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High-dose chemotherapy and blood autologous stem-cell rescue compared with standard chemotherapy in localized high-risk ewing sarcoma : Results of Euro-E.W.I.N.G.99 and Ewing-2008

Whelan, Jeremy ; Le Deley, Marie Cecile ; Dirksen, Uta ; Teuff, Gwénaël Le ; Brennan, Bernadette ; Gaspar, Nathalie ; Hawkins, Douglas S. ; Amler, Susanne ; Bauer, Sebastian and Bielack, Stefan , et al. (2018) In Journal of Clinical Oncology 36(31). p.3110-3119
Abstract

Purpose For over 30 years, the place of consolidation high-dose chemotherapy in Ewing sarcoma (ES) has been controversial. A randomized study was conducted to determine whether consolidation high-dose chemotherapy improved survival in patients with localized ES at high risk for relapse. Methods Randomization between busulfan and melphalan (BuMel) or standard chemotherapy (vincristine, dactinomycin, and ifosfamide [VAI], seven courses) was offered to patients if they were younger than 50 years of age with poor histologic response (≥ 10% viable cells) after receiving vincristine, ifosfamide, doxorubicin, and etoposide (six courses); or had a tumor volume at diagnosis >200 mL if unresected, or initially resected, or resected after... (More)

Purpose For over 30 years, the place of consolidation high-dose chemotherapy in Ewing sarcoma (ES) has been controversial. A randomized study was conducted to determine whether consolidation high-dose chemotherapy improved survival in patients with localized ES at high risk for relapse. Methods Randomization between busulfan and melphalan (BuMel) or standard chemotherapy (vincristine, dactinomycin, and ifosfamide [VAI], seven courses) was offered to patients if they were younger than 50 years of age with poor histologic response (≥ 10% viable cells) after receiving vincristine, ifosfamide, doxorubicin, and etoposide (six courses); or had a tumor volume at diagnosis >200 mL if unresected, or initially resected, or resected after radiotherapy. A 15% improvement in 3-year eventfree survival (EFS) was sought (hazard ratio [HR], 0.60). Results Between 2000 and 2015, 240 patients classified as high risk (median age, 17.1 years) were randomly assigned to VAI (n = 118) or BuMel (n = 122). Seventy-eight percent entered the trial because of poor histologic response after chemotherapy alone. Median follow-up was 7.8 years. In an intent-to-treat analysis, the risk of event was significantly decreased by BuMel comparedwith VAI: HR, 0.64 (95%CI, 0.43 to 0.95; P = .026); 3- and 8-year EFS were, respectively, 69.0%(95% CI, 60.2%to 76.6%) versus 56.7%(95%CI, 47.6%to 65.4%) and 60.7%(95%CI, 51.1%to 69.6%) versus 47.1%(95%CI, 37.7% to 56.8%). Overall survival (OS) also favored BuMel: HR, 0.63 (95% CI, 0.41 to 0.95; P = .028); 3- and 8-year OS were, respectively, 78.0% (95% CI, 69.6% to 84.5%) versus 72.2% (95% CI, 63.3% to 79.6%) and 64.5%(95%CI, 54.4% to 73.5%) versus 55.6%(95%CI, 45.8%to 65.1%). Results were consistent in the sensitivity analysis. Two patients died as a result of BuMel-related toxicity, one after standard chemotherapy. Significantly more BuMel patients experienced severe acute toxicities from this course of chemotherapy compared with multiple VAI courses. Conclusion BuMel improved EFS and OS when given after vincristine, ifosfamide, doxorubicin, and etoposide induction in localized ES with predefined high-risk factors. For this group of patients, BuMel may be an important addition to the standard of care.

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Journal of Clinical Oncology
volume
36
issue
31
pages
10 pages
publisher
American Society of Clinical Oncology
external identifiers
  • pmid:30188789
  • scopus:85055841281
ISSN
0732-183X
DOI
10.1200/JCO.2018.78.2516
language
English
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yes
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0dc80c90-3f1f-4bd6-976c-001246b60220
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2018-11-15 09:20:47
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2020-10-25 03:42:25
@article{0dc80c90-3f1f-4bd6-976c-001246b60220,
  abstract     = {<p>Purpose For over 30 years, the place of consolidation high-dose chemotherapy in Ewing sarcoma (ES) has been controversial. A randomized study was conducted to determine whether consolidation high-dose chemotherapy improved survival in patients with localized ES at high risk for relapse. Methods Randomization between busulfan and melphalan (BuMel) or standard chemotherapy (vincristine, dactinomycin, and ifosfamide [VAI], seven courses) was offered to patients if they were younger than 50 years of age with poor histologic response (≥ 10% viable cells) after receiving vincristine, ifosfamide, doxorubicin, and etoposide (six courses); or had a tumor volume at diagnosis &gt;200 mL if unresected, or initially resected, or resected after radiotherapy. A 15% improvement in 3-year eventfree survival (EFS) was sought (hazard ratio [HR], 0.60). Results Between 2000 and 2015, 240 patients classified as high risk (median age, 17.1 years) were randomly assigned to VAI (n = 118) or BuMel (n = 122). Seventy-eight percent entered the trial because of poor histologic response after chemotherapy alone. Median follow-up was 7.8 years. In an intent-to-treat analysis, the risk of event was significantly decreased by BuMel comparedwith VAI: HR, 0.64 (95%CI, 0.43 to 0.95; P = .026); 3- and 8-year EFS were, respectively, 69.0%(95% CI, 60.2%to 76.6%) versus 56.7%(95%CI, 47.6%to 65.4%) and 60.7%(95%CI, 51.1%to 69.6%) versus 47.1%(95%CI, 37.7% to 56.8%). Overall survival (OS) also favored BuMel: HR, 0.63 (95% CI, 0.41 to 0.95; P = .028); 3- and 8-year OS were, respectively, 78.0% (95% CI, 69.6% to 84.5%) versus 72.2% (95% CI, 63.3% to 79.6%) and 64.5%(95%CI, 54.4% to 73.5%) versus 55.6%(95%CI, 45.8%to 65.1%). Results were consistent in the sensitivity analysis. Two patients died as a result of BuMel-related toxicity, one after standard chemotherapy. Significantly more BuMel patients experienced severe acute toxicities from this course of chemotherapy compared with multiple VAI courses. Conclusion BuMel improved EFS and OS when given after vincristine, ifosfamide, doxorubicin, and etoposide induction in localized ES with predefined high-risk factors. For this group of patients, BuMel may be an important addition to the standard of care.</p>},
  author       = {Whelan, Jeremy and Le Deley, Marie Cecile and Dirksen, Uta and Teuff, Gwénaël Le and Brennan, Bernadette and Gaspar, Nathalie and Hawkins, Douglas S. and Amler, Susanne and Bauer, Sebastian and Bielack, Stefan and Blay, Jean Yves and Burdach, Stefan and Castex, Marie Pierre and Dilloo, Dagmar and Eggert, Angelika and Gelderblom, Hans and Gentet, Jean Claude and Hartmann, Wolfgang and Hassenpflug, Wolf Achim and Hjorth, Lars and Jimenez, Marta and Klingebiel, Thomas and Kontny, Udo and Kruseova, Jarmila and Ladenstein, Ruth and Laurence, Valerie and Lervat, Cyril and Marec-Berard, Perrine and Marreaud, Sandrine and Michon, Jean and Morland, Bruce and Paulussen, Michael and Ranft, Andreas and Reichardt, Peter and Van Den Berg, Hendrik and Wheatley, Keith and Judson, Ian and Lewis, Ian and Craft, Alan and Juergens, Heribert and Oberlin, Odile},
  issn         = {0732-183X},
  language     = {eng},
  number       = {31},
  pages        = {3110--3119},
  publisher    = {American Society of Clinical Oncology},
  series       = {Journal of Clinical Oncology},
  title        = {High-dose chemotherapy and blood autologous stem-cell rescue compared with standard chemotherapy in localized high-risk ewing sarcoma : Results of Euro-E.W.I.N.G.99 and Ewing-2008},
  url          = {http://dx.doi.org/10.1200/JCO.2018.78.2516},
  doi          = {10.1200/JCO.2018.78.2516},
  volume       = {36},
  year         = {2018},
}