CREAT-X, Capcetabine for Residual Cancer as Adjuvant Therapy trial is the first of it’s kind to look into further adjuvant chemotherapy in patients who received neoadjuvant chemotherapy.
Capecitabine adjuvant therapy is beneficial in Her2-negative Breast cancer with residual disease following Neoadjuvant therapy.
Background: I discussed neoadjuvant chemotherapy, at this moment the standard of care for patients who had residual disease following neoadjuvant chemotherapy does not include any further chemotherapy. This is may be the first study to evaluate the benefit of further chemotherapy in such patients in improving disease-free survival and overall survival.
Study design: this was an open-label, multicenter study (in Japan and South Korea) randomized phase 3 trial. The study population were patients with the following eligibility criteria
- HER2-negative breast cancer.
- Stage I-IIIB before neoadjuvant therapy and surger.y
- Age 20-74 years.
- Received neoadjuvant chemotherapy with Anthracycline or taxane or both, followed by surgery.
- Continue to have a Residual disease.
Residual disease was defined as no complete response on pathological assessment or a complete response with positive lymph nodes. All patients i.e. the capecitabine arm and the control arm received standard therapy as indicated in the form of radiation therapy or endocrine therapy. Eligible patients were centrally randomized (1:1 between both arms) with balancing adjustment for tumor size at diagnosis, age, hormonal status(ER-positive vs ER-negative, neoadjuvant therapy type received, and also balanced with regard need or no need for endocrine therapy and or radiation therapy.
The capecitabine dose was 1250/metered squared, twice a day, on days 1-14 q21 days, for six to eight cycles.
|Capcitabine plus standard therapy||Standard therapy only|
|3 years DFS||82.8%||73.9%|
|5 years DFS||74.1%||67.6%|
|HR 0.70, 95% CI|
CI, 0.53 TO 0.92; P=0.01
|3 years overall |
|5 years overall|
|HR 0.59; 95% CI|
CI, 0.39 to 0.90; P=0.01
The basic results are summarized in the table above. At pre-specified interim analysis the primary endpoint of the study, disease-free survival (DFS), was met and the study was terminated. The benefit of adding capecitabine in DFS and overall survival was seen in all subgroups i.e. hormone positive as well as hormone negative, for actual HR please refer to the study publication. The side effects noted and listed in the publication are the expected side effects of the capecitabine namely hand-foot syndrome and the usual hematologic toxicity, severe toxicity was noted rarely. The investigators recommend attention to the different pharmacokinetic profile of capecitabine between Asian and non-Asian patients and consideration of necessary dose modification when capecitabine used in Western patient population.
Summary: In this study, adjuvant capecitabine was shown to prolong disease-free survival and overall survival in HER2 negative patient who had residual disease following neoadjuvant therapy.
Conclusion: this is definitely a thought-provoking, and if confirmed by future trials it may lead to practice changing. Up till now breast cancer patients who have a high risk of recurrence are recommended to receive either neoadjuvant chemotherapy i.e. chemotherapy before definitive surgery or adjuvant chemotherapy i.e. chemotherapy after surgery. The literature indicates that there is no difference in overall survival between either neoadjuvant chemotherapy or adjuvant chemotherapy. This study is showing that in a specific subset of patients who received neoadjuvant chemotherapy overall survival can be further improved. As I mentioned above if this study is confirmed I can definitely see practice change not only in offering the HER2-negative patient with residual disease further adjuvant chemotherapy but actually more high-risk HER2-negative patients treated initially with neoadjuvant chemotherapy. The CREAT-X study was published in NEJM and citation link can be found here.