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Less Toxic Treatment for Aggressive Breast Cancers?

A new study shows that a shorter, less toxic chemotherapy regimen that includes the drug Herceptin appears to be just as effective in women with HER-2 positive breast cancer as using a standard three-drug therapy with Herceptin, a strategy that can be harder on the heart.

Oct. 5, 2011 -- For women with certain kinds of aggressive breast tumors, treatment has often come with a significant trade-off: The drugs that kill their cancer can sometimes permanently damage the heart.

"Those are patients, many of whom are going to be cured of their breast cancer, but now they've got symptomatic heart failure. And that's typically a long-term problem," says Amelia Zelnak, MD, a breast oncologist and assistant professor of hematology and oncology at Emory University's Winship Cancer Institute in Atlanta.

Now a new study shows that a shorter, less toxic chemotherapy regimen that includes the drug Herceptin appears to be just as effective in women with HER-2 positive breast cancer as using a standard three-drug therapy with Herceptin, a strategy that can be harder on the heart.

Zelnak says the study, which has been presented at several large cancer conferences, has already changed clinical practice. She says many doctors have begun offering the less toxic combination along with Herceptin as "one of our standards of care," particularly for women who have a low risk of recurrence. She was not involved in the research.

About one in five women with breast cancer test positive for a protein called HER-2. HER-2 spurs the growth of cancer cells, making these types of tumors particularly quick to spread.

Previous studies have shown that the drug Herceptin, which directly interferes with a cell's ability to be stimulated by the HER-2 protein, can slow or stop the growth of these cancers when they have spread beyond the breast.

As effective as it can be, Herceptin can also cause serious side effects, including damage to the heart muscle that can lead to heart failure. It can also cause serious and life-threatening breathing problems.

For that reason, doctors have been unsure whether Herceptin is safe enough to use in women with early-stage cancers.

Adding Herceptin to Chemotherapy

The new study, which is published in the New England Journal of Medicine, is one of four large clinical trials designed to see if the benefits of Herceptin might outweigh the risks if the drug was used earlier in the course of cancer treatment.

The study randomly assigned 3,222 women with early-stage HER-2 positive tumors to one of three treatment groups. The first group was given a standard cocktail of three chemotherapy drugs that all slow or stop the growth of rapidly dividing cells -- doxorubicin and cyclophosphamide, followed by docetaxel.

Doxorubicin is a type of drug called an anthracycline, and it's sold under the brand names Adriamycin, Doxil, and Rubex. Like Herceptin, doxorubicin can damage the heart. Using the two drugs together increases that danger.

The second group got the same three-drug regimen along with a year of Herceptin.

The third group was given docetaxel and a newer drug called carboplatin along with a year of Herceptin.

The study found that adding Herceptin increased the odds that a woman would still be alive and cancer-free more than five years after treatment. It didn't seem to matter whether she was on the standard, more toxic regimen or the newer, less toxic drugs.

Overall, 87% of the women on the standard, three-drug combination were still alive and 75% were cancer-free more than five years later, while 92% of the women were still alive and 84% were cancer-free when Herceptin was added to that treatment.

Of the women on the newer, two-drug regimen with added Herceptin, 91% were still alive and 81% were cancer-free more than five years later.

The differences between the two groups that got Herceptin were not statistically significant.

The benefit for Herceptin was seen whether tumors were small or large and even in women who had positive lymph nodes, indicating that their cancer had spread.

Fewer Side Effects

The biggest difference came when researchers looked at side effects patients experienced.

Patients on the newer, two-drug combination had less joint and muscle pain, less irritation and peeling of the skin and mucous membranes, and less vomiting. There were also fewer reports of low white blood cell counts in the group on the two-drug regimen.

Seven patients on the three-drug regimen developed leukemia, compared to one patient on the newer regimen, but that patient had received another drug, an agent linked with leukemia, outside the study to treat another cancer that arose after her breast cancer.

There was more heart failure in patients treated with Herceptin. But the incidence of heart failure was five times higher in the patients taking the standard three-drug regimen that included Herceptin. Overall, 2% of those patients had heart failure compared to those on the newer drugs with Herceptin. Just 0.4% in that group was diagnosed with heart failure.

What's more, about twice as many patients (18.6% vs. 9.4%) developed heart damage that didn't cause symptoms in the group taking the standard three-drug combination plus Herceptin compared to the newer two-drug combination with Herceptin.

"There's been only one significant problem with Herceptin, and that significant problem is that it increases cardiac toxicity by about four- to fivefold when it's given with anthracycline," says researcher Dennis Slamon, MD, PhD, director of clinical and translational research at the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles.

"You get comparable efficacy, but a dramatically significant difference in some of the acute and chronic toxicities," when a different chemotherapy regimen is used, Slamon tells WebMD.

"The mainstay of breast cancer chemotherapy has been anthracyclines not just in the U.S. but worldwide," he says. "Given the data in this study, it makes one really question what role Adriamycin should play in the treatment of HER-2 positive early breast cancer or in the treatment of early breast cancer at all."

"This trial should impact the way these breast cancers are treated, with a non-anthracycline regimen being our preferred option. I think this is a change that is going to be slow in coming, unfortunately, as many of our ... treatments for breast cancer are built on the backbone of anthracyclines. While they're effective, whatever gain patients may receive is more than made up for in the serious and chronic long-term side effects."

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