Use of "dose-dense" adjuvant chemotherapy in premenopausal breast cancer patients is associated with a significant improvement in overall survival, according to new findings presented at the 10th European Breast Cancer Conference (EBCC-10).
Adjuvant chemotherapy given every 2 weeks improved overall survival at 10 years by 29% in comparison with chemotherapy given at the standard interval of 3 weeks.
The regimen did not appear to put patients at a higher risk for treatment-induced amenorrhea.
"To date, according to treatment guidelines, there is no evidence to recommend a specific chemotherapy regimen for premenopausal women requiring adjuvant chemotherapy," said lead author Matteo Lambertini, MD, a medical oncologist at IRCCS AOU San Martino–IST, National Institute for Cancer Research, Genoa, Italy.
"Our study showed that dose-dense chemotherapy is associated with a significant and clinically relevant improved overall survival, and hence, we believe this should be considered the standard treatment option in high-risk premenopausal breast cancer patients," he told Medscape Medical News.
In the United States, dose-dense chemotherapy is the preferred adjuvant regimen, and its use has become more common over the years, Dr Lambertini explained. However, that is not the case in Europe, where there are no clear recommendations, and dose-dense regimens are less commonly used.
Aside from the survival advantage, the dose-dense schedule might be more convenient for premenopausal patients, who are generally employed at the time of breast cancer diagnosis.
"With the use of dose-dense schedule, the overall duration of adjuvant chemotherapy as well as the recovery from its side effects, including alopecia, would be reduced as compared to standard- interval chemotherapy, with subsequent possible advantages for the return-to-work process," he said.
In the current study, dose-dense chemotherapy seemed to be effective irrespective of hormone-receptor status; 10-year overall survival was improved in patients with hormone receptor–positive tumors by 22%, and by 35% in those with hormone receptor–negative tumors.
Dr Lambertini pointed out that the available evidence from prior studies in breast cancer, which were not restricted to premenopausal women, suggests that the benefit of dose-dense chemotherapy seems to be restricted to patients with hormone receptor–negative breast cancer.
Although in this study, the benefit was greater in women with hormone receptor–negative tumors, a benefit was also observed in patients with hormone receptor–positive tumors.
"This finding might be explained by the fact that premenopausal patients are known to be more sensitive to chemotherapy," he said. "Young age is an independent factor associated with higher risk of relapse and death, and premenopausal patients are more likely to develop more aggressive breast cancer subtypes, which are less responsive to conventional therapy."
For these reasons, all premenopausal patients at high risk for relapse, irrespective of hormone-receptor status, might represent the best candidates for dose-dense chemotherapy regimens, Dr Lambertini explained.
Pooled Results Show Advantage
In their study, Dr Lambertini and his colleagues conducted a meta-analysis of two large, randomized, phase 3 clinical trials that compared adjuvant chemotherapy given every 2 weeks (dose dense) or every 3 weeks (the standard interval).
In the MIG1 study (J Natl Cancer Inst. 2005 Dec 7;97:1724-33), patients with node-positive or high-risk node-negative breast cancer were randomly assigned to receive either six cycles of fluorouracil/epirubicin/cyclophosphamide (FEC 600/60/600 mg/m2) every 2 weeks (dose dense [DD]) or every 3 weeks (standard interval [SI]).
In the GIM2 study (Lancet. 2015 May 9;385:1863-72), patients with early node-positive breast cancer were randomly assigned to receive four cycles of DD or SI epirubicin/cyclophosphamide (EC) or fluorouracil/epirubicin/cyclophosphamide followed by four cycles of DD or SI paclitaxel.
The number of cycles (four with EC or FEC and four with paclitaxel) and the dosing (F, 600 mg/m2; E, 90 mg/m2; C, 600 mg/m2; paclitaxel, 175 mg/m2) were the same in all treatment arms.
In the MIG1 study, treatment-induced amenorrhea was defined as the absence of menses for at least 3 months during chemotherapy or within 3 months after the end of chemotherapy; in the GIM2 study, it was defined as absence of menses 12 months after the end of chemotherapy.
A total of 1549 patients were included in the study by Dr Lambertini and colleagues: 528 of 1214 from the MIG1 study, and 1021 of 2091 from the GIM2 study.
In the MIGI study, the 10-year overall survival was 84.9% in the DD arm and 79.1% in the SI arm (HR = 0.72; P = .137).
Similar results were seen in the GIM2 study: 88.0% and 77.3%, respectively (HR = 0.71; P = .079).
The pooled analysis showed that DD chemotherapy significantly improved overall survival compared with SI (HR = 0.71; P = .021; test for heterogeneity P = .953).
Dose-dense chemotherapy was not associated with an increased risk of developing treatment-induced amenorrhea (OR = 1.05; P = .646; test for heterogeneity P = .592).
in the MIG1 study, 160 patients (59.9%) in the DD arm and 159 patients (60.9%) in the SI arm developed treatment-induced amenorrhea (OR = 1.15; P = .484).
In the GIM2 study, 229 (46.3%) and 235 (44.7%) developed treatment-induced amenorrhea (OR = 1.01; P = .925).
Impact of Treatment-Induced Amenorrhea
The prognostic impact of treatment-induced amenorrhea has not been well defined. Some research has shown improved survival outcomes with amenorrhea. In others, increased survival was found only in patients with hormone receptor–positive disease. Yet in other studies, it had no impact, Dr Lambertini noted.
Thus, how chemotherapy mediates its benefit remains controversial. It may occur through direct cytotoxicity with or without indirect endocrine effect in hormone-sensitive tumors, and there may be therapeutic consequences of developing treatment-induced amenorrhea.
"In our study, treatment-induced amenorrhea was not associated with a significant difference in overall survival," said Dr Lambertini. "However, although not statistically significant, a trend towards an increased overall survival probability was shown for women with hormone receptor–positive tumors who developed treatment-induced amenorrhea, and that was mainly restricted to the MIG1 study."
In contrast with the GIM2 study, in the MIG1 study, patients received a suboptimal treatment according to current guidelines (ie, six cycles of low-dose anthracycline-based chemotherapy, no taxanes, tamoxifen alone as endocrine therapy).
"Thus, the potential chemoendocrine effect of chemotherapy might have been highlighted in this situation," Dr Lambertini noted.
Recent data have elucidated the optimal strategies for manipulation of the menopausal status to improve disease outcomes, he added.
"In particular, the results of the SOFT [Suppression of Ovarian Function Trial] study demonstratedexcellent survival outcomes in premenopausal breast cancer patients who resumed their ovarian function after chemotherapy and were treated with ovarian suppression for 5 years as part of adjuvant endocrine therapy," Dr Lambertini said.
"Nowadays, ovarian suppression as part of adjuvant endocrine therapy is recommended by international guidelines in high-risk breast cancer patients," he added.
Standard of Care in the United States
Commenting on the study, Tracey O'Connor, MD, associate professor, Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York, noted that in the Unites States, dose-dense therapy is the standard of care for this population of patients.
"The dose-dense approach is preferred by many oncologists due to the survival advantage," she told Medscape Medical News. "And it's an approach that we use very frequently. This is the preferred regimen in guidelines."
Dr O'Connor pointed out that patients are not treated on the basis of their menopausal status. "We tend to use the dose-dense therapy in the US because when it was compared to the standard every-3-week treatment ― with the same doses, same drugs, same regimen — it improved disease-free survival and overall survival, and that's why we use it."
There is also no additional toxicity with a dose-dense regimen, she added.
"They did find that some of the women on the study were becoming amenorrheic at a higher rate than those treated with standard therapy," Dr O'Connor said. "This is potentially a therapeutic advantage, and it sounds like the researchers are going to be investigating that further."
The authors have disclosed no relevant financial relationships.
10th European Breast Cancer Conference (EBCC-10): Abstract 5, presented March 10, 2016.
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