Breast Cancer

, Volume 26, Issue 6, pp 826–834 | Cite as

Fatal events during clinical trials: an evaluation of deaths during breast cancer studies

  • Jenny FurlanettoEmail author
  • Gunter von Minckwitz
  • Bianca Lederer
  • Volker Möbus
  • Andreas Schneeweiss
  • Jens Huober
  • Peter A. Fasching
  • Bernd Gerber
  • Ingo Bauerfeind
  • Ulrike Nitz
  • Hans-Joachim Lück
  • Claus Hanusch
  • Christoph Thomssen
  • Michael Untch
  • Valentina Nekljudova
  • Keyur Mehta
  • Sibylle Loibl
Original Article



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.


Death 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.

Author contributions

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.


  1. 1.
    Shamoo AE. Adverse events reporting—the tip of an iceberg. Account Res. 2001;8(3):197–218.CrossRefGoogle Scholar
  2. 2.
  3. 3.
    Mansi BA, Clark J, David FS, Gesell TM, Glasser S, Gonzalez J, et al. Ten recommendations for closing the credibility gap in reporting industry-sponsored clinical research: a joint journal and pharmaceutical industry perspective. Mayo Clin Proc. 2012;87(5):424–9.CrossRefGoogle Scholar
  4. 4.
    Penninckx B, Van de Voorde WM, Casado A, Reed N, Moulin C, Karrasch M. A systemic review of toxic death in clinical oncology trials: an Achilles’ heel in safety reporting revisited. Br J Cancer. 2012;107(1):1–6.CrossRefGoogle Scholar
  5. 5.
    von Minckwitz G, Kümmel S, Vogel P, Hanusch C, Eidtmann H, Hilfrich J, et al. Neoadjuvant vinorelbine–capecitabine versus docetaxel–doxorubicin–cyclophosphamide in early nonresponsive breast cancer: phase III randomized GeparTrio trial. J Natl Cancer Inst. 2008;100(8):542–51.CrossRefGoogle Scholar
  6. 6.
    von Minckwitz G, Rezai M, Fasching PA, Huober J, Tesch H, Bauerfeind I, et al. Survival after adding capecitabine and trastuzumab to neoadjuvant anthracycline–taxane-based chemotherapy for primary breast cancer (GBG 40–GeparQuattro). Ann Oncol. 2014;25(1):81–9.CrossRefGoogle Scholar
  7. 7.
    von Minckwitz G, Loibl S, Untch M, Eidtmann H, Rezai M, Fasching PA, et al. Survival after neoadjuvant chemotherapy with or without bevacizumab or everolimus for HER2-negative primary breast cancer (GBG 44-GeparQuinto). Ann Oncol. 2014;25(12):2363–72.CrossRefGoogle Scholar
  8. 8.
    von Minckwitz G, Schneeweiss A, Loibl S, Salat C, Denkert C, Rezai M, et al. Neoadjuvant carboplatin in patients with triple-negative and HER2-positive early breast cancer (GeparSixto; GBG 66): a randomised phase 2 trial. Lancet Oncol. 2014;15(7):747–56.CrossRefGoogle Scholar
  9. 9.
    Untch M, Jackisch C, Schneeweiss A, Conrad B, Aktas B, Denkert C, et al. Nab-paclitaxel versus solvent-based paclitaxel in neoadjuvant chemotherapy for early breast cancer (GeparSepto-GBG 69): a randomised, phase 3 trial. Lancet Oncol. 2016;17(3):345–56.CrossRefGoogle Scholar
  10. 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. 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. 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
  13. 13.
    Thomssen C, Kantelhardt EJ, Plueckhahn K, Veyret C, Augustin D, Hanf V, et al. Report of toxicities from the multicenter, randomized NNBC 3-Europe trial: 6xFEC versus 3xFEC-3xDoc for high-risk node-negative breast cancer patients. J Clin Oncol. 2010;28(15_suppl):554.CrossRefGoogle Scholar
  14. 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. 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. 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. 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
  18. 18.
    Lück HJ, Lübbe K, Reinisch M, Maass N, Feisel-Schwickardi G, Tomé O, et al. Phase III study on efficacy of taxanes plus bevacizumab with or without capecitabine as first-line chemotherapy in metastatic breast cancer. Breast Cancer Res Treat. 2015;149(1):141–9.CrossRefGoogle Scholar
  19. 19.
    Kaufmann M, Maass N, Costa SD, Schneeweiss A, Loibl S, Sütterlin MW, et al. First-line therapy with moderate dose capecitabine in metastatic breast cancer is safe and active: results of the MONICA trial. Eur J Cancer. 2010;46(18):3184–91.CrossRefGoogle Scholar
  20. 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. 21.
  22. 22.
    Klastersky J, Paesmans M, Georgala A, Muanza F, Plehiers B, Dubreucq L, et al. Outpatient oral antibiotics for febrile neutropenic cancer patients using a score predictive for complications. J Clin Oncol. 2006;24(25):4129–34.CrossRefGoogle Scholar
  23. 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
  24. 24.
    Reinisch M, von Minckwitz G, Harbeck N, Janni W, Kümmel S, Kaufmann M, et al. Side effects of standard adjuvant and neoadjuvant chemotherapy regimens according to age groups in primary breast cancer. Breast Care (Basel). 2013;8(1):60–6.CrossRefGoogle Scholar
  25. 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
  26. 26.
    Pal SK, Hurria A. Impact of age, sex, and comorbidity on cancer therapy and disease progression. J Clin Oncol. 2010;28(26):4086–93.CrossRefGoogle Scholar
  27. 27.
    Khorana AA, Francis CW, Culakova E, Fisher RI, Kuderer NM, Lyman GH. Thromboembolism in hospitalized neutropenic cancer patients. J Clin Oncol. 2006;24(3):484–90.CrossRefGoogle Scholar
  28. 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
  29. 29.
    Aune D, Sen A, Prasad M, Norat T, Janszky I, Tonstad S, et al. BMI and all cause mortality: systematic review and non-linear dose-response meta-analysis of 230 cohort studies with 3.74 million deaths among 30.3 million participants. BMJ. 2016;353:i2156.CrossRefGoogle Scholar
  30. 30.
    Hourdequin KC, Schpero WL, McKenna DR, Piazik BL, Larson RJ. Toxic effect of chemotherapy dosing using actual body weight in obese versus normal-weight patients: a systematic review and meta-analysis. Ann Oncol. 2013;24(12):2952–62.CrossRefGoogle Scholar
  31. 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
  32. 32.
    Hunter RJ, Navo MA, Thaker PH, Bodurka DC, Wolf JK, Smith JA. Dosing chemotherapy in obese patients: actual versus assigned body surface area (BSA). Cancer Treat Rev. 2009;35(1):69–78.CrossRefGoogle Scholar
  33. 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
  34. 34.
    Kelly WN. Can the frequency and risks of fatal adverse drug events be determined? Pharmacotherapy. 2001;21(5):521–7.CrossRefGoogle Scholar
  35. 35.
    Kircher T, Nelson J, Burdo H. The autopsy as a measure of accuracy of the death certificate. N Engl J Med. 1985;313(20):1263–9.CrossRefGoogle Scholar

Copyright information

© The Japanese Breast Cancer Society 2019

Authors and Affiliations

  • Jenny Furlanetto
    • 1
    Email author
  • Gunter von Minckwitz
    • 1
  • Bianca Lederer
    • 1
  • Volker Möbus
    • 2
  • Andreas Schneeweiss
    • 3
  • Jens Huober
    • 4
  • Peter A. Fasching
    • 5
  • Bernd Gerber
    • 6
  • Ingo Bauerfeind
    • 7
  • Ulrike Nitz
    • 8
  • Hans-Joachim Lück
    • 9
  • Claus Hanusch
    • 10
  • Christoph Thomssen
    • 11
  • Michael Untch
    • 12
  • Valentina Nekljudova
    • 1
  • Keyur Mehta
    • 1
  • Sibylle Loibl
    • 1
  1. 1.German Breast GroupGBG Forschungs GmbHNeu-IsenburgGermany
  2. 2.Department of Gynecology and ObstetricsKlinikum Frankfurt HöchstFrankfurtGermany
  3. 3.Nationales Centrum für TumorerkrankungenHeidelbergGermany
  4. 4.Klinik für Frauenheilkunde und Geburtshilfe, Universitätsklinikum UlmUlmGermany
  5. 5.Universitätsklinikum ErlangenErlangenGermany
  6. 6.Universitäts-FrauenklinikRostockGermany
  7. 7.Klinikum LandshutMunichGermany
  8. 8.Frauenklinik, Universitätsklinikum DüsseldorfDüsseldorfGermany
  9. 9.Gynäkologisch-Onkologische Praxis HannoverHannoverGermany
  10. 10.Department of GynecologyRotkreuzklinikumMunichGermany
  11. 11.Department of GynecologyMartin-Luther University Halle-WittenbergHalle (Saale)Germany
  12. 12.Department of Gynecology and ObstetricsHelios Klinikum Berlin-BuchBerlinGermany

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