Effect of adjuvant carboplatin intensified chemotherapy versus standard chemotherapy on survival in women with high risk, early stage, triple negative breast cancer (CITRINE): randomised, open label phase 3 trial

1. Adjuvant carboplatin intensified chemotherapy was superior to standard chemotherapy in improving survival outcomes in patients with high-risk, early-stage, triple-negative breast cancer.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Although anthracycline-taxane sequential chemotherapy is the standard for adjuvant treatment in early-stage triple-negative breast cancer, approximately 30-40% of patients at high risk still experience disease recurrence. Platinum agents are cytotoxic, damaging DNA and leading to cell apoptosis. Platinum-based agents have been shown to increase the pathological complete response rate to neoadjuvant therapy in patients with triple-negative breast cancer. However, their impact on long-term survival remains controversial and requires further exploration. This study examined whether adding the platinum agent carboplatin to a standard adjuvant chemotherapy regimen of anthracyclines followed by weekly paclitaxel improves survival outcomes in patients with high-risk, early-stage, triple-negative breast cancer.

This randomised controlled trial included female patients aged 18-70 years with early-stage, high-risk, unilateral invasive triple-negative breast cancer in China. Patients were randomised 1:1 into either the carboplatin arm (epirubicin + cyclophosphamide followed by paclitaxel + carboplatin) or the control arm (epirubicin + cyclophosphamide followed by paclitaxel alone). The primary outcome was disease-free survival. Secondary outcomes included recurrence-free survival, distant disease-free survival, overall survival, and safety. Of the 808 patients enrolled, 398 (98.5%) patients in the control arm and 380 (94.1%) patients in the carboplatin arm completed chemotherapy. During a median follow-up of 44.7 months, the carboplatin arm had a higher estimated disease-free survival (93%) at three years than the control arm (85.8%) and had a 36% lower overall risk of disease recurrence or death, although this risk varied over time. The carboplatin arm was also associated with improved outcomes in three-year recurrence-free survival, three-year distant disease-free survival, and three-year overall survival.

Overall, this study found that adding carboplatin to adjuvant anthracycline/taxane-based chemotherapy improved survival outcomes in patients with high-risk, early-stage, triple-negative breast cancer.

Click to read the study in the BMJ

Relevant reading: Adjuvant chemotherapy for resected triple negative breast cancer patients: A network meta-analysis

In-Depth [randomised clinical trial]:

This randomised, open-label, phase 3, two-arm controlled trial included female patients aged 18-70 years with early-stage, operable, high-risk, unilateral invasive triple-negative breast cancer after definitive surgery from a cancer center in China between March 2020 and March 2022. Eligible patients were pathologically confirmed as either regional node positive or node negative with a Ki-67 index > 50%. Patients were randomised 1:1 into either the carboplatin arm or the control arm. The carboplatin arm included four cycles of two weekly epirubicin and cyclophosphamide followed by four cycles of weekly paclitaxel combined with carboplatin. The control arm included four cycles of three weekly or two weekly epirubicin and cyclophosphamide followed by four cycles of weekly paclitaxel alone. The primary outcome was disease-free survival, defined as the time from randomisation to the occurrence of a first local or regional or distant event, contralateral or second primary tumours, or death from any cause. Secondary outcomes included recurrence-free survival, distant disease-free survival, overall survival, and safety. Of the 808 patients enrolled, 404 were randomised to the carboplatin arm (mean [range] age = 47 [22-70] and 404 to the control arm (mean [range] age = 48 [24-70]). In total, 398 (98.5%) patients in the control arm and 380 (94.1%) patients in the carboplatin arm completed chemotherapy. During a median follow-up of 44.7 months, the carboplatin arm had a higher estimated disease-free survival (93%) at three years than the control arm (85.8%) and had a 36% lower overall risk of disease recurrence or death (hazard ratio (HR) 0.64, 95% confidence interval (CI) 0.43 to 0.95). During the first 12 months, the risk of disease recurrence in the carboplatin arm was 69% lower than the control arm (HR 0.31, 95% CI 0.13 to 0.73), but no statistically significant differences were observed for 12-36 months (HR 0.65, 95% CI 0.39 to 1.09) or beyond 36 months (HR 1.98, 95% CI 0.69 to 5.69). For secondary outcomes, the carboplatin arm was associated with improved outcomes in three-year recurrence-free survival (93.8% v 88.3%; HR 0.59, 95% CI 0.37 to 0.93), three-year distant disease-free survival (94.8% v 89.8%; HR 0.61, 0.37 to 0.98), and three-year overall survival (98.0% v 94.0%; HR 0.41, 0.20 to 0.83). Grade 3-4 treatment-related adverse events occurred in 66.7% of patients in the carboplatin arm and 55.0% in the control arm. Overall, this study found that adding carboplatin to adjuvant anthracycline/taxane-based chemotherapy improved survival outcomes in patients with high-risk, early-stage, triple-negative breast cancer, primarily by reducing the risk of early recurrence. Although a higher incidence of adverse events was observed with carboplatin, the safety profile was consistent with known safety profiles for carboplatin-containing chemotherapy. Strengths of this study include the focus on high-risk patients requiring adjuvant therapy, the use of an optimised control arm regimen, and subgroup analyses that consistently favoured the carboplatin arm. Some limitations of this study include some deviation from the current standard of care, the homogeneity of an all-Chinese population, and the open-label study design that may have introduced bias. Future long-term studies are needed to validate these findings in other populations. 

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