Clinical trial focused exclusively on TNBC patients
Current breast cancer treatment guidelines suggest that capecitabine (Xeloda) should be considered for adjuvant treatment after standard neoadjuvant therapy with taxane- and anthracycline-based chemotherapy. However, although randomized trials have evaluated capecitabine as adjuvant treatment in breast cancer overall as well as in elderly patients, none have focused solely on patients with triple-negative breast cancer (TNBC).
Evidence for the efficacy and safety of adjuvant capecitabine concomitant use with standard chemotherapy for TNBC is limited, and this is a key unmet need for clinicians when determining optimal therapeutic strategies for their patients, said Junjie Li, MD, of Fudan University Shanghai Cancer Center in China, and colleagues, writing in the Journal of Clinical Oncology. They conducted the randomized, open-label, phase III CBCSG010 clinical trial, which included 585 patients with TNBC. They were assigned to either capecitabine (three cycles of capecitabine and docetaxel followed by three cycles of capecitabine, epirubicin, and cyclophosphamide) or a control treatment (three cycles of docetaxel followed by three cycles of fluorouracil, epirubicin, and cyclophosphamide).
At a median follow-up of 67 months, the 5-year disease-free survival (DFS) rate was higher for patients receiving capecitabine than for those on the control treatment (86.3% vs 80.4%, HR 0.66, 95% CI 0.44-0.99, P=0.044). “The results of our study indicate that capecitabine concomitantly used with docetaxel and epirubicin (XT-XEC) is an alternative adjuvant regimen for TNBC, with clinically meaningful improvement in disease-free survival and modest toxicity,” the researchers concluded.
In the following interview, Li discussed the dosage and design of the regimen used in the trial, additional benefit in patient subgroups, and safety and tolerability issues.
For CBCSG010, you selected a regimen for optimal capecitabine treatment benefit while minimizing toxicity — what was the thinking behind that?
Li: The regimen was XT: capecitabine plus docetaxel (capecitabine 1,000 mg/m2 bid, d1-14; docetaxel 75 mg/m2 q3w) for three cycles, followed by XEC: capecitabine, epirubicin, and cyclophosphamide (capecitabine 1,000 mg/m2 bid, d1-14; epirubicin 75 mg/m2, and cyclophosphamide 500 mg/m2 q3w) for three cycles.
Currently, adjuvant taxane- and anthracycline-based chemotherapy is the standard of care. Previous studies showed a moderate reduction in 10-year risk of recurrence and death with an increase in the dose intensity and density of adjuvant chemotherapy, especially for TNBC. However, increase in the dose intensity and density may also reduce the tolerance of treatment. So the positive result of CBCSG010 indicated that capecitabine concomitantly used with XT-XEC is an alternative adjuvant regimen for TNBC, with clinically meaningful improvement in DFS and modest toxicity.
We hope guidelines will change after CBCSG010, listing this new chemotherapy option, that capecitabine concomitantly used with docetaxel and epirubicin is an alternative adjuvant regimen for TNBC.
Was capecitabine therapy especially beneficial in any patient subgroups in your trial?
Li: Our trial had no pre-set stratification factors; we found that capecitabine benefits for DFS were consistent across patient subgroups, as treatment effect interactions were not significant for any of the subgroups considered. However, patients with high risk (such as node positive disease) may benefit more when adding capecitabine, with HR 0.51 (0.29 to 0.90).
What is known about the mechanism of action of capecitabine in patients with breast cancer?
Li: Capecitabine, an oral prodrug of fluorouracil, is metabolized in the liver and malignant tumors and is ultimately converted to cytotoxic fluorouracil by thymidine phosphorylase (TP), which is highly expressed in breast tumors. In xenograft models, administration of docetaxel, paclitaxel, or cyclophosphamide boosted TP expression in tumor tissue, which suggests possible synergy with capecitabine. Other possible mechanisms might be:
- TNBC may be more sensitive to capecitabine treatment: Subgroup analysis in patients with TNBC (USON 01062) demonstrated that four cycles of capecitabine (concomitantly with docetaxel) suggest benefit in overall survival from the addition of capecitabine. Exploratory analysis in the FinXX trial showed that use of six cycles of additional capecitabine was associated with longer relapse-free survival
- Concomitant use or sequential monotherapy: The CREATE-X trial demonstrated improved survival with the addition of adjuvant capecitabine monotherapy in HER2-negative patients with residual invasive disease after standard neoadjuvant chemotherapy, particularly in the TNBC subpopulation. GEICAM 2003-11 in the overall TNBC population after standard adjuvant chemotherapy evaluated sequential monotherapy of capecitabine, showed that capecitabine did not significantly increase DFS, while CBCSG010, along with FinXX and USON 01062, showed that concomitant use of capecitabine significantly improved DFS in TNBC.
What safety and tolerability issues did you encounter in your trial?
Li: The most common grade 3 hematologic toxicities were neutropenia (in 136 patients on capecitabine [45.8%] and 118 control patients [41.0%]) and febrile neutropenia (capecitabine, 50 patients [16.8%]; control, 46 patients [16.0%]). Patients who received capecitabine had a higher incidence (52.5%) of hand-foot syndrome, of which 8.4% was grade 3. More patients treated with capecitabine had grade 3 stomatitis (5.1% v 1.0%), and no patients died during chemotherapy.
Overall, 85% of patients completed all six planned chemotherapy cycles, 113 patients (39.1%) had capecitabine dose reductions, seven required a capecitabine dose reduction to 750 mg/m2, and all others had a dose reduction to 900 mg/m2 or 825 mg/m2.
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