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... Show moreImportance 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 >= 10 involved axillary lymph nodes). High-dose chemotherapy did not affect long-term risk of a second malignant neoplasm or major cardiovascular events. Show less
Steenbruggen, T.G.; Steggink, L.C.; Seynaeve, C.M.; Hoeven, J.J.M. van der; Hooning, M.J.; Jager, A.; ... ; Gietema, J.A. 2018
Background: Lapatinib, a tyrosine kinase inhibitor of human epidermal growth factor receptor 2 (HER2), has shown activity in combination with capecitabine in patients with HER2-positive advanced... Show moreBackground: Lapatinib, a tyrosine kinase inhibitor of human epidermal growth factor receptor 2 (HER2), has shown activity in combination with capecitabine in patients with HER2-positive advanced breast cancer progressive on standard treatment regimens. We present results on preapproval drug access for this combination in such patients occurring in the general oncology practice in the Netherlands. Methods: Patients with HER2-positive advanced breast cancer progressive on schedules containing anthracyclines, taxanes, and trastuzumab were eligible. Brain metastases were allowed if stable. Lapatinib 1250 mg/day was given continuously in combination with capecitabine moo mg/m(2) twice daily for two weeks in a three-week cycle. Efficacy was assessed by use of response evaluation criteria in solid tumours version I.O. Progression-free survival (PFS) and overall survival (OS) were calculated. Results: Eighty-three patients were enrolled from January 2007 until July 2008. The combination was generally well tolerated and the most common drug-related serious adverse events were nausea and/or vomiting (5%) and diarrhoea (2%). Seventy-eight patients were evaluable for response. Clinical benefit (response or stable disease for at least 12 weeks) was observed in 50 patients (64%) of whom 15 had a partial response and 35 stable disease. The median PFS and OS were 17 weeks (95% CI: 13 to 21) and 39 weeks (95% CI: 24 to 54), respectively. For OS, higher Eastern Cooperative Oncology Group (ECOG) status (p= 0.016), brain metastases at study entry (p=0.010) and higher number of metastatic sites (p=0.012) were significantly negative predictive factors. Conclusion: In a patient population with heavily pretreated HER2-positive advanced breast cancer lapatinib plus capecitabine was well tolerated and offered clinical benefit. Show less
Deenik, W.; Janssen, J.J.W.M.; Holt, B. van der; Verhoef, G.E.G.; Smit, W.M.; Kersten, M.J.; ... ; Cornelissen, J.J. 2010
