Shortening the interval between chemotherapy cycles or administrating anthracycline and a taxane sequentially instead of giving them together significantly lowers the risk for breast cancer recurrence and death from breast cancer compared to standard chemotherapy given every 3 weeks, a major meta-analysis demonstrates.
"If you can cram more dose into the same time, you are intensifying treatment and you don't give the cancer as much time to grow back as you do with standard chemotherapy, so you are more likely to eradicate it," Richard Gray, PhD, professor of medical statistics, University of Oxford, United Kingdom, said at a press briefing here.
You don't give the cancer as much time to grow back. Dr Richard Gray
"And we found that all patients benefited from dose intensification, so this helps us fine-tune what we are giving, and we might as well optimize the chemotherapy that patients are going to get anyway," he added.
The study was presented here at the San Antonio Breast Cancer Symposium (SABCS) 2017.
The meta-analysis included 25 trials in which 34,122 patients with early-stage breast cancer were treated with some form of dose-intensification regimen.
Dose intensity trials included seven trials in which the same chemotherapy drugs and the same doses were given in either dose-dense, 2-weekly cycles or as a standard 3-weekly regimen. Five trials evaluated the same two schedules, but there were some differences in the drugs that were compared.
Five other trials evaluated the benefit of giving the same drugs sequentially in 3-weekly cycles vs giving the same drugs concurrently, again in 3-weekly cycles. One trial evaluated the same sequential vs concurrent schedules, but there were some differences in the drugs used between trials.
Six trials evaluated whether drugs given sequentially in 2-weekly cycles led to superior outcomes compared with a concurrent, 3-weekly cycle. Importantly, there were some differences in drugs used in these six trials.
In all trials, patients were required to receive concurrent treatment with granulocyte colony-stimulating factor for immune system support.
Breast cancer recurrence rates as well as mortality from breast cancer at 10 years were the coprimary endpoints of the meta-analysis.
Primary Outcome
Trials involving over 10,000 women showed that giving patients the same drugs but for a shorter interval reduced the absolute risk for breast cancer recurrence by 4.3% at 10 years compared to the standard every-3-week regimen (24% vs 28.3%; P = .00004).
Mortality from breast cancer at 10 years was 2.8% lower with dose-dense regimens compared with standard chemotherapy (16.8% vs 19.6%; P = .004),
More than 11,000 women were treated with either sequential or concurrent chemotherapy, both given every 3 weeks.
Here again, Dr Gray and colleagues found that the risk for recurrence was lower when the drugs were given sequentially instead of together.
At 10 years, 28.1% of women who were treated sequentially experienced disease recurrence, compared with 31.2% of those treated concurrently ( P = .0006).
The mortality at 10 years was 1.9% lower in favor of the sequential vs the concurrent approach (17.7% vs 19.8%; P = .03),.
Trials in which more than 6500 women were treated using both a sequential approach and a shorter interval between cycles again showed a major benefit in favor of dual intensification.
At 10 years, absolute recurrence rates were 4.5% lower among women receiving sequential therapy every 2 weeks compared with those receiving concurrent chemotherapy every 3 weeks (30.4% vs 34.9%; P = .0001).
Mortality from breast cancer at 10 years was reduced by 3.9% in favor of dose intensification compared with standard chemotherapy (P = .001), with mortality rates of 22.1% for sequential, every-2-week regimens compared to 26% for concurrent every-3-week schedules.
Pooled analysis of all 25 dose intensification trials showed very similar results, Dr Gray observed. At 10 years, the risk for recurrence was 4.4% lower in favor of dose intensification, at 28.4%, compared with 32% for standard every-3-week chemotherapy (P < .00001).
In the pooled analysis, mortality from breast cancer at 10 years was 3.7% lower in favor of dose-dense regimens (P < .00001), with mortality rates of 19.5% for dose-dense regimens compared with 22.2% for standard chemotherapy schedules.
The investigators also found that reductions in rates of recurrence were similar for both estrogen-receptor (ER) positive and ER-negative disease. Tumor type or patient characteristics did not influence outcomes.
Importantly, there was no increase in mortality from non-breast-cancer causes between dose-intense treatment and standard chemotherapy.
Indeed, if anything, there were fewer deaths from causes other than breast cancer during the first year in which chemotherapy was given, the investigators noted.
Growth factor support is required for the administration of dose-dense chemotherapy, yet there did not appear to be any significant increase in toxicity with the dose-dense approach, although toxicity is difficult to measure in meta-analyses, Dr Gray noted.
"However, these trials achieved dose intensification. There were fewer recurrences and lower mortality rates at 10 years compared with standard chemotherapy, and it is quite remarkable how consistent all of these various approaches were in favoring dose intensification," Dr Gray emphasized.
"Since a standard schedule of anthracycline followed by a taxane reduces breast cancer mortality by about one third, using a dose-intensification approach means you get almost a 50% reduction in the [relative] risk of breast cancer mortality [compared to no chemotherapy], so it's very important to identify the step-by-step gains we've been making in this disease," Dr Gray concluded.
Commenting on the study, conference moderator Virginia Kaklamani, MD, professor of medicine, UT Health Science Center, San Antonio, Texas, told the press that in fact, many oncologists in the United States are already using dose-intensification strategies for the treatment of breast cancer on the basis of findings from several previously reported pivotal trials that support the superiority of dose intensification over conventional chemotherapy.
"What's interesting is we used to give chemotherapy over 6 months, and with this approach, we can give it over 4 months, so patients prefer it, and with growth factor support, the toxicity can actually be less than it is with standard chemotherapy," Dr Kaklamani said.
"So if you give chemotherapy the right way, you greatly enhance its benefit, and even though we are all talking about new treatments like immunotherapy, the main treatment I offer my patients every single day is still chemotherapy, and I'd rather make that chemotherapy better ― and better tolerated," Dr Kaklamani added.
The study was funded by Cancer Research UK, the Medical Research Council, the British Heart Foundation, and the University of Oxford. Dr Gray and Dr Kaklamani have disclosed no relevant financial relationships.
San Antonio Breast Cancer Symposium (SABCS) 2017: Abstract GS1-0. Presented December 6, 2017.
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