SAN ANTONIO (FRONTLINE MEDICAL NEWS) – Increasing the dose intensity of adjuvant chemotherapy for breast cancer by spacing cycles more closely or by giving drugs sequentially instead of concurrently improves outcomes, confirms a meta-analysis conducted by the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG).

Investigators led by Richard Gray, MSc , a professor of medical statistics in the Nuffield Department of Population Health at the University of Oxford in Oxford, England, analyzed individual patient data from 25 randomized trials among 34,122 women with early-stage breast cancer.

Results showed that depending on which specific strategy was used, women were 13%-18% less likely to experience recurrence and 11%-18% less likely to die from breast cancer if they were given dose-intensified chemotherapy instead of standard chemotherapy, he reported in a press briefing and a session at the San Antonio Breast Cancer Symposium.

“Shortening the interval between cycles and sequential administration of anthracycline and taxane chemotherapy reduces both recurrence and death from breast cancer,” Mr. Gray summarized. “The reductions are about 15%. They were seen in both estrogen receptor [ER]–positive and ER-negative disease and did not differ significantly by any other tumor or patient characteristics.”

“The beauty of this is these are the exact same drugs and, in many cases, similar doses. It’s just the schedule that changes,” commented press briefing moderator Virginia Kaklamani, MD , a professor of medicine in the division of hematology/oncology at the University of Texas Health Science Center San Antonio and a leader of the Breast Cancer Program at the UT Health San Antonio Cancer Center. “We used to give chemotherapy over 6 months, and with this approach, we can give it over 4 months, so the patients prefer it. The toxicity, with the growth factors for support, can be less. So everybody wins here.”

“Most of us [U.S. oncologists] have been using these [dose-intensification] approaches for the past several years because of a couple pivotal trials. But the benefits from those pivotal trials were not as impressive by themselves,” she added. The meta-analysis shows that “when you give chemotherapy in the right way, you almost double the benefit. So this is huge, even in the era of having immunotherapeutic drugs and all these other targeted drugs. The main treatment I offer my patients every single day is still chemotherapy, and I’d rather make it better and better tolerated.”

Study details

“We know that adjuvant chemotherapy can really help reduce recurrence and prevent breast cancer death. It reduces breast cancer death by about a third,” Mr. Gray noted, giving some background to the analysis. “We are still looking at ways to improve that even further. One of the approaches, which is based on cytokinetic modeling, is to try and increase the dose intensity of the chemotherapy.”

For the meta-analysis, the investigators identified trials that achieved dose intensification by reducing the interval between treatment cycles (a dose-dense approach) and/or by giving drugs sequentially rather than concurrently (allowing delivery of higher doses of each drug).

In all, seven trials, which included 10,004 women in total, tested chemotherapy given every 2 weeks (dose-dense chemotherapy) versus the same chemotherapy given every 3 weeks. Results showed that the former approach netted significantly lower risks of recurrence (rate ratio [RR], 0.83; P = .00004) and breast cancer mortality (RR, 0.86; P = .004), Mr. Gray reported. Absolute gains at 10 years were 4.3% and 2.8%, respectively. Findings were similar after adding five more trials, with another 5,508 women, that had some differences in chemotherapy treatments between arms.

Six trials, which included 11,028 women in total, tested sequential chemotherapy every 3 weeks versus concurrent chemotherapy every 3 weeks. Results showed similarly that the former strategy yielded lower risks of recurrence (RR, 0.87; P = .0006) and breast cancer death (RR, 0.89; P = .03). Absolute gains at 10 years were 3.2% and 2.1%, respectively.

Another six trials, which included a total of 6,532 women, tested sequential chemotherapy given every 2 weeks versus concurrent chemotherapy given every 3 weeks. Results here showed once again that the former yielded lower risks of recurrence (RR, 0.82; P = .0001) and breast cancer mortality (RR, 0.82; P = .001). Absolute gains at 10 years were 4.5% and 3.9%, respectively.

Finally, a pooled analysis of all trials showed that dose intensification reduced the risk of recurrence (RR, 0.85; P less than .00001) and breast cancer mortality (RR, 0.87; P less than .00001). Absolute gains at 10 years were 3.6% and 2.7%, respectively.

“That 13% reduction in breast cancer mortality may seem relatively modest, but given that taxane and anthracycline on a standard schedule reduces your chance of breast cancer death by a third, if you then reduce that by another 15%, then you have got almost 50% of breast cancer deaths by dose-dense taxane and anthracycline chemotherapy,” Mr. Gray pointed out. “So these little step-by-step improvements, it’s really important to identify them, and you get incremental gains which result in breast cancer deaths being about half of what they were 25 or 30 years ago.”

The proportional reduction in risk was similar whether tumors were ER positive or negative, but additional follow-up, especially for the positive tumors, will be important. “We do need longer follow-up in these trials, and sadly, many of the funding bodies are not providing funding for long-term follow-up,” he commented. “This is really valuable information, and we should be following these women up further, out to 20 years, given the long natural history of breast cancer.”

In terms of safety, the dose-intensification strategies were actually associated with lower risks of death without recurrence (RR, 0.85; P less than .02) and all-cause mortality (RR, 0.87; P less than .00001). Findings were similar when analyses focused on the first year of treatment.

Tolerability and toxicities of dose-intense regimens relative to standard regimens were not evaluated by the meta-analysis because these outcomes were reported differently across trials, according to Mr. Gray. However, the investigators did perform a systematic review of health-related quality of life studies that will be part of the final manuscript.

“We found surprisingly little extra toxicity” with the dose intensification, he reported. “It’s not very much considering the extra benefits we are getting. And when you know you are getting more benefit, it makes it easy to tolerate a drug.”

“In the U.S., people have moved toward the accelerated chemotherapy much more than they have in Europe. I think people have the mindset, ‘Well, we’ve always done it this way,’ ” Mr. Gray concluded. “This evidence being so clear and definite will help change that mindset. I wouldn’t be surprised if practice in the U.K. and many other parts of Europe doesn’t switch as a result of these very definite findings.”


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