Trastuzumab with docetaxel for breast cancer is less cardiotoxic

NEW YORK (Reuters Health) - Patients with HER2-positive breast cancer who receive trastuzumab (Herceptin) along with docetaxel have a lower risk of heart problems than if they receive it with anthracyclines, according to an update of a study involving 3,222 women.

Studies have shown that trastuzumab delays recurrence and improves survival in women whose breast cancer overexpresses the HER2 receptor, but giving it with anthracyclines boosts their odds of congestive heart failure four- to five-fold.

The research team, led by Dr. Dennis Slamon of the University of California, Los Angeles found that replacing the anthracycline doxorubicin with docetaxel in a regimen known as TCH produced a similar benefit without the heart problems.

The benefit "is not identical but it's comparable, and you lose all that toxicity," Dr. Slamon told Reuters Health.

The study results, published online today in the New England Journal of Medicine, "definitively show that a non-anthracycline-containing regimen is a valid and important option for some patients, even (those) who are thought to be at highest risk for recurrence," said Dr. Eleni Andreopoulou of the Montefiore Medical Center and Albert Einstein College of Medicine, who was not involved in the research.

"The TCH regimen is particularly relevant for patients with a cardiac history or who have been treated with prior cardiotoxic regimens. This is especially important in situations where toxicities associated with anthracycline, mainly cardiotoxicity and leukemia, is of a particular concern," she told Reuters Health in an email.

Earlier results from the study, known as BCIRG 006, prompted the U.S. Food and Drug Administration to approve the docetaxel-trastuzumab-carboplatin treatment for HER2-positive early breast cancer in May 2008. The earlier results have already prompted many physicians to adopt the TCH treatment, Dr. Slamon and Dr. Andreopoulou said.

"The fact that (the improvement) remains significant is good news for women with HER-2 positive breast cancer," Dr. Slamon said.

Trastuzumab is expensive -- $70,000 to $100,000 per year. But the researchers said using docetaxel instead of an anthracycline should not add to the expense.

The study was financed by Sanofi-Aventis, which sells docetaxel as Taxotere, and Genentech, a unit of Roche Holding AG which sells Herceptin.

Although doctors were hoping that the docetaxel-trastuzumab combination would outperform the older regimen, the results show that it is "another (but not 'the') standard of care for adjuvant treatment of HER2-positive early stage breast cancer," Dr. Daniel Hayes of the University of Michigan Comprehensive Cancer Center in Ann Arbor wrote in a Journal editorial.

"Taken together, these data do not clearly favor one regime over the other," he wrote. The number of cases of irreversible congestive heart failure or secondary leukemia caused by a protocol that included doxorubicin-trastuzumab would "arguably" be the same as the number of lives saved by using the docetaxel-trastuzumab treatment.

The study included women from 41 countries with high-risk adenocarcinoma (stages T1, T2 or T3).

With a median follow-up of 65 months, the 1,073 women getting doxorubicin and cyclophosphamide for four cycles, followed by docetaxel for four more cycles, had an estimated five-year disease-free survival rate of 75% and an overall survival rate of 87%.

The 1,074 who also got 52 weeks of trastuzumab concurrently had five year disease-free survival of 84% and overall survival of 92%, an improvement of at least 27% (P=0.001 for both measures).

The remaining 1,075 who got carboplatin and docetaxel every three weeks for six cycles, along with trastuzumab (but not doxorubicin and cyclophosphamide) had a disease-free survival rate of 81% and an overall survival rate of 91%. That's a survival rate improvement of at least 25% over the group getting doxorubicin but not trastuzumab (P=0.04 for both).

Left ventricular ejection fraction measurements, done seven times throughout the study for each patient, found that the risk of congestive heart failure among trastuzumab recipients was five times higher if they were also getting doxorubicin, and even subclinical damage persisted for years.

Heart failure rates were 0.4% for the docetaxel-trastuzumab group, 2.0% for the doxorubicin-trastuzumab group, and 0.7% among the patients who didn't get trastuzumab at all (P<0.001 for the comparison between the two trastuzumab groups).

In addition, 18.6% in the doxorubicin-trastuzumab group lost more than 10% of their left ventricular ejection fraction, vs 9.4% in the docetaxel-trastuzumab group (P<0.001). The rate with doxorubicin without trastuzumab was 11.2%.

Previous studies have suggested that such heart problems are temporary.

But in the new study, the ejection fraction loss persisted for at least four years in 33% of the doxorubicin-trastuzumab patients who experienced it. In fact, 2.1% of the women assigned to that group never got their trastuzumab because the doxorubicin alone did so much damage to their heart.

With doxorubicin-trastuzumab therapy, "there's a doubling of the subclinical damage we can measure in the heart. It's not manifested now, but as these patients age, this problem is going to augment itself," Dr. Slamon said. "We're going to see a much bigger problem down the line if we stick with the same old one-size-fits-all regimen" in cases of HER2 positive breast cancer.

Members of the docetaxel-trastuzumab-carboplatin group were less likely to have Grade 3 or 4 arthralgias, myalgias, vomiting, stomatitis and the hand-foot syndrome, or to develop acute leukemia, than those in the other trastuzumab group, whereas those in the TCH group were more likely to experience anemia and thrombocytopenia.

Dr. Slamon originally reported the updated results in December 2009 at the San Antonio Breast Cancer Symposium.

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