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Ewing sarcoma

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Glossary

Portrait of Elizabeth J. Davis, MD

Section editor

Elizabeth J. Davis, MD
Vanderbilt University
Nashville, TN, USA

Count last updated on :
22 regimens on this page
36 variants on this page


Related pages

Clinical practice guidelines

Given the rapid evolution of evidence in hematology and oncology, any guideline older than five years should be regarded as historical information only.


National Comprehensive Cancer Network® (NCCN®) guidelines


Regimens for resectable disease, neoadjuvant therapy

EVAIA

EVAIA: Etoposide, Vincristine, Adriamycin (Doxorubicin), Ifosfamide, DActinomycin

Regimen details

Summary of evidence
Study Dates of enrollment Study design Comparator Comparative efficacy
Paulussen et al. (EICESS-92) to Phase 3 (E-esc) VAIA Did not meet primary endpoint of EFS at 3 years

Note: The primary reference does not comment about the use of mesna.

Eligibility criteria
  • High-risk
Chemotherapy

21-day cycle for 4 cycles

Subsequent treatment
  • Surgical removal of tumors is done when possible.
  • EICESS-92, patients not undergoing surgery, with incomplete surgical resection, or poor histologic response: Definitive external beam radiotherapy x 5,440 cGy, then adjuvant EVAIA
  • EICESS-92, patients with a good histologic response: Adjuvant External beam radiotherapy 4,480 cGy, then adjuvant EVAIA
  • Additional details about particular clinical scenarios can be found in the original reference

References

  1. EICESS-92: Paulussen M, Craft AW, Lewis I, Hackshaw A, Douglas C, Dunst J, Schuck A, Winkelmann W, Köhler G, Poremba C, Zoubek A, Ladenstein R, van den Berg H, Hunold A, Cassoni A, Spooner D, Grimer R, Whelan J, McTiernan A, Jürgens H; European Intergroup Cooperative Ewing's Sarcoma Study-92. Results of the EICESS-92 Study: two randomized trials of Ewing's sarcoma treatment--cyclophosphamide compared with ifosfamide in standard-risk patients and assessment of benefit of etoposide added to standard treatment in high-risk patients. J Clin Oncol. 2008 Sep 20;26(27):4385-93. link to original article link to EuroPMC abstract link to clinical trial record NCT00002516 Dosing details in manuscript have been reviewed by our editors


VACA

VACA: Vincristine, Adriamycin (Doxorubicin), Cyclophosphamide, DActinomycin

Regimen details: Variant #1

Summary of evidence
Study Dates of enrollment Study design Comparator Comparative efficacy
Grier et al. (INT-0091) to Phase 3 (C) VACA/IE Most likely has shorter OS

Note: The survival disadvantage in Grier et al. was only noted for patients with non-metastatic disease at diagnosis.

Chemotherapy
Supportive therapy
  • Mesna (Mesnex) after cyclophosphamide for prevention of hemorrhagic cystitis; primary reference did not list dosage/schedule

21-day cycle for 17 cycles

Subsequent treatment
  • Definitive local therapy is planned to take place on week 12
  • Surgery can be performed for resectable tumors. No radiation therapy is given for completely resected primary tumors with negative margins.
    • INT-0091, residual tumor after surgery: 4,500 cGy radiation is administered to the original tumor volume plus a 1 cm margin
  • If only radiation therapy is used, 4,500 cGy of radiation is administered to the tumor volume plus a 3 cm margin, followed by 1,080 cGy to only the preradiation tumor volume, for a total dose of 5,580 cGy

Regimen details: Variant #2

Summary of evidence
Study Dates of enrollment Study design
Paulussen et al. (CESS 86) to Non-randomized
Eligibility criteria
  • Standard-risk
Chemotherapy
Supportive therapy

9-week "block", then proceed to local therapy:

Local therapy
Subsequent treatment

References

  1. CESS 86: Paulussen M, Ahrens S, Dunst J, Winkelmann W, Exner GU, Kotz R, Amann G, Dockhorn-Dworniczak B, Harms D, Müller-Weihrich S, Welte K, Kornhuber B, Janka-Schaub G, Göbel U, Treuner J, Voûte PA, Zoubek A, Gadner H, Jürgens H. Localized Ewing tumor of bone: final results of the cooperative Ewing's Sarcoma Study CESS 86. J Clin Oncol. 2001 Mar 15;19(6):1818-29. link to original article link to EuroPMC abstract Dosing details in manuscript have been reviewed by our editors
  2. INT-0091: Grier HE, Krailo MD, Tarbell NJ, Link MP, Fryer CJ, Pritchard DJ, Gebhardt MC, Dickman PS, Perlman EJ, Meyers PA, Donaldson SS, Moore S, Rausen AR, Vietti TJ, Miser JS; CCG; POG. Addition of ifosfamide and etoposide to standard chemotherapy for Ewing's sarcoma and primitive neuroectodermal tumor of bone. N Engl J Med. 2003 Feb 20;348(8):694-701. link to original article link to EuroPMC abstract Dosing details in manuscript have been reviewed by our editors


VACA/IE

VACA/IE: Vincristine, Adriamycin (Doxorubicin), Cyclophosphamide, DActinomycin alternating with Ifosfamide, Etoposide

Protocol details

Summary of evidence
Study Dates of enrollment Study design Comparator Comparative efficacy
Grier et al. (INT-0091) to Phase 3 (E-esc) VACA Most likely has longer OS1

1The survival advantage in Grier et al. was only noted for patients with non-metastatic disease at diagnosis.

Note: The dosing schedule here assumes that the patient is doxorubicin-naive.

Induction

Chemotherapy, VACA portion (cycles 1 and 3)
Supportive therapy, VACA portion (cycles 1 and 3)
  • Mesna (Mesnex) after cyclophosphamide for prevention of hemorrhagic cystitis; primary reference did not list dosage/schedule
Chemotherapy, IE portion (cycles 2 and 4)
Supportive therapy, IE portion (cycles 2 and 4)
  • Mesna (Mesnex) with ifosfamide; primary reference did not list dosage/schedule

21-day cycle for 4 cycles, followed by:


Definitive

Local therapy is planned to take place on week 12, according to this schedule:

  • Surgery can be performed for resectable tumors. No radiation therapy is given for completely resected primary tumors with negative margins.
    • INT-0091, residual tumor after surgery: 4,500 cGy radiation is administered to the original tumor volume plus a 1 cm margin
  • If only radiation therapy is used, 4,500 cGy of radiation is administered to the tumor volume plus a 3 cm margin, followed by 1,080 cGy to only the preradiation tumor volume, for a total dose of 5,580 cGy

Consolidation

Chemotherapy, VACA portion
  • Vincristine (Oncovin) according to this schedule:
    • Cycles 5, 7, 9, 11, 13: 2 mg/m2 (maximum dose of 2 mg) IV once on day 1
  • Doxorubicin (Adriamycin) according to this schedule:
    • Cycle 5: 75 mg/m2 IV bolus once on day 1
    • Stop once cumulative dose received by the patient exceeds 375 mg/m2
  • Cyclophosphamide (Cytoxan) according to this schedule:
    • Cycles 5, 7, 9, 11, 13: 1,200 mg/m2 IV once on day 1
  • Dactinomycin (Cosmegen) according to this schedule:
    • Cycles 7, 9, 11, 13: 1.25 mg/m2 IV once on day 1, once cumulative doxorubicin dose received by the patient exceeds 375 mg/m2
Supportive therapy, VACA portion (cycles 5, 7, 9, 11, 13)
  • Mesna (Mesnex) after cyclophosphamide for prevention of hemorrhagic cystitis; primary reference did not list dosage/schedule
Chemotherapy, IE portion (cycles 6, 8, 10, 12)
Supportive therapy, IE portion (cycles 6, 8, 10, 12)
  • Mesna (Mesnex) with ifosfamide; primary reference did not list dosage/schedule

21-day cycle for 13 cycles (17 total cycles of chemotherapy)

References

  1. INT-0091: Grier HE, Krailo MD, Tarbell NJ, Link MP, Fryer CJ, Pritchard DJ, Gebhardt MC, Dickman PS, Perlman EJ, Meyers PA, Donaldson SS, Moore S, Rausen AR, Vietti TJ, Miser JS. Addition of ifosfamide and etoposide to standard chemotherapy for Ewing's sarcoma and primitive neuroectodermal tumor of bone. N Engl J Med. 2003 Feb 20;348(8):694-701. link to original article link to EuroPMC abstract Dosing details in manuscript have been reviewed by our editors


VAIA

VAIA: Vincristine, Adriamycin (Doxorubicin), Ifosfamide, Actinomycin-D (Dactinomycin)

Regimen details: Variant #1

Summary of evidence
Study Dates of enrollment Study design Comparator Comparative efficacy
Paulussen et al. (EICESS-92) to Phase 3 (C) EVAIA (high-risk) Did not meet primary endpoint of EFS at 3 years

Note: high-risk patients were randomized to this regimen versus EVAIA. Standard-risk patients were not randomized at this point of the protocol.

Chemotherapy

21-day cycle for 4 cycles, then proceed to local therapy:

Local therapy
  • Surgical removal of tumors is done when possible.
  • EICESS-92, patients not undergoing surgery, with incomplete surgical resection, or poor histologic response: External beam radiotherapy 5,440 cGy
  • EICESS-92, patients with a good histologic response: External beam radiotherapy 4,480 cGy
  • Additional details about particular clinical scenarios can be found in the original reference
Subsequent treatment
  • EICESS-92, high-risk patients: Adjuvant VAIA
  • EICESS-92, standard-risk patients: Adjuvant VAIA versus VACA

Regimen details: Variant #2

Summary of evidence
Study Dates of enrollment Study design
Paulussen et al. (CESS 86) to Non-randomized
Eligibility criteria
  • High-risk
Chemotherapy
Supportive therapy

9-week "block", then proceed to local therapy:

Local therapy
Subsequent treatment

References

  1. CESS 86: Paulussen M, Ahrens S, Dunst J, Winkelmann W, Exner GU, Kotz R, Amann G, Dockhorn-Dworniczak B, Harms D, Müller-Weihrich S, Welte K, Kornhuber B, Janka-Schaub G, Göbel U, Treuner J, Voûte PA, Zoubek A, Gadner H, Jürgens H. Localized Ewing tumor of bone: final results of the cooperative Ewing's Sarcoma Study CESS 86. J Clin Oncol. 2001 Mar 15;19(6):1818-29. link to original article link to EuroPMC abstract Dosing details in manuscript have been reviewed by our editors
  2. EICESS-92: Paulussen M, Craft AW, Lewis I, Hackshaw A, Douglas C, Dunst J, Schuck A, Winkelmann W, Köhler G, Poremba C, Zoubek A, Ladenstein R, van den Berg H, Hunold A, Cassoni A, Spooner D, Grimer R, Whelan J, McTiernan A, Jürgens H; European Intergroup Cooperative Ewing's Sarcoma Study-92. Results of the EICESS-92 Study: two randomized trials of Ewing's sarcoma treatment--cyclophosphamide compared with ifosfamide in standard-risk patients and assessment of benefit of etoposide added to standard treatment in high-risk patients. J Clin Oncol. 2008 Sep 20;26(27):4385-93. link to original article link to EuroPMC abstract link to clinical trial record NCT00002516 Dosing details in manuscript have been reviewed by our editors
  3. CWS/RMS-96: Sparber-Sauer M, Ferrari A, Kosztyla D, Ladenstein R, Cecchetto G, Kazanowska B, Scarzello G, Ljungman G, Milano GM, Niggli F, Alaggio R, Vokuhl C, Casanova M, Klingebiel T, Zin A, Koscielniak E, Bisogno G. Long-term results from the multicentric European randomized phase 3 trial CWS/RMS-96 for localized high-risk soft tissue sarcoma in children, adolescents, and young adults. Pediatr Blood Cancer. 2022 Sep;69(9):e29691. Epub 2022 Apr 19. link to original article link to EuroPMC abstract


VDC/IE

VDC/IE: Vincristine, Doxorubicin, Cyclophosphamide, alternating with Ifosfamide and Etoposide
VAdriaC/IE: Vincristine, Adriamycin (Doxorubicin), Cyclophosphamide, alternating with Ifosfamide and Etoposide

Regimen details: Variant #1, q2wk

Summary of evidence
Study Dates of enrollment Study design Comparator Comparative efficacy
Womer et al. (COG AEWS0031) to Phase 3 (E-esc) VDC/IE; standard Seems to have longer EFS (primary endpoint)
EFS at 5 years: 73% vs 65%
(HR 0.74, 95% CI, 0.54-0.99)
Seems to have longer OS (secondary endpoint)
OS at 5 years: 83% vs 77%
(HR 0.69, 95% CI, 0.47-1.00)
Brennan et al. (EE2012) to Phase 3 (E-de-esc) VIDE Most likely has longer EFS (primary endpoint)
EFS at 3 years: 67% vs 61%
(aHR 0.71, 95% CI, 0.55-0.92)
DuBois et al. (COG AEWS1221) to Phase 3 (C) VDC/IE and Ganitumab Did not meet primary endpoint of EFS
EFS at 3 years: 37.4% vs 39.1%
(sHR 1.00, 95% CI, 0.75-1.32)
Chemotherapy, VDC portion (cycles 1, 3, 5)
Supportive therapy, VDC portion (cycles 1, 3, 5)
Chemotherapy, IE portion (cycles 2, 4, 6)
Supportive therapy, IE portion (cycles 2, 4, 6)

14-day cycle for 6 cycles (VDC/IE x 3)

Subsequent treatment
  • Definitive local therapy, then adjuvant VDC/IE

Regimen details: Variant #2, q2wk with extra vincristine

Summary of evidence
Study Dates of enrollment Study design Comparator Comparative efficacy
Leavey et al. (COG AEWS1031) to Phase 3 (C) VDC/IE/VTC Did not meet primary endpoint of EFS

Note: the only difference between this and variant #1 is the additional dose of vincristine in the second week of each VDC cycle.

Chemotherapy, VDC portion (cycles 1, 3, 5)
Chemotherapy, IE portion (cycles 2, 4, 6)
Supportive therapy, both portions (cycles 1 to 6)

14-day cycle for 6 cycles (VDC/IE x 3)

Subsequent treatment
  • Definitive local therapy, then VDC/IE continuation

Regimen details: Variant #3, q3wk

Summary of evidence
Study Dates of enrollment Study design Comparator Comparative efficacy
Womer et al. (COG AEWS0031) to Phase 3 (C) VDC/IE; dose-intense Seems to have shorter EFS (primary endpoint)
EFS at 5 years: 65% vs 73%
(HR 1.35, 95% CI, 1.01-1.85)
Chemotherapy, VDC portion (cycles 1 and 3)
Supportive therapy, VDC portion (cycles 1 and 3)
Chemotherapy, IE portion (cycles 2 and 4)
Supportive therapy, IE portion (cycles 2 and 4)

21-day cycle for 4 cycles

Subsequent treatment
  • Definitive local therapy, then adjuvant VDC/IE

References

  1. COG AEWS0031: Womer RB, West DC, Krailo MD, Dickman PS, Pawel BR, Grier HE, Marcus K, Sailer S, Healey JH, Dormans JP, Weiss AR; Children's Oncology Group. Randomized controlled trial of interval-compressed chemotherapy for the treatment of localized Ewing sarcoma: a report from the Children's Oncology Group. J Clin Oncol. 2012 Nov 20;30(33):4148-54. Epub 2012 Oct 22. Erratum in: J Clin Oncol. 2015 Mar 1;33(7):814. Dosage error in article text. link to original article free full text available at EuroPMC link to EuroPMC abstract link to clinical trial record NCT00006734 Dosing details in manuscript have been reviewed by our editors
    1. Update: Cash T, Krailo MD, Buxton AB, Pawel BR, Healey JH, Binitie O, Marcus KJ, Grier HE, Grohar PJ, Reed DR, Weiss AR, Gorlick R, Janeway KA, DuBois SG, Womer RB. Long-Term Outcomes in Patients With Localized Ewing Sarcoma Treated With Interval-Compressed Chemotherapy on Children's Oncology Group Study AEWS0031. J Clin Oncol. 2023 Oct 20;41(30):4724-4728. Epub 2023 Aug 31. link to original article free full text available at EuroPMC link to EuroPMC abstract
  2. COG AEWS1031: Leavey PJ, Laack NN, Krailo MD, Buxton A, Randall RL, DuBois SG, Reed DR, Grier HE, Hawkins DS, Pawel B, Nadel H, Womer RB, Letson GD, Bernstein M, Brown K, Maciej A, Chuba P, Ahmed AA, Indelicato DJ, Wang D, Marina N, Gorlick R, Janeway KA, Mascarenhas L. Phase III Trial Adding Vincristine-Topotecan-Cyclophosphamide to the Initial Treatment of Patients With Nonmetastatic Ewing Sarcoma: A Children's Oncology Group Report. J Clin Oncol. 2021 Dec 20;39(36):4029-4038. Epub 2021 Oct 15. link to original article free full text available at EuroPMC link to EuroPMC abstract link to clinical trial record NCT01231906 Dosing details in manuscript have been reviewed by our editors
  3. EE2012: Brennan B, Kirton L, Marec-Bérard P, Gaspar N, Laurence V, Martín-Broto J, Sastre A, Gelderblom H, Owens C, Fenwick N, Strauss S, Moroz V, Whelan J, Wheatley K. Comparison of two chemotherapy regimens in patients with newly diagnosed Ewing sarcoma (EE2012): an open-label, randomised, phase 3 trial. Lancet. 2022 Oct 29;400(10362):1513-1521. link to original article link to EuroPMC abstract EudraCT 2012-002107-17
  4. COG AEWS1221: DuBois SG, Krailo MD, Glade-Bender J, Buxton A, Laack N, Randall RL, Chen HX, Seibel NL, Boron M, Terezakis S, Hill-Kayser C, Hayes A, Reid JM, Teot L, Rakheja D, Womer R, Arndt C, Lessnick SL, Crompton BD, Kolb EA, Daldrup-Link H, Eutsler E, Reed DR, Janeway KA, Gorlick RG. Randomized Phase III Trial of Ganitumab With Interval-Compressed Chemotherapy for Patients With Newly Diagnosed Metastatic Ewing Sarcoma: A Report From the Children's Oncology Group. J Clin Oncol. 2023 Apr 10;41(11):2098-2107. Epub 2023 Jan 20. link to original article free full text available at EuroPMC link to EuroPMC abstract link to clinical trial record NCT02306161


VIDE

VIDE: Vincristine, Ifosfamide, Doxorubicin, Etoposide

Regimen details: Variant #1

Summary of evidence
Study Dates of enrollment Study design
Juergens et al. (EURO-E.W.I.N.G. 99) Not reported Phase 2
Koch et al. (Ewing 2008R3) to Non-randomized part of phase 3 RCT
Chemotherapy
Supportive therapy
  • Mesna (Mesnex) 1,000 mg/m2 IV push once on day 1, administered 1 hour before ifosfamide, then 3,000 mg/m2/day IV continuous infusion over 72 hours (total dose per cycle: 10,000 mg/m2)
  • 2 to 3 liters/m2 hydration per day
  • Recommended, but not required: Filgrastim (Neupogen) 5 mcg/kg SC once per day on days 4 to 13, starting 24 hours after completion of chemotherapy

21-day cycle for 6 cycles

Subsequent treatment
  • EURO-E.W.I.N.G. 99: Further therapy is dictated by patient characteristics and response; details can be found in the primary reference
  • Ewing 2008R3: Surgery when feasible followed by adjuvant VAC x 8 or VAI x 8, then Treosulfan and Melphalan, then auto HSCT consolidation versus No further treatment

Regimen details: Variant #2

Summary of evidence
Study Dates of enrollment Study design
Strauss et al. to Phase 2
Chemotherapy
Supportive therapy
  • Mesna (Mesnex) 3,000 mg/m2/day IV continuous infusion over 72 hours, started on day 1 (total dose per cycle: 9,000 mg/m2)

21-day cycle for up to 6 cycles

Subsequent treatment
  • Strauss et al. , patients with resectable localized disease: complete surgical removal of tumors when possible, then adjuvant VAI
  • Strauss et al. , patients with unresectable localized disease: VAI and RT consolidation

References

  1. Strauss SJ, McTiernan A, Driver D, Hall-Craggs M, Sandison A, Cassoni AM, Kilby A, Michelagnoli M, Pringle J, Cobb J, Briggs T, Cannon S, Witt J, Whelan JS. Single center experience of a new intensive induction therapy for Ewing's family of tumors: feasibility, toxicity, and stem cell mobilization properties. J Clin Oncol. 2003 Aug 1;21(15):2974-81. link to original article link to EuroPMC abstract Dosing details in manuscript have been reviewed by our editors
  2. EURO-E.W.I.N.G. 99: Juergens C, Weston C, Lewis I, Whelan J, Paulussen M, Oberlin O, Michon J, Zoubek A, Juergens H, Craft A. Safety assessment of intensive induction with vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) in the treatment of Ewing tumors in the EURO-EWING 99 clinical trial. Pediatr Blood Cancer. 2006 Jul;47(1):22-9. link to original article link to EuroPMC abstract Dosing details in abstract have been reviewed by our editors
  3. Euro-EWING99-R1: Le Deley MC, Paulussen M, Lewis I, Brennan B, Ranft A, Whelan J, Le Teuff G, Michon J, Ladenstein R, Marec-Bérard P, van den Berg H, Hjorth L, Wheatley K, Judson I, Juergens H, Craft A, Oberlin O, Dirksen U. Cyclophosphamide compared with ifosfamide in consolidation treatment of standard-risk Ewing sarcoma: results of the randomized noninferiority Euro-EWING99-R1 trial. J Clin Oncol. 2014 Aug 10;32(23):2440-8. Epub 2014 Jun 30. link to original article link to EuroPMC abstract link to clinical trial record NCT00020566 Dosing details are not present in the manuscript
  4. Ewing 2008R3: Koch R, Gelderblom H, Haveman L, Brichard B, Jürgens H, Cyprova S, van den Berg H, Hassenpflug W, Raciborska A, Ek T, Baumhoer D, Egerer G, Eich HT, Renard M, Hauser P, Burdach S, Bovee J, Bonar F, Reichardt P, Kruseova J, Hardes J, Kühne T, Kessler T, Collaud S, Bernkopf M, Butterfaß-Bahloul T, Dhooge C, Bauer S, Kiss J, Paulussen M, Hong A, Ranft A, Timmermann B, Rascon J, Vieth V, Kanerva J, Faldum A, Metzler M, Hartmann W, Hjorth L, Bhadri V, Dirksen U. High-Dose Treosulfan and Melphalan as Consolidation Therapy Versus Standard Therapy for High-Risk (Metastatic) Ewing Sarcoma. J Clin Oncol. 2022 Jul 20;40(21):2307-2320. Epub 2022 Apr 15. link to original article link to EuroPMC abstract link to clinical trial record NCT00987636 Dosing details in supplement have been reviewed by our editors
  5. EE2012: Brennan B, Kirton L, Marec-Bérard P, Gaspar N, Laurence V, Martín-Broto J, Sastre A, Gelderblom H, Owens C, Fenwick N, Strauss S, Moroz V, Whelan J, Wheatley K. Comparison of two chemotherapy regimens in patients with newly diagnosed Ewing sarcoma (EE2012): an open-label, randomised, phase 3 trial. Lancet. 2022 Oct 29;400(10362):1513-1521. link to original article link to EuroPMC abstract EudraCT 2012-002107-17
  6. Ewing 2008R1: Koch R, Haveman L, Ladenstein R, Brichard B, Jürgens H, Cyprova S, van den Berg H, Hassenpflug W, Raciborska A, Ek T, Baumhoer D, Egerer G, Kager L, Renard M, Hauser P, Burdach S, Bovee JVMG, Hong AM, Reichardt P, Kruseova J, Streitbürger A, Kühne T, Kessler T, Bernkopf M, Butterfaß-Bahloul T, Dhooge C, Bauer S, Kiss J, Paulussen M, Bonar F, Ranft A, Timmermann B, Rascon J, Vieth V, Kanerva J, Faldum A, Hartmann W, Hjorth L, Bhadri VA, Metzler M, Gelderblom H, Dirksen U. Zoledronic Acid Add-on Therapy for Standard-Risk Ewing Sarcoma Patients in the Ewing 2008R1 Trial. Clin Cancer Res. 2023 Dec 15;29(24):5057-5068. link to original article link to EuroPMC abstract EudraCT 2008-003658-13


Regimens for resected disease, adjuvant therapy

Busulfan and Melphalan, then auto HSCT

BuMel: Busulfan and Melphalan

Regimen details

Summary of evidence
Study Dates of enrollment Study design Comparator Comparative efficacy
Atra et al. Not reported Phase 2, fewer than 20 pts
Whelan et al. (R2Loc) to Phase 3 (E-esc) VAI Most likely has longer EFS (primary endpoint)
EFS at 8 years: 60.7% vs 47.1%
(HR 0.64, 95% CI, 0.43-0.95)
Most likely has longer OS (secondary endpoint)
OS at 8 years: 64.5% vs 55.6%
(HR 0.63, 95% CI, 0.41-0.95)
Preceding treatment
Chemotherapy
Supportive therapy

One course

References

  1. Atra A, Whelan JS, Calvagna V, Shankar AG, Ashley S, Shepherd V, Souhami RL, Pinkerton CR. High-dose busulphan/melphalan with autologous stem cell rescue in Ewing's sarcoma. Bone Marrow Transplant. 1997 Nov;20(10):843-6. link to original article link to EuroPMC abstract Dosing details in manuscript have been reviewed by our editors
  2. R2Loc: Whelan J, Le Deley MC, Dirksen U, Le Teuff G, Brennan B, Gaspar N, Hawkins DS, Amler S, Bauer S, Bielack S, Blay JY, Burdach S, Castex MP, Dilloo D, Eggert A, Gelderblom H, Gentet JC, Hartmann W, Hassenpflug WA, Hjorth L, Jimenez M, Klingebiel T, Kontny U, Kruseova J, Ladenstein R, Laurence V, Lervat C, Marec-Berard P, Marreaud S, Michon J, Morland B, Paulussen M, Ranft A, Reichardt P, van den Berg H, Wheatley K, Judson I, Lewis I, Craft A, Juergens H, Oberlin O; Euro-EWING-99 and EWING-2008 Investigators. High-dose chemotherapy and blood autologous stem-cell rescue compared with standard chemotherapy in localized high-risk Ewing sarcoma: results of Euro-EWING99 and Ewing-2008. J Clin Oncol. 2018 Nov 1;36(31):3110-9. Epub 2018 Sep 6. link to original article free full text available at EuroPMC link to EuroPMC abstract link to clinical trial record NCT00020566 Dosing details in supplement have been reviewed by our editors


EVAIA

EVAIA: Etoposide, Vincristine, Adriamycin (Doxorubicin), Ifosfamide, DActinomycin

Regimen details

Summary of evidence
Study Dates of enrollment Study design
Paulussen et al. (EICESS-92) to Non-randomized part of phase 3 RCT
Eligibility criteria
  • High-risk
Preceding treatment
Chemotherapy

21-day cycle for 10 cycles

References

  1. EICESS-92: Paulussen M, Craft AW, Lewis I, Hackshaw A, Douglas C, Dunst J, Schuck A, Winkelmann W, Köhler G, Poremba C, Zoubek A, Ladenstein R, van den Berg H, Hunold A, Cassoni A, Spooner D, Grimer R, Whelan J, McTiernan A, Jürgens H; European Intergroup Cooperative Ewing's Sarcoma Study-92. Results of the EICESS-92 Study: two randomized trials of Ewing's sarcoma treatment--cyclophosphamide compared with ifosfamide in standard-risk patients and assessment of benefit of etoposide added to standard treatment in high-risk patients. J Clin Oncol. 2008 Sep 20;26(27):4385-93. link to original article link to EuroPMC abstract link to clinical trial record NCT00002516 Dosing details in manuscript have been reviewed by our editors


VACA

VACA: Vincristine, Adriamycin (Doxorubicin), Cyclophosphamide, DActinomycin

Regimen details: Variant #1

Summary of evidence
Study Dates of enrollment Study design Comparator Comparative efficacy
Paulussen et al. (EICESS-92) to Phase 3 (E-switch-ic) VAIA Did not meet primary endpoint of EFS at 3 years
Eligibility criteria
  • Standard-risk
Preceding treatment
Chemotherapy

21-day cycle for 10 cycles


Regimen details: Variant #2

Summary of evidence
Study Dates of enrollment Study design
Paulussen et al. (CESS 86) to Non-randomized
Eligibility criteria
  • Standard-risk
Preceding treatment
Chemotherapy
Supportive therapy

9-week "block" for 3 blocks


Regimen details: Variant #3

Summary of evidence
Study Dates of enrollment Study design
Craft et al. (ET-1) to Non-randomized
Registrational trial
Preceding treatment
Chemotherapy

21-day cycle for 18 cycles (1 year)

References

  1. ET-1: Craft AW, Cotterill SJ, Bullimore JA, Pearson D; United Kingdom Children's Cancer Study Group; Medical Research Council Bone Sarcoma Working Party. Long-term results from the first UKCCSG Ewing's Tumour Study (ET-1). Eur J Cancer. 1997 Jun;33(7):1061-9. link to original article link to EuroPMC abstract Dosing details in manuscript have been reviewed by our editors
  2. CESS 86: Paulussen M, Ahrens S, Dunst J, Winkelmann W, Exner GU, Kotz R, Amann G, Dockhorn-Dworniczak B, Harms D, Müller-Weihrich S, Welte K, Kornhuber B, Janka-Schaub G, Göbel U, Treuner J, Voûte PA, Zoubek A, Gadner H, Jürgens H. Localized Ewing tumor of bone: final results of the cooperative Ewing's Sarcoma Study CESS 86. J Clin Oncol. 2001 Mar 15;19(6):1818-29. link to original article link to EuroPMC abstract Dosing details in manuscript have been reviewed by our editors
  3. EICESS-92: Paulussen M, Craft AW, Lewis I, Hackshaw A, Douglas C, Dunst J, Schuck A, Winkelmann W, Köhler G, Poremba C, Zoubek A, Ladenstein R, van den Berg H, Hunold A, Cassoni A, Spooner D, Grimer R, Whelan J, McTiernan A, Jürgens H; European Intergroup Cooperative Ewing's Sarcoma Study-92. Results of the EICESS-92 Study: two randomized trials of Ewing's sarcoma treatment--cyclophosphamide compared with ifosfamide in standard-risk patients and assessment of benefit of etoposide added to standard treatment in high-risk patients. J Clin Oncol. 2008 Sep 20;26(27):4385-93. link to original article link to EuroPMC abstract link to clinical trial record NCT00002516 Dosing details in manuscript have been reviewed by our editors


VAI

VAI: Vincristine, DActinomycin, Ifosfamide
IVA: Ifosfamide, Vincristine, DActinomycin

Regimen details: Variant #1, capped dactinomycin

Summary of evidence
Study Dates of enrollment Study design Comparator Comparative efficacy
Le Deley et al. (Euro-EWING99-R1) to Phase 3 (C) VAC Inconclusive whether non-inferior EFS at 3 years (primary endpoint)
EFS at 3 years: 78.2% vs 75.4%

Note: To our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, before becoming a standard comparator arm.

Preceding treatment
  • Neoadjuvant VIDE x 6, then complete surgical excision if feasible; radiotherapy if surgery incomplete or infeasible
Chemotherapy
Supportive therapy

21-day cycle for 8 cycles


Regimen details: Variant #2, uncapped dactinomycin

Summary of evidence
Study Dates of enrollment Study design
Strauss et al. to Phase 2
Preceding treatment
Chemotherapy
Supportive therapy
  • Mesna (Mesnex) 3,000 mg/m2/day IV continuous infusion over 48 hours, started on day 1 (total dose per cycle: 6,000 mg/m2)

21-day cycle for up to 8 cycles

References

  1. Strauss SJ, McTiernan A, Driver D, Hall-Craggs M, Sandison A, Cassoni AM, Kilby A, Michelagnoli M, Pringle J, Cobb J, Briggs T, Cannon S, Witt J, Whelan JS. Single center experience of a new intensive induction therapy for Ewing's family of tumors: feasibility, toxicity, and stem cell mobilization properties. J Clin Oncol. 2003 Aug 1;21(15):2974-81. link to original article link to EuroPMC abstract Dosing details in manuscript have been reviewed by our editors
  2. Euro-EWING99-R1: Le Deley MC, Paulussen M, Lewis I, Brennan B, Ranft A, Whelan J, Le Teuff G, Michon J, Ladenstein R, Marec-Bérard P, van den Berg H, Hjorth L, Wheatley K, Judson I, Juergens H, Craft A, Oberlin O, Dirksen U. Cyclophosphamide compared with ifosfamide in consolidation treatment of standard-risk Ewing sarcoma: results of the randomized noninferiority Euro-EWING99-R1 trial. J Clin Oncol. 2014 Aug 10;32(23):2440-8. Epub 2014 Jun 30. link to original article link to EuroPMC abstract link to clinical trial record NCT00020566 Dosing details in manuscript have been reviewed by our editors


VAIA

VAIA: Vincristine, Adriamycin (Doxorubicin), Ifosfamide, Actinomycin-D (Dactinomycin)

Regimen details: Variant #1

Summary of evidence
Study Dates of enrollment Study design Comparator Comparative efficacy
Paulussen et al. (EICESS-92) to Phase 3 (C) VACA (standard-risk) Did not meet primary endpoint of EFS at 3 years

Note: standard-risk patients were randomized to this regimen versus VACA. High-risk patients were not randomized at this point of the protocol.

Preceding treatment
Chemotherapy

21-day cycle for 10 cycles


Regimen details: Variant #2

Summary of evidence
Study Dates of enrollment Study design
Paulussen et al. (CESS 86) to Non-randomized
Eligibility criteria
  • High-risk
Preceding treatment
Chemotherapy
Supportive therapy

9-week "block" for 3 blocks

References

  1. CESS 86: Paulussen M, Ahrens S, Dunst J, Winkelmann W, Exner GU, Kotz R, Amann G, Dockhorn-Dworniczak B, Harms D, Müller-Weihrich S, Welte K, Kornhuber B, Janka-Schaub G, Göbel U, Treuner J, Voûte PA, Zoubek A, Gadner H, Jürgens H. Localized Ewing tumor of bone: final results of the cooperative Ewing's Sarcoma Study CESS 86. J Clin Oncol. 2001 Mar 15;19(6):1818-29. link to original article link to EuroPMC abstract Dosing details in manuscript have been reviewed by our editors
  2. EICESS-92: Paulussen M, Craft AW, Lewis I, Hackshaw A, Douglas C, Dunst J, Schuck A, Winkelmann W, Köhler G, Poremba C, Zoubek A, Ladenstein R, van den Berg H, Hunold A, Cassoni A, Spooner D, Grimer R, Whelan J, McTiernan A, Jürgens H; European Intergroup Cooperative Ewing's Sarcoma Study-92. Results of the EICESS-92 Study: two randomized trials of Ewing's sarcoma treatment--cyclophosphamide compared with ifosfamide in standard-risk patients and assessment of benefit of etoposide added to standard treatment in high-risk patients. J Clin Oncol. 2008 Sep 20;26(27):4385-93. link to original article link to EuroPMC abstract link to clinical trial record NCT00002516 Dosing details in manuscript have been reviewed by our editors


Regimens for relapsed or refractory or metastatic disease, salvage therapy

Busulfan and Melphalan, then auto HSCT

Regimen details: Variant #1, PO busulfan, mel 140 mg/m2

Summary of evidence
Study Dates of enrollment Study design
Atra et al. Not reported Phase 2, fewer than 20 pts
Chemotherapy
Supportive therapy

One course


Regimen details: Variant #2, PO busulfan, mel 160 mg/m2

Summary of evidence
Study Dates of enrollment Study design
Atra et al. Not reported Phase 2, fewer than 20 pts
Chemotherapy
Supportive therapy

One course


Regimen details: Variant #3, IV busulfan

Summary of evidence
Study Dates of enrollment Study design
Strauss et al. to Phase 2

Note that melphalan is reported as given on day 2 (not day -2) in the original reference but this is surely an error.

Preceding treatment
  • Adjuvant VAI x 1 or more cycles
Chemotherapy
Supportive therapy

One course

References

  1. Atra A, Whelan JS, Calvagna V, Shankar AG, Ashley S, Shepherd V, Souhami RL, Pinkerton CR. High-dose busulphan/melphalan with autologous stem cell rescue in Ewing's sarcoma. Bone Marrow Transplant. 1997 Nov;20(10):843-6. link to original article link to EuroPMC abstract Dosing details in manuscript have been reviewed by our editors
  2. Strauss SJ, McTiernan A, Driver D, Hall-Craggs M, Sandison A, Cassoni AM, Kilby A, Michelagnoli M, Pringle J, Cobb J, Briggs T, Cannon S, Witt J, Whelan JS. Single center experience of a new intensive induction therapy for Ewing's family of tumors: feasibility, toxicity, and stem cell mobilization properties. J Clin Oncol. 2003 Aug 1;21(15):2974-81. link to original article link to EuroPMC abstract Dosing details in manuscript have been reviewed by our editors


Cyclophosphamide and Topotecan

Regimen details: Variant #1, standard-dose

Summary of evidence
Study Dates of enrollment Study design
Saylors et al. Not reported Phase 2

Note: Some guidelines state that Vincristine (Oncovin) can be added to this regimen. No primary reference for this is available.

Chemotherapy
Supportive therapy
  • 500 mL/m/2 fluids IV or PO once per day on days 1 to 5, administered 2 to 4 hours before chemotherapy
  • Antiemetics once per day on days 1 to 5, administered before chemotherapy
  • 3 liters/m2 IV or PO over 24 hours after chemotherapy
  • Filgrastim (Neupogen) 5 mcg/kg SC once per day, starting on day 6, to continue until ANC is at least 1,500/μL above nadir

21-day cycle for 12 to 14 cycles


Regimen details: Variant #2, standard-dose with local therapy

Summary of evidence
Study Dates of enrollment Study design
Hunold et al. to Phase 2

Note: Some guidelines state that vincristine can be added to this regimen. No primary reference for this is available.

Chemotherapy
Supportive therapy

21-day cycle for 12 to 14 cycles

Subsequent treatment

Regimen details: Variant #3, high-dose

Summary of evidence
Study Dates of enrollment Study design
Kushner et al. Not reported Non-randomized

Note: Some guidelines state that Vincristine (Oncovin) can be added to this regimen. No primary reference for this is available.

Chemotherapy
  • Cyclophosphamide (Cytoxan) 2,100 mg/m2/day IV continuous infusion over 48 hours, started on day 1, administered second (total dose per cycle: 4,200 mg/m2)
    • Children 10 years or younger received 70 mg/kg/day IV continuous infusion over 48 hours, started on day 1 (total dose per cycle: 140 mg/kg)
  • Topotecan (Hycamtin) 2 mg/m2/day IV continuous infusion over 72 hours, started on day 1, administered third (total dose per cycle: 6 mg/m2)
Supportive therapy
  • Mesna (Mesnex) 2,100 mg/m2/day IV continuous infusion over 72 hours, started on day 1, administered first (total dose per cycle: 6,300 mg/m2)
    • Children 10 years or younger received 70 mg/kg/day IV continuous infusion over 72 hours, started on day 1 (total dose per cycle: 210 mg/kg)
      • If body surface area less than 1 m2, mesna is given in 500 mL NS over 24 hours
      • If body surface area is at least 1 m2, mesna is given in 1,000 mL NS over 24 hours
  • On day 1, before chemotherapy, 20 mL/kg NS IV over 30 minutes, then D5 1/2 NS with 15 mEq KCl per 500 mL at 200 mL/m2/H until urine specific gravity less than 1.010, then start mesna and cyclophosphamide
  • Additional hydration fluid on days 1 and 2 so that, when added to volumes of cyclophosphamide, mesna, and topotecan, total volume of fluids is 3,000 mL/m2/24 hours
  • Additional hydration fluid on day 3 at 150 mL/m2/hour for 6 to 12 hours after completion of cyclophosphamide infusion
  • Cyclophosphamide is given in D5NS with 10 mEq potassium chloride (KCl) and 5 mg Furosemide (Lasix) per 500 mL fluid. 500 mL total volume is used for patients with body surface area less than 1 m2; 1,000 mL total volume is used for patients with BSA of at least 1 m2
  • Filgrastim (Neupogen) 5 mcg/kg SC once per day, starting on day 5, to continue until ANC is at least 1,000/μL

Subsequent cycles to start when ANC greater than 1,000/μL and platelets greater than 75 x 109/L

References

  1. Kushner BH, Kramer K, Meyers PA, Wollner N, Cheung NK. Pilot study of topotecan and high-dose cyclophosphamide for resistant pediatric solid tumors. Med Pediatr Oncol. 2000 Nov;35(5):468-74. link to original article link to EuroPMC abstract Dosing details in manuscript have been reviewed by our editors
  2. Saylors RL 3rd, Stine KC, Sullivan J, Kepner JL, Wall DA, Bernstein ML, Harris MB, Hayashi R, Vietti TJ; Pediatric Oncology Group. Cyclophosphamide plus topotecan in children with recurrent or refractory solid tumors: a Pediatric Oncology Group phase II study. J Clin Oncol. 2001 Aug 1;19(15):3463-9. link to original article link to EuroPMC abstract Dosing details in manuscript have been reviewed by our editors
  3. Hunold A, Weddeling N, Paulussen M, Ranft A, Liebscher C, Jürgens H. Topotecan and cyclophosphamide in patients with refractory or relapsed Ewing tumors. Pediatr Blood Cancer. 2006 Nov;47(6):795-800. link to original article link to EuroPMC abstract Dosing details in manuscript have been reviewed by our editors


ICE

ICE: Ifosfamide, Carboplatin, Etoposide

Regimen details

Summary of evidence
Study Dates of enrollment Study design
Van Winkle et al. (CCG-0894) to Phase 2
Van Winkle et al. (CCG-0924) to Phase 1, >20 pts
Van Winkle et al. (CCG-0931) to Non-randomized, <20 pts

Note: Some guidelines state that Vincristine (Oncovin) can be added to this regimen. No primary reference for this is available. The reference did not mention Mesna (Mesnex) being used.

Chemotherapy
Supportive therapy
  • Depending on the study the patients were enrolled on, they received one of these growth factors:
    • CCG-0894: Filgrastim (Neupogen) 5 or 10 mcg/kg SC once per day, starting 24 hours after completing ICE, and to continue until day 18 if ANC is at least 1,000/μL, or until ANC is at least 1,000/μL above nadir, whichever comes later
    • CCG-0924: PIXY 321 at doses of 500/750/1,000 mcg/m2 SC once per day or 500 mcg/m2 SC twice per day, starting on day 5 and to continue until day 18 unless ANC reached 20,000/μL or platelet count is at least 900 x 109/L for 2 days between days 13 to 18, or until ANC is at least 1,000/μL and platelet count is at least 100 x 109/L, whichever comes later
    • CCG-0931: Filgrastim (Neupogen) 5 mcg/kg SC once per day and IL-6 at 2.5, 3.75, or 5 mcg/kg SC twice per day, starting 24 hours after completing ICE. Filgrastim is continued until ANC is at least 1,000/μL, and IL-6 is continued until platelets are at least 100 x 109/L for 2 consecutive days or until day 35, whichever comes sooner.

21-day cycles, with next cycle starting as soon as ANC is at least 1,000/μL and platelet count is at least 100 x 109/L

Subsequent treatment
  • Resection of disease was allowed after 4 cycles based on patient's response to ICE

References

  1. CCG-0894: Van Winkle P, Angiolillo A, Krailo M, Cheung YK, Anderson B, Davenport V, Reaman G, Cairo MS; Children's Cancer Group. Ifosfamide, carboplatin, and etoposide (ICE) reinduction chemotherapy in a large cohort of children and adolescents with recurrent/refractory sarcoma: the Children's Cancer Group (CCG) experience. Pediatr Blood Cancer. 2005 Apr;44(4):338-47. link to original article link to EuroPMC abstract Dosing details in manuscript have been reviewed by our editors
  2. CCG-0924: Van Winkle P, Angiolillo A, Krailo M, Cheung YK, Anderson B, Davenport V, Reaman G, Cairo MS; Children's Cancer Group. Ifosfamide, carboplatin, and etoposide (ICE) reinduction chemotherapy in a large cohort of children and adolescents with recurrent/refractory sarcoma: the Children's Cancer Group (CCG) experience. Pediatr Blood Cancer. 2005 Apr;44(4):338-47. link to original article link to EuroPMC abstract Dosing details in manuscript have been reviewed by our editors
  3. CCG-0931: Van Winkle P, Angiolillo A, Krailo M, Cheung YK, Anderson B, Davenport V, Reaman G, Cairo MS; Children's Cancer Group. Ifosfamide, carboplatin, and etoposide (ICE) reinduction chemotherapy in a large cohort of children and adolescents with recurrent/refractory sarcoma: the Children's Cancer Group (CCG) experience. Pediatr Blood Cancer. 2005 Apr;44(4):338-47. link to original article link to EuroPMC abstract Dosing details in manuscript have been reviewed by our editors


IE

IE: Ifosfamide, Etoposide

Regimen details

Summary of evidence
Study Dates of enrollment Study design
Miser et al. to Phase 2

Note: Some guidelines state that Vincristine (Oncovin) can be added to this regimen. No primary reference for this is available.

Chemotherapy
  • Ifosfamide (Ifex) 1,800 mg/m2 IV once per day on days 1 to 5, administered second, with loading dose of mesna
  • Etoposide (Vepesid) 100 mg/m2 IV over 1 hour once per day on days 1 to 5, administered first
Supportive therapy
  • Mesna (Mesnex) 360 mg/m2 IV loading dose over 1 hour, administered with ifosfamide, then 120 mg/m2/hour IV over 3 hours, then 360 mg/m2/dose IV or PO over 15 minutes every 3 hours for 6 doses, administered at hours 5, 8, 11, 14, 17, 20

21-day cycle for 12 cycles

Subsequent treatment
  • Miser et al. , patients responding to therapy after 4 cycles: local therapy with surgery or radiation is used to try to achieve a complete remission.
    • Radiation therapy consisted of 180 cGy fractions given for a total dose of 5,000 to 5,500 cGy.

References

  1. Miser JS, Kinsella TJ, Triche TJ, Tsokos M, Jarosinski P, Forquer R, Wesley R, Magrath I. Ifosfamide with mesna uroprotection and etoposide: an effective regimen in the treatment of recurrent sarcomas and other tumors of children and young adults. J Clin Oncol. 1987 Aug;5(8):1191-8. link to original article link to EuroPMC abstract Dosing details in manuscript have been reviewed by our editors


TC, then IE, VDoxoC, VEC

TC, then IE, VDoxoC, VEC: Topotecan, Cyclophosphamide followed by Ifosfamide, Etoposide, then Vincristine, Doxorubicin, Cyclophosphamide, then Vincristine, Etoposide, Cyclophosphamide

Protocol details

Summary of evidence
Study Dates of enrollment Study design
Bernstein et al. (POG 9457) Not reported Phase 2

Note: This was a complex regimen, and we suggest that you refer to the primary reference and figure 1 for the protocol schema. One arm of patients in this trial received Amifostine (Ethyol), but its usage is not described here since it did not result in improved outcomes. Treatment starts with an optional topotecan window for stable patients without significantly impaired function or life-threatening disease:

Topotecan window

Chemotherapy
Supportive therapy
  • Filgrastim (Neupogen) 5 mcg/kg SC once per day, starting on day 6, to continue until ANC is at least 5,000/μL above nadir

5-day course, followed by upfront window, starting at week 0:


Upfront window

Chemotherapy
Supportive therapy
  • Prehydration with 500 mL/m2 D5 1/4 NS
  • 1500 mL/m2 IV or PO hydration continuous for 24 hours after chemotherapy
  • Filgrastim (Neupogen) 5 mcg/kg SC once per day, starting on day 6, to continue until ANC is at least 5,000/μL above nadir

21-day cycle for up to 2 cycles Patients with progression after the first cycle moved immediately to induction therapy; others proceeded to induction after the second cycle, starting at week 6 with IE:


Induction

Chemotherapy, IE portion
  • Ifosfamide (Ifex) according to this schedule:
    • Cycle 1: 3,600 mg/m2 IV over 2 hours once per day on days 1 to 5, administered second, after etoposide
      • Administered in 200 mL/m2 D5 1/2 NS
    • Cycles 2 and 3: 2,800 mg/m2 IV over 2 hours once per day on days 1 to 5, administered second, after etoposide
      • Administered in 200 mL/m2 D5 1/2 NS
  • Etoposide (Vepesid) 100 mg/m2 IV over 45 minutes once per day on days 1 to 5, administered first, before ifosfamide
    • Administered in 250 mL/m2 of D5 1/2 NS
Supportive therapy, IE portion
  • Mesna (Mesnex) 4,000 mg/m2 IV once per day on days 1 to 5
  • "Vigorous hydration"
  • Antiemetics
  • Filgrastim (Neupogen) 5 mcg/kg SC once per day, starting 24 to 48 hours after completion of chemotherapy

21-day cycle for a total of 3 cycles, alternating with VDoxoC

Chemotherapy, VDoxoC portion
  • Vincristine (Oncovin) 2 mg/m2 (maximum dose of 2 mg) IV bolus once per day on days 1, 8, 15, administered first
  • Doxorubicin (Adriamycin) 37.5 mg/m2/day IV continuous infusion over 48 hours, started on day 1, administered third (total dose per cycle: 75 mg/m2)
    • Administered in 2,400 mL/m2/day (4800 mL/m2 total volume) of D5 1/2 NS
  • Cyclophosphamide (Cytoxan) 2,100 mg/m2 IV over 30 minutes once per day on days 1 and 2, administered second
    • Administered in 200 mL/m2 D5 1/2 NS
Supportive therapy, VDoxoC portion
  • Mesna (Mesnex) 2,400 mg/m2 total dose IV; exact schedule not specified by reference
  • Filgrastim (Neupogen) 5 mcg/kg SC once per day, starting on day 4, 24 hours after chemotherapy is complete

21-day cycle for a total of 2 cycles, alternating with IE Local therapy for primary disease along with ongoing chemotherapy starts at week 21:


Definitive therapy, primary

Chemotherapy, VDoxoC portion
Supportive therapy, VDoxoC portion

21-day course, followed by local control:

Local therapy, after week 21
  • Choice of modality between surgical and radiation therapy options is at the discretion of the provider
  • POG 9457, patients treated with radiation alone: External beam radiotherapy 4,500 cGy in 180 cGy fractions to the initial tumor volume; additional treatment up to a total of 5,580 cGy was administered to original bony tumors and the postinduction chemotherapy soft tissue volumes plus a 2 cm margin
  • Refer to the primary reference for details about radiation therapy in a variety of clinical scenarios
Chemotherapy, VEC portion
Supportive therapy, VEC portion

21-day cycle for 2 cycles, followed by:


Continuation

Chemotherapy, IE portion
Supportive therapy, IE portion

21-day cycle for a total of 2 cycles, alternating with VDoxoC

Chemotherapy, VDoxoC portion
Supportive therapy, VDoxoC portion

21-day course, in between IE Local therapy for metastatic disease along with ongoing chemotherapy starts at week 39:


Definitive therapy, metastases

Chemotherapy, VDoxoC potion
Supportive therapy, VDoxoC portion

21-day course, followed by local control of metastatic disease:

Local therapy, metastatic disease (after week 39)
  • Choice of modality between surgical and radiation therapy options is at the discretion of the provider
  • External beam radiotherapy could be used to treat up to three sites of metastatic disease
  • Refer to the primary reference for details about radiation therapy in a variety of clinical scenarios
Chemotherapy, VEC portion
Supportive therapy, VEC portion

21-day cycle for 2 cycles

References

  1. POG 9457: Bernstein ML, Devidas M, Lafreniere D, Souid AK, Meyers PA, Gebhardt M, Stine K, Nicholas R, Perlman EJ, Dubowy R, Wainer IW, Dickman PS, Link MP, Goorin A, Grier HE; Pediatric Oncology Group; Children's Cancer Group; Children's Oncology Group. Intensive therapy with growth factor support for patients with Ewing tumor metastatic at diagnosis: Pediatric Oncology Group/Children's Cancer Group Phase II Study 9457--a report from the Children's Oncology Group. J Clin Oncol. 2006 Jan 1;24(1):152-9. link to original article link to EuroPMC abstract link to clinical trial record NCT00002643 Dosing details in manuscript have been reviewed by our editors


VAdCA

VAdCA: Vincristine, Adriamycin (Doxorubicin), Cyclophosphamide, DActinomycin

Regimen details

Summary of evidence
Study Dates of enrollment Study design Comparator Comparative efficacy
Miser et al. to Phase 3 (C) VAdCA/IE Did not meet co-primary endpoint of EFS
Did not meet co-primary endpoint of OS

Note: This is essentially a sub-group analysis of the protocol published in Grier et al. , but some key details differ, so we report it separately.

Chemotherapy
  • Vincristine (Oncovin) 2 mg/m2 IV once on day 1
    • Note: Miser et al. does not say the dose is capped at a maximum dose of 2 mg, but Grier et al. uses a capped dose and is from the same trial
  • Doxorubicin (Adriamycin) 75 mg/m2 IV once on day 1
    • Stop once cumulative dose received by the patient exceeds 375 mg/m2 (after 5 courses)
  • Cyclophosphamide (Cytoxan) 1,200 mg/m2 IV once on day 1
  • Dactinomycin (Cosmegen) 1.25 mg/m2 IV once on day 1, once cumulative doxorubicin dose received by the patient exceeds 375 mg/m2

21-day cycle for 17 cycles

Local therapy

Local therapy is planned to take place on week 9, according to this schedule:

  • Surgical removal of tumors is done when possible.
  • External beam radiotherapy to all metastatic sites of disease in addition to any radiation planned for primary tumor.
  • If only radiation therapy is used, External beam radiotherapy 4,500 cGy is administered to the tumor volume plus a 3 cm margin, followed by 1,080 cGy to only the preradiation tumor volume, for a total dose of 5,580 cGy
  • Residual tumor after surgery and lung metastases are treated with "dose-volume guidelines for gross residual disease"

References

  1. Miser JS, Krailo MD, Tarbell NJ, Link MP, Fryer CJ, Pritchard DJ, Gebhardt MC, Dickman PS, Perlman EJ, Meyers PA, Donaldson SS, Moore S, Rausen AR, Vietti TJ, Grier HE; Children's Cancer Group; Pediatric Oncology Group. Treatment of metastatic Ewing's sarcoma or primitive neuroectodermal tumor of bone: evaluation of combination ifosfamide and etoposide--a Children's Cancer Group and Pediatric Oncology Group study. J Clin Oncol. 2004 Jul 15;22(14):2873-6. link to original article link to EuroPMC abstract Dosing details in manuscript have been reviewed by our editors


VAdCA/IE

VAdCA/IE: Vincristine, Adriamycin (Doxorubicin), Cyclophosphamide, DActinomycin alternating with Ifosfamide, Etoposide

Regimen details

Summary of evidence
Study Dates of enrollment Study design Comparator Comparative efficacy
Miser et al. to Phase 3 (E-esc) VAdCA Did not meet co-primary endpoint of EFS
Did not meet co-primary endpoint of OS

Note: This is essentially a sub-group analysis of the protocol published in Grier et al. , but some key details differ, so we report it separately.

Chemotherapy, VAdCA portion (cycles 1, 3, 5, 7, 9, 11, 13, 15, 17)
  • Vincristine (Oncovin) 2 mg/m2 IV once on day 1
    • Note: Miser et al. does not say the dose is capped at a maximum dose of 2 mg, but Grier et al. uses a capped dose and is from the same trial
  • Doxorubicin (Adriamycin) 75 mg/m2 IV once on day 1
    • Stop once cumulative dose received by the patient exceeds 375 mg/m2 (after 5 courses)
  • Cyclophosphamide (Cytoxan) 1,200 mg/m2 IV once on day 1
  • Dactinomycin (Cosmegen) 1.25 mg/m2 IV once on day 1, once cumulative doxorubicin dose received by the patient exceeds 375 mg/m2
Chemotherapy, IE portion (cycles 2, 4, 6, 8, 10, 12, 14, 16)
Supportive therapy, IE portion (cycles 2, 4, 6, 8, 10, 12, 14, 16)
  • Mesna (Mesnex) with ifosfamide; primary reference did not list dosage/schedule

21-day cycle for 17 cycles

Local therapy

Local therapy is planned to take place on week 9, according to this schedule:

  • Surgical removal of tumors is done when possible.
  • External beam radiotherapy to all metastatic sites of disease in addition to any radiation planned for primary tumor.
  • If only radiation therapy is used, External beam radiotherapy 4,500 cGy is administered to the tumor volume plus a 3 cm margin, followed by 1,080 cGy to only the preradiation tumor volume, for a total dose of 5,580 cGy
  • Residual tumor after surgery and lung metastases are treated with "dose-volume guidelines for gross residual disease"

References

  1. Miser JS, Krailo MD, Tarbell NJ, Link MP, Fryer CJ, Pritchard DJ, Gebhardt MC, Dickman PS, Perlman EJ, Meyers PA, Donaldson SS, Moore S, Rausen AR, Vietti TJ, Grier HE; Children's Cancer Group; Pediatric Oncology Group. Treatment of metastatic Ewing's sarcoma or primitive neuroectodermal tumor of bone: evaluation of combination ifosfamide and etoposide--a Children's Cancer Group and Pediatric Oncology Group study. J Clin Oncol. 2004 Jul 15;22(14):2873-6. link to original article link to EuroPMC abstract Dosing details in manuscript have been reviewed by our editors


VAI

VAI: Vincristine, DActinomycin, Ifosfamide

Regimen details

Summary of evidence
Study Dates of enrollment Study design
Strauss et al. to Phase 2

Note: The reference does not clearly describe how many cycles of VAI were used.

Eligibility criteria
  • Metastatic disease
Preceding treatment
  • Induction VIDE for up to 6 cycles
Chemotherapy
Supportive therapy
  • Mesna (Mesnex) 3,000 mg/m2/day IV continuous infusion over 48 hours, started on day 1 (total dose per cycle: 6,000 mg/m2)

21-day cycle for one or more cycles

Subsequent treatment

References

  1. Strauss SJ, McTiernan A, Driver D, Hall-Craggs M, Sandison A, Cassoni AM, Kilby A, Michelagnoli M, Pringle J, Cobb J, Briggs T, Cannon S, Witt J, Whelan JS. Single center experience of a new intensive induction therapy for Ewing's family of tumors: feasibility, toxicity, and stem cell mobilization properties. J Clin Oncol. 2003 Aug 1;21(15):2974-81. link to original article link to EuroPMC abstract Dosing details in manuscript have been reviewed by our editors
  2. R2Pulm: Dirksen U, Brennan B, Le Deley MC, Cozic N, van den Berg H, Bhadri V, Brichard B, Claude L, Craft A, Amler S, Gaspar N, Gelderblom H, Goldsby R, Gorlick R, Grier HE, Guinbretiere JM, Hauser P, Hjorth L, Janeway K, Juergens H, Judson I, Krailo M, Kruseova J, Kuehne T, Ladenstein R, Lervat C, Lessnick SL, Lewis I, Linassier C, Marec-Berard P, Marina N, Morland B, Pacquement H, Paulussen M, Randall RL, Ranft A, Le Teuff G, Wheatley K, Whelan J, Womer R, Oberlin O, Hawkins DS; Euro-E.W.I.N.G. 99 and Ewing 2008 Investigators. 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. J Clin Oncol. 2019 Dec 1;37(34):3192-3202. Epub 2019 Sep 25. link to original article free full text available at EuroPMC link to EuroPMC abstract link to clinical trial record NCT00987636


VIDE

VIDE: Vincristine, Ifosfamide, Doxorubicin, Etoposide

Regimen details

Summary of evidence
Study Dates of enrollment Study design Efficacy
Strauss et al. to Phase 2 ORR: 88%
Eligibility criteria
  • Metastatic disease
Chemotherapy
Supportive therapy
  • Mesna (Mesnex) 3,000 mg/m2/day IV continuous infusion over 72 hours, started on day 1 (total dose per cycle: 9,000 mg/m2)

21-day cycle for up to 6 cycles

Subsequent treatment

References

  1. Strauss SJ, McTiernan A, Driver D, Hall-Craggs M, Sandison A, Cassoni AM, Kilby A, Michelagnoli M, Pringle J, Cobb J, Briggs T, Cannon S, Witt J, Whelan JS. Single center experience of a new intensive induction therapy for Ewing's family of tumors: feasibility, toxicity, and stem cell mobilization properties. J Clin Oncol. 2003 Aug 1;21(15):2974-81. link to original article link to EuroPMC abstract Dosing details in manuscript have been reviewed by our editors


Regimens for relapsed or refractory or metastatic disease, non-curative therapy

Docetaxel and Gemcitabine

Regimen details

Summary of evidence
Study Dates of enrollment Study design
Navid et al. Not reported Retrospective

Note: Some guidelines state that Vincristine (Oncovin) can be added to this regimen. No primary reference for this is available. Only 2 of the 22 patients in this retrospective review had Ewing sarcoma.

Chemotherapy
Supportive therapy

21-day cycles

References

  1. Retrospective: Navid F, Willert JR, McCarville MB, Furman W, Watkins A, Roberts W, Daw NC. Combination of gemcitabine and docetaxel in the treatment of children and young adults with refractory bone sarcoma. Cancer. 2008 Jul 15;113(2):419-25. link to original article link to EuroPMC abstract Dosing details in manuscript have been reviewed by our editors


Irinotecan and Temozolomide

Regimen details: Variant #1

Summary of evidence
Study Dates of enrollment Study design
Wagner et al. to Phase 1, fewer than 20 pts

Note: Some guidelines state that Vincristine (Oncovin) can be added to this regimen. No primary reference for this is available. Note that irinotecan 15 mg/m2 was also studied, but this dose was not recommended due to dose-limiting toxicities of diarrhea and infection.

Chemotherapy
  • Irinotecan (Camptosar) 10 mg/m2 IV over 1 hour once per day on days 1 to 5, 8 to 12, administered second on days 1 to 5, 1 hour after temozolomide
  • Temozolomide (Temodar) 100 mg/m2 PO once per day on days 1 to 5, administered first
Supportive therapy

28-day cycles


Regimen details: Variant #2

Summary of evidence
Study Dates of enrollment Study design
Casey et al. to Retrospective

Note: Some guidelines state that Vincristine (Oncovin) can be added to this regimen. No primary reference for this is available.

Chemotherapy
  • Irinotecan (Camptosar) 20 mg/m2 IV over 1 hour once per day on days 1 to 5, 8 to 12, administered second on days 1 to 5, 1 hour after temozolomide
  • Temozolomide (Temodar) 100 mg/m2 PO once per day on days 1 to 5, administered first
Supportive therapy
  • Cefixime (Suprax) prophylaxis starting 1 to 2 days before irinotecan, continuing until the completion of each cycle
  • Activated charcoal, with 5x the dose in mg of the irinotecan dose, maximum of 260 mg/dose PO three times per day during irinotecan therapy
  • Loperamide (Imodium) prn diarrhea
  • Patient "advised to maintain hydration"

21-day cycles

References

  1. Phase I: Wagner LM, Crews KR, Iacono LC, Houghton PJ, Fuller CE, McCarville MB, Goldsby RE, Albritton K, Stewart CF, Santana VM. Phase I trial of temozolomide and protracted irinotecan in pediatric patients with refractory solid tumors. Clin Cancer Res. 2004 Feb 1;10(3):840-8. link to original article link to EuroPMC abstract Dosing details in manuscript have been reviewed by our editors
  2. Retrospective: Wagner LM, McAllister N, Goldsby RE, Rausen AR, McNall-Knapp RY, McCarville MB, Albritton K. Temozolomide and intravenous irinotecan for treatment of advanced Ewing sarcoma. Pediatr Blood Cancer. 2007 Feb;48(2):132-9. link to original article link to EuroPMC abstract
  3. Retrospective: Casey DA, Wexler LH, Merchant MS, Chou AJ, Merola PR, Price AP, Meyers PA. Irinotecan and temozolomide for Ewing sarcoma: the Memorial Sloan-Kettering experience. Pediatr Blood Cancer. 2009 Dec;53(6):1029-34. link to original article link to EuroPMC abstract Dosing details in manuscript have been reviewed by our editors


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