Safety and Relative Dose Intensity of Dose-dense Doxorubicin and Cyclophosphamide Followed by Dose-dense Paclitaxel

Results

Patient characteristics. Patient characteristics are summarized in Table I. The median age of the patients was 51.5 years (age range=34-69 years). All patients belonged to Eastern Cooperative Oncology Group performance status (ECOG PS) 0 or 1. Stage IIA, IIB, and IIIA accounted for 77.3% of cases; 75% of cases were ER/PgR⁺, HER2⁻, and 25% were ER/PgR⁻, HER2⁻. The neoadjuvant setting was represented by 43.2% of the cases.

Hospitalization for monitoring. Treatment-related death was not observed. To be on the safe side, patients with adverse events were proactively hospitalized for effective monitoring. As a result of this policy, the recovery of five patients with adverse events was monitored by maintaining them as inpatients. Three patients with fever (grade 2 fever on day 15 of the 4th cycle of ddAC, grade 1 fever on day 15 of the 1st cycle of ddP, and grade 1 fever on day 16 of the 2nd cycle of ddP), one patient with dizziness (grade 2 on day 7 of the 4th cycle of ddAC), and one patient with pneumonitis (grade 3 on day 18 of the 4th cycle of ddAC) were hospitalized for approximately 1 week. Four of the five patients rapidly recovered after being treated only with hydration. None of them received intensive care, such as vasopressor therapy or respiratory management. One patient with pneumonitis received oxygen for 3 days and was discharged after 6 days of hospitalization.

Adverse events. Adverse events are summarized in Table II. The common (≥50%) non-hematological toxicities were peripheral neuropathy (90.5%) and arthritis/myalgia (79%). Most of these were grade 1 or 2, with only two patients experiencing grade 3 peripheral neuropathy. None of the patients experienced grade 3 or 4 arthritis/myalgia. Eight (18.2%) patients had fever, and all were either grade 1 or 2. The most common hematological toxicity was lymphopenia (52.3%). The patients neither experienced febrile neutropenia (FN) nor did they require blood transfusion. One patient (2.3%) on ddP developed grade 2 pneumonitis; we could not exclude Pneumocystis jiroveci pneumonia (PCP) owing to the presence of a ground-glass pattern on computed tomography (CT) images; hence, a treatment course of trimethoprim/sulfamethoxazole (TMP/SMX) (15 mg/kg) was initiated. However, serum β-D-glucan levels did not increase, and the patient recovered 7 days later in the absence of steroid treatment. One patient (2.3%) on ddAC developed grade 3 pneumonitis. We suspected PCP or interstitial lung disease (ILD) because of the ground-glass pattern observed on CT, and the patient recovered following a course of TMP/SMX without steroids. Bronchoscopy was not performed, which precluded a definitive diagnosis. Nevertheless, serum β-D-glucan levels did not increase, suggesting that ILD was more probable than PCP.

Treatment discontinuation, dose delay, and dose reduction. ddP was discontinued in cycle 1 in one patient (2.3%), because of strong anxiety after the development of grade 2 pneumonitis. Treatment delay occurred in 34.1% of ddAC-treated patients and in 31.8% of ddP-treated patients. The major reasons for delaying ddAC therapy were holiday (33.3%, 5/15), grade 1/2 fever in cycles 1, 3, and 4 (33.3%, 5/15), and grade 1/2 upper respiratory infection (13.3%, 2/15) in cycles 1 and 2. The prime factors for delaying ddP treatment were holiday (35.7%, 5/14) and grade 1 fever in cycles 1 and 2 (28.6%, 4/14).

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Figure 1.

The mean percent relative dose intensity (RDI) per treatment cycle. Black bars represent ddAC and gray bars represent ddP. The mean RDI of cycles 1-4 were 98%, 97.2%, 96.6%, and 93.2% for ddAC, and 95.6%, 93.3%, 92.9%, and 92.6% for ddP, respectively.

Although no dose reduction occurred in the ddAC-treated patients, it was required in 22.7% (n=10) of the ddP-treated patients. The major contributing factors were grade 2/3 peripheral sensory neuropathy (80%) during cycle 2 (1/8), cycle 3 (3/8), and cycle 4 (4/8). Additionally, dose reduction was required in one patient for grade 2 myalgia.

RDI. The mean percent of RDIs per treatment cycle are shown in Figure 1. The mean values for ddAC-P, ddAC, and ddP were 95.0%, 94.5%, and 93.3%, respectively. The percentage of prevalence of high RDI (≥85%) for ddAC-P, ddAC, and ddP was 90.9%, 84.1%, and 88.6%, respectively. Low RDI was observed in 10 patients owing to grade 1 or 2 fever (7/10; Table III).

The risk factors that may account for the low RDI were also investigated. The proportion of elderly patients (>65 years) with low RDI vs. high RDI for ddAC were 28.6% (2/7) vs. 8.1% (3/37) (odds ratio 4.7, p=0.15; Fisher's exact test). Although the difference was not significant, the trend suggests that elderly patients may be at risk of low RDI. Eight patients developed grade 1 or 2 fever. Seven of the eight patients (87.5%) with fever suffered from low RDI.

Treatment efficacy. Among the 19 patients who received ddAC-P as neoadjuvant chemotherapy, the clinical complete response (cCR) rate and clinical partial response (cPR) rates were 15.8% (n=3) and 68.4% (n=13), respectively. In the neoadjuvant setting, the rate of lumpectomy was 21.1% (n=4).

The median duration of follow-up was 17.8 months, and all patients survived without recurrence.