NEW YORKAn 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
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
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
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
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.