Ewing's sarcoma

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19 regimens on this page
27 variants on this page

Contents


Guidelines

ESMO

NCCN

Neoadjuvant therapy

EVAIA

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

Regimen

Study Evidence Comparator Efficacy
Paulussen et al. 2008 (EICESS-92) Phase III 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, 54.4 Gy of radiation is administered
  • For patients with a good histologic response, 44.8 Gy of radiation is administered
  • Additional details about particular clinical scenarios can be found in the original reference

Treatment followed by adjuvant EVAIA.

References

  1. 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

Regimen #1

Study Evidence Comparator Efficacy
Grier et al. 2003 Phase III 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:

Local therapy

  • 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

Regimen #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 60 Gy radiation 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 44.8 Gy of radiation

Treatment followed by adjuvant VACA.

References

  1. 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 Efficacy
Grier et al. 2003 Phase III 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:

Local therapy

  • 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, DActinomycin

Regimen #1

Study Evidence Comparator Efficacy
Paulussen et al. 2008 (EICESS-92) Phase III 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, 54.4 Gy of radiation is administered
  • For patients with a good histologic response, 44.8 Gy of radiation is administered
  • Additional details about particular clinical scenarios can be found in the original reference

High-risk patients proceeded to adjuvant VAIA. Standard-risk patients were randomized to adjvuant VAIA versus adjuvant VACA.

Regimen #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 60 Gy radiation 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 44.8 Gy of radiation

Treatment followed by adjuvant VAIA.

References

  1. 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. 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

VIDE

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VIDE: Vincristine, Ifosfamide, Doxorubicin, Etoposide

Regimen #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 1 hour prior to Ifosfamide (Ifex) on day 1, then 3000 mg/m2/day IV continuous 24-hour infusion on days 1 to 3
  • 2 to 3 liters/m2 hydration per day
  • Recommended, but not required: Filgrastim (Neupogen) 5 mcg/kg SC once per day for 10 days, starting 24 hours after completion of chemotherapy

21-day cycle for 6 initial cycles

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

Regimen #2

Study Evidence
Strauss et al. 2003 Phase II

Chemotherapy

Supportive medications

  • Mesna (Mesnex) 3000 mg/m2/day IV continuous 24-hour infusion on days 1 to 3

21-day cycle for up to 6 initial cycles

For patients with localized disease, treatment followed by complete surgical removal of tumors when possible, followed by adjuvant VAI. For patients with localized disease "not amenable to surgery," treatment followed by 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. 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-E.W.I.N.G. 99 clinical trial. Pediatr Blood Cancer. 2006 Jul;47(1):22-9. link to original article contains protocol PubMed

Adjuvant therapy

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. 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

Regimen #1

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

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

Preceding treatment

Chemotherapy

21-day cycle for 10 cycles

Regimen #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. 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. 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

Regimen

Study Evidence
Strauss et al. 2003 Phase II

Preceding treatment

Chemotherapy

Supportive medications

  • Mesna (Mesnex) 3000 mg/m2/day IV continuous 24-hour infusion on days 1 & 2

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

VAIA

back to top

VAIA: Vincristine, Adriamycin (Doxorubicin), Ifosfamide, DActinomycin

Regimen #1

Study Evidence Comparator Efficacy
Paulussen et al. 2008 (EICESS-92) Phase III 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

Regimen #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. 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. 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

Cyclophosphamide & Topotecan

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Regimen #1

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 PO/IV 2 to 4 hours before chemotherapy
  • Antiemetics as premedication before chemotherapy
  • 3 liters/m2 PO/IV 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

Regimen #2

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

  • Surgical removal of tumors is done when possible.
  • Radiation therapy for all other lesions.

Regimen #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 24-hour infusion on days 1 & 2; infusion starts second after Mesna (Mesnex) has started (total dose per cycle: 4200 mg/m2)
    • Children 10 years or younger received 70 mg/kg/day IV continuous 24-hour infusion on days 1 & 2 (total dose per cycle: 140 mg/kg)
    • 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
  • Topotecan (Hycamtin) 2 mg/m2/day IV continuous 24-hour infusion on days 1 to 3; suspended in D5W; infusion starts third after Mesna (Mesnex) and Cyclophosphamide (Cytoxan) have started (total dose per cycle: 6 mg/m2)

Supportive medications

  • Mesna (Mesnex) 2100 mg/m2/day IV continuous 24-hour infusion on days 1 to 3; infusion starts first (total dose per cycle: 6300 mg/m2)
    • Children 10 years or younger received 70 mg/kg/day IV continuous 24-hour infusion on days 1 to 3 (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 normal saline IV bolus 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
  • Filgrastim (Neupogen) 5 mcg/kg SC once per day starting one day after completion of chemotherapy, 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/day 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 once per day or 500 mcg/m2 BID SC, 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/day SC once per day and IL-6 at 2.5, 3.75, or 5.0 mcg/kg SC BID, 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

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 continuous infusion x 3 hours, then
    • 360 mg/m2 over 15 minutes Q3hours (given at hours 5, 8, 11, 14, 17, 20) x 6 doses; 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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Regimen #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

Supportive medications

28-day cycles

Regimen #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

Supportive medications

21-day cycles, given until progression of disease or unacceptable toxicity

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:

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:

Upfront window

Supportive medications

  • Prehydration with 500 mL/m2 D5 1/4 NS
  • 1500 mL/m2 PO/IV 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:

Induction therapy, 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

Induction therapy, VDoxoC portion

  • Vincristine (Oncovin) 2 mg/m2 (maximum dose per cycle is 2mg) IV bolus once per day on days 1, 8, 15, given first, prior to cyclophosphamide
  • Doxorubicin (Adriamycin) 37.5 mg/m2/day IV continuous 24-hour infusion on days 1 & 2, 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/day IV over 30 minutes once per day on days 1 & 2, given second after vincristine
    • 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:

Local therapy, primary, VDoxoC portion

Supportive medications

21-day cycle for 1 cycle, followed by local control

Local control (after week 21)

  • Choice of modality between surgical and radiation therapy options is at the discretion of the provider
  • Patients treated with radiation along received 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

Local therapy, primary, VEC portion

Supportive medications

21-day cycle for 2 cycles, followed by:

Continuation therapy, IE portion

Supportive medications

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

Continuation therapy, 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:

Local therapy, metastases, VDoxoC potion

Supportive medications

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

Local control of metastatic disease (after week 39)

  • Choice of modality between surgical and radiation therapy options is at the discretion of the provider
  • Radiation therapy 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

Local therapy, metastases, VEC portion

Supportive medications

21-day cycle for 2 cycles

References

  1. 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 Efficacy
Miser et al. 2004 Phase III 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

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.
  • Radiation therapy to all metastatic sites of disease in addition to any radiation planned for primary tumor.
  • 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
  • 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 Efficacy
Miser et al. 2004 Phase III 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

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.
  • Radiation therapy to all metastatic sites of disease in addition to any radiation planned for primary tumor.
  • 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
  • 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, then HD SCT

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VAI: Vincristine, DActinomycin, Ifosfamide
HD SCT: High Dose chemotherapy with busulphan and melphalan and Stem Cell Transplant

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. 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

  • VIDE for up to 6 cycles

Chemotherapy, VAI portion

Supportive medications

  • Mesna (Mesnex) 3000 mg/m2/day IV continuous 24-hour infusion on days 1 & 2

21-day cycle for one or more cycles, followed by:

Chemotherapy, high-dose portion

  • Busulfan (Myleran) 150 mg/m2 IV once per day on days -6 to -3
  • Melphalan (Alkeran) 140 mg/m2 IV once on day -2
  • Peripheral blood stem cell rescue on day 0, using at least 2 x 106 CD34+ cells/kg

One course

Radiation therapy, if indicated, is given 2 months after recovery from high-dose 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 ORR
Strauss et al. 2003 Phase II 88%

This protocol was intended for patients with metastatic disease.

Chemotherapy

Supportive medications

  • Mesna (Mesnex) 3000 mg/m2/day IV continuous 24-hour infusion on days 1 to 3

21-day cycle for up to 6 initial cycles

Treatment followed by adjuvant VAI, then HD SCT.

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