Clinical trialBreast cancer

Trastuzumab plus Adjuvant Chemotherapy for Operable HER2-Positive Breast Cancer

N Engl J Med · 2005Number of patients not stated in the abstract (394 events reported at the first interim analysis)

Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE, Davidson NE, et al. N Engl J Med. 2005. 353:1673-1684

Study type: Clinical trial
Study name: NSABP B-31 / NCCTG N9831
Design: Joint analysis of two comparative trials (NSABP B-31 and NCCTG N9831) of adjuvant chemotherapy with or without concurrent trastuzumab
Sample size: Number of patients not stated in the abstract (394 events reported at the first interim analysis)
Source: N Engl J Med · 2005
Trial registration: NCT00004067, NCT00005970

In plain words

This research combined the results of two large studies in women with HER2-positive breast cancer whose tumour had been removed by surgery. Adding the drug trastuzumab to chemotherapy after surgery greatly lowered the risk of the cancer coming back or of death. At 3 years, 12% more patients were free of the cancer coming back, and the risk of death was 33% lower. Trastuzumab can affect the heart, so heart function should be monitored during treatment.

Key results

133 events in the trastuzumab group vs 261 events in the control group (total 394)

Number of events (recurrence, second primary cancer or death before recurrence) up to 15 March 2005

First planned interim analysis

0.48

Hazard ratio for disease-free survival

P<0.0001; crossed the early stopping boundary

12%

Absolute difference in disease-free survival at 3 years

In favour of the trastuzumab group

33%

Reduction in risk of death

P=0.015

4.1% in B-31 and 2.9% in N9831

3-year cumulative incidence of class III or IV congestive heart failure or cardiac death (trastuzumab group)

Comparison with the control group not stated in the abstract

Drugs in this study:Cyclophosphamide (Endoxan)Doxorubicin (Adriamycin)Paclitaxel (Taxol)Trastuzumab (Herceptin)

Dose and schedule cards

AC then paclitaxel + trastuzumab (NSABP B31 / N9831)

HER2-positive breast cancer, adjuvant treatmentCycle length: —On the page “Trastuzumab (Herceptin)” · Dose and schedule (FDA label)

HER2-positive breast cancer, adjuvant treatment

Drug	Dose	Route	Schedule
4 cycles
Doxorubicin + cyclophosphamide	60 + 600 mg/m²	IV	Day 1 every 3 weeks
12 weeks
Paclitaxel	80 mg/m² weekly (or 175 mg/m² every 3 weeks in B31)	IV	Weekly
With the taxane
Weekly trastuzumab	Initial dose 4 mg/kg, then 2 mg/kg	IV infusion; initial 90 minutes, then 30 minutes	Weekly, 12 weeks
One week after the last weekly dose
Trastuzumab	6 mg/kg	IV infusion over 30 to 90 minutes	Every 3 weeks

Cycle length: —
Duration: Trastuzumab 52 weeks in total; continuing beyond one year is not recommended

Chemotherapy doses as described for the trials in the label.

On the page “Trastuzumab (Herceptin)” · Dose and schedule (FDA label)

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

1Control group (group 1 in B-31 and group A in N9831)

Doxorubicin and cyclophosphamide followed by paclitaxel. In B-31 paclitaxel was given every 3 weeks and in N9831 weekly.

Doxorubicin 60 mg/m² + cyclophosphamide 600 mg/m² every 21 days for 4 cycles, then paclitaxel for 12 weeks: in B-31 weekly 80 mg/m² or every 3 weeks 175 mg/m²; in N9831 weekly 80 mg/m² only. ER/PR-positive patients received hormone therapy.

2Trastuzumab group (group 2 in B-31 and group C in N9831)

The same chemotherapy regimen plus 52 weeks of trastuzumab, starting with the first dose of paclitaxel.

The same chemotherapy; trastuzumab 4 mg/kg on the day paclitaxel starts, then 2 mg/kg weekly for a total of 52 weeks.

3Group B in N9831 (excluded from the joint analysis)

The same chemotherapy regimen followed by 52 weeks of trastuzumab after completion of paclitaxel. This group was excluded from the joint analysis because trastuzumab was not given concurrently with paclitaxel.

Source of the regimen details: FDA label for Herceptin (DailyMed, section 14.1, NSABP B31 and NCCTG N9831)

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

Women with surgically removed HER2-positive breast cancer. Detailed eligibility criteria are not stated in the abstract.

Endpoints

Events of interest were recurrence, second primary cancer or death before recurrence (disease-free survival). The abstract also reports overall survival and the incidence of heart failure. Primary and secondary endpoints are not explicitly separated in the abstract.

Safety and side effects

The 3-year cumulative incidence of class III or IV congestive heart failure or death from cardiac causes in the trastuzumab group was 4.1% in trial B-31 and 2.9% in trial N9831. Other adverse events are not reported in the abstract.

Clinical significance and place in guidelines

Based on the abstract, adding 52 weeks of trastuzumab to adjuvant chemotherapy (doxorubicin and cyclophosphamide followed by paclitaxel) improves outcomes in operable HER2-positive breast cancer. Because of the risk of heart failure, cardiac monitoring is important. The status of this regimen in current guidelines and drug approvals should be checked in up-to-date sources, as the abstract says nothing about them.

Limitations

The abstract reports only the results of the first interim analysis and follow-up is still short. The number of patients, population characteristics and doses are not given in the abstract. Group B of N9831 (sequential trastuzumab) was excluded from the joint analysis. Cardiac statistics for the control group are not stated in the abstract.

Original article (DOI)PubMed ClinicalTrials.gov

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.