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High-Dose Chemotherapy Compared With Standard Chemotherapy and Lung Radiation in Ewing Sarcoma With Pulmonary Metastases : Results of the European Ewing Tumour Working Initiative of National Groups, 99 Trial and EWING 2008

Dirksen, Uta ; Brennan, Bernadette ; Le Deley, Marie Cécile ; Cozic, Nathalie ; van den Berg, Henk ; Bhadri, Vivek ; Brichard, Bénédicte ; Claude, Line ; Craft, Alan and Amler, Susanne , et al. (2019) In Journal of Clinical Oncology 37(34). p.3192-3202
Abstract

PURPOSE: The R2Pulm trial was conducted to evaluate the effect of busulfan-melphalan high-dose chemotherapy with autologous stem-cell rescue (BuMel) without whole-lung irradiation (WLI) on event-free survival (main end point) and overall survival, compared with standard chemotherapy with WLI in Ewing sarcoma (ES) presenting with pulmonary and/or pleural metastases. METHODS: From 2000 to 2015, we enrolled patients younger than 50 years of age with newly diagnosed ES and with only pulmonary or pleural metastases. Patients received chemotherapy with six courses of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) and one course of vincristine, dactinomycin, and ifosfamide (VAI) before either BuMel or seven courses of VAI and WLI... (More)

PURPOSE: The R2Pulm trial was conducted to evaluate the effect of busulfan-melphalan high-dose chemotherapy with autologous stem-cell rescue (BuMel) without whole-lung irradiation (WLI) on event-free survival (main end point) and overall survival, compared with standard chemotherapy with WLI in Ewing sarcoma (ES) presenting with pulmonary and/or pleural metastases. METHODS: From 2000 to 2015, we enrolled patients younger than 50 years of age with newly diagnosed ES and with only pulmonary or pleural metastases. Patients received chemotherapy with six courses of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) and one course of vincristine, dactinomycin, and ifosfamide (VAI) before either BuMel or seven courses of VAI and WLI (VAI plus WLI) by randomized assignment. The analysis was conducted as intention to treat. The estimates of the hazard ratio (HR), 95% CI, and P value were corrected for the three previous interim analyses by the inverse normal method. RESULTS: Of 543 potentially eligible patients, 287 were randomly assigned to VAI plus WLI (n = 143) or BuMel (n = 144). Selected patients requiring radiotherapy to an axial primary site were excluded from randomization to avoid excess organ toxicity from interaction between radiotherapy and busulfan. Median follow-up was 8.1 years. We did not observe any significant difference in survival outcomes between treatment groups. Event-free survival was 50.6% versus 56.6% at 3 years and 43.1% versus 52.9% at 8 years, for VAI plus WLI and BuMel patients, respectively, resulting in an HR of 0.79 (95% CI, 0.56 to 1.10; P = .16). For overall survival, the HR was 1.00 (95% CI, 0.70 to 1.44; P = .99). Four patients died as a result of BuMel-related toxicity, and none died after VAI plus WLI. Significantly more patients in the BuMel arm experienced severe acute toxicities than in the VAI plus WLI arm. CONCLUSION: In ES with pulmonary or pleural metastases, there is no clear benefit from BuMel compared with conventional VAI plus WLI.

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published
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Journal of Clinical Oncology
volume
37
issue
34
pages
11 pages
publisher
American Society of Clinical Oncology
external identifiers
  • scopus:85075814144
  • pmid:31553693
ISSN
0732-183X
DOI
10.1200/JCO.19.00915
language
English
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yes
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ffec299a-f80f-4af6-9a59-121343a8b9b9
date added to LUP
2019-12-17 09:17:58
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2021-01-26 03:28:50
@article{ffec299a-f80f-4af6-9a59-121343a8b9b9,
  abstract     = {<p>PURPOSE: The R2Pulm trial was conducted to evaluate the effect of busulfan-melphalan high-dose chemotherapy with autologous stem-cell rescue (BuMel) without whole-lung irradiation (WLI) on event-free survival (main end point) and overall survival, compared with standard chemotherapy with WLI in Ewing sarcoma (ES) presenting with pulmonary and/or pleural metastases. METHODS: From 2000 to 2015, we enrolled patients younger than 50 years of age with newly diagnosed ES and with only pulmonary or pleural metastases. Patients received chemotherapy with six courses of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) and one course of vincristine, dactinomycin, and ifosfamide (VAI) before either BuMel or seven courses of VAI and WLI (VAI plus WLI) by randomized assignment. The analysis was conducted as intention to treat. The estimates of the hazard ratio (HR), 95% CI, and P value were corrected for the three previous interim analyses by the inverse normal method. RESULTS: Of 543 potentially eligible patients, 287 were randomly assigned to VAI plus WLI (n = 143) or BuMel (n = 144). Selected patients requiring radiotherapy to an axial primary site were excluded from randomization to avoid excess organ toxicity from interaction between radiotherapy and busulfan. Median follow-up was 8.1 years. We did not observe any significant difference in survival outcomes between treatment groups. Event-free survival was 50.6% versus 56.6% at 3 years and 43.1% versus 52.9% at 8 years, for VAI plus WLI and BuMel patients, respectively, resulting in an HR of 0.79 (95% CI, 0.56 to 1.10; P = .16). For overall survival, the HR was 1.00 (95% CI, 0.70 to 1.44; P = .99). Four patients died as a result of BuMel-related toxicity, and none died after VAI plus WLI. Significantly more patients in the BuMel arm experienced severe acute toxicities than in the VAI plus WLI arm. CONCLUSION: In ES with pulmonary or pleural metastases, there is no clear benefit from BuMel compared with conventional VAI plus WLI.</p>},
  author       = {Dirksen, Uta and Brennan, Bernadette and Le Deley, Marie Cécile and Cozic, Nathalie and van den Berg, Henk and Bhadri, Vivek and Brichard, Bénédicte and Claude, Line and Craft, Alan and Amler, Susanne and Gaspar, Natalie and Gelderblom, Hans and Goldsby, Robert and Gorlick, Richard and Grier, Holcombe E. and Guinbretiere, Jean Marc and Hauser, Peter and Hjorth, Lars and Janeway, Katherine and Juergens, Heribert and Judson, Ian and Krailo, Mark and Kruseova, Jarmila and Kuehne, Thomas and Ladenstein, Ruth and Lervat, Cyril and Lessnick, Stephen L. and Lewis, Ian and Linassier, Claude and Marec-Berard, Perrine and Marina, Neyssa and Morland, Bruce and Pacquement, Hélène and Paulussen, Michael and Randall, R. Lor and Ranft, Andreas and Le Teuff, Gwénaël and Wheatley, Keith and Whelan, Jeremy and Womer, Richard and Oberlin, Odile and Hawkins, Douglas S.},
  issn         = {0732-183X},
  language     = {eng},
  number       = {34},
  pages        = {3192--3202},
  publisher    = {American Society of Clinical Oncology},
  series       = {Journal of Clinical Oncology},
  title        = {High-Dose Chemotherapy Compared With Standard Chemotherapy and Lung Radiation in Ewing Sarcoma With Pulmonary Metastases : Results of the European Ewing Tumour Working Initiative of National Groups, 99 Trial and EWING 2008},
  url          = {http://dx.doi.org/10.1200/JCO.19.00915},
  doi          = {10.1200/JCO.19.00915},
  volume       = {37},
  year         = {2019},
}