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Randomized phase III trial of low-molecular-weight heparin enoxaparin in addition to standard treatment in small-cell lung cancer : The RASTEN trial

Ek, L. LU ; Gezelius, E. LU ; Bergman, B.; Bendahl, P. O. LU ; Anderson, H. LU ; Sundberg, J.; Wallberg, M. LU ; Falkmer, U.; Verma, S. and Belting, M. LU , et al. (2018) In Annals of Oncology 29(2). p.398-404
Abstract

Background: Coagulation activation and venous thromboembolism (VTE) are hallmarks of malignant disease and represent a major cause of morbidity and mortality in cancer. Coagulation inhibition with low-molecular-weight heparin (LMWH) may improve survival specifically in small-cell lung cancer (SCLC) patients by preventing VTE and tumor progression; however, randomized trials with well-defined patient populations are needed to obtain conclusive data. The aim of RASTEN was to investigate the survival effect of LMWH enoxaparin in a homogenous population of SCLC patients. Patients and methods: We carried out a randomized, multicenter, open-label trial to investigate the addition of enoxaparin at a supraprophylactic dose (1 mg/kg) to standard... (More)

Background: Coagulation activation and venous thromboembolism (VTE) are hallmarks of malignant disease and represent a major cause of morbidity and mortality in cancer. Coagulation inhibition with low-molecular-weight heparin (LMWH) may improve survival specifically in small-cell lung cancer (SCLC) patients by preventing VTE and tumor progression; however, randomized trials with well-defined patient populations are needed to obtain conclusive data. The aim of RASTEN was to investigate the survival effect of LMWH enoxaparin in a homogenous population of SCLC patients. Patients and methods: We carried out a randomized, multicenter, open-label trial to investigate the addition of enoxaparin at a supraprophylactic dose (1 mg/kg) to standard treatment in patients with newly diagnosed SCLC. The primary outcome was overall survival (OS), and secondary outcomes were progression-free survival (PFS), incidence of VTE and hemorrhagic events. Results: In RASTEN, 390 patients were randomized over an 8-year period (2008-2016), of whom 186 and 191 were included in the final analysis in the LMWH and control arm, respectively. We found no evidence of a difference in OS or PFS by the addition of enoxaparin [hazard ratio (HR), 1.11; 95% confidence interval (CI) 0.89-1.38; P=0.36 and HR, 1.18; 95% CI 0.95-1.46; P=0.14, respectively]. Subgroup analysis of patients with limited and extensive disease did not show reduced mortality by enoxaparin. The incidence of VTE was significantly reduced in the LMWH arm (HR, 0.31; 95% CI 0.11-0.84; P=0.02). Hemorrhagic events were more frequent in the LMWH-treated group but fatal bleedings occurred in both arms. Conclusion: LMWH enoxaparin in addition to standard therapy did not improve OS in SCLC patients despite being administered at a supraprophylactic dose and despite resulting in a significant reduction in VTE incidence. Addition of LMWH cannot be generally recommended in the management of SCLC patients, and predictive biomarkers of VTE and LMWHassociated bleeding in cancer patients are warranted.

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published
subject
keywords
Coagulation, Enoxaparin, Low-molecular-weight heparin, Randomized phase III trial, Small-cell lung cancer, Venous thromboembolism
in
Annals of Oncology
volume
29
issue
2
pages
398 - 404
publisher
Oxford University Press
external identifiers
  • scopus:85042556248
ISSN
0923-7534
DOI
10.1093/annonc/mdx716
language
English
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yes
id
1a24c6c7-383b-41e4-8e6e-47ad69e42328
date added to LUP
2018-03-12 17:21:10
date last changed
2018-09-02 04:45:34
@article{1a24c6c7-383b-41e4-8e6e-47ad69e42328,
  abstract     = {<p>Background: Coagulation activation and venous thromboembolism (VTE) are hallmarks of malignant disease and represent a major cause of morbidity and mortality in cancer. Coagulation inhibition with low-molecular-weight heparin (LMWH) may improve survival specifically in small-cell lung cancer (SCLC) patients by preventing VTE and tumor progression; however, randomized trials with well-defined patient populations are needed to obtain conclusive data. The aim of RASTEN was to investigate the survival effect of LMWH enoxaparin in a homogenous population of SCLC patients. Patients and methods: We carried out a randomized, multicenter, open-label trial to investigate the addition of enoxaparin at a supraprophylactic dose (1 mg/kg) to standard treatment in patients with newly diagnosed SCLC. The primary outcome was overall survival (OS), and secondary outcomes were progression-free survival (PFS), incidence of VTE and hemorrhagic events. Results: In RASTEN, 390 patients were randomized over an 8-year period (2008-2016), of whom 186 and 191 were included in the final analysis in the LMWH and control arm, respectively. We found no evidence of a difference in OS or PFS by the addition of enoxaparin [hazard ratio (HR), 1.11; 95% confidence interval (CI) 0.89-1.38; P=0.36 and HR, 1.18; 95% CI 0.95-1.46; P=0.14, respectively]. Subgroup analysis of patients with limited and extensive disease did not show reduced mortality by enoxaparin. The incidence of VTE was significantly reduced in the LMWH arm (HR, 0.31; 95% CI 0.11-0.84; P=0.02). Hemorrhagic events were more frequent in the LMWH-treated group but fatal bleedings occurred in both arms. Conclusion: LMWH enoxaparin in addition to standard therapy did not improve OS in SCLC patients despite being administered at a supraprophylactic dose and despite resulting in a significant reduction in VTE incidence. Addition of LMWH cannot be generally recommended in the management of SCLC patients, and predictive biomarkers of VTE and LMWHassociated bleeding in cancer patients are warranted.</p>},
  author       = {Ek, L. and Gezelius, E. and Bergman, B. and Bendahl, P. O. and Anderson, H. and Sundberg, J. and Wallberg, M. and Falkmer, U. and Verma, S. and Belting, M. and , },
  issn         = {0923-7534},
  keyword      = {Coagulation,Enoxaparin,Low-molecular-weight heparin,Randomized phase III trial,Small-cell lung cancer,Venous thromboembolism},
  language     = {eng},
  month        = {02},
  number       = {2},
  pages        = {398--404},
  publisher    = {Oxford University Press},
  series       = {Annals of Oncology},
  title        = {Randomized phase III trial of low-molecular-weight heparin enoxaparin in addition to standard treatment in small-cell lung cancer : The RASTEN trial},
  url          = {http://dx.doi.org/10.1093/annonc/mdx716},
  volume       = {29},
  year         = {2018},
}