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

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/m2, epirubicin, 90 mg/m2, and cyclophosphamide, 500 mg/m2, or HDCT in which the first 4 cycles were identical to CDCT and the fifth cycle was replaced by cyclophosphamide, 6000 mg/m2, thiotepa, 480 mg/m2, and carboplatin, 1600 mg/m2, 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 ≥10 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.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Steenbruggen reported receiving grants from the Dutch Health Insurance Council (OG 94-051) during the conduct of the study; and a grant for development of a podcast for women treated for breast cancer from Memidis Pharma outside the submitted work. Dr van der Hoeven reported receiving travel, accommodations, and/or expenses from Roche and Pfizer, all unrelated to the current study. Dr Tjan-Heijnen reported receiving grants from Dutch Health Insurance Council during the conduct of the study; and receiving honoraria from Pfizer; serving in a consulting or advisory role for Pfizer, Lilly, and Roche; receiving research funding for her institution from Roche, Eisai, Pfizer, and Novartis; and receiving travel, accommodations, and/or expenses from Pfizer, Novartis, and Roche, all unrelated to the current study. Dr Linn reported being an inventor of a BRCA1-like patent; receiving grants from Health Insurance Council during the conduct of the study; grants from Amgen and Eurocept Pharmaceuticals outside the submitted work; grants, nonfinancial support, and institutional research support from AstraZeneca outside the submitted work; serving as an advisory board member for Cergentis and IBM outside the submitted work; grants and nonfinancial support from Genentech, Novartis, and Roche outside the submitted work; grants and institutional research support from Pfizer outside the submitted work; research funding from AstraZeneca, Roche, Genentech, Amgen, Sanofi, BMS, and Tesaro; and consultation fees from Novartis, IBM Health, AstraZeneca, Roche, and Sanofi, all unrelated to the current study. Dr Schaapveld reported receiving grants from the Dutch Health Insurance Council during the conduct of the study. Dr de Vries reported institutional research support from Synthon, Pfizer, Sanofi, The National Surgical Adjuvant Breast and Bowel Project, and Daiichi Sankyo; and grants from Novartis, Amgen, Roche, Genentech, Regeneron, Chugai, Synthon, AstraZeneca, Radius Health, CytomX Therapeutics, Nordic Nanovector, Bayer, and G1 Therapeutics outside the submitted work. Dr Sonke reported receiving institutional research support from AstraZeneca, Merck, Novartis, and Roche outside the submitted work. Dr Gietema reported receiving grants from Abbvie, Roche, and Siemens outside the submitted work. No other disclosures were reported.

Figures

Figure 1.. CONSORT Flow Diagram

CONSORT flow diagram showing the 885 patients who were included in the intention-to-treat analysis and safety population. Information on the number of patients screened for eligibility was not collected and is thus not reported.

Figure 2.. Overall Survival (OS) in All Patients and Subgroups

A, All patients. B, Patients with triple-negative breast cancer. C, Patients with 10 or more involved axillary lymph nodes. D, Patients with 4 to 9 involved axillary lymph nodes. For the OS analysis for all patients and subgroups, 20-year estimates with corresponding 95% CIs and hazard ratios (HRs) with corresponding 95% CIs are reported. CDCT indicates conventional-dose chemotherapy; and HDCT, high-dose chemotherapy.

Figure 3.. Stratified Overall Survival Analysis in Subgroups

CDCT indicates conventional-dose chemotherapy; ER+, estrogen receptor–positive; ERBB2−, Erb-B2 receptor tyrosine kinase 2 negative; ERBB2+, Erb-B2 receptor tyrosine kinase 2 positive; HDCT, high-dose chemotherapy; and OS, overall survival.