Soft tissue sarcoma

Section editor
	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:

• Alveolar soft part sarcoma (ASPS)
• Dermatofibrosarcoma protuberans
• Desmoid tumors
• Epithelioid sarcoma
• Gastrointestinal stromal tumor (GIST)
• Inflammatory myofibroblastic tumor (IMT)
• Leiomyosarcoma
• Liposarcoma
• PEComa
• Rhabdomyosarcoma
• Tenosynovial giant cell tumor (TGCT)

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. Soft tissue and visceral sarcomas: ESMO–EURACAN–GENTURIS Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed
  • 2018: Casali et al. Soft tissue and visceral sarcomas: ESMO–EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed
  • 2014: Soft tissue and visceral sarcomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed
  • 2010: Casali & Blay. Soft tissue sarcomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed
  • 2009: Casali et al. Soft tissue sarcomas: ESMO clinical recommendations for diagnosis, treatment and follow-up PubMed
  • 2007: Leyvraz. Soft tissue sarcomas: ESMO clinical recommendations for diagnosis, treatment and follow-up PubMed
  • 2005: Leyvraz & Jelic. ESMO Minimum Clinical Recommendations for diagnosis, treatment and follow-up of soft tissue sarcomas PubMed

NCCN

• NCCN Guidelines - Soft Tissue Sarcoma
  • 2022: von Mehren et al. Soft Tissue Sarcoma, Version 2.2022, NCCN Clinical Practice Guidelines in Oncology. PubMed
  • 2016: von Mehren et al. Soft Tissue Sarcoma, Version 2.2016, NCCN Clinical Practice Guidelines in Oncology. PubMed
  • 2014: von Mehren et al. Soft tissue sarcoma, version 2.2014. PubMed
  • 2010: Demetri et al. Soft tissue sarcoma. PubMed
  • 2007: Demetri et al. Soft tissue sarcoma. PubMed
  • 2005: Demetri et al. [ Soft tissue sarcoma clinical practice guidelines in oncology.] PubMed

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

• Epirubicin (Ellence) 60 mg/m² IV once per day on days 1 & 2
• Ifosfamide (Ifex) 3000 mg/m² IV once per day on days 1 to 3

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

• Gronchi et al. 2012: Surgery, then adjuvant EI x 2 versus no further treatment
• ISG-STS 1001: Surgery

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

• Etoposide (Vepesid) 125 mg/m² IV once per day on days 1 & 4
• Ifosfamide (Ifex) 1500 mg/m² IV once per day on days 1 to 4
• Doxorubicin (Adriamycin) 50 mg/m² IV once on day 1

21-day cycle for 4 cycles

Subsequent treatment

• Surgery, then RT, then adjuvant EIA x 4

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

• Neoadjuvant EIA x 4, then surgery, then adjuvant RT

Chemotherapy

• Etoposide (Vepesid) 125 mg/m² IV once per day on days 1 & 4
• Ifosfamide (Ifex) 1500 mg/m² IV once per day on days 1 to 4
• Doxorubicin (Adriamycin) 50 mg/m² IV once on day 1

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

• Cisplatin (Platinol) 75 mg/m² IV over 120 minutes once on day 1

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

• Dacarbazine (DTIC) 1200 mg/m² 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

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

• Doxorubicin (Adriamycin) 75 mg/m² IV bolus once on day 1

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

• Doxorubicin (Adriamycin) 75 mg/m² 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

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

• Doxorubicin (Adriamycin) 75 mg/m² IV bolus once on day 1

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

• Doxorubicin (Adriamycin) 80 mg/m² IV bolus once on day 1

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

• Epirubicin (Ellence) 75 mg/m² IV bolus once on day 1

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

• Pazopanib (Votrient) 800 mg PO once per day on days 1 to 28

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

• Regorafenib (Stivarga) 160 mg PO once per day on days 1 to 21

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

• "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

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

• Trabectedin (Yondelis) 1.2 mg/m² IV continuous infusion over 24 hours, started on day 1

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

• Trabectedin (Yondelis) 1.5 mg/m² IV continuous infusion over 24 hours, started on day 1

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

• Dacarbazine (DTIC) 500 mg/m² IV over 20 minutes once on day 1, given second
• Gemcitabine (Gemzar) 1800 mg/m² IV at fixed dosed rate over 3 hours once on day 1, given first

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

• Docetaxel (Taxotere) 75 mg/m² IV over 60 minutes once on day 8, given second
• Gemcitabine (Gemzar) 675 mg/m² 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):
  • 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

• Doxorubicin (Adriamycin) 50 mg/m² IV once on day 1
• Ifosfamide (Ifex) 5000 mg/m² IV once on day 1

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

• Doxorubicin (Adriamycin) 25 mg/m²/day IV continuous infusion over 72 hours, started on day 1 (total dose per cycle: 75 mg/m²)
• Ifosfamide (Ifex) 2000 mg/m² IV over 2 hours once per day on days 1 to 5

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

• Doxorubicin (Adriamycin) 30 mg/m²/day IV continuous infusion over 72 hours, started on day 1 (total dose per cycle: 90 mg/m²)
• Ifosfamide (Ifex) 2500 mg/m² IV over 3 hours once per day on days 1 to 4

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

• Concurrent External beam radiotherapy beginning with cycle 2

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

• Gemcitabine (Gemzar) 800 mg/m² IV over 90 minutes once per day on days 1 & 8
• Vinorelbine (Navelbine) 25 mg/m² IV over 10 minutes once per day on days 1 & 8

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