ALEXANDRIA, VaPreliminary findings from four of five randomized studies show no survival advantage for high-dose chemotherapy/autologous bone marrow transplantation (HDC/ABMT) in breast cancer patients with metastatic or high-risk disease (10 or more positive axillary lymph nodes), researchers said at an ASCO teleconference.
The negative findings in the largest of the studies in metastatic breast cancer are unlikely to change over time, said lead author Edward Stadtmauer, MD, of the University of Pennsylvania. However, William Peters, MD, of the Karmanos Cancer Institute, who led the largest of the high-risk breast cancer trials, said that, at least in high-risk patients, its not that these are inconclusive studies, its that its too early to draw conclusions.
In his study, the statistics call for at least 3 more years of follow-up. We believe that it will be about 2001 before well have a sufficient number of events to draw conclusions, Dr. Peters said.
Allen Lichter, MD, professor of radiation oncology, University of Michigan, and president of ASCO, said that the five abstracts released at the teleconference and on ASCOs website, will be presented in detail for the scientific community at ASCOs annual meeting. He briefly summarized the findings of all five studies, starting with the three studies of women with high-risk breast cancer.
The first study by CALGB (Cancer and Leukemia Group B), with Dr. Peters as the senior author, involved 783 high-risk women randomized, after receiving standard chemotherapy, to either high-dose or intermediate-dose continuation chemotherapy. With follow-up of 37 months, disease-free survival is 68% for women who had high-dose chemotherapy/transplant vs 64% for patients on intermediate-dose therapy without transplant.
Obviously, there is no statistical difference between those two numbers, Dr. Lichter said, but it should be pointed out that the results in both arms are about 20% better than weve seen in historical groups of patients, so maybe one of the good news features of this is the fact that standard therapy is doing much better than in the past. Whether these two curves will separate as additional time goes on remains to be seen.
A Positive Study
A South African study, led by Dr. W.R. Bezwoda, included 154 high-risk women. Those on high-dose therapy had fewer relapses (25% vs 66%) and reduced mortality (17% vs 35%), compared with women in the standard-dose arm. This study, which is more mature, with follow-up extending out beyond 5 years, shows that in this setting, high-dose therapy was beneficial, Dr. Lichter said.
However, this finding may have been due to inadequacies of the so-called standard-dose regimen. This study was the only true comparison between high-dose chemotherapy with transplant and standard-dose therapy in these patients, Dr. Peters said. He explained that in the CALGB study, all patients initially received standard-dose therapy and then were randomized between high-dose chemotherapy/transplant and an intermediate-dose regimen requiring substantial additional clinical support but not transplant. He noted that in his study, patients on both arms are doing very well, 20% better than anticipated.
The Scandinavian Study
The third study of high-risk women was done in Scandinavia by Dr. Jonas Berg and colleagues. The researchers enrolled 525 women. With a median of 20 months follow-up, the number of deaths in both arms is the same, Dr. Lichter said, 40 with standard therapy and 40 in the high-dose arm.
Dr. Lichter next reviewed the two studies performed in patients with metastatic breast cancer. These women received their primary treatment, then had a recurrence, he said. The question here is, in a disease that is essentially incurable today, could high-dose therapy extend survival and potentially even cure some of these patients?
Dr. Stadtmauers ECOG study involved 553 women treated initially with chemotherapy; 199 responded and agreed to continue, with 184 finally eligible for analysis. Three-year survival was virtually identical in high-dose and standard- dose patients, 32% for high dose and 38% for standard dose, Dr. Lichter said.
The other metastatic disease study, from Dr. Jean-Pierre Lotz and colleagues in Paris, was a much smaller trial of 61 women. At the ASCO meeting, this study will be presented at a poster session, while the other four will be discussed at the plenary session, Dr. Lichter said.
Dr. Lotz said that it was difficult to accrue patients because so many patients wanted to be transplanted. He pointed out that although overall survival was not significantly different at 5 years, there was a significant difference at 3 years (P = .02), because of a difference in time to relapse (P = .013).
In this small study, he said, we were able to delay the time of relapse with high-dose therapy, and when the relapse occurred, we were able to induce a new complete response. Dr. Lotz and his colleagues find these results encouraging. Its not the end of high-dose therapy in breast cancer; it is the beginning for us, he said, adding that another French study is ongoing with 180 patients randomized after four cycles of conventional chemotherapy to receive high-dose therapy with transplant or observation.
In terms of the ability of high-dose therapy to delay relapse, Dr. Lichter said that for some patients, being alive without disease involves a much improved quality of life. He said that although delay in relapse is not as powerful an endpoint as overall survival, it is an endpoint that, in oncology, we think is very much worth looking for, and our patients tell us its important.
Dr. Peters noted that in the CALGB study, the primary endpoint is disease-free survival, so time to failure of the treatment is actually very important. He explained that in this study, patients who were randomzied to the intermediate-dose arm were eligible to receive a transplant later, which complicates the determination of overall survival. Improved overall survival generally follows improved disease-free survival, he said, but usually requires far larger numbers of patients to determine.
In the question-and-answer session, Dr. Lichter was asked if the issue of high-dose therapy/transplant in metastatic breast cancer was now closed. Its uncommon for a very important issue like this to be decided on the results of a single study, Dr. Lichter said, pointing out that the ECOG study with 184 analyzed patients is not an incredibly large trial. Rather, he said, the findings should stimulate additional research.
Dr. Peters pointed to the history of adjuvant therapy of breast cancer using standard doses. It took 144 trials involving 77,000 women before we finally were able to conclude that adjuvant chemotherapy offered an advantage to patients.
Dr. Lichter said that he hoped the results would encourage more women to participate in trials of high-dose therapy. Of some 12,000 transplants performed in breast cancer patients in this country to date, only about 1,000 have been done in the context of a clinical trial.
I hope that ratio will shift, he said. I hope these studies will begin to dispel the concerns of women who have been reluctant to go on study because of a tacit assumption that high-dose chemotherapy has to be better.