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Dose-intense adjuvant chemotherapy is associated with significant if modest improvements in recurrence-free, breast cancer–specific, and overall survival among women with early breast cancer, results of a meta-analysis of data on individual patients showed.
Among more than 37,000 patients treated in 26 clinical trials with a median follow-up of 7.4 years, there was a 14% reduction in relative risk and 3.4% reduction in absolute 10-year risk of breast cancer recurrence for women who were treated either with accelerated-schedule or sequential chemotherapy, reported members of the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG).
There were no differences in deaths from cardiovascular disease, acute myeloid leukemia, or other cancers between patients treated with dose-intense regimens or schedules and those treated with standard chemotherapy, although patients on dose-intense regimens had higher incidence of grade 3 or 4 anemia, and more did not complete the prescribed courses compared with standard chemotherapy, the investigators noted.
“The balance of benefit versus toxicity, therefore, appears to favor more dose-intense chemotherapy. A further advantage of 2-weekly versus 3-weekly chemotherapy – but not of sequential versus concurrent chemotherapy – is treatment is completed sooner,” they wrote in The Lancet.
The investigators examined individual patient data for 26 of 33 trials comparing either 2-weekly chemotherapy with 3-weekly therapy, or sequential vs. concurrent anthracycline and taxane-based chemotherapy.
The trials comprised a total cohort of 37,297 women randomized, most of whom were younger than 70 years at the time of diagnose and had node-positive disease.
The 10 year-risk for breast cancer recurrence, one of two primary endpoints, was 28% with dose intensification vs. 31.4% with standard dosing, translating into a first-event rate ratio (RR) for recurrence of 0.86 (P less than .0001).
Ten-year breast-cancer mortality, the other primary endpoint, was 18.9% among patients treated with dose-intensified regimens or schedules, compared with 21.3% for patients treated under standard protocols.
All-cause mortality was lower with dose intensification (22.1% vs. 24.8%, P less than .0001), and death without recurrence was also slightly but significantly lower (4.1% vs. 4.6%, respectively, P = .034).
The reductions in recurrence rates were similar among trials comparing 2-week vs. 3-week chemotherapy cycles, sequential vs. concurrent schedules, and both strategies together.
“The proportional reductions in recurrence with dose-intense chemotherapy were similar and highly significant [P less than .0001) in estrogen receptor (ER)-positive and ER-negative disease and did not differ significantly by other patient or tumor characteristics,” the investigators wrote.
“The present findings are of limited relevance to the question of which women with early breast cancer should be offered chemotherapy, although they do indicate that chemotherapy can reduce breast cancer mortality rates by 40% rather than a third. The absolute gain from this proportional reduction in recurrence depends chiefly on what the risk of distant recurrence would be without chemotherapy, which varies greatly from one woman to another, and is the subject of much ongoing research,” the investigators wrote.
“The findings are, however, directly relevant to selection of what regimen to use, and they show that, if chemotherapy is to be given, a dose-intense regimen should at least be considered,” they wrote.
The meta-analysis was funded by Cancer Research UK and the Medical Research Council. All authors reported having no relevant disclosures.
SOURCE: EBCTCG. The Lancet. 2019 Feb 7. doi: 10.1016/S0140-6736(18)33137-4.
Although these results are meaningful, several limitations should be recognized as we translate these findings into practice. First, the benefits of dose intensification have not been established in the era of targeted therapy. Given that these studies enrolled women from 1985 to 2011, HER2 status was known for only 50% of tumors. Of those tested, 16% (n = 2,994) were HER2 positive. Use of trastuzumab was not reported but was probably uncommon since adjuvant trastuzumab was not approved until 2006. The remaining 18,625 patients did not have HER2 testing; thus, no HER2-directed therapy would have been given. Therefore, the majority of patients with HER2- positive breast cancer did not receive targeted therapy.
Although the authors report that women with HER2-positive and HER2-negative disease benefit similarly from dose intensification, it is impossible to know whether dose intensification benefits trastuzumab-treated patients or those who receive more than one HER2-targeted therapy (pertuzumab, neratinib, or trastuzumab-emtansine). Similarly, if other targeted therapies such as CDK4/6 inhibitors and PARP inhibitors show significant benefit in the curative setting for high-risk estrogen receptor (ER)-positive or BRCA-mutated breast cancer, prospective studies will be required to establish whether dose-intensive chemotherapy is better than standard chemotherapy in those settings.
Second, it is premature to conclude that patients older than 70 years or those with node-negative disease benefit from dose intensification, given the small number of patients in those groups and the fact that no significant benefit was observed for these patients. Moreover, gene-expression profiling was not used in these studies; thus, the benefit, if any, of a dose-intense approach for women with lymph-node-negative, high-risk, ER-positive disease is impossible to know. Finally, the use of dose intensification has not been studied in non-anthracycline, taxane-based regimens, which are being increasingly evaluated and used in women with node-negative, ER-positive disease.
With these caveats in mind, the results of this meta-analysis are undoubtedly clinically important. In modern practice, if anthracycline-based chemotherapy is warranted, these data provide convincing evidence that a dose-intense approach should be considered.
Sara A Hurvitz, MD, is from the David Geffen School of Medicine at UCLA, Santa Monica, Calif. Her remarks are excerpted from an editorial accompanying the study. She reports institutional research funding and fees for abstract and manuscript writing from several pharmaceutical companies outside of the submitted work, and travel reimbursement from Lilly outside of the submitted work.
Although these results are meaningful, several limitations should be recognized as we translate these findings into practice. First, the benefits of dose intensification have not been established in the era of targeted therapy. Given that these studies enrolled women from 1985 to 2011, HER2 status was known for only 50% of tumors. Of those tested, 16% (n = 2,994) were HER2 positive. Use of trastuzumab was not reported but was probably uncommon since adjuvant trastuzumab was not approved until 2006. The remaining 18,625 patients did not have HER2 testing; thus, no HER2-directed therapy would have been given. Therefore, the majority of patients with HER2- positive breast cancer did not receive targeted therapy.
Although the authors report that women with HER2-positive and HER2-negative disease benefit similarly from dose intensification, it is impossible to know whether dose intensification benefits trastuzumab-treated patients or those who receive more than one HER2-targeted therapy (pertuzumab, neratinib, or trastuzumab-emtansine). Similarly, if other targeted therapies such as CDK4/6 inhibitors and PARP inhibitors show significant benefit in the curative setting for high-risk estrogen receptor (ER)-positive or BRCA-mutated breast cancer, prospective studies will be required to establish whether dose-intensive chemotherapy is better than standard chemotherapy in those settings.
Second, it is premature to conclude that patients older than 70 years or those with node-negative disease benefit from dose intensification, given the small number of patients in those groups and the fact that no significant benefit was observed for these patients. Moreover, gene-expression profiling was not used in these studies; thus, the benefit, if any, of a dose-intense approach for women with lymph-node-negative, high-risk, ER-positive disease is impossible to know. Finally, the use of dose intensification has not been studied in non-anthracycline, taxane-based regimens, which are being increasingly evaluated and used in women with node-negative, ER-positive disease.
With these caveats in mind, the results of this meta-analysis are undoubtedly clinically important. In modern practice, if anthracycline-based chemotherapy is warranted, these data provide convincing evidence that a dose-intense approach should be considered.
Sara A Hurvitz, MD, is from the David Geffen School of Medicine at UCLA, Santa Monica, Calif. Her remarks are excerpted from an editorial accompanying the study. She reports institutional research funding and fees for abstract and manuscript writing from several pharmaceutical companies outside of the submitted work, and travel reimbursement from Lilly outside of the submitted work.
Although these results are meaningful, several limitations should be recognized as we translate these findings into practice. First, the benefits of dose intensification have not been established in the era of targeted therapy. Given that these studies enrolled women from 1985 to 2011, HER2 status was known for only 50% of tumors. Of those tested, 16% (n = 2,994) were HER2 positive. Use of trastuzumab was not reported but was probably uncommon since adjuvant trastuzumab was not approved until 2006. The remaining 18,625 patients did not have HER2 testing; thus, no HER2-directed therapy would have been given. Therefore, the majority of patients with HER2- positive breast cancer did not receive targeted therapy.
Although the authors report that women with HER2-positive and HER2-negative disease benefit similarly from dose intensification, it is impossible to know whether dose intensification benefits trastuzumab-treated patients or those who receive more than one HER2-targeted therapy (pertuzumab, neratinib, or trastuzumab-emtansine). Similarly, if other targeted therapies such as CDK4/6 inhibitors and PARP inhibitors show significant benefit in the curative setting for high-risk estrogen receptor (ER)-positive or BRCA-mutated breast cancer, prospective studies will be required to establish whether dose-intensive chemotherapy is better than standard chemotherapy in those settings.
Second, it is premature to conclude that patients older than 70 years or those with node-negative disease benefit from dose intensification, given the small number of patients in those groups and the fact that no significant benefit was observed for these patients. Moreover, gene-expression profiling was not used in these studies; thus, the benefit, if any, of a dose-intense approach for women with lymph-node-negative, high-risk, ER-positive disease is impossible to know. Finally, the use of dose intensification has not been studied in non-anthracycline, taxane-based regimens, which are being increasingly evaluated and used in women with node-negative, ER-positive disease.
With these caveats in mind, the results of this meta-analysis are undoubtedly clinically important. In modern practice, if anthracycline-based chemotherapy is warranted, these data provide convincing evidence that a dose-intense approach should be considered.
Sara A Hurvitz, MD, is from the David Geffen School of Medicine at UCLA, Santa Monica, Calif. Her remarks are excerpted from an editorial accompanying the study. She reports institutional research funding and fees for abstract and manuscript writing from several pharmaceutical companies outside of the submitted work, and travel reimbursement from Lilly outside of the submitted work.
Dose-intense adjuvant chemotherapy is associated with significant if modest improvements in recurrence-free, breast cancer–specific, and overall survival among women with early breast cancer, results of a meta-analysis of data on individual patients showed.
Among more than 37,000 patients treated in 26 clinical trials with a median follow-up of 7.4 years, there was a 14% reduction in relative risk and 3.4% reduction in absolute 10-year risk of breast cancer recurrence for women who were treated either with accelerated-schedule or sequential chemotherapy, reported members of the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG).
There were no differences in deaths from cardiovascular disease, acute myeloid leukemia, or other cancers between patients treated with dose-intense regimens or schedules and those treated with standard chemotherapy, although patients on dose-intense regimens had higher incidence of grade 3 or 4 anemia, and more did not complete the prescribed courses compared with standard chemotherapy, the investigators noted.
“The balance of benefit versus toxicity, therefore, appears to favor more dose-intense chemotherapy. A further advantage of 2-weekly versus 3-weekly chemotherapy – but not of sequential versus concurrent chemotherapy – is treatment is completed sooner,” they wrote in The Lancet.
The investigators examined individual patient data for 26 of 33 trials comparing either 2-weekly chemotherapy with 3-weekly therapy, or sequential vs. concurrent anthracycline and taxane-based chemotherapy.
The trials comprised a total cohort of 37,297 women randomized, most of whom were younger than 70 years at the time of diagnose and had node-positive disease.
The 10 year-risk for breast cancer recurrence, one of two primary endpoints, was 28% with dose intensification vs. 31.4% with standard dosing, translating into a first-event rate ratio (RR) for recurrence of 0.86 (P less than .0001).
Ten-year breast-cancer mortality, the other primary endpoint, was 18.9% among patients treated with dose-intensified regimens or schedules, compared with 21.3% for patients treated under standard protocols.
All-cause mortality was lower with dose intensification (22.1% vs. 24.8%, P less than .0001), and death without recurrence was also slightly but significantly lower (4.1% vs. 4.6%, respectively, P = .034).
The reductions in recurrence rates were similar among trials comparing 2-week vs. 3-week chemotherapy cycles, sequential vs. concurrent schedules, and both strategies together.
“The proportional reductions in recurrence with dose-intense chemotherapy were similar and highly significant [P less than .0001) in estrogen receptor (ER)-positive and ER-negative disease and did not differ significantly by other patient or tumor characteristics,” the investigators wrote.
“The present findings are of limited relevance to the question of which women with early breast cancer should be offered chemotherapy, although they do indicate that chemotherapy can reduce breast cancer mortality rates by 40% rather than a third. The absolute gain from this proportional reduction in recurrence depends chiefly on what the risk of distant recurrence would be without chemotherapy, which varies greatly from one woman to another, and is the subject of much ongoing research,” the investigators wrote.
“The findings are, however, directly relevant to selection of what regimen to use, and they show that, if chemotherapy is to be given, a dose-intense regimen should at least be considered,” they wrote.
The meta-analysis was funded by Cancer Research UK and the Medical Research Council. All authors reported having no relevant disclosures.
SOURCE: EBCTCG. The Lancet. 2019 Feb 7. doi: 10.1016/S0140-6736(18)33137-4.
Dose-intense adjuvant chemotherapy is associated with significant if modest improvements in recurrence-free, breast cancer–specific, and overall survival among women with early breast cancer, results of a meta-analysis of data on individual patients showed.
Among more than 37,000 patients treated in 26 clinical trials with a median follow-up of 7.4 years, there was a 14% reduction in relative risk and 3.4% reduction in absolute 10-year risk of breast cancer recurrence for women who were treated either with accelerated-schedule or sequential chemotherapy, reported members of the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG).
There were no differences in deaths from cardiovascular disease, acute myeloid leukemia, or other cancers between patients treated with dose-intense regimens or schedules and those treated with standard chemotherapy, although patients on dose-intense regimens had higher incidence of grade 3 or 4 anemia, and more did not complete the prescribed courses compared with standard chemotherapy, the investigators noted.
“The balance of benefit versus toxicity, therefore, appears to favor more dose-intense chemotherapy. A further advantage of 2-weekly versus 3-weekly chemotherapy – but not of sequential versus concurrent chemotherapy – is treatment is completed sooner,” they wrote in The Lancet.
The investigators examined individual patient data for 26 of 33 trials comparing either 2-weekly chemotherapy with 3-weekly therapy, or sequential vs. concurrent anthracycline and taxane-based chemotherapy.
The trials comprised a total cohort of 37,297 women randomized, most of whom were younger than 70 years at the time of diagnose and had node-positive disease.
The 10 year-risk for breast cancer recurrence, one of two primary endpoints, was 28% with dose intensification vs. 31.4% with standard dosing, translating into a first-event rate ratio (RR) for recurrence of 0.86 (P less than .0001).
Ten-year breast-cancer mortality, the other primary endpoint, was 18.9% among patients treated with dose-intensified regimens or schedules, compared with 21.3% for patients treated under standard protocols.
All-cause mortality was lower with dose intensification (22.1% vs. 24.8%, P less than .0001), and death without recurrence was also slightly but significantly lower (4.1% vs. 4.6%, respectively, P = .034).
The reductions in recurrence rates were similar among trials comparing 2-week vs. 3-week chemotherapy cycles, sequential vs. concurrent schedules, and both strategies together.
“The proportional reductions in recurrence with dose-intense chemotherapy were similar and highly significant [P less than .0001) in estrogen receptor (ER)-positive and ER-negative disease and did not differ significantly by other patient or tumor characteristics,” the investigators wrote.
“The present findings are of limited relevance to the question of which women with early breast cancer should be offered chemotherapy, although they do indicate that chemotherapy can reduce breast cancer mortality rates by 40% rather than a third. The absolute gain from this proportional reduction in recurrence depends chiefly on what the risk of distant recurrence would be without chemotherapy, which varies greatly from one woman to another, and is the subject of much ongoing research,” the investigators wrote.
“The findings are, however, directly relevant to selection of what regimen to use, and they show that, if chemotherapy is to be given, a dose-intense regimen should at least be considered,” they wrote.
The meta-analysis was funded by Cancer Research UK and the Medical Research Council. All authors reported having no relevant disclosures.
SOURCE: EBCTCG. The Lancet. 2019 Feb 7. doi: 10.1016/S0140-6736(18)33137-4.
FROM THE LANCET
Key clinical point: Consider dose-intensification or sequential therapy for patients undergoing chemotherapy.
Major finding: Ten-year recurrence rates were 28% with dose intensification vs. 31.4% for standard dosing.
Study details: Meta-analysis of individual data on 37,298 women enrolled in 26 randomized trials.
Disclosures: The meta-analysis was funded by Cancer Research UK and the Medical Research Council. All authors reported having no relevant disclosures.
Source: EBCTCG. The Lancet. 2019 Feb 7. doi: 10.1016/S0140-6736(18)33137-4.