Low Risk of CHF With Paclitaxel/Trastuzumab Adjuvant Rx

SAN ANTONIO—In the treatment of breast cancer, cardiomyopathy has represented a possible barrier to the use of trastuzumab (Herceptin) in the adjuvant setting. But a study by the Eastern Cooperative Oncology Group (ECOG) now suggests the risk is small when trastuzumab is combined with paclitaxel (Taxol), and, for the most part, cardiac changes are reversible.

George W. Sledge, MD, professor of medicine, Indiana University School of Medicine, presented the results at the 24th Annual San Antonio Breast Cancer Symposium (abstract 4). ECOG 2198 examined the cardiac effects of paclitaxel plus trastuzumab (TH) given prior to doxorubicin plus cyclophosphamide (AC) in 234 HER-2-positive (2+ or 3+) stage II breast cancer patients.

Patients were randomized to paclitaxel 175 mg/m² every 3 weeks for 4 weeks plus trastuzumab for 10 weeks followed by AC (60/600 mg/m²) every 3 weeks for 4 weeks, or to the same treatment with trastuzumab given for 52 weeks.

"We now know that the underlying hypothesis about Herceptin clearance was probably incorrect," Dr. Sledge pointed out. "Patients who got Herceptin for 10 weeks probably still had a significant amount of Herceptin on board when they got AC."

The endpoints were the rate of clinical congestive heart failure (CHF) and greater than 10% absolute decline in left ventricular ejection fraction (LVEF).

Four Cases of CHF

At 15 months median follow-up, there were four cases of clinical CHF during treatment (1.7%), including one patient during TH and three after receiving the AC regimen. There were no cardiac fatalities. "It’s instructive to look at these four events," Dr. Sledge said, describing the CHF patients, all of whom had predisposing factors for organic heart disease:

Patient #1 was a 58-year-old woman with a history of left bundle branch block and hyperlipidemia. She had a family history for early-onset coronary artery disease (CAD) and a baseline LVEF of 54%. While on weekly trastuzumab, she developed a septal infarct with dilated cardiomyopathy and a drop in LVEF of 20%. She had a subsequent LVEF recovery to 51%.

Patient #2 was a 71-year-old cigarette smoker with a history of CAD and a baseline LVEF of 70%. While on TH, she developed severe dyspnea on exertion, her LVEF declined to 45%, and she developed ST T-wave abnormalities on ECG. Off study, her LVEF recovered to 50% to 60%. She subsequently relapsed and was placed on trastuzumab, an ACE inhibitor, and a diuretic.

Patient #3 was a 54-year-old woman with a prior history of myocardial infarction, hypertension, and hyperlipidemia, with a baseline LVEF of 61.5%. While on weekly trastuzumab, she developed dyspnea and orthopnea; her LVEF declined to 39%, and she was found to have an anteroseptal myocardial infarction on ECG. She relapsed and has been treated with vinorelbine (Navelbine) and trastuzumab.

Patient #4 was a 78-year-old woman with prior history of CAD and a baseline LVEF of 75%. Following four cycles of AC, she developed dyspnea and edema; she had cardiomegaly on chest x-ray and an LVEF of 51%. Her symptoms subsequently resolved while continuing on therapy.

Drops in LVEF

For 214 patients , LVEF was measured pre- and post-TH. Mean pretreatment LVEF was 63%, dropping to 61% after TH. Twenty patients (9%) had a drop of over 10% in LVEF, and for the majority of these patients, their LVEF recovered despite going on to AC therapy. Six patients (2.8%) had an LVEF drop below the lower limits of normal. For 182 patients with LVEF measured pre- and post-AC, LVEF dropped from 63% at baseline to 59% post-AC. Twenty four patients (13%) had a drop of LVEF of greater than 10%, and 11 patients (6%) had a drop below the lower limits of normal.

The researchers concluded that paclitaxel plus trastuzumab followed by AC was associated with a "low but real" incidence of CHF (less than 2% in this trial). More commonly, there was an asymptomatic decline in LVEF, Dr. Sledge said.