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First Data From High-Dose Chemo Trials Due in 3 Years

First Data From High-Dose Chemo Trials Due in 3 Years

FORT LAUDERDALE, Fla--In view of the absence of data from large randomized studies of high-dose chemotherapy in breast cancer, the NCCN breast cancer guidelines' relegation of such therapy to a footnote is appropriate, M. John Kennedy, MD, said in his review of the important issues on this question.

The breast cancer guidelines state that dose-intensive chemotherapy should be reserved for clinical trials, and enrollment in such trials is "especially appropriate" for women with 10 or more positive nodes, stage IIIB disease, or metastatic or recurrent disease.

Dr. Kennedy, originally of Dublin, Ireland, and now associate professor of oncology, Johns Hopkins Oncology Center, noted that there are three ongoing large randomized US breast cancer trials of standard versus high-dose therapy with transplant (two as adjuvant therapy and one for metastatic disease).

Patient accrual is expected to be completed by November of this year, "so we should be able to start analyzing data probably about two to two and a half years after that," he said.

Results of these trials and half a dozen others in Europe are expected to aid oncologists in writing guidelines for use of high-dose therapy in breast cancer. Yet Dr. Kennedy suggested that ultimately the findings may be less than definitive. "I'm trying to prepare people for the notion that the results will be open to various interpretations."

Both standard regimens and transplant regimens have evolved over the years since the randomized trials began, he said. Thus, if the transplant trials yield results in favor of high-dose chemotherapy, critics may say that the standard regimens used were too low or did not include taxanes. If the studies show that transplant is no more effective than standard therapy, people may say that the high-dose regimens used were outdated.

"That's the problem with any large randomized trial that begins at Point A and moves over several years to Point B, when the field may have moved past Point B by the time the study is finished," Dr. Kennedy said.

Another problem of the ongoing trials is that they may not take into account our growing knowledge of the biology of breast cancer. He cited a CALGB study showing that breast tumors that expressed high levels of HER2/neu responded significantly better to intensive doxorubicin-based therapy than to lower doses, whereas those that were low expressers of the protein showed no difference in outcome based on dose.

"Breast cancer is a collection of diseases," Dr. Kennedy said, "and the suggestion from this subgroup analysis is that when we look at the question of dose in breast cancer, we might well do best not to look at all patients, but to consider the biology of the patients and to look at subgroups."

Preliminary Data: Adjuvant Setting

To date, Dr. Kennedy said, only one randomized trial of adjuvant high-dose chemotherapy in breast cancer has reported results. Preliminary data from a Dutch trial with 80 randomized patients and maximum follow-up of only 2.5 years showed overall survival of 75% for standard therapy versus 80% for transplant.

Patients received either standard FEC (5-FU, epirubicin, cyclophosphamide) or FEC plus transplant with a STAMP-5 regimen (cyclophosphamide, thiotepa, carboplatin, irradiation, and tamoxi-fen). One encouraging result, he noted, was that no toxic deaths have occurred in either arm of the study.

With the results of the large phase III adjuvant studies awaited, oncologists involved in writing guidelines have looked to the phase II adjuvant therapy trials, the results of which "have been endlessly debated," he said. In these trials, he pointed out, statistically significant differences in survival between standard and high-dose chemotherapy may be due simply to stage migration.

He explained that in the high-dose arm, patients are very intensively screened, such that if they have any abnormalities, they may not be enrolled in the study, "perhaps leaving behind a patient population that is going to do well no matter what treatment we give them."

Problems With Historical Controls

On the other hand, Dr. Kennedy said, the historical controls used in these studies often were treated 10 to 15 years earlier and did not have the benefit of intensive staging procedures. "The result is that a substantial number of patients entered into those studies probably had minor abnormalities, which, in fact, were metastatic disease," he said, "and therefore the historical controls did more poorly than might be expected."

Dr. Kennedy noted that the endpoints for breast cancer studies vary widely, as does the very definition of high-dose therapy, which may refer to total dose, dose intensity (the amount of chemotherapy per meter squared per unit of time), or dose density (more frequent administration of drugs).

He concluded that "all of these issues factor into the discussion and make the ultimate analysis of the role of high-dose chemotherapy extremely difficult."

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