December 5, 2011 — A huge meta-analysis of clinical trials in breast cancer conducted over the past 40 years has shown that chemotherapy reduces deaths from the disease by about one third, compared with no chemotherapy.
The meta-analysis, which involved more than 100,000 breast cancer patients, is the latest in a series from the from the Early Breast Cancer Trialists' Collaborative Group (EBCTCG), from the Clinical Trial Service Unit at the University of Oxford, United Kingdom.
It was published online December 6 in the Lancet.
"The EBCTCG meta-analyses continue to show that polychemotherapy saves lives," according to an accompanying editorial by Carlo Palmieri, MD, from the division of cancer at Imperial College London, and Alison Jones, MD, from the Department of Medical Oncology, University College Hospital, London, United Kingdom. On average, chemotherapy reduces breast cancer mortality by about one third, they note.
The benefit is even greater for many women, said Sir Richard Peto, FRS, cofounder and codirector of the Clinical Trials Service Unit, and one of the authors of the meta-analysis. He pointed out that most breast cancers are estrogen-receptor (ER) positive; in cases where these types of tumor appear "to have been completely removed by surgery, the 10-year risk of recurrence and death can be reduced by at least half by giving a few months of modern chemotherapy plus 5 years of endocrine therapy."
However, the editorialists note that ER positivity is a "crude descriptive term for a heterogeneous group of cancers." Tumors that are labeled ER positive vary greatly in their risk for recurrence, and the researchers and the editorialists raise the possibility that some of these women might have been treated with chemotherapy unnecessarily. Both groups also emphasize the need for more detailed biomarkers so that treatment can be stratified according to an individual patient's risk.
"Retrospective genomic analysis might be able not only to predict which ER-positive tumors are at high and low risk of recurrence, but also which could derive the greatest benefit from chemotherapy," the editorialists suggest. "We look forward to the day when treatment of fewer women with a personalized approach achieves more," they conclude.
Improvements in Survival
This meta-analysis involved data from 123 randomized trials.
Some of the older trials compared chemotherapy with no chemotherapy. These older chemotherapy regimens included CMF (cyclophosphamide, methotrexate, and fluorouracil) and standard 4AC (doxorubicin and cyclophosphamide), which were equally effective, the researchers note. The meta-analysis shows that they reduced annual breast cancer mortality rates by around 20% to 25%.
The data from these older trials confirm a significant reduction in breast-cancer-specific mortality and in overall mortality, add the editorialists. "These old studies in which controls received no adjunct chemotherapy underpin the rationale for use of systemic chemotherapy after surgery to improve survival," they note.
More recent trials compared the older chemotherapy regimens with modern regimens, such as those in which a taxane is added to anthracyclines and those in which the cumulative doses of chemotherapy are higher than in 4AC. The meta-analysis shows that these modern regimens reduced breast cancer mortality by about one sixth, compared with the older regimens.
When all of the trials were analyzed together, the authors calculated that, compared with no chemotherapy, these modern regimens reduce breast cancer by about one third in a wide range of patients.
This reduction of one third in breast cancer mortality appears to apply to all women, irrespective of age, size of the tumor, whether or not it had spread to the lymph nodes, and whether or not it was ER positive, the researchers note.
This last finding is both "unexpected and important," say the editorialists.
A previous EBCTCG overview showed that in the older trials, the proportional reduction in mortality with chemotherapy was independent of ER status and was not modified by tamoxifen, they note (Lancet 2005;365:1687-1717).
The meta-analysis extends this finding to the newer taxane trials, they continue. It suggests that neither ER status nor age can be used as a predictor of benefit for adjuvant polychemotherapy, they add.
Endocrine Therapy
This is the first EBCTCG meta-analysis to include trials of adjuvant endocrine treatment, the editorialists note, adding that "the relevance of endocrine therapy...is unclear."
However, they point out that "even the trials of chemoendocrine therapy vs endocrine therapy alone still found substantial extra benefit from chemotherapy," which is in opposition to results from some adjuvant studies that have questioned the benefit of chemotherapy in ER-positive disease.
The researchers emphasize that chemoendocrine therapy performed better than endocrine therapy alone. "Even in strongly ER-positive disease, chemotherapy did at least somewhat affect outcome, although not necessarily to the same extent as in less strongly ER-positive disease," they write.
However, they suggest that there might be some ER-positive breast cancer that could be treated with endocrine therapy alone; for these women, chemotherapy might not add any large benefit but would add toxicity.
They point out that the breast cancer seen in this meta-analysis (which was based on trials that began in 1973 to 2003) is different from the breast cancer that is now being found on regular mammographic screening.
Very few of the women in the trials that were considered had small well-differentiated tumors, they note. In contrast, widespread mammographic screening finds many breast cancers that have a low disease burden and low proliferative index, and hence have a high probability of being endocrine-responsive luminal A tumors. This is the sort of low-risk ER-positive breast cancer that could perhaps be treated with endocrine therapy alone and for which chemotherapy would increase toxicity but generally not add any large benefit.
"We could not test such hypotheses," the researchers explain. However, they note that there are ongoing trials that are doing just that, and are using gene expression profiles to randomly allocate women with ER-positive breast cancer to treatment with chemoendocrine therapy or the same endocrine therapy used alone. Three trials (MINADACT, TAILORx, and RxPONDER) have enrolled more than 10,000 women, and the results are eagerly awaited.
"The challenge now is not only to save lives, but to reduce the number of women given polychemotherapy unnecessarily," the editorialists conclude.
The EBCTCG is funded by Cancer Research UK, the British Heart Foundation, and UK Medical Research Council grants. Staff of the Clinical Trials Service Unit are prohibited from accepting honoraria or consultancy fees, but several of the external coauthors report accepting honoraria or consulting fees from a number of pharmaceutical companies. One of the external coauthors (Martine Piccart) holds patents on a genome grade index and recurrence score (marketed by Ipsogen, Qiagen). Dr. Palmieri reports receiving research funding and honoraria from Cephalon, Novartis, Roche, and sanofi-aventis. Dr. Jones reports receiving honoraria from AstraZeneca, Novartis, GlaxoSmithKline, and Roche.
Lancet. Published online December 6, 2011. Abstract, Editorial
The meta-analysis, which involved more than 100,000 breast cancer patients, is the latest in a series from the from the Early Breast Cancer Trialists' Collaborative Group (EBCTCG), from the Clinical Trial Service Unit at the University of Oxford, United Kingdom.
It was published online December 6 in the Lancet.
"The EBCTCG meta-analyses continue to show that polychemotherapy saves lives," according to an accompanying editorial by Carlo Palmieri, MD, from the division of cancer at Imperial College London, and Alison Jones, MD, from the Department of Medical Oncology, University College Hospital, London, United Kingdom. On average, chemotherapy reduces breast cancer mortality by about one third, they note.
The benefit is even greater for many women, said Sir Richard Peto, FRS, cofounder and codirector of the Clinical Trials Service Unit, and one of the authors of the meta-analysis. He pointed out that most breast cancers are estrogen-receptor (ER) positive; in cases where these types of tumor appear "to have been completely removed by surgery, the 10-year risk of recurrence and death can be reduced by at least half by giving a few months of modern chemotherapy plus 5 years of endocrine therapy."
However, the editorialists note that ER positivity is a "crude descriptive term for a heterogeneous group of cancers." Tumors that are labeled ER positive vary greatly in their risk for recurrence, and the researchers and the editorialists raise the possibility that some of these women might have been treated with chemotherapy unnecessarily. Both groups also emphasize the need for more detailed biomarkers so that treatment can be stratified according to an individual patient's risk.
"Retrospective genomic analysis might be able not only to predict which ER-positive tumors are at high and low risk of recurrence, but also which could derive the greatest benefit from chemotherapy," the editorialists suggest. "We look forward to the day when treatment of fewer women with a personalized approach achieves more," they conclude.
Improvements in Survival
This meta-analysis involved data from 123 randomized trials.
Some of the older trials compared chemotherapy with no chemotherapy. These older chemotherapy regimens included CMF (cyclophosphamide, methotrexate, and fluorouracil) and standard 4AC (doxorubicin and cyclophosphamide), which were equally effective, the researchers note. The meta-analysis shows that they reduced annual breast cancer mortality rates by around 20% to 25%.
The data from these older trials confirm a significant reduction in breast-cancer-specific mortality and in overall mortality, add the editorialists. "These old studies in which controls received no adjunct chemotherapy underpin the rationale for use of systemic chemotherapy after surgery to improve survival," they note.
More recent trials compared the older chemotherapy regimens with modern regimens, such as those in which a taxane is added to anthracyclines and those in which the cumulative doses of chemotherapy are higher than in 4AC. The meta-analysis shows that these modern regimens reduced breast cancer mortality by about one sixth, compared with the older regimens.
When all of the trials were analyzed together, the authors calculated that, compared with no chemotherapy, these modern regimens reduce breast cancer by about one third in a wide range of patients.
This reduction of one third in breast cancer mortality appears to apply to all women, irrespective of age, size of the tumor, whether or not it had spread to the lymph nodes, and whether or not it was ER positive, the researchers note.
This last finding is both "unexpected and important," say the editorialists.
A previous EBCTCG overview showed that in the older trials, the proportional reduction in mortality with chemotherapy was independent of ER status and was not modified by tamoxifen, they note (Lancet 2005;365:1687-1717).
The meta-analysis extends this finding to the newer taxane trials, they continue. It suggests that neither ER status nor age can be used as a predictor of benefit for adjuvant polychemotherapy, they add.
Endocrine Therapy
This is the first EBCTCG meta-analysis to include trials of adjuvant endocrine treatment, the editorialists note, adding that "the relevance of endocrine therapy...is unclear."
However, they point out that "even the trials of chemoendocrine therapy vs endocrine therapy alone still found substantial extra benefit from chemotherapy," which is in opposition to results from some adjuvant studies that have questioned the benefit of chemotherapy in ER-positive disease.
The researchers emphasize that chemoendocrine therapy performed better than endocrine therapy alone. "Even in strongly ER-positive disease, chemotherapy did at least somewhat affect outcome, although not necessarily to the same extent as in less strongly ER-positive disease," they write.
However, they suggest that there might be some ER-positive breast cancer that could be treated with endocrine therapy alone; for these women, chemotherapy might not add any large benefit but would add toxicity.
They point out that the breast cancer seen in this meta-analysis (which was based on trials that began in 1973 to 2003) is different from the breast cancer that is now being found on regular mammographic screening.
Very few of the women in the trials that were considered had small well-differentiated tumors, they note. In contrast, widespread mammographic screening finds many breast cancers that have a low disease burden and low proliferative index, and hence have a high probability of being endocrine-responsive luminal A tumors. This is the sort of low-risk ER-positive breast cancer that could perhaps be treated with endocrine therapy alone and for which chemotherapy would increase toxicity but generally not add any large benefit.
"We could not test such hypotheses," the researchers explain. However, they note that there are ongoing trials that are doing just that, and are using gene expression profiles to randomly allocate women with ER-positive breast cancer to treatment with chemoendocrine therapy or the same endocrine therapy used alone. Three trials (MINADACT, TAILORx, and RxPONDER) have enrolled more than 10,000 women, and the results are eagerly awaited.
"The challenge now is not only to save lives, but to reduce the number of women given polychemotherapy unnecessarily," the editorialists conclude.
The EBCTCG is funded by Cancer Research UK, the British Heart Foundation, and UK Medical Research Council grants. Staff of the Clinical Trials Service Unit are prohibited from accepting honoraria or consultancy fees, but several of the external coauthors report accepting honoraria or consulting fees from a number of pharmaceutical companies. One of the external coauthors (Martine Piccart) holds patents on a genome grade index and recurrence score (marketed by Ipsogen, Qiagen). Dr. Palmieri reports receiving research funding and honoraria from Cephalon, Novartis, Roche, and sanofi-aventis. Dr. Jones reports receiving honoraria from AstraZeneca, Novartis, GlaxoSmithKline, and Roche.
Lancet. Published online December 6, 2011. Abstract, Editorial
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