“You get about a one-third reduction in mortality with standard chemotherapy and then a highly significant additional reduction of 13% with dose-dense chemotherapy, reducing mortality by about half compared to no chemotherapy.”

— Richard G. Gray, MSc

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INCREASING THE DOSE density of chemotherapy lowers the risk of recurrence and breast cancer death by about 15% in women with early breast cancer, according to a large, meticulously conducted meta-analysis by the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG).¹ The trials included in the meta-analysis achieved dose intensification either by shortening the intervals between chemotherapy cycles or by sequential administration of anthracycline and taxane chemotherapy. 

Reductions in recurrence with dose-intense chemotherapy were similar in estrogen receptor–positive and estrogen receptor–negative disease and did not differ significantly by tumor type and patient characteristics, including age, hormone receptor status, nodal status, tumor size, and tumor grade. Death from noncancer causes was not significantly different between women treated with dose-dense chemotherapy and those given standard chemotherapy. 

“You get about a one-third reduction in mortality with standard chemotherapy and then a highly significant additional reduction of 13% with dose-dense chemotherapy, reducing mortality by almost a half compared with no chemotherapy. These step-by-step increments in breast cancer survival are each just moderate but add up to a big improvement in survival,” said Richard G. Gray, MSc, of the Nuffield Department of Population Health Medical Sciences Division, University of Oxford, United Kingdom. Prof. Gray presented the results of the meta-analysis on behalf of the EBCTCG at the 2017 San Antonio Breast Cancer Symposium.¹ 

“We know from previous research that giving chemotherapy with an anthracycline and taxane can reduce the risk of mortality by about one-third. We are still trying to find the best way to deliver this chemotherapy. The rationale for dose intensification is based on cytokinetic modeling showing that increased dose intensity increases the likelihood of eradicating cancer cells. A series of trials was conducted to test this hypothesis,” he said. 

Meta-analysis Details 

THE META-ANALYSIS included 25 trials (with a total of about 34,000 women) and was based on individual patient data, which is a more difficult but more accurate way to conduct a meta-analysis. A total of 12 trials looked at dose-dense chemotherapy given every 2 weeks vs standard 3-weekly chemotherapy. Seven of these trials (with a total of 10,004 patients) used the same dose and chemotherapy, whereas 5 of the trials (with 5,508 patients) had some differences in chemotherapy. 

“The optimal approach to dose intensification is to give the drugs in shorter intervals, every 2 weeks instead of every 3 weeks, along with [granulocyte colony-stimulating factor] drugs to stimulate white cell recovery. The average weekly dose is 1.5 times higher in the dose-dense group than with the standard-schedule comparator,” Prof. Gray explained. 

“Another way of increasing the dose density is to give chemotherapeutics sequentially—anthracycline first and taxane second—rather than at the same time, allowing higher doses of each drug in each cycle while keeping side effects manageable,” he said. 

Six trials compared 3-weekly sequential chemotherapy vs 3-weekly concurrent chemotherapy (11,028 patients). Six trials compared 2-weekly sequential therapy vs concurrent 3-weekly chemotherapy (6,352 patients). 

Study Results 

PROF. GRAY SAID the “cleanest” comparison was in the 7 trials that evaluated every-2-week dose-dense chemotherapy vs the same doses and chemotherapy given every 3 weeks. In that group of studies, dose intensification reduced the likelihood of recurrence by 17% (P = .00004) and the likelihood of breast cancer death by 14% (P = .004). This represents a 10-year gain of 4.3% for recurrence and a 10-year gain of 2.8% for breast cancer mortality. 

The next group of studies looked at sequential (3-weekly) vs concurrent (3-weekly) chemotherapy and also found significant reductions in recurrence and breast cancer mortality with the sequential strategy. The likelihood of recurrence was reduced by 13% (P = .0006) and the likelihood of breast cancer death by 11% (P = .03) among women in the sequential 3-weekly group. Looking at a comparison of sequential 2-weekly vs concurrent 3-weekly chemotherapy, sequential therapy reduced the likelihood of any recurrence by 18% (P = .0001) and the likelihood of breast cancer death by 18% (P = .001). 

A pooled analysis of all 25 trials in 34,122 women showed a highly significant 15% reduction in recurrence (P = .00001) and 13% reduction in breast cancer death (P = .00001). The 10-year recurrence rate was 32% for standard chemotherapy and 28.4% for dose-dense chemotherapy. The rate of breast cancer mortality was 22.2% vs 19.5%, respectively. 

In the pooled analysis, both estrogen receptor–negative and estrogen receptor–positive patients benefited from dose intensification. Dose intensification reduced the risk of recurrence by 18% in estrogen receptor–negative patients (P = .00004) and by 14% in estrogen receptor–positive patients (P = .00001). 

“Whatever approach you use for dose intensification, there is improved recurrence and mortality. [In the pooled analysis], dose intensification reduced recurrence by 15% and breast cancer mortality by 13%. Across all trials, the absolute difference in recurrence was 3.6% and in mortality was 2.6%,” Prof. Gray said. 

“It is hard to say which method of acceleration is best. Longer treatment seemed to be a little better than short treatment. We still need trials to answer simple questions like how long to give chemotherapy. Also, we need longer follow-up beyond 10 years given the long natural history of breast cancer,” he told listeners. 

Regarding toxicity, Prof. Gray said that it is difficult to look at side effects in a meta-analysis. “We found surprisingly little extra toxicity considering the extra benefits. Knowing that you are getting benefits in recurrence and mortality makes it easier for patients to tolerate toxicity,” he noted. 

Prof. Gray pointed out that many U.S. oncologists are already using dose intensification, whereas those in the United Kingdom continue to hold out for standard chemotherapy. “This might be because the big TACT2 trial in the UK did not show significant benefits,” he commented. 

“This meta-analysis is a confirmation for me that dose-dense chemotherapy is better.”

— Virginia Kaklamani, MD

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‘Everybody Wins’ 

“PEOPLE IN THE United States are using dose-dense chemotherapy for early breast cancer. The only reason not to do it is habit. This meta-analysis is a confirmation for me that dose-dense chemotherapy is better,” stated press conference moderator Virginia Kaklamani, MD, of The University of Texas Health Science Center, San Antonio. 

“The beauty of dose intensification is giving the exact same drugs over a shorter time and getting even more benefit. The toxicity can be reduced with growth factor support, and the treatment is completed in 4 months instead of 6 months. Everybody wins,” she said. 

“Meta-analyses are not easy to do. This one is based on individual patient data, and it shows an incremental benefit. If you give chemotherapy the right way, you almost double the benefit over no chemotherapy. This is huge. Even though we have advances like immunotherapy and targeted therapy, chemotherapy is the main therapy I offer my patients with early breast cancer, and I would rather make it better,” Dr. Kaklamani continued. 

“I use dose-dense chemotherapy in my practice. These data are compelling enough to suggest that everyone should be doing it. The meta-analysis shows a greater magnitude of benefit than the individual trials,” she said. 

“All these incremental improvements should be applauded, but we need equivalent review of the toxicities and tolerability of these different approaches... to enable wise decision-making.”

— Dame Lesley Fallowfield, FMedSci, DPhil, BSc

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Toxicity Concerns 

TOXICITY IS A CONCERN with dose-dense chemotherapy. Dr. Kaklamani said that the toxicity she measures (in blood cell counts) shows improvement when dose-dense chemotherapy is given with growth factor support. 

“Patients do report being more tired with every-2-week cycles, but...there is light at the end of the tunnel. When they hear about the benefits and the shorter treatment cycles, they are willing to tolerate toxicity,” she said. 

“We as oncologists are not good at reporting patient toxicity. We have to get better at it and so do our patients. Patient-reported outcomes tools are being developed that will help us characterize toxicity better,” she added. 

Speaking from the audience after Prof. Gray’s presentation, Dame Lesley Fallowfield, FMedSci, DPhil, BSc, Professor of Psycho-Oncology, University of Sussex Medical School, Brighton, United Kingdom, expressed concerns about toxicities. 

“All these incremental improvements should be applauded, but we need equivalent review of the toxicities and tolerability of these different approaches. Such data are important to have to enable wise decision-making,” Prof. Fallowfield said. 

Prof. Gray agreed that toxicity is important but said that those data were not part of the meta-analysis. ■

DISCLOSURE: Profs. Gray and Fallowfield and Dr. Kaklamani reported no conflicts of interest. 

REFERENCE 

1. Gray R, Bradley R, Braybrooke J, et al; for the Early Breast Cancer Trialists Collaborative Group: Increasing the dose density of adjuvant chemotherapy by shortening intervals between courses or by sequential drug administration significantly reduces both disease recurrence and breast cancer mortality: An EBCTCG meta-analysis of 21,000 women in 16 randomised trials. 2017 San Antonio Breast Cancer Symposium. Abstract GS1-01. Presented December 6, 2017.