Clinical trialBreast cancer

Adjuvant Capecitabine for Breast Cancer after Preoperative Chemotherapy

N Engl J Med · 2017910 patients

Masuda N, Lee SJ, Ohtani S, Im YH, Lee ES, Yokota I, et al. N Engl J Med. 2017. 376:2147-2159

Study type: Clinical trial
Study name: CREATE-X
Design: Randomised, controlled trial (registration number UMIN000000843); stopped early because the primary endpoint was met at a prespecified interim analysis
Sample size: 910 patients
Source: N Engl J Med · 2017

In plain words

In some patients with breast cancer, some cancer cells can still be seen in the removed tissue after chemotherapy given before surgery, and the risk of the disease coming back is higher. In this study, adding the chemotherapy tablet capecitabine after surgery meant patients stayed free of the disease for longer and lived longer. This benefit was most noticeable in patients with triple-negative breast cancer. The most common side effect was hand-foot syndrome (skin changes on the palms and soles). Treatment should only be given on the advice of the treating doctor.

Key results

74.1% vs 67.6%

Disease-free survival at 5 years (all patients)

HR for recurrence, second cancer or death 0.70; 95% CI 0.53–0.92; P=0.01

89.2% vs 83.6%

Overall survival at 5 years (all patients)

HR for death 0.59; 95% CI 0.39–0.90; P=0.01

69.8% vs 56.1%

Disease-free survival in triple-negative patients

HR 0.58; 95% CI 0.39–0.87

78.8% vs 70.3%

Overall survival in triple-negative patients

HR 0.52; 95% CI 0.30–0.90

Drugs in this study:Capecitabine (Xeloda)

Dose and schedule cards

Adjuvant capecitabine (CREATE-X)

HER2-negative breast cancer with residual invasive disease after neoadjuvant chemotherapy containing an anthracycline and/or a taxane; greatest benefit in triple-negative diseaseCycle length: Every 21 daysOn the page “Breast cancer” · Early HER2-negative disease: chemotherapy, immunotherapy and adjuvant therapy

HER2-negative breast cancer with residual invasive disease after neoadjuvant chemotherapy containing an anthracycline and/or a taxane; greatest benefit in triple-negative disease

Drug	Dose	Route	Schedule
Capecitabine	1250 mg/m² twice daily	Oral	Days 1–14

Cycle length: Every 21 days
Duration: 6 to 8 cycles

CREATE-X dose and schedule from a published review of post-neoadjuvant trials. Pan-Asian ESMO: for residual disease in patients who have not received an immune checkpoint inhibitor, 6 to 8 cycles of capecitabine [I, A]; the combination of olaparib and capecitabine in BRCA carriers is not recommended [I, E]; for residual disease after ICI-containing neoadjuvant therapy, concurrent ICI and capecitabine may be considered on an individual basis [V, C].

Before starting: DPYD genetic testing (complete DPD deficiency carries a risk of fatal toxicity, and capecitabine should be avoided in these patients). Kidneys: reduce the dose by 25% for CrCl 30 to 50 mL/min; no dose has been established for CrCl below 30. With vitamin K antagonists (such as warfarin), the risk of bleeding increases (boxed warning).

On the page “Breast cancer” · Early HER2-negative disease: chemotherapy, immunotherapy and adjuvant therapy

Capecitabine (CREATE-X)

HER2-negative breast cancer with residual disease after surgeryCycle length: Every 21 daysOn the page “Adjuvant capecitabine after neoadjuvant treatment (CREATE-X)”

HER2-negative breast cancer with residual disease after surgery

Drug	Dose	Route	Schedule
Capecitabine	1250 mg/m² twice a day	Oral, after food	Days 1 to 14

Cycle length: Every 21 days
Duration: 6 to 8 cycles

Dose as in CREATE-X.

Dose source:.

On the page “Adjuvant capecitabine after neoadjuvant treatment (CREATE-X)”

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Capecitabine group

Standard postoperative treatment plus capecitabine 1250 mg/m² orally twice daily, days 1 to 14 every 3 weeks, for 6 to 8 cycles.

2Control group

Standard postoperative treatment without capecitabine (including endocrine therapy in HR-positive tumours).

Source of the regimen details: Published review of post-neoadjuvant trials (Matuschek et al., Cancers 2022; PMC8909560, Table 1) reporting the CREATE-X dose; the full text of the original paper is not open access

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Patients with HER2-negative invasive breast cancer who had residual invasive disease after preoperative (neoadjuvant) chemotherapy containing an anthracycline, a taxane or both.

Endpoints

Primary endpoint: disease-free survival (DFS). Secondary endpoints: including overall survival (OS).

Safety and side effects

Hand-foot syndrome was the most common adverse event of capecitabine and occurred in 73.4% of patients in the capecitabine group. The authors conclude that adding capecitabine was safe. The rate of grade 3 or higher adverse events is not given in the abstract.

Clinical significance and place in guidelines

This trial shows that in patients with HER2-negative breast cancer with residual invasive disease after neoadjuvant chemotherapy (containing an anthracycline, a taxane or both), adding adjuvant capecitabine improves disease-free and overall survival; the effect was marked in the triple-negative subgroup. Its place in clinical guidelines and drug approval status should be checked against up-to-date sources, as the abstract gives no information on them.

Limitations

The trial was stopped early because the primary endpoint was met at the interim analysis. The abstract gives no information on the rate of grade 3 or higher adverse events or the exact drug dose, and these should be checked in the full text of the paper. Results for the triple-negative subgroup are reported in the abstract with confidence intervals but no P value.

Original article (DOI)PubMed

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.