High-Dose Chemo Most Benefits Patients With High-Risk Breast Cancer

In Clinical Studies News by Barbara Jacoby

By: Maggie L. Shaw

From: ajmc.com

A 20-year follow-up comprising a secondary analysis to an original study shows that high-dose chemotherapy plus hematopoietic stem cell transplant benefit patients with high-risk stage III disease with 10 or more axillary lymph nodes involved.

Adjuvant high-dose chemotherapy (HDCT) with cyclophosphamide/thiotepa/carboplatin plus hematopoietic stem cell transplant (HSCT), compared with conventional-dose chemotherapy (CDCT), was shown to benefit overall long-term breast cancer–specific survival among patients with high-risk stage III disease with 10 or more axillary lymph nodes (ALNs) involved, according to JAMA Oncology study results.

“Our analysis with 20-year follow-up data from, to our knowledge, the largest randomized clinical trial of HDCT for BC suggests that selected subgroups may benefit from this treatment,” the authors noted.

They performed this follow-up study because although previous trials have not shown a benefit to HDCT, long-term follow-up data are lacking in the space. The primary outcome was 2-fold: overall survival and safety coupled with risk of second malignant neoplasm or cardiovascular events.

Updated data were collected from June 1, 2016, through December 31, 2017, with analysis occurring from February 1, 2018, to October 14, 2019. The original study took place between August 1, 1993, and July 31, 1999, at 10 hospitals in the Netherlands.

This secondary analysis of a phase 3 trial comprised 2 patient groups, randomized 1:1, with the following characteristics:

  • CDCT group (n = 443) received 5 cycles of fluorouracil 500 mg/m2, epirubicin 90 mg/m2, and cyclophosphamide 500 mg/m2
  • HDCT group (n = 442) received 4 cycles of fluorouracil 500 mg/m2, epirubicin 90 mg/m2, and cyclophosphamide 500mg/m2 plus a fifth cycle of cyclophosphamide, 6000 mg/ m2, thiotepa 480 mg/m2, and carboplatin 1600 mg/m2 plus HSCT

The mean (SD) patient age was 44.5 (6.6) years, and there was a mean (interquartile range [IQR]) follow-up of 20.4 (19.2-22.0) years.

Results show the HDCT group had an almost 10% higher chance of 20-year overall survival (OS) compared with the CDCT group: 45.3% vs 41.5% (HR, 0.89; 95% CI, 0.75-1.06).

In addition, patients with 10 or more ALNs involved, compared with 4 to 9 involved, saw a much larger improvement in their 20-year OS: 14.6% (HR, 0.72; 95% CI, 0.54-0.95) vs 2.2% (HR, 1.01; 95% CI, 0.81-1.27).

Meanwhile, those with triple-negative disease saw an improvement in their 20-year OS of 15.4% (HR, 0.67; 95% CI, 0.42-1.05) compared with 7.0% (HR, 0.80; 95% CI, 0.63-1.02) for patients with estrogen receptor–positive and ERBB2-negative disease.

Other results were mixed. The data show comparable 20-year outcomes between the HDCT and CDCT groups for a second malignant neoplasm (data for this measure were available for 99% of all patients): 12.1% (95% CI, 11.8%-12.4%) vs 16.2% (95% CI, 15.9%-16.6%) after CDCT (P = .10).

However, there were greater risks of several cardiovascular events in the HDCT group compared with the CDCT group:

  • Hypertension: 21.7% vs 14.3% (P = .02)
  • Hypercholesterolemia: 15.7% vs 10.6% (P = .04)
  • Dysrhythmias: 8.6% vs 4.6% (P = .005)

For the cardiovascular outcomes measure, data were available for only 85.8% of all patients.

“Adjuvant high-dose chemotherapy with stem cell support should not be used in unselected patients with stage III breast cancer, but the survival benefit in subgroups of patients suggests that further research is needed,” the authors concluded.

A new trial among patients with stage III breast cancer, SUBITO (Substantially Improving the Cure Rate of High-risk BRCA1-like Breast Cancer Patients With Personalized Therapy), is investigating the safety, efficacy, and cost-effectiveness of HDCT compared with current standard of care dose-dense doxorubicin/cyclophosphamide/paclitaxel-carboplatin, and a PARP inhibitor.


Steenbruggen TG, Steggink LC, Seynaeve CM, et al. High-dose chemotherapy with hematopoietic stem cell transplant in patients with high-risk breast cancer and 4 or more involved axillary lymph nodes: 20-year follow-up of a phase 3 randomized clinical trial. JAMA Oncol. 2020;6(4):528-534. doi:10.1001/jamaoncol.2019.627