Fatal events during clinical trials: an evaluation of deaths during breast cancer studies
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Information on deaths occurring during oncological clinical trials has never been systematically assessed. Here, we examine the incidence of death and the profile of patients who died during randomized clinical breast cancer (BC) trials.
Information on fatal events during German Breast Group (GBG) led BC trials was prospectively captured. Data were derived from the trial databases and death narratives. All deaths were evaluated for possible causes, underlying conditions, treatment relatedness, time point and rate of autopsies.
From 12/1996 to 01/2017, 23,387 patients were treated within 32 trials. Of those 88 (0.4%) died on therapy within 17 trials. Median age was 64 [range 35–84] years, 63.2% of patients had a body mass index (BMI) ≥ 25 kg/m2; 65.9% 1–3 and 22.7% ≥ 4 comorbidities; 61.4% 1–2 cardiovascular risk factors (CRFs); 26.4% took > 3 drugs; 81.7% had ECOG 0; 50.0% stage III, 76.7% luminal BC. The main causes of death were infection (38.6%; of those, 82.3% sepsis, 17.6% pneumonia), heart failure (14.8%), and pulmonary embolism (13.6%). Fatal events mainly occurred within the first 4 therapy cycles (55.7%), in the investigational arm (66.7%) and under anthracycline–taxane-based chemotherapy (51.1%). A relationship with the treatment was declared in 27.3% of the cases. An autopsy was performed in 13.6% of patients.
Death during study treatment was mainly related to infections, and patients with advanced disease, high BMI, underlying comorbidities, CRFs and concomitant medications. If considered for study participation these patients need careful monitoring due to their higher risk for death on study.
KeywordsDeath in clinical trial Cause of death Chemotherapy-related death Serious adverse events Rate of autopsy
We would like to thank all patients participating in the studies and the study teams of the involved studies.
The data were analyzed by JF and BL. All authors interpreted the data. The first draft of the manuscript was written by JF and BL. The decision to submit the manuscript for publication was made by all the authors. All authors contributed to the review of the manuscript. No persons other than the listed authors contributed to the writing of the manuscript.
Compliance with ethical standards
Conflict of interest
The authors declare no potential conflict of interest related to this work.
Statement of ethics
All patients included in the studies analyzed have provided written informed consent for study participation and data collection. All the analyzed trials were approved by the relevant ethics committees.
- 2.Food and Drug Administration. https://www.gpo.gov/fdsys/granule/CFR-2011-title21-vol5/CFR-2011-title21-vol5-sec312-33. Accessed 02 Oct 2018.
- 10.Schneeweiss A, Moebus V, Tesch H, Hanusch C, Denkert C, Luebbe K, et al. A randomised phase III trial comparing two dose-dense, dose-intensified approaches (EPC and PM(Cb)) for neoadjuvant treatment of patients with high-risk early breast cancer (GeparOcto). J Clin Oncol. 2017;35(15_suppl):518.CrossRefGoogle Scholar
- 11.Kümmel S, Paepke S, Huober J, Schem C, Untch M, Blohmer JU, et al. Randomised, open-label, phase II study comparing the efficacy and the safety of cabazitaxel versus weekly paclitaxel given as neoadjuvant treatment in patients with operable triple-negative or luminal B/HER2-negative breast cancer (GENEVIEVE). Eur J Cancer. 2017;84:1–8.CrossRefGoogle Scholar
- 12.von Minckwitz G, Reimer T, Potenberg J, Conrad B, Schürer U, Eidtmann H, et al. The phase III ICE study: adjuvant Ibandronate with or without capecitabine in elderly patients with moderate or high risk early breast cancer. Cancer Res. 2015;75(9 Supplement):S3–04.Google Scholar
- 14.Moebus V, von Minckwitz G, Jackisch C, Lück HJ, Schneeweiss A, Tesch H, et al. German Adjuvant Intergroup Node-positive Study (GAIN): a phase III trial comparing two dose-dense regimens (iddEPC vs. ddEC-PwX) in high-risk early breast cancer patients. Ann Oncol. 2017;28:1803–10.Google Scholar
- 15.Möbus V, Lück HJ, Forstbauer H, Wachsmann G, Ober A, Schneeweiss A, et al. GAIN-2: adjuvant phase III trial to compare intense dose-dense (idd) treatment with EnPC to tailored dose-dense (dt) therapy with dtEC-dtD for patients with high-risk early breast cancer: results of the second safety interim analyses. Cancer Res. 2016;76:1–13.Google Scholar
- 16.von Minckwitz G, Bear H, Bonnefoi H, Colleoni M, Gelmon K, Gnant M, et al. PENELOPE: phase III study evaluating palbociclib (PD-0332991), a cyclin-dependent kinase (CDK) 4/6 inhibitor in patients with hormone-receptor-positive, HER2-normal primary breast cancer with high relapse risk after neoadjuvant chemotherapy (GBG-78/BIG1-13). Cancer Res. 2013;73(24 Supplement):6–11.Google Scholar
- 17.von Minckwitz G, Conrad B, Reimer T, Decker T, Eidtmann H, Eiermann W, et al. A randomized phase 2 study comparing EC or CMF versus nab-paclitaxel plus capecitabine as adjuvant chemotherapy for nonfrail elderly patients with moderate to high-risk early breast cancer (ICE II-GBG 52). Cancer. 2015;121:3639–48.CrossRefGoogle Scholar
- 20.Bischoff J, Barinoff J, Mundhenke C, Bauerschlag D, Costa SD, Herr D, et al. A randomized phase II study to determine the efficacy and tolerability of two doses of eribulin plus lapatinib in trastuzumab pre-treated patients with Her2-positive metastatic breast cancer—E-vita. Ann Oncol. 2016;27(6 suppl_6):273.Google Scholar
- 21.http://www.preventcancerinfections.org/. Accessed 02 Oct 2018.
- 23.Gafter-Gvili A, Fraser A, Paul M, Vidal L, Lawrie TA, van de Wetering MD, et al. Antibiotic prophylaxis for bacterial infections in afebrile neutropenic patients following chemotherapy. Cochrane Database Syst Rev. 2012;1:CD004386.Google Scholar
- 25.Aapro MS, Bohlius J, Cameron DA, Dal Lago L, Donnelly JP, Kearney N, et al. 2010 update of EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphoproliferative disorders and solid tumours. Eur J Cancer. 2011;47(1):8–32.CrossRefGoogle Scholar
- 28.Mandalà M, Falanga A, Roila F, ESMO Guidelines Working Group. Management of venous thromboembolism (VTE) in cancer patients: ESMO clinical practice guidelines. Ann Oncol. 2011;22(Suppl 6):85–92.Google Scholar
- 31.Furlanetto J, Eiermann W, Marmé F, Reimer T, Reinisch M, Schmatloch S, et al. Higher rate of severe toxicities in obese patients receiving dose-dense (dd) chemotherapy according to unadjusted body surface area: results of the prospectively randomized GAIN study. Ann Oncol. 2016;27(11):2053–9.CrossRefGoogle Scholar
- 33.Early Breast Cancer Trialists Collaborative Group (EBCTCG). Increasing the dose intensity of chemotherapy by more frequent administration or sequential scheduling: a patient-level meta-analysis of 37,298 women with early breast cancer in 26 randomised trials. Lancet. 2019;393(10179):1440–52.CrossRefGoogle Scholar