The risk of cardiotoxicity is five times higher in breast cancer patients given trastuzumab than in those receiving a standard chemotherapy regimen alone, according to a new systematic review from the Cochrane Collaboration.
The review found that regimens containing trastuzumab (Herceptin) significantly increased congestive heart failure and left ventricular ejection fraction (LVEF) decline, with relative risks of 5.11 and 1.83, respectively, in women with HER2-positive early and locally advanced breast cancer (Cochrane Database Syst. Rev. 2012;4 [doi: 10.1002/14651858.CD006243.pub2]).
However, trastuzumab regimens also significantly increased overall and disease-free survival, with hazard ratios of 0.66 and 0.60, respectively, noted Dr. Lorenzo Moja of the University of Milan and his coauthors. All these results were highly significant, with P values ranging from less than .0008 for risk of LVEF decline to less than .00001 for the others.
In a plain-language summary comparing trastuzumab-containing regimens with standard therapy alone in 1,000 women, the investigators wrote that 33 more women would have their lives prolonged with trastuzumab (933 women vs. 900 women with standard therapy alone). However, about 26 in 1,000 women taking trastuzumab would have serious heart toxicity, which is 21 more than the group treated with standard therapy alone.
Trastuzumab’s cardiotoxic effects have been well known, but the magnitude of the effect reported in the systematic review may be larger than what people have thought, commented Dr. Daniel J. Lenihan, director of clinical research in the cardiovascular medicine division at Vanderbilt University, Nashville, Tenn., in an interview.
And that risk may be even greater in the world outside of clinical studies, said Dr. Melinda Telli of Stanford (Calif.) University. The patients in the studies included in the systematic review were younger, and none had baseline cardiac disease, observed Dr. Telli, also in an interview.
Another issue: In practice, oncologists are offering trastuzumab to women at lower risk for cancer recurrence than those in the trials. Thus, she said, "it’s more likely the risks are underestimated in this Cochrane review."
Although the data in the systematic review were previously published, having them encapsulated – along with a number of scenarios outlining potential risks and benefits in women with different cancer recurrence and cardiac risk factors – is a significant addition to the literature, said Dr. Telli.
Cochrane reviews are known for being thorough and balanced. This review began by looking at about 3,900 studies; after applying exclusion criteria, the list was winnowed down to 35 publications that covered 8 randomized controlled clinical trials enrolling 11,991 women. A little more than 7,000 women were assigned to a trastuzumab-containing arm, and 4,971 women to a regimen without trastuzumab. The median age in the trials was 49 years. Pre- and postmenopausal women were included, but those with metastatic disease or preexisting heart conditions were excluded.
The review concluded that high-risk women with few cardiac risk factors would benefit from trastuzumab, while those at lower risk "must be carefully evaluated," adding, "The oncologist should share the decision with the patient concerning whether and how to start the treatment."
Dr. Lenihan said he was concerned that the potential cardiotoxicity might cause oncologists to steer away from trastuzumab. He is a proponent of a multidisciplinary team that involves a cardiologist at the outset of therapy.
If cardiac effects develop, "the key is not to ignore it, but to pay attention," said Dr. Lenihan, who is also president of the International CardiOncology Society USA/Canada.
Early identification enables rapid treatment, which can stabilize or correct the heart issues, he said. That allows patients to return to their cancer therapy.
Dr. Lenihan and his colleagues at Vanderbilt University are currently conducting a study testing various cardiac biomarkers to detect toxicity during chemotherapy.
It is still unknown, however, whether the cardiotoxicity that develops during therapy is ultimately reversible, or becomes a lifelong issue. While the ejection fraction may recover after withdrawal of trastuzumab, at least one study – the Herceptin Adjuvant (HERA) trial – has shown that some women had long-term loss of heart muscle cells, said Dr. Telli.
"So we know that the heart is taking a hit," she said, adding that the trastuzumab damage is not "some sort of reversible thing."
The key, she said, is for oncologists to weigh the risks and benefits individually in each patient.
A targeted therapy, trastuzumab is approved for treatment of HER2-positive breast cancer and of metastatic HER2-positive adenocarcinoma of the stomach or gastroesophageal junction. About 20% of tumors in women with early breast cancer are HER2-positive.
Dr. Telli reported no conflicts of interest. Dr. Lenihan reported receiving consulting fees from Roche and AstraZeneca and research support from Acorda.