Journal of the National Cancer Institute Advance Access originally published online on April 29, 2008
JNCI Journal of the National Cancer Institute 2008 100(9):618-619; doi:10.1093/jnci/djn143
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© Oxford University Press 2008.
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End of High-Dose Chemotherapy for High-Risk Breast Cancer Patients?
High-dose chemotherapy does not improve overall survival in women with high-risk nonmetastatic breast cancer relative to standard chemotherapy, according to a meta-analysis presented last December at the San Antonio Breast Cancer Symposium. This is not the first meta-analysis to show that the approach does not improve breast cancer survival, but it could be the final one; many researchers hope it will end the period in breast cancer care in which opinions seemed to outweigh evidence. However, even with the new data, not everyone is ready to let go of high-dose chemotherapy just yet.
The idea behind the treatment is simple: If standard-dose cytotoxic chemotherapy kills some of the tumor cells, then a substantially larger dose should kill most or all of the cancer cells and thereby prolong patient survival. Unfortunately, the massive dose of chemotherapy also wipes out the patient's bone marrow, which means that some of her marrow, or stem cells, must be harvested before surgery and then transplanted back again after treatment. Despite this difficulty, high-dose chemotherapy with bone marrow or stem cell transplantation became popular in the late 1980s and 1990s. Early small trials showed a high response rate in women with high-risk breast cancer—and the approach seemed so logical.
"High-dose chemotherapy is still a compelling idea," said Donald Berry, Ph.D., professor and head of the division of quantitative sciences at the University of Texas M. D. Anderson Cancer Center in Houston, who led the meta-analysis. "We see a dose response. In any therapy that is effective, it automatically has to have a dose response, especially with cytotoxic therapies. If you can give more of it, by whatever means, you are going to kill more cells. And so it is a very compelling idea and a hard one to put to rest—and I think for good reason. Maybe this analysis will put it to rest."
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To determine whether the treatment improved patient outcomes, Berry and his colleagues analyzed individual patient data from 15 randomized clinical trials conducted between 1988 and 2002. With 6,210 women included in the meta-analysis, the team found a 13% improvement in relapse-free survival for women treated with high-dose therapy compared with standard therapy. There was no benefit in overall survival, however.
"I am very pleased to hear they have come up with the same conclusion, though I’m not surprised," said Cynthia Farquhar, M.D., postgraduate professor of obstetrics and gynecology at the University of Auckland in New Zealand. Farquhar has also published meta-analyses on the effect of high-dose chemotherapy on survival among women with high-risk nonmetastatic breast cancer and women with metastatic breast cancer. Unlike Farquhar, however, Berry and his colleagues had access to individual patient data. "He can do much more detailed analyses and work out which patients were more likely to benefit," she said.
In fact, the ability to look for subgroups of patients who might benefit from the therapy was a key reason for doing the new meta-analysis, Berry said. "There have been statements made by people over time, even after the publication of many of these trials, that there are subsets of patients that benefit—for example, younger patients or HER2-negative patients," he said. "So we addressed subsets."
Berry concluded that none of the subgroups benefited, although he and some of his coauthors disagree on that point. The subgroup that appeared to show an overall improvement in survival after high-dose chemotherapy was women whose tumors were both estrogen receptor negative and HER2 negative. However, HER2 data were not available for all the women. Berry tried to confirm the possibility that these women did benefit from high-dose therapy by looking for an increase in response in all the women whose tumors were estrogen receptor negative, but he found none. Therefore, he concluded that the apparent benefit was a false conclusion. "My statement at the end is that we didn’t find any subgroups that had a significant benefit from high-dose chemotherapy," he said.
Some of his coauthors, though, still think that this patient subgroup might benefit from the approach—and they are not the only ones. "I look at high-dose chemotherapy not as the answer to all questions, but for a highly selected patient population, it could have a place," said George Somlo, M.D., codirector of the breast cancer program at the City of Hope Cancer Center in Duarte, Calif., who is still using high-dose chemotherapy in a clinical trial. He thinks the approach could improve clinical outcomes for patients with inflammatory breast cancer or with tumors that are triple negative—lacking expression of the estrogen receptor, progesterone receptor, and HER2.
Somlo also pointed out that the meta-analysis included randomized trials that had tested many chemotherapy regimens. "When you put the good, the bad, and the ugly in the analysis, then the final analysis may not be too helpful," he said.
In response to that concern, which others have expressed as well, Berry is currently reanalyzing a narrower subset of the trials. When asked whether the reanalysis was likely to alter the outcome or identify subgroups that benefited from high-dose chemotherapy, Berry declined to answer directly but said, "I have looked at the data every which way but loose, so it is difficult to imagine any subset of studies that would show a benefit."
Berry and his colleagues are also in the midst of a meta-analysis of eight randomized trials that tested high-dose chemotherapy in patients with metastatic disease, hoping to get the final answer in that setting as well. However, for many researchers high-dose chemotherapy is no longer an issue.
"In my mind, it is a done deal," said Larry Norton, M.D., deputy physician in chief for breast cancer programs at Memorial Sloan-Kettering Cancer Center in New York. "It was quite an interesting time in the evolution of medical therapy in breast cancer, and I am glad it is over," he said.
Early enthusiasm for high-dose chemotherapy drastically delayed completion of the randomized controlled trials needed to test the therapy. Instead of enrolling patients in such a trial, many physicians and patients were so convinced that high-dose chemotherapy worked that they wouldn't risk participating in a trial in which the patient might not get the therapy.
Referring to the current analysis, Norton said, "It is a victory for the system of evaluation of new therapies, in terms of prospective randomized trials, to bring us to the point where we can definitively say we have tested it and we have found it not to be a useful therapy for our patients.
"I put the nail in the box a long time ago myself," he said, "but I am very glad that Don Berry did this analysis because it should finally end all this discussion."
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