Difference between revisions of "Staging page"

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[[#top|Back to Top]]
 
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</div>
 
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{{#lst:Section editor transclusions|sarcoma}}
 
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<big>'''Note: certain regimens have been moved to dedicated pages:
 
−
*'''[[Ewing sarcoma, pediatric|Pediatric Ewing sarcoma]]
 
−
</big>
 
−
{| class="wikitable" style="float:right; margin-right: 5px;"
 
−
|-
 
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|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div>
 
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<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div>
 
−
|}
 
−
{{TOC limit|limit=3}}
 
−
=Guidelines=
 
−
==[http://www.esmo.org/ ESMO]==
 
−
*'''2014:''' [http://annonc.oxfordjournals.org/content/25/suppl_3/iii113.full.pdf+html Bone sarcomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/25210081 PubMed]
 
−
==ESMO/PaedCan/EURACAN==
 
−
*'''2018:''' Casali et al. [https://www.esmo.org/Guidelines/Sarcoma-and-GIST/Bone-Sarcomas Bone sarcomas: ESMO–PaedCan–EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up]
 
−
==[https://www.nccn.org/ NCCN]==
 
−
*[https://www.nccn.org/professionals/physician_gls/pdf/bone.pdf NCCN Guidelines - Bone Cancer]
 
−
=Neoadjuvant therapy=
 
−
==EVAIA {{#subobject:4d4fee|Regimen=1}}==
 
−
EVAIA: '''<u>E</u>'''toposide, '''<u>V</u>'''incristine, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>I</u>'''fosfamide, D'''<u>A</u>'''ctinomycin
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen {{#subobject:11e269|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
−
!style="width: 20%"|Study
 
−
!style="width: 20%"|Years of enrollment
 
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 20%"|Comparator
 
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
−
|-
 
−
|[https://doi.org/10.1200/jco.2008.16.5720 Paulussen et al. 2008 (EICESS-92)]
 
−
|1992-1997
 
−
|style="background-color:#1a9851"|Phase 3 (E-esc)
 
−
|[[#VAIA|VAIA]]
 
−
|style="background-color:#ffffbf"|Did not meet primary endpoint of EFS36
 
−
|-
 
−
|}
 
−
''Note: This regimen is intended for high-risk patients.''
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[Etoposide (Vepesid)]] 150 mg/m<sup>2</sup> IV once per day on days 1 to 3
 
−
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> IV once on day 1
 
−
*[[Doxorubicin (Adriamycin)]] 30 mg/m<sup>2</sup> IV once per day on days 2 & 4
 
−
*[[Ifosfamide (Ifex)]] 2000 mg/m<sup>2</sup> IV once per day on days 1 to 3
 
−
**Note: primary reference does not comment about the use of mesna
 
−
*[[Dactinomycin (Cosmegen)]] 0.5 mg/m<sup>2</sup> IV once per day on days 1, 3, 5
 
−
'''21-day cycle for 4 cycles'''
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*[[Surgery#Surgical_resection|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, then adjuvant [[#EVAIA_2|EVAIA]]
 
−
*For patients with a good histologic response: [[External beam radiotherapy]] 44.8 Gy, then adjuvant [[#EVAIA_2|EVAIA]]
 
−
*Additional details about particular clinical scenarios can be found in the original reference
 
−
</div></div>
 
−
===References===
 
−
# '''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. [https://doi.org/10.1200/jco.2008.16.5720 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18802150 PubMed] NCT0000251
 
−
==VACA {{#subobject:4a10e9|Regimen=1}}==
 
−
VACA: '''<u>V</u>'''incristine, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>C</u>'''yclophosphamide, D'''<u>A</u>'''ctinomycin
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen variant #1 {{#subobject:72ab30|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
−
!style="width: 20%"|Study
 
−
!style="width: 20%"|Years of enrollment
 
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 20%"|Comparator
 
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
−
|-
 
−
|[https://doi.org/10.1056/NEJMoa020890 Grier et al. 2003 (INT-0091)]
 
−
|1988-1992
 
−
|style="background-color:#1a9851"|Phase 3 (C)
 
−
|[[#VACA.2FIE|VACA/IE]]
 
−
|style="background-color:#d73027"|Inferior OS
 
−
|-
 
−
|}
 
−
''Note: The survival disadvantage in Grier et al. 2003 was only noted for patients with non-metastatic disease at diagnosis.''
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[Vincristine (Oncovin)]] 2 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once on day 1
 
−
*[[Doxorubicin (Adriamycin)]] 75 mg/m<sup>2</sup> IV bolus once on day 1
 
−
**Stop once cumulative dose received by the patient exceeds 375 mg/m<sup>2</sup>
 
−
*[[Cyclophosphamide (Cytoxan)]] 1200 mg/m<sup>2</sup> IV once on day 1
 
−
*[[Dactinomycin (Cosmegen)]] 1.25 mg/m<sup>2</sup> IV once on day 1, once cumulative doxorubicin dose received by the patient exceeds 375 mg/m<sup>2</sup>
 
−
====Supportive therapy====
 
−
*[[Mesna (Mesnex)]] after [[Cyclophosphamide (Cytoxan)]] for prevention of hemorrhagic cystitis; primary reference did not list dosage/schedule
 
−
'''21-day cycle for 17 cycles'''
 
−
''Local therapy is planned to take place on week 12, as follows:''
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*[[Surgery#Surgical_resection|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
 
−
</div></div><br>
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen variant #2 {{#subobject:c30ab5|Variant=1}}===
 
−
{| class="wikitable" style="width: 40%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://doi.org/10.1200/jco.2001.19.6.1818 Paulussen et al. 2001 (CESS 86)]
 
−
|style="background-color:#91cf61"|Non-randomized
 
−
|-
 
−
|}
 
−
''Note: This regimen is intended for standard risk patients.''
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
 
−
*[[Doxorubicin (Adriamycin)]] 30 mg/m<sup>2</sup> IV once per day on days 1, 2, 43, 44
 
−
*[[Cyclophosphamide (Cytoxan)]] 1200 mg/m<sup>2</sup> IV once on day 1, then 400 mg/m<sup>2</sup> IV once per day on days 22, 23, 24, then 1200 mg/m<sup>2</sup> IV once on day 43
 
−
*[[Dactinomycin (Cosmegen)]] 0.5 mg/m<sup>2</sup> IV once per day on days 22, 23, 24
 
−
====Supportive therapy====
 
−
*[[Mesna (Mesnex)]] "as appropriate"
 
−
'''9-week "block", then proceed to local therapy:'''
 
−
====Local therapy====
 
−
*Complete [[Surgery#Surgical_resection|surgical removal]] of tumors is done when possible.
 
−
*Patients not undergoing surgery: [[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: [[External beam radiotherapy]] 44.8 Gy
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*Adjuvant [[#VACA_2|VACA]]
 
−
</div></div>
 
−
===References===
 
−
# '''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. [https://doi.org/10.1200/jco.2001.19.6.1818 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/11251014 PubMed]
 
−
# '''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. [https://doi.org/10.1056/NEJMoa020890 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/12594313 PubMed]
 
−
==VACA/IE {{#subobject:ed89d8|Regimen=1}}==
 
−
VACA/IE: '''<u>V</u>'''incristine, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>C</u>'''yclophosphamide, D'''<u>A</u>'''ctinomycin alternating with '''<u>I</u>'''fosfamide, '''<u>E</u>'''toposide
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Protocol {{#subobject:2f582d|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
−
!style="width: 20%"|Study
 
−
!style="width: 20%"|Years of enrollment
 
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 20%"|Comparator
 
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
−
|-
 
−
|[https://doi.org/10.1056/NEJMoa020890 Grier et al. 2003 (INT-0091)]
 
−
|1988-1992
 
−
|style="background-color:#1a9851"|Phase 3 (E-esc)
 
−
|[[#VACA|VACA]]
 
−
|style="background-color:#1a9850"|Superior OS
 
−
|-
 
−
|}
 
−
''Note: The survival advantage in Grier et al. 2003 was only noted for patients with non-metastatic disease at diagnosis.''
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy, VACA portion====
 
−
*[[Vincristine (Oncovin)]] 2 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once on day 1
 
−
*[[Doxorubicin (Adriamycin)]] 75 mg/m<sup>2</sup> IV bolus once on day 1
 
−
**Stop once cumulative dose received by the patient exceeds 375 mg/m<sup>2</sup>
 
−
*[[Cyclophosphamide (Cytoxan)]] 1200 mg/m<sup>2</sup> IV once on day 1
 
−
*[[Dactinomycin (Cosmegen)]] 1.25 mg/m<sup>2</sup> IV once on day 1, once cumulative doxorubicin dose received by the patient exceeds 375 mg/m<sup>2</sup>
 
−
====Supportive therapy====
 
−
*[[Mesna (Mesnex)]] after [[Cyclophosphamide (Cytoxan)]] for prevention of hemorrhagic cystitis; primary reference did not list dosage/schedule
 
−
'''21-day cycle, alternating with IE, for 17 total cycles of chemotherapy'''
 
−
====Chemotherapy, IE portion====
 
−
*[[Ifosfamide (Ifex)]] 1800 mg/m<sup>2</sup> IV once per day on days 1 to 5
 
−
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV once per day on days 1 to 5
 
−
====Supportive therapy====
 
−
*[[Mesna (Mesnex)]] with [[Ifosfamide (Ifex)]]; primary reference did not list dosage/schedule
 
−
'''21-day cycle, alternating with VACA, for 17 total cycles of chemotherapy'''
 
−
''Local therapy is planned to take place on week 12, as follows:''
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*[[Surgery#Surgical_resection|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
 
−
</div></div>
 
−
===References===
 
−
# '''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. [https://doi.org/10.1056/NEJMoa020890 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/12594313 PubMed]
 
−
==VAIA {{#subobject:84f65e|Regimen=1}}==
 
−
VAIA: '''<u>V</u>'''incristine, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>I</u>'''fosfamide, '''<u>A</u>'''ctinomycin-D (Dactinomycin)
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen variant #1 {{#subobject:195911|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
−
!style="width: 20%"|Study
 
−
!style="width: 20%"|Years of enrollment
 
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 20%"|Comparator
 
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
−
|-
 
−
|[https://doi.org/10.1200/jco.2008.16.5720 Paulussen et al. 2008 (EICESS-92)]
 
−
|1992-1997
 
−
|style="background-color:#1a9851"|Phase 3 (C)
 
−
|[[#EVAIA|EVAIA (high-risk)]]
 
−
|style="background-color:#ffffbf"|Did not meet primary endpoint of EFS36
 
−
|-
 
−
|}
 
−
''Note: high-risk patients were randomized to this regimen versus EVAIA. Standard-risk patients were not randomized at this point of the protocol.''
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> IV once on day 1
 
−
*[[Doxorubicin (Adriamycin)]] 30 mg/m<sup>2</sup> IV once per day on days 2 & 4
 
−
*[[Ifosfamide (Ifex)]] 2000 mg/m<sup>2</sup> IV once per day on days 1 to 3
 
−
**Note: primary reference does not comment about the use of mesna
 
−
*[[Dactinomycin (Cosmegen)]] 0.5 mg/m<sup>2</sup> IV once per day on days 1, 3, 5
 
−
'''21-day cycle for 4 cycles, then proceed to local therapy:'''
 
−
====Local therapy====
 
−
*[[Surgery#Surgical_resection|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
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*High-risk patients: Adjuvant [[#VAIA_2|VAIA]]
 
−
*Standard-risk patients: Adjuvant [[#VAIA_2|VAIA]] versus [[#VACA_2|VACA]]
 
−
</div></div><br>
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen variant #2 {{#subobject:fc21ca|Variant=1}}===
 
−
{| class="wikitable" style="width: 40%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://doi.org/10.1200/jco.2001.19.6.1818 Paulussen et al. 2001 (CESS 86)]
 
−
|style="background-color:#91cf61"|Non-randomized
 
−
|-
 
−
|}
 
−
''Note: This regimen is intended for high risk patients.''
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
 
−
*[[Doxorubicin (Adriamycin)]] 30 mg/m<sup>2</sup> IV once per day on days 1, 2, 43, 44
 
−
*[[Ifosfamide (Ifex)]] 3000 mg/m<sup>2</sup> IV once per day on days 1, 2, 22, 23, 43, 44
 
−
*[[Dactinomycin (Cosmegen)]] 0.5 mg/m<sup>2</sup> IV once per day on days 22, 23, 24
 
−
====Supportive therapy====
 
−
*[[Mesna (Mesnex)]] "as appropriate"
 
−
'''9-week "block", then proceed to local therapy:'''
 
−
====Local therapy====
 
−
*Complete [[Surgery#Surgical_resection|surgical removal]] of tumors is done when possible.
 
−
*Patients not undergoing surgery: [[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: [[External beam radiotherapy]] 44.8 Gy
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*Adjuvant [[#VAIA_2|VAIA]]
 
−
</div></div>
 
−
===References===
 
−
# '''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. [https://doi.org/10.1200/jco.2001.19.6.1818 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/11251014 PubMed]
 
−
# '''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. [https://doi.org/10.1200/jco.2008.16.5720 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18802150 PubMed] NCT0000251
 
−
#'''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. [https://doi.org/10.1002/pbc.29691 link to original article] [https://pubmed.ncbi.nlm.nih.gov/35441463/ PubMed]
 
−
==VDC/IE {{#subobject:5bcde5|Regimen=1}}==
 
−
VDC/IE: '''<u>V</u>'''incristine, '''<u>D</u>'''oxorubicin, '''<u>C</u>'''yclophosphamide, alternating with '''<u>I</u>'''fosfamide & '''<u>E</u>'''toposide
 
−
<br>VAdriaC/IE: '''<u>V</u>'''incristine, '''<u>Adria</u>'''mycin (Doxorubicin), '''<u>C</u>'''yclophosphamide, alternating with '''<u>I</u>'''fosfamide & '''<u>E</u>'''toposide
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen variant #1, q2wk {{#subobject:47963f|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
−
!style="width: 20%"|Study
 
−
!style="width: 20%"|Years of enrollment
 
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 20%"|Comparator
 
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3494838/ Womer et al. 2012 (AEWS0031)]
 
−
|2001-2005
 
−
|style="background-color:#1a9851"|Phase 3 (E-esc)
 
−
|[[#VDC.2FIE|VDC/IE]]; standard
 
−
| style="background-color:#91cf60" |Seems to have superior EFS
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy, VDC portion====
 
−
*[[Vincristine (Oncovin)]] as follows:
 
−
**Cycles 1, 3, 5: 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once on day 1
 
−
*[[Doxorubicin (Adriamycin)]] as follows:
 
−
**Cycles 1, 3, 5: 37.5 mg/m<sup>2</sup> IV once per day on days 1 & 2
 
−
*[[Cyclophosphamide (Cytoxan)]] as follows:
 
−
**Cycles 1, 3, 5: 1200 mg/m<sup>2</sup> IV once on day 1
 
−
====Supportive therapy, VDC portion====
 
−
*[[Mesna (Mesnex)]] as follows:
 
−
**Cycles 1, 3, 5: with [[Cyclophosphamide (Cytoxan)]]; primary reference did not list dosage/schedule
 
−
*[[Filgrastim (Neupogen)]] as follows:
 
−
**Cycles 1, 3, 5: Schedule not specified
 
−
====Chemotherapy, IE portion====
 
−
*[[Ifosfamide (Ifex)]] as follows:
 
−
**Cycles 2, 4, 6: 1800 mg/m<sup>2</sup> IV once per day on days 1 to 5
 
−
*[[Etoposide (Vepesid)]] as follows:
 
−
**Cycles 2, 4, 6: 100 mg/m<sup>2</sup> IV once per day on days 1 to 5
 
−
====Supportive therapy, IE portion====
 
−
*[[Mesna (Mesnex)]] as follows:
 
−
**Cycles 2, 4, 6: with [[Ifosfamide (Ifex)]]; primary reference did not list dosage/schedule
 
−
*[[Filgrastim (Neupogen)]] as follows:
 
−
**Cycles 2, 4, 6: Schedule not specified
 
−
'''14-day cycle for 6 cycles'''
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*Local therapy, then adjuvant [[#VDC.2FIE_88|VDC/IE]]
 
−
</div></div><br>
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Protocol variant #2, q2wk with extra vincristine {{#subobject:4ug63f|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
−
!style="width: 20%"|Study
 
−
!style="width: 20%"|Years of enrollment
 
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 20%"|Comparator
 
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8677904/ Leavey et al. 2021 (COG AEWS1031)]
 
−
|2010-2016
 
−
|style="background-color:#1a9851"|Phase 3 (C)
 
−
|[[#VDC.2FIE.2FVTC_99|VDC/IE/VTC]]
 
−
| style="background-color:#ffffbf" |Did not meet primary endpoint of EFS
 
−
|-
 
−
|}
 
−
''Note: the only difference between this and the variant above is the additional dose of vincristine in the second week of each VDC cycle.''
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy, VDC portion====
 
−
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1 & 8
 
−
*[[Doxorubicin (Adriamycin)]] 37.5 mg/m<sup>2</sup> IV once per day on days 1 & 2
 
−
*[[Cyclophosphamide (Cytoxan)]] 1200 mg/m<sup>2</sup> IV once on day 1
 
−
====Supportive therapy====
 
−
*[[Filgrastim (Neupogen)]]
 
−
'''14-day cycle, alternating with IE, for 6 total cycles of chemotherapy'''
 
−
====Chemotherapy, IE portion====
 
−
*[[Ifosfamide (Ifex)]] 1800 mg/m<sup>2</sup> IV once per day on days 1 to 5
 
−
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV once per day on days 1 to 5
 
−
====Supportive therapy====
 
−
*[[Filgrastim (Neupogen)]]
 
−
'''14-day cycle, alternating with VDC, for 6 total cycles of chemotherapy'''
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*Local therapy, then [[#VDC.2FIE_88|VDC/IE]] continuation
 
−
</div></div><br>
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Protocol variant #3, q3wk {{#subobject:6c6df0|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
−
!style="width: 20%"|Study
 
−
!style="width: 20%"|Years of enrollment
 
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 20%"|Comparator
 
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3494838/ Womer et al. 2012 (AEWS0031)]
 
−
|2001-2005
 
−
|style="background-color:#1a9851"|Phase 3 (C)
 
−
|[[#VDC.2FIE|VDC/IE]]; dose-intense
 
−
| style="background-color:#fc8d59" |Seems to have inferior EFS
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy, VDC portion====
 
−
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once on day 1
 
−
*[[Doxorubicin (Adriamycin)]] 37.5 mg/m<sup>2</sup> IV once per day on days 1 & 2
 
−
*[[Cyclophosphamide (Cytoxan)]] 1200 mg/m<sup>2</sup> IV once on day 1
 
−
====Supportive therapy====
 
−
*[[Mesna (Mesnex)]] with [[Cyclophosphamide (Cytoxan)]]; primary reference did not list dosage/schedule
 
−
*[[Filgrastim (Neupogen)]]
 
−
'''21-day cycle, alternating with IE, for 4 total cycles of chemotherapy'''
 
−
====Chemotherapy, IE portion====
 
−
*[[Ifosfamide (Ifex)]] 1800 mg/m<sup>2</sup> IV once per day on days 1 to 5
 
−
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV once per day on days 1 to 5
 
−
====Supportive therapy====
 
−
*[[Mesna (Mesnex)]] with [[Ifosfamide (Ifex)]]; primary reference did not list dosage/schedule
 
−
*[[Filgrastim (Neupogen)]]
 
−
'''21-day cycle, alternating with VDC, for 4 total cycles of chemotherapy'''
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*Local therapy, then adjuvant [[#VDC.2FIE_88|VDC/IE]]
 
−
</div></div>
 
−
===References===
 
−
# '''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. [https://doi.org/10.1200/JCO.2011.41.5703 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3494838/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/23091096 PubMed] NCT00006734
 
−
# '''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. [https://doi.org/10.1200/jco.21.00358 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8677904/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/34652968 PubMed] NCT01231906
 
−
==VIDE {{#subobject:be5278|Regimen=1}}==
 
−
VIDE: '''<u>V</u>'''incristine, '''<u>I</u>'''fosfamide, '''<u>D</u>'''oxorubicin, '''<u>E</u>'''toposide
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen variant #1 {{#subobject:6b3582|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 
−
!style="width: 33%"|Study
 
−
!style="width: 33%"|Years of enrollment
 
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://doi.org/10.1002/pbc.20820 Juergens et al. 2006 (EURO-E.W.I.N.G. 99)]
 
−
|NR in abstract
 
−
|style="background-color:#91cf61"|Phase 2
 
−
|-
 
−
|[https://doi.org/10.1200/jco.21.01942 Koch et al. 2022 (Ewing 2008R3)]
 
−
|2009-2018
 
−
|style="background-color:#91cf61"|Non-randomized portion of phase 3 RCT
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV push once on day 1
 
−
*[[Ifosfamide (Ifex)]] 3000 mg/m<sup>2</sup> IV over 1 to 3 hours once per day on days 1 to 3
 
−
*[[Doxorubicin (Adriamycin)]] 20 mg/m<sup>2</sup> IV over 4 hours once per day on days 1 to 3
 
−
*[[Etoposide (Vepesid)]] 150 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 3
 
−
====Supportive therapy====
 
−
*[[Mesna (Mesnex)]] 1000 mg/m<sup>2</sup> IV push once on day 1; 60 minutes prior to [[Ifosfamide (Ifex)]], then 3000 mg/m<sup>2</sup>/day IV continuous infusion over 72 hours (total dose per cycle: 10,000 mg/m<sup>2</sup>)
 
−
*2 to 3 liters/m<sup>2</sup> 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'''
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*EURO-E.W.I.N.G. 99: Further therapy is dictated by patient characteristics & response; details can be found in the primary reference
 
−
*Ewing 2008R3: Surgery when feasible, then [[#VAC_88|VAC]] x 8 or [[#VAI|VAI]] x 8, then [[#Treosulfan_.26_Melphalan.2C_then_auto_HSCT_99|Treosulfan & Melphalan, then auto HSCT]] versus [[#Observation_88|No further treatment]]
 
−
</div></div><br>
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen variant #2 {{#subobject:bd4d04|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 
−
!style="width: 33%"|Study
 
−
!style="width: 33%"|Years of enrollment
 
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://doi.org/10.1200/jco.2003.04.106 Strauss et al. 2003]
 
−
|NR in abstract
 
−
|style="background-color:#91cf61"|Phase 2
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[Vincristine (Oncovin)]] 1.4 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once on day 1
 
−
*[[Ifosfamide (Ifex)]] 3000 mg/m<sup>2</sup> IV once per day on days 1 to 3
 
−
*[[Doxorubicin (Adriamycin)]] 20 mg/m<sup>2</sup> IV once per day on days 1 to 3
 
−
*[[Etoposide (Vepesid)]] 150 mg/m<sup>2</sup> IV once per day on days 1 to 3
 
−
====Supportive therapy====
 
−
*[[Mesna (Mesnex)]] 3000 mg/m<sup>2</sup>/day IV continuous infusion over 72 hours, started on day 1 (total dose per cycle: 9000 mg/m<sup>2</sup>)
 
−
'''21-day cycle for up to 6 cycles'''
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*Patients with resectable localized disease: complete [[Surgery#Surgical_resection|surgical removal]] of tumors when possible, then adjuvant [[#VAI|VAI]]
 
−
*Patients with unresectable localized disease: [[#VAI|VAI & RT]] consolidation
 
−
</div></div>
 
−
===References===
 
−
# 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. [https://doi.org/10.1200/jco.2003.04.106 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/12885818 PubMed]
 
−
# '''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. [https://doi.org/10.1002/pbc.20820 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/16572419 PubMed]
 
−
# '''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. [https://doi.org/10.1200/JCO.2013.54.4833 link to original article] '''does not contain dosing details''' [https://pubmed.ncbi.nlm.nih.gov/24982464 PubMed] NCT00020566
 
−
#'''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. [https://doi.org/10.1200/jco.21.01942 link to original article] '''contains dosing details in supplement''' [https://pubmed.ncbi.nlm.nih.gov/35427190/ PubMed] NCT00987636
 
−
=Adjuvant therapy=
 
−
==Busulfan & Melphalan, then auto HSCT {{#subobject:484436|Regimen=1}}==
 
−
BuMel: '''<u>Bu</u>'''sulfan & '''<u>Mel</u>'''phalan
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen {{#subobject:75d2e0|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
−
!style="width: 20%"|Study
 
−
!style="width: 20%"|Years of enrollment
 
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 20%"|Comparator
 
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
−
|-
 
−
|[https://doi.org/10.1038/sj.bmt.1700992 Atra et al. 1997]
 
−
|NR
 
−
| style="background-color:#ffffbe" |Phase 2, <20 pts
 
−
| style="background-color:#d3d3d3" |
 
−
| style="background-color:#d3d3d3" |
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6209090/ Whelan et al. 2018 (R2Loc)]
 
−
|2000-2015
 
−
| style="background-color:#1a9851" |Phase 3 (E-esc)
 
−
|[[Ewing_sarcoma#VAI|VAI]]
 
−
| style="background-color:#91cf60" |Seems to have superior OS
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#cbd5e8">
 
−
====Preceding treatment====
 
−
*[[#VIDE|VIDE]] x 6, then [[Surgery#Surgical_resection|surgery]], then [[#VAI|VAI]] x 1
 
−
{{#lst:Autologous HSCT|75d2e0}}
 
−
</div></div>
 
−
===References===
 
−
# 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. [https://doi.org/10.1038/sj.bmt.1700992 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/9404924 PubMed]
 
−
# '''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. [https://doi.org/10.1200/JCO.2018.78.2516 link to original article] '''contains dosing details in supplement''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6209090/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30188789 PubMed] NCT00020566
 
−
==EVAIA {{#subobject:a56448|Regimen=1}}==
 
−
EVAIA: '''<u>E</u>'''toposide, '''<u>V</u>'''incristine, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>I</u>'''fosfamide, D'''<u>A</u>'''ctinomycin
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen {{#subobject:342685|Variant=1}}===
 
−
{| class="wikitable" style="width: 40%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://doi.org/10.1200/jco.2008.16.5720 Paulussen et al. 2008 (EICESS-92)]
 
−
|style="background-color:#91cf61"|Non-randomized portion of RCT
 
−
|-
 
−
|}
 
−
''Note: This regimen is intended for high-risk patients.''
 
−
<div class="toccolours" style="background-color:#cbd5e8">
 
−
</div>
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Preceding treatment====
 
−
*Neoadjuvant [[#EVAIA|EVAIA]] and [[Surgery#Surgical_resection|local therapy]]
 
−
</div>
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[Etoposide (Vepesid)]] 150 mg/m<sup>2</sup> IV once per day on days 1 to 3
 
−
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> IV once on day 1
 
−
*[[Doxorubicin (Adriamycin)]] 30 mg/m<sup>2</sup> IV once per day on days 2 & 4
 
−
*[[Ifosfamide (Ifex)]] 2000 mg/m<sup>2</sup> IV once per day on days 1 to 3
 
−
**Note: primary reference does not comment about the use of Mesna (Mesnex)
 
−
*[[Dactinomycin (Cosmegen)]] 0.5 mg/m<sup>2</sup> IV once per day on days 1, 3, 5
 
−
'''21-day cycle for 10 cycles'''
 
−
</div></div>
 
−
===References===
 
−
# '''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. [https://doi.org/10.1200/jco.2008.16.5720 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18802150 PubMed] NCT0000251
 
−
==VACA {{#subobject:f92366|Regimen=1}}==
 
−
VACA: '''<u>V</u>'''incristine, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>C</u>'''yclophosphamide, D'''<u>A</u>'''ctinomycin
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen variant #1 {{#subobject:835ca4|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
−
!style="width: 20%"|Study
 
−
!style="width: 20%"|Years of enrollment
 
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 20%"|Comparator
 
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
−
|-
 
−
|[https://doi.org/10.1200/jco.2008.16.5720 Paulussen et al. 2008 (EICESS-92)]
 
−
|1992-1997
 
−
|style="background-color:#1a9851"|Phase 3 (E-switch-ic)
 
−
|[[#VAIA_2|VAIA]]
 
−
|style="background-color:#ffffbf"|Did not meet primary endpoint of EFS36
 
−
|-
 
−
|}
 
−
''Note: this regimen was intended for standard-risk patients.''
 
−
<div class="toccolours" style="background-color:#cbd5e8">
 
−
====Preceding treatment====
 
−
*Neoadjuvant [[#VAIA|VAIA]] and [[Surgery#Surgical_resection|local therapy]]
 
−
</div>
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> IV once on day 1
 
−
*[[Doxorubicin (Adriamycin)]] 30 mg/m<sup>2</sup> IV once per day on days 2 & 4
 
−
*[[Cyclophosphamide (Cytoxan)]] 1200 mg/m<sup>2</sup> IV once on day 1
 
−
*[[Dactinomycin (Cosmegen)]] 0.5 mg/m<sup>2</sup> IV once per day on days 1, 3, 5
 
−
'''21-day cycle for 10 cycles'''
 
−
</div></div><br>
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen variant #2 {{#subobject:26bab6|Variant=1}}===
 
−
{| class="wikitable" style="width: 40%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://doi.org/10.1200/jco.2001.19.6.1818 Paulussen et al. 2001 (CESS 86)]
 
−
|style="background-color:#91cf61"|Non-randomized
 
−
|-
 
−
|}
 
−
''Note: This regimen is intended for standard risk patients.''
 
−
<div class="toccolours" style="background-color:#cbd5e8">
 
−
====Preceding treatment====
 
−
*Neoadjuvant [[#VACA|VACA]] and [[Surgery#Surgical_resection|local therapy]]
 
−
</div>
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
 
−
*[[Doxorubicin (Adriamycin)]] 30 mg/m<sup>2</sup> IV once per day on days 1, 2, 43, 44
 
−
*[[Cyclophosphamide (Cytoxan)]] 1200 mg/m<sup>2</sup> IV once on day 1, then 400 mg/m<sup>2</sup> IV once per day on days 22, 23, 24, then 1200 mg/m<sup>2</sup> IV once on day 43
 
−
*[[Dactinomycin (Cosmegen)]] 0.5 mg/m<sup>2</sup> IV once per day on days 22, 23, 24
 
−
====Supportive therapy====
 
−
*[[Mesna (Mesnex)]] "as appropriate"
 
−
'''9-week "block" for 3 blocks'''
 
−
</div></div><br>
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen variant #3 {{#subobject:26bab6|Variant=1}}===
 
−
{| class="wikitable" style="width: 60%; text-align:center;"
 
−
!style="width: 33%"|Study
 
−
!style="width: 33%"|Years of enrollment
 
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://www.ejcancer.com/article/S0959-8049(97)00043-9/pdf Craft et al. 1997 (ET-1)]
 
−
|1978-1986
 
−
|style="background-color:#91cf61"|Non-randomized (RT)
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[Vincristine (Oncovin)]]
 
−
*[[Doxorubicin (Adriamycin)]]
 
−
*[[Cyclophosphamide (Cytoxan)]]
 
−
*[[Dactinomycin (Cosmegen)]]
 
−
</div></div>
 
−
===References===
 
−
# '''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. [https://www.ejcancer.com/article/S0959-8049(97)00043-9/pdf link to original article] [https://pubmed.ncbi.nlm.nih.gov/9376188 PubMed]
 
−
# '''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. [https://doi.org/10.1200/jco.2001.19.6.1818 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/11251014 PubMed]
 
−
# '''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. [https://doi.org/10.1200/jco.2008.16.5720 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18802150 PubMed] NCT0000251
 
−
==VAI {{#subobject:560a3d|Regimen=1}}==
 
−
VAI: '''<u>V</u>'''incristine, D'''<u>A</u>'''ctinomycin, '''<u>I</u>'''fosfamide
 
−
<br>IVA: '''<u>I</u>'''fosfamide, '''<u>V</u>'''incristine, D'''<u>A</u>'''ctinomycin
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen variant #1, capped dactinomycin {{#subobject:9b2e40|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
−
!style="width: 20%"|Study
 
−
!style="width: 20%"|Years of enrollment
 
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 20%"|Comparator
 
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
−
|-
 
−
|[https://doi.org/10.1200/JCO.2013.54.4833 Le Deley et al. 2014 (Euro-EWING99-R1)]
 
−
|2000-2010
 
−
| style="background-color:#1a9851" |Phase 3 (C)
 
−
|[[#VAC_99|VAC]]
 
−
| style="background-color:#ffffbf" |Inconclusive whether non-inferior EFS
 
−
|-
 
−
|}
 
−
''Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.''
 
−
<div class="toccolours" style="background-color:#cbd5e8">
 
−
====Preceding treatment====
 
−
*Neoadjuvant [[#VIDE|VIDE]] x 6, then complete [[Surgery#Surgical_resection|surgical excision]] if feasible; radiotherapy if surgery incomplete or infeasible
 
−
</div>
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once on day 1
 
−
*[[Dactinomycin (Cosmegen)]] 0.75 mg/m<sup>2</sup> (maximum dose of 1.5 mg) IV once per day on days 1 & 2
 
−
*[[Ifosfamide (Ifex)]] 3000 mg/m<sup>2</sup> IV once per day on days 1 & 2
 
−
====Supportive therapy====
 
−
*[[Mesna (Mesnex)]] is not described
 
−
'''21-day cycle for 8 cycles'''
 
−
</div></div><br>
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen variant #2, uncapped dactinomycin {{#subobject:ddb896|Variant=1}}===
 
−
{| class="wikitable" style="width: 40%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://doi.org/10.1200/jco.2003.04.106 Strauss et al. 2003]
 
−
|style="background-color:#91cf61"|Phase 2
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#cbd5e8">
 
−
====Preceding treatment====
 
−
*Neoadjuvant [[#VIDE|VIDE]] and [[Surgery#Surgical_resection|local therapy]] if it was possible
 
−
</div>
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[Vincristine (Oncovin)]] 1.4 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once on day 1
 
−
*[[Dactinomycin (Cosmegen)]] 0.75 mg/m<sup>2</sup> IV once per day on days 1 & 2
 
−
*[[Ifosfamide (Ifex)]] 3000 mg/m<sup>2</sup> IV once per day on days 1 & 2
 
−
*If appropriate, concurrent radiation therapy given sometime during the first 3 cycles
 
−
====Supportive therapy====
 
−
*[[Mesna (Mesnex)]] 3000 mg/m<sup>2</sup>/day IV continuous infusion over 48 hours, started on day 1 (total dose per cycle: 6000 mg/m<sup>2</sup>)
 
−
'''21-day cycle for up to 8 cycles'''
 
−
</div></div>
 
−
===References===
 
−
# 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. [https://doi.org/10.1200/jco.2003.04.106 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/12885818 PubMed]
 
−
# '''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. [https://doi.org/10.1200/JCO.2013.54.4833 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/24982464 PubMed] NCT00020566
 
−
==VAIA {{#subobject:05e476|Regimen=1}}==
 
−
VAIA: '''<u>V</u>'''incristine, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>I</u>'''fosfamide, '''<u>A</u>'''ctinomycin-D (Dactinomycin)
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen variant #1 {{#subobject:f72b80|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
−
!style="width: 20%"|Study
 
−
!style="width: 20%"|Years of enrollment
 
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 20%"|Comparator
 
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
−
|-
 
−
|[https://doi.org/10.1200/jco.2008.16.5720 Paulussen et al. 2008 (EICESS-92)]
 
−
|1992-1997
 
−
|style="background-color:#1a9851"|Phase 3 (C)
 
−
|[[#VACA_2|VACA (standard-risk)]]
 
−
|style="background-color:#ffffbf"|Did not meet primary endpoint of EFS36
 
−
|-
 
−
|}
 
−
''Note: standard-risk patients were randomized to this regimen versus VACA. High-risk patients were not randomized at this point of the protocol.''
 
−
<div class="toccolours" style="background-color:#cbd5e8">
 
−
====Preceding treatment====
 
−
*Neoadjuvant [[#VAIA|VAIA]] and [[Surgery#Surgical_resection|local therapy]]
 
−
</div>
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> IV once on day 1
 
−
*[[Doxorubicin (Adriamycin)]] 30 mg/m<sup>2</sup> IV once per day on days 2 & 4
 
−
*[[Ifosfamide (Ifex)]] 2000 mg/m<sup>2</sup> IV once per day on days 1 to 3
 
−
**Note: primary reference does not comment about the use of mesna
 
−
*[[Dactinomycin (Cosmegen)]] 0.5 mg/m<sup>2</sup> IV once per day on days 1, 3, 5
 
−
'''21-day cycle for 10 cycles'''
 
−
</div></div><br>
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen variant #2 {{#subobject:7bd984|Variant=1}}===
 
−
{| class="wikitable" style="width: 40%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://doi.org/10.1200/jco.2001.19.6.1818 Paulussen et al. 2001 (CESS 86)]
 
−
|style="background-color:#91cf61"|Non-randomized
 
−
|-
 
−
|}
 
−
''Note: This regimen is intended for high risk patients.''
 
−
<div class="toccolours" style="background-color:#cbd5e8">
 
−
====Preceding treatment====
 
−
*Neoadjuvant [[#VAIA|VAIA]] and [[Surgery#Surgical_resection|local therapy]]
 
−
</div>
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
 
−
*[[Doxorubicin (Adriamycin)]] 30 mg/m<sup>2</sup> IV once per day on days 1, 2, 43, 44
 
−
*[[Ifosfamide (Ifex)]] 3000 mg/m<sup>2</sup> IV once per day on days 1, 2, 22, 23, 43, 44
 
−
*[[Dactinomycin (Cosmegen)]] 0.5 mg/m<sup>2</sup> IV once per day on days 22, 23, 24
 
−
====Supportive therapy====
 
−
*[[Mesna (Mesnex)]] "as appropriate"
 
−
'''9-week "block" for 3 blocks'''
 
−
</div></div>
 
−
===References===
 
−
# '''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. [https://doi.org/10.1200/jco.2001.19.6.1818 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/11251014 PubMed]
 
−
# '''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. [https://doi.org/10.1200/jco.2008.16.5720 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18802150 PubMed] NCT0000251
 
−
=Relapsed or refractory or metastatic=
 
−
==Busulfan & Melphalan, then auto HSCT {{#subobject:484436|Regimen=1}}==
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen variant #1, PO busulfan, mel 140 mg/m<sup>2</sup> {{#subobject:75d2e0|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 
−
!style="width: 33%"|Study
 
−
!style="width: 33%"|Years of enrollment
 
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://doi.org/10.1038/sj.bmt.1700992 Atra et al. 1997]
 
−
|NR
 
−
| style="background-color:#ffffbe" |Phase 2, <20 pts
 
−
|-
 
−
|}
 
−
{{#lst:Autologous HSCT|75d2e0}}
 
−
</div></div><br>
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen variant #2, PO busulfan, mel 160 mg/m<sup>2</sup> {{#subobject:75d2e1|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 
−
!style="width: 33%"|Study
 
−
!style="width: 33%"|Years of enrollment
 
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://doi.org/10.1038/sj.bmt.1700992 Atra et al. 1997]
 
−
|NR
 
−
| style="background-color:#ffffbe" |Phase 2, <20 pts
 
−
|-
 
−
|}
 
−
{{#lst:Autologous HSCT|75d2e1}}
 
−
</div></div><br>
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen variant #3, IV busulfan {{#subobject:a61951|Variant=1}}===
 
−
{| class="wikitable" style="width: 40%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://doi.org/10.1200/jco.2003.04.106 Strauss et al. 2003]
 
−
| style="background-color:#91cf61" |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.''
 
−
<div class="toccolours" style="background-color:#cbd5e8">
 
−
====Preceding treatment====
 
−
*[[#VAI_2|VAI]] x 1 or more cycles
 
−
{{#lst:Autologous HSCT|a61951}}
 
−
</div></div>
 
−
===References===
 
−
# 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. [https://doi.org/10.1038/sj.bmt.1700992 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/9404924 PubMed]
 
−
# 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. [https://doi.org/10.1200/jco.2003.04.106 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/12885818 PubMed]
 
−
==Cyclophosphamide & Topotecan {{#subobject:2535b6|Regimen=1}}==
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen variant #1, standard-dose {{#subobject:f13281|Variant=1}}===
 
−
{| class="wikitable" style="width: 40%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://doi.org/10.1200/jco.2001.19.15.3463 Saylors et al. 2001]
 
−
|style="background-color:#91cf61"|Phase 2
 
−
|-
 
−
|}
 
−
''Note: Some guidelines state that [[Vincristine (Oncovin)]] can be added to this regimen. No primary reference for this is available.''
 
−
</div>
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[Cyclophosphamide (Cytoxan)]] 250 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 to 5, '''given first'''
 
−
*[[Topotecan (Hycamtin)]] 0.75 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 to 5, '''given second'''
 
−
====Supportive therapy====
 
−
*500 mL/m/2 fluids IV or PO once per day on days 1 to 5; 2 to 4 hours prior to chemotherapy
 
−
*[[:Category:Emesis_prevention|Antiemetics]] once per day on days 1 to 5, prior to chemotherapy
 
−
*3 liters/m<sup>2</sup> 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'''
 
−
</div></div><br>
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen variant #2, standard-dose with local therapy {{#subobject:c531e2|Variant=1}}===
 
−
{| class="wikitable" style="width: 40%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://doi.org/10.1002/pbc.20719 Hunold et al. 2006]
 
−
|style="background-color:#91cf61"|Phase 2
 
−
|-
 
−
|}
 
−
''Note: Some guidelines state that vincristine can be added to this regimen. No primary reference for this is available.''
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[Cyclophosphamide (Cytoxan)]] 250 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 to 5
 
−
*[[Topotecan (Hycamtin)]] 0.75 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 to 5
 
−
====Supportive therapy====
 
−
*[[Mesna (Mesnex)]], antiemetics, fluids, and [[Filgrastim (Neupogen)]] "according to institutional standards"
 
−
'''21-day cycle for 12 to 14 cycles'''
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*Surgical candidate lesions: [[Surgery#Surgical_resection|Surgical removal]] of tumors is done when possible.
 
−
*All other lesions: [[External beam radiotherapy]]
 
−
</div></div><br>
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen variant #3, high-dose {{#subobject:230266|Variant=1}}===
 
−
{| class="wikitable" style="width: 40%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://doi.org/10.1002/1096-911X%2820001101%2935:5%3C468::AID-MPO5%3E3.0.CO;2-P Kushner et al. 2000]
 
−
|style="background-color:#91cf61"|Non-randomized
 
−
|-
 
−
|}
 
−
''Note: Some guidelines state that [[Vincristine (Oncovin)]] can be added to this regimen. No primary reference for this is available.''
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[Cyclophosphamide (Cytoxan)]] 2100 mg/m<sup>2</sup>/day IV continuous infusion over 48 hours, started on day 1, '''given second''' (total dose per cycle: 4200 mg/m<sup>2</sup>)
 
−
**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/m<sup>2</sup>/day IV continuous infusion over 72 hours, started on day 1, '''given third''' (total dose per cycle: 6 mg/m<sup>2</sup>)
 
−
====Supportive therapy====
 
−
*[[Mesna (Mesnex)]] 2100 mg/m<sup>2</sup>/day IV continuous infusion over 72 hours, started on day 1, '''given first''' (total dose per cycle: 6300 mg/m<sup>2</sup>)
 
−
**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 m<sup>2</sup>, mesna is given in 500 mL NS over 24 hours
 
−
***If body surface area is at least 1 m<sup>2</sup>, 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/m<sup>2</sup>/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/m<sup>2</sup>/24 hours
 
−
*Additional hydration fluid on day 3 at 150 mL/m<sup>2</sup>/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 m<sup>2</sup>; 1000 mL total volume is used for patients with BSA of at least 1 m<sup>2</sup>
 
−
*[[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 10<sup>9</sup>/L'''
 
−
</div></div>
 
−
===References===
 
−
# 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. [https://doi.org/10.1002/1096-911X%2820001101%2935:5%3C468::AID-MPO5%3E3.0.CO;2-P link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/11070479 PubMed]
 
−
# 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. [https://doi.org/10.1200/jco.2001.19.15.3463 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/11481351 PubMed]
 
−
# 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. [https://doi.org/10.1002/pbc.20719 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16411206 PubMed]
 
−
==Docetaxel & Gemcitabine {{#subobject:f4062c|Regimen=1}}==
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen {{#subobject:a99189|Variant=1}}===
 
−
{| class="wikitable" style="width: 40%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://doi.org/10.1002/cncr.23586 Navid et al. 2008]
 
−
|style="background-color:#ffffbe"|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.''
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[Docetaxel (Taxotere)]] 75 to 100 mg/m<sup>2</sup> IV over 60 minutes once on day 8, '''given second'''
 
−
*[[Gemcitabine (Gemzar)]] 675 mg/m<sup>2</sup> IV over 90 minutes once per day on days 1 & 8, '''given first on day 8'''
 
−
====Supportive therapy====
 
−
*[[Ondansetron (Zofran)]] once per day on days 1 & 8, prior to chemotherapy
 
−
*[[Dexamethasone (Decadron)]] starting either the day before or the day of [[Docetaxel (Taxotere)]], and continued for 2 days after [[Docetaxel (Taxotere)]]
 
−
*H1 or H2 blockers such as [[Diphenhydramine (Benadryl)]] and [[Ranitidine (Zantac)]] prior to chemotherapy on days 1 & 8 per physician discretion
 
−
*Some patients received [[Filgrastim (Neupogen)]] starting on day 9
 
−
'''21-day cycles'''
 
−
</div></div>
 
−
===References===
 
−
# '''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. [https://doi.org/10.1002/cncr.23586 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18484657 PubMed]
 
−
==ICE {{#subobject:456f0a|Regimen=1}}==
 
−
ICE: '''<u>I</u>'''fosfamide, '''<u>C</u>'''arboplatin, '''<u>E</u>'''toposide
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen {{#subobject:d99fb7|Variant=1}}===
 
−
{| class="wikitable" style="width: 40%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://doi.org/10.1002/pbc.20227 Van Winkle et al. 2005]
 
−
|style="background-color:#91cf61"|Phase 2
 
−
|-
 
−
|}
 
−
''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.''
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[Ifosfamide (Ifex)]] 1800 mg/m<sup>2</sup> IV once per day on days 1 to 5
 
−
*[[Carboplatin (Paraplatin)]] 400 mg/m<sup>2</sup> IV "for 2 days"
 
−
**Note: the reference did not explicitly say which 2 days carboplatin should be given on
 
−
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV once per day on days 1 to 5
 
−
====Supportive therapy====
 
−
*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/m<sup>2</sup> SC once per day or 500 mcg/m<sup>2</sup> 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 10<sup>9</sup>/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 10<sup>9</sup>/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 1000/uL, and IL-6 is continued until platelets are at least 100 x 10<sup>9</sup>/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 10<sup>9</sup>/L
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*Resection of disease was allowed after 4 cycles based on patient's response to ICE
 
−
</div></div>
 
−
===References===
 
−
# 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. [https://doi.org/10.1002/pbc.20227 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/15503297 PubMed]
 
−
==IE {{#subobject:ba75ef|Regimen=1}}==
 
−
IE: '''<u>I</u>'''fosfamide, '''<u>E</u>'''toposide
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen {{#subobject:4cd5c8|Variant=1}}===
 
−
{| class="wikitable" style="width: 40%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://doi.org/10.1200/jco.1987.5.8.1191 Miser et al. 1987]
 
−
|style="background-color:#91cf61"|Phase 2
 
−
|-
 
−
|}
 
−
''Note: Some guidelines state that [[Vincristine (Oncovin)]] can be added to this regimen. No primary reference for this is available.''
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[Ifosfamide (Ifex)]] 1800 mg/m<sup>2</sup> IV once per day on days 1 to 5, '''given second, with loading dose of mesna'''
 
−
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 5, '''given first'''
 
−
====Supportive therapy====
 
−
*[[Mesna (Mesnex)]] 360 mg/m<sup>2</sup> IV loading dose over 1 hour, '''given with [[Ifosfamide (Ifex)]]''', then 120 mg/m<sup>2</sup>/hour IV over 3 hours, then 360 mg/m<sup>2</sup> IV or PO over 15 minutes every 3 hours for 6 doses, '''given at hours 5, 8, 11, 14, 17, 20'''
 
−
'''21-day cycle for 12 cycles'''
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*For patients responding to therapy after 4 cycles: local therapy with [[Surgery#Surgical_resection|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.
 
−
</div></div>
 
−
===References===
 
−
# 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. [https://doi.org/10.1200/jco.1987.5.8.1191 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/3114435 PubMed]
 
−
==Irinotecan & Temozolomide {{#subobject:2e2a5c|Regimen=1}}==
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen variant #1 {{#subobject:c62d11|Variant=1}}===
 
−
{| class="wikitable" style="width: 40%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[http://clincancerres.aacrjournals.org/content/10/3/840.long Wagner et al. 2004]
 
−
|style="background-color:#ffffbe"|Phase 1, <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/m<sup>2</sup> was also studied, but this dose was not recommended due to dose-limiting toxicities of diarrhea and infection.''
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[Irinotecan (Camptosar)]] 10 mg/m<sup>2</sup> 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/m<sup>2</sup> PO once per day on days 1 to 5, '''given first'''
 
−
====Supportive therapy====
 
−
*[[Loperamide (Imodium)]] prn diarrhea
 
−
'''28-day cycles'''
 
−
</div></div><br>
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen variant #2 {{#subobject:620185|Variant=1}}===
 
−
{| class="wikitable" style="width: 40%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://doi.org/10.1002/pbc.22206 Casey et al. 2009]
 
−
|style="background-color:#ffffbe"|Retrospective
 
−
|-
 
−
|}
 
−
''Note: Some guidelines state that [[Vincristine (Oncovin)]] can be added to this regimen. No primary reference for this is available.''
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[Irinotecan (Camptosar)]] 20 mg/m<sup>2</sup> 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/m<sup>2</sup> PO once per day on days 1 to 5, '''given first'''
 
−
====Supportive therapy====
 
−
*[[Cefixime (Suprax)]] prophylaxis starting 1 to 2 days prior to [[Irinotecan (Camptosar)]], continuing until the completion of each cycle
 
−
*Activated charcoal, with 5x the dose in mg of the irinotecan dose, maximum of 260 mg PO three times per day during [[Irinotecan (Camptosar)]] therapy
 
−
*[[Loperamide (Imodium)]] prn diarrhea
 
−
*Patient "advised to maintain hydration"
 
−
'''21-day cycles'''
 
−
</div></div>
 
−
===References===
 
−
# '''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. [http://clincancerres.aacrjournals.org/content/10/3/840.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/14871959 PubMed]
 
−
# '''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. [https://doi.org/10.1002/pbc.20697 link to original article] [https://pubmed.ncbi.nlm.nih.gov/16317751 PubMed]
 
−
# '''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. [https://doi.org/10.1002/pbc.22206 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19637327 PubMed]
 
−
==TC, then IE, VDoxoC, VEC {{#subobject:c31c79|Regimen=1}}==
 
−
TC, then IE, VDoxoC, VEC: '''<u>T</u>'''opotecan, '''<u>C</u>'''yclophosphamide followed by '''<u>I</u>'''fosfamide, '''<u>E</u>'''toposide, then '''<u>V</u>'''incristine, '''<u>Doxo</u>'''rubicin, '''<u>C</u>'''yclophosphamide, then '''<u>V</u>'''incristine, '''<u>E</u>'''toposide, '''<u>C</u>'''yclophosphamide
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Protocol {{#subobject:87b074|Variant=1}}===
 
−
{| class="wikitable" style="width: 40%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://doi.org/10.1200/jco.2005.02.1717 Bernstein et al. 2006 (POG 9457)]
 
−
|style="background-color:#91cf61"|Phase 2
 
−
|-
 
−
|}
 
−
''Note: 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:''
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy, topotecan window====
 
−
*[[Topotecan (Hycamtin)]] 2.4 mg/m<sup>2</sup> IV once per day on days 1 to 5
 
−
====Supportive therapy====
 
−
*[[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====
 
−
*[[Topotecan (Hycamtin)]] 0.75 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 to 5
 
−
*[[Cyclophosphamide (Cytoxan)]] 250 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 to 5, '''given first'''
 
−
====Supportive therapy====
 
−
*Prehydration with 500 mL/m<sup>2</sup> D5 1/4 NS
 
−
*1500 mL/m<sup>2</sup> 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:
 
−
**Cycle 1: 3600 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 to 5, '''given second, after etoposide'''
 
−
***Administered in 200 mL/m<sup>2</sup> D5 1/2 NS
 
−
**Cycles 2 & 3: 2800 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 to 5, '''given second, after etoposide'''
 
−
***Administered in 200 mL/m<sup>2</sup> D5 1/2 NS
 
−
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV over 45 minutes once per day on days 1 to 5, '''given first, before ifosfamide'''
 
−
**Administered in 250 mL/m<sup>2</sup> of D5 1/2 NS
 
−
====Supportive therapy====
 
−
*[[Mesna (Mesnex)]] 4000 mg/m<sup>2</sup> 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/m<sup>2</sup> (maximum dose of 2 mg) IV bolus once per day on days 1, 8, 15, '''given first'''
 
−
*[[Doxorubicin (Adriamycin)]] 37.5 mg/m<sup>2</sup>/day IV continuous infusion over 48 hours, started on day 1, '''given third''' (total dose per cycle: 75 mg/m<sup>2</sup>)
 
−
**Administered in 2400 mL/m<sup>2</sup>/day (4800 mL/m<sup>2</sup> total volume) of D5 1/2 NS
 
−
*[[Cyclophosphamide (Cytoxan)]] 2100 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 2, '''given second'''
 
−
**Administered in 200 mL/m<sup>2</sup> D5 1/2 NS
 
−
====Supportive therapy====
 
−
*[[Mesna (Mesnex)]] 2400 mg/m<sup>2</sup> 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====
 
−
*[[Vincristine (Oncovin)]] 2 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1 & 8
 
−
*[[Doxorubicin (Adriamycin)]] 37.5 mg/m<sup>2</sup>/day IV continuous infusion over 48 hours, started on day 1 (total dose per cycle: 75 mg/m<sup>2</sup>)
 
−
*[[Cyclophosphamide (Cytoxan)]] 1500 mg/m<sup>2</sup> IV once on day 1
 
−
====Supportive therapy====
 
−
*[[Mesna (Mesnex)]], dosage & schedule not specified by reference
 
−
*[[Filgrastim (Neupogen)]] 5 mcg/kg SC once per day, starting 24 to 48 hours after completion of chemotherapy
 
−
'''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====
 
−
*[[Vincristine (Oncovin)]] 2 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1 & 8
 
−
*[[Etoposide (Vepesid)]] 150 mg/m<sup>2</sup> IV once per day on days 1 to 3
 
−
*[[Cyclophosphamide (Cytoxan)]] 1500 mg/m<sup>2</sup> IV once on day 1
 
−
====Supportive therapy====
 
−
*Use of [[Mesna (Mesnex)]] not specified by reference
 
−
*[[Filgrastim (Neupogen)]] 5 mcg/kg SC once per day, starting 24 to 48 hours after completion of chemotherapy
 
−
'''21-day cycle for 2 cycles, followed by:'''
 
−
====Chemotherapy, continuation, IE portion====
 
−
*[[Ifosfamide (Ifex)]] 2100 mg/m<sup>2</sup> IV once per day on days 1 to 5
 
−
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV once per day on days 1 to 5
 
−
====Supportive therapy====
 
−
*[[Mesna (Mesnex)]], dosage & schedule not specified by reference
 
−
*[[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 2 cycles, alternating with VDoxoC'''
 
−
====Chemotherapy, continuation, VDoxoC portion====
 
−
*[[Vincristine (Oncovin)]] 2 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 8, 15
 
−
*[[Doxorubicin (Adriamycin)]] 37.5 mg/m<sup>2</sup>/day IV continuous infusion over 48 hours, started on day 1 (total dose per cycle: 75 mg/m<sup>2</sup>)
 
−
*[[Cyclophosphamide (Cytoxan)]] 1500 mg/m<sup>2</sup> IV once on day 1
 
−
====Supportive therapy====
 
−
*[[Mesna (Mesnex)]] dosage & schedule not specified by reference
 
−
*[[Filgrastim (Neupogen)]] 5 mcg/kg SC once per day, starting 24 to 48 hours after completion of chemotherapy
 
−
'''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====
 
−
*[[Vincristine (Oncovin)]] 2 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1 & 8
 
−
**Note: the day 8 dose is not described in the text but is described in figure 1
 
−
*[[Doxorubicin (Adriamycin)]] 37.5 mg/m<sup>2</sup>/day IV continuous infusion over 48 hours, started on day 1 (total dose per cycle: 75 mg/m<sup>2</sup>)
 
−
*[[Cyclophosphamide (Cytoxan)]] 1500 mg/m<sup>2</sup> IV once on day 1
 
−
====Supportive therapy====
 
−
*[[Mesna (Mesnex)]] dosage & schedule not specified by reference
 
−
*[[Filgrastim (Neupogen)]] 5 mcg/kg SC once per day, starting 24 to 48 hours after completion of chemotherapy
 
−
'''21-day cycle for 1 cycle, 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
 
−
*See primary reference for details about radiation therapy in a variety of clinical scenarios
 
−
====Chemotherapy, metastases, VEC portion====
 
−
*[[Vincristine (Oncovin)]] 2 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1 & 8
 
−
*[[Etoposide (Vepesid)]] 150 mg/m<sup>2</sup> IV once per day on days 1 to 3
 
−
*[[Cyclophosphamide (Cytoxan)]] 1500 mg/m<sup>2</sup> IV once on day 1
 
−
====Supportive therapy====
 
−
*Use of [[Mesna (Mesnex)]] not specified by reference
 
−
*[[Filgrastim (Neupogen)]] 5 mcg/kg SC once per day, starting 24 to 48 hours after completion of chemotherapy
 
−
'''21-day cycle for 2 cycles'''
 
−
</div></div>
 
−
===References===
 
−
# '''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. [https://doi.org/10.1200/jco.2005.02.1717 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16382125 PubMed] NCT00002643
 
−
==VAdCA {{#subobject:dd0198|Regimen=1}}==
 
−
VAdCA: '''<u>V</u>'''incristine, '''<u>Ad</u>'''riamycin (Doxorubicin), '''<u>C</u>'''yclophosphamide, D'''<u>A</u>'''ctinomycin
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen {{#subobject:cb5fae|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
−
!style="width: 20%"|Study
 
−
!style="width: 20%"|Years of enrollment
 
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 20%"|Comparator
 
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
−
|-
 
−
|[https://doi.org/10.1200/jco.2004.01.041 Miser et al. 2004]
 
−
|1988-1992
 
−
|style="background-color:#1a9851"|Phase 3 (C)
 
−
|[[#VAdCA.2FIE|VAdCA/IE]]
 
−
|style="background-color:#ffffbf"|Did not meet primary endpoints of EFS/OS
 
−
|-
 
−
|}
 
−
''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.''
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[Vincristine (Oncovin)]] 2 mg/m<sup>2</sup> 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/m<sup>2</sup> IV once on day 1
 
−
**Stop once cumulative dose received by the patient exceeds 375 mg/m<sup>2</sup> (after 5 courses)
 
−
*[[Cyclophosphamide (Cytoxan)]] 1200 mg/m<sup>2</sup> IV once on day 1
 
−
*[[Dactinomycin (Cosmegen)]] 1.25 mg/m<sup>2</sup> IV once on day 1, once cumulative doxorubicin dose received by the patient exceeds 375 mg/m<sup>2</sup>
 
−
'''21-day cycle for 17 cycles'''
 
−
''Local therapy is planned to take place on week 9, as follows:''
 
−
====Local therapy====
 
−
*[[Surgery#Surgical_resection|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"
 
−
</div></div>
 
−
===References===
 
−
# 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. [https://doi.org/10.1200/jco.2004.01.041 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/15254055 PubMed]
 
−
==VAdCA/IE {{#subobject:a6863c|Regimen=1}}==
 
−
VAdCA/IE: '''<u>V</u>'''incristine, '''<u>Ad</u>'''riamycin (Doxorubicin), '''<u>C</u>'''yclophosphamide, D'''<u>A</u>'''ctinomycin alternating with '''<u>I</u>'''fosfamide, '''<u>E</u>'''toposide
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Protocol {{#subobject:a2770e|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
−
!style="width: 20%"|Study
 
−
!style="width: 20%"|Years of enrollment
 
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 20%"|Comparator
 
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
−
|-
 
−
|[https://doi.org/10.1200/jco.2004.01.041 Miser et al. 2004]
 
−
|1988-1992
 
−
|style="background-color:#1a9851"|Phase 3 (E-esc)
 
−
|[[#VAdCA|VAdCA]]
 
−
|style="background-color:#ffffbf"|Did not meet primary endpoints of EFS/OS
 
−
|-
 
−
|}
 
−
''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.''
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy, VAdCA portion====
 
−
*[[Vincristine (Oncovin)]] 2 mg/m<sup>2</sup> 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/m<sup>2</sup> IV once on day 1
 
−
**Stop once cumulative dose received by the patient exceeds 375 mg/m<sup>2</sup> (after 5 courses)
 
−
*[[Cyclophosphamide (Cytoxan)]] 1200 mg/m<sup>2</sup> IV once on day 1
 
−
*[[Dactinomycin (Cosmegen)]] 1.25 mg/m<sup>2</sup> IV once on day 1, once cumulative doxorubicin dose received by the patient exceeds 375 mg/m<sup>2</sup>
 
−
'''21-day cycle, alternating with IE, for 17 total cycles'''
 
−
====Chemotherapy, IE portion====
 
−
*[[Ifosfamide (Ifex)]] 1800 mg/m<sup>2</sup> IV once per day on days 1 to 5
 
−
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV once per day on days 1 to 5
 
−
====Supportive therapy====
 
−
*[[Mesna (Mesnex)]] with [[Ifosfamide (Ifex)]]; primary reference did not list dosage/schedule
 
−
'''21-day cycle, alternating with VAC, for 17 total cycles'''
 
−
''Local therapy is planned to take place on week 9, as follows:''
 
−
====Local therapy====
 
−
*[[Surgery#Surgical_resection|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"
 
−
</div></div>
 
−
===References===
 
−
# 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. [https://doi.org/10.1200/jco.2004.01.041 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/15254055 PubMed]
 
−
==VAI {{#subobject:547404|Regimen=1}}==
 
−
VAI: '''<u>V</u>'''incristine, D'''<u>A</u>'''ctinomycin, '''<u>I</u>'''fosfamide
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen {{#subobject:020e4c|Variant=1}}===
 
−
{| class="wikitable" style="width: 40%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://doi.org/10.1200/jco.2003.04.106 Strauss et al. 2003]
 
−
|style="background-color:#91cf61"|Phase 2
 
−
|-
 
−
|}
 
−
''Note: This protocol was intended for patients with metastatic disease. The reference does not clearly describe how many cycles of VAI might be used.''
 
−
<div class="toccolours" style="background-color:#cbd5e8">
 
−
====Preceding treatment====
 
−
*[[#VIDE_2|VIDE]] for up to 6 cycles
 
−
</div>
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[Vincristine (Oncovin)]] 1.4 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once on day 1
 
−
*[[Dactinomycin (Cosmegen)]] 0.75 mg/m<sup>2</sup> IV once per day on days 1 & 2
 
−
*[[Ifosfamide (Ifex)]] 3000 mg/m<sup>2</sup> IV once per day on days 1 & 2
 
−
====Supportive therapy====
 
−
*[[Mesna (Mesnex)]] 3000 mg/m<sup>2</sup>/day IV continuous infusion over 48 hours, started on day 1 (total dose per cycle: 6000 mg/m<sup>2</sup>)
 
−
'''21-day cycle for one or more cycles'''
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*[[#Busulfan_.26_Melphalan.2C_then_auto_HSCT|Busulfan & Melphalan, then auto HSCT]]
 
−
</div></div>
 
−
===References===
 
−
# 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. [https://doi.org/10.1200/jco.2003.04.106 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/12885818 PubMed]
 
−
# '''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. [https://doi.org/10.1200/JCO.19.00915 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6881099/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31553693 PubMed] NCT00987636
 
−
==VIDE {{#subobject:737059|Regimen=1}}==
 
−
VIDE: '''<u>V</u>'''incristine, '''<u>I</u>'''fosfamide, '''<u>D</u>'''oxorubicin, '''<u>E</u>'''toposide
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen {{#subobject:2601fd|Variant=1}}===
 
−
{| class="wikitable" style="width: 60%; text-align:center;"
 
−
!style="width: 33%"|Study
 
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 33%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
−
|-
 
−
|[https://doi.org/10.1200/jco.2003.04.106 Strauss et al. 2003]
 
−
|style="background-color:#91cf61"|Phase 2
 
−
|ORR: 88%
 
−
|-
 
−
|}
 
−
''Note: This protocol was intended for patients with metastatic disease.''
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[Vincristine (Oncovin)]] 1.4 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once on day 1
 
−
*[[Ifosfamide (Ifex)]] 3000 mg/m<sup>2</sup> IV once per day on days 1 to 3
 
−
*[[Doxorubicin (Adriamycin)]] 20 mg/m<sup>2</sup> IV once per day on days 1 to 3
 
−
*[[Etoposide (Vepesid)]] 150 mg/m<sup>2</sup> IV once per day on days 1 to 3
 
−
====Supportive therapy====
 
−
*[[Mesna (Mesnex)]] 3000 mg/m<sup>2</sup>/day IV continuous infusion over 72 hours, started on day 1 (total dose per cycle: 9000 mg/m<sup>2</sup>)
 
−
'''21-day cycle for up to 6 cycles'''
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*[[#VAI_2|VAI]], then [[Regimen_classes#High-dose_chemotherapy_with_auto_HSCT|HD with auto HSCT]]
 
−
</div></div>
 
−
===References===
 
−
# 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. [https://doi.org/10.1200/jco.2003.04.106 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/12885818 PubMed]
 
−
[[Category:Ewing sarcoma regimens]]
 
−
[[Category:Disease-specific pages]]
 
−
[[Category:Bone sarcomas]]
 
−
[[Category:Pediatric solid tumors]]
 

Latest revision as of 00:13, 18 June 2023

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