Researchers have temporarily halted the accrual of new patients into one of three arms of a large phase III study designed to examine the activity and safety of the biological agent trastuzumab (Herceptin®) in treating women with early-stage breast cancer.
Study leaders took this precaution in January after a small number of patients in one arm of the trial developed congestive heart failure within a one-week period. Investigators will continue to assess the data in the next few months to determine whether it is prudent to reopen this arm to patients. Meanwhile, the two other study arms remain open to enrollment.
Women eligible for Breast Intergroup trial N9831 have early-stage breast tumors that express human epidermal growth factor-2 (HER-2) and disease that has spread to the lymph nodes. About 20% to 30% of women with breast cancer have tumors that overexpress the HER-2 protein, and these patients have a poorer prognosis than women whose tumors lack this alteration.
Trastuzumab is a monoclonal antibody that targets the HER-2 protein. It was approved in 1998 by the U.S. Food and Drug Administration for the treatment of metastatic breast tumors that overexpress HER-2.
The principal aim of the trial is to determine whether adding trastuzumab to chemotherapy regimens can improve outcomes in women with HER-2-positive, lymph node-positive breast cancer. According to the protocol, all patients receive 4 courses of the anthracycline, doxorubicin, and cyclophosphamide, after which they are randomized into one of three arms. In Arm A, the control arm, patients receive paclitaxel for 12 weeks; in Arm B paclitaxel is administered for 12 weeks followed by trastuzumab for 52 weeks; and in Arm C paclitaxel is given concurrently with trastuzumab for 12 weeks followed by trastuzumab for 40 weeks.
The study is also examining whether cardiotoxic effects vary in the different arms of the trial. Cardiac dysfunction is a known side effect of trastuzumab that surfaced in clinical trials of the agent for metastatic breast cancer. A recent retrospective study found that patients who receive trastuzumab with an anthracycline are at the greatest risk for cardiac dysfunction.
While trastuzumab and doxorubicin are not administered concomitantly in this trial, the risk of cardioitoxicity still exists when trastuzumab is administered after the anthracycline. For this reason the protocol includes a rigorous cardiac monitoring system to allow quick detection of cardiac dysfunction.
The recent excess of cardiac events reported in patients enrolled in Arm C raised concern that the treatment sequence in that arm might be more cardiotoxic than that of Arm B. Edith Perez, M.D., professor of medicine at the Mayo Clinic, Jacksonville, Fla., and chairperson for the study, emphasized that the number of patients who experienced congestive heart failure was low and that these patients all responded to treatment and recovered within a few days.
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Nevertheless, to make sure patients are not exposed to undue risk, the internal protocol cardiac safety monitoring committee for the trial and the North Central Cancer Treatment Group Data Monitoring Committee reviewed the recent data. Both groups concurred that the potential increase in cardiac dysfunction warranted further scrutiny and that it would be prudent to temporarily suspend enrollment into Arm C. Women enrolled in this arm are being asked to continue on the trial and to discuss with their physician whether to continue with the protocol as specified or to wait to initiate trastuzumab until they are finished with paclitaxel.
It will take a few months before patient assessment and statistical analysis will allow researchers to determine whether there is a higher than expected risk of cardiotoxicity for patients receiving the therapy in this arm, said Perez. By summer the study leaders should be able to make a decision as to whether they should reopen that arm of the trial or permanently close it. She noted that patient advocates as well as physicians and scientists will be involved in this decision, as they have been from the beginning and all through the process.
"I think the Intergroup did a smart and judicious and cautious thing in suspending accrual temporarily while they could see how the patients already on the trial do over time," said Andrew Seidman, M.D., associate attending physician, Breast Cancer Medical Service, Memorial Sloan-Kettering Cancer Center, who echoed the sentiments of other physicians. Seidman added that the risk-benefit ratio in the adjuvant trials is not as clear. "Accepting the certain risk of causing heart failure because youre controlling cancer is perhaps one of the most complex of risk-benefit analyses," he said.
For this reason the "meticulous monitoring" of patients thats being done is crucial to the study, said Hyman Muss, M.D., associate director of clinical research, Vermont Cancer Center, Burlington. Such vigilance, he said, is a credit to the NCI system, the cooperative groups, and to Perez. Muss said he finds it an encouraging sign that the women who have experienced heart failure in the studyincluding one of his patientshave recovered quickly when the drug is stopped. "We need to be careful, we cant put patients at great risk, but it is important to remember that we are looking at a treatment that might improve curability for a potentially fatal disease."
Perez said that she hopes the data will justify reopening the trial arm especially now that there have been no more cardiac events reported since January and the patients who experienced congestive heart failure continue to respond well to medical therapy. "I dont want to lose the opportunity to find a therapy that that may improve the cure rate for breast cancer," she said. "But at the same time we really have to be critical in balancing toxicity."
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