Difference between revisions of "Soft tissue sarcoma"

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Revision as of 15:11, 5 April 2018


Section editor
Jim chen.jpeg
 James L. Chen, MD, MS
Columbus, OH
LinkedIn
19 regimens on this page
28 variants on this page


Note: this page is for subtype-nonspecific soft tissue sarcoma regimens, as well as for sarcomas that are not readily categorized, e.g., alveolar soft part sarcoma. Please see the category page for links to other sarcoma types.

Guidelines

ESMO

NCCN

Neoadjuvant therapy

Epirubicin & Ifosfamide

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Regimen

Study Evidence Comparator Efficacy
Gronchi et al. 2017 (ISG-STS 1001) Phase III Histotype-tailored therapy Seems not superior

Chemotherapy

Supportive medications

21-day cycle for 3 cycles, followed by surgery

References

  1. 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 protocol PubMed

Locally advanced or metastatic disease, single-agent regimens

Cisplatin monotherapy

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Regimen

Study Evidence Comparator Efficacy
Blay et al. 2015 Phase III (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. 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 protocol PubMed

Dacarbazine monotherapy

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Variant #1, 850 mg/m2

Study Evidence Comparator Efficacy
Schöffski et al. 2016 Phase III Eribulin Seems to have inferior OS

Chemotherapy

21-day cycles

Variant #2, 1000 mg/m2

Study Evidence Comparator Efficacy
Demetri et al. 2015 Phase III Trabectedin Inferior PFS
Schöffski et al. 2016 Phase III Eribulin Seems to have inferior OS

Note: this is listed as a "starting dose" in Demetri et al. 2015, but no adjustment instructions were provided in the manuscript.

Chemotherapy

21-day cycles

Variant #3, 1200 mg/m2

Study Evidence Comparator Efficacy
Buesa et al. 1991 Phase II
García-Del-Muro et al. 2011 Randomized phase II Dacarbazine & Gemcitabine Seems to have inferior OS
Schöffski et al. 2016 Phase III Eribulin Seems to have inferior OS

Chemotherapy

Supportive medications

  • 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. 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. link to original article contains verified protocol 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 verified protocol PubMed
  3. Demetri GD, von Mehren M, Jones RL, Hensley ML, Schuetze SM, Staddon A, Milhem M, Elias A, Ganjoo K, Tawbi H, Van Tine BA, Spira A, Dean A, Khokhar NZ, Park YC, Knoblauch RE, Parekh TV, Maki RG, Patel SR. Efficacy and safety of trabectedin or dacarbazine for metastatic liposarcoma or leiomyosarcoma after failure of conventional chemotherapy: results of a phase III randomized multicenter clinical trial. J Clin Oncol. 2016 Mar 10;34(8):786-93. Epub 2015 Sep 14. link to original article contains verified protocol link to PMC article PubMed
    1. Subgroup analysis: Hensley ML, Patel SR, von Mehren M, Ganjoo K, Jones RL, Staddon A, Rushing D, Milhem M, Monk B, Wang G, McCarthy S, Knoblauch RE, Parekh TV, Maki RG, Demetri GD. Efficacy and safety of trabectedin or dacarbazine in patients with advanced uterine leiomyosarcoma after failure of anthracycline-based chemotherapy: Subgroup analysis of a phase 3, randomized clinical trial. Gynecol Oncol. 2017 Sep;146(3):531-537. Epub 2017 Jun 24. PubMed
  4. Schöffski P, Chawla S, Maki RG, Italiano A, Gelderblom H, Choy E, Grignani G, Camargo V, Bauer S, Rha SY, Blay JY, Hohenberger P, D'Adamo D, Guo M, Chmielowski B, Le Cesne A, Demetri GD, Patel SR. Eribulin versus dacarbazine in previously treated patients with advanced liposarcoma or leiomyosarcoma: a randomised, open-label, multicentre, phase 3 trial. Lancet. 2016 Apr 16;387(10028):1629-37. Epub 2016 Feb 10. link to original article PubMed
    1. Subgroup analysis: Demetri GD, Schöffski P, Grignani G, Blay JY, Maki RG, Van Tine BA, Alcindor T, Jones RL, D'Adamo DR, Guo M, Chawla S. Activity of eribulin in patients with advanced liposarcoma demonstrated in a subgroup analysis from a randomized phase III study of eribulin versus dacarbazine. J Clin Oncol. 2017 Oct 20;35(30):3433-3439. Epub 2017 Aug 30. link to original article contains verified protocol PubMed

Doxorubicin monotherapy

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Regimen

Study Evidence Comparator Efficacy
Mouridsen et al. 1987 Phase III Epirubicin Seems not superior
Lorigan et al. 2007 Phase III Ifos 3 Seems not superior
Ifos 9 Seems not superior
Judson et al. 2014 (EORTC 62012) Phase III Intensified Doxorubicin & Ifosfamide Might have inferior OS
Tap et al. 2016 Randomized Phase II Doxorubicin & Olaratumab Inferior OS
Tap et al. 2017 (TH CR-406/SARC021) Phase III Doxorubicin & Evofosfamide Seems not superior
Seddon et al. 2017 (GeDDiS) Phase III Docetaxel & Gemcitabine Might have superior PFS

Chemotherapy

Supportive medications

  • In Tap et al. 2016, Dexrazoxane (Zinecard) (dose not specified) could be used on day 1 of every cycle to reduce the potential for doxorubicin-related cardiotoxicity in cycles 5 to 8

21-day cycle for up to 6 to 8 cycles, until progression of disease, unacceptable toxicity, or patient refusal

Note: 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.

References

  1. 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. link to original article contains verified protocol PubMed
  2. 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
  3. 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. link to original article contains verified protocol PubMed
  4. 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
  5. 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. link to original article contains verified protocol PubMed
  6. 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 protocol PubMed
  7. 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 verified protocol PubMed

Epirubicin monotherapy

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Regimen

Study Evidence Comparator Efficacy
Mouridsen et al. 1987 Phase III Doxorubicin Seems not superior

Chemotherapy

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)

References

  1. 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. link to SD article contains verified protocol PubMed

Eribulin monotherapy

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Regimen

Study Evidence Comparator Efficacy
Schöffski et al. 2016 Phase III Dacarbazine Seems to have superior OS

Chemotherapy

21-day cycles until progression

References

  1. Schöffski P, Chawla S, Maki RG, Italiano A, Gelderblom H, Choy E, Grignani G, Camargo V, Bauer S, Rha SY, Blay JY, Hohenberger P, D'Adamo D, Guo M, Chmielowski B, Le Cesne A, Demetri GD, Patel SR. Eribulin versus dacarbazine in previously treated patients with advanced liposarcoma or leiomyosarcoma: a randomised, open-label, multicentre, phase 3 trial. Lancet. 2016 Apr 16;387(10028):1629-37. Epub 2016 Feb 10. link to original article contains protocol PubMed
    1. Subgroup analysis: Demetri GD, Schöffski P, Grignani G, Blay JY, Maki RG, Van Tine BA, Alcindor T, Jones RL, D'Adamo DR, Guo M, Chawla S. Activity of eribulin in patients with advanced liposarcoma demonstrated in a subgroup analysis from a randomized phase III study of eribulin versus dacarbazine. J Clin Oncol. 2017 Oct 20;35(30):3433-3439. Epub 2017 Aug 30. link to original article contains verified protocol PubMed

Ifosfamide monotherapy

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Variant #1, short infusion (Ifos 3)

Study Evidence Comparator Efficacy
Lorigan et al. 2007 Phase III Doxorubicin Seems not superior
Ifos 9 Seems not superior

Chemotherapy

  • Ifosfamide (Ifex) 3000 mg/m2 IV over 4 hours on days 1 to 3
    • Each day's dose of ifosfamide is mixed together with Mesna (Mesnex) in 1 liter of normal saline

Supportive medications

  • Mesna (Mesnex) as follows:
    • 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 together with Ifosfamide (Ifex), then
    • 1200 mg/m2 IV two times 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 two times 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, progression of disease, unacceptable toxicity, or patient refusal

Variant #2, continuous infusion (Ifos 9)

Study Evidence Comparator Efficacy
Lorigan et al. 2007 Phase III Doxorubicin Seems not superior
Ifos 3 Seems not superior

Chemotherapy

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

Supportive medications

  • Mesna (Mesnex) as follows:
    • 600 mg/m2 IV bolus once on day 1, immediately prior to mesna/ifosfamide infusion, then
    • 3000 mg/m2/day IV continuous infusion over 72 hours (total dose per cycle: 9000 mg/m2) on days 1 to 3, given together with Ifosfamide (Ifex), 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, progression of disease, unacceptable toxicity, or patient refusal

Variant #3

Study Evidence
van Oosterom et al. 2002 Phase II

Chemotherapy

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

Supportive medications

  • Mesna (Mesnex) as follows:
    • 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 together with Ifosfamide (Ifex), then
    • 500 mg/m2 IV two times 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 two times 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; continued until disease progression or unacceptable toxicity or patient refusal

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 verified protocol PubMed content property of HemOnc.org
  2. 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. link to original article contains verified protocol PubMed

Pazopanib monotherapy

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Regimen

Study Evidence Comparator Efficacy
van der Graaf et al. 2012 (PALETTE) Phase III Placebo Superior PFS

Chemotherapy

Given until progression of disease, unacceptable toxicity, withdrawal of consent, or death

References

  1. 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. Epub 2012 May 16. link to original article contains verified protocol PubMed

Placebo

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Regimen

Study Evidence Comparator Efficacy
van der Graaf et al. 2012 (PALETTE) Phase III Pazopanib Inferior PFS
Kawai et al. 2015 Randomized Phase II Trabectedin Inferior PFS
Mir et al. 2016 (REGOSARC) Randomized Phase II Regorafenib Inferior PFS (*)

No active antineoplastic treatment. Used as a comparator arm and here for reference purposes only. Note: reported efficacy in REGOSARC is for the leiomyosarcoma, synovial sarcoma, and other sarcoma cohorts; there was no significant difference in outcome for the liposarcoma cohort.

References

  1. 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. Epub 2012 May 16. link to original article contains verified protocol PubMed
  2. 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 protocol PubMed
  3. 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 protocol PubMed

Regorafenib monotherapy

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Regimen

Study Evidence Comparator Efficacy
Mir et al. 2016 (REGOSARC) Randomized Phase II Placebo Superior PFS

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

Chemotherapy

28-day cycles

References

  1. 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 protocol PubMed

Temozolomide monotherapy

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Variant #1

Study Evidence
Talbot et al. 2003 Phase II

Chemotherapy

  • 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, 90 mg/m2 PO once every 12 hours x 9 doses (total of 10 doses per cycle) on days 1 to 5, on an empty stomach

Supportive medications

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

28-day cycles, given until progression of disease or 1 year; patients on study could be reconsented to receive therapy beyond 1 year

Variant #2

Study Evidence
Garcia del Muro et al. 2005 Phase II

Chemotherapy

  • Temozolomide (Temodar) 100 mg/m2 PO once per day on days 1 to 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

Supportive medications

9-week cycle for up to 3 cycles, progression of disease, or unacceptable toxicity

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 verified protocol 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 verified protocol PubMed

Trabectedin monotherapy

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Variant #1

Study Evidence Comparator Efficacy
Demetri et al. 2015 Phase III Dacarbazine Superior PFS

Note: this is listed as a "starting dose," but no adjustment instructions were provided in the manuscript.

Chemotherapy

Supportive medications

21-day cycles

Variant #2

Study Evidence Comparator Efficacy
Kawai et al. 2015 Randomized Phase II Placebo Superior PFS

Chemotherapy

21-day cycles

References

  1. Demetri GD, Chawla SP, von Mehren M, Ritch P, Baker LH, Blay JY, Hande KR, Keohan ML, Samuels BL, Schuetze S, Lebedinsky C, Elsayed YA, Izquierdo MA, Gómez J, Park YC, Le Cesne A. Efficacy and safety of trabectedin in patients with advanced or metastatic liposarcoma or leiomyosarcoma after failure of prior anthracyclines and ifosfamide: results of a randomized phase II study of two different schedules. J Clin Oncol. 2009 Sep 1;27(25):4188-96. Epub 2009 Aug 3. link to original article PubMed
  2. 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 protocol PubMed
  3. Demetri GD, von Mehren M, Jones RL, Hensley ML, Schuetze SM, Staddon A, Milhem M, Elias A, Ganjoo K, Tawbi H, Van Tine BA, Spira A, Dean A, Khokhar NZ, Park YC, Knoblauch RE, Parekh TV, Maki RG, Patel SR. Efficacy and safety of trabectedin or dacarbazine for metastatic liposarcoma or leiomyosarcoma after failure of conventional chemotherapy: results of a phase III randomized multicenter clinical trial. J Clin Oncol. 2016 Mar 10;34(8):786-93. Epub 2015 Sep 14. link to original article contains verified protocol link to PMC article PubMed
    1. Subgroup analysis: Hensley ML, Patel SR, von Mehren M, Ganjoo K, Jones RL, Staddon A, Rushing D, Milhem M, Monk B, Wang G, McCarthy S, Knoblauch RE, Parekh TV, Maki RG, Demetri GD. Efficacy and safety of trabectedin or dacarbazine in patients with advanced uterine leiomyosarcoma after failure of anthracycline-based chemotherapy: Subgroup analysis of a phase 3, randomized clinical trial. Gynecol Oncol. 2017 Sep;146(3):531-537. Epub 2017 Jun 24. PubMed

Locally advanced or metastatic disease, combination regimens

Doxorubicin & Ifosfamide (AIM)

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AIM: Adriamycin (doxorubicin), Ifosfamide, Mesna

Variant #1, 5-day course, lower dose doxorubicin - AI 75/10

Study Evidence
Patel et al. 1998 Pilot, <20 patients reported

Chemotherapy

  • Doxorubicin (Adriamycin) 25 mg/m2/day IV continuous infusion over 72 hours on days 1 to 3 (total dose per cycle: 75 mg/m2)
  • Ifosfamide (Ifex) 2000 mg/m2 IV over 2 hours once per day on days 1 to 5 (total dose per cycle: 10,000 mg/m2)

Supportive medications

  • Mesna (Mesnex) 400 mg/m2 IV once on day 1, given simultaneously with the first dose of Ifosfamide (Ifex)
  • Mesna (Mesnex) 1200 mg/m2/day IV continuous infusion over 5 days on days 1 to 5 (total dose per cycle: 6000 mg/m2)
    • 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 cycles, given until maximum response, 6 cycles of therapy, progression of disease, or unacceptable toxicity

Variant #2, 4-day course, higher dose doxorubicin - AI 90/10

Study Evidence
Patel et al. 1998 Pilot, <20 patients reported

Chemotherapy

  • Doxorubicin (Adriamycin) 30 mg/m2/day IV continuous infusion over 72 hours on days 1 to 3 (total dose per cycle: 90 mg/m2)
  • Ifosfamide (Ifex) 2500 mg/m2 IV over 3 hours once per day on days 1 to 4 (total dose per cycle: 10,000 mg/m2)

Supportive medications

  • Mesna (Mesnex) 500 mg/m2 IV once on day 1, given simultaneously with the first dose of Ifosfamide (Ifex)
  • Mesna (Mesnex) 1500 mg/m2/day IV continuous infusion over 4 days on days 1 to 4 (total dose per cycle: 6000 mg/m2)
    • 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 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/uL

21-day cycles, given until maximum response, 6 cycles of therapy, progression of disease, or unacceptable toxicity

Variant #3, 3-day course, lower dose doxorubicin and ifosfamide (COG ARST0332 Arm D, NCT00346164)

Study Evidence
Venkatramani et al. 2015 Non-randomized prospective trial, minimum 20 patients

Chemotherapy

  • Doxorubicin (Adriamycin) 37.5 mg/m2/day (maximum 75 mg/dose) IV continuous infusion over 24 hours on days 1 and 2 (total dose per cycle: 75 mg/m2)
    • Given only 5 out of 6 cycles, for a total regimen dose of 375 mg/m2.
    • Doxorubicin (Adriamycin) 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) 3 g/m2 IV over 3 hours once per day on days 1 to 3 (total dose per cycle: 9 g/m2)
    • Given all 6 cycles, for a total regimen dose of 54 g/m2.

Supportive medications

  • Mesna (Mesnex) 600 mg/m2 IV over 15 minutes given at 15 minutes before each dose of Ifosfamide (Ifex), then at 3 hours, 6 hours, and 9 hours after start of Ifosfamide (Ifex)
  • Hydration:
    • Before first Ifosfamide (Ifex) infusion: D5 1/2 NS IV at rate of 200 mL/m2/hr IV until urine output > 2 cc/kg/hr
    • With Ifosfamide (Ifex) 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 5 mcg/kg (max 480 mcg) SC once per day, starting on day 4, given until ANC is at least 2,000/uL after nadir. Filgrastim should not be administered within 24 hours of chemotherapy.

21-day cycles, given until 6 cycles of therapy, progression of disease, or unacceptable toxicity

Radiotherapy

  • Beginning with cycle 2 (week 4)
  • Doxorubicin is held for cycles which occur while receiving radiation therapy.

Surgery

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

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 verified protocol PubMed
  2. 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). link to original abstract contains protocol

Dacarbazine & Gemcitabine

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Regimen

Study Evidence Comparator Efficacy
García-Del-Muro et al. 2011 Randomized phase II Dacarbazine Seems to have superior OS

Chemotherapy

14-day cycle for 12 cycles, or longer per clinician discretion

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 verified protocol PubMed

Docetaxel & Gemcitabine

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Variant #1, 60/675

Study Evidence Comparator Efficacy
Hensley et al. 2015 (GOG-250) Phase III (C) Docetaxel, Gemcitabine, Bevacizumab Seems not superior

This regimen was intended for patients who received prior radiation.

Chemotherapy

21-day cycles

Variant #2, 75/675

Study Evidence
Hensley et al. 2002 Phase II

This regimen was intended for patients who received prior radiation.

Chemotherapy

Supportive medications

  • Dexamethasone (Decadron) 8 mg PO BID on days 7-9 (the day before, the day of, and day after Docetaxel (Taxotere))
  • 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 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/uL on two separate measurements
    • Pegfilgrastim (Neulasta) 6 mg SC once on either day 9 or 10 (only one dose given)

21-day cycle for 6 to 8 cycles; Hensley et al. 2008 did not specify a maximum number of cycles

Variant #3, 75/900

Study Evidence Comparator Efficacy
Hensley et al. 2015 (GOG-250) Phase III (C) Docetaxel, Gemcitabine, Bevacizumab Seems not superior

This regimen was intended for patients with no prior radiation.

Chemotherapy

21-day cycles

Variant #3, 100/900

Study Evidence
Hensley et al. 2002 Phase II

This regimen was intended for patients with no prior radiation.

Chemotherapy

Supportive medications

  • Dexamethasone (Decadron) 8 mg PO BID on days 7 to 9 (the day before, the day of, and day after Docetaxel (Taxotere))
  • 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 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/uL on two separate measurements
    • Pegfilgrastim (Neulasta) 6 mg SC once on either day 9 or 10 (only one dose given)

21-day cycle for 6 to 8 cycles; Hensley et al. 2008 did not specify a maximum number of cycles

References

  1. 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. link to original article contains verified protocol PubMed
  2. 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. link to original article contains verified protocol link to PMC article PubMed
  3. GOG-250: Hensley ML, Miller A, O'Malley DM, Mannel RS, Behbakht K, Bakkum-Gamez JN, Michael H. Randomized phase III trial of gemcitabine plus docetaxel plus bevacizumab or placebo as first-line treatment for metastatic uterine leiomyosarcoma: an NRG Oncology/Gynecologic Oncology Group study. J Clin Oncol. 2015 Apr 1;33(10):1180-5. Epub 2015 Feb 23. link to original article link to PMC article PubMed
  4. 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 PubMed

Doxorubicin & Olaratumab

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Regimen

Study Evidence Comparator Efficacy
Tap et al. 2016 Randomized Phase II Doxorubicin Superior OS

Chemotherapy

21-day cycles

Supportive medications

  • In Tap et al. 2016, Dexrazoxane (Zinecard) (dose not specified) could be used on day 1 of every cycle to reduce the potential for doxorubicin-related cardiotoxicity in cycles 5 to 8

References

  1. 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 verified protocol PubMed

Epirubicin & Ifosfamide

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Regimen

Study Evidence
Reichardt et al. 1998 Phase II

Chemotherapy

  • Epirubicin (Ellence) 45 mg/m2/day IV continuous infusion over 2 days on days 2 & 3 (total dose per cycle: 90 mg/m2)
  • Ifosfamide (Ifex) 2500 mg/m2/day IV continuous infusion over 5 days on days 1 to 5 (total dose per cycle: 12,500 mg/m2)
    • Each day's dose is mixed together with Mesna (Mesnex) in 3 liters of "fluids with electrolytes"

Supportive medications

21-day cycles

References

  1. 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. link to original article contains verified protocol PubMed

Gemcitabine & Vinorelbine

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Regimen

Study Evidence
Dileo et al. 2007 Phase II

Chemotherapy

21-day cycles

Reference

  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 verified protocol PubMed

Liposarcoma, all lines of therapy

Note: this will be moved to a histology-specific page, shortly.

Eribulin monotherapy

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Regimen

Study Evidence Comparator Efficacy
Schöffski et al. 2016 Phase III Dacarbazine Superior OS (*)

Efficacy is based on the 2017 subgroup analysis.

Chemotherapy

21-day cycles until progression

References

  1. Schöffski P, Chawla S, Maki RG, Italiano A, Gelderblom H, Choy E, Grignani G, Camargo V, Bauer S, Rha SY, Blay JY, Hohenberger P, D'Adamo D, Guo M, Chmielowski B, Le Cesne A, Demetri GD, Patel SR. Eribulin versus dacarbazine in previously treated patients with advanced liposarcoma or leiomyosarcoma: a randomised, open-label, multicentre, phase 3 trial. Lancet. 2016 Apr 16;387(10028):1629-37. Epub 2016 Feb 10. link to original article contains protocol PubMed
    1. Subgroup analysis: Demetri GD, Schöffski P, Grignani G, Blay JY, Maki RG, Van Tine BA, Alcindor T, Jones RL, D'Adamo DR, Guo M, Chawla S. Activity of eribulin in patients with advanced liposarcoma demonstrated in a subgroup analysis from a randomized phase III study of eribulin versus dacarbazine. J Clin Oncol. 2017 Oct 20;35(30):3433-3439. Epub 2017 Aug 30. link to original article contains verified protocol PubMed

Rhabdomyosarcoma, all lines of therapy

Note: this will be moved to a histology-specific page, shortly.

VAC

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VAC: Vincristine, Actinomycin D, Cyclophosphamide

Regimen

Study Evidence Comparator Efficacy
Crist et al. 2001 (IRS-IV) Phase III VAI Seems not superior
VIE Seems not superior

To be completed

Chemotherapy

References

  1. Crist WM, Anderson JR, Meza JL, Fryer C, Raney RB, Ruymann FB, Breneman J, Qualman SJ, Wiener E, Wharam M, Lobe T, Webber B, Maurer HM, Donaldson SS. Intergroup rhabdomyosarcoma study-IV: results for patients with nonmetastatic disease. J Clin Oncol. 2001 Jun 15;19(12):3091-102. link to original article PubMed

VAI

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VAI: Vincristine, Actinomycin D, Ifosfamide
IVA: Ifosfamide, Vincristine, Actinomycin D

Regimen

Study Evidence Comparator Efficacy
Crist et al. 2001 (IRS-IV) Phase III VAC Seems not superior
VIE Seems not superior
Oberlin et al. 2012 (SIOP MMT95) Phase III (C) IVA/CEV/IVE Seems not superior

To be completed

Chemotherapy

References

  1. Crist WM, Anderson JR, Meza JL, Fryer C, Raney RB, Ruymann FB, Breneman J, Qualman SJ, Wiener E, Wharam M, Lobe T, Webber B, Maurer HM, Donaldson SS. Intergroup rhabdomyosarcoma study-IV: results for patients with nonmetastatic disease. J Clin Oncol. 2001 Jun 15;19(12):3091-102. link to original article PubMed
  2. Oberlin O, Rey A, Sanchez de Toledo J, Martelli H, Jenney ME, Scopinaro M, Bergeron C, Merks JH, Bouvet N, Ellershaw C, Kelsey A, Spooner D, Stevens MC. Randomized comparison of intensified six-drug versus standard three-drug chemotherapy for high-risk nonmetastatic rhabdomyosarcoma and other chemotherapy-sensitive childhood soft tissue sarcomas: long-term results from the International Society of Pediatric Oncology MMT95 study. J Clin Oncol. 2012 Jul 10;30(20):2457-65. Epub 2012 Jun 4. link to original article PubMed

VI, then VDC/IE, then VAC, then VI

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VI, then VDC/IE, then VAC, then VI: Vincristine & Irinotecan, followed by Vincristine, Doxorubicin, Cyclophosphamide alternating with Ifosfamide & Etoposide, followed by Vincristine, Actinomycin D, Cyclophosphamide, followed by Vincristine & Irinotecan

Regimen

Study Evidence
Weigel et al. 2015 (COG ARST0431) Phase II

Note: this is a complicated 54-week regimen with no immediate plans to add it to HemOnc.org. Please refer to the original article.

References

  1. Weigel BJ, Lyden E, Anderson JR, Meyer WH, Parham DM, Rodeberg DA, Michalski JM, Hawkins DS, Arndt CA. Intensive multiagent therapy, including dose-compressed cycles of ifosfamide/etoposide and vincristine/doxorubicin/cyclophosphamide, irinotecan, and radiation, in patients with high-risk rhabdomyosarcoma: A report from the Children's Oncology Group. J Clin Oncol. 2016 Jan 10;34(2):117-22. Epub 2015 Oct 26. link to original article link to PMC article PubMed

VIE

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VIE: Vincristine, Ifosfamide, Etoposide

Regimen

Study Evidence Comparator Efficacy
Crist et al. 2001 (IRS-IV) Phase III VAC Seems not superior
VAI Seems not superior

To be completed

Chemotherapy

References

  1. Crist WM, Anderson JR, Meza JL, Fryer C, Raney RB, Ruymann FB, Breneman J, Qualman SJ, Wiener E, Wharam M, Lobe T, Webber B, Maurer HM, Donaldson SS. Intergroup rhabdomyosarcoma study-IV: results for patients with nonmetastatic disease. J Clin Oncol. 2001 Jun 15;19(12):3091-102. link to original article PubMed

Gastrointestinal stromal tumor (GIST), all lines of therapy

Please see the dedicated GIST page.

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