Overview Helps Clarify Nature of Herceptin-Related Cardiotoxicity

NEW YORK—An overview of clinical trials of trastuzumab (Herceptin) has provided additional evidence that the agent has cardiotoxic effects, especially when used with anthracycline chemotherapy, according to data presented at the San Antonio Breast Cancer Symposium.

The most notable findings of cardiotoxicity emerged from a trial that compared doxorubicin and cyclophosphamide (AC) with paclitaxel (Taxol). Both regimens were compared with and without Herceptin, which appeared to increase the incidence of cardiotoxicity regardless of which chemotherapeutic agent was used. The overall incidence of cardiotoxicity was 13%, including 27% in patients who received AC plus Herceptin.

“Early in clinical trials of Herceptin, it became apparent that several cases of congestive heart failure had been reported,” said Andrew Seidman, MD, an oncologist at Memorial Sloan-Kettering Cancer Center. “This was an unexpected finding on the basis of the cumulative doxorubicin exposure in the patients. The reports prompted increased safety surveillance in the form of a data monitoring committee.”

Cardiac Review Committee

A post hoc Cardiac Review and Evaluation Committee (CREC) performed an extensive query of the Genentech database in an effort to determine the incidence and characteristics of cardiac dysfunction that occurred in Herceptin clinical trials. Dr. Seidman said that the CREC was charged with defining cardiac dysfunction, determining the incidence of cardiac dysfunction in Herceptin clinical trials, assessing the onset and severity of the dysfunction, and examining outcomes with medical management.

The committee defined cardiac dysfunction as any signs or symptoms of congestive heart failure (CHF), including S3 gallop, jugular-venous distension, dyspnea, orthopnea, tachycardia, edema, or paroxysmal nocturnal dyspnea. Cardiomyopathy was defined as a fall in ejection fraction that was global or more severe in the septum.

The group looked for two types of dysfunction: (1) a 10% absolute but asymptomatic decline in ejection fraction to less than 55%, and (2) a symptomatic decline of 5% or more to an ejection fraction of less than 55%.

Of the five studies reviewed, four had cardiotoxicity rates that ranged between 3% and 6%. Those trials included single-agent and extension studies, some of which permitted the addition of other agents to Herceptin. The fifth study was the comparison of the AC regimen with paclitaxel, and Dr. Seidman devoted most of his review to details of that trial.

Patients treated with AC had a 7% incidence of cardiotoxicity vs 1% in patients who received monotherapy with paclitaxel (see Table). The addition of Herceptin to the anthracycline regimen was associated with a 27% incidence of cardiotoxicity vs 12% with the addition of paclitaxel.

A Qualitative Difference

Patients who received Herceptin also had a higher incidence of marked or severe cardiac dysfunction, defined as New York Heart Association Class III or IV. The incidence of class III-IV dysfunction was considerably higher in the AC-Herceptin group, 16% (9% class IV) than in the paclitaxel-Herceptin group, 2% (all class III).

“There appears to be some qualitative, as well as quantitative, difference in the nature of cardiac dysfunction that was observed,” Dr. Seidman commented.

Patients who developed cardiac dysfunction on chemotherapy were treated with a variety of agents, including digitalis, diuretics, angiotensin-converting enzyme (ACE) inhibitors, calcium channel blockers, and inotropic drugs. Among patients who had marked or severe impairment in cardiac function, 6% had significant dysfunction after treatment in the AC-Herceptin group, whereas no patient in the paclitaxel-Herceptin cohort had significant impairment after treatment.

A multivariate analysis of factors associated with an increased risk of cardiac dysfunction identified only advanced age and concomitant anthracycline therapy as significant predictors.

“I think it is apparent that Herceptin is associated with some cardiotoxicity, either as a single agent or, perhaps somewhat more commonly, with combination therapy,” Dr. Seidman said. “Cardiotoxicity seems to be most common and most severe when Herceptin is used in association with anthracycline-containing chemotherapy. There is also an association with advanced age. The syndrome is very reminiscent of what has been observed with anthracyclines, and it is generally responsive to standard medical management.”

Clearly, he added, more work is needed to define the pathophysiologic mechanisms underlying this cardiac dysfunction.