Difference between revisions of "Soft tissue sarcoma"

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'''Use of this site is subject to you reading and agreeing with the terms set forth in the [[HemOnc.org_-_A_Hematology_Oncology_Wiki:General_disclaimer|disclaimer]].'''
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Is there a regimen missing from this list?  Would you like to share a different dosage/schedule or an additional reference for a regimen?  Have you noticed an error?  Do you have an idea that will help the site grow to better meet your needs and the needs of many others?  You are [[How_to_contribute|invited to contribute to the site]].
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[[#top|Back to Top]]
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</div>
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{{#lst:Editorial board transclusions|sarcoma}}
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{| class="wikitable" style="float:right; margin-right: 5px;"
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|-
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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>
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|}
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''Are you looking for a regimen but can't find it here? It is possible that we've moved it to the [[Soft_tissue_sarcoma_-_historical|historical regimens page]]. For placebo or observational studies in this condition, please visit [[Soft tissue sarcoma - null regimens|this page]]. If you still can't find it, please let us know so we can add it!''.
 +
<br>Note: this page is for subtype-nonspecific soft tissue sarcoma regimens, some subtypes with very few subtype-specific regimens, as well as for sarcomas that are not readily categorized. Please see the [[:Category:Soft tissue sarcomas|category page]] for links to other sarcoma types or use one of these links:
 +
*[[Alveolar soft part sarcoma|Alveolar soft part sarcoma (ASPS)]]
 +
*[[Dermatofibrosarcoma protuberans]]
 +
*[[Desmoid tumors]]
 +
*[[Epithelioid sarcoma]]
 +
*[[Gastrointestinal stromal tumor|Gastrointestinal stromal tumor (GIST)]]
 +
*[[Inflammatory myofibroblastic tumor|Inflammatory myofibroblastic tumor (IMT)]]
 +
*[[Leiomyosarcoma]]
 +
*[[Liposarcoma]]
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*[[PEComa]]
 +
*[[Rhabdomyosarcoma]]
 +
*[[Tenosynovial giant cell tumor|Tenosynovial giant cell tumor (TGCT)]]
 
{{TOC limit|limit=3}}
 
{{TOC limit|limit=3}}
 +
=Guidelines=
 +
'''Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.'''
 +
==ESMO/EURACAN/GENTURIS==
 +
*'''2021:''' Gronchi et al. [https://doi.org/10.1016/j.annonc.2021.07.006 Soft tissue and visceral sarcomas: ESMO–EURACAN–GENTURIS Clinical Practice Guidelines for diagnosis, treatment and follow-up] [https://www.ncbi.nlm.nih.gov/pubmed/34303806 PubMed]
 +
**'''2018:''' Casali et al. [https://doi.org/10.1093/annonc/mdy096 Soft tissue and visceral sarcomas: ESMO–EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/29846498/ PubMed]
 +
**'''2014:''' [https://doi.org/10.1093/annonc/mdu254 Soft tissue and visceral sarcomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/25210080/ PubMed]
 +
**'''2010:''' Casali & Blay. [https://doi.org/10.1093/annonc/mdq209 Soft tissue sarcomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/20555081/ PubMed]
 +
**'''2009:''' Casali et al. [https://doi.org/10.1093/annonc/mdp153 Soft tissue sarcomas: ESMO clinical recommendations for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/19454434/ PubMed]
 +
**'''2007:''' Leyvraz. [https://doi.org/10.1093/annonc/mdm046 Soft tissue sarcomas: ESMO clinical recommendations for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/17491057/ PubMed]
 +
**'''2005:''' Leyvraz & Jelic. [https://doi.org/10.1093/annonc/mdi830 ESMO Minimum Clinical Recommendations for diagnosis, treatment and follow-up of soft tissue sarcomas] [https://pubmed.ncbi.nlm.nih.gov/15888762/ PubMed]
  
−
=Single-agent regimens=
+
==NCCN==
−
 
+
*[https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1464 NCCN Guidelines - Soft Tissue Sarcoma]
−
==Dacarbazine (DTIC)==
+
**'''2022:''' von Mehren et al. [https://doi.org/10.6004/Jnccn.2022.0035 Soft Tissue Sarcoma, Version 2.2022, NCCN Clinical Practice Guidelines in Oncology.] [https://pubmed.ncbi.nlm.nih.gov/35830886/ PubMed]
−
 
+
**'''2016:''' von Mehren et al. [https://doi.org/10.6004/Jnccn.2016.0078 Soft Tissue Sarcoma, Version 2.2016, NCCN Clinical Practice Guidelines in Oncology.] [https://pubmed.ncbi.nlm.nih.gov/27283169/ PubMed]
−
===Regimen, Buesa, et al. 1991===
+
**'''2014:''' von Mehren et al. [https://doi.org/10.6004/Jnccn.2014.0053 Soft tissue sarcoma, version 2.2014.] [https://pubmed.ncbi.nlm.nih.gov/24717567/ PubMed]
−
*[[Dacarbazine (DTIC)]] 1200 mg/m2 in 200 mL normal saline IV over 20 minutes once on day 1
+
**'''2010:''' Demetri et al. [https://doi.org/10.6004/Jnccn.2010.0049 Soft tissue sarcoma.] [https://pubmed.ncbi.nlm.nih.gov/20581298/ PubMed]
−
 
+
**'''2007:''' Demetri et al. [https://doi.org/10.6004/Jnccn.2007.0034 Soft tissue sarcoma.] [https://pubmed.ncbi.nlm.nih.gov/17442230/ PubMed]
−
'''21-day cycles, given until progression of disease'''
+
**'''2005:''' Demetri et al. [ Soft tissue sarcoma clinical practice guidelines in oncology.] [https://pubmed.ncbi.nlm.nih.gov/19817028/ PubMed]
−
 
 
−
Supportive medications:
 
−
*Calcium gluconate (10% solution) 5 mL IV every 10 minutes x 3 doses (total of 15 mL) after the start of dacarbazine; 2 additional doses of calcium gluconate (10% solution) 5 mL IV every 10 minutes were given to patients whose systolic blood pressure decreased below 80 mmHg or heart rate ≥160 beat/minute.
 
  
 +
=Neoadjuvant therapy=
 +
==Epirubicin & Ifosfamide {{#subobject:eeb76b|Regimen=1}}==
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:aea2c8|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates 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.2011.37.7218 Gronchi et al. 2012]
 +
|2002-2007
 +
| style="background-color:#91cf61" |Non-randomized part of phase 3 RCT
 +
| style="background-color:#d3d3d3" |
 +
| style="background-color:#d3d3d3" |
 +
|-
 +
|[https://doi.org/10.1016/S1470-2045(17)30334-0 Gronchi et al. 2017 (ISG-STS 1001)]
 +
|2011-2016
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|Histotype-tailored therapy
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS<sup>1</sup>
 +
|-
 +
|}
 +
''<sup>1</sup>Reported efficacy for ISG-STS 1001 is based on the 2020 update.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Epirubicin (Ellence)]] 60 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 to 3
 +
====Supportive therapy====
 +
*[[Mesna (Mesnex)]] 1000 mg/m<sup>2</sup> IV every 3 hours to every 4 hours on days 1 to 3
 +
'''21-day cycle for 3 cycles'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*Gronchi et al. 2012: [[Surgery#Surgical_resection|Surgery]], then adjuvant [[#Epirubicin_.26_Ifosfamide|EI]] x 2 versus [[#Observation|no further treatment]]
 +
*ISG-STS 1001: [[Surgery#Surgical_resection|Surgery]]
 +
</div></div>
 
===References===
 
===References===
−
# Buesa JM, Mouridsen HT, van Oosterom AT, Verweij J, Wagener T, Steward W, Poveda A, Vestlev PM, Thomas D, Sylvester R. High-dose DTIC in advanced soft-tissue sarcomas in the adult. A phase II study of the E.O.R.T.C. Soft Tissue and Bone Sarcoma Group. Ann Oncol. 1991 Apr;2(4):307-9. [http://annonc.oxfordjournals.org/content/2/4/307.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/1868027 PubMed]
+
# Gronchi A, Frustaci S, Mercuri M, Martin J, Lopez-Pousa A, Verderio P, Mariani L, Valagussa P, Miceli R, Stacchiotti S, Dei Tos AP, De Paoli A, Longhi A, Poveda A, Quagliuolo V, Comandone A, Casali PG, Picci P; Italian Sarcoma Group; Spanish Sarcoma Group. Short, full-dose adjuvant chemotherapy in high-risk adult soft tissue sarcomas: a randomized clinical trial from the Italian Sarcoma Group and the Spanish Sarcoma Group. J Clin Oncol. 2012 Mar 10;30(8):850-6. Epub 2012 Feb 6. [https://doi.org/10.1200/JCO.2011.37.7218 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/22312103/ PubMed] EudraCT 2004-003979-36
−
 
+
# '''ISG-STS 1001:''' Gronchi A, Ferrari S, Quagliuolo V, Broto JM, Pousa AL, Grignani G, Basso U, Blay JY, Tendero O, Beveridge RD, Ferraresi V, Lugowska I, Merlo DF, Fontana V, Marchesi E, Donati DM, Palassini E, Palmerini E, De Sanctis R, Morosi C, Stacchiotti S, Bagué S, Coindre JM, Dei Tos AP, Picci P, Bruzzi P, Casali PG. Histotype-tailored neoadjuvant chemotherapy versus standard chemotherapy in patients with high-risk soft-tissue sarcomas (ISG-STS 1001): an international, open-label, randomised, controlled, phase 3, multicentre trial. Lancet Oncol. 2017 Jun;18(6):812-822. Epub 2017 May 9. [https://doi.org/10.1016/S1470-2045(17)30334-0 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/28499583/ PubMed] [https://clinicaltrials.gov/study/NCT01710176 NCT01710176]
−
==Doxorubicin (Adriamycin)==
+
##'''Update:''' Gronchi A, Palmerini E, Quagliuolo V, Martin Broto J, Lopez Pousa A, Grignani G, Brunello A, Blay JY, Tendero O, Diaz Beveridge R, Ferraresi V, Lugowska I, Merlo DF, Fontana V, Marchesi E, Braglia L, Donati DM, Palassini E, Bianchi G, Marrari A, Morosi C, Stacchiotti S, Bagué S, Coindre JM, Dei Tos AP, Picci P, Bruzzi P, Casali PG. Neoadjuvant Chemotherapy in High-Risk Soft Tissue Sarcomas: Final Results of a Randomized Trial From Italian (ISG), Spanish (GEIS), French (FSG), and Polish (PSG) Sarcoma Groups. J Clin Oncol. 2020 Jul 1;38(19):2178-2186. Epub 2020 May 18. [https://doi.org/10.1200/jco.19.03289 link to original article] [https://pubmed.ncbi.nlm.nih.gov/32421444/ PubMed]
−
 
+
==EIA {{#subobject:0608ad|Regimen=1}}==
−
===Regimen===
+
EIA: '''<u>E</u>'''toposide, '''<u>I</u>'''fosfamide, '''<u>A</u>'''driamycin (Doxorubicin)
−
*[[Doxorubicin (Adriamycin)]] 75 mg/m2 IV bolus once on day 1
+
<div class="toccolours" style="background-color:#eeeeee">
−
 
+
===Regimen {{#subobject:52e303|Variant=1}}===
−
'''21-day cycles x up to 6 cycles, until progression of disease, unacceptable toxicity, or patient refusal'''.  In Mouridsen, et al. 1987, treatment was given until progression of disease, unacceptable toxicity, or cumulative doxorubicin dosage of 550 mg/m2, though the ultimate decision to stop treatment based on cumulative doxorubicin dosage was at the discretion of the treating physician.
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"
−
 
+
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates 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/PMC3517819/ Issels et al. 2010 (EORTC 62961/ESHO 95)]
 +
|1997-2006
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#EIA_.26_regional_hyperthemia_888|EIA & regional hyperthermia]]
 +
| style="background-color:#fc8d59" |Seems to have inferior OS
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Etoposide (Vepesid)]] 125 mg/m<sup>2</sup> IV once per day on days 1 & 4
 +
*[[Ifosfamide (Ifex)]] 1500 mg/m<sup>2</sup> IV once per day on days 1 to 4
 +
*[[Doxorubicin (Adriamycin)]] 50 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycle for 4 cycles'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[Surgery#Surgical_resection|Surgery]], then [[Regimen_classes#Radiotherapy-based_regimen|RT]], then adjuvant [[#EIA_2|EIA]] x 4
 +
</div></div>
 
===References===
 
===References===
−
# Mouridsen HT, Bastholt L, Somers R, Santoro A, Bramwell V, Mulder JH, van Oosterom AT, Buesa J, Pinedo HM, Thomas D, et al. Adriamycin versus epirubicin in advanced soft tissue sarcomas. A randomized phase II/phase III study of the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer Clin Oncol. 1987 Oct;23(10):1477-83. '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/3479329 PubMed]
+
# '''EORTC 62961/ESHO 95:''' Issels RD, Lindner LH, Verweij J, Wust P, Reichardt P, Schem BC, Abdel-Rahman S, Daugaard S, Salat C, Wendtner CM, Vujaskovic Z, Wessalowski R, Jauch KW, Dürr HR, Ploner F, Baur-Melnyk A, Mansmann U, Hiddemann W, Blay JY, Hohenberger P; [[Study_Groups#EORTC|EORTC]] Soft Tissue and Bone Sarcoma Group; European Society for Hyperthermic Oncology. Neo-adjuvant chemotherapy alone or with regional hyperthermia for localised high-risk soft-tissue sarcoma: a randomised phase 3 multicentre study. Lancet Oncol. 2010 Jun;11(6):561-70. Epub 2010 Apr 29. [https://doi.org/10.1016/S1470-2045(10)70071-1 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3517819/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/20434400/ PubMed] [https://clinicaltrials.gov/study/NCT00003052 NCT00003052]
−
# Bramwell VH, Anderson D, Charette ML. Doxorubicin-based chemotherapy for the palliative treatment of adult patients with locally advanced or metastatic soft-tissue sarcoma: a meta-analysis and clinical practice guideline. Sarcoma. 2000;4(3):103-12. doi: 10.1080/13577140020008066. [http://www.hindawi.com/journals/srcm/2000/149793/abs/ link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/18521288 PubMed]
+
## '''Update:''' Issels RD, Lindner LH, Verweij J, Wessalowski R, Reichardt P, Wust P, Ghadjar P, Hohenberger P, Angele M, Salat C, Vujaskovic Z, Daugaard S, Mella O, Mansmann U, Dürr HR, Knösel T, Abdel-Rahman S, Schmidt M, Hiddemann W, Jauch KW, Belka C, Gronchi A; European Organization for the Research and Treatment of Cancer-Soft Tissue and Bone Sarcoma Group; European Society for Hyperthermic Oncology. Effect of neoadjuvant chemotherapy plus regional hyperthermia on long-term outcomes among patients with localized high-risk soft tissue sarcoma: the EORTC 62961-ESHO 95 randomized clinical trial. JAMA Oncol. 2018 Apr 1;4(4):483-492. [https://doi.org/10.1001/jamaoncol.2017.4996 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5885262/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29450452/ PubMed]
−
# Lorigan P, Verweij J, Papai Z, Rodenhuis S, Le Cesne A, Leahy MG, Radford JA, Van Glabbeke MM, Kirkpatrick A, Hogendoorn PC, Blay JY; European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group Study. Phase III trial of two investigational schedules of ifosfamide compared with standard-dose doxorubicin in advanced or metastatic soft tissue sarcoma: a European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group Study. J Clin Oncol. 2007 Jul 20;25(21):3144-50. [http://jco.ascopubs.org/content/25/21/3144.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/17634494 PubMed]
+
=Adjuvant therapy=
−
 
+
==EIA {{#subobject:8d8ff1|Regimen=1}}==
−
==Epirubicin (Ellence)==
+
EIA: '''<u>E</u>'''toposide, '''<u>I</u>'''fosfamide, '''<u>A</u>'''driamycin (Doxorubicin)
−
 
+
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen===
+
===Regimen {{#subobject:6d8a81|Variant=1}}===
−
*[[Epirubicin (Ellence)]] 75 mg/m2 IV bolus once on day 1
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"
−
 
+
!style="width: 20%"|Study
−
'''21-day cycles, given until progression of disease, unacceptable toxicity, or cumulative epirubicin dosage of 550 mg/m2''' (though the ultimate decision to stop treatment based on cumulative epirubicin dosage was at the discretion of the treating physician)
+
!style="width: 20%"|Dates 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/PMC3517819/ Issels et al. 2010 (EORTC 62961/ESHO 95)]
 +
|1997-2006
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#EIA_.26_regional_hyperthemia_888|EIA & regional hyperthermia]]
 +
| style="background-color:#fc8d59" |Seems to have inferior OS
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*Neoadjuvant [[#EIA|EIA]] x 4, then [[Surgery#Surgical_resection|surgery]], then adjuvant [[#Radiation_therapy_888|RT]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Etoposide (Vepesid)]] 125 mg/m<sup>2</sup> IV once per day on days 1 & 4
 +
*[[Ifosfamide (Ifex)]] 1500 mg/m<sup>2</sup> IV once per day on days 1 to 4
 +
*[[Doxorubicin (Adriamycin)]] 50 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycle for 4 cycles'''
 +
</div></div>
 
===References===
 
===References===
−
# Mouridsen HT, Bastholt L, Somers R, Santoro A, Bramwell V, Mulder JH, van Oosterom AT, Buesa J, Pinedo HM, Thomas D, et al. Adriamycin versus epirubicin in advanced soft tissue sarcomas. A randomized phase II/phase III study of the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer Clin Oncol. 1987 Oct;23(10):1477-83. '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/3479329 PubMed]
+
# '''EORTC 62961/ESHO 95:''' Issels RD, Lindner LH, Verweij J, Wust P, Reichardt P, Schem BC, Abdel-Rahman S, Daugaard S, Salat C, Wendtner CM, Vujaskovic Z, Wessalowski R, Jauch KW, Dürr HR, Ploner F, Baur-Melnyk A, Mansmann U, Hiddemann W, Blay JY, Hohenberger P; [[Study_Groups#EORTC|EORTC]] Soft Tissue and Bone Sarcoma Group; European Society for Hyperthermic Oncology. Neo-adjuvant chemotherapy alone or with regional hyperthermia for localised high-risk soft-tissue sarcoma: a randomised phase 3 multicentre study. Lancet Oncol. 2010 Jun;11(6):561-70. Epub 2010 Apr 29. [https://doi.org/10.1016/S1470-2045(10)70071-1 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3517819/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/20434400/ PubMed] [https://clinicaltrials.gov/study/NCT00003052 NCT00003052]
−
 
+
## '''Update:''' Issels RD, Lindner LH, Verweij J, Wessalowski R, Reichardt P, Wust P, Ghadjar P, Hohenberger P, Angele M, Salat C, Vujaskovic Z, Daugaard S, Mella O, Mansmann U, Dürr HR, Knösel T, Abdel-Rahman S, Schmidt M, Hiddemann W, Jauch KW, Belka C, Gronchi A; European Organization for the Research and Treatment of Cancer-Soft Tissue and Bone Sarcoma Group; European Society for Hyperthermic Oncology. Effect of neoadjuvant chemotherapy plus regional hyperthermia on long-term outcomes among patients with localized high-risk soft tissue sarcoma: the EORTC 62961-ESHO 95 randomized clinical trial. JAMA Oncol. 2018 Apr 1;4(4):483-492. [https://doi.org/10.1001/jamaoncol.2017.4996 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5885262/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29450452/ PubMed]
−
==Ifosfamide (Ifex)==
+
=Locally advanced or metastatic disease, single-agent regimens=
−
 
+
==Cisplatin monotherapy {{#subobject:6e93fa|Regimen=1}}==
−
===Regimen #1, van Oosterom, et al. 2002===
+
<div class="toccolours" style="background-color:#eeeeee">
−
*[[Ifosfamide (Ifex)]] 3000 mg/m2 IV over 4 hours once daily on days 1-3
+
===Regimen {{#subobject:2ff0fe|Variant=1}}===
−
**Each day's dose of ifosfamide is dissolved in 125 mL sterile water per 1000 mg of ifosfamide, mixed together with mesna in an additional 1 liter of dextrose/saline
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"
−
*[[Mesna (Mesnex)]] 600 mg/m2 IV bolus once on day 1, immediately prior to mesna/ifosfamide infusion
+
!style="width: 20%"|Study
−
*[[Mesna (Mesnex)]] 1500 mg/m2 IV over 4 hours on days 1-3, given together with ifosfamide
+
!style="width: 20%"|Dates of enrollment
−
*[[Mesna (Mesnex)]] 500 mg/m2 IV two times per day on days 1-3, given at 4 and 8 hours after completion of ifosfamide and mesna
+
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
−
 
+
!style="width: 20%"|Comparator
−
'''21-day cycles x at least 2 cycles, except in cases of rapid disease progression; continued until disease progression or unacceptable toxicity or patient refusal'''
+
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
−
 
+
|-
−
Supportive medications:
+
|[https://doi.org/10.1016/S1470-2045(15)70102-6 Blay et al. 2015 (EFC10145)]
−
*"[[Antiemesis|Antiemetics]] were prescribed according to local conventions"
+
|2008-2012
−
*1 liter of fluid PO two times per day on days 1-3, taken 4 and 8 hours after completion of ifosfamide and mesna
+
| style="background-color:#1a9851" |Phase 3 (C)
−
 
+
|[[#Cisplatin_.26_Ombrabulin_777|Cisplatin & Ombrabulin]]
−
===Regimen #2, Lorigan, et al. 2007 - short infusion, Ifos 3===
+
| style="background-color:#fc8d59" |Seems to have inferior PFS
−
*[[Ifosfamide (Ifex)]] 3000 mg/m2 IV over 4 hours on days 1-3, given together with mesna
+
|-
−
**Each day's dose of ifosfamide is mixed together with mesna in 1 liter of normal saline
+
|}
−
*[[Mesna (Mesnex)]] 600 mg/m2 IV bolus once on day 1, immediately prior to mesna/ifosfamide infusion
+
''Note: PFS was very poor in both groups (less than 2 months); the difference was not considered clinically meaningful.''
−
*[[Mesna (Mesnex)]] 1500 mg/m2 IV over 4 hours on days 1-3, given together with ifosfamide
+
<div class="toccolours" style="background-color:#b3e2cd">
−
*[[Mesna (Mesnex)]] 1200 mg/m2 IV two times per day on days 1-3, given at 4 and 8 hours after completion of ifosfamide and mesna
+
====Chemotherapy====
−
**An alternative is to use oral mesna instead of intravenous: [[Mesna (Mesnex)]] 1200 mg/m2 PO two times per day on days 1-3, given at 2 and 6 hours after completion of ifosfamide and mesna
+
*[[Cisplatin (Platinol)]] 75 mg/m<sup>2</sup> IV over 120 minutes once on day 1
−
 
+
'''21-day cycles'''
−
'''21-day cycles x up to 6 cycles, until progression of disease, unacceptable toxicity, or patient refusal'''
+
</div></div>
−
 
 
−
Supportive medications:
 
−
*Sodium bicarbonate 150 mmol IV once daily on days 1-3
 
−
*Patient with somnolesence or other signs of encephalopathy with ifosfamide received methylene blue 50 mg IV every 4 hours until resolution of symptoms.  During cycles thereafter, patients would receive methylene blue 50 mg IV every 4 hours, starting 4 hours prior to ifosfamide on day 1, continuing until 72 hours after completion
 
−
 
 
−
===Regimen #3, Lorigan, et al. 2007 - continuous infusion, Ifos 9===
 
−
*[[Ifosfamide (Ifex)]] 3000 mg/m2/day IV continuous infusion over 72 hours (total dose per cycle: 9000 mg/m2) on days 1-3, given together with mesna
 
−
**Each day's dose of ifosfamide is mixed together with mesna in 3 liters of normal saline
 
−
*[[Mesna (Mesnex)]] 600 mg/m2 IV bolus once on day 1, immediately prior to mesna/ifosfamide infusion
 
−
*[[Mesna (Mesnex)]] 3000 mg/m2/day IV continuous infusion over 72 hours (total dose per cycle: 9000 mg/m2) on days 1-3, given together with ifosfamide
 
−
*[[Mesna (Mesnex)]] 1800 mg/m2 IV over 12 hours once on day 4, starting after completion of ifosfamide and mesna
 
−
**An alternative is to use oral mesna instead of intravenous: [[Mesna (Mesnex)]] 1200 mg/m2 PO three times on day 4, given 0, 2, and 6 hours after completion of ifosfamide and mesna
 
−
 
 
−
'''21-day cycles x up to 6 cycles, until progression of disease, unacceptable toxicity, or patient refusal'''
 
−
 
 
−
Supportive medications:
 
−
*Sodium bicarbonate 150 mmol IV once daily on days 1-3
 
−
*Patient with somnolesence or other signs of encephalopathy with ifosfamide received methylene blue 50 mg IV every 4 hours until resolution of symptoms.  During cycles thereafter, patients would receive methylene blue 50 mg IV every 4 hours, starting 4 hours prior to ifosfamide on day 1, continuing until 72 hours after completion
 
−
 
 
 
===References===
 
===References===
−
# van Oosterom AT, Mouridsen HT, Nielsen OS, Dombernowsky P, Krzemieniecki K, Judson I, Svancarova L, Spooner D, Hermans C, Van Glabbeke M, Verweij J; EORTC Soft Tissue and Bone Sarcoma Group. Results of randomised studies of the EORTC Soft Tissue and Bone Sarcoma Group (STBSG) with two different ifosfamide regimens in first- and second-line chemotherapy in advanced soft tissue sarcoma patients.  Eur J Cancer. 2002 Dec;38(18):2397-406 [http://www.ejcancer.info/article/S0959-8049(02)00491-4/abstract link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/12460784 PubMed] content property of [http://hemonc.org HemOnc.org]
+
# '''EFC10145:''' Blay JY, Pápai Z, Tolcher AW, Italiano A, Cupissol D, López-Pousa A, Chawla SP, Bompas E, Babovic N, Penel N, Isambert N, Staddon AP, Saâda-Bouzid E, Santoro A, Franke FA, Cohen P, Le-Guennec S, Demetri GD. Ombrabulin plus cisplatin versus placebo plus cisplatin in patients with advanced soft-tissue sarcomas after failure of anthracycline and ifosfamide chemotherapy: a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2015 May;16(5):531-40. Epub 2015 Apr 8. [https://doi.org/10.1016/S1470-2045(15)70102-6 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/25864104/ PubMed] [https://clinicaltrials.gov/study/NCT00699517 NCT00699517]
−
# Lorigan P, Verweij J, Papai Z, Rodenhuis S, Le Cesne A, Leahy MG, Radford JA, Van Glabbeke MM, Kirkpatrick A, Hogendoorn PC, Blay JY; European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group Study. Phase III trial of two investigational schedules of ifosfamide compared with standard-dose doxorubicin in advanced or metastatic soft tissue sarcoma: a European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group Study. J Clin Oncol. 2007 Jul 20;25(21):3144-50. [http://jco.ascopubs.org/content/25/21/3144.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/17634494 PubMed]
 
−
 
 
−
==Pazopanib (Votrient)==
 
−
 
 
−
===Regimen, van der Graaf, et al. 2012 - PALETTE===
 
−
*[[Pazopanib (Votrient)]] 800 mg PO once daily
 
−
 
 
−
'''given until progression of disease, unacceptable toxicity, withdrawal of consent, or death'''
 
  
 +
==Dacarbazine monotherapy {{#subobject:62426f|Regimen=1}}==
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:2c183b|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates 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/10.1093/oxfordjournals.annonc.a057942 Buesa et al. 1991]
 +
|1984-1986
 +
| style="background-color:#91cf61" |Phase 2
 +
| style="background-color:#d3d3d3" |
 +
| style="background-color:#d3d3d3" |
 +
|-
 +
|[https://doi.org/10.1200/JCO.2010.33.6107 García-Del-Muro et al. 2011]
 +
|2005-2008
 +
| style="background-color:#1a9851" |Randomized Phase 2 (C)
 +
|[[#Dacarbazine_.26_Gemcitabine|Dacarbazine & Gemcitabine]]
 +
| style="background-color:#fc8d59" |Seems to have inferior OS
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Dacarbazine (DTIC)]] 1200 mg/m<sup>2</sup> IV over 20 minutes once on day 1
 +
====Supportive therapy====
 +
*'''Buesa et al. 1991:''' Calcium gluconate (10% solution) 5 mL IV every 10 minutes x 3 doses (total of 15 mL) after the start of dacarbazine; 2 additional doses of calcium gluconate (10% solution) 5 mL IV every 10 minutes were given to patients whose systolic blood pressure decreased below 80 mmHg or heart rate more than 160 bpm.
 +
'''21-day cycles'''
 +
</div></div>
 
===References===
 
===References===
−
# van der Graaf WT, Blay JY, Chawla SP, Kim DW, Bui-Nguyen B, Casali PG, Sch�ffski P, Aglietta M, Staddon AP, Beppu Y, Le Cesne A, Gelderblom H, Judson IR, Araki N, Ouali M, Marreaud S, Hodge R, Dewji MR, Coens C, Demetri GD, Fletcher CD, Dei Tos AP, Hohenberger P; EORTC Soft Tissue and Bone Sarcoma Group; PALETTE study group. Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2012 May 19;379(9829):1879-86. doi: 10.1016/S0140-6736(12)60651-5. Epub 2012 May 16. [http://www.sciencedirect.com/science/article/pii/S0140673612606515 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/22595799 PubMed]
+
# Buesa JM, Mouridsen HT, van Oosterom AT, Verweij J, Wagener T, Steward W, Poveda A, Vestlev PM, Thomas D, Sylvester R; [[Study_Groups#EORTC|EORTC]] Soft Tissue and Bone Sarcoma Group. High-dose DTIC in advanced soft-tissue sarcomas in the adult: a phase II study of the EORTC Soft Tissue and Bone Sarcoma Group. Ann Oncol. 1991 Apr;2(4):307-9. [https://doi.org/10.1093/oxfordjournals.annonc.a057942 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/1868027/ PubMed]
−
 
+
# García-Del-Muro X, López-Pousa A, Maurel J, Martín J, Martínez-Trufero J, Casado A, Gómez-España A, Fra J, Cruz J, Poveda A, Meana A, Pericay C, Cubedo R, Rubió J, De Juan A, Laínez N, Carrasco JA, de Andrés R, Buesa JM; Spanish Group for Research on Sarcomas. Randomized phase II study comparing gemcitabine plus dacarbazine versus dacarbazine alone in patients with previously treated soft tissue sarcoma: a Spanish Group for Research on Sarcomas study. J Clin Oncol. 2011 Jun 20;29(18):2528-33. Epub 2011 May 23. [https://doi.org/10.1200/JCO.2010.33.6107 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/21606430/ PubMed] EudraCT 2005-001709-24
−
==Temozolomide (Temodar)==
+
#APROMISS: [https://clinicaltrials.gov/study/NCT03016819 NCT03016819]
−
 
 
−
===Regimen #1, Talbot, et al. 2003===
 
−
*[[Temozolomide (Temodar)]] 200 mg/m2 (doses rounded up if needed to next available dosage based on capsule doses) PO once on day 1, on an empty stomach; then 12 hours later, [[Temozolomide (Temodar)]] 90 mg/m2 PO once every 12 hours x 9 doses (total of 10 doses per cycle) on days 1-5, on an empty stomach
 
−
 
 
−
'''28-day cycles, given until progression of disease x 1 year; patients on study could be reconsented to receive therapy beyond 1 year'''
 
−
 
 
−
Supportive medications:
 
−
*[[Antiemesis|Antiemetics]] "prescribed as clinically indicated by the treating physician"
 
−
 
 
−
===Regimen #2, Garcia del Muro, et al. 2005===
 
−
*[[Temozolomide (Temodar)]] 100 mg/m2 PO once daily on days 1-42 (6 weeks), with no food 1 hour before and after temozolomide doses
 
−
**Initial dose used in the study was 75 mg/m2, but due to lack of toxicity, protocol was amended to use 100 mg/m2 doses
 
−
 
 
−
'''9-week cycles x up to 3 cycles, progression of disease, or unacceptable toxicity'''
 
−
 
 
−
Supportive medications:
 
−
*"[[Antiemesis|Antiemetics]], mainly oral metoclopramide and ondansetron, were prescribed as clinically indicated by the treating physician"
 
−
 
 
−
===References===
 
−
# Talbot SM, Keohan ML, Hesdorffer M, Orrico R, Bagiella E, Troxel AB, Taub RN. A phase II trial of temozolomide in patients with unresectable or metastatic soft tissue sarcoma. Cancer. 2003 Nov 1;98(9):1942-6. [http://onlinelibrary.wiley.com/doi/10.1002/cncr.11730/full link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/14584078 PubMed]
 
−
# Garcia del Muro X, Lopez-Pousa A, Martin J, Buesa JM, Martinez-Trufero J, Casado A, Poveda A, Cruz J, Bover I, Maurel J; Spanish Group for Research on Sarcomas. A phase II trial of temozolomide as a 6-week, continuous, oral schedule in patients with advanced soft tissue sarcoma: a study by the Spanish Group for Research on Sarcomas. Cancer. 2005 Oct 15;104(8):1706-12. [http://onlinelibrary.wiley.com/doi/10.1002/cncr.21384/full link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/16134177 PubMed]
 
−
 
 
−
=Combination regimens=
 
−
 
 
−
==AIM==
 
−
AIM: '''<u>A</u>'''driamycin, '''<u>I</u>'''fosfamide, '''<u>M</u>'''esna
 
−
 
 
−
===Regimen #1, Patel, et al. 1998 - 5-day course, lower dose doxorubicin - AI 75/10===
 
−
*[[Doxorubicin (Adriamycin)]] 25 mg/m2/day IV continuous infusion over 72 hours (total dose per cycle: 75 mg/m2) on days 1-3
 
−
*[[Ifosfamide (Ifex)]] 2000 mg/m2 IV over 2 hours once daily on days 1-5 (total dose per cycle: 10,000 mg/m2)
 
−
*[[Mesna (Mesnex)]] 400 mg/m2 IV once on day 1, given simultaneously with the first dose of ifosfamide
 
−
*[[Mesna (Mesnex)]] 1200 mg/m2/day IV continuous infusion over 5 days (total dose per cycle: 6000 mg/m2) on days 1-5
 
−
**Each day's dose of mesna is given in 2 liters of D5W with 100 mEq/L sodium acetate, 20 mEq/L potassium acetate, and 4 mEq/L magnesium sulfate
 
−
 
 
−
'''21-day cycles, given until maximum response, 6 cycles of therapy, progression of disease, or unacceptable toxicity'''
 
−
 
 
−
Supportive medications:
 
−
*If febrile neutropenia occurs, [[Filgrastim (Neupogen)|G-CSF]] is used in subsequent cycles
 
−
 
 
−
===Regimen #2, Patel, et al. 1998 - 4-day course, higher dose doxorubicin - AI 90/10===
 
−
*[[Doxorubicin (Adriamycin)]] 30 mg/m2/day IV continuous infusion over 72 hours (total dose per cycle: 90 mg/m2) on days 1-3
 
−
*[[Ifosfamide (Ifex)]] 2500 mg/m2 IV over 3 hours once daily on days 1-4 (total dose per cycle: 10,000 mg/m2)
 
−
*[[Mesna (Mesnex)]] 500 mg/m2 IV once on day 1, given simultaneously with the first dose of ifosfamide
 
−
*[[Mesna (Mesnex)]] 1500 mg/m2/day IV continuous infusion over 4 days (total dose per cycle: 6000 mg/m2) on days 1-4
 
−
**Each day's dose of mesna is given in 2 liters of D5W with 100 mEq/L sodium acetate, 20 mEq/L potassium acetate, and 4 mEq/L magnesium sulfate
 
−
 
 
−
'''21-day cycles, given until maximum response, 6 cycles of therapy, progression of disease, or unacceptable toxicity'''
 
−
 
 
−
Supportive medications:
 
−
*[[Filgrastim (Neupogen)|G-CSF]] 5 mcg/kg (dose rounded to 300 or 480 mcg) SC once daily, starting on day 5, given until ANC is at least 10,000
 
−
 
 
−
===References===
 
−
# Patel SR, Vadhan-Raj S, Burgess MA, Plager C, Papadopolous N, Jenkins J, Benjamin RS. Results of two consecutive trials of dose-intensive chemotherapy with doxorubicin and ifosfamide in patients with sarcomas. Am J Clin Oncol. 1998 Jun;21(3):317-21. [http://journals.lww.com/amjclinicaloncology/pages/articleviewer.aspx?year=1998&issue=06000&article=00025&type=abstract link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/9626808 PubMed]
 
−
 
 
−
==Epirubicin (Ellence) & Ifosfamide (Ifex)==
 
−
 
 
−
===Regimen===
 
−
*[[Epirubicin (Ellence)]] 45 mg/m2/day IV continuous infusion over 2 days (total dose per cycle: 90 mg/m2) on days 2-3
 
−
*[[Ifosfamide (Ifex)]] 2500 mg/m2/day IV continuous infusion over 5 days (total dose per cycle: 12,500 mg/m2) on days 1-5, given together with mesna
 
−
**Each day's dose of ifosfamide is mixed together with mesna in 3 liters of "fluids with electrolytes"
 
−
*[[Mesna (Mesnex)]] 1500 mg/m2 IV continuous infusion over 5 days (total dose per cycle: 7500 mg/m2) on days 1-5, given together with ifosfamide
 
  
 +
==Doxorubicin monotherapy {{#subobject:826f82|Regimen=1}}==
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1, 75 mg/m<sup>2</sup> x 6 {{#subobject:62faa6|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates 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/10.1002/jso.2930110406 Cruz et al. 1979 (COG 7231A)]
 +
|NR
 +
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 +
|1. [[#Actinomycin_.26_Melphalan_888|Actinomycin & Melphalan]]<br>2. [[#Melphalan_.26_Vincristine_888|Melphalan & Vincristine]]<br> 3. [[#Melphalan_.26_1-aminocyclopentanecarboxylic_acid_777|Melphalan & NSC-1026]]
 +
| style="background-color:#1a9850" |Superior ORR
 +
|-
 +
|[https://doi.org/10.1016/0277-5379(87)90089-7 Mouridsen et al. 1987 (EORTC 62801)]
 +
|1980-1983
 +
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 +
|[[#Epirubicin_monotherapy|Epirubicin]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR
 +
|-
 +
| rowspan="2" |[https://doi.org/10.1200/jco.2006.09.7717 Lorigan et al. 2007 (EORTC 62971)]
 +
|rowspan=2|1998-2001
 +
| rowspan="2" style="background-color:#1a9851" |Phase 3 (C)
 +
|1. [[#Ifosfamide_monotherapy|Ifos 3]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
 +
|-
 +
|2. [[#Ifosfamide_monotherapy|Ifos 9]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
 +
|-
 +
|[https://doi.org/10.1016/S1470-2045(14)70063-4 Judson et al. 2014 (EORTC 62012)]
 +
|2003-2010
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Doxorubicin_.26_Ifosfamide|Doxorubicin & Ifosfamide]]; intensified
 +
| style="background-color:#fee08b" |Might have inferior OS
 +
|-
 +
|[https://doi.org/10.1016/j.ejca.2014.01.012 Blay et al. 2014 (CR015769)]
 +
|2008-2012
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Trabectedin_monotherapy|Trabectedin]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
 +
|-
 +
|[https://doi.org/10.1200/JCO.2016.67.6684 Ryan et al. 2016 (PICASSO III)]
 +
|2010-2012
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Doxorubicin_.26_Palifosfamide_999|Doxorubicin & Palifosfamide]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5622179/ Seddon et al. 2017 (GeDDiS)]
 +
|2010-2014
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Docetaxel_.26_Gemcitabine|Docetaxel & Gemcitabine]]
 +
| style="background-color:#d9ef8b" |Might have superior PFS
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7771354/ Tap et al. 2017 (TH CR-406/SARC021)]
 +
|2011-2014
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Doxorubicin_.26_Evofosfamide_999|Doxorubicin & Evofosfamide]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 +
|-
 +
|}
 +
''Note: in EORTC 62801, treatment was given until progression of disease, unacceptable toxicity, or cumulative doxorubicin dosage of 550 mg/m<sup>2</sup>, though the ultimate decision to stop treatment based on cumulative doxorubicin dosage was at the discretion of the treating physician. Patients in CR015769 had translocation-related sarcomas.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Doxorubicin (Adriamycin)]] 75 mg/m<sup>2</sup> IV bolus once on day 1
 +
'''21-day cycle for 6 cycles (see note)'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2, 75 mg/m<sup>2</sup> x 8 {{#subobject:82faa6|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates 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/10.1016/j.ejca.2014.01.012 Blay et al. 2014 (CR015769)]
 +
|2008-2012
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Trabectedin_monotherapy|Trabectedin]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5647653/ Tap et al. 2016 (CP15-0806)]
 +
|2010-2013
 +
| style="background-color:#1a9851" |Randomized Phase 2 (C)
 +
|[[Soft_tissue_sarcoma_-_historical#Doxorubicin_.26_Olaratumab|Doxorubicin & Olaratumab]]
 +
| style="background-color:#d73027" |Inferior OS
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7139275/ Tap et al. 2020 (ANNOUNCE)]
 +
|2015-2018
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[Soft_tissue_sarcoma_-_historical#Doxorubicin_.26_Olaratumab|Doxorubicin & Olaratumab]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 +
|-
 +
|}
 +
''Note: Patients in CR015769 had translocation-related sarcomas.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Doxorubicin (Adriamycin)]] 75 mg/m<sup>2</sup> IV bolus once on day 1
 +
====Supportive therapy====
 +
*CP15-0806, optional: [[Dexrazoxane (Zinecard)]] as follows:
 +
**Cycles 5 to 8: (dose not specified) IV once on day 1
 +
'''21-day cycle for 8 cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #3, 75 mg/m<sup>2</sup> indefinite {{#subobject:82fain|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates 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.1995.13.7.1537 Santoro et al. 1995]
 +
|1985-1990
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|1. [[#Doxorubicin_.26_Ifosfamide|Doxorubicin & Ifosfamide]]<br>2. [[Stub#CYVADIC|CYVADIC]]
 +
| style="background-color:#ffffbf" |Did not meet endpoints of ORR/DOR/OS
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2063236/ Nielsen et al. 1998]
 +
|NR
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Epirubicin_monotherapy|Epirubicin]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Doxorubicin (Adriamycin)]] 75 mg/m<sup>2</sup> IV bolus once on day 1
 +
'''21-day cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #4, 80 mg/m<sup>2</sup> {{#subobject:fcfa1c|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
| rowspan="2" |[https://doi.org/10.1200/JCO.1993.11.7.1269 Edmonson et al. 1993]
 +
|rowspan=2|1987-1990
 +
| rowspan="2" style="background-color:#1a9851" |Phase 3 (C)
 +
|1. [[#Doxorubicin_.26_Ifosfamide|Doxorubicin & Ifosfamide]]
 +
| style="background-color:#fc8d59" |Seems to have inferior ORR
 +
|-
 +
|2. [[#MAC_333|MAC]]
 +
| style="background-color:#fee08b" |Might have inferior ORR
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Doxorubicin (Adriamycin)]] 80 mg/m<sup>2</sup> IV bolus once on day 1
 
'''21-day cycles'''
 
'''21-day cycles'''
−
 
+
</div></div>
−
Supportive medications:
 
−
*[[Filgrastim (Neupogen)|G-CSF]] 5 mcg/kg SC once daily on days 6-15 or "until recovery of leukocytes"
 
−
*Ondansetron (Zofran) 8-24 mg per day prn nausea
 
−
*[[Dexamethasone (Decadron)]] (dose/schedule not specified) for [[antiemesis]] if necessary
 
−
 
 
 
===References===
 
===References===
−
# Reichardt P, Tilgner J, Hohenberger P, D�rken B. Dose-intensive chemotherapy with ifosfamide, epirubicin, and filgrastim for adult patients with metastatic or locally advanced soft tissue sarcoma: a phase II study. J Clin Oncol. 1998 Apr;16(4):1438-43. [http://jco.ascopubs.org/content/16/4/1438.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/9552049 PubMed]
+
# '''COG 7231A:''' Cruz AB Jr, Thames EA Jr, Aust JB, Metter G, Ramirez G, Fletcher WS, Altman SJ, Frelick RW, Hill GJ 2nd. Combination chemotherapy for soft-tissue sarcomas: a phase III study. J Surg Oncol. 1979;11(4):313-23. [https://doi.org/10.1002/jso.2930110406 link to original article] [https://pubmed.ncbi.nlm.nih.gov/376950/ PubMed]
−
 
+
# '''EORTC 62801:''' Mouridsen HT, Bastholt L, Somers R, Santoro A, Bramwell V, Mulder JH, van Oosterom AT, Buesa J, Pinedo HM, Thomas D, Sylvester R; [[Study_Groups#EORTC|EORTC]] Soft Tissue and Bone Sarcoma Group. Adriamycin versus epirubicin in advanced soft tissue sarcomas: a randomized phase II/phase III study of the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer Clin Oncol. 1987 Oct;23(10):1477-83. [https://doi.org/10.1016/0277-5379(87)90089-7 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/3479329/ PubMed]
−
==Gemcitabine (Gemzar) & Docetaxel (Taxotere)==
+
# Edmonson JH, Ryan LM, Blum RH, Brooks JS, Shiraki M, Frytak S, Parkinson DR. Randomized comparison of doxorubicin alone versus ifosfamide plus doxorubicin or mitomycin, doxorubicin, and cisplatin against advanced soft tissue sarcomas. J Clin Oncol. 1993 Jul;11(7):1269-75. [https://doi.org/10.1200/JCO.1993.11.7.1269 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/8315424/ PubMed]
−
 
+
# Santoro A, Tursz T, Mouridsen H, Verweij J, Steward W, Somers R, Buesa J, Casali P, Spooner D, Rankin E, Kirkpatrick A, van Glabbeke M, van Oosterom A; [[Study_Groups#EORTC|EORTC]] Soft Tissue and Bone Sarcoma Group. Doxorubicin versus CYVADIC versus doxorubicin plus ifosfamide in first-line treatment of advanced soft tissue sarcomas: a randomized study of the European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group. J Clin Oncol. 1995 Jul;13(7):1537-45. [https://doi.org/10.1200/JCO.1995.13.7.1537 link to original article] [https://pubmed.ncbi.nlm.nih.gov/7602342/ PubMed]
−
===Regimen #1, Hensley, et al. 2002 & 2008 - no prior radiation===
+
# Nielsen OS, Dombernowsky P, Mouridsen H, Crowther D, Verweij J, Buesa J, Steward W, Daugaard S, van Glabbeke M, Kirkpatrick A, Tursz T; [[Study_Groups#EORTC|EORTC]] soft tissue and bone sarcoma group. High-dose epirubicin is not an alternative to standard-dose doxorubicin in the treatment of advanced soft tissue sarcomas: a study of the EORTC soft tissue and bone sarcoma group. Br J Cancer. 1998 Dec;78(12):1634-9. [https://doi.org/10.1038/bjc.1998.735 linkt o original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2063236/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/9862576/ PubMed]
−
*[[Gemcitabine (Gemzar)]] 900 mg/m2 IV over 90 minutes once daily on days 1 & 8, given first
+
# '''Meta-analysis:''' Bramwell VH, Anderson D, Charette ML. Doxorubicin-based chemotherapy for the palliative treatment of adult patients with locally advanced or metastatic soft-tissue sarcoma: a meta-analysis and clinical practice guideline. Sarcoma. 2000;4(3):103-12. [https://doi.org/10.1080/13577140020008066 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2395439/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/18521288/ PubMed]
−
*[[Docetaxel (Taxotere)]] 100 mg/m2 IV over 1 hour once on day 8, given second
+
# '''EORTC 62971:''' Lorigan P, Verweij J, Papai Z, Rodenhuis S, Le Cesne A, Leahy MG, Radford JA, Van Glabbeke MM, Kirkpatrick A, Hogendoorn PC, Blay JY; [[Study_Groups#EORTC|EORTC]] Soft Tissue and Bone Sarcoma Group. Phase III trial of two investigational schedules of ifosfamide compared with standard-dose doxorubicin in advanced or metastatic soft tissue sarcoma: a European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group Study. J Clin Oncol. 2007 Jul 20;25(21):3144-50. [https://doi.org/10.1200/jco.2006.09.7717 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17634494/ PubMed] [https://clinicaltrials.gov/study/NCT00003212 NCT00003212]
−
 
+
# '''CR015769:''' Blay JY, Leahy MG, Nguyen BB, Patel SR, Hohenberger P, Santoro A, Staddon AP, Penel N, Piperno-Neumann S, Hendifar A, Lardelli P, Nieto A, Alfaro V, Chawla SP. Randomised phase III trial of trabectedin versus doxorubicin-based chemotherapy as first-line therapy in translocation-related sarcomas. Eur J Cancer. 2014 Apr;50(6):1137-47. Epub 2014 Feb 7. [https://doi.org/10.1016/j.ejca.2014.01.012 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/24512981/ PubMed] [https://clinicaltrials.gov/study/NCT00796120 NCT00796120]
−
'''21-day cycles x 6-8 cycles, given until progression of disease or unacceptable toxicity'''; Hensley, et al. 2008 did not specify a maximum number of cycles
+
# '''EORTC 62012:''' Judson I, Verweij J, Gelderblom H, Hartmann JT, Schöffski P, Blay JY, Kerst JM, Sufliarsky J, Whelan J, Hohenberger P, Krarup-Hansen A, Alcindor T, Marreaud S, Litière S, Hermans C, Fisher C, Hogendoorn PC, dei Tos AP, van der Graaf WT; European Organisation and Treatment of Cancer Soft Tissue and Bone Sarcoma Group. Doxorubicin alone versus intensified doxorubicin plus ifosfamide for first-line treatment of advanced or metastatic soft-tissue sarcoma: a randomised controlled phase 3 trial. Lancet Oncol. 2014 Apr;15(4):415-23. Epub 2014 Mar 5. [https://doi.org/10.1016/S1470-2045(14)70063-4 link to original article] [https://pubmed.ncbi.nlm.nih.gov/24618336/ PubMed] [https://clinicaltrials.gov/study/NCT00061984 NCT00061984]
−
 
+
# '''CP15-0806:''' Tap WD, Jones RL, Van Tine BA, Chmielowski B, Elias AD, Adkins D, Agulnik M, Cooney MM, Livingston MB, Pennock G, Hameed MR, Shah GD, Qin A, Shahir A, Cronier DM, Ilaria R Jr, Conti I, Cosaert J, Schwartz GK. Olaratumab and doxorubicin versus doxorubicin alone for treatment of soft-tissue sarcoma: an open-label phase 1b and randomised phase 2 trial. Lancet. 2016 Jul 30;388(10043):488-97. Epub 2016 Jun 9. Erratum in: Lancet. 2016 Jul 30;388(10043):464. [https://doi.org/10.1016/S0140-6736(16)30587-6 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5647653/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/27291997/ PubMed] [https://clinicaltrials.gov/study/NCT01185964 NCT01185964]
−
Supportive medications:
+
# '''PICASSO III:''' Ryan CW, Merimsky O, Agulnik M, Blay JY, Schuetze SM, Van Tine BA, Jones RL, Elias AD, Choy E, Alcindor T, Keedy VL, Reed DR, Taub RN, Italiano A, Garcia Del Muro X, Judson IR, Buck JY, Lebel F, Lewis JJ, Maki RG, Schöffski P. PICASSO III: A Phase III, Placebo-Controlled Study of Doxorubicin With or Without Palifosfamide in Patients With Metastatic Soft Tissue Sarcoma. J Clin Oncol. 2016 Nov 10;34(32):3898-3905. Epub 2016 Sep 30. [https://doi.org/10.1200/JCO.2016.67.6684 link to original article] [https://pubmed.ncbi.nlm.nih.gov/27621408/ PubMed] [https://clinicaltrials.gov/study/NCT01168791 NCT01168791]
−
*[[Dexamethasone (Decadron)]] 8 mg PO BID on days 7-9 (the day before, the day of, and day after docetaxel)
+
# '''TH CR-406/SARC021:''' Tap WD, Papai Z, Van Tine BA, Attia S, Ganjoo KN, Jones RL, Schuetze S, Reed D, Chawla SP, Riedel RF, Krarup-Hansen A, Toulmonde M, Ray-Coquard I, Hohenberger P, Grignani G, Cranmer LD, Okuno S, Agulnik M, Read W, Ryan CW, Alcindor T, Del Muro XFG, Budd GT, Tawbi H, Pearce T, Kroll S, Reinke DK, Schöffski P. Doxorubicin plus evofosfamide versus doxorubicin alone in locally advanced, unresectable or metastatic soft-tissue sarcoma (TH CR-406/SARC021): an international, multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2017 Aug;18(8):1089-1103. Epub 2017 Jun 23. [https://doi.org/10.1016/S1470-2045(17)30381-9 link to original article] '''contains dosing details in abstract''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7771354/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28651927/ PubMed] [https://clinicaltrials.gov/study/NCT01440088 NCT01440088]
−
*Patients could receive diuretics at physician discretion for peripheral edema related to docetaxel
+
# '''GeDDiS:''' Seddon B, Strauss SJ, Whelan J, Leahy M, Woll PJ, Cowie F, Rothermundt C, Wood Z, Benson C, Ali N, Marples M, Veal GJ, Jamieson D, Küver K, Tirabosco R, Forsyth S, Nash S, Dehbi HM, Beare S. Gemcitabine and docetaxel versus doxorubicin as first-line treatment in previously untreated advanced unresectable or metastatic soft-tissue sarcomas (GeDDiS): a randomised controlled phase 3 trial. Lancet Oncol. 2017 Oct;18(10):1397-1410. Epub 2017 Sep 4. [https://doi.org/10.1016/S1470-2045(17)30622-8 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5622179/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/28882536/ PubMed] ISRCTN07742377
−
*One of the following growth factors (varies depending on reference):
+
# '''ANNOUNCE:''' Tap WD, Wagner AJ, Schöffski P, Martin-Broto J, Krarup-Hansen A, Ganjoo KN, Yen CC, Abdul Razak AR, Spira A, Kawai A, Le Cesne A, Van Tine BA, Naito Y, Park SH, Fedenko A, Pápai Z, Soldatenkova V, Shahir A, Mo G, Wright J, Jones RL; ANNOUNCE Investigators. Effect of Doxorubicin Plus Olaratumab vs Doxorubicin Plus Placebo on Survival in Patients With Advanced Soft Tissue Sarcomas: The ANNOUNCE Randomized Clinical Trial. JAMA. 2020 Apr 7;323(13):1266-1276. [https://doi.org/10.1001/jama.2020.1707 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7139275/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/32259228/ PubMed] [https://clinicaltrials.gov/study/NCT02451943 NCT02451943]
−
**[[Filgrastim (Neupogen)|G-CSF]] 150 mcg/m2 (dose rounded to 300 or 480 mcg) SC once daily on days 9-15 as primary neutropenia prophylaxis; could be stopped before day 15 if ANC >1200/uL on two separate measurements
+
#'''GERICO14:''' [https://clinicaltrials.gov/study/NCT04757337 NCT04757337]
−
**[[Pegfilgrastim (Neulasta)]] 6 mg SC once on either day 9 or 10 (only one dose given)
 
−
 
 
−
===Regimen #2, Hensley, et al. 2002 & 2008 - patients who received prior radiation===
 
−
*[[Gemcitabine (Gemzar)]] 675 mg/m2 IV over 90 minutes once daily on days 1 & 8, given first
 
−
*[[Docetaxel (Taxotere)]] 75 mg/m2 IV over 1 hour once on day 8, given second
 
−
 
 
−
'''21-day cycles x 6-8 cycles, given until progression of disease or unacceptable toxicity'''; Hensley, et al. 2008 did not specify a maximum number of cycles
 
−
 
 
−
Supportive medications:
 
−
*[[Dexamethasone (Decadron)]] 8 mg PO BID on days 7-9 (the day before, the day of, and day after docetaxel)
 
−
*Patients could receive diuretics at physician discretion for peripheral edema related to docetaxel
 
−
*One of the following growth factors (varies depending on reference):
 
−
**[[Filgrastim (Neupogen)|G-CSF]] 150 mcg/m2 (dose rounded to 300 or 480 mcg) SC once daily on days 9-15 as primary neutropenia prophylaxis; could be stopped before day 15 if ANC >1200/uL on two separate measurements
 
−
**[[Pegfilgrastim (Neulasta)]] 6 mg SC once on either day 9 or 10 (only one dose given)
 
  
 +
==Epirubicin monotherapy {{#subobject:d976a5|Regimen=1}}==
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:a1dd30|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates 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/10.1016/0277-5379(87)90089-7 Mouridsen et al. 1987 (EORTC 62801)]
 +
|1980-1983
 +
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 +
|[[#Doxorubicin_monotherapy|Doxorubicin]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Epirubicin (Ellence)]] 75 mg/m<sup>2</sup> IV bolus once on day 1
 +
'''21-day cycle for up to 7 cycles (cumulative epirubicin dosage of 550 mg/m<sup>2</sup>)''' (though the ultimate decision to stop treatment based on cumulative epirubicin dosage was at the discretion of the treating physician)
 +
</div></div>
 
===References===
 
===References===
−
# Hensley ML, Maki R, Venkatraman E, Geller G, Lovegren M, Aghajanian C, Sabbatini P, Tong W, Barakat R, Spriggs DR. Gemcitabine and docetaxel in patients with unresectable leiomyosarcoma: results of a phase II trial. J Clin Oncol. 2002 Jun 15;20(12):2824-31. [http://jco.ascopubs.org/content/20/12/2824.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/12065559 PubMed]
+
# '''EORTC 62801:''' Mouridsen HT, Bastholt L, Somers R, Santoro A, Bramwell V, Mulder JH, van Oosterom AT, Buesa J, Pinedo HM, Thomas D, Sylvester R. Adriamycin versus epirubicin in advanced soft tissue sarcomas: a randomized phase II/phase III study of the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer Clin Oncol. 1987 Oct;23(10):1477-83. [https://doi.org/10.1016/0277-5379(87)90089-7 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/3479329/ PubMed]
−
# Hensley ML, Blessing JA, Mannel R, Rose PG. Fixed-dose rate gemcitabine plus docetaxel as first-line therapy for metastatic uterine leiomyosarcoma: a Gynecologic Oncology Group phase II trial. Gynecol Oncol. 2008 Jun;109(3):329-34. [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2504727/ link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/18534250 PubMed]
+
==Ifosfamide monotherapy {{#subobject:88d059|Regimen=1}}==
−
 
+
<div class="toccolours" style="background-color:#eeeeee">
−
==Gemcitabine (Gemzar) & Vinorelbine (Navelbine)==
+
===Regimen variant #1, short infusion (Ifos 3) {{#subobject:89c8f1|Variant=1}}===
−
 
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"
−
===Regimen, Dileo, et al. 2007===
+
!style="width: 20%"|Study
−
*[[Gemcitabine (Gemzar)]] 800 mg/m2 IV over 90 minutes once daily on days 1 & 8
+
!style="width: 20%"|Dates of enrollment
−
*[[Vinorelbine (Navelbine)]] 25 mg/m2 IV over 10 minutes once daily on days 1 & 8
+
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
−
 
+
!style="width: 20%"|Comparator
−
'''21-day cycles, given until progression of disease or unacceptable toxicity'''
+
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
−
 
+
|-
−
===Reference===
+
| rowspan="2" |[https://doi.org/10.1200/jco.2006.09.7717 Lorigan et al. 2007 (EORTC 62971)]
−
# Dileo P, Morgan JA, Zahrieh D, Desai J, Salesi JM, Harmon DC, Quigley MT, Polson K, Demetri GD, George S. Gemcitabine and vinorelbine combination chemotherapy for patients with advanced soft tissue sarcomas: results of a phase II trial. Cancer. 2007 May 1;109(9):1863-9. [http://onlinelibrary.wiley.com/doi/10.1002/cncr.22609/full link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/17385194 PubMed]
+
|rowspan=2|1998-2001
−
 
+
| rowspan="2" style="background-color:#1a9851" |Phase 3 (E-switch-ic)
−
=Giant-cell tumor of bone=
+
|1. [[#Doxorubicin_monotherapy|Doxorubicin]]
−
==Denosumab (Xgeva)==
+
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
−
===Regimen, Thomas, et. al 2010===
+
|-
−
*[[Denosumab (Xgeva)]] 120 mg SC once daily on days 1, 8, 15 of cycle 1; then on subsequent cycles [[Denosumab (Xgeva)]] 120 mg SC once on day 1
+
|2. [[#Ifosfamide_monotherapy|Ifosfamide]]; Ifos 9
−
 
+
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
−
'''28-day cycles, given until complete tumor resection, progression of disease, or patient choice'''
+
|-
−
 
+
|}
−
Supportive medications:
+
<div class="toccolours" style="background-color:#b3e2cd">
−
*Calcium 500 mg PO once daily
+
====Chemotherapy====
−
*Vitamin D 400 IU PO once daily
+
*[[Ifosfamide (Ifex)]] 3000 mg/m<sup>2</sup> IV over 4 hours on days 1 to 3, mixed with mesna in 1 liter of normal saline
 +
====Supportive therapy====
 +
*[[Mesna (Mesnex)]] 600 mg/m<sup>2</sup> IV bolus once on day 1, '''given immediately prior to mesna/ifosfamide infusion''', then 1500 mg/m<sup>2</sup> IV over 4 hours on days 1 to 3, given with ifosfamide, then 1200 mg/m<sup>2</sup> IV twice per day on days 1 to 3, given at 4 and 8 hours after completion of ifosfamide and mesna
 +
**An alternative is to use oral mesna instead of intravenous: [[Mesna (Mesnex)]] 1200 mg/m<sup>2</sup> PO twice per day on days 1 to 3, given at 2 and 6 hours after completion of ifosfamide and mesna
 +
*[[Sodium bicarbonate]] 150 mmol IV once per day on days 1 to 3
 +
*Patient with somnolence or other signs of encephalopathy with ifosfamide received methylene blue 50 mg IV every 4 hours until resolution of symptoms. During cycles thereafter, patients would receive methylene blue 50 mg IV every 4 hours, starting 4 hours prior to ifosfamide on day 1, continuing until 72 hours after completion
 +
'''21-day cycle for up to 6 cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2, continuous infusion (Ifos 9) {{#subobject:ad63a|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
| rowspan="2" |[https://doi.org/10.1200/jco.2006.09.7717 Lorigan et al. 2007 (EORTC 62971)]
 +
|rowspan=2|1998-2001
 +
| rowspan="2" style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|1. [[#Doxorubicin_monotherapy|Doxorubicin]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
 +
|-
 +
|2. [[#Ifosfamide_monotherapy|Ifosfamide]]; Ifos 3
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Ifosfamide (Ifex)]] 3000 mg/m<sup>2</sup>/day IV continuous infusion over 72 hours, started on day 1, '''given with mesna''' (total dose per cycle: 9000 mg/m<sup>2</sup>)
 +
**Each day's dose is mixed with mesna in 3 liters of normal saline
 +
====Supportive therapy====
 +
*[[Mesna (Mesnex)]] 600 mg/m<sup>2</sup> IV bolus once on day 1, '''given immediately prior to mesna/ifosfamide infusion''', then 3000 mg/m<sup>2</sup>/day IV continuous infusion over 72 hours, starting on day 1, given with ifosfamide, then 1800 mg/m<sup>2</sup> IV over 12 hours once on day 4, starting after completion of ifosfamide and mesna
 +
**An alternative is to use oral mesna instead of intravenous: [[Mesna (Mesnex)]] 1200 mg/m<sup>2</sup> PO three times on day 4, given 0, 2, and 6 hours after completion of ifosfamide and mesna
 +
*[[Sodium bicarbonate]] 150 mmol IV once per day on days 1 to 3
 +
*Patient with somnolence or other signs of encephalopathy with ifosfamide received methylene blue 50 mg IV every 4 hours until resolution of symptoms. During cycles thereafter, patients would receive methylene blue 50 mg IV every 4 hours, starting 4 hours prior to ifosfamide on day 1, continuing until 72 hours after completion
 +
'''21-day cycle for up to 6 cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
  
 +
===Regimen variant #3 {{#subobject:210d2d|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://doi.org/10.1016/s0959-8049(02)00491-4 van Oosterom et al. 2002]
 +
|1992-1994
 +
| style="background-color:#91cf61" |Phase 2
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Ifosfamide (Ifex)]] 3000 mg/m<sup>2</sup> IV over 4 hours once per day on days 1 to 3, dissolved in 125 mL sterile water per 1000 mg of ifosfamide, mixed with mesna in an additional 1 liter of dextrose/saline
 +
====Supportive therapy====
 +
*[[Mesna (Mesnex)]] 600 mg/m<sup>2</sup> IV bolus once on day 1, '''immediately prior to mesna/ifosfamide infusion''', then 1500 mg/m<sup>2</sup> IV over 4 hours on days 1 to 3, '''given with ifosfamide''', then 500 mg/m<sup>2</sup> IV twice per day on days 1 to 3, '''given at 4 and 8 hours after completion of ifosfamide and mesna'''
 +
*"[[:Category:Emesis_prevention|Antiemetics]] were prescribed according to local conventions"
 +
*1 liter of fluid PO twice per day on days 1 to 3, taken 4 and 8 hours after completion of ifosfamide and mesna
 +
'''21-day cycle for at least 2 cycles, except in cases of rapid disease progression'''
 +
</div></div>
 
===References===
 
===References===
−
# Thomas D, Henshaw R, Skubitz K, Chawla S, Staddon A, Blay JY, Roudier M, Smith J, Ye Z, Sohn W, Dansey R, Jun S. Denosumab in patients with giant-cell tumour of bone: an open-label, phase 2 study. Lancet Oncol. 2010 Mar;11(3):275-80. [http://www.sciencedirect.com/science/article/pii/S1470204510700103 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/20149736 PubMed]
+
# van Oosterom AT, Mouridsen HT, Nielsen OS, Dombernowsky P, Krzemieniecki K, Judson I, Svancarova L, Spooner D, Hermans C, Van Glabbeke M, Verweij J; [[Study_Groups#EORTC|EORTC]] Soft Tissue and Bone Sarcoma Group. Results of randomised studies of the EORTC Soft Tissue and Bone Sarcoma Group (STBSG) with two different ifosfamide regimens in first- and second-line chemotherapy in advanced soft tissue sarcoma patients. Eur J Cancer. 2002 Dec;38(18):2397-406. [https://doi.org/10.1016/s0959-8049(02)00491-4 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/12460784/ PubMed] content property of [https://hemonc.org HemOnc.org]
−
 
+
# '''EORTC 62971:''' Lorigan P, Verweij J, Papai Z, Rodenhuis S, Le Cesne A, Leahy MG, Radford JA, Van Glabbeke MM, Kirkpatrick A, Hogendoorn PC, Blay JY; [[Study_Groups#EORTC|EORTC]] Soft Tissue and Bone Sarcoma Group. Phase III trial of two investigational schedules of ifosfamide compared with standard-dose doxorubicin in advanced or metastatic soft tissue sarcoma: a European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group Study. J Clin Oncol. 2007 Jul 20;25(21):3144-50. [https://doi.org/10.1200/jco.2006.09.7717 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17634494/ PubMed] [https://clinicaltrials.gov/study/NCT00003212 NCT00003212]
−
=GIST (Gastrointestinal Stromal Tumor) - neoadjuvant therapy=
 
−
==Imatinib (Gleevec)==
 
−
===Regimen, Eisenberg, et al. 2009 - RTOG 0132===
 
−
*[[Imatinib (Gleevec)]] 600 mg PO once daily
 
−
 
 
−
'''given for 8-12 weeks prior to surgery, stopped on the day prior to surgery, resumed as soon as possible postoperatively, and continued for 2 years as postoperative adjuvant therapy'''
 
  
 +
==Pazopanib monotherapy {{#subobject:644c8f|Regimen=1}}==
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:332a64|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates 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/10.1016/S0140-6736(12)60651-5 van der Graaf et al. 2012 (PALETTE)]
 +
<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
 +
|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-201-1 <span style="color:white;">ESMO-MCBS (3)</span>]'''
 +
|-
 +
|} -->
 +
|2008-2010
 +
| style="background-color:#1a9851" |Phase 3 (E-RT-esc)
 +
|[[Soft_tissue_sarcoma_-_null_regimens#Placebo|Placebo]]
 +
| style="background-color:#1a9850" |Superior PFS (primary endpoint)<br>Median PFS: 4.6 vs 1.6 mo<br>(HR 0.31, 95% CI 0.24-0.40)
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Targeted therapy====
 +
*[[Pazopanib (Votrient)]] 800 mg PO once per day on days 1 to 28
 +
'''28-day cycles'''
 +
</div></div>
 
===References===
 
===References===
−
# Eisenberg BL, Harris J, Blanke CD, Demetri GD, Heinrich MC, Watson JC, Hoffman JP, Okuno S, Kane JM, von Mehren M. Phase II trial of neoadjuvant/adjuvant imatinib mesylate (IM) for advanced primary and metastatic/recurrent operable gastrointestinal stromal tumor (GIST): early results of RTOG 0132/ACRIN 6665. J Surg Oncol. 2009 Jan 1;99(1):42-7. [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2606912/ link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/18942073 PubMed]
+
# '''PALETTE:''' van der Graaf WT, Blay JY, Chawla SP, Kim DW, Bui-Nguyen B, Casali PG, Schöffski P, Aglietta M, Staddon AP, Beppu Y, Le Cesne A, Gelderblom H, Judson IR, Araki N, Ouali M, Marreaud S, Hodge R, Dewji MR, Coens C, Demetri GD, Fletcher CD, Dei Tos AP, Hohenberger P; [[Study_Groups#EORTC|EORTC]] Soft Tissue and Bone Sarcoma Group; PALETTE study group. Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2012 May 19;379(9829):1879-86. Epub 2012 May 16. [https://doi.org/10.1016/S0140-6736(12)60651-5 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/22595799/ PubMed] [https://clinicaltrials.gov/study/NCT00753688 NCT00753688]
−
 
+
## '''Subgroup analysis:''' Kawai A, Araki N, Hiraga H, Sugiura H, Matsumine A, Ozaki T, Ueda T, Ishii T, Esaki T, Machida M, Fukasawa N. A randomized, double-blind, placebo-controlled, phase III study of pazopanib in patients with soft tissue sarcoma: results from the Japanese subgroup. Jpn J Clin Oncol. 2016 Mar;46(3):248-53. Epub 2016 Feb 10. [https://doi.org/10.1093/jjco/hyv184 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4777611/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26864131/ PubMed]
−
=GIST (Gastrointestinal Stromal Tumor) - adjuvant therapy=
 
−
==Imatinib (Gleevec)==
 
−
 
 
−
===Regimen #1, Joensuu, et al. 2012 - 3 years of treatment===
 
−
''Showed improved recurrence-free survival with 36 months of therapy as compared to 12 months of therapy.''
 
−
*[[Imatinib (Gleevec)]] 400 mg PO once daily
 
−
 
 
−
'''36-month course, treatment started within 12 weeks after surgery'''
 
−
 
 
−
===Regimen #2, Dematteo, et al. 2009 - 1 year of treatment===
 
−
*[[Imatinib (Gleevec)]] 400 mg PO once daily
 
−
 
 
−
'''1-year course; treatment started within 12 weeks after surgery'''
 
  
 +
==Regorafenib monotherapy {{#subobject:c9fc2c|Regimen=1}}==
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:b5ff4e|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates 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/10.1016/S1470-2045(16)30507-1 Mir et al. 2016 (REGOSARC)]
 +
|2013-08-05 to 2014-11-26
 +
| style="background-color:#1a9851" |Randomized Phase 2 (E-esc)
 +
|[[Soft_tissue_sarcoma_-_null_regimens#Placebo|Placebo]]
 +
| style="background-color:#1a9850" |Superior PFS (primary endpoint)
 +
|-
 +
|}
 +
''Note: reported efficacy is for the leiomyosarcoma, synovial sarcoma, and other sarcoma cohorts; there was no significant difference in outcome for the liposarcoma cohort.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Targeted therapy====
 +
*[[Regorafenib (Stivarga)]] 160 mg PO once per day on days 1 to 21
 +
'''28-day cycles'''
 +
</div></div>
 
===References===
 
===References===
−
# Dematteo RP, Ballman KV, Antonescu CR, Maki RG, Pisters PW, Demetri GD, Blackstein ME, Blanke CD, von Mehren M, Brennan MF, Patel S, McCarter MD, Polikoff JA, Tan BR, Owzar K; American College of Surgeons Oncology Group (ACOSOG) Intergroup Adjuvant GIST Study Team. Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: a randomised, double-blind, placebo-controlled trial. Lancet. 2009 Mar 28;373(9669):1097-104. [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2915459/ link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/19303137 PubMed]
+
# '''REGOSARC:''' Mir O, Brodowicz T, Italiano A, Wallet J, Blay JY, Bertucci F, Chevreau C, Piperno-Neumann S, Bompas E, Salas S, Perrin C, Delcambre C, Liegl-Atzwanger B, Toulmonde M, Dumont S, Ray-Coquard I, Clisant S, Taieb S, Guillemet C, Rios M, Collard O, Bozec L, Cupissol D, Saada-Bouzid E, Lemaignan C, Eisterer W, Isambert N, Chaigneau L, Cesne AL, Penel N. Safety and efficacy of regorafenib in patients with advanced soft tissue sarcoma (REGOSARC): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol. 2016 Dec;17(12):1732-1742. Epub 2016 Oct 14. [https://doi.org/10.1016/S1470-2045(16)30507-1 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/27751846/ PubMed] [https://clinicaltrials.gov/study/NCT01900743 NCT01900743]
−
# Joensuu H, Eriksson M, Sundby Hall K, Hartmann JT, Pink D, Sch�tte J, Ramadori G, Hohenberger P, Duyster J, Al-Batran SE, Schlemmer M, Bauer S, Wardelmann E, Sarlomo-Rikala M, Nilsson B, Sihto H, Monge OR, Bono P, Kallio R, Vehtari A, Leinonen M, Alveg�rd T, Reichardt P. One vs three years of adjuvant imatinib for operable gastrointestinal stromal tumor: a randomized trial. JAMA. 2012 Mar 28;307(12):1265-72. doi: 10.1001/jama.2012.347. [http://jama.jamanetwork.com/article.aspx?articleid=1105116 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/22453568 PubMed]
 
−
 
 
−
=GIST (Gastrointestinal Stromal Tumor) - metastatic or unresectable disease=
 
−
==Imatinib (Gleevec)==
 
−
===Regimen #1, Blanke, et al. 2008===
 
−
====Standard dose therapy====
 
−
*[[Imatinib (Gleevec)]] 400 mg PO once daily
 
−
 
 
−
'''given until progression of disease or unacceptable toxicity'''; patients who progressed on imatinib 400 mg PO once daily could receive high-dose therapy, as described below
 
−
 
 
−
====High-dose therapy====
 
−
*[[Imatinib (Gleevec)]] 400 mg PO twice per day
 
−
 
 
−
'''given until progression of disease or unacceptable toxicity'''
 
−
 
 
−
===Regimen #2, Verweij, et al. 2003 & MetaGIST 2010===
 
−
*[[Imatinib (Gleevec)]] 400 mg PO twice a day, taken after a meal
 
  
−
'''given until progression of disease or unacceptable toxicity'''
+
==Temozolomide monotherapy {{#subobject:5929ed|Regimen=1}}==
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1, 5 out of 28 days {{#subobject:63d3d8|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://doi.org/10.1002/cncr.11730 Talbot et al. 2003]
 +
|1998-2000
 +
| style="background-color:#91cf61" |Phase 2
 +
|-
 +
|}
 +
''Note: patients on study could be reconsented to receive therapy beyond 1 year. Treatment given on an empty stomach, and doses rounded up if needed to next available dosage based on capsule doses.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Temozolomide (Temodar)]] 200 mg/m<sup>2</sup> PO once on day 1, then 90 mg/m<sup>2</sup> PO every 12 hours on days 1 to 5 (total of 10 doses per cycle)
  
−
===Regimen #3, Demetri, et al. 2002 & MetaGIST 2010===
+
====Supportive therapy====
−
*[[Imatinib (Gleevec)]] 400 mg PO once daily, taken with food
+
*[[:Category:Emesis_prevention|Antiemetics]] "prescribed as clinically indicated by the treating physician"
 +
'''28-day cycle for up to 13 cycles (1 year)'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2, 6 out of 9 weeks {{#subobject:892d65|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://doi.org/10.1002/cncr.21384 Garcia del Muro et al. 2005]
 +
|1999-2001
 +
| style="background-color:#91cf61" |Phase 2
 +
|-
 +
|}
 +
''Note: Initial dose used in the study was 75 mg/m<sup>2</sup>, but due to lack of toxicity, protocol was amended to use 100 mg/m<sup>2</sup> doses.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Temozolomide (Temodar)]] 100 mg/m<sup>2</sup> PO once per day on days 1 to 42 (no food within 1 hour before and after temozolomide doses)
 +
====Supportive therapy====
 +
*"[[:Category:Emesis_prevention|Antiemetics]], mainly oral [[Metoclopramide (Reglan)]] and [[Ondansetron (Zofran)]], were prescribed as clinically indicated by the treating physician"
 +
'''9-week cycle for up to 3 cycles'''
 +
</div></div>
  
 
===References===
 
===References===
−
# Demetri GD, von Mehren M, Blanke CD, Van den Abbeele AD, Eisenberg B, Roberts PJ, Heinrich MC, Tuveson DA, Singer S, Janicek M, Fletcher JA, Silverman SG, Silberman SL, Capdeville R, Kiese B, Peng B, Dimitrijevic S, Druker BJ, Corless C, Fletcher CD, Joensuu H. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med. 2002 Aug 15;347(7):472-80. [http://www.nejm.org/doi/full/10.1056/NEJMoa020461 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/12181401 PubMed]
+
# Talbot SM, Keohan ML, Hesdorffer M, Orrico R, Bagiella E, Troxel AB, Taub RN. A phase II trial of temozolomide in patients with unresectable or metastatic soft tissue sarcoma. Cancer. 2003 Nov 1;98(9):1942-6. [https://doi.org/10.1002/cncr.11730 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/14584078/ PubMed]
−
# Verweij J, van Oosterom A, Blay JY, Judson I, Rodenhuis S, van der Graaf W, Radford J, Le Cesne A, Hogendoorn PC, di Paola ED, Brown M, Nielsen OS. Imatinib mesylate (STI-571 Glivec, Gleevec) is an active agent for gastrointestinal stromal tumours, but does not yield responses in other soft-tissue sarcomas that are unselected for a molecular target. Results from an EORTC Soft Tissue and Bone Sarcoma Group phase II study. Eur J Cancer. 2003 Sep;39(14):2006-11. [http://www.ejcancer.com/article/S0959-8049%2802%2900836-5/abstract link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/12957454 PubMed]
+
# Garcia del Muro X, Lopez-Pousa A, Martin J, Buesa JM, Martinez-Trufero J, Casado A, Poveda A, Cruz J, Bover I, Maurel J; Spanish Group for Research on Sarcomas. A phase II trial of temozolomide as a 6-week, continuous, oral schedule in patients with advanced soft tissue sarcoma: a study by the Spanish Group for Research on Sarcomas. Cancer. 2005 Oct 15;104(8):1706-12. [https://doi.org/10.1002/cncr.21384 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16134177/ PubMed]
−
# Blanke CD, Rankin C, Demetri GD, Ryan CW, von Mehren M, Benjamin RS, Raymond AK, Bramwell VH, Baker LH, Maki RG, Tanaka M, Hecht JR, Heinrich MC, Fletcher CD, Crowley JJ, Borden EC. Phase III randomized, intergroup trial assessing imatinib mesylate at two dose levels in patients with unresectable or metastatic gastrointestinal stromal tumors expressing the kit receptor tyrosine kinase: S0033. J Clin Oncol. 2008 Feb 1;26(4):626-32. doi: 10.1200/JCO.2007.13.4452. [http://jco.ascopubs.org/content/26/4/626.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/18235122 PubMed]
+
==Trabectedin monotherapy {{#subobject:cfc3ed|Regimen=1}}==
−
# Gastrointestinal Stromal Tumor Meta-Analysis Group (MetaGIST). Comparison of two doses of imatinib for the treatment of unresectable or metastatic gastrointestinal stromal tumors: a meta-analysis of 1,640 patients. J Clin Oncol. 2010 Mar 1;28(7):1247-53. doi: 10.1200/JCO.2009.24.2099. Epub 2010 Feb 1. [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2834472/ link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/20124181 PubMed]
+
<div class="toccolours" style="background-color:#eeeeee">
−
 
+
===Regimen variant #1, 1.2 mg/m<sup>2</sup> {{#subobject:33de2b|Variant=1}}===
−
==Regorafenib (Stivarga)==
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"
−
 
+
!style="width: 20%"|Study
−
===Regimen - GRID===
+
!style="width: 20%"|Dates of enrollment
−
''Patients in this study already had treatment failure with imatinib and sunitinib.''
+
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
−
*[[Regorafenib (Stivarga)]] 160 mg PO once daily on days 1-21
+
!style="width: 20%"|Comparator
−
 
+
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
−
'''28-day cycles, given until progression of disease or unacceptable toxicity'''
+
|-
 +
|[https://doi.org/10.1016/S1470-2045(15)70098-7 Kawai et al. 2015]
 +
|2012-2014
 +
| style="background-color:#1a9851" |Randomized Phase 2 (E-esc)
 +
|[[Soft_tissue_sarcoma_-_null_regimens#Placebo|Placebo]]
 +
| style="background-color:#1a9850" |Superior PFS (primary endpoint)<br>Median PFS: 5.6 vs 0.9 mo<br>(HR 0.07, 95% CI 0.03-0.16)
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Trabectedin (Yondelis)]] 1.2 mg/m<sup>2</sup> IV continuous infusion over 24 hours, started on day 1
 +
'''21-day cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2, 1.5 mg/m<sup>2</sup> {{#subobject:33523b|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates 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/10.1016/j.annonc.2021.04.014 Le Cesne et al. 2021 (T-SAR)]
 +
|2015-01-26 to 2015-11-05
 +
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|[[Soft_tissue_sarcoma_-_null_regimens#Best_supportive_care|Best supportive care]]
 +
| style="background-color:#1a9850" |Superior PFS (primary endpoint)<br>Median PFS: 3.1 vs 1.5 mo<br>(HR 0.39, 95% CI 0.24-0.64)
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Trabectedin (Yondelis)]] 1.5 mg/m<sup>2</sup> IV continuous infusion over 24 hours, started on day 1
 +
'''21-day cycles'''
 +
</div></div>
  
 
===References===
 
===References===
−
# Demetri GD, Reichardt P, Kang YK, Blay JY, Rutkowski P, Gelderblom H, Hohenberger P, Leahy M, von Mehren M, Joensuu H, Badalamenti G, Blackstein M, Le Cesne A, Sch�ffski P, Maki RG, Bauer S, Nguyen BB, Xu J, Nishida T, Chung J, Kappeler C, Kuss I, Laurent D, Casali PG; GRID study investigators. Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013 Jan 26;381(9863):295-302. doi: 10.1016/S0140-6736(12)61857-1. Epub 2012 Nov 22. [http://www.sciencedirect.com/science/article/pii/S0140673612618571 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/23177515 PubMed]
+
# Kawai A, Araki N, Sugiura H, Ueda T, Yonemoto T, Takahashi M, Morioka H, Hiraga H, Hiruma T, Kunisada T, Matsumine A, Tanase T, Hasegawa T, Takahashi S. Trabectedin monotherapy after standard chemotherapy versus best supportive care in patients with advanced, translocation-related sarcoma: a randomised, open-label, phase 2 study. Lancet Oncol. 2015 Apr;16(4):406-16. Epub 2015 Mar 18. [https://doi.org/10.1016/S1470-2045(15)70098-7 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/25795406/ PubMed] JapicCTI-121850
−
 
+
# '''T-SAR:''' Le Cesne A, Blay JY, Cupissol D, Italiano A, Delcambre C, Penel N, Isambert N, Chevreau C, Bompas E, Bertucci F, Chaigneau L, Piperno-Neumann S, Salas S, Rios M, Guillemet C, Bay JO, Ray-Coquard I, Haddag L, Bonastre J, Kapso R, Fraslin A, Bouvet N, Mir O, Foulon S. A randomized phase III trial comparing trabectedin to best supportive care in patients with pre-treated soft tissue sarcoma: T-SAR, a French Sarcoma Group trial. Ann Oncol. 2021 Aug;32(8):1034-1044. Epub 2021 Apr 29. [https://doi.org/10.1016/j.annonc.2021.04.014 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/33932507/ PubMed] [https://clinicaltrials.gov/study/NCT02672527 NCT02672527]
−
==Sunitinib (Sutent)==
+
=Locally advanced or metastatic disease, combination regimens=
−
 
+
==Dacarbazine & Gemcitabine {{#subobject:cd9068|Regimen=1}}==
−
===Regimen===
+
<div class="toccolours" style="background-color:#eeeeee">
−
''Patients in this study had treatment failure with imatinib.''
+
===Regimen {{#subobject:9aaddf|Variant=1}}===
−
*[[Sunitinib (Sutent)]] 50 mg PO once daily on days 1-28
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"
−
**Dose may be decreased to 37.5 mg or 25 mg depending on tolerability
+
!style="width: 20%"|Study
−
 
+
!style="width: 20%"|Dates of enrollment
−
'''42-day cycles, given until progression of disease or unacceptable toxicity'''
+
!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.2010.33.6107 García-Del-Muro et al. 2011]
 +
|2005-2008
 +
| style="background-color:#ffffbe" |Randomized Phase 2, fewer than 20 pts in this subgroup (E-esc)
 +
|[[#Dacarbazine_monotherapy|Dacarbazine]]
 +
| style="background-color:#91cf60" |Seems to have superior OS (secondary endpoint)
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Dacarbazine (DTIC)]] 500 mg/m<sup>2</sup> IV over 20 minutes once on day 1, '''given second'''
 +
*[[Gemcitabine (Gemzar)]] 1800 mg/m<sup>2</sup> IV at fixed dosed rate over 3 hours once on day 1, '''given first'''
 +
'''14-day cycle for at least 12 cycles'''
 +
</div></div>
 
===References===
 
===References===
−
# Demetri GD, van Oosterom AT, Garrett CR, Blackstein ME, Shah MH, Verweij J, McArthur G, Judson IR, Heinrich MC, Morgan JA, Desai J, Fletcher CD, George S, Bello CL, Huang X, Baum CM, Casali PG. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet. 2006 Oct 14;368(9544):1329-38. [http://www.sciencedirect.com/science/article/pii/S0140673606694464 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/17046465 PubMed]
+
# García-Del-Muro X, López-Pousa A, Maurel J, Martín J, Martínez-Trufero J, Casado A, Gómez-España A, Fra J, Cruz J, Poveda A, Meana A, Pericay C, Cubedo R, Rubió J, De Juan A, Laínez N, Carrasco JA, de Andrés R, Buesa JM; Spanish Group for Research on Sarcomas. Randomized phase II study comparing gemcitabine plus dacarbazine versus dacarbazine alone in patients with previously treated soft tissue sarcoma: a Spanish Group for Research on Sarcomas study. J Clin Oncol. 2011 Jun 20;29(18):2528-33. Epub 2011 May 23. [https://doi.org/10.1200/JCO.2010.33.6107 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/21606430/ PubMed] EudraCT 2005-001709-24
−
# Prior JO, Montemurro M, Orcurto MV, Michielin O, Luthi F, Benhattar J, Guillou L, Elsig V, Stupp R, Delaloye AB, Leyvraz S. Early prediction of response to sunitinib after imatinib failure by 18F-fluorodeoxyglucose positron emission tomography in patients with gastrointestinal stromal tumor. J Clin Oncol. 2009 Jan 20;27(3):439-45. doi: 10.1200/JCO.2008.17.2742. Epub 2008 Dec 8. [http://jco.ascopubs.org/content/27/3/439.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/19064982 PubMed]
+
==Docetaxel & Gemcitabine {{#subobject:1e718f|Regimen=1}}==
−
 
+
<div class="toccolours" style="background-color:#eeeeee">
−
==Temozolomide (Temodar)==
+
===Regimen {{#subobject:2898f9|Variant=1}}===
−
*Regimen is the same as [[#Temozolomide_.28Temodar.29|Temozolomide (Temodar) single-agent therapy in soft tissue sarcoma, Garcia del Muro, et al. 2005]]
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"
−
 
+
!style="width: 20%"|Study
−
=Angiosarcoma=
+
!style="width: 20%"|Dates of enrollment
−
 
+
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
−
==Bevacizumab (Avastin)==
+
!style="width: 20%"|Comparator
−
 
+
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
−
===Regimen, Agulnik et al. 2013===
+
|-
−
*[[Bevacizumab (Avastin)]] 15 mg/kg IV once on day 1
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5622179/ Seddon et al. 2017 (GeDDiS)]
−
 
+
|2010-2014
−
'''21-day cycles, given until progression of disease, intolerance, unacceptable toxicity, patient refusal, or physician discretion'''
+
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
−
 
+
|[[#Doxorubicin_monotherapy|Doxorubicin]]
 +
| style="background-color:#fee08b" |Might have inferior PFS (secondary endpoint)
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Docetaxel (Taxotere)]] 75 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'''
 +
====Supportive therapy====
 +
*[[Dexamethasone (Decadron)]] 8 mg PO twice per day on days 7 to 9 (the day before, the day of, and day after docetaxel)
 +
*Patients could receive diuretics at physician discretion for peripheral edema related to docetaxel
 +
*One of the following growth factors (varies depending on reference):
 +
**[[:Category:Granulocyte colony-stimulating factors|G-CSF]] (type not specified) 150 mcg/m<sup>2</sup> (dose rounded to 300 or 480 mcg) SC once per day on days 9 to 15 as primary neutropenia prophylaxis; could be stopped before day 15 if ANC greater than 1200/μL on two separate measurements
 +
**[[Pegfilgrastim (Neulasta)]] 6 mg SC once on either day 9 or 10
 +
'''21-day cycle for 6 to 8 cycles'''
 +
</div></div>
 
===References===
 
===References===
−
# Agulnik M, Yarber JL, Okuno SH, von Mehren M, Jovanovic BD, Brockstein BE, Evens AM, Benjamin RS. An open-label, multicenter, phase II study of bevacizumab for the treatment of angiosarcoma and epithelioid hemangioendotheliomas. Ann Oncol. 2013 Jan;24(1):257-63. doi: 10.1093/annonc/mds237. [http://annonc.oxfordjournals.org/content/24/1/257.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/22910841 PubMed]
+
# '''GeDDiS:''' Seddon B, Strauss SJ, Whelan J, Leahy M, Woll PJ, Cowie F, Rothermundt C, Wood Z, Benson C, Ali N, Marples M, Veal GJ, Jamieson D, Küver K, Tirabosco R, Forsyth S, Nash S, Dehbi HM, Beare S. Gemcitabine and docetaxel versus doxorubicin as first-line treatment in previously untreated advanced unresectable or metastatic soft-tissue sarcomas (GeDDiS): a randomised controlled phase 3 trial. Lancet Oncol. 2017 Oct;18(10):1397-1410. Epub 2017 Sep 4. [https://doi.org/10.1016/S1470-2045(17)30622-8 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5622179/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/28882536/ PubMed] ISRCTN07742377
−
 
 
−
==Paclitaxel (Taxol)==
 
−
===Regimen, Penel et al. 2008 - ANGIOTAX===
 
−
*[[Paclitaxel (Taxol)]] 80 mg/m2 IV over 60 minutes once daily on days 1, 8, 15
 
−
 
 
−
'''28-day cycles x 6 cycles, given until progression of disease or unacceptable toxicity'''
 
−
 
 
−
Supportive medications:
 
−
*[[Dexamethasone (Decadron)]] 8 mg IV once prior to paclitaxel
 
−
*Cimetidine (Tagamet) 200 mg IV once prior to paclitaxel
 
−
*Dexchlorpheniramine (note: was spelled as dexchloropheramine in the Penel, et al. 2008) (Polaramine) 5 mg IV once prior to paclitaxel
 
−
*"Standard [[Antiemesis|antiemetics]] (mainly metoclopramide) were prescribed as clinically indicated by the treating physician"
 
  
 +
==Doxorubicin & Ifosfamide {{#subobject:e28770|Regimen=1}}==
 +
AIM: '''<u>A</u>'''driamycin (Doxorubicin), '''<u>I</u>'''fosfamide, '''<u>M</u>'''esna
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1, 50/5000 {{#subobject:78d03a|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates 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.2000.18.14.2676 Le Cesne et al. 2000 (EORTC 62903)]
 +
|1992-1995
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Doxorubicin_.26_Ifosfamide|AIM]]; 75/5000
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Doxorubicin (Adriamycin)]] 50 mg/m<sup>2</sup> IV once on day 1
 +
*[[Ifosfamide (Ifex)]] 5000 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2, 5-day course, lower dose doxorubicin - AI 75/10,000 {{#subobject:9c1374|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://doi.org/10.1097/00000421-199806000-00025 Patel et al. 1998]
 +
|1995-1996
 +
| style="background-color:#ffffbe" |Pilot, fewer than 20 patients reported
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Doxorubicin (Adriamycin)]] 25 mg/m<sup>2</sup>/day IV continuous infusion over 72 hours, started on day 1 (total dose per cycle: 75 mg/m<sup>2</sup>)
 +
*[[Ifosfamide (Ifex)]] 2000 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 to 5
 +
====Supportive therapy====
 +
*[[Mesna (Mesnex)]] 400 mg/m<sup>2</sup> IV once on day 1, given simultaneously with the first dose of ifosfamide, then 1200 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours
 +
**Each day's dose is given in 2 liters of D5W with 100 mEq/L sodium acetate, 20 mEq/L potassium acetate, and 4 mEq/L magnesium sulfate
 +
*If febrile neutropenia occurs, [[:Category:Granulocyte colony-stimulating factors|G-CSF]] is used in subsequent cycles
 +
'''21-day cycle for up to 6 cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #3, 4-day course, higher dose doxorubicin - AI 90/10,000 {{#subobject:2fd91c|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://doi.org/10.1097/00000421-199806000-00025 Patel et al. 1998]
 +
|1995-1996
 +
| style="background-color:#ffffbe" |Pilot, fewer than 20 patients reported
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Doxorubicin (Adriamycin)]] 30 mg/m<sup>2</sup>/day IV continuous infusion over 72 hours, started on day 1 (total dose per cycle: 90 mg/m<sup>2</sup>)
 +
*[[Ifosfamide (Ifex)]] 2500 mg/m<sup>2</sup> IV over 3 hours once per day on days 1 to 4
 +
====Supportive therapy====
 +
*[[Mesna (Mesnex)]] 500 mg/m<sup>2</sup> IV once on day 1, given simultaneously with the first dose of ifosfamide, then 1500 mg/m<sup>2</sup>/day IV continuous infusion over 96 hours
 +
***Each day's dose is given in 2 liters of D5W with 100 mEq/L sodium acetate, 20 mEq/L potassium acetate, and 4 mEq/L magnesium sulfate
 +
*[[:Category:Granulocyte colony-stimulating factors|G-CSF]] (type not specified) 5 mcg/kg (dose rounded to 300 or 480 mcg) SC once per day, starting on day 5, given until ANC is at least 10,000/μL
 +
'''21-day cycle for up to 6 cycles'''
 +
</div></div>
 
===References===
 
===References===
−
# Penel N, Bui BN, Bay JO, Cupissol D, Ray-Coquard I, Piperno-Neumann S, Kerbrat P, Fournier C, Taieb S, Jimenez M, Isambert N, Peyrade F, Chevreau C, Bompas E, Brain EG, Blay JY. Phase II trial of weekly paclitaxel for unresectable angiosarcoma: the ANGIOTAX Study. J Clin Oncol. 2008 Nov 10;26(32):5269-74. doi:  10.1200/JCO.2008.17.3146. Epub 2008 Sep 22. [http://jco.ascopubs.org/content/26/32/5269.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/18809609 PubMed]
+
# Patel SR, Vadhan-Raj S, Burgess MA, Plager C, Papadopolous N, Jenkins J, Benjamin RS. Results of two consecutive trials of dose-intensive chemotherapy with doxorubicin and ifosfamide in patients with sarcomas. Am J Clin Oncol. 1998 Jun;21(3):317-21. [https://doi.org/10.1097/00000421-199806000-00025 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/9626808/ PubMed]
−
 
+
# '''EORTC 62903:''' Le Cesne A, Judson I, Crowther D, Rodenhuis S, Keizer HJ, Van Hoesel Q, Blay JY, Frisch J, Van Glabbeke M, Hermans C, Van Oosterom A, Tursz T, Verweij J. Randomized phase III study comparing conventional-dose doxorubicin plus ifosfamide versus high-dose doxorubicin plus ifosfamide plus recombinant human granulocyte-macrophage colony-stimulating factor in advanced soft tissue sarcomas: A trial of the European Organisation for Research and Treatment of Cancer/Soft Tissue and Bone Sarcoma Group. J Clin Oncol. 2000 Jul;18(14):2676-84. [https://doi.org/10.1200/JCO.2000.18.14.2676 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/10894866/ PubMed]
−
=HIV/AIDS-associated Kaposi Sarcoma=
+
==Doxorubicin, Ifosfamide, RT {{#subobject:e36470|Regimen=1}}==
−
 
+
AIM & RT: '''<u>A</u>'''driamycin (Doxorubicin), '''<u>I</u>'''fosfamide, '''<u>M</u>'''esna, '''<u>R</u>'''adiation '''<u>T</u>'''herapy
−
==ABV==
+
<div class="toccolours" style="background-color:#eeeeee">
−
ABV: '''<u>A</u>'''driamycin, '''<u>B</u>'''leomycin, '''<u>V</u>'''incristine
+
===Regimen {{#subobject:0acb5d|Variant=1}} ===
−
 
+
{| class="wikitable sortable" style="width: 60%; text-align:center;"
−
===Regimen #1, Northfelt, et al. 1998===
+
!style="width: 33%"|Study
−
*[[Doxorubicin (Adriamycin)]] 20 mg/m2 IV once on day 1
+
!style="width: 33%"|Dates of enrollment
−
*[[Bleomycin (Blenoxane)]] 10 mg/m2 IV once on day 1
+
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
−
*[[Vincristine (Oncovin)]] 1 mg IV once on day 1
+
|-
−
 
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6946838/ Spunt et al. 2019 (COG ARST0332 Arm D)]
−
'''14-day cycles x up to 6 cycles'''
+
|2007-2012
−
 
+
| style="background-color:#91cf61" |Phase 3b
−
Supportive medications:
+
|-
−
*"Colony-stimulating factors (CSFs) were prescribed at the discretion of the investigators."
+
|}
−
 
+
''Note: Regimen details are derived from ClinicalTrials.gov.''
−
===Regimen #2, Gill, et al. 1996===
+
<div class="toccolours" style="background-color:#b3e2cd">
−
''Gill, et al. 1996 did not clearly say in the paper when these drugs were given, but this schedule is assumed based on the Northfelt, et al. 1998 ABV regimen.''
+
====Chemotherapy====
−
*[[Doxorubicin (Adriamycin)]] 10 mg/m2 IV once on day 1
+
*[[Doxorubicin (Adriamycin)]] as follows:
−
*[[Bleomycin (Blenoxane)]] 15 units IV on day 1
+
**Cycles 1 to 5: 37.5 mg/m<sup>2</sup>/day (maximum dose of 75 mg/day) IV continuous infusion over 48 hours, started on day 1 (total dose per cycle: 75 mg/m<sup>2</sup>)
−
*[[Vincristine (Oncovin)]] 1 mg IV on day 1
+
**Doses are held when patients are receiving concurrent radiation therapy (for example, held during cycles 2 and 3, if radiation therapy is initiated with cycle 2). The missed doses are then administered in a different cycle, to maintain a total regimen dose of 375 mg/m<sup>2</sup>. If doses are held in 2 of 6 cycles, a doxorubicin-only "Cycle 7" may be given 21 days following cycle 6. 
−
 
+
*[[Ifosfamide (Ifex)]] 3000 mg/m<sup>2</sup> IV over 3 hours once per day on days 1 to 3
−
'''14-day cycles x minimum of 2 cycles; given until complete remission, unacceptable toxicity, disease progression, patient refusal, or death'''
+
====Supportive therapy====
−
 
+
*[[Mesna (Mesnex)]] 600 mg/m<sup>2</sup> IV over 15 minutes once per day on days 1 to 3, given 15 minutes prior to each dose of ifosfamide, then at 3 hours, 6 hours, and 9 hours after start of ifosfamide
−
Supportive medications:
+
*Hydration:
−
*"No routine premedication was established by the protocol, but it could be provided at the discretion of the investigator"
+
**Before first ifosfamide infusion: D5 1/2 NS IV at rate of 200 mL/m<sup>2</sup>/hr IV until urine output > 2 mL/kg/hr
−
 
+
**With ifosfamide infusion: D5 1/2 NS with 10 mEq KCL/L IV at rate of 125 mL/m<sup>2</sup>/hr IV beginning immediately after ifosfamide infusion and continuing until next ifosfamide dose, or until 24 hours after last dose.
 +
*[[:Category:Granulocyte colony-stimulating factors|G-CSF]] (type not specified) 5 mcg/kg (max 480 mcg) SC once per day, starting on day 4, given until ANC is at least 2000/μL after nadir. Filgrastim should not be administered within 24 hours of chemotherapy.
 +
====Radiotherapy====
 +
*Concurrent [[External beam radiotherapy]] beginning with cycle 2
 +
'''21-day cycle for up to 6 cycles'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
* Definitive [[Surgery#Surgical_resection|resection]] of primary tumor after recovery from cycle 3 (week 13)
 +
* Definitive [[Surgery#Surgical_resection|resection]] of residual metastasis after completion of chemotherapy
 +
</div></div>
 
===References===
 
===References===
−
# Gill PS, Wernz J, Scadden DT, Cohen P, Mukwaya GM, von Roenn JH, Jacobs M,Kempin S, Silverberg I, Gonzales G, Rarick MU, Myers AM, Shepherd F, Sawka C, Pike MC, Ross ME. Randomized phase III trial of liposomal daunorubicin versus doxorubicin, bleomycin, and vincristine in AIDS-related Kaposi's sarcoma. J Clin Oncol. 1996 Aug;14(8):2353-64. [http://jco.ascopubs.org/content/14/8/2353.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/8708728 PubMed]
+
<!-- # '''Abstract:''' Venkatramani R, Anderson JR, Million L, Coffin CM, McCarville B, Randall RL, et al. Risk-based treatment for synovial sarcoma in patients under 30 years of age: Children’s Oncology Group study ARST0332. J Clin Oncol [Internet]. 2015;33(15). [https://doi.org/10.1200/jco.2015.33.15_suppl.10012 link to original abstract] -->
−
# Northfelt DW, Dezube BJ, Thommes JA, Miller BJ, Fischl MA, Friedman-Kien A, Kaplan LD, Du Mond C, Mamelok RD, Henry DH. Pegylated-liposomal doxorubicin versus doxorubicin, bleomycin, and vincristine in the treatment of AIDS-related Kaposi's sarcoma: results of a randomized phase III clinical trial. J Clin Oncol. 1998 Jul;16(7):2445-51. [http://jco.ascopubs.org/content/16/7/2445.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/9667262 PubMed]
+
#'''COG ARST0332:''' Spunt SL, Million L, Chi YY, Anderson J, Tian J, Hibbitts E, Coffin C, McCarville MB, Randall RL, Parham DM, Black JO, Kao SC, Hayes-Jordan A, Wolden S, Laurie F, Speights R, Kawashima E, Skapek SX, Meyer W, Pappo AS, Hawkins DS. A risk-based treatment strategy for non-rhabdomyosarcoma soft-tissue sarcomas in patients younger than 30 years (ARST0332): a Children's Oncology Group prospective study. Lancet Oncol. 2020 Jan;21(1):145-161. Epub 2019 Nov 27. [https://doi.org/10.1016/s1470-2045(19)30672-2 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6946838/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31786124/ PubMed] [https://clinicaltrials.gov/study/NCT00346164 NCT00346164]
−
 
+
==Epirubicin & Ifosfamide {{#subobject:820f20|Regimen=1}}==
−
==Bevacizumab (Avastin)==
+
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen, Uldrick et al. 2012===
+
===Regimen {{#subobject:55e5db|Variant=1}}===
−
====Loading dose====
+
{| class="wikitable sortable" style="width: 60%; text-align:center;"
−
*[[Bevacizumab (Avastin)]] 15 mg/kg IV once as a loading dose; start regular therapy 7 days later after this loading dose
+
!style="width: 33%"|Study
−
 
+
!style="width: 33%"|Dates of enrollment
−
====Regular therapy====
+
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
−
*[[Bevacizumab (Avastin)]] 15 mg/kg IV once on day 1
+
|-
−
 
+
|[https://doi.org/10.1200/jco.1998.16.4.1438 Reichardt et al. 1998]
−
'''21-day cycles, given until progression of disease requiring cytotoxic therapy, lack of adherence to protocol (including HAART), or patient-requested discontinuation'''
+
|1993-1996
−
 
+
| style="background-color:#91cf61" |Phase 2
−
Supportive medications:
+
|-
−
*"Antihypertensive therapy was initiated for systolic blood pressure greater than 160 mmHg or diastolic blood pressure greater than 95 mmHg persisting for more than 1 week or for systolic blood pressure greater than 210 mmHg or diastolic blood pressure greater than 120 mmHg at any time."
+
|}
−
*"HIV-positive patients with CD4 count of less than 200 cells/μL received Pneumocystis jiroveci prophylaxis."
+
<div class="toccolours" style="background-color:#b3e2cd">
−
*"Mycobacterium avium prophylaxis was considered if CD4 count was less than 75 cells/μL."
+
====Chemotherapy====
−
*Patients with HIV/AIDS continued HAART
+
*[[Epirubicin (Ellence)]] 45 mg/m<sup>2</sup>/day IV continuous infusion over 48 hours, started on day 2 (total dose per cycle: 90 mg/m<sup>2</sup>)
−
*[[Filgrastim (Neupogen)]] "used as clinically indicated"
+
*[[Ifosfamide (Ifex)]] 2500 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 12,500 mg/m<sup>2</sup>)
−
 
+
**Each day's dose is mixed with mesna in 3 liters of "fluids with electrolytes"
 +
====Supportive therapy====
 +
*[[Mesna (Mesnex)]] 1500 mg/m<sup>2</sup> IV continuous infusion over 120 hours, started on day 1, '''given with ifosfamide''' (total dose per cycle: 7500 mg/m<sup>2</sup>)
 +
*[[:Category:Granulocyte colony-stimulating factors|G-CSF]] (type not specified) 5 mcg/kg SC once per day on days 6 to 15 or "until recovery of leukocytes"
 +
*[[Ondansetron (Zofran)]] 8 to 24 mg/day (route not specified) prn nausea
 +
*[[Dexamethasone (Decadron)]] (dose/schedule not specified) for antiemesis if necessary
 +
'''21-day cycles'''
 +
</div></div>
 
===References===
 
===References===
−
# Uldrick TS, Wyvill KM, Kumar P, O'Mahony D, Bernstein W, Aleman K, Polizzotto MN, Steinberg SM, Pittaluga S, Marshall V, Whitby D, Little RF, Yarchoan R. Phase II study of bevacizumab in patients with HIV-associated Kaposi's sarcoma receiving antiretroviral therapy. J Clin Oncol. 2012 May 1;30(13):1476-83. doi: 10.1200/JCO.2011.39.6853. Epub 2012 Mar 19. [http://jco.ascopubs.org/content/30/13/1476.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/22430271 PubMed]
+
# Reichardt P, Tilgner J, Hohenberger P, Dörken B. Dose-intensive chemotherapy with ifosfamide, epirubicin, and filgrastim for adult patients with metastatic or locally advanced soft tissue sarcoma: a phase II study. J Clin Oncol. 1998 Apr;16(4):1438-43. [https://doi.org/10.1200/jco.1998.16.4.1438 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/9552049/ PubMed]
−
 
+
==Gemcitabine & Vinorelbine {{#subobject:4dd538|Regimen=1}}==
−
==Daunorubicin liposomal (DaunoXome)==
+
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen, Gill, et al. 1996===
+
===Regimen {{#subobject:b605f7|Variant=1}}===
−
*[[Daunorubicin liposomal (DaunoXome)]] 40 mg/m2 IV over 30 to 60 minutes on day 1
+
{| class="wikitable sortable" style="width: 60%; text-align:center;"
−
 
+
!style="width: 33%"|Study
−
'''14-day cycles x minimum of 2 cycles; given until complete remission, unacceptable toxicity, disease progression, patient refusal, or death'''
+
!style="width: 33%"|Dates of enrollment
−
 
+
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
−
Supportive medications:
+
|-
−
*"No routine premedication was established by the protocol, but it could be provided at the discretion of the investigator"
+
|[https://doi.org/10.1002/cncr.22609 Dileo et al. 2007]
−
 
+
|2003-2005
 +
| style="background-color:#91cf61" |Phase 2
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Gemcitabine (Gemzar)]] 800 mg/m<sup>2</sup> IV over 90 minutes once per day on days 1 & 8
 +
*[[Vinorelbine (Navelbine)]] 25 mg/m<sup>2</sup> IV over 10 minutes once per day on days 1 & 8
 +
'''21-day cycles'''
 +
</div></div>
 
===References===
 
===References===
−
# Gill PS, Wernz J, Scadden DT, Cohen P, Mukwaya GM, von Roenn JH, Jacobs M,Kempin S, Silverberg I, Gonzales G, Rarick MU, Myers AM, Shepherd F, Sawka C, Pike MC, Ross ME. Randomized phase III trial of liposomal daunorubicin versus doxorubicin, bleomycin, and vincristine in AIDS-related Kaposi's sarcoma. J Clin Oncol. 1996 Aug;14(8):2353-64. [http://jco.ascopubs.org/content/14/8/2353.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/8708728 PubMed]
+
# Dileo P, Morgan JA, Zahrieh D, Desai J, Salesi JM, Harmon DC, Quigley MT, Polson K, Demetri GD, George S. Gemcitabine and vinorelbine combination chemotherapy for patients with advanced soft tissue sarcomas: results of a phase II trial. Cancer. 2007 May 1;109(9):1863-9. [https://doi.org/10.1002/cncr.22609 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17385194/ PubMed]
−
 
+
==MAID {{#subobject:71cfab|Regimen=1}}==
−
==Doxorubicin liposomal (Doxil)==
+
MAID: '''<u>M</u>'''esna, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>I</u>'''fosfamide, '''<u>D</u>'''acarbazine
−
 
+
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen, Northfelt, et al. 1998===
+
===Regimen {{#subobject:156439|Variant=1}}===
−
*[[Doxorubicin liposomal (Doxil)]] 20 mg/m2 IV over 30 minues once on day 1
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"
−
 
+
!style="width: 20%"|Study
−
'''14-day cycles x up to 6 cycles'''
+
!style="width: 20%"|Dates of enrollment
−
 
+
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
−
Supportive medications:
+
!style="width: 20%"|Comparator
−
*"Colony-stimulating factors (CSFs) were prescribed at the discretion of the investigators."
+
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
−
 
+
|-
 +
|[https://doi.org/10.1200/JCO.1993.11.7.1276 Antman et al. 1993 (SWOG S8616)]
 +
|1987-1989
 +
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|[[Soft_tissue_sarcoma_-_historical#Dacarbazine_.26_Doxorubicin|AD]]
 +
| style="background-color:#fc8d59" |Seems to have inferior OS<sup>1</sup>
 +
|-
 +
|[https://doi.org/10.1007/s10637-008-9217-1 Fayette et al. 2009]
 +
|1994-1997
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#MAID|MAID]]; higher-intensity
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR
 +
|-
 +
|[https://doi.org/10.1093/annonc/mdr282 Bui-Nguyen et al. 2011]
 +
|2000-2008
 +
| style="background-color:#91cf61" |Non-randomized part of phase 3 RCT
 +
| style="background-color:#d3d3d3" |
 +
| style="background-color:#d3d3d3" |
 +
|-
 +
|}
 +
''<sup>1</sup>In SWOG S8616, although this arm seemed to have superior TTP, the control arm seemed to have superior OS.''<br>
 +
''Note: this was the ifosfamide dosing after a mid-protocol amendment due to excess myelosuppression.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Doxorubicin (Adriamycin)]] 15 mg/m<sup>2</sup>/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 60 mg/m<sup>2</sup>)
 +
*[[Ifosfamide (Ifex)]] 2000 mg/m<sup>2</sup>/day IV continuous infusion over 72 hours, started on day 1 (total dose per cycle: 6000 mg/m<sup>2</sup>)
 +
*[[Dacarbazine (DTIC)]] 250 mg/m<sup>2</sup>/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 1000 mg/m<sup>2</sup>)
 +
====Supportive therapy====
 +
*[[Mesna (Mesnex)]] 2500 mg/m<sup>2</sup>/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 10,000 mg/m<sup>2</sup>)
 +
'''21-day cycles'''
 +
</div></div>
 
===References===
 
===References===
−
# Northfelt DW, Dezube BJ, Thommes JA, Miller BJ, Fischl MA, Friedman-Kien A, Kaplan LD, Du Mond C, Mamelok RD, Henry DH. Pegylated-liposomal doxorubicin versus doxorubicin, bleomycin, and vincristine in the treatment of AIDS-related Kaposi's sarcoma: results of a randomized phase III clinical trial. J Clin Oncol. 1998 Jul;16(7):2445-51. [http://jco.ascopubs.org/content/16/7/2445.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/9667262 PubMed]
+
# '''SWOG S8616:''' Antman K, Crowley J, Balcerzak SP, Rivkin SE, Weiss GR, Elias A, Natale RB, Cooper RM, Barlogie B, Trump DL, Doroshow JH, Aisner J, Pugh RP, Weiss RB, Cooper BA, Clamond GH, Baker LH. An intergroup phase III randomized study of doxorubicin and dacarbazine with or without ifosfamide and mesna in advanced soft tissue and bone sarcomas. J Clin Oncol. 1993 Jul;11(7):1276-85. [https://doi.org/10.1200/JCO.1993.11.7.1276 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/8315425/ PubMed]
−
 
+
# Fayette J, Penel N, Chevreau C, Blay JY, Cupissol D, Thyss A, Guillemet C, Rios M, Rolland F, Fargeot P, Bay JO, Mathoulin-Pelissier S, Coindre JM, Bui-Nguyen B. Phase III trial of standard versus dose-intensified doxorubicin, ifosfamide and dacarbazine (MAID) in the first-line treatment of metastatic and locally advanced soft tissue sarcoma. Invest New Drugs. 2009 Oct;27(5):482-9. Epub 2009 Jan 16. [https://doi.org/10.1007/s10637-008-9217-1 link to original article] [https://pubmed.ncbi.nlm.nih.gov/19148579/ PubMed]
−
==Etoposide (Vepesid)==
+
# Bui-Nguyen B, Ray-Coquard I, Chevreau C, Penel N, Bay JO, Coindre JM, Cupissol D, Italiano A, Bonichon F, Lotz JP, Thyss A, Jimenez M, Mathoulin-Pélissier S, Blay JY; GSF-GETO. High-dose chemotherapy consolidation for chemosensitive advanced soft tissue sarcoma patients: an open-label, randomized controlled trial. Ann Oncol. 2012 Mar;23(3):777-84. Epub 2011 Jun 7. [https://doi.org/10.1093/annonc/mdr282 link to original article] [https://pubmed.ncbi.nlm.nih.gov/21652583/ PubMed]
−
===Regimen, Evans et al. 2002===
 
−
*[[Etoposide (Vepesid)]] 50 mg PO once daily on days 1 to 7
 
−
 
 
−
'''14-day cycles'''
 
  
−
===References===
+
[[Category:Soft tissue sarcoma regimens]]
−
# Evans SR, Krown SE, Testa MA, Cooley TP, Von Roenn JH. Phase II evaluation of low-dose oral etoposide for the treatment of relapsed or progressive AIDS-related Kaposi's sarcoma: an AIDS Clinical Trials Group clinical study. J Clin Oncol. 2002 Aug 1;20(15):3236-41. [http://jco.ascopubs.org/content/20/15/3236.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/12149296 PubMed]
+
[[Category:Disease-specific pages]]
 +
[[Category:Soft tissue sarcomas]]

Revision as of 00:12, 30 June 2024

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Section editor
Elizabethdavis2.jpg
 Elizabeth J. Davis, MD
Vanderbilt University
Nashville, TN, USA
19 regimens on this page
28 variants on this page

Are you looking for a regimen but can't find it here? It is possible that we've moved it to the historical regimens page. For placebo or observational studies in this condition, please visit this page. If you still can't find it, please let us know so we can add it!.
Note: this page is for subtype-nonspecific soft tissue sarcoma regimens, some subtypes with very few subtype-specific regimens, as well as for sarcomas that are not readily categorized. Please see the category page for links to other sarcoma types or use one of these links:


Guidelines

Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.

ESMO/EURACAN/GENTURIS

NCCN

Neoadjuvant therapy

Epirubicin & Ifosfamide

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Gronchi et al. 2012 2002-2007 Non-randomized part of phase 3 RCT
Gronchi et al. 2017 (ISG-STS 1001) 2011-2016 Phase 3 (C) Histotype-tailored therapy Did not meet primary endpoint of DFS1

1Reported efficacy for ISG-STS 1001 is based on the 2020 update.

Chemotherapy

Supportive therapy

  • Mesna (Mesnex) 1000 mg/m2 IV every 3 hours to every 4 hours on days 1 to 3

21-day cycle for 3 cycles

Subsequent treatment

References

  1. Gronchi A, Frustaci S, Mercuri M, Martin J, Lopez-Pousa A, Verderio P, Mariani L, Valagussa P, Miceli R, Stacchiotti S, Dei Tos AP, De Paoli A, Longhi A, Poveda A, Quagliuolo V, Comandone A, Casali PG, Picci P; Italian Sarcoma Group; Spanish Sarcoma Group. Short, full-dose adjuvant chemotherapy in high-risk adult soft tissue sarcomas: a randomized clinical trial from the Italian Sarcoma Group and the Spanish Sarcoma Group. J Clin Oncol. 2012 Mar 10;30(8):850-6. Epub 2012 Feb 6. link to original article contains dosing details in manuscript PubMed EudraCT 2004-003979-36
  2. ISG-STS 1001: Gronchi A, Ferrari S, Quagliuolo V, Broto JM, Pousa AL, Grignani G, Basso U, Blay JY, Tendero O, Beveridge RD, Ferraresi V, Lugowska I, Merlo DF, Fontana V, Marchesi E, Donati DM, Palassini E, Palmerini E, De Sanctis R, Morosi C, Stacchiotti S, Bagué S, Coindre JM, Dei Tos AP, Picci P, Bruzzi P, Casali PG. Histotype-tailored neoadjuvant chemotherapy versus standard chemotherapy in patients with high-risk soft-tissue sarcomas (ISG-STS 1001): an international, open-label, randomised, controlled, phase 3, multicentre trial. Lancet Oncol. 2017 Jun;18(6):812-822. Epub 2017 May 9. link to original article contains dosing details in abstract PubMed NCT01710176
    1. Update: Gronchi A, Palmerini E, Quagliuolo V, Martin Broto J, Lopez Pousa A, Grignani G, Brunello A, Blay JY, Tendero O, Diaz Beveridge R, Ferraresi V, Lugowska I, Merlo DF, Fontana V, Marchesi E, Braglia L, Donati DM, Palassini E, Bianchi G, Marrari A, Morosi C, Stacchiotti S, Bagué S, Coindre JM, Dei Tos AP, Picci P, Bruzzi P, Casali PG. Neoadjuvant Chemotherapy in High-Risk Soft Tissue Sarcomas: Final Results of a Randomized Trial From Italian (ISG), Spanish (GEIS), French (FSG), and Polish (PSG) Sarcoma Groups. J Clin Oncol. 2020 Jul 1;38(19):2178-2186. Epub 2020 May 18. link to original article PubMed

EIA

EIA: Etoposide, Ifosfamide, Adriamycin (Doxorubicin)

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Issels et al. 2010 (EORTC 62961/ESHO 95) 1997-2006 Phase 3 (C) EIA & regional hyperthermia Seems to have inferior OS

Chemotherapy

21-day cycle for 4 cycles

Subsequent treatment

References

  1. EORTC 62961/ESHO 95: Issels RD, Lindner LH, Verweij J, Wust P, Reichardt P, Schem BC, Abdel-Rahman S, Daugaard S, Salat C, Wendtner CM, Vujaskovic Z, Wessalowski R, Jauch KW, Dürr HR, Ploner F, Baur-Melnyk A, Mansmann U, Hiddemann W, Blay JY, Hohenberger P; EORTC Soft Tissue and Bone Sarcoma Group; European Society for Hyperthermic Oncology. Neo-adjuvant chemotherapy alone or with regional hyperthermia for localised high-risk soft-tissue sarcoma: a randomised phase 3 multicentre study. Lancet Oncol. 2010 Jun;11(6):561-70. Epub 2010 Apr 29. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00003052
    1. Update: Issels RD, Lindner LH, Verweij J, Wessalowski R, Reichardt P, Wust P, Ghadjar P, Hohenberger P, Angele M, Salat C, Vujaskovic Z, Daugaard S, Mella O, Mansmann U, Dürr HR, Knösel T, Abdel-Rahman S, Schmidt M, Hiddemann W, Jauch KW, Belka C, Gronchi A; European Organization for the Research and Treatment of Cancer-Soft Tissue and Bone Sarcoma Group; European Society for Hyperthermic Oncology. Effect of neoadjuvant chemotherapy plus regional hyperthermia on long-term outcomes among patients with localized high-risk soft tissue sarcoma: the EORTC 62961-ESHO 95 randomized clinical trial. JAMA Oncol. 2018 Apr 1;4(4):483-492. link to original article link to PMC article PubMed

Adjuvant therapy

EIA

EIA: Etoposide, Ifosfamide, Adriamycin (Doxorubicin)

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Issels et al. 2010 (EORTC 62961/ESHO 95) 1997-2006 Phase 3 (C) EIA & regional hyperthermia Seems to have inferior OS

Preceding treatment

Chemotherapy

21-day cycle for 4 cycles

References

  1. EORTC 62961/ESHO 95: Issels RD, Lindner LH, Verweij J, Wust P, Reichardt P, Schem BC, Abdel-Rahman S, Daugaard S, Salat C, Wendtner CM, Vujaskovic Z, Wessalowski R, Jauch KW, Dürr HR, Ploner F, Baur-Melnyk A, Mansmann U, Hiddemann W, Blay JY, Hohenberger P; EORTC Soft Tissue and Bone Sarcoma Group; European Society for Hyperthermic Oncology. Neo-adjuvant chemotherapy alone or with regional hyperthermia for localised high-risk soft-tissue sarcoma: a randomised phase 3 multicentre study. Lancet Oncol. 2010 Jun;11(6):561-70. Epub 2010 Apr 29. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00003052
    1. Update: Issels RD, Lindner LH, Verweij J, Wessalowski R, Reichardt P, Wust P, Ghadjar P, Hohenberger P, Angele M, Salat C, Vujaskovic Z, Daugaard S, Mella O, Mansmann U, Dürr HR, Knösel T, Abdel-Rahman S, Schmidt M, Hiddemann W, Jauch KW, Belka C, Gronchi A; European Organization for the Research and Treatment of Cancer-Soft Tissue and Bone Sarcoma Group; European Society for Hyperthermic Oncology. Effect of neoadjuvant chemotherapy plus regional hyperthermia on long-term outcomes among patients with localized high-risk soft tissue sarcoma: the EORTC 62961-ESHO 95 randomized clinical trial. JAMA Oncol. 2018 Apr 1;4(4):483-492. link to original article link to PMC article PubMed

Locally advanced or metastatic disease, single-agent regimens

Cisplatin monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Blay et al. 2015 (EFC10145) 2008-2012 Phase 3 (C) Cisplatin & Ombrabulin Seems to have inferior PFS

Note: PFS was very poor in both groups (less than 2 months); the difference was not considered clinically meaningful.

Chemotherapy

21-day cycles

References

  1. EFC10145: Blay JY, Pápai Z, Tolcher AW, Italiano A, Cupissol D, López-Pousa A, Chawla SP, Bompas E, Babovic N, Penel N, Isambert N, Staddon AP, Saâda-Bouzid E, Santoro A, Franke FA, Cohen P, Le-Guennec S, Demetri GD. Ombrabulin plus cisplatin versus placebo plus cisplatin in patients with advanced soft-tissue sarcomas after failure of anthracycline and ifosfamide chemotherapy: a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2015 May;16(5):531-40. Epub 2015 Apr 8. link to original article contains dosing details in manuscript PubMed NCT00699517

Dacarbazine monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Buesa et al. 1991 1984-1986 Phase 2
García-Del-Muro et al. 2011 2005-2008 Randomized Phase 2 (C) Dacarbazine & Gemcitabine Seems to have inferior OS

Chemotherapy

Supportive therapy

  • Buesa et al. 1991: Calcium gluconate (10% solution) 5 mL IV every 10 minutes x 3 doses (total of 15 mL) after the start of dacarbazine; 2 additional doses of calcium gluconate (10% solution) 5 mL IV every 10 minutes were given to patients whose systolic blood pressure decreased below 80 mmHg or heart rate more than 160 bpm.

21-day cycles

References

  1. Buesa JM, Mouridsen HT, van Oosterom AT, Verweij J, Wagener T, Steward W, Poveda A, Vestlev PM, Thomas D, Sylvester R; EORTC Soft Tissue and Bone Sarcoma Group. High-dose DTIC in advanced soft-tissue sarcomas in the adult: a phase II study of the EORTC Soft Tissue and Bone Sarcoma Group. Ann Oncol. 1991 Apr;2(4):307-9. link to original article contains dosing details in manuscript PubMed
  2. García-Del-Muro X, López-Pousa A, Maurel J, Martín J, Martínez-Trufero J, Casado A, Gómez-España A, Fra J, Cruz J, Poveda A, Meana A, Pericay C, Cubedo R, Rubió J, De Juan A, Laínez N, Carrasco JA, de Andrés R, Buesa JM; Spanish Group for Research on Sarcomas. Randomized phase II study comparing gemcitabine plus dacarbazine versus dacarbazine alone in patients with previously treated soft tissue sarcoma: a Spanish Group for Research on Sarcomas study. J Clin Oncol. 2011 Jun 20;29(18):2528-33. Epub 2011 May 23. link to original article contains dosing details in manuscript PubMed EudraCT 2005-001709-24
  3. APROMISS: NCT03016819

Doxorubicin monotherapy

Regimen variant #1, 75 mg/m2 x 6

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Cruz et al. 1979 (COG 7231A) NR Phase 3 (E-switch-ic) 1. Actinomycin & Melphalan
2. Melphalan & Vincristine
3. Melphalan & NSC-1026 		Superior ORR
Mouridsen et al. 1987 (EORTC 62801) 1980-1983 Phase 3 (E-switch-ic) Epirubicin Did not meet primary endpoint of ORR
Lorigan et al. 2007 (EORTC 62971) 1998-2001 Phase 3 (C) 1. Ifos 3 Did not meet primary endpoint of PFS
2. Ifos 9 Did not meet primary endpoint of PFS
Judson et al. 2014 (EORTC 62012) 2003-2010 Phase 3 (C) Doxorubicin & Ifosfamide; intensified Might have inferior OS
Blay et al. 2014 (CR015769) 2008-2012 Phase 3 (C) Trabectedin Did not meet primary endpoint of PFS
Ryan et al. 2016 (PICASSO III) 2010-2012 Phase 3 (C) Doxorubicin & Palifosfamide Did not meet primary endpoint of PFS
Seddon et al. 2017 (GeDDiS) 2010-2014 Phase 3 (C) Docetaxel & Gemcitabine Might have superior PFS
Tap et al. 2017 (TH CR-406/SARC021) 2011-2014 Phase 3 (C) Doxorubicin & Evofosfamide Did not meet primary endpoint of OS

Note: in EORTC 62801, treatment was given until progression of disease, unacceptable toxicity, or cumulative doxorubicin dosage of 550 mg/m2, though the ultimate decision to stop treatment based on cumulative doxorubicin dosage was at the discretion of the treating physician. Patients in CR015769 had translocation-related sarcomas.

Chemotherapy

21-day cycle for 6 cycles (see note)


Regimen variant #2, 75 mg/m2 x 8

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Blay et al. 2014 (CR015769) 2008-2012 Phase 3 (C) Trabectedin Did not meet primary endpoint of PFS
Tap et al. 2016 (CP15-0806) 2010-2013 Randomized Phase 2 (C) Doxorubicin & Olaratumab Inferior OS
Tap et al. 2020 (ANNOUNCE) 2015-2018 Phase 3 (C) Doxorubicin & Olaratumab Did not meet primary endpoint of OS

Note: Patients in CR015769 had translocation-related sarcomas.

Chemotherapy

Supportive therapy

21-day cycle for 8 cycles


Regimen variant #3, 75 mg/m2 indefinite

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Santoro et al. 1995 1985-1990 Phase 3 (C) 1. Doxorubicin & Ifosfamide
2. CYVADIC 		Did not meet endpoints of ORR/DOR/OS
Nielsen et al. 1998 NR Phase 3 (C) Epirubicin Did not meet primary endpoint of ORR

Chemotherapy

21-day cycles


Regimen variant #4, 80 mg/m2

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Edmonson et al. 1993 1987-1990 Phase 3 (C) 1. Doxorubicin & Ifosfamide Seems to have inferior ORR
2. MAC Might have inferior ORR

Chemotherapy

21-day cycles

References

  1. COG 7231A: Cruz AB Jr, Thames EA Jr, Aust JB, Metter G, Ramirez G, Fletcher WS, Altman SJ, Frelick RW, Hill GJ 2nd. Combination chemotherapy for soft-tissue sarcomas: a phase III study. J Surg Oncol. 1979;11(4):313-23. link to original article PubMed
  2. EORTC 62801: Mouridsen HT, Bastholt L, Somers R, Santoro A, Bramwell V, Mulder JH, van Oosterom AT, Buesa J, Pinedo HM, Thomas D, Sylvester R; EORTC Soft Tissue and Bone Sarcoma Group. Adriamycin versus epirubicin in advanced soft tissue sarcomas: a randomized phase II/phase III study of the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer Clin Oncol. 1987 Oct;23(10):1477-83. link to original article contains dosing details in manuscript PubMed
  3. Edmonson JH, Ryan LM, Blum RH, Brooks JS, Shiraki M, Frytak S, Parkinson DR. Randomized comparison of doxorubicin alone versus ifosfamide plus doxorubicin or mitomycin, doxorubicin, and cisplatin against advanced soft tissue sarcomas. J Clin Oncol. 1993 Jul;11(7):1269-75. link to original article contains dosing details in abstract PubMed
  4. Santoro A, Tursz T, Mouridsen H, Verweij J, Steward W, Somers R, Buesa J, Casali P, Spooner D, Rankin E, Kirkpatrick A, van Glabbeke M, van Oosterom A; EORTC Soft Tissue and Bone Sarcoma Group. Doxorubicin versus CYVADIC versus doxorubicin plus ifosfamide in first-line treatment of advanced soft tissue sarcomas: a randomized study of the European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group. J Clin Oncol. 1995 Jul;13(7):1537-45. link to original article PubMed
  5. Nielsen OS, Dombernowsky P, Mouridsen H, Crowther D, Verweij J, Buesa J, Steward W, Daugaard S, van Glabbeke M, Kirkpatrick A, Tursz T; EORTC soft tissue and bone sarcoma group. High-dose epirubicin is not an alternative to standard-dose doxorubicin in the treatment of advanced soft tissue sarcomas: a study of the EORTC soft tissue and bone sarcoma group. Br J Cancer. 1998 Dec;78(12):1634-9. linkt o original article link to PMC article contains dosing details in manuscript PubMed
  6. Meta-analysis: Bramwell VH, Anderson D, Charette ML. Doxorubicin-based chemotherapy for the palliative treatment of adult patients with locally advanced or metastatic soft-tissue sarcoma: a meta-analysis and clinical practice guideline. Sarcoma. 2000;4(3):103-12. link to original article link to PMC article PubMed
  7. EORTC 62971: Lorigan P, Verweij J, Papai Z, Rodenhuis S, Le Cesne A, Leahy MG, Radford JA, Van Glabbeke MM, Kirkpatrick A, Hogendoorn PC, Blay JY; EORTC Soft Tissue and Bone Sarcoma Group. Phase III trial of two investigational schedules of ifosfamide compared with standard-dose doxorubicin in advanced or metastatic soft tissue sarcoma: a European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group Study. J Clin Oncol. 2007 Jul 20;25(21):3144-50. link to original article contains dosing details in manuscript PubMed NCT00003212
  8. CR015769: Blay JY, Leahy MG, Nguyen BB, Patel SR, Hohenberger P, Santoro A, Staddon AP, Penel N, Piperno-Neumann S, Hendifar A, Lardelli P, Nieto A, Alfaro V, Chawla SP. Randomised phase III trial of trabectedin versus doxorubicin-based chemotherapy as first-line therapy in translocation-related sarcomas. Eur J Cancer. 2014 Apr;50(6):1137-47. Epub 2014 Feb 7. link to original article contains dosing details in abstract PubMed NCT00796120
  9. EORTC 62012: Judson I, Verweij J, Gelderblom H, Hartmann JT, Schöffski P, Blay JY, Kerst JM, Sufliarsky J, Whelan J, Hohenberger P, Krarup-Hansen A, Alcindor T, Marreaud S, Litière S, Hermans C, Fisher C, Hogendoorn PC, dei Tos AP, van der Graaf WT; European Organisation and Treatment of Cancer Soft Tissue and Bone Sarcoma Group. Doxorubicin alone versus intensified doxorubicin plus ifosfamide for first-line treatment of advanced or metastatic soft-tissue sarcoma: a randomised controlled phase 3 trial. Lancet Oncol. 2014 Apr;15(4):415-23. Epub 2014 Mar 5. link to original article PubMed NCT00061984
  10. CP15-0806: Tap WD, Jones RL, Van Tine BA, Chmielowski B, Elias AD, Adkins D, Agulnik M, Cooney MM, Livingston MB, Pennock G, Hameed MR, Shah GD, Qin A, Shahir A, Cronier DM, Ilaria R Jr, Conti I, Cosaert J, Schwartz GK. Olaratumab and doxorubicin versus doxorubicin alone for treatment of soft-tissue sarcoma: an open-label phase 1b and randomised phase 2 trial. Lancet. 2016 Jul 30;388(10043):488-97. Epub 2016 Jun 9. Erratum in: Lancet. 2016 Jul 30;388(10043):464. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01185964
  11. PICASSO III: Ryan CW, Merimsky O, Agulnik M, Blay JY, Schuetze SM, Van Tine BA, Jones RL, Elias AD, Choy E, Alcindor T, Keedy VL, Reed DR, Taub RN, Italiano A, Garcia Del Muro X, Judson IR, Buck JY, Lebel F, Lewis JJ, Maki RG, Schöffski P. PICASSO III: A Phase III, Placebo-Controlled Study of Doxorubicin With or Without Palifosfamide in Patients With Metastatic Soft Tissue Sarcoma. J Clin Oncol. 2016 Nov 10;34(32):3898-3905. Epub 2016 Sep 30. link to original article PubMed NCT01168791
  12. TH CR-406/SARC021: Tap WD, Papai Z, Van Tine BA, Attia S, Ganjoo KN, Jones RL, Schuetze S, Reed D, Chawla SP, Riedel RF, Krarup-Hansen A, Toulmonde M, Ray-Coquard I, Hohenberger P, Grignani G, Cranmer LD, Okuno S, Agulnik M, Read W, Ryan CW, Alcindor T, Del Muro XFG, Budd GT, Tawbi H, Pearce T, Kroll S, Reinke DK, Schöffski P. Doxorubicin plus evofosfamide versus doxorubicin alone in locally advanced, unresectable or metastatic soft-tissue sarcoma (TH CR-406/SARC021): an international, multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2017 Aug;18(8):1089-1103. Epub 2017 Jun 23. link to original article contains dosing details in abstract link to PMC article PubMed NCT01440088
  13. GeDDiS: Seddon B, Strauss SJ, Whelan J, Leahy M, Woll PJ, Cowie F, Rothermundt C, Wood Z, Benson C, Ali N, Marples M, Veal GJ, Jamieson D, Küver K, Tirabosco R, Forsyth S, Nash S, Dehbi HM, Beare S. Gemcitabine and docetaxel versus doxorubicin as first-line treatment in previously untreated advanced unresectable or metastatic soft-tissue sarcomas (GeDDiS): a randomised controlled phase 3 trial. Lancet Oncol. 2017 Oct;18(10):1397-1410. Epub 2017 Sep 4. link to original article link to PMC article contains dosing details in manuscript PubMed ISRCTN07742377
  14. ANNOUNCE: Tap WD, Wagner AJ, Schöffski P, Martin-Broto J, Krarup-Hansen A, Ganjoo KN, Yen CC, Abdul Razak AR, Spira A, Kawai A, Le Cesne A, Van Tine BA, Naito Y, Park SH, Fedenko A, Pápai Z, Soldatenkova V, Shahir A, Mo G, Wright J, Jones RL; ANNOUNCE Investigators. Effect of Doxorubicin Plus Olaratumab vs Doxorubicin Plus Placebo on Survival in Patients With Advanced Soft Tissue Sarcomas: The ANNOUNCE Randomized Clinical Trial. JAMA. 2020 Apr 7;323(13):1266-1276. link to original article link to PMC article contains dosing details in manuscript PubMed NCT02451943
  15. GERICO14: NCT04757337

Epirubicin monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Mouridsen et al. 1987 (EORTC 62801) 1980-1983 Phase 3 (E-switch-ic) Doxorubicin Did not meet primary endpoint of ORR

Chemotherapy

21-day cycle for up to 7 cycles (cumulative epirubicin dosage of 550 mg/m2) (though the ultimate decision to stop treatment based on cumulative epirubicin dosage was at the discretion of the treating physician)

References

  1. EORTC 62801: Mouridsen HT, Bastholt L, Somers R, Santoro A, Bramwell V, Mulder JH, van Oosterom AT, Buesa J, Pinedo HM, Thomas D, Sylvester R. Adriamycin versus epirubicin in advanced soft tissue sarcomas: a randomized phase II/phase III study of the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer Clin Oncol. 1987 Oct;23(10):1477-83. link to original article contains dosing details in manuscript PubMed

Ifosfamide monotherapy

Regimen variant #1, short infusion (Ifos 3)

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Lorigan et al. 2007 (EORTC 62971) 1998-2001 Phase 3 (E-switch-ic) 1. Doxorubicin Did not meet primary endpoint of PFS
2. Ifosfamide; Ifos 9 Did not meet primary endpoint of PFS

Chemotherapy

  • Ifosfamide (Ifex) 3000 mg/m2 IV over 4 hours on days 1 to 3, mixed with mesna in 1 liter of normal saline

Supportive therapy

  • Mesna (Mesnex) 600 mg/m2 IV bolus once on day 1, given immediately prior to mesna/ifosfamide infusion, then 1500 mg/m2 IV over 4 hours on days 1 to 3, given with ifosfamide, then 1200 mg/m2 IV twice per day on days 1 to 3, given at 4 and 8 hours after completion of ifosfamide and mesna
    • An alternative is to use oral mesna instead of intravenous: Mesna (Mesnex) 1200 mg/m2 PO twice per day on days 1 to 3, given at 2 and 6 hours after completion of ifosfamide and mesna
  • Sodium bicarbonate 150 mmol IV once per day on days 1 to 3
  • Patient with somnolence or other signs of encephalopathy with ifosfamide received methylene blue 50 mg IV every 4 hours until resolution of symptoms. During cycles thereafter, patients would receive methylene blue 50 mg IV every 4 hours, starting 4 hours prior to ifosfamide on day 1, continuing until 72 hours after completion

21-day cycle for up to 6 cycles


Regimen variant #2, continuous infusion (Ifos 9)

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Lorigan et al. 2007 (EORTC 62971) 1998-2001 Phase 3 (E-esc) 1. Doxorubicin Did not meet primary endpoint of PFS
2. Ifosfamide; Ifos 3 Did not meet primary endpoint of PFS

Chemotherapy

  • Ifosfamide (Ifex) 3000 mg/m2/day IV continuous infusion over 72 hours, started on day 1, given with mesna (total dose per cycle: 9000 mg/m2)
    • Each day's dose is mixed with mesna in 3 liters of normal saline

Supportive therapy

  • Mesna (Mesnex) 600 mg/m2 IV bolus once on day 1, given immediately prior to mesna/ifosfamide infusion, then 3000 mg/m2/day IV continuous infusion over 72 hours, starting on day 1, given with ifosfamide, then 1800 mg/m2 IV over 12 hours once on day 4, starting after completion of ifosfamide and mesna
    • An alternative is to use oral mesna instead of intravenous: Mesna (Mesnex) 1200 mg/m2 PO three times on day 4, given 0, 2, and 6 hours after completion of ifosfamide and mesna
  • Sodium bicarbonate 150 mmol IV once per day on days 1 to 3
  • Patient with somnolence or other signs of encephalopathy with ifosfamide received methylene blue 50 mg IV every 4 hours until resolution of symptoms. During cycles thereafter, patients would receive methylene blue 50 mg IV every 4 hours, starting 4 hours prior to ifosfamide on day 1, continuing until 72 hours after completion

21-day cycle for up to 6 cycles


Regimen variant #3

Study Dates of enrollment Evidence
van Oosterom et al. 2002 1992-1994 Phase 2

Chemotherapy

  • Ifosfamide (Ifex) 3000 mg/m2 IV over 4 hours once per day on days 1 to 3, dissolved in 125 mL sterile water per 1000 mg of ifosfamide, mixed with mesna in an additional 1 liter of dextrose/saline

Supportive therapy

  • Mesna (Mesnex) 600 mg/m2 IV bolus once on day 1, immediately prior to mesna/ifosfamide infusion, then 1500 mg/m2 IV over 4 hours on days 1 to 3, given with ifosfamide, then 500 mg/m2 IV twice per day on days 1 to 3, given at 4 and 8 hours after completion of ifosfamide and mesna
  • "Antiemetics were prescribed according to local conventions"
  • 1 liter of fluid PO twice per day on days 1 to 3, taken 4 and 8 hours after completion of ifosfamide and mesna

21-day cycle for at least 2 cycles, except in cases of rapid disease progression

References

  1. van Oosterom AT, Mouridsen HT, Nielsen OS, Dombernowsky P, Krzemieniecki K, Judson I, Svancarova L, Spooner D, Hermans C, Van Glabbeke M, Verweij J; EORTC Soft Tissue and Bone Sarcoma Group. Results of randomised studies of the EORTC Soft Tissue and Bone Sarcoma Group (STBSG) with two different ifosfamide regimens in first- and second-line chemotherapy in advanced soft tissue sarcoma patients. Eur J Cancer. 2002 Dec;38(18):2397-406. link to original article contains dosing details in manuscript PubMed content property of HemOnc.org
  2. EORTC 62971: Lorigan P, Verweij J, Papai Z, Rodenhuis S, Le Cesne A, Leahy MG, Radford JA, Van Glabbeke MM, Kirkpatrick A, Hogendoorn PC, Blay JY; EORTC Soft Tissue and Bone Sarcoma Group. Phase III trial of two investigational schedules of ifosfamide compared with standard-dose doxorubicin in advanced or metastatic soft tissue sarcoma: a European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group Study. J Clin Oncol. 2007 Jul 20;25(21):3144-50. link to original article contains dosing details in manuscript PubMed NCT00003212

Pazopanib monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
van der Graaf et al. 2012 (PALETTE) 2008-2010 Phase 3 (E-RT-esc) Placebo Superior PFS (primary endpoint)
Median PFS: 4.6 vs 1.6 mo
(HR 0.31, 95% CI 0.24-0.40)

Targeted therapy

28-day cycles

References

  1. PALETTE: van der Graaf WT, Blay JY, Chawla SP, Kim DW, Bui-Nguyen B, Casali PG, Schöffski P, Aglietta M, Staddon AP, Beppu Y, Le Cesne A, Gelderblom H, Judson IR, Araki N, Ouali M, Marreaud S, Hodge R, Dewji MR, Coens C, Demetri GD, Fletcher CD, Dei Tos AP, Hohenberger P; EORTC Soft Tissue and Bone Sarcoma Group; PALETTE study group. Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2012 May 19;379(9829):1879-86. Epub 2012 May 16. link to original article contains dosing details in manuscript PubMed NCT00753688
    1. Subgroup analysis: Kawai A, Araki N, Hiraga H, Sugiura H, Matsumine A, Ozaki T, Ueda T, Ishii T, Esaki T, Machida M, Fukasawa N. A randomized, double-blind, placebo-controlled, phase III study of pazopanib in patients with soft tissue sarcoma: results from the Japanese subgroup. Jpn J Clin Oncol. 2016 Mar;46(3):248-53. Epub 2016 Feb 10. link to original article link to PMC article PubMed

Regorafenib monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Mir et al. 2016 (REGOSARC) 2013-08-05 to 2014-11-26 Randomized Phase 2 (E-esc) Placebo Superior PFS (primary endpoint)

Note: reported efficacy is for the leiomyosarcoma, synovial sarcoma, and other sarcoma cohorts; there was no significant difference in outcome for the liposarcoma cohort.

Targeted therapy

28-day cycles

References

  1. REGOSARC: Mir O, Brodowicz T, Italiano A, Wallet J, Blay JY, Bertucci F, Chevreau C, Piperno-Neumann S, Bompas E, Salas S, Perrin C, Delcambre C, Liegl-Atzwanger B, Toulmonde M, Dumont S, Ray-Coquard I, Clisant S, Taieb S, Guillemet C, Rios M, Collard O, Bozec L, Cupissol D, Saada-Bouzid E, Lemaignan C, Eisterer W, Isambert N, Chaigneau L, Cesne AL, Penel N. Safety and efficacy of regorafenib in patients with advanced soft tissue sarcoma (REGOSARC): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol. 2016 Dec;17(12):1732-1742. Epub 2016 Oct 14. link to original article contains dosing details in abstract PubMed NCT01900743

Temozolomide monotherapy

Regimen variant #1, 5 out of 28 days

Study Dates of enrollment Evidence
Talbot et al. 2003 1998-2000 Phase 2

Note: patients on study could be reconsented to receive therapy beyond 1 year. Treatment given on an empty stomach, and doses rounded up if needed to next available dosage based on capsule doses.

Chemotherapy

  • Temozolomide (Temodar) 200 mg/m2 PO once on day 1, then 90 mg/m2 PO every 12 hours on days 1 to 5 (total of 10 doses per cycle)

Supportive therapy

  • Antiemetics "prescribed as clinically indicated by the treating physician"

28-day cycle for up to 13 cycles (1 year)


Regimen variant #2, 6 out of 9 weeks

Study Dates of enrollment Evidence
Garcia del Muro et al. 2005 1999-2001 Phase 2

Note: Initial dose used in the study was 75 mg/m2, but due to lack of toxicity, protocol was amended to use 100 mg/m2 doses.

Chemotherapy

  • Temozolomide (Temodar) 100 mg/m2 PO once per day on days 1 to 42 (no food within 1 hour before and after temozolomide doses)

Supportive therapy

9-week cycle for up to 3 cycles

References

  1. Talbot SM, Keohan ML, Hesdorffer M, Orrico R, Bagiella E, Troxel AB, Taub RN. A phase II trial of temozolomide in patients with unresectable or metastatic soft tissue sarcoma. Cancer. 2003 Nov 1;98(9):1942-6. link to original article contains dosing details in manuscript PubMed
  2. Garcia del Muro X, Lopez-Pousa A, Martin J, Buesa JM, Martinez-Trufero J, Casado A, Poveda A, Cruz J, Bover I, Maurel J; Spanish Group for Research on Sarcomas. A phase II trial of temozolomide as a 6-week, continuous, oral schedule in patients with advanced soft tissue sarcoma: a study by the Spanish Group for Research on Sarcomas. Cancer. 2005 Oct 15;104(8):1706-12. link to original article contains dosing details in manuscript PubMed

Trabectedin monotherapy

Regimen variant #1, 1.2 mg/m2

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Kawai et al. 2015 2012-2014 Randomized Phase 2 (E-esc) Placebo Superior PFS (primary endpoint)
Median PFS: 5.6 vs 0.9 mo
(HR 0.07, 95% CI 0.03-0.16)

Chemotherapy

21-day cycles


Regimen variant #2, 1.5 mg/m2

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Le Cesne et al. 2021 (T-SAR) 2015-01-26 to 2015-11-05 Phase 3 (E-esc) Best supportive care Superior PFS (primary endpoint)
Median PFS: 3.1 vs 1.5 mo
(HR 0.39, 95% CI 0.24-0.64)

Chemotherapy

21-day cycles

References

  1. Kawai A, Araki N, Sugiura H, Ueda T, Yonemoto T, Takahashi M, Morioka H, Hiraga H, Hiruma T, Kunisada T, Matsumine A, Tanase T, Hasegawa T, Takahashi S. Trabectedin monotherapy after standard chemotherapy versus best supportive care in patients with advanced, translocation-related sarcoma: a randomised, open-label, phase 2 study. Lancet Oncol. 2015 Apr;16(4):406-16. Epub 2015 Mar 18. link to original article contains dosing details in abstract PubMed JapicCTI-121850
  2. T-SAR: Le Cesne A, Blay JY, Cupissol D, Italiano A, Delcambre C, Penel N, Isambert N, Chevreau C, Bompas E, Bertucci F, Chaigneau L, Piperno-Neumann S, Salas S, Rios M, Guillemet C, Bay JO, Ray-Coquard I, Haddag L, Bonastre J, Kapso R, Fraslin A, Bouvet N, Mir O, Foulon S. A randomized phase III trial comparing trabectedin to best supportive care in patients with pre-treated soft tissue sarcoma: T-SAR, a French Sarcoma Group trial. Ann Oncol. 2021 Aug;32(8):1034-1044. Epub 2021 Apr 29. link to original article contains dosing details in manuscript PubMed NCT02672527

Locally advanced or metastatic disease, combination regimens

Dacarbazine & Gemcitabine

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
García-Del-Muro et al. 2011 2005-2008 Randomized Phase 2, fewer than 20 pts in this subgroup (E-esc) Dacarbazine Seems to have superior OS (secondary endpoint)

Chemotherapy

14-day cycle for at least 12 cycles

References

  1. García-Del-Muro X, López-Pousa A, Maurel J, Martín J, Martínez-Trufero J, Casado A, Gómez-España A, Fra J, Cruz J, Poveda A, Meana A, Pericay C, Cubedo R, Rubió J, De Juan A, Laínez N, Carrasco JA, de Andrés R, Buesa JM; Spanish Group for Research on Sarcomas. Randomized phase II study comparing gemcitabine plus dacarbazine versus dacarbazine alone in patients with previously treated soft tissue sarcoma: a Spanish Group for Research on Sarcomas study. J Clin Oncol. 2011 Jun 20;29(18):2528-33. Epub 2011 May 23. link to original article contains dosing details in manuscript PubMed EudraCT 2005-001709-24

Docetaxel & Gemcitabine

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Seddon et al. 2017 (GeDDiS) 2010-2014 Phase 3 (E-switch-ic) Doxorubicin Might have inferior PFS (secondary endpoint)

Chemotherapy

Supportive therapy

  • Dexamethasone (Decadron) 8 mg PO twice per day on days 7 to 9 (the day before, the day of, and day after docetaxel)
  • Patients could receive diuretics at physician discretion for peripheral edema related to docetaxel
  • One of the following growth factors (varies depending on reference):
    • G-CSF (type not specified) 150 mcg/m2 (dose rounded to 300 or 480 mcg) SC once per day on days 9 to 15 as primary neutropenia prophylaxis; could be stopped before day 15 if ANC greater than 1200/μL on two separate measurements
    • Pegfilgrastim (Neulasta) 6 mg SC once on either day 9 or 10

21-day cycle for 6 to 8 cycles

References

  1. GeDDiS: Seddon B, Strauss SJ, Whelan J, Leahy M, Woll PJ, Cowie F, Rothermundt C, Wood Z, Benson C, Ali N, Marples M, Veal GJ, Jamieson D, Küver K, Tirabosco R, Forsyth S, Nash S, Dehbi HM, Beare S. Gemcitabine and docetaxel versus doxorubicin as first-line treatment in previously untreated advanced unresectable or metastatic soft-tissue sarcomas (GeDDiS): a randomised controlled phase 3 trial. Lancet Oncol. 2017 Oct;18(10):1397-1410. Epub 2017 Sep 4. link to original article link to PMC article contains dosing details in manuscript PubMed ISRCTN07742377

Doxorubicin & Ifosfamide

AIM: Adriamycin (Doxorubicin), Ifosfamide, Mesna

Regimen variant #1, 50/5000

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Le Cesne et al. 2000 (EORTC 62903) 1992-1995 Phase 3 (C) AIM; 75/5000 Did not meet primary endpoint of ORR

Chemotherapy

21-day cycles


Regimen variant #2, 5-day course, lower dose doxorubicin - AI 75/10,000

Study Dates of enrollment Evidence
Patel et al. 1998 1995-1996 Pilot, fewer than 20 patients reported

Chemotherapy

Supportive therapy

  • Mesna (Mesnex) 400 mg/m2 IV once on day 1, given simultaneously with the first dose of ifosfamide, then 1200 mg/m2/day IV continuous infusion over 120 hours
    • Each day's dose is given in 2 liters of D5W with 100 mEq/L sodium acetate, 20 mEq/L potassium acetate, and 4 mEq/L magnesium sulfate
  • If febrile neutropenia occurs, G-CSF is used in subsequent cycles

21-day cycle for up to 6 cycles


Regimen variant #3, 4-day course, higher dose doxorubicin - AI 90/10,000

Study Dates of enrollment Evidence
Patel et al. 1998 1995-1996 Pilot, fewer than 20 patients reported

Chemotherapy

Supportive therapy

  • Mesna (Mesnex) 500 mg/m2 IV once on day 1, given simultaneously with the first dose of ifosfamide, then 1500 mg/m2/day IV continuous infusion over 96 hours
      • Each day's dose is given in 2 liters of D5W with 100 mEq/L sodium acetate, 20 mEq/L potassium acetate, and 4 mEq/L magnesium sulfate
  • G-CSF (type not specified) 5 mcg/kg (dose rounded to 300 or 480 mcg) SC once per day, starting on day 5, given until ANC is at least 10,000/μL

21-day cycle for up to 6 cycles

References

  1. Patel SR, Vadhan-Raj S, Burgess MA, Plager C, Papadopolous N, Jenkins J, Benjamin RS. Results of two consecutive trials of dose-intensive chemotherapy with doxorubicin and ifosfamide in patients with sarcomas. Am J Clin Oncol. 1998 Jun;21(3):317-21. link to original article contains dosing details in manuscript PubMed
  2. EORTC 62903: Le Cesne A, Judson I, Crowther D, Rodenhuis S, Keizer HJ, Van Hoesel Q, Blay JY, Frisch J, Van Glabbeke M, Hermans C, Van Oosterom A, Tursz T, Verweij J. Randomized phase III study comparing conventional-dose doxorubicin plus ifosfamide versus high-dose doxorubicin plus ifosfamide plus recombinant human granulocyte-macrophage colony-stimulating factor in advanced soft tissue sarcomas: A trial of the European Organisation for Research and Treatment of Cancer/Soft Tissue and Bone Sarcoma Group. J Clin Oncol. 2000 Jul;18(14):2676-84. link to original article contains dosing details in abstract PubMed

Doxorubicin, Ifosfamide, RT

AIM & RT: Adriamycin (Doxorubicin), Ifosfamide, Mesna, Radiation Therapy

Regimen

Study Dates of enrollment Evidence
Spunt et al. 2019 (COG ARST0332 Arm D) 2007-2012 Phase 3b

Note: Regimen details are derived from ClinicalTrials.gov.

Chemotherapy

  • Doxorubicin (Adriamycin) as follows:
    • Cycles 1 to 5: 37.5 mg/m2/day (maximum dose of 75 mg/day) IV continuous infusion over 48 hours, started on day 1 (total dose per cycle: 75 mg/m2)
    • Doses are held when patients are receiving concurrent radiation therapy (for example, held during cycles 2 and 3, if radiation therapy is initiated with cycle 2). The missed doses are then administered in a different cycle, to maintain a total regimen dose of 375 mg/m2. If doses are held in 2 of 6 cycles, a doxorubicin-only "Cycle 7" may be given 21 days following cycle 6.
  • Ifosfamide (Ifex) 3000 mg/m2 IV over 3 hours once per day on days 1 to 3

Supportive therapy

  • Mesna (Mesnex) 600 mg/m2 IV over 15 minutes once per day on days 1 to 3, given 15 minutes prior to each dose of ifosfamide, then at 3 hours, 6 hours, and 9 hours after start of ifosfamide
  • Hydration:
    • Before first ifosfamide infusion: D5 1/2 NS IV at rate of 200 mL/m2/hr IV until urine output > 2 mL/kg/hr
    • With ifosfamide infusion: D5 1/2 NS with 10 mEq KCL/L IV at rate of 125 mL/m2/hr IV beginning immediately after ifosfamide infusion and continuing until next ifosfamide dose, or until 24 hours after last dose.
  • G-CSF (type not specified) 5 mcg/kg (max 480 mcg) SC once per day, starting on day 4, given until ANC is at least 2000/μL after nadir. Filgrastim should not be administered within 24 hours of chemotherapy.

Radiotherapy

21-day cycle for up to 6 cycles

Subsequent treatment

  • Definitive resection of primary tumor after recovery from cycle 3 (week 13)
  • Definitive resection of residual metastasis after completion of chemotherapy

References

  1. COG ARST0332: Spunt SL, Million L, Chi YY, Anderson J, Tian J, Hibbitts E, Coffin C, McCarville MB, Randall RL, Parham DM, Black JO, Kao SC, Hayes-Jordan A, Wolden S, Laurie F, Speights R, Kawashima E, Skapek SX, Meyer W, Pappo AS, Hawkins DS. A risk-based treatment strategy for non-rhabdomyosarcoma soft-tissue sarcomas in patients younger than 30 years (ARST0332): a Children's Oncology Group prospective study. Lancet Oncol. 2020 Jan;21(1):145-161. Epub 2019 Nov 27. link to original article link to PMC article PubMed NCT00346164

Epirubicin & Ifosfamide

Regimen

Study Dates of enrollment Evidence
Reichardt et al. 1998 1993-1996 Phase 2

Chemotherapy

  • Epirubicin (Ellence) 45 mg/m2/day IV continuous infusion over 48 hours, started on day 2 (total dose per cycle: 90 mg/m2)
  • Ifosfamide (Ifex) 2500 mg/m2/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 12,500 mg/m2)
    • Each day's dose is mixed with mesna in 3 liters of "fluids with electrolytes"

Supportive therapy

  • Mesna (Mesnex) 1500 mg/m2 IV continuous infusion over 120 hours, started on day 1, given with ifosfamide (total dose per cycle: 7500 mg/m2)
  • G-CSF (type not specified) 5 mcg/kg SC once per day on days 6 to 15 or "until recovery of leukocytes"
  • Ondansetron (Zofran) 8 to 24 mg/day (route not specified) prn nausea
  • Dexamethasone (Decadron) (dose/schedule not specified) for antiemesis if necessary

21-day cycles

References

  1. Reichardt P, Tilgner J, Hohenberger P, Dörken B. Dose-intensive chemotherapy with ifosfamide, epirubicin, and filgrastim for adult patients with metastatic or locally advanced soft tissue sarcoma: a phase II study. J Clin Oncol. 1998 Apr;16(4):1438-43. link to original article contains dosing details in manuscript PubMed

Gemcitabine & Vinorelbine

Regimen

Study Dates of enrollment Evidence
Dileo et al. 2007 2003-2005 Phase 2

Chemotherapy

21-day cycles

References

  1. Dileo P, Morgan JA, Zahrieh D, Desai J, Salesi JM, Harmon DC, Quigley MT, Polson K, Demetri GD, George S. Gemcitabine and vinorelbine combination chemotherapy for patients with advanced soft tissue sarcomas: results of a phase II trial. Cancer. 2007 May 1;109(9):1863-9. link to original article contains dosing details in manuscript PubMed

MAID

MAID: Mesna, Adriamycin (Doxorubicin), Ifosfamide, Dacarbazine

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Antman et al. 1993 (SWOG S8616) 1987-1989 Phase 3 (E-esc) AD Seems to have inferior OS1
Fayette et al. 2009 1994-1997 Phase 3 (C) MAID; higher-intensity Did not meet primary endpoint of ORR
Bui-Nguyen et al. 2011 2000-2008 Non-randomized part of phase 3 RCT

1In SWOG S8616, although this arm seemed to have superior TTP, the control arm seemed to have superior OS.
Note: this was the ifosfamide dosing after a mid-protocol amendment due to excess myelosuppression.

Chemotherapy

  • Doxorubicin (Adriamycin) 15 mg/m2/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 60 mg/m2)
  • Ifosfamide (Ifex) 2000 mg/m2/day IV continuous infusion over 72 hours, started on day 1 (total dose per cycle: 6000 mg/m2)
  • Dacarbazine (DTIC) 250 mg/m2/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 1000 mg/m2)

Supportive therapy

  • Mesna (Mesnex) 2500 mg/m2/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 10,000 mg/m2)

21-day cycles

References

  1. SWOG S8616: Antman K, Crowley J, Balcerzak SP, Rivkin SE, Weiss GR, Elias A, Natale RB, Cooper RM, Barlogie B, Trump DL, Doroshow JH, Aisner J, Pugh RP, Weiss RB, Cooper BA, Clamond GH, Baker LH. An intergroup phase III randomized study of doxorubicin and dacarbazine with or without ifosfamide and mesna in advanced soft tissue and bone sarcomas. J Clin Oncol. 1993 Jul;11(7):1276-85. link to original article contains dosing details in manuscript PubMed
  2. Fayette J, Penel N, Chevreau C, Blay JY, Cupissol D, Thyss A, Guillemet C, Rios M, Rolland F, Fargeot P, Bay JO, Mathoulin-Pelissier S, Coindre JM, Bui-Nguyen B. Phase III trial of standard versus dose-intensified doxorubicin, ifosfamide and dacarbazine (MAID) in the first-line treatment of metastatic and locally advanced soft tissue sarcoma. Invest New Drugs. 2009 Oct;27(5):482-9. Epub 2009 Jan 16. link to original article PubMed
  3. Bui-Nguyen B, Ray-Coquard I, Chevreau C, Penel N, Bay JO, Coindre JM, Cupissol D, Italiano A, Bonichon F, Lotz JP, Thyss A, Jimenez M, Mathoulin-Pélissier S, Blay JY; GSF-GETO. High-dose chemotherapy consolidation for chemosensitive advanced soft tissue sarcoma patients: an open-label, randomized controlled trial. Ann Oncol. 2012 Mar;23(3):777-84. Epub 2011 Jun 7. link to original article PubMed
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