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The cumulative incidence of cardiac dysfunction associated with the use of trastuzumab for HER2-positive, node-positive breast cancer did not increase after 5 years of follow-up in a pivotal clinical trial, Dr. Priya Rastogi reported on behalf of the National Surgical Adjuvant Breast and Bowel Project (NSABP).
Updated results of the NSABP B-31 trial showed the incidence of cardiac events in patients taking trastuzumab (Herceptin) remained essentially unchanged from its value 2 years before, at 3.8%, Dr. Rastogi said.
In the original NSABP B-31 trial data, trastuzumab significantly improved 3-year disease-free survival and overall survival when combined with an anthracycline-based chemotherapy plus paclitaxel. However, the incidence of cardiotoxicity, specifically congestive heart failure, among the 850 patients randomized to the regimen containing trastuzumab, was 4.1%, compared with 0.8% among the 814 patients who did not get trastuzumab ( J. Clin. Oncol. 2005:23;7811-9).
With 2 more years of follow-up, the cumulative incidence of cardiac events in the patients who received chemotherapy plus trastuzumab was 3.8%, compared with 0.9% in those who received chemotherapy alone. Importantly, most patients who had a decline in cardiac function experienced a recovery in ejection fraction within 18 months of taking trastuzumab. "We were very heartened by this result," Dr. Rastogi, of the University of Pittsburgh Medical Center, said at a press briefing.
The NSABP investigators created a model to predict which women would be most likely to develop cardiotoxicity from trastuzumab. Age, use of antihypertensive medications, and poor heart function as measured by a low ejection fraction at baseline, were the most important predictors of risk.
"Incorporating these factors into the model allows us to calculate a cardiac risk score, which gives a percentage of risk of a cardiac event within 3 years. This is important because it now lets us choose trastuzumab-containing regimens based on an individual patient's risk and benefit profile," Dr. Rastogi said in an interview. The next step is to validate the model in similar patients.
"But we do have the model now, and it can be used. So you can tell the patient who is sitting face to face with you that, based on these risk factors of age, hypertensive medication, and baseline cardiac function, this is her risk for developing a cardiac event," she said.
Dr. Julie Gralow, moderator of the press briefing, told reporters that such a model represented a very important development for women with HER2-positive breast cancer, who account for roughly 25% of breast cancer patients. "I am thrilled to have a new risk model to help me discuss with my patients the risks and benefits from adding trastuzumab," said Dr. Gralow of the University of Washington, Seattle.
Dr. Gralow noted that as trastuzumab cut the incidence of recurrence by almost 50% and deaths by about one-third, it was reassuring to see no increase in cardiotoxicity in the update.
In the discussion that followed Dr. Rastogi's formal presentation, Dr. Sharon Hunt, professor of medicine at Stanford (Calif.) University, cautioned that 5 years of follow-up is not long enough to assuage concerns about the cardiotoxic effects of trastuzumab. The cardiotoxicity that is being noted with these 3- and 5-year follow-ups is "probably the tip of a very big iceberg. Left ventricular dysfunction, which you are rather simply measuring as ejection fraction, is a lifelong problem in many patients, and even though the numbers may improve, the structural damage done to the heart persists for the life of the patient," Dr. Hunt said.
Decrying the lack of information about whether any therapy for heart failure had been given to B-31 patients, Dr. Hunt called for greater collaboration between oncologists and cardiologists. "We need to know the time course of this cardiotoxicity. Is the optimistic view that it is reversible and not a cause for concern valid? Will preemptive therapy with well-proven heart failure prevention medications such as ACE inhibitors and ?-blockers abrogate any of this cardiotoxicity?" she asked.
Finding the balance between improved survival from breast cancer and the down side of cardiotoxicity "is one of the most important things we need to do in the field," she said.
Rastogi P. et al. Five year update of cardiac dysfunction on NSABP B-31, a randomized trial of sequential doxorubicin/cyclophosphamide (AC)??paclitaxel (T) vs. AC??T with trastuzumab(H). Abstract LBA513.
Commentary |
This study demonstrates that the risk of cardiotoxicity essentially stops after trastuzumab is discontinued. Cardiac function improves, and there is no evidence for continued adverse events. Clearly, more follow-up is required to be certain of the lack of long-term effects. Validation of the risk-assessment model developed by the National Surgical Adjuvant Breast and Bowel Project (NSABP) would add to our abilities to assess risk versus benefit and to choose potentially less toxic therapies for women at high risk for trastuzumab-associated cardiotoxicity. Data from the Breast Cancer International Research Group study by Pegram et al. suggest the nonanthracycline regimen of docetaxel, carboplatin, and trastuzumab might provide similar benefits without a similar increase in cardiotoxicity. — Hope S. Rugo, M.D.
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