Ewing sarcoma

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James L. Chen, MD, MS
The Ohio State University
Columbus, OH

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21 regimens on this page
33 variants on this page

Contents


Guidelines

ESMO

ESMO/PaedCan/EURACAN

NCCN

Neoadjuvant therapy

EVAIA

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

Regimen

Study Evidence Comparator Comparative Efficacy
Paulussen et al. 2008 (EICESS-92) Phase III (E) VAIA Seems not superior

This regimen is intended for high-risk patients.

Chemotherapy

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

Local therapy

  • Surgical removal of tumors is done when possible.
  • For patients not undergoing surgery, with incomplete surgical resection, or poor histologic response, External beam radiotherapy 54.4 Gy
  • For patients with a good histologic response, External beam radiotherapy 44.8 Gy
  • Additional details about particular clinical scenarios can be found in the original reference

Subsequent treatment

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 contains verified protocol PubMed

VACA

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

Variant #1

Study Evidence Comparator Comparative Efficacy
Grier et al. 2003 Phase III (C) VACA/IE Inferior OS

Note: The survival disadvantage in Grier et al. 2003 was only noted for patients with non-metastatic disease at diagnosis.

Chemotherapy

Supportive medications

21-day cycle for 17 cycles

Local therapy is planned to take place on week 12, as follows:

Subsequent treatment

  • Surgery can be performed for resectable tumors. No radiation therapy is given for completely resected primary tumors with negative margins.
    • For residual tumor after surgery, 4500 cGy radiation is administered to the original tumor volume plus a 1 cm margin
  • If only radiation therapy is used, 4500 cGy of radiation is administered to the tumor volume plus a 3 cm margin, followed by 1080 cGy to only the preradiation tumor volume, for a total dose of 5580 cGy

Variant #2

Study Evidence
Paulussen et al. 2001 (CESS 86) Non-randomized

This regimen is intended for standard risk patients.

Chemotherapy

Supportive medications

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

Local therapy

  • Complete surgical removal of tumors is done when possible.
  • Patients not undergoing surgery receive External beam radiotherapy 60 Gy to the tumor bulk, with the tumor-bearing compartment receiving at least 44.8 Gy
  • Patients with incomplete surgical resection or poor histologic response received External beam radiotherapy 44.8 Gy

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 contains verified protocol PubMed
  2. 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 contains verified protocol PubMed

VACA/IE

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

Regimen

Study Evidence Comparator Comparative Efficacy
Grier et al. 2003 Phase III (E) VACA Superior OS

Note: The survival advantage in Grier et al. 2003 was only noted for patients with non-metastatic disease at diagnosis.

Chemotherapy, VACA portion

Supportive medications

21-day cycle, alternating with IE, for 17 total cycles of chemotherapy

Chemotherapy, IE portion

Supportive medications

21-day cycle, alternating with VACA, for 17 total cycles of chemotherapy

Local therapy is planned to take place on week 12, as follows:

Subsequent treatment

  • Surgery can be performed for resectable tumors. No radiation therapy is given for completely resected primary tumors with negative margins.
    • For residual tumor after surgery, 4500 cGy radiation is administered to the original tumor volume plus a 1 cm margin
  • If only radiation therapy is used, 4500 cGy of radiation is administered to the tumor volume plus a 3 cm margin, followed by 1080 cGy to only the preradiation tumor volume, for a total dose of 5580 cGy

References

  1. 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 contains verified protocol PubMed

VAIA

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

Variant #1

Study Evidence Comparator Comparative Efficacy
Paulussen et al. 2008 (EICESS-92) Phase III (C) EVAIA (high-risk) Seems not superior

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.
  • For patients not undergoing surgery, with incomplete surgical resection, or poor histologic response, External beam radiotherapy 54.4 Gy
  • For patients with a good histologic response, External beam radiotherapy 44.8 Gy
  • Additional details about particular clinical scenarios can be found in the original reference

Subsequent treatment

Variant #2

Study Evidence
Paulussen et al. 2001 (CESS 86) Non-randomized

This regimen is intended for high risk patients.

Chemotherapy

Supportive medications

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

Local therapy

  • Complete surgical removal of tumors is done when possible.
  • Patients not undergoing surgery receive External beam radiotherapy 60 Gy to the tumor bulk, with the tumor-bearing compartment receiving at least 44.8 Gy
  • Patients with incomplete surgical resection or poor histologic response received External beam radiotherapy 44.8 Gy

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 contains verified protocol PubMed
  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 contains verified protocol PubMed

VDC/IE

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

Variant #1, q2wk

Study Evidence Comparator Comparative Efficacy
Womer et al. 2012 (AEWS0031) Phase III (E) Standard VDC/IE Seems to have superior EFS

Chemotherapy, VDC portion

Supportive medications

14-day cycle, alternating with IE, for 6 total cycles of chemotherapy

Chemotherapy, IE portion

Supportive medications

14-day cycle, alternating with VDC, for 6 total cycles of chemotherapy

Subsequent treatment

  • Local therapy, then adjuvant VDC/IE

Variant #2, q3wk

Study Evidence Comparator Comparative Efficacy
Womer et al. 2012 (AEWS0031) Phase III (C) Dose-intense VDC/IE Seems to have inferior EFS

Chemotherapy, VDC portion

Supportive medications

21-day cycle, alternating with IE, for 4 total cycles of chemotherapy

Chemotherapy, IE portion

Supportive medications

21-day cycle, alternating with VDC, for 4 total cycles of chemotherapy

Subsequent treatment

  • Local therapy, then adjuvant VDC/IE

References

  1. AEWS0031: Womer RB, West DC, Krailo MD, Dickman PS, Pawel BR, Grier HE, Marcus K, Sailer S, Healey JH, Dormans JP, Weiss AR. 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 link to PMC article contains verified protocol PubMed

VIDE

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VIDE: Vincristine, Ifosfamide, Doxorubicin, Etoposide

Variant #1

Study Evidence
Juergens et al. 2006 (EURO-E.W.I.N.G. 99) Phase II

Chemotherapy

Supportive medications

  • Mesna (Mesnex) 1000 mg/m2 IV push once on day 1; 60 minutes prior to Ifosfamide (Ifex), then 3000 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

  • Further therapy is dictated by patient characteristics & response; details can be found in the primary reference

Variant #2

Study Evidence
Strauss et al. 2003 Phase II

Chemotherapy

Supportive medications

  • Mesna (Mesnex) 3000 mg/m2/day IV continuous infusion over 72 hours, started on day 1 (total dose per cycle: 9000 mg/m2)

21-day cycle for up to 6 cycles

Subsequent treatment

  • Patients with resectable localized disease: complete surgical removal of tumors when possible, then adjuvant VAI
  • Patients with unresectable localized disease: VAI & 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 contains verified protocol PubMed
  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 contains protocol PubMed
  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 does not contain protocol PubMed

Adjuvant therapy

Busulfan & Melphalan, then auto HSCT

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BuMel: Busulfan & Melphalan

Regimen

Study Evidence Comparator Comparative Efficacy
Atra et al. 1997 Phase II, <20 pts
Whelan et al. 2018 (R2Loc) Phase III (E) VAI Seems to have superior OS

Preceding treatment

Chemotherapy

Stem cells re-infused on day 0

References

  1. 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 contains verified protocol in supplement link to PMC article PubMed

EVAIA

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

Regimen

Study Evidence
Paulussen et al. 2008 (EICESS-92) Non-randomized portion of RCT

This regimen is intended for high-risk patients.

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 contains verified protocol PubMed

VACA

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

Variant #1

Study Evidence Comparator Comparative Efficacy
Paulussen et al. 2008 (EICESS-92) Phase III (E) VAIA Seems not superior

Note: this regimen was intended for standard-risk patients.

Preceding treatment

Chemotherapy

21-day cycle for 10 cycles

Variant #2

Study Evidence
Paulussen et al. 2001 (CESS 86) Non-randomized

This regimen is intended for standard risk patients.

Preceding treatment

Chemotherapy

Supportive medications

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 contains verified protocol PubMed
  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 contains verified protocol PubMed

VAI

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

Variant #1, capped dactinomycin

Study Evidence Comparator Comparative Efficacy
Le Deley et al. 2014 (Euro-EWING99-R1) Phase III (C) VAC Inconclusive whether non-inferior

Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT prior to 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 medications

21-day cycle for 8 cycles

Variant #2, uncapped dactinomycin

Study Evidence
Strauss et al. 2003 Phase II

Preceding treatment

Chemotherapy

Supportive medications

  • Mesna (Mesnex) 3000 mg/m2/day IV continuous infusion over 48 hours, started on day 1 (total dose per cycle: 6000 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 contains verified protocol PubMed
  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 contains verified protocol PubMed

VAIA

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

Variant #1

Study Evidence Comparator Comparative Efficacy
Paulussen et al. 2008 (EICESS-92) Phase III (C) VACA (standard-risk) Seems not superior

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

Variant #2

Study Evidence
Paulussen et al. 2001 (CESS 86) Non-randomized

This regimen is intended for high risk patients.

Preceding treatment

Chemotherapy

Supportive medications

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 contains verified protocol PubMed
  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 contains verified protocol PubMed

Relapsed or refractory or metastatic

Busulfan & Melphalan, then auto HSCT

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Variant #1, PO busulfan, mel 140 mg/m2

Study Evidence
Atra et al. 1997 Phase II, <20 pts

Chemotherapy

Stem cells re-infused on day 0

Variant #2, PO busulfan, mel 160 mg/m2

Study Evidence
Atra et al. 1997 Phase II, <20 pts

Chemotherapy

Stem cells re-infused on day 0

Variant #3, IV busulfan

Study Evidence
Strauss et al. 2003 Phase II

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

  • VAI x 1 or more cycles

Chemotherapy

Stem cells re-infused on day 0

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 contains verified protocol PubMed
  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 contains verified protocol PubMed

Cyclophosphamide & Topotecan

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Variant #1, standard-dose

Study Evidence
Saylors et al. 2001 Phase II

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

Chemotherapy

Supportive medications

  • 500 mL/m/2 fluids IV or PO once per day on days 1 to 5; 2 to 4 hours prior to chemotherapy
  • Antiemetics once per day on days 1 to 5, prior to 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 1500/uL above nadir

21-day cycle for 12 to 14 cycles

Variant #2, standard-dose with local therapy

Study Evidence
Hunold et al. 2006 Phase II

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

Chemotherapy

Supportive medications

21-day cycle for 12 to 14 cycles

Local therapy

Variant #3, high-dose

Study Evidence
Kushner et al. 2000 Non-randomized

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

Chemotherapy

  • Cyclophosphamide (Cytoxan) 2100 mg/m2/day IV continuous infusion over 48 hours, started on day 1, given second (total dose per cycle: 4200 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, given third (total dose per cycle: 6 mg/m2)

Supportive medications

  • Mesna (Mesnex) 2100 mg/m2/day IV continuous infusion over 72 hours, started on day 1, given first (total dose per cycle: 6300 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 1000 mL NS over 24 hours
  • On day 1, prior to 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 & cyclophosphamide
  • Additional hydration fluid on days 1 & 2 so that, when added to volumes of cyclophosphamide, mesna, and topotecan, total volume of fluids is 3000 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; 1000 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 1000/uL

Subsequent cycles to start when ANC greater than 1000/uL 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 contains verified protocol PubMed
  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 contains verified protocol PubMed
  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 contains verified protocol PubMed

Docetaxel & Gemcitabine

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Regimen

Study Evidence
Navid et al. 2008 Retrospective

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 medications

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 contains verified protocol PubMed

ICE

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ICE: Ifosfamide, Carboplatin, Etoposide

Regimen

Study Evidence
Van Winkle et al. 2005 Phase II

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 medications

  • Depending on the study the patients were enrolled on, they received one of the following:
    • 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 1000/uL, or until ANC is at least 1000/uL post nadir, whichever comes later
    • CCG-0924: PIXY 321 at doses of 500/750/1000 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/uL or platelet count is at least 900 x 109/L for 2 days between days 13 to 18, or until ANC is at least 1000/uL 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 5.0 mcg/kg SC twice per day, starting 24 hours after completing ICE. Filgrastim is continued until ANC is at least 1000/uL, 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 1000/uL 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. Van Winkle P, Angiolillo A, Krailo M, Cheung YK, Anderson B, Davenport V, Reaman G, Cairo MS. 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 contains verified protocol PubMed

IE

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IE: Ifosfamide, Etoposide

Regimen

Study Evidence
Miser et al. 1987 Phase II

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

Chemotherapy

Supportive medications

  • Mesna (Mesnex) given with Ifosfamide (Ifex) as follows:
    • 360 mg/m2 IV loading dose over 1 hour, then
    • 120 mg/m2/hour IV over 3 hours, then
    • 360 mg/m2 IV over 15 minutes every 3 hours for 6 doses, given at hours 5, 8, 11, 14, 17, 20
      • Doses after hour 5 can be given PO or IV

21-day cycle for 12 cycles

For 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 1.8 Gy fractions given for a total dose of 50 to 55 Gy.

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 contains verified protocol PubMed

Irinotecan & Temozolomide

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Variant #1

Study Evidence
Wagner et al. 2004 Phase I, <20 pts

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 60 minutes once per day on days 1 to 5, 8 to 12, given second on days 1 to 5, 1 hour after temozolomide
  • Temozolomide (Temodar) 100 mg/m2 PO once per day on days 1 to 5, given first

Supportive medications

28-day cycles

Variant #2

Study Evidence
Casey et al. 2009 Retrospective

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 60 minutes once per day on days 1 to 5, 8 to 12, given second on days 1 to 5, 1 hour after temozolomide
  • Temozolomide (Temodar) 100 mg/m2 PO once per day on days 1 to 5, given first

Supportive medications

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 contains verified protocol PubMed
  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 PubMed
  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 contains verified protocol PubMed

TC, then IE, VDoxoC, VEC

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

Regimen

Study Evidence
Bernstein et al. 2006 (POG 9457) Phase II

This is a complex regimen, and it is suggested to 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 below 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:

Chemotherapy, topotecan window

Supportive medications

  • Filgrastim (Neupogen) 5 mcg/kg SC once per day, starting on day 6, to continue until ANC is at least 5000/uL above nadir

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

Chemotherapy, upfront window

Supportive medications

  • 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 5000/uL 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:

Chemotherapy, IE portion

  • Ifosfamide (Ifex) as follows:
    • First cycle: 3600 mg/m2 IV over 2 hours once per day on days 1 to 5, given second, after etoposide
      • Administered in 200 mL/m2 D5 1/2 NS
    • Second and third cycle: 2800 mg/m2 IV over 2 hours once per day on days 1 to 5, given 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, given first, before ifosfamide
    • Administered in 250 mL/m2 of D5 1/2 NS

Supportive medications

  • Mesna (Mesnex) 4000 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, given first
  • Doxorubicin (Adriamycin) 37.5 mg/m2/day IV continuous infusion over 48 hours, started on day 1, given third (total dose per cycle: 75 mg/m2)
    • Administered in 2400 mL/m2/day (4800 mL/m2 total volume) of D5 1/2 NS
  • Cyclophosphamide (Cytoxan) 2100 mg/m2 IV over 30 minutes once per day on days 1 & 2, given second
    • Administered in 200 mL/m2 D5 1/2 NS

Supportive medications

  • Mesna (Mesnex) 2400 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:

Chemotherapy, primary, VDoxoC portion

Supportive medications

21-day cycle for 1 cycle, 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
  • Patients treated with radiation alone received External beam radiotherapy 45 Gy in 1.8 Gy fractions to the initial tumor volume; additional treatment up to a total of 55.8 Gy was administered to original bony tumors and the postinduction chemotherapy soft tissue volumes plus a 2 cm margin
  • See primary reference for details about radiation therapy in a variety of clinical scenarios

Chemotherapy, primary, VEC portion

Supportive medications

21-day cycle for 2 cycles, followed by:

Chemotherapy, continuation, IE portion

Supportive medications

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

Chemotherapy, continuation, VDoxoC portion

Supportive medications

21-day cycle for 1 cycle, in between IE

Local therapy for metastatic disease along with ongoing chemotherapy starts at week 39:

Chemotherapy, metastases, VDoxoC potion

Supportive medications

21-day cycle for 1 cycle, followed by local control of metastatic disease:

Local therapy of 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
  • See primary reference for details about radiation therapy in a variety of clinical scenarios

Chemotherapy, metastases, VEC portion

Supportive medications

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 Phase II Study 9457; 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 contains verified protocol PubMed

VAdCA

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

Regimen

Study Evidence Comparator Comparative Efficacy
Miser et al. 2004 Phase III (C) VAdCA/IE Seems not superior

Note: this is essentially a sub-group analysis of the protocol published in Grier et al. 2003, 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. 2004 does not say the dose is capped at a maximum dose of 2 mg, but Grier et al. 2003 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) 1200 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 is planned to take place on week 9, as follows:

Local therapy

  • 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 4500 cGy is administered to the tumor volume plus a 3 cm margin, followed by 1080 cGy to only the preradiation tumor volume, for a total dose of 5580 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. 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 contains verified protocol PubMed

VAdCA/IE

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

Regimen

Study Evidence Comparator Comparative Efficacy
Miser et al. 2004 Phase III (E) VAdCA Seems not superior

Note: this is essentially a sub-group analysis of the protocol published in Grier et al. 2003, but some key details differ, so we report it separately.

Chemotherapy, VAdCA portion

  • Vincristine (Oncovin) 2 mg/m2 IV once on day 1
    • Note: Miser et al. 2004 does not say the dose is capped at a maximum dose of 2 mg, but Grier et al. 2003 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) 1200 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, alternating with IE, for 17 total cycles

Chemotherapy, IE portion

Supportive medications

21-day cycle, alternating with VAC, for 17 total cycles

Local therapy is planned to take place on week 9, as follows:

Local therapy

  • 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 4500 cGy is administered to the tumor volume plus a 3 cm margin, followed by 1080 cGy to only the preradiation tumor volume, for a total dose of 5580 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. 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 contains verified protocol PubMed

VAI

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VAI: Vincristine, DActinomycin, Ifosfamide

Regimen

Study Evidence
Strauss et al. 2003 Phase II

This protocol was intended for patients with metastatic disease. The reference does not clearly describe how many cycles of VAI might be used.

Preceding treatment

  • VIDE for up to 6 cycles

Chemotherapy

Supportive medications

  • Mesna (Mesnex) 3000 mg/m2/day IV continuous infusion over 48 hours, started on day 1 (total dose per cycle: 6000 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 contains verified protocol PubMed

VIDE

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VIDE: Vincristine, Ifosfamide, Doxorubicin, Etoposide

Regimen

Study Evidence Efficacy
Strauss et al. 2003 Phase II ORR: 88%

This protocol was intended for patients with metastatic disease.

Chemotherapy

Supportive medications

  • Mesna (Mesnex) 3000 mg/m2/day IV continuous infusion over 72 hours, started on day 1 (total dose per cycle: 9000 mg/m2)

21-day cycle for up to 6 cycles

Subsequent treatment

  • Adjuvant VAI, then HD with auto HSCT

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 contains verified protocol PubMed