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

April 1, 1997

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.

FORT LAUDERDALE, Fla--In view of the absence of data from large randomizedstudies of high-dose chemotherapy in breast cancer, the NCCN breast cancerguidelines' 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 chemotherapyshould 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 professorof oncology, Johns Hopkins Oncology Center, noted that there are threeongoing large randomized US breast cancer trials of standard versus high-dosetherapy with transplant (two as adjuvant therapy and one for metastaticdisease).

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

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

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show that transplant is no more effective than standardtherapy, people may say that the high-dose regimens used were outdated.

"That's the problem with any large randomized trial that beginsat Point A and moves over several years to Point B, when the field mayhave moved past Point B by the time the study is finished," Dr. Kennedysaid.

Another problem of the ongoing trials is that they may not take intoaccount our growing knowledge of the biology of breast cancer. He citeda CALGB study showing that breast tumors that expressed high levels ofHER2/neu responded significantly better to intensive doxorubicin-basedtherapy than to lower doses, whereas those that were low expressers ofthe 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 lookat the question of dose in breast cancer, we might well do best not tolook at all patients, but to consider the biology of the patients and tolook at subgroups."

Preliminary Data: Adjuvant Setting

To date, Dr. Kennedy said, only one randomized trial of adjuvant high-dosechemotherapy in breast cancer has reported results. Preliminary data froma Dutch trial with 80 randomized patients and maximum follow-up of only2.5 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, oncologistsinvolved in writing guidelines have looked to the phase II adjuvant therapytrials, the results of which "have been endlessly debated," hesaid. In these trials, he pointed out, statistically significant differencesin survival between standard and high-dose chemotherapy may be due simplyto stage migration.

He explained that in the high-dose arm, patients are very intensivelyscreened, such that if they have any abnormalities, they may not be enrolledin the study, "perhaps leaving behind a patient population that isgoing 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 inthese studies often were treated 10 to 15 years earlier and did not havethe benefit of intensive staging procedures. "The result is that asubstantial number of patients entered into those studies probably hadminor abnormalities, which, in fact, were metastatic disease," hesaid, "and therefore the historical controls did more poorly thanmight be expected."

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

He concluded that "all of these issues factor into the discussionand make the ultimate analysis of the role of high-dose chemotherapy extremelydifficult."