High-Dose Chemotherapy With Hematopoietic Stem Cell Transplant in Patients With High-Risk Breast Cancer and 4 or More Involved Axillary Lymph Nodes

Abstract

IMPORTANCE Trials of adjuvant high-dose chemotherapy (HDCT) have failed to show a survival benefit in unselected patients with breast cancer, but long-term follow-up is lacking. OBJECTIVE To determine 20-year efficacy and safety outcomes of a large trial of adjuvant HDCT vs conventional-dose chemotherapy (CDCT) for patients with stage III breast cancer. DESIGN, SETTING, AND PARTICIPANTS This secondary analysis used data from a randomized phase 3 multicenter clinical trial of 885 women younger than 56 years with breast cancer and 4 or more involved axillary lymph nodes conducted from August 1, 1993, to July 31, 1999. Additional follow-up data were collected between June 1, 2016, and December 31, 2017, from medical records, general practitioners, the Dutch national statistical office, and nationwide cancer registries. Analysis was performed on an intention-to-treat basis. Statistical analysis was performed from February 1, 2018, to October 14, 2019. INTERVENTIONS Participants were randomized 1:1 to receive 5 cycles of CDCT consisting of fluorouracil, 500 mg/m 2 , epirubicin, 90 mg/m 2 , and cyclophosphamide, 500 mg/m 2 , or HDCT in which the first 4 cycles were identical to CDCT and the fifth cycle was replaced by cyclophosphamide, 6000 mg/m 2 , thiotepa, 480 mg/m 2 , and carboplatin, 1600 mg/m 2 , followed by hematopoietic stem cell transplant. MAIN OUTCOMES AND MEASURES Main end points were overall survival and safety and cumulative incidence risk of a second malignant neoplasm or cardiovascular events. RESULTS Of the 885 women in the study (mean [SD] age, 44.5 [6.6] years), 442 were randomized to receive HDCT, and 443 were randomized to receive CDCT. With 20.4 years median follow-up (interquartile range, 19.2-22.0 years), the 20-year overall survival was 45.3% with HDCT and 41.5% with CDCT (hazard ratio, 0.89; 95% CI, 0.75-1.06). The absolute improvement in 20-year overall survival was 14.6% (hazard ratio, 0.72; 95% CI, 0.54-0.95) for patients with 10 or more invoved axillary lymph nodes and 15.4% (hazard ratio, 0.67; 95% CI, 0.42-1.05) for patients with triple-negative breast cancer. The cumulative incidence risk of a second malignant neoplasm at 20 years or major cardiovascular events was similar in both treatment groups (20-year cumulative incidence risk for second malignant neoplasm was 12.1% in the HDCT group vs 16.2% in the CDCT group, P = .10), although patients in the HDCT 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). CONCLUSIONS AND RELEVANCE High-dose chemotherapy provided no long-term survival benefit in unselected patients with stage III breast cancer but did provide improved overall survival in very high-risk patients (ie, with Ն10 involved axillary lymph nodes). High-dose chemotherapy did not affect long-term risk of a second malignant neoplasm or major cardiovascular events. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT03087409

Identification of Potential Hub Genes and Therapeutic Drugs in Malignant Pleural Mesothelioma by Integrated Bioinformatics Analysis

“…The application of valrubicin has been reported to have benefits for the treatment of skin tumors [59], and it also has a certain effect on some bladder cancers [60]. Epirubicin has a certain effect on the combined treatment of breast cancer, and there is certain evidence in many clinical trials [61, 62]. Enoxacin, as an antibacterial drug, may be a useful option for cervical cancer treatment [63].…”

Treating Metastatic Brain Cancers With Stem Cells

“…There is no conclusive data on high dose chemotherapy and stem cell long term benefits compared to standard therapy ( Chen B. B. et al, 2016 ; Steenbruggen et al, 2020 ). While the combination of chemotherapy and stem cell therapy is hopeful as a treatment for cancer, there is conflicting literature at this time to unequivocally predict its efficacy in humans, as it can be dependent on type of chemotherapy, type of stem cells, and type of cancer ( Somlo et al, 1994 ; VanderWalde et al, 2012 ; Qian et al, 2017 ).…”

“…High dose chemotherapy in combination with stem cells for breast cancer patients show long-term event-free survival, but an overall survival benefit is not significant ( Berry et al, 2011 ). Likewise, high dose adjuvant chemotherapy with autologous hematopoietic stem cells has no significant overall survival value compared to control ( Steenbruggen et al, 2020 ). However, there is evidence in breast cancers that involve at least ten axillary lymph nodes, HER2 negative breast cancer, and triple negative breast cancer ( Steenbruggen et al, 2020 ).…”

“…Likewise, high dose adjuvant chemotherapy with autologous hematopoietic stem cells has no significant overall survival value compared to control ( Steenbruggen et al, 2020 ). However, there is evidence in breast cancers that involve at least ten axillary lymph nodes, HER2 negative breast cancer, and triple negative breast cancer ( Steenbruggen et al, 2020 ).…”

High-Dose Chemotherapy with Stem Cell Rescue to Treat Stage III Homologous Deficient Breast Cancer: Factors Influencing Clinical Implementation

“…A promising treatment to improve overall survival is high-dose chemotherapy with autologous stem cell rescue (HDCT). Unfortunately, HDCT has only shown limited clinical bene t in high-risk breast cancer, at the expense of considerable toxicity during the rst year after diagnosis, and long-term toxicity comparable to conventional chemotherapy [4,5,6]. For example, pre-planned analyses of Dutch and American randomized controlled trials showed that HDCT improved 5-year relapse-free survival up to 10% for breast cancer patients with 10 or more positive lymph nodes [7,8].…”