High-dose chemotherapy may improve outcomes in very high-risk breast cancer
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High-dose chemotherapy followed by hematopoietic stem cell transplantation improved OS among very high-risk patients with breast cancer compared with conventional-dose chemotherapy, according to long-term follow-up of a randomized study published in JAMA Oncology.
However, high-dose chemotherapy did not improve survival among unselected patients with stage III breast cancer.
“We think our results urge evaluation of the high-dose regimen of chemotherapy compared with a contemporary control arm in patients with high-risk, triple-negative or HER2-negative breast cancer,” Gabe S. Sonke, MD, PhD, medical oncologist in the division of medical oncology at Netherlands Cancer Institute, told Healio. “Also, given the increased knowledge of cancer biology, we have learned that tumors that harbor homologous recombination deficiency may be particularly sensitive to high-dose chemotherapy.”
Several phase 3 studies in the 1980s and 1990s evaluated high-dose chemotherapy with autologous stem cell support for breast cancer; however, those trials were halted after high-dose chemotherapy did not improve survival compared with conventional-dose chemotherapy. High-dose chemotherapy also has been associated with risks, including severe mucositis, myeloablation-causing transfusion dependency and prolonged neutropenia.
However, subsequent subgroup analyses have suggested that certain very high-risk patients — including those with 10 or more involved axillary lymph nodes — may benefit from high-dose chemotherapy.
Due to the lack of long-term follow-up data from the earlier studies, Sonke and colleagues conducted 20-year follow-up from a randomized multicenter phase 3 study conducted in the Netherlands between 1993 and 1999.
The study included 885 women (mean age, 44.5 years at time of randomization) with at least four involved axillary lymph nodes who were randomly assigned to conventional-dose chemotherapy (n = 443) or high-dose chemotherapy (n = 442) followed by HSCT.
Women in the conventional-dose group received five cycles of 500 mg/m2 fluorouracil, 90 mg/m2 epirubicin and 500 mg/m2 cyclophosphamide. Women in the high-dose group received four cycles of the conventional dose plus one cycle of 6,000 mg/m2 cyclophosphamide, 480 mg/m2 thiotepa and 1,600 mg/m2 carboplatin.
OS, safety and cumulative incidence risk for a second malignant neoplasm or cardiovascular event served as the study’s primary endpoints.
Median follow-up was 20.4 years (interquartile range, 19.2-22 years).
Results showed a 20-year OS rate of 45.3% among those in the high-dose group and 41.5% among those in the conventional-dose group, which did not represent a significant difference (HR = 0.89; 95% CI, 0.75-1.06).
Absolute difference in 20-year OS was 14.6% (HR = 0.72; 95% CI, 0.54-0.95) for patients with 10 or more involved axillary lymph nodes, in favor of the high-dose regimen, compared with 2.2% (HR = 1.01; 95% CI, 0.81-1.27) for patients with four to nine lymph nodes.
Researchers also observed a 15.4% (HR = 0.67; 95% CI, 0.42-1.05) absolute difference in 20-year OS for those with triple-negative breast cancer with the high-dose regimen, compared with a 7% difference for ER-positive and ERBB2-negative disease (HR = 0.8; 95% CI, 0.63-1.02).
Researchers observed similar cumulative incidence risks for a second malignant neoplasm at 20 years in both treatment groups (high-dose group, 12.1% vs. conventional-dose group, 16.2%).
Although the incidence of major cardiovascular events did not differ between the groups, patients in the high-dose group more often had hypertension (21.7% vs. 14.3%; P = .02), hypercholesterolemia (15.7% vs. 10.6%, P = .04) and dysrhythmias (8.6% vs. 4.6%; P = .005).
“At 20-years median follow-up, we did not see a difference in incidence of second malignancies or in major cardiovascular events,” Sonke said. “However, we did see an increase in hypertension, hypercholesterolemia and dysthymia in the group of patients allocated to high-dose chemotherapy. Part of this increase could be attributed to the induction of early menopause in patients receiving high-dose chemotherapy.”
The type of dysrhythmia was often not specified, which makes it hard to draw conclusions about whether high-dose chemotherapy was the cause, he added.
“We recommend assessing cardiovascular risk factors, monitoring and, if necessary, treatment according to guidelines for patients previously treated with high-dose chemotherapy.” – by John DeRosier
For more information:
Gabe S. Sonke, MD, PhD, can be reached at g.sonke@nki.nl.
Disclosures: Sonke reports research funding to his institution from AstraZeneca, Merck, Novartis and Roche. Please see the study for all other authors’ relevant financial disclosures.
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