women who received all eight cycles of chemotherapy was 99.6% versus 97.9% for the 12- and 6-month groups (P = 0.112), respectively. Treatment-related adverse events was the only reason for chemotherapy discontinuation. These were an allergic reaction to docetaxel (n = 1), febrile neutropenia with skin rash (n = 1), atrial fibrillation (n = 1), hepatitis (n = 1), neutropenia grade III with asthenia (n = 1). The proportion of women who completed the postchemotherapy trastuzumab was 100% versus 96.2% for the 12- and 6-month groups (P = 0.002), respectively. The reasons for trastuzumab discontinuation were patient refusal to continue (n = 4), atrial fibrillation (n = 1), hepatitis (n = 1), borderline LVEF of 50% (n = 1), local complication of surgery required a second procedure (n = 1), and early disease relapse (n = 1).
After a median follow-up of 47 and 51 months, 17 (7.1%) and 28 (11.7%) patients had disease recurrence in the 12- and 6-month group, respectively (P = 0.08). The majority of patients experienced a distant relapse (15 and 21 in the 12- and 6-month groups, respectively), 1 patient in the 12-month group developed contralateral breast cancer, while 6 patients in the 6-month group developed locoregional recurrence. Ten (4.1%) and eight (3.3%) patients had died (P = 0.6) in the 12- and 6-month groups, respectively, with all but one death in each arm to be related to breast cancer. Although the median DFS has not yet been reached, there was no significant difference between the 12- and the 6-month treated groups (HR = 1.57; 95% CI 0.86–2.10; P = 0.137). Figure 2A illustrates the Kaplan–Meier curves for DFS in the two treatment groups. The 3-year DFS rates were 95.7% and 93.3% for the 12- and 6-month groups, respectively. Similarly, there was no difference in the OS between the two groups (P = 0.436; Figure 2B). A univariate forest plot including patient, disease, and treatment characteristics related to DFS is illustrated in Figure 3.
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Figure 2.
(A) Disease-free survival and (B) overall survival for the two treatment groups.
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Figure 3.
Univariate forest plot including patient, disease, and treatment characteristics related to disease-free survival.
A summary of clinically relevant grade II–IV toxicities is presented in Table 2 . Serious adverse events were very rare. Early stopping of postchemotherapy trastuzumab due to toxicities was not reported in the 12-month group and occurred in only two patients (0.8%) in the 6-month group. These interruptions were due to atrial fibrillation and decreased LVEF to 50% in two patients. Cardiac toxicity did not differ between the two arms. No toxic deaths were reported.
Results
Patients
Between June 2004 and May 2012, 493 patients were assessed for eligibility, of whom 481 (98%) were eligible for the study. Seven patients did not meet all the eligibility criteria and five patients withdrew their consent. Therefore, 481 patients were centrally randomized to receive either 12-month (n = 241 patients) or 6-month (n = 240 patients) trastuzumab treatment (Figure 1; CONSORT diagram of the study). The two patient groups were well-balanced regarding their prognostic characteristics ( Table 1 ). The only difference was the slightly older median age of women in the 6-month treatment group (56 versus 54 years, P = 0.008). Approximately 21% of the patients had node-negative disease, while 14% had more than 10 infiltrated axillary nodes. The tumor expressed ER, PR, or both in roughly 67% of patients and was negative for both in 33%.
(Enlarge Image)
Figure 1.
CONSORT diagram of the trial.
Treatment
The proportion of women who received all eight cycles of chemotherapy was 99.6% versus 97.9% for the 12- and 6-month groups (P = 0.112), respectively. Treatment-related adverse events was the only reason for chemotherapy discontinuation. These were an allergic reaction to docetaxel (n = 1), febrile neutropenia with skin rash (n = 1), atrial fibrillation (n = 1), hepatitis (n = 1), neutropenia grade III with asthenia (n = 1). The proportion of women who completed the postchemotherapy trastuzumab was 100% versus 96.2% for the 12- and 6-month groups (P = 0.002), respectively. The reasons for trastuzumab discontinuation were patient refusal to continue (n = 4), atrial fibrillation (n = 1), hepatitis (n = 1), borderline LVEF of 50% (n = 1), local complication of surgery required a second procedure (n = 1), and early disease relapse (n = 1).
Disease-free and Overall Survival
After a median follow-up of 47 and 51 months, 17 (7.1%) and 28 (11.7%) patients had disease recurrence in the 12- and 6-month group, respectively (P = 0.08). The majority of patients experienced a distant relapse (15 and 21 in the 12- and 6-month groups, respectively), 1 patient in the 12-month group developed contralateral breast cancer, while 6 patients in the 6-month group developed locoregional recurrence. Ten (4.1%) and eight (3.3%) patients had died (P = 0.6) in the 12- and 6-month groups, respectively, with all but one death in each arm to be related to breast cancer. Although the median DFS has not yet been reached, there was no significant difference between the 12- and the 6-month treated groups (HR = 1.57; 95% CI 0.86–2.10; P = 0.137). Figure 2A illustrates the Kaplan–Meier curves for DFS in the two treatment groups. The 3-year DFS rates were 95.7% and 93.3% for the 12- and 6-month groups, respectively. Similarly, there was no difference in the OS between the two groups (P = 0.436; Figure 2B). A univariate forest plot including patient, disease, and treatment characteristics related to DFS is illustrated in Figure 3.
(Enlarge Image)
Figure 2.
(A) Disease-free survival and (B) overall survival for the two treatment groups.
(Enlarge Image)
Figure 3.
Univariate forest plot including patient, disease, and treatment characteristics related to disease-free survival.
Adverse Events
A summary of clinically relevant grade II–IV toxicities is presented in Table 2 . Serious adverse events were very rare. Early stopping of postchemotherapy trastuzumab due to toxicities was not reported in the 12-month group and occurred in only two patients (0.8%) in the 6-month group. These interruptions were due to atrial fibrillation and decreased LVEF to 50% in two patients. Cardiac toxicity did not differ between the two arms. No toxic deaths were reported.