Difference between revisions of "Osteosarcoma"

From HemOnc.org - A Hematology Oncology Wiki
Jump to navigation Jump to search
Line 36: Line 36:
 
|≥ 3 years
 
|≥ 3 years
 
|70 mg
 
|70 mg
 +
|-
 +
|≥ 12 years
 +
|150 mg
 
|}
 
|}
  

Revision as of 01:18, 18 January 2022

Section editor
Elizabethdavis2.jpg
Elizabeth J. Davis, MD
Vanderbilt University
Nashville, TN

Social-twitter-icon.png ejdavis25

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!

26 regimens on this page
37 variants on this page


Guidelines

ESMO

ESMO/PaedCan/EURACAN

NCCN


Karan

Age Initial Dose
1 - 1.99 years 30 mg
2 - 2.99 years 50 mg
≥ 3 years 70 mg
≥ 12 years 150 mg

COG AOST0331 MAP Group

Induction

Received by all patients and consists of 2 cycles of MAP.

Chemotherapy

10 Week Course

References

  1. COG AOST0331: Marina NM, Smeland S, Bielack SS, Bernstein M, Jovic G, Krailo MD, Hook JM, Arndt C, Berg H, Brennan B, Brichard B, Brown KLB, Butterfass-Bahloul T, Calaminus G, Daldrup-Link HE, Eriksson M, Gebhardt MC, Gelderblom H, Gerss J, Goldsby R, Goorin A, Gorlick R, Grier H, Hale JP, Hall KS, Hardes J, Hawkins DS, Helmke K, Hogendoorn PCW, Isakoff MS, JAneway KA, Jurgens H, Kager L, Kuhne T, Lau CC, Leavey PJ, Lessnick SL, Mascarenhas L, Meyers PA, Mottl H, Nathrath M, Papai Z, Randall RL, Reichardt P, Renard M, Safwat AA, Schwartz CL, Stevens MCG, Strauss SJ, Teot L, Werner M, Sydes MR, Whelan JS. Comparison of MAPIE versus MAP in patients with a poor response to preoperative chemotherapy for newly diagnosed high-grade osteosarcoma (EURAMOS-1): an open-label, international randomized controlled trial. J Clin Oncol. 2020 Fe1b 20;38(6):602-62. Epub 2019 Dec 11. link to original article link to PMC article contains verified protocol PubMed NCT00134030

MAP Cycles 3-4

Good Responders and Poor Responders

Chemotherapy

10 Week Course

References

  1. COG AOST0331: Marina NM, Smeland S, Bielack SS, Bernstein M, Jovic G, Krailo MD, Hook JM, Arndt C, Berg H, Brennan B, Brichard B, Brown KLB, Butterfass-Bahloul T, Calaminus G, Daldrup-Link HE, Eriksson M, Gebhardt MC, Gelderblom H, Gerss J, Goldsby R, Goorin A, Gorlick R, Grier H, Hale JP, Hall KS, Hardes J, Hawkins DS, Helmke K, Hogendoorn PCW, Isakoff MS, JAneway KA, Jurgens H, Kager L, Kuhne T, Lau CC, Leavey PJ, Lessnick SL, Mascarenhas L, Meyers PA, Mottl H, Nathrath M, Papai Z, Randall RL, Reichardt P, Renard M, Safwat AA, Schwartz CL, Stevens MCG, Strauss SJ, Teot L, Werner M, Sydes MR, Whelan JS. Comparison of MAPIE versus MAP in patients with a poor response to preoperative chemotherapy for newly diagnosed high-grade osteosarcoma (EURAMOS-1): an open-label, international randomized controlled trial. J Clin Oncol. 2020 Feb 20;38(6):602-612. Epub 2019 Dec 11. link to original article link to PMC article contains verified protocol PubMed NCT00134030

MAP Cycles 5-6

Good Responders and Poor Responders

Chemotherapy

10 Week Course

References

  1. COG AOST0331: Marina NM, Smeland S, Bielack SS, Bernstein M, Jovic G, Krailo MD, Hook JM, Arndt C, Berg H, Brennan B, Brichard B, Brown KLB, Butterfass-Bahloul T, Calaminus G, Daldrup-Link HE, Eriksson M, Gebhardt MC, Gelderblom H, Gerss J, Goldsby R, Goorin A, Gorlick R, Grier H, Hale JP, Hall KS, Hardes J, Hawkins DS, Helmke K, Hogendoorn PCW, Isakoff MS, JAneway KA, Jurgens H, Kager L, Kuhne T, Lau CC, Leavey PJ, Lessnick SL, Mascarenhas L, Meyers PA, Mottl H, Nathrath M, Papai Z, Randall RL, Reichardt P, Renard M, Safwat AA, Schwartz CL, Stevens MCG, Strauss SJ, Teot L, Werner M, Sydes MR, Whelan JS. Comparison of MAPIE versus MAP in patients with a poor response to preoperative chemotherapy for newly diagnosed high-grade osteosarcoma (EURAMOS-1): an open-label, international randomized controlled trial. J Clin Oncol. 2020 Feb 20;38(6):602-612. Epub 2019 Dec 11. link to original article link to PMC article contains verified protocol PubMed NCT00134030

COG AOST0331 MAPifn Group

Induction

Received by all patients and consists of 2 cycles of MAP.

Chemotherapy

10 Week Course

References

  1. COG AOST0331: Marina NM, Smeland S, Bielack SS, Bernstein M, Jovic G, Krailo MD, Hook JM, Arndt C, Berg H, Brennan B, Brichard B, Brown KLB, Butterfass-Bahloul T, Calaminus G, Daldrup-Link HE, Eriksson M, Gebhardt MC, Gelderblom H, Gerss J, Goldsby R, Goorin A, Gorlick R, Grier H, Hale JP, Hall KS, Hardes J, Hawkins DS, Helmke K, Hogendoorn PCW, Isakoff MS, JAneway KA, Jurgens H, Kager L, Kuhne T, Lau CC, Leavey PJ, Lessnick SL, Mascarenhas L, Meyers PA, Mottl H, Nathrath M, Papai Z, Randall RL, Reichardt P, Renard M, Safwat AA, Schwartz CL, Stevens MCG, Strauss SJ, Teot L, Werner M, Sydes MR, Whelan JS. Comparison of MAPIE versus MAP in patients with a poor response to preoperative chemotherapy for newly diagnosed high-grade osteosarcoma (EURAMOS-1): an open-label, international randomized controlled trial. J Clin Oncol. 2020 Feb 20;38(6):602-612. Epub 2019 Dec 11. link to original article link to PMC article contains verified protocol PubMed NCT00134030

MAPifn Cycles 3-4

Good Responders

Chemotherapy

10 Week Course

References

  1. COG AOST0331: Marina NM, Smeland S, Bielack SS, Bernstein M, Jovic G, Krailo MD, Hook JM, Arndt C, Berg H, Brennan B, Brichard B, Brown KLB, Butterfass-Bahloul T, Calaminus G, Daldrup-Link HE, Eriksson M, Gebhardt MC, Gelderblom H, Gerss J, Goldsby R, Goorin A, Gorlick R, Grier H, Hale JP, Hall KS, Hardes J, Hawkins DS, Helmke K, Hogendoorn PCW, Isakoff MS, JAneway KA, Jurgens H, Kager L, Kuhne T, Lau CC, Leavey PJ, Lessnick SL, Mascarenhas L, Meyers PA, Mottl H, Nathrath M, Papai Z, Randall RL, Reichardt P, Renard M, Safwat AA, Schwartz CL, Stevens MCG, Strauss SJ, Teot L, Werner M, Sydes MR, Whelan JS. Comparison of MAPIE versus MAP in patients with a poor response to preoperative chemotherapy for newly diagnosed high-grade osteosarcoma (EURAMOS-1): an open-label, international randomized controlled trial. J Clin Oncol. 2020 Feb 20;38(6):602-612. Epub 2019 Dec 11. link to original article link to PMC article contains verified protocol PubMed NCT00134030

MAPifn Cycles 5-6

Good Responders

Chemotherapy

10 Week Course

References

  1. COG AOST0331: Marina NM, Smeland S, Bielack SS, Bernstein M, Jovic G, Krailo MD, Hook JM, Arndt C, Berg H, Brennan B, Brichard B, Brown KLB, Butterfass-Bahloul T, Calaminus G, Daldrup-Link HE, Eriksson M, Gebhardt MC, Gelderblom H, Gerss J, Goldsby R, Goorin A, Gorlick R, Grier H, Hale JP, Hall KS, Hardes J, Hawkins DS, Helmke K, Hogendoorn PCW, Isakoff MS, JAneway KA, Jurgens H, Kager L, Kuhne T, Lau CC, Leavey PJ, Lessnick SL, Mascarenhas L, Meyers PA, Mottl H, Nathrath M, Papai Z, Randall RL, Reichardt P, Renard M, Safwat AA, Schwartz CL, Stevens MCG, Strauss SJ, Teot L, Werner M, Sydes MR, Whelan JS. Comparison of MAPIE versus MAP in patients with a poor response to preoperative chemotherapy for newly diagnosed high-grade osteosarcoma (EURAMOS-1): an open-label, international randomized controlled trial. J Clin Oncol. 2020 Feb 20;38(6):602-612. Epub 2019 Dec 11. link to original article link to PMC article contains verified protocol PubMed NCT00134030

MAPifn Weeks 30-104

Good Responders

Chemotherapy

75 Week Course

References

  1. COG AOST0331: Marina NM, Smeland S, Bielack SS, Bernstein M, Jovic G, Krailo MD, Hook JM, Arndt C, Berg H, Brennan B, Brichard B, Brown KLB, Butterfass-Bahloul T, Calaminus G, Daldrup-Link HE, Eriksson M, Gebhardt MC, Gelderblom H, Gerss J, Goldsby R, Goorin A, Gorlick R, Grier H, Hale JP, Hall KS, Hardes J, Hawkins DS, Helmke K, Hogendoorn PCW, Isakoff MS, JAneway KA, Jurgens H, Kager L, Kuhne T, Lau CC, Leavey PJ, Lessnick SL, Mascarenhas L, Meyers PA, Mottl H, Nathrath M, Papai Z, Randall RL, Reichardt P, Renard M, Safwat AA, Schwartz CL, Stevens MCG, Strauss SJ, Teot L, Werner M, Sydes MR, Whelan JS. Comparison of MAPIE versus MAP in patients with a poor response to preoperative chemotherapy for newly diagnosed high-grade osteosarcoma (EURAMOS-1): an open-label, international randomized controlled trial. J Clin Oncol. 2020 Feb 20;38(6):602-612. Epub 2019 Dec 11. link to original article link to PMC article contains verified protocol PubMed NCT00134030

COG AOST0331 MAPIE Group

Induction

Received by all patients and consists of 2 cycles of MAP.

Chemotherapy

10 Week Course

References

  1. COG AOST0331: Marina NM, Smeland S, Bielack SS, Bernstein M, Jovic G, Krailo MD, Hook JM, Arndt C, Berg H, Brennan B, Brichard B, Brown KLB, Butterfass-Bahloul T, Calaminus G, Daldrup-Link HE, Eriksson M, Gebhardt MC, Gelderblom H, Gerss J, Goldsby R, Goorin A, Gorlick R, Grier H, Hale JP, Hall KS, Hardes J, Hawkins DS, Helmke K, Hogendoorn PCW, Isakoff MS, JAneway KA, Jurgens H, Kager L, Kuhne T, Lau CC, Leavey PJ, Lessnick SL, Mascarenhas L, Meyers PA, Mottl H, Nathrath M, Papai Z, Randall RL, Reichardt P, Renard M, Safwat AA, Schwartz CL, Stevens MCG, Strauss SJ, Teot L, Werner M, Sydes MR, Whelan JS. Comparison of MAPIE versus MAP in patients with a poor response to preoperative chemotherapy for newly diagnosed high-grade osteosarcoma (EURAMOS-1): an open-label, international randomized controlled trial. J Clin Oncol. 2020 Feb 20;38(6):602-612. Epub 2019 Dec 11. link to original article link to PMC article contains verified protocol PubMed NCT00134030

MAPIE Cycles 3 and 7

Poor Responders

Chemotherapy

5-Week Courses

References

  1. COG AOST0331: Marina NM, Smeland S, Bielack SS, Bernstein M, Jovic G, Krailo MD, Hook JM, Arndt C, Berg H, Brennan B, Brichard B, Brown KLB, Butterfass-Bahloul T, Calaminus G, Daldrup-Link HE, Eriksson M, Gebhardt MC, Gelderblom H, Gerss J, Goldsby R, Goorin A, Gorlick R, Grier H, Hale JP, Hall KS, Hardes J, Hawkins DS, Helmke K, Hogendoorn PCW, Isakoff MS, JAneway KA, Jurgens H, Kager L, Kuhne T, Lau CC, Leavey PJ, Lessnick SL, Mascarenhas L, Meyers PA, Mottl H, Nathrath M, Papai Z, Randall RL, Reichardt P, Renard M, Safwat AA, Schwartz CL, Stevens MCG, Strauss SJ, Teot L, Werner M, Sydes MR, Whelan JS. Comparison of MAPIE versus MAP in patients with a poor response to preoperative chemotherapy for newly diagnosed high-grade osteosarcoma (EURAMOS-1): an open-label, international randomized controlled trial. J Clin Oncol. 2020 Feb 20;38(6):602-612. Epub 2019 Dec 11. link to original article link to PMC article contains verified protocol PubMed NCT00134030

MAP Cycles 4, 6, and 8

Poor Responders

Chemotherapy

  • Ifosfamide (Ifex) 2.8 g/m2/dose IV over 4 hours once per day on days 1 through 5 of weeks 16, 24, and 32.
  • Etoposide (Vepesid) 100 mg/m2/dose IV over 60 minutes once per day on days 1 through 5 of weeks 16, 24, and 32.
  • Mesna (Mesnex) 2.8 g/m2/24 hours IV continuous infusion over 24 hours on days 1 through 5 of weeks 16, 24, and 32.
  • Methotrexate (MTX) 12 g/m2 (MAX DOSE = 20 grams) IV over 4 hours once on day 1 of weeks 19, 27, and 35.
  • Folinic acid (Leucovorin) 15 mg/m2 PO or IV every 6 hours beginning 24 hours after the beginning of the Methotrexate (MTX) infusion and continuing until the serum Methotrexate (MTX) level is less than 0.1 μM.

5-Week Courses

References

  1. COG AOST0331: Marina NM, Smeland S, Bielack SS, Bernstein M, Jovic G, Krailo MD, Hook JM, Arndt C, Berg H, Brennan B, Brichard B, Brown KLB, Butterfass-Bahloul T, Calaminus G, Daldrup-Link HE, Eriksson M, Gebhardt MC, Gelderblom H, Gerss J, Goldsby R, Goorin A, Gorlick R, Grier H, Hale JP, Hall KS, Hardes J, Hawkins DS, Helmke K, Hogendoorn PCW, Isakoff MS, JAneway KA, Jurgens H, Kager L, Kuhne T, Lau CC, Leavey PJ, Lessnick SL, Mascarenhas L, Meyers PA, Mottl H, Nathrath M, Papai Z, Randall RL, Reichardt P, Renard M, Safwat AA, Schwartz CL, Stevens MCG, Strauss SJ, Teot L, Werner M, Sydes MR, Whelan JS. Comparison of MAPIE versus MAP in patients with a poor response to preoperative chemotherapy for newly diagnosed high-grade osteosarcoma (EURAMOS-1): an open-label, international randomized controlled trial. J Clin Oncol. 2020 Feb 20;38(6):602-612. Epub 2019 Dec 11. link to original article link to PMC article contains verified protocol PubMed NCT00134030

MAP Cycle 5

Poor Responders

Chemotherapy

5-Week Courses

References

  1. COG AOST0331: Marina NM, Smeland S, Bielack SS, Bernstein M, Jovic G, Krailo MD, Hook JM, Arndt C, Berg H, Brennan B, Brichard B, Brown KLB, Butterfass-Bahloul T, Calaminus G, Daldrup-Link HE, Eriksson M, Gebhardt MC, Gelderblom H, Gerss J, Goldsby R, Goorin A, Gorlick R, Grier H, Hale JP, Hall KS, Hardes J, Hawkins DS, Helmke K, Hogendoorn PCW, Isakoff MS, JAneway KA, Jurgens H, Kager L, Kuhne T, Lau CC, Leavey PJ, Lessnick SL, Mascarenhas L, Meyers PA, Mottl H, Nathrath M, Papai Z, Randall RL, Reichardt P, Renard M, Safwat AA, Schwartz CL, Stevens MCG, Strauss SJ, Teot L, Werner M, Sydes MR, Whelan JS. Comparison of MAPIE versus MAP in patients with a poor response to preoperative chemotherapy for newly diagnosed high-grade osteosarcoma (EURAMOS-1): an open-label, international randomized controlled trial. J Clin Oncol. 2020 Feb 20;38(6):602-612. Epub 2019 Dec 11. link to original article link to PMC article contains verified protocol PubMed NCT00134030

MAP Cycle 9

Poor Responders

Chemotherapy

5-Week Courses

References

  1. COG AOST0331: Marina NM, Smeland S, Bielack SS, Bernstein M, Jovic G, Krailo MD, Hook JM, Arndt C, Berg H, Brennan B, Brichard B, Brown KLB, Butterfass-Bahloul T, Calaminus G, Daldrup-Link HE, Eriksson M, Gebhardt MC, Gelderblom H, Gerss J, Goldsby R, Goorin A, Gorlick R, Grier H, Hale JP, Hall KS, Hardes J, Hawkins DS, Helmke K, Hogendoorn PCW, Isakoff MS, JAneway KA, Jurgens H, Kager L, Kuhne T, Lau CC, Leavey PJ, Lessnick SL, Mascarenhas L, Meyers PA, Mottl H, Nathrath M, Papai Z, Randall RL, Reichardt P, Renard M, Safwat AA, Schwartz CL, Stevens MCG, Strauss SJ, Teot L, Werner M, Sydes MR, Whelan JS. Comparison of MAPIE versus MAP in patients with a poor response to preoperative chemotherapy for newly diagnosed high-grade osteosarcoma (EURAMOS-1): an open-label, international randomized controlled trial. J Clin Oncol. 2020 Feb 20;38(6):602-612. Epub 2019 Dec 11. link to original article link to PMC article contains verified protocol PubMed NCT00134030

Neoadjuvant therapy

Cisplatin & Doxorubicin

back to top

AP: Adriamycin (Doxorubicin) & Platinol (Cisplatin)

Regimen variant #1

Study Years of enrollment Evidence Comparator Comparative Efficacy
Bramwell et al. 1992 1983-1986 Phase III (E-switch-ic) MAP Seems to have superior DFS
Souhami et al. 1997 1986-1991 Phase III (E-de-esc) Multi-drug T10 protocol Did not meet primary endpoints of PFS/OS

Chemotherapy

Supportive medications

  • Prehydration: normal saline 400 mL/m2 and D5W 400 mL/m2 over 2 hours--the reference did not clarify if these two solutions are given at the same time
  • The volume of fluid for cisplatin continuous infusion is 2400 mL/m2 NS, with KCl 80 mEq/L and mannitol 32,000 mg/m2
  • Posthydration: D5W 600 mL/m2 over 6 hours, with KCl 20 mEq/L and mannitol 8000 mg/m2; and NS 600 mL/m2 over 6 hours, with KCl 20 mEq/L, magnesium sulfate 2 mmol/L, and calcium gluconate 0.6 mmol/L--the reference did not clarify if these two solutions are given at the same time. Then D5W 600 mL/m2 over 12 hours, with KCl 20 mEq/L and mannitol 8000 mg/m2.
  • Furosemide (Lasix) 20 to 40 mg IV if urine output is less than 400 mL/m2 over 6 hours

21-day cycle for 3 cycles

Subsequent treatment

Regimen variant #2

Study Years of enrollment Evidence Comparator Comparative Efficacy
Lewis et al. 2007 (EORTC 80931) 1993-2002 Phase III (C) Cisplatin & Doxorubicin; dose-intense Did not meet primary endpoint of OS

Chemotherapy

Supportive medications

  • 4 hours of prehydration prior to cisplatin
  • 24 hours of posthydration & mannitol after cisplatin
  • Recommended that fluid for cisplatin is isotonic saline with potassium chloride and mannitol

21-day cycle for 2 cycles

Subsequent treatment

References

  1. Bramwell VH, Burgers M, Sneath R, Souhami R, van Oosterom AT, Voûte PA, Rouesse J, Spooner D, Craft AW, Somers R, Pringle J, Malcolm AJ, van der Eiiken J, Thomas D, Uscinska B, Machin D, van Glabbeke M; European Osteosarcoma Intergroup. A comparison of two short intensive adjuvant chemotherapy regimens in operable osteosarcoma of limbs in children and young adults: the first study of the European Osteosarcoma Intergroup. J Clin Oncol. 1992 Oct;10(10):1579-91. link to original article contains verified protocol PubMed
  2. Souhami RL, Craft AW, Van der Eijken JW, Nooij M, Spooner D, Bramwell VH, Wierzbicki R, Malcolm AJ, Kirkpatrick A, Uscinska BM, Van Glabbeke M, Machin D; European Osteosarcoma Intergroup. Randomised trial of two regimens of chemotherapy in operable osteosarcoma: a study of the European Osteosarcoma Intergroup. Lancet. 1997 Sep 27;350(9082):911-7. link to original article PubMed
  3. EORTC 80931: Lewis IJ, Nooij MA, Whelan J, Sydes MR, Grimer R, Hogendoorn PC, Memon MA, Weeden S, Uscinska BM, van Glabbeke M, Kirkpatrick A, Hauben EI, Craft AW, Taminiau AH; MRC BO06 and EORTC 80931 collaborators; European Osteosarcoma Intergroup. Improvement in histologic response but not survival in osteosarcoma patients treated with intensified chemotherapy: a randomized phase III trial of the European Osteosarcoma Intergroup. J Natl Cancer Inst. 2007 Jan 17;99(2):112-28. link to original article contains verified protocol PubMed NCT00002539

Cisplatin, Epirubicin, Ifosfamide

back to top

Regimen

Study Evidence
Basaran et al. 2007 Phase II

Chemotherapy

Supportive medications

21-day cycle for 3 cycles

Subsequent treatment

References

  1. Basaran M, Bavbek ES, Saglam S, Eralp L, Sakar B, Atalar AC, Bilgic B, Ozger H, Onat H. A phase II study of cisplatin, ifosfamide and epirubicin combination chemotherapy in adults with nonmetastatic and extremity osteosarcomas. Oncology. 2007;72(3-4):255-60. Epub 2008 Jan 10. link to original article contains verified protocol PubMed

MA

back to top

MA: High-dose Methotrexate, Adriamycin (Doxorubicin)

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Le Deley et al. 2007 (SFOP OS94) 1994-2001 Phase III (C) M-EI Might have inferior EFS

Chemotherapy

  • Methotrexate (MTX) as follows:
    • Cycles 1, 2, 3, 6, 7, 10, 11: 12,000 mg/m2 IV over 4 hours once on day 1
    • Given in D5W 1L with sodium bicarbonate 1 mEq/kg
  • Doxorubicin (Adriamycin) as follows:
    • Cycles 4 & 8: 70 mg/m2 IV over 6 hours once on day 1

Supportive medications

  • Folinic acid (Leucovorin) 15 mg PO every 6 hours for up to 11 doses on weeks 1, 2, 3, 6, 7, 10, 11, starting 20 hours after the completion of Methotrexate (MTX) infusion
  • For methotrexate: hydration & urine alkalinization by PO and IV routes to maintain 1.6 L/m2 urine output over the first 24 hours and 2 L/m2 on days 2 & 3, with urine pH greater than 7
  • Daily monitoring of methotrexate levels and creatinine

7-day cycle for 11 cycles

Subsequent treatment

  • Surgery occurs during week 12, with risk-adapted treatment as follows:

References

  1. SFOP OS94: Le Deley MC, Guinebretière JM, Gentet JC, Pacquement H, Pichon F, Marec-Bérard P, Entz-Werlé N, Schmitt C, Brugières L, Vanel D, Dupoüy N, Tabone MD, Kalifa C; Société Française d'Oncologie Pédiatrique (SFOP). SFOP OS94: a randomised trial comparing preoperative high-dose methotrexate plus doxorubicin to high-dose methotrexate plus etoposide and ifosfamide in osteosarcoma patients. Eur J Cancer. 2007 Mar;43(4):752-61. Epub 2007 Jan 30. link to original article contains verified protocol PubMed NCT00180908

MAP

back to top

MAP: High-dose Methotrexate, Adriamycin (Doxorubicin), Platinol (Cisplatin)

Regimen variant #1

Study Years of enrollment Evidence Comparator Comparative Efficacy
Bramwell et al. 1992 1983-1986 Phase III (E-esc) Cisplatin & Doxorubicin Seems to have inferior DFS

Note: The body of Bramwell et al. 1992 says that methotrexate is given over 4 hours, whereas Bramwell et al. 1992 figure 1's text says that methotrexate is given over 6 hours.

Chemotherapy

Supportive medications

  • Folinic acid (Leucovorin) 12 mg/m2 IV every 6 hours x 10 doses or 15 mg/m2 PO every 6 hours x 10 doses, starting 24 hours after the start of Methotrexate (MTX) infusion
    • Monitor methotrexate level at "24 hours and 48 hours"--it is unclear in the reference if this is time after the start/end of methotrexate, beginning of leucovorin, or something else
    • Methotrexate levels higher than 100 nmol/L at 48 hours required additional leucovorin rescue
  • Prehydration for methotrexate: "0.9 NaCl:D5W"--unclear if this means either normal saline or D5W can be used--750 mL/m2 over 6 hours, with KCl 20 mEq/L
  • The volume of fluid for methotrexate is D5W 1000 mL, to be given over 6 hours
  • Posthydration for methotrexate: Alternating liters of D5W and NS 3000 mL/m2 over 24 hours, with KCl 60 mEq/L.
  • Sodium bicarbonate 3 g PO Q6H, starting 12 hours before methotrexate, and sodium bicarbonate 167 mmol/L IV until serum methotrexate level is less than 8000 to 10,000 nmol/L. Note: the reference is not clear about when/if PO sodium bicarbonate is stopped, when IV sodium bicarbonate is started, or the administration rate of IV sodium bicarbonate.
  • Prehydration for Cisplatin (Platinol): normal saline 400 mL/m2 and D5W 400 mL/m2 over 2 hours--the reference did not clarify if these two solutions are given at the same time
  • The volume of fluid for cisplatin continuous infusion is 2400 mL/m2 NS, with KCl 80 mEq/L and mannitol 32,000 mg/m2
  • Posthydration for Cisplatin (Platinol): D5W 600 mL/m2 over 6 hours, with KCl 20 mEq/L and mannitol 8000 mg/m2; and NS 600 mL/m2 over 6 hours, with KCl 20 mEq/L, magnesium sulfate 2 mmol/L, and calcium gluconate 0.6 mmol/L--the reference did not clarify if these two solutions are given at the same time. Then D5W 600 mL/m2 over 12 hours, with KCl 20 mEq/L and mannitol 8000 mg/m2.
  • Furosemide (Lasix) 20 to 40 mg IV if urine output is less than 400 mL/m2 over 6 hours during Cisplatin (Platinol)

21-day cycle for 2 cycles

Subsequent treatment

Regimen variant #2

Study Evidence
Bacci et al. 1993 (IOR/OS-2) Phase II

Chemotherapy

Supportive medications

27-day cycle for 2 cycles

Subsequent treatment

  • Definitive surgery, then risk-adapted therapy. Amputated patients restart chemotherapy 3 to 5 days after surgery; patients who undergo limb salvage or rotation plasty restart chemotherapy 10 to 21 days after surgery.
    • At least 90% tumor necrosis in the surgically removed specimen: Adjuvant MAP
    • Less than 90% tumor necrosis in the surgically removed specimen: Adjuvant MAPIE

Regimen variant #3

Study Years of enrollment Evidence Comparator Comparative Efficacy
Winkler et al. 1988 (COSS-82) 1982-1984 Phase III (E-switch-ic) M-BCD Superior ORR

Note: The exact schedule is unclear based on limited information in the reference, as schedule of doses is primarily extrapolated from Figure 1, which does not contain clear delineations in time. The dose/schedule of cisplatin reflects the protocol amendment that was done because of nephrotoxicity.

Chemotherapy

  • Methotrexate (MTX) 12,000 mg/m2 (maximum dose of 20,000 mg) IV over 4 hours once per day on days 22 & 29
    • MTX is dissolved at a concentration of 20,000 mg/L in a solution containing 5% glucose
  • Doxorubicin (Adriamycin) 30 mg/m2 IV bolus once per day on days 1 & 2
  • Cisplatin (Platinol) 90 mg/m2 IV over 4 hours once on day 3

Supportive medications

  • Folinic acid (Leucovorin) 15 mg/m2 PO every 6 hours x 12 hours once per day on days 23 & 30, starting 24 hours after the completion of Methotrexate (MTX) infusion; additional leucovorin used for delayed methotrexate elimination
  • Sodium bicarbonate urine alkalinization prior to high-dose Methotrexate (MTX)
  • NS 4.5 L/m2 on day 1 after methotrexate; NS 3 L/m2 on day 2, with adjustments made to keep urine pH greater than 7.4
  • 12 hours of hydration prior to Cisplatin (Platinol) & 20 hours of hydration after Cisplatin (Platinol); total amount of fluid given over 36hours of prehydration, cisplatin, and posthydration is NS 6 L/m2 with mannitol 8 g/L and potassium 20 mval/L.
  • Magnesium 180 mg/m2 PO "per day throughout the whole chemotherapy time"--as described in COSS-80

35-day cycle for 2 cycles

Subsequent treatment

Protocol variant #4

Study Years of enrollment Evidence Comparator Comparative Efficacy
Winkler et al. 1984 (COSS-80) 1979-1982 Phase III (E-switch-ic) MA-BCD Did not meet primary endpoint of CDF rate

Note: The exact schedule is unclear based on limited/conflicting information in the reference. For example, Figure 1 appears to depict high-dose methotrexate starting 2 weeks after adriamycin, but the text says that methotrexate begins after a 3-week rest period. Additionally, the diagram in Figure 1 implies that the later therapies are given 4 times (once, then repeated x 3 cycles), but based on the cumulative doses listed, they are only given for a total of 3 cycles. The optional interferon arm is omitted given lack of benefit seen in the study.

Chemotherapy, part 1

21-day course, followed by:

Chemotherapy, part 2

See note above about uncertainty about the exact schedule.

  • Methotrexate (MTX) 12,000 mg/m2 (maximum dose of 20,000 mg) IV over 4 hours once per day on days 1 & 8
    • MTX is dissolved at a concentration of 20,000 mg/L in a solution containing 5% glucose
  • Cisplatin (Platinol) 120 mg/m2 IV over 5 hours once on day 15

Supportive medications

  • Folinic acid (Leucovorin) 15 mg/m2 PO every 6 hours x 12 hours once per day on days 2 & 9, starting 24 hours after the completion of Methotrexate (MTX) infusion; additional leucovorin used for delayed methotrexate elimination
  • Sodium bicarbonate urine alkalinization prior to high-dose Methotrexate (MTX)
  • NS 4.5 L/m2 on day 1 after Methotrexate (MTX); NS 3 L/m2 on day 2, with adjustments made to keep urine pH greater than 7.4
  • 3 hours of hydration prior to Cisplatin (Platinol) & 3 hours of hydration after Cisplatin (Platinol); total amount of fluid given over 11 hours of prehydration, cisplatin, and posthydration is NS 2.5 L/m2 with mannitol 8 g/L and potassium 20 mval/L.
  • Magnesium 180 mg/m2 PO "per day throughout the whole chemotherapy time" with Cisplatin (Platinol)

35-day course, followed by:

Chemotherapy, part 3

See note above about uncertainty about the exact schedule.

  • Methotrexate (MTX) 12,000 mg/m2 (maximum dose of 20,000 mg) IV over 4 hours once per day on days 1, 8, 29, 36
    • MTX is dissolved at a concentration of 20,000 mg/L in a solution containing 5% glucose
  • Doxorubicin (Adriamycin) 45 mg/m2 IV bolus once per day on days 15 & 16 (delayed during cycle 1 until after surgery)
  • Cisplatin (Platinol) 120 mg/m2 IV over 5 hours once on day 43

Supportive medications

  • Folinic acid (Leucovorin) 15 mg/m2 PO every 6 hours x 12 hours once per day on days 2, 9, 30, 37, starting 24 hours after the completion of Methotrexate (MTX) infusion; additional leucovorin used for delayed methotrexate elimination
  • Sodium bicarbonate urine alkalinization prior to high-dose Methotrexate (MTX)
  • NS 4.5 L/m2 on day 1 after Methotrexate (MTX); NS 3 L/m2 on day 2, with adjustments made to keep urine pH greater than 7.4
  • 3 hours of hydration prior to Cisplatin (Platinol) & 3 hours of hydration after Cisplatin (Platinol); total amount of fluid given over 11 hours of prehydration, cisplatin, and posthydration is NS 2.5 L/m2 with mannitol 8 g/L and potassium 20 mval/L.
  • Magnesium 180 mg/m2 PO "per day throughout the whole chemotherapy time" with Cisplatin (Platinol)

8-week cycle for 3 cycles, with surgery done during cycle 1 before doxorubicin; surgery is done 9 to 18 weeks after the start of chemotherapy

References

  1. COSS-80: Winkler K, Beron G, Kotz R, Salzer-Kuntschik M, Beck J, Beck W, Brandeis W, Ebell W, Erttmann R, Göbel U, Havers W, Henze G, Hinderfeld L, Höcker P, Jobke A, Jürgens H, Kabisch H, Preusser P, Prindull G, Ramach W, Ritter J, Sekera J, Treuner J, Wist G, Landbeck G. Neoadjuvant chemotherapy for osteogenic sarcoma: results of a Cooperative German/Austrian study. J Clin Oncol. 1984 Jun;2(6):617-24. link to original article contains verified protocol PubMed
  2. COSS-82: Winkler K, Beron G, Delling G, Heise U, Kabisch H, Purfürst C, Berger J, Ritter J, Jürgens H, Gerein V, Graf N, Russe W, Gruemayer ER, Ertelt W, Kotz R, Preuzzer P, Prindull G, Brandeis W, Landbeck G. Neoadjuvant chemotherapy of osteosarcoma: results of a randomized cooperative trial (COSS-82) with salvage chemotherapy based on histological tumor response. J Clin Oncol. 1988 Feb;6(2):329-37. link to original article contains verified protocol PubMed
  3. Bramwell VH, Burgers M, Sneath R, Souhami R, van Oosterom AT, Voûte PA, Rouesse J, Spooner D, Craft AW, Somers R, Pringle J, Malcolm AJ, van der Eiiken J, Thomas D, Uscinska B, Machin D, van Glabbeke M; European Osteosarcoma Intergroup. A comparison of two short intensive adjuvant chemotherapy regimens in operable osteosarcoma of limbs in children and young adults: the first study of the European Osteosarcoma Intergroup. J Clin Oncol. 1992 Oct;10(10):1579-91. link to original article contains verified protocol PubMed content property of HemOnc.org
  4. IOR/OS-2: Bacci G, Picci P, Ferrari S, Ruggieri P, Casadei R, Tienghi A, Brach del Prever A, Gherlinzoni F, Mercuri M, Monti C. Primary chemotherapy and delayed surgery for nonmetastatic osteosarcoma of the extremities: results in 164 patients preoperatively treated with high doses of methotrexate followed by cisplatin and doxorubicin. Cancer. 1993 Dec 1;72(11):3227-38. link to original article PubMed
    1. Update: Bacci G, Ferrari S, Bertoni F, Ruggieri P, Picci P, Longhi A, Casadei R, Fabbri N, Forni C, Versari M, Campanacci M. Long-term outcome for patients with nonmetastatic osteosarcoma of the extremity treated at the Istituto Ortopedico Rizzoli according to the Istituto Ortopedico Rizzoli/Osteosarcoma-2 protocol: an updated report. J Clin Oncol. 2000 Dec 15;18(24):4016-27. link to original article contains verified protocol PubMed

MAPI

back to top

MAPI: High-dose Methotrexate, Adriamycin (Doxorubicin), Platinol (Cisplatin), Ifosfamide

Regimen

Study Evidence
Bacci et al. 2003 Phase II

Chemotherapy

  • Methotrexate (MTX) 12,000 mg/m2 IV over 4 hours once on day 1
    • If 4-hour methotrexate level is less than 10,000 nmol/L, the next cycle's dose is increased by 2000 mg/m2
  • Cisplatin (Platinol) 60 mg/m2/day IV continuous infusion over 48 hours, started on day 8 (total dose per cycle: 120 mg/m2)
  • Doxorubicin (Adriamycin) 75 mg/m2 IV continuous infusion over 24 hours, started on day 10
  • Ifosfamide (Ifex) 3000 mg/m2/day IV continuous infusion over 120 hours, started on day 29, given with Mesna (Mesnex) (total dose per cycle: 15,000 mg/m2)

Supportive medications

  • Folinic acid (Leucovorin) 15 mg (route not specified) every 6 hours x 11 doses (note: the reference says "11 cycles," but it is assumed this is the intended meaning), starting day 2, 24 hours after the start of Methotrexate (MTX)
  • Hydration during and after methotrexate as described by: Rosen G, Nirenberg A. Chemotherapy for osteogenic sarcoma: an investigative method, not a recipe. Cancer Treat Rep. 1982 Sep;66(9):1687-97. PubMed
  • Mesna (Mesnex) 3000 mg/m2/day IV continuous infusion over 120 hours, started on day 29, given with Ifosfamide (Ifex) (total dose: 15,000 mg/m2)

42-day cycle for 2 cycles

Subsequent treatment

References

  1. Bacci G, Briccoli A, Rocca M, Ferrari S, Donati D, Longhi A, Bertoni F, Bacchini P, Giacomini S, Forni C, Manfrini M, Galletti S. Neoadjuvant chemotherapy for osteosarcoma of the extremities with metastases at presentation: recent experience at the Rizzoli Institute in 57 patients treated with cisplatin, doxorubicin, and a high dose of methotrexate and ifosfamide. Ann Oncol. 2003 Jul;14(7):1126-34. link to original article contains verified protocol PubMed

M-EI

back to top

M-EI: Methotrexate, Etoposide, Ifosfamide

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Le Deley et al. 2007 (SFOP OS94) 1994-2001 Phase III (E-switch-ic) MA Might have superior EFS
Piperno-Neumann et al. 2016 (OS2006) 2007-2014 Phase III (C) M-EI & Zoledronic acid Might have superior EFS

Note: this regimen information is from SFOP OS94.

Chemotherapy

  • Methotrexate (MTX) as follows:
    • Cycles 1, 2, 3, 7, 8, 12, 13: 12,000 mg/m2 IV over 4 hours once on day 1
    • Given in D5W 1L with sodium bicarbonate 1 mEq/kg
  • Etoposide (Vepesid) as follows:
    • Cycles 4 & 9: 75 mg/m2 IV over 60 minutes once per day on days 1 to 4
    • Given in NS 250 to 500 mL
  • Ifosfamide (Ifex) as follows:
    • Cycles 4 & 9: 3000 mg/m2 IV over 3 hours once per day on days 1 to 4, given with Mesna (Mesnex)
    • Given in NS 250 to 500 mL

Supportive medications

  • Folinic acid (Leucovorin) 15 mg PO every 6 hours for up to 11 doses on weeks 1, 2, 3, 7, 8, 12, 13, starting 20 hours after the completion of methotrexate infusion
  • For methotrexate: hydration & urine alkalinization by PO and IV routes to maintain 1.6 L/m2 urine output over the first 24 hours and 2 L/m2 on days 2 & 3, with urine pH greater than 7
  • Daily monitoring of methotrexate levels and creatinine
  • Mesna (Mesnex) 3600 mg/m2/day IV continuous infusion over 96 hours, started on day 22 (week 4) and 57 (week 9), given with Ifosfamide (Ifex) (total dose: 14,400 mg/m2)
  • Up to 2 L/day hydration with ifosfamide & mesna

7-day cycle for 13 cycles

Subsequent treatment

  • Surgery occurs during week 14, with further treatment based on pathologic response:

References

  1. SFOP OS94: Le Deley MC, Guinebretière JM, Gentet JC, Pacquement H, Pichon F, Marec-Bérard P, Entz-Werlé N, Schmitt C, Brugières L, Vanel D, Dupoüy N, Tabone MD, Kalifa C; Société Française d'Oncologie Pédiatrique (SFOP). SFOP OS94: a randomised trial comparing preoperative high-dose methotrexate plus doxorubicin to high-dose methotrexate plus etoposide and ifosfamide in osteosarcoma patients. Eur J Cancer. 2007 Mar;43(4):752-61. Epub 2007 Jan 30. link to original article contains verified protocol PubMed NCT00180908
  2. OS2006: Piperno-Neumann S, Le Deley MC, Rédini F, Pacquement H, Marec-Bérard P, Petit P, Brisse H, Lervat C, Gentet JC, Entz-Werlé N, Italiano A, Corradini N, Bompas E, Penel N, Tabone MD, Gomez-Brouchet A, Guinebretière JM, Mascard E, Gouin F, Chevance A, Bonnet N, Blay JY, Brugières L; Sarcoma Group of UNICANCER; SFCE; GSF-GETO. Zoledronate in combination with chemotherapy and surgery to treat osteosarcoma (OS2006): a randomised, multicentre, open-label, phase 3 trial. Lancet Oncol. 2016 Aug;17(8):1070-1080. Epub 2016 Jun 17. link to original article PubMed NCT00470223
    1. Update: Gaspar N, Occean BV, Pacquement H, Bompas E, Bouvier C, Brisse HJ, Castex MP, Cheurfa N, Corradini N, Delaye J, Entz-Werlé N, Gentet JC, Italiano A, Lervat C, Marec-Berard P, Mascard E, Redini F, Saumet L, Schmitt C, Tabone MD, Verite-Goulard C, Le Deley MC, Piperno-Neumann S, Brugieres L; SFCE; GSF-GETO; UNICANCER sarcoma group. Results of methotrexate-etoposide-ifosfamide based regimen (M-EI) in osteosarcoma patients included in the French OS2006/sarcome-09 study. Eur J Cancer. 2018 Jan;88:57-66. Epub 2017 Nov 28. link to original article PubMed

Adjuvant therapy

Cisplatin & Doxorubicin

back to top

AP: Adriamycin (Doxorubicin) & Platinol (Cisplatin)

Regimen variant #1

Study Years of enrollment Evidence Comparator Comparative Efficacy
Bramwell et al. 1992 1983-1986 Phase III (E-esc) MAP Seems to have superior DFS
Souhami et al. 1997 1986-1991 Phase III (E-de-esc) Multi-drug T10 protocol Did not meet primary endpoints of PFS/OS

Preceding treatment

Chemotherapy

Supportive medications

  • Prehydration: normal saline 400 mL/m2 and D5W 400 mL/m2 over 2 hours--the reference did not clarify if these two solutions are given at the same time
  • The volume of fluid for cisplatin continuous infusion is 2400 mL/m2 NS, with KCl 80 mEq/L and mannitol 32,000 mg/m2
  • Posthydration: D5W 600 mL/m2 over 6 hours, with KCl 20 mEq/L and mannitol 8000 mg/m2; and NS 600 mL/m2 over 6 hours, with KCl 20 mEq/L, magnesium sulfate 2 mmol/L, and calcium gluconate 0.6 mmol/L--the reference did not clarify if these two solutions are given at the same time. Then D5W 600 mL/m2 over 12 hours, with KCl 20 mEq/L and mannitol 8000 mg/m2.
  • Furosemide (Lasix) 20 to 40 mg IV if urine output is less than 400 mL/m2 over 6 hours

21-day cycle for 3 cycles

Regimen variant #2

Study Years of enrollment Evidence Comparator Comparative Efficacy
Lewis et al. 2007 (EORTC 80931) 1993-2002 Phase III (C) Cisplatin & Doxorubicin; dose-intense Inferior good histologic response rate

Preceding treatment

Chemotherapy

Supportive medications

  • 4 hours of prehydration prior to cisplatin
  • 24 hours of posthydration & mannitol after cisplatin
  • Recommended that fluid for cisplatin is isotonic saline with potassium chloride and mannitol

21-day cycle for 4 cycles

Regimen variant #3, dose intense

Study Years of enrollment Evidence Comparator Comparative Efficacy
Lewis et al. 2007 (EORTC 80931) 1993-2002 Phase III (E-esc) Cisplatin & Doxorubicin; conventional Superior good histologic response rate

Preceding treatment

Chemotherapy

Supportive medications

14-day cycle for 3 cycles

Regimen variant #4

Study Evidence
Winkler et al. 1988 (COSS-82) Non-randomized portion of RCT

Note: The exact schedule is unclear based on limited information in the reference, as schedule of doses is primarily extrapolated from Figure 1, which does not contain clear delineations in time.

Preceding treatment

Chemotherapy

Supportive medications

  • 12 hours of hydration prior to cisplatin & 20 hours of hydration after cisplatin; total amount of fluid given over 36hours of prehydration, cisplatin, and posthydration is NS 6 L/m2 with mannitol 8 g/L and potassium 20 mval/L.
  • Magnesium 180 mg/m2 PO "per day throughout the whole chemotherapy time"--as described in COSS-80

21-day cycle for 6 cycles

Regimen variant #5

Study Evidence
Le Deley et al. 2007 (SFOP OS94) Non-randomized portion of RCT

Details were not listed about the precise schedule. Other regimens have used both medications both on day 1, with 21-day cycles.

Preceding treatment

Chemotherapy

5 cycles (length not specified)

References

  1. COSS-82: Winkler K, Beron G, Delling G, Heise U, Kabisch H, Purfürst C, Berger J, Ritter J, Jürgens H, Gerein V, Graf N, Russe W, Gruemayer ER, Ertelt W, Kotz R, Preuzzer P, Prindull G, Brandeis W, Landbeck G. Neoadjuvant chemotherapy of osteosarcoma: results of a randomized cooperative trial (COSS-82) with salvage chemotherapy based on histological tumor response. J Clin Oncol. 1988 Feb;6(2):329-37. link to original article contains verified protocol PubMed
  2. Bramwell VH, Burgers M, Sneath R, Souhami R, van Oosterom AT, Voûte PA, Rouesse J, Spooner D, Craft AW, Somers R, Pringle J, Malcolm AJ, van der Eiiken J, Thomas D, Uscinska B, Machin D, van Glabbeke M; European Osteosarcoma Intergroup. A comparison of two short intensive adjuvant chemotherapy regimens in operable osteosarcoma of limbs in children and young adults: the first study of the European Osteosarcoma Intergroup. J Clin Oncol. 1992 Oct;10(10):1579-91. link to original article contains verified protocol PubMed
  3. Souhami RL, Craft AW, Van der Eijken JW, Nooij M, Spooner D, Bramwell VH, Wierzbicki R, Malcolm AJ, Kirkpatrick A, Uscinska BM, Van Glabbeke M, Machin D; European Osteosarcoma Intergroup. Randomised trial of two regimens of chemotherapy in operable osteosarcoma: a study of the European Osteosarcoma Intergroup. Lancet. 1997 Sep 27;350(9082):911-7. link to original article PubMed
  4. EORTC 80931: Lewis IJ, Nooij MA, Whelan J, Sydes MR, Grimer R, Hogendoorn PC, Memon MA, Weeden S, Uscinska BM, van Glabbeke M, Kirkpatrick A, Hauben EI, Craft AW, Taminiau AH; MRC BO06 and EORTC 80931 collaborators; European Osteosarcoma Intergroup. Improvement in histologic response but not survival in osteosarcoma patients treated with intensified chemotherapy: a randomized phase III trial of the European Osteosarcoma Intergroup. J Natl Cancer Inst. 2007 Jan 17;99(2):112-28. link to original article contains verified protocol PubMed NCT00002539
  5. SFOP OS94: Le Deley MC, Guinebretière JM, Gentet JC, Pacquement H, Pichon F, Marec-Bérard P, Entz-Werlé N, Schmitt C, Brugières L, Vanel D, Dupoüy N, Tabone MD, Kalifa C; Société Française d'Oncologie Pédiatrique (SFOP). SFOP OS94: a randomised trial comparing preoperative high-dose methotrexate plus doxorubicin to high-dose methotrexate plus etoposide and ifosfamide in osteosarcoma patients. Eur J Cancer. 2007 Mar;43(4):752-61. Epub 2007 Jan 30. link to original article contains verified protocol PubMed NCT00180908

Cisplatin, Epirubicin, Ifosfamide

back to top

Regimen

Study Evidence
Basaran et al. 2007 Phase II

Preceding treatment

Chemotherapy

Supportive medications

28-day cycle for 3 cycles

References

  1. Basaran M, Bavbek ES, Saglam S, Eralp L, Sakar B, Atalar AC, Bilgic B, Ozger H, Onat H. A phase II study of cisplatin, ifosfamide and epirubicin combination chemotherapy in adults with nonmetastatic and extremity osteosarcomas. Oncology. 2007;72(3-4):255-60. Epub 2008 Jan 10. link to original article contains verified protocol PubMed

Doxorubicin monotherapy

back to top

Regimen

Study Evidence
Cortes et al. 1974 Non-randomized

Of historic interest.

Preceding treatment

Chemotherapy

4- to 6-week cycle for 6 cycles

References

  1. Cortes EP, Holland JF, Wang JJ, Sinks LF, Blom J, Senn H, Bank A, Glidewell O. Amputation and adriamycin in primary osteosarcoma. N Engl J Med. 1974 Nov 7;291(19):998-1000. link to original article contains protocol PubMed

IE

back to top

IE: Ifosfamide, Etoposide

Regimen

Study Evidence
Le Deley et al. 2007 (SFOP OS94) Non-randomized portion of RCT

Details were not listed about the length of each cycle. Other regimens have used 21 to 28-day cycles.

Preceding treatment

Chemotherapy

Supportive medications

  • Mesna (Mesnex) 3600 mg/m2/day IV continuous infusion over 96 hours, started on day 1 (total dose: 14,400 mg/m2)
  • Up to 2 L/day hydration with ifosfamide & mesna

5 cycles

References

  1. SFOP OS94: Le Deley MC, Guinebretière JM, Gentet JC, Pacquement H, Pichon F, Marec-Bérard P, Entz-Werlé N, Schmitt C, Brugières L, Vanel D, Dupoüy N, Tabone MD, Kalifa C; Société Française d'Oncologie Pédiatrique (SFOP). SFOP OS94: a randomised trial comparing preoperative high-dose methotrexate plus doxorubicin to high-dose methotrexate plus etoposide and ifosfamide in osteosarcoma patients. Eur J Cancer. 2007 Mar;43(4):752-61. Epub 2007 Jan 30. link to original article contains verified protocol PubMed NCT00180908

MA

back to top

MA: High-dose Methotrexate, Adriamycin (Doxorubicin)

Protocol

Study Evidence
Le Deley et al. 2007 (SFOP OS94) Non-randomized portion of RCT

Preceding treatment

Chemotherapy, part 1

Supportive medications

  • Folinic acid (Leucovorin) 15 mg PO every 6 hours for up to 11 doses, starting on days 1, 8, 15, starting 20 hours after the completion of Methotrexate (MTX) infusion
  • For methotrexate: hydration & urine alkalinization by PO and IV routes to maintain 1.6 L/m2 urine output over the first 24 hours and 2 L/m2 on days 2 & 3, with urine pH greater than 7
  • Daily monitoring of methotrexate levels and creatinine

28-day cycle for 3 cycles, followed by:

Chemotherapy, part 2

  • Methotrexate (MTX) 12,000 mg/m2 IV over 4 hours once per day on days 1, 8, 15
    • Given in D5W 1L with sodium bicarbonate 1 mEq/kg

Supportive medications

  • Folinic acid (Leucovorin) 15 mg PO every 6 hours for up to 11 doses, starting on days 1, 8, 15, starting 20 hours after the completion of Methotrexate (MTX) infusion
  • For methotrexate: hydration & urine alkalinization by PO and IV routes to maintain 1.6 L/m2 urine output over the first 24 hours and 2 L/m2 on days 2 & 3, with urine pH greater than 7
  • Daily monitoring of methotrexate levels and creatinine

21-day course

References

  1. SFOP OS94: Le Deley MC, Guinebretière JM, Gentet JC, Pacquement H, Pichon F, Marec-Bérard P, Entz-Werlé N, Schmitt C, Brugières L, Vanel D, Dupoüy N, Tabone MD, Kalifa C; Société Française d'Oncologie Pédiatrique (SFOP). SFOP OS94: a randomised trial comparing preoperative high-dose methotrexate plus doxorubicin to high-dose methotrexate plus etoposide and ifosfamide in osteosarcoma patients. Eur J Cancer. 2007 Mar;43(4):752-61. Epub 2007 Jan 30. link to original article contains verified protocol PubMed NCT00180908

MAP

back to top

MAP: High-dose Methotrexate, Adriamycin (Doxorubicin), Platinol (Cisplatin)

Regimen variant #1, 8000/75/100

Study Years of enrollment Evidence Comparator Comparative Efficacy
Bramwell et al. 1992 1983-1986 Phase III (E-esc) Cisplatin & Doxorubicin Seems to have inferior DFS

Note: The body of Bramwell et al. 1992 says that methotrexate is given over 4 hours, whereas Bramwell et al. 1992 figure 1's text says that methotrexate is given over 6 hours.

Preceding treatment

Chemotherapy

Supportive medications

  • Folinic acid (Leucovorin) 12 mg/m2 IV every 6 hours x 10 doses or 15 mg/m2 PO every 6 hours x 10 doses, starting 24 hours after the start of methotrexate infusion
    • Monitor methotrexate level at "24 hours and 48 hours"--it is unclear in the reference if this is time after the start/end of methotrexate, beginning of leucovorin, or something else
    • Methotrexate levels higher than 100 nmol/L at 48 hours required additional leucovorin rescue
  • Prehydration for methotrexate: "0.9 NaCl:D5W"--unclear if this means either normal saline or D5W can be used--750 mL/m2 over 6 hours, with KCl 20 mEq/L
  • The volume of fluid for methotrexate is D5W 1000 mL, to be given over 6 hours
  • Posthydration for methotrexate: Alternating liters of D5W and NS 3000 mL/m2 over 24 hours, with KCl 60 mEq/L.
  • Sodium bicarbonate 3 g PO Q6H, starting 12 hours before methotrexate, and sodium bicarbonate 167 mmol/L IV until serum methotrexate level is less than 8000 to 10,000 nmol/L. Note: the reference is not clear about when/if PO sodium bicarbonate is stopped, when IV sodium bicarbonate is started, or the administration rate of IV sodium bicarbonate.
  • Prehydration for cisplatin: normal saline 400 mL/m2 and D5W 400 mL/m2 over 2 hours--the reference did not clarify if these two solutions are given at the same time
  • The volume of fluid for cisplatin continuous infusion is 2400 mL/m2 NS, with KCl 80 mEq/L and mannitol 32,000 mg/m2
  • Posthydration for cisplatin: D5W 600 mL/m2 over 6 hours, with KCl 20 mEq/L and mannitol 8000 mg/m2; and NS 600 mL/m2 over 6 hours, with KCl 20 mEq/L, magnesium sulfate 2 mmol/L, and calcium gluconate 0.6 mmol/L--the reference did not clarify if these two solutions are given at the same time. Then D5W 600 mL/m2 over 12 hours, with KCl 20 mEq/L and mannitol 8000 mg/m2.
  • With cisplatin, Furosemide (Lasix) 20 to 40 mg IV if urine output is less than 400 mL/m2 over 6 hours

21-day cycle for 2 cycles

Protocol variant #2, 8000/90/120

Study Evidence
Bacci et al. 1993 (IOR/OS-2) Phase II

Preceding treatment

Chemotherapy, part 1

Supportive medications

48-day cycle for 3 cycles, then--note: Figure 1 of Bacci et al. 2000 actually depicted the first cycle as being 47 days, and cycles 2 & 3 being 48 days.

Chemotherapy, part 2

Given once after cycle 3

Regimen variant #3, 12,000/60/90

Study Evidence
Winkler et al. 1988 (COSS-82) Non-randomized portion of RCT

Preceding treatment

Chemotherapy

  • Methotrexate (MTX) 12,000 mg/m2 (maximum dose of 20,000 mg) IV over 4 hours once per day on days 22 & 29
    • MTX is dissolved at a concentration of 20,000 mg/L in a solution containing 5% glucose
  • Doxorubicin (Adriamycin) 30 mg/m2 IV bolus once per day on days 1 & 2
  • Cisplatin (Platinol) 90 mg/m2 IV over 4 hours once on day 3

Supportive medications

  • Folinic acid (Leucovorin) 15 mg/m2 PO every 6 hours x 12 hours once per day on days 23 & 30, starting 24 hours after the completion of methotrexate infusion; additional leucovorin used for delayed methotrexate elimination
  • Sodium bicarbonate urine alkalinization prior to high-dose methotrexate
  • NS 4.5 L/m2 on day 1 after methotrexate; NS 3 L/m2 on day 2, with adjustments made to keep urine pH greater than 7.4
  • 12 hours of hydration prior to cisplatin & 20 hours of hydration after cisplatin; total amount of fluid given over 36hours of prehydration, cisplatin, and posthydration is NS 6 L/m2 with mannitol 8 g/L and potassium 20 mval/L.
  • Magnesium 180 mg/m2 PO "per day throughout the whole chemotherapy time"--as described in COSS-80

35-day cycle for 2 cycles

Regimen variant #4, 12,000/75/120

Study Years of enrollment Evidence Comparator Comparative Efficacy
Marina et al. 2016 (EURAMOS-1 poor response) 2005-2011 Phase III (C) MAPIE Did not meet primary endpoint of EFS

Preceding treatment

Chemotherapy

  • Methotrexate (MTX) as follows:
    • Non-COG sites: 12,000 mg/m2 IV over 4 hours once per day on days 22 & 29
    • COG sites: 12,000 mg/m2 (maximum dose of 20,000 mg) IV over 4 hours once per day on days 22 & 29
  • Doxorubicin (Adriamycin) 37.5 mg/m2 IV once per day on days 1 & 2
  • Cisplatin (Platinol) 40 mg/m2/day IV continuous infusion over 72 hours, started on day 1 (total dose per cycle: 120 mg/m2)
    • COG sites: 60 mg/m2 IV once per day on days 1 & 2

Supportive medications

35-day cycle for 2 cycles

Subsequent treatment

References

  1. COSS-82: Winkler K, Beron G, Delling G, Heise U, Kabisch H, Purfürst C, Berger J, Ritter J, Jürgens H, Gerein V, Graf N, Russe W, Gruemayer ER, Ertelt W, Kotz R, Preuzzer P, Prindull G, Brandeis W, Landbeck G. Neoadjuvant chemotherapy of osteosarcoma: results of a randomized cooperative trial (COSS-82) with salvage chemotherapy based on histological tumor response. J Clin Oncol. 1988 Feb;6(2):329-37. link to original article contains verified protocol PubMed
  2. Bramwell VH, Burgers M, Sneath R, Souhami R, van Oosterom AT, Voûte PA, Rouesse J, Spooner D, Craft AW, Somers R, Pringle J, Malcolm AJ, van der Eiiken J, Thomas D, Uscinska B, Machin D, van Glabbeke M; European Osteosarcoma Intergroup. A comparison of two short intensive adjuvant chemotherapy regimens in operable osteosarcoma of limbs in children and young adults: the first study of the European Osteosarcoma Intergroup. J Clin Oncol. 1992 Oct;10(10):1579-91. link to original article contains verified protocol PubMed
  3. IOR/OS-2: Bacci G, Picci P, Ferrari S, Ruggieri P, Casadei R, Tienghi A, Brach del Prever A, Gherlinzoni F, Mercuri M, Monti C. Primary chemotherapy and delayed surgery for nonmetastatic osteosarcoma of the extremities: results in 164 patients preoperatively treated with high doses of methotrexate followed by cisplatin and doxorubicin. Cancer. 1993 Dec 1;72(11):3227-38. link to original article PubMed
    1. Update: Bacci G, Ferrari S, Bertoni F, Ruggieri P, Picci P, Longhi A, Casadei R, Fabbri N, Forni C, Versari M, Campanacci M. Long-term outcome for patients with nonmetastatic osteosarcoma of the extremity treated at the Istituto Ortopedico Rizzoli according to the Istituto Ortopedico Rizzoli/Osteosarcoma-2 protocol: an updated report. J Clin Oncol. 2000 Dec 15;18(24):4016-27. link to original article contains verified protocol PubMed
  4. EURAMOS-1 good response: Bielack SS, Smeland S, Whelan JS, Marina N, Jovic G, Hook JM, Krailo MD, Gebhardt M, Pápai Z, Meyer J, Nadel H, Randall RL, Deffenbaugh C, Nagarajan R, Brennan B, Letson GD, Teot LA, Goorin A, Baumhoer D, Kager L, Werner M, Lau CC, Sundby Hall K, Gelderblom H, Meyers P, Gorlick R, Windhager R, Helmke K, Eriksson M, Hoogerbrugge PM, Schomberg P, Tunn PU, Kühne T, Jürgens H, van den Berg H, Böhling T, Picton S, Renard M, Reichardt P, Gerss J, Butterfass-Bahloul T, Morris C, Hogendoorn PC, Seddon B, Calaminus G, Michelagnoli M, Dhooge C, Sydes MR, Bernstein M; EURAMOS-1 investigators. Methotrexate, doxorubicin, and cisplatin (MAP) plus maintenance pegylated interferon alfa-2b versus MAP alone in patients with resectable high-grade osteosarcoma and good histologic response to preoperative map: first results of the EURAMOS-1 good response randomized controlled trial. J Clin Oncol. 2015 Jul 10;33(20):2279-87. Epub 2015 Jun 1. link to original article link to PMC article PubMed
  5. EURAMOS-1 poor response: Marina NM, Smeland S, Bielack SS, Bernstein M, Jovic G, Krailo MD, Hook JM, Arndt C, van den Berg H, Brennan B, Brichard B, Brown KL, Butterfass-Bahloul T, Calaminus G, Daldrup-Link HE, Eriksson M, Gebhardt MC, Gelderblom H, Gerss J, Goldsby R, Goorin A, Gorlick R, Grier HE, Hale JP, Hall KS, Hardes J, Hawkins DS, Helmke K, Hogendoorn PC, Isakoff MS, Janeway KA, Jürgens H, Kager L, Kühne T, Lau CC, Leavey PJ, Lessnick SL, Mascarenhas L, Meyers PA, Mottl H, Nathrath M, Papai Z, Randall RL, Reichardt P, Renard M, Safwat AA, Schwartz CL, Stevens MC, Strauss SJ, Teot L, Werner M, Sydes MR, Whelan JS. Comparison of MAPIE versus MAP in patients with a poor response to preoperative chemotherapy for newly diagnosed high-grade osteosarcoma (EURAMOS-1): an open-label, international, randomised controlled trial. Lancet Oncol. 2016 Oct;17(10):1396-1408. Epub 2016 Aug 25. link to original article link to PMC article contains verified protocol PubMed NCT00134030

MAPI

back to top

MAPI: High-dose Methotrexate, Adriamycin (Doxorubicin), Platinol (Cisplatin), Ifosfamide

Regimen

Study Evidence
Bacci et al. 2003 Phase II

Preceding treatment

Chemotherapy

  • Methotrexate (MTX) 12,000 mg/m2 IV over 4 hours once on day 36
    • If 4-hour methotrexate level is less than 10,000 nmol/L, the next cycle's dose is increased by 2000 mg/m2
  • Doxorubicin (Adriamycin) 90 mg/m2 IV continuous infusion over 24 hours, started on day 1
  • Cisplatin (Platinol) 60 mg/m2/day IV continuous infusion over 48 hours, started on day 43 (total dose per cycle: 120 mg/m2)
  • Ifosfamide (Ifex) 3000 mg/m2/day IV continuous infusion over 120 hours, started on day 22, given with Mesna (Mesnex) (total dose per cycle: 15,000 mg/m2)

Supportive medications

  • Mesna (Mesnex) 3000 mg/m2/day IV continuous infusion over 120 hours, started on day 22, given with Ifosfamide (Ifex) (total dose per cycle: 15,000 mg/m2)
  • Folinic acid (Leucovorin) 15 mg (route not specified) every 6 hours x 11 doses, starting day 36, 24 hours after the start of Methotrexate (MTX)
  • Hydration during and after Methotrexate (MTX) as described by: Rosen G, Nirenberg A. Chemotherapy for osteogenic sarcoma: an investigative method, not a recipe. Cancer Treat Rep. 1982 Sep;66(9):1687-97. PubMed

9-week cycle for 3 cycles

References

  1. Bacci G, Briccoli A, Rocca M, Ferrari S, Donati D, Longhi A, Bertoni F, Bacchini P, Giacomini S, Forni C, Manfrini M, Galletti S. Neoadjuvant chemotherapy for osteosarcoma of the extremities with metastases at presentation: recent experience at the Rizzoli Institute in 57 patients treated with cisplatin, doxorubicin, and a high dose of methotrexate and ifosfamide. Ann Oncol. 2003 Jul;14(7):1126-34. link to original article contains verified protocol PubMed

MAPIE

back to top

MAPIE: High-dose Methotrexate, Adriamycin (Doxorubicin), Platinol (Cisplatin), Ifosfamide, Etoposide

Protocol

Study Evidence
Bacci et al. 1993 (IOR/OS-2) Phase II

Preceding treatment

Chemotherapy, part 1

Supportive medications

69-day cycle for 3 cycles, then--note: Figure 1 of Bacci et al. 2000 actually depicted the first cycle as being 68 days, and cycles 2 & 3 being 69 days.

Chemotherapy, part 2

Given once after postoperative chemotherapy cycle 3

References

  1. IOR/OS-2: Bacci G, Picci P, Ferrari S, Ruggieri P, Casadei R, Tienghi A, Brach del Prever A, Gherlinzoni F, Mercuri M, Monti C. Primary chemotherapy and delayed surgery for nonmetastatic osteosarcoma of the extremities: results in 164 patients preoperatively treated with high doses of methotrexate followed by cisplatin and doxorubicin. Cancer. 1993 Dec 1;72(11):3227-38. link to original article PubMed
    1. Update: Bacci G, Ferrari S, Bertoni F, Ruggieri P, Picci P, Longhi A, Casadei R, Fabbri N, Forni C, Versari M, Campanacci M. Long-term outcome for patients with nonmetastatic osteosarcoma of the extremity treated at the Istituto Ortopedico Rizzoli according to the Istituto Ortopedico Rizzoli/Osteosarcoma-2 protocol: an updated report. J Clin Oncol. 2000 Dec 15;18(24):4016-27. link to original article contains verified protocol PubMed
  2. EURAMOS-1 poor response: Marina NM, Smeland S, Bielack SS, Bernstein M, Jovic G, Krailo MD, Hook JM, Arndt C, van den Berg H, Brennan B, Brichard B, Brown KL, Butterfass-Bahloul T, Calaminus G, Daldrup-Link HE, Eriksson M, Gebhardt MC, Gelderblom H, Gerss J, Goldsby R, Goorin A, Gorlick R, Grier HE, Hale JP, Hall KS, Hardes J, Hawkins DS, Helmke K, Hogendoorn PC, Isakoff MS, Janeway KA, Jürgens H, Kager L, Kühne T, Lau CC, Leavey PJ, Lessnick SL, Mascarenhas L, Meyers PA, Mottl H, Nathrath M, Papai Z, Randall RL, Reichardt P, Renard M, Safwat AA, Schwartz CL, Stevens MC, Strauss SJ, Teot L, Werner M, Sydes MR, Whelan JS. Comparison of MAPIE versus MAP in patients with a poor response to preoperative chemotherapy for newly diagnosed high-grade osteosarcoma (EURAMOS-1): an open-label, international, randomised controlled trial. Lancet Oncol. 2016 Oct;17(10):1396-1408. Epub 2016 Aug 25. link to original article link to PMC article PubMed NCT00134030

M-EI

back to top

M-EI: Methotrexate, Etoposide, Ifosfamide

Protocol

Study Evidence
Le Deley et al. 2007 (SFOP OS94) Non-randomized portion of RCT

Preceding treatment

Chemotherapy, part 1

  • Methotrexate (MTX) 12,000 mg/m2 IV over 4 hours once per day on days 1, 8, 15
    • Given in D5W 1L with sodium bicarbonate 1 mEq/kg
  • Etoposide (Vepesid) 75 mg/m2 IV over 60 minutes once per day on days 22 to 25 (week 4)
    • Given in NS 250 to 500 mL
  • Ifosfamide (Ifex) 3000 mg/m2 IV over 3 hours once per day on days 22 to 25 (week 4), given during Mesna (Mesnex) infusion (total dose per cycle: 12,000 mg/m2)
    • Given in NS 250 to 500 mL

Supportive medications

  • Folinic acid (Leucovorin) 15 mg PO every 6 hours for up to 11 doses, starting on days 1, 8, 15, starting 20 hours after the completion of Methotrexate (MTX) infusion
  • For methotrexate: hydration & urine alkalinization by PO and IV routes to maintain 1.6 L/m2 urine output over the first 24 hours and 2 L/m2 on days 2 & 3, with urine pH greater than 7
  • Daily monitoring of methotrexate levels and creatinine
  • Mesna (Mesnex) 3600 mg/m2/day IV continuous infusion over 96 hours, started on day 22 (week 4) (total dose per cycle: 14,400 mg/m2)
  • Up to 2 L/day hydration with ifosfamide & mesna

28-day cycle for 3 cycles, followed by:

Chemotherapy, part 2

  • Methotrexate (MTX) 12,000 mg/m2 IV over 4 hours once per day on days 1, 8, 15
    • Given in D5W 1L with sodium bicarbonate 1 mEq/kg

Supportive medications

  • Folinic acid (Leucovorin) 15 mg PO every 6 hours for up to 11 doses, starting on days 1, 8, 15, starting 20 hours after the completion of Methotrexate (MTX) infusion
  • For methotrexate: hydration & urine alkalinization by PO and IV routes to maintain 1.6 L/m2 urine output over the first 24 hours and 2 L/m2 on days 2 & 3, with urine pH greater than 7
  • Daily monitoring of methotrexate levels and creatinine

21-day course

References

  1. SFOP OS94: Le Deley MC, Guinebretière JM, Gentet JC, Pacquement H, Pichon F, Marec-Bérard P, Entz-Werlé N, Schmitt C, Brugières L, Vanel D, Dupoüy N, Tabone MD, Kalifa C; Société Française d'Oncologie Pédiatrique (SFOP). SFOP OS94: a randomised trial comparing preoperative high-dose methotrexate plus doxorubicin to high-dose methotrexate plus etoposide and ifosfamide in osteosarcoma patients. Eur J Cancer. 2007 Mar;43(4):752-61. Epub 2007 Jan 30. link to original article contains verified protocol PubMed NCT00180908
  2. OS2006: Piperno-Neumann S, Le Deley MC, Rédini F, Pacquement H, Marec-Bérard P, Petit P, Brisse H, Lervat C, Gentet JC, Entz-Werlé N, Italiano A, Corradini N, Bompas E, Penel N, Tabone MD, Gomez-Brouchet A, Guinebretière JM, Mascard E, Gouin F, Chevance A, Bonnet N, Blay JY, Brugières L; Sarcoma Group of UNICANCER; SFCE; GSF-GETO. Zoledronate in combination with chemotherapy and surgery to treat osteosarcoma (OS2006): a randomised, multicentre, open-label, phase 3 trial. Lancet Oncol. 2016 Aug;17(8):1070-1080. Epub 2016 Jun 17. link to original article PubMed NCT00470223
    1. Update: Gaspar N, Occean BV, Pacquement H, Bompas E, Bouvier C, Brisse HJ, Castex MP, Cheurfa N, Corradini N, Delaye J, Entz-Werlé N, Gentet JC, Italiano A, Lervat C, Marec-Berard P, Mascard E, Redini F, Saumet L, Schmitt C, Tabone MD, Verite-Goulard C, Le Deley MC, Piperno-Neumann S, Brugieres L; SFCE; GSF-GETO; UNICANCER sarcoma group. Results of methotrexate-etoposide-ifosfamide based regimen (M-EI) in osteosarcoma patients included in the French OS2006/sarcome-09 study. Eur J Cancer. 2018 Jan;88:57-66. Epub 2017 Nov 28. link to original article PubMed

Methotrexate & Vincristine

back to top

Regimen

Study Evidence
Jaffe et al. 1974 Non-randomized

Of historic interest.

Preceding treatment

Chemotherapy

Supportive medications

21-day cycle for up to 35 cycles (2 years)

References

  1. Jaffe N, Frei E 3rd, Traggis D, Bishop Y. Adjuvant methotrexate and citrovorum-factor treatment of osteogenic sarcoma. N Engl J Med. 1974 Nov 7;291(19):994-7. link to original article PubMed

Relapsed, refractory, or metastatic, first-line

Cisplatin & Doxorubicin

back to top

AP: Adriamycin (Doxorubicin) & Platinol (Cisplatin)

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Bramwell et al. 1997 (EOI 80831/MRC B002) 1983-1986 Phase III (E-de-esc) MAP Inferior OS

Note: the authors state that "[i]t is likely that random bias in the population..accounts for the difference in outcome favoring the three-drug treatment in patients with metastatic disease."

Chemotherapy

Supportive medications

  • Prehydration: normal saline 400 mL/m2 and D5W 400 mL/m2 over 2 hours--the reference did not clarify if these two solutions are given at the same time
  • The volume of fluid for cisplatin continuous infusion is 2400 mL/m2 NS, with KCl 80 mEq/L and mannitol 32,000 mg/m2
  • Posthydration: D5W 600 mL/m2 over 6 hours, with KCl 20 mEq/L and mannitol 8000 mg/m2; and NS 600 mL/m2 over 6 hours, with KCl 20 mEq/L, magnesium sulfate 2 mmol/L, and calcium gluconate 0.6 mmol/L--the reference did not clarify if these two solutions are given at the same time. Then D5W 600 mL/m2 over 12 hours, with KCl 20 mEq/L and mannitol 8000 mg/m2.
  • Furosemide (Lasix) 20 to 40 mg IV if urine output is less than 400 mL/m2 over 6 hours

21-day cycle for 6 cycles

References

  1. EOI 80831/MRC B002: Bramwell VH, Burgers MV, Souhami RL, Taminiau AH, Van Der Eijken JW, Craft AW, Malcolm AJ, Uscinska B, Kirkpatrick AL, Machin D, Van Glabbeke MM; European Osteosarcoma Intergroup. A randomized comparison of two short intensive chemotherapy regimens in children and young adults with osteosarcoma: results in patients with metastases: a study of the European Osteosarcoma Intergroup. Sarcoma. 1997;1(3-4):155-60. link to original article contains verified partial protocol link to PMC article PubMed

Doxorubicin monotherapy

back to top

Regimen

Study Evidence
Cores et al. 1972 Non-randomized, <20 pts

Of historic interest.

Chemotherapy

References

  1. Cores EP, Holland JF, Wang JJ, Sinks LF. Doxorubicin in disseminated osteosarcoma. JAMA. 1972 Sep 4;221(10):1132-8. link to original article PubMed

MAP

back to top

MAP: High-dose Methotrexate, Adriamycin (Doxorubicin), Platinol (Cisplatin)

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Bramwell et al. 1997 (EOI 80831/MRC B002) 1983-1986 Phase III (E-esc) Cisplatin & Doxorubicin Superior OS

Note: the authors state that "[i]t is likely that random bias in the population..accounts for the difference in outcome favoring the three-drug treatment in patients with metastatic disease."

Chemotherapy

Supportive medications

  • Folinic acid (Leucovorin) 12 mg/m2 IV every 6 hours x 10 doses or 15 mg/m2 PO every 6 hours x 10 doses, starting 24 hours after the start of methotrexate infusion
    • Monitor methotrexate level at "24 hours and 48 hours"--it is unclear in the reference if this is time after the start/end of methotrexate, beginning of leucovorin, or something else
    • Methotrexate levels higher than 100 nmol/L at 48 hours required additional leucovorin rescue
  • Prehydration for methotrexate: "0.9 NaCl:D5W"--unclear if this means either normal saline or D5W can be used--750 mL/m2 over 6 hours, with KCl 20 mEq/L
  • The volume of fluid for methotrexate is D5W 1000 mL, to be given over 6 hours
  • Posthydration for methotrexate: Alternating liters of D5W and NS 3000 mL/m2 over 24 hours, with KCl 60 mEq/L.
  • Sodium bicarbonate 3 g PO Q6H, starting 12 hours before methotrexate, and sodium bicarbonate 167 mmol/L IV until serum methotrexate level is less than 8000 to 10,000 nmol/L. Note: the reference is not clear about when/if PO sodium bicarbonate is stopped, when IV sodium bicarbonate is started, or the administration rate of IV sodium bicarbonate.
  • Prehydration for cisplatin: normal saline 400 mL/m2 and D5W 400 mL/m2 over 2 hours--the reference did not clarify if these two solutions are given at the same time
  • The volume of fluid for cisplatin continuous infusion is 2400 mL/m2 NS, with KCl 80 mEq/L and mannitol 32,000 mg/m2
  • Posthydration for cisplatin: D5W 600 mL/m2 over 6 hours, with KCl 20 mEq/L and mannitol 8000 mg/m2; and NS 600 mL/m2 over 6 hours, with KCl 20 mEq/L, magnesium sulfate 2 mmol/L, and calcium gluconate 0.6 mmol/L--the reference did not clarify if these two solutions are given at the same time. Then D5W 600 mL/m2 over 12 hours, with KCl 20 mEq/L and mannitol 8000 mg/m2.
  • With cisplatin, Furosemide (Lasix) 20 to 40 mg IV if urine output is less than 400 mL/m2 over 6 hours

21-day cycle for 4 cycles

References

  1. EOI 80831/MRC B002: Bramwell VH, Burgers MV, Souhami RL, Taminiau AH, Van Der Eijken JW, Craft AW, Malcolm AJ, Uscinska B, Kirkpatrick AL, Machin D, Van Glabbeke MM; European Osteosarcoma Intergroup. A randomized comparison of two short intensive chemotherapy regimens in children and young adults with osteosarcoma: results in patients with metastases: a study of the European Osteosarcoma Intergroup. Sarcoma. 1997;1(3-4):155-60. link to original article contains verified partial protocol link to PMC article PubMed

Relapsed, refractory, or metastatic, subsequent lines

Cabozantinib monotherapy

back to top

Regimen variant #1, adult dosing

Study Years of enrollment Evidence
Italiano et al. 2020 (CABONE) 2015-2018 Phase II

Targeted therapy

28-day cycles

Regimen variant #2, pediatric dosing

Study Years of enrollment Evidence
Italiano et al. 2020 (CABONE) 2015-2018 Phase II

Note: this dosing was for children aged less than 16 years.

Targeted therapy

28-day cycles

References

  1. CABONE: Italiano A, Mir O, Mathoulin-Pelissier S, Penel N, Piperno-Neumann S, Bompas E, Chevreau C, Duffaud F, Entz-Werlé N, Saada E, Ray-Coquard I, Lervat C, Gaspar N, Marec-Berard P, Pacquement H, Wright J, Toulmonde M, Bessede A, Crombe A, Kind M, Bellera C, Blay JY. Cabozantinib in patients with advanced Ewing sarcoma or osteosarcoma (CABONE): a multicentre, single-arm, phase 2 trial. Lancet Oncol. 2020 Mar;21(3):446-455. Epub 2020 Feb 17. link to original article contains protocol PubMed NCT02243605

Cyclophosphamide & Etoposide

back to top

Regimen

Study Evidence
Berger et al. 2009 Phase II

Chemotherapy

Supportive medications

At least 21-day cycle for 2 cycles, then restaging

Subsequent treatment

  • Patients with no progression received an experimental protocol with:
    • Samarium-153 10 mCi/kg and/or carboplatin & etoposide based on status of bone metastases (no further details about dose/schedule given)
    • Progression-free patients received reduced intensity stem cell transplant (preferably from a matched sibling donor (MSD))
    • Patients with no MSD received IL-2 maintenance, 5 days a week every 2 weeks x 12 cycles (reference did not specify if a cycle was 2 weeks, 4 weeks, or another length)

References

  1. Berger M, Grignani G, Ferrari S, Biasin E, Brach del Prever A, Aliberti S, Saglio F, Aglietta M, Fagioli F. Phase 2 trial of two courses of cyclophosphamide and etoposide for relapsed high-risk osteosarcoma patients. Cancer. 2009 Jul 1;115(13):2980-7. link to original article contains verified protocol PubMed

Cyclophosphamide & Topotecan

back to top

Regimen

Study Evidence
Saylors et al. 2001 Phase II

Chemotherapy

Supportive medications

  • 500 mL/m/2 fluids IV or PO once per day on days 1 to 5; 2 to 4 hours prior to chemotherapy
  • Antiemetics once per day on days 1 to 5, prior to chemotherapy
  • 3 liters/m2 fluids IV or PO over 24 hours after chemotherapy
  • Filgrastim (Neupogen) 5 mcg/kg SC once per day, starting on day 6, to continue until post-nadir ANC is at least 1500/uL

21-day cycle for 12 to 14 cycles

References

  1. Saylors RL 3rd, Stine KC, Sullivan J, Kepner JL, Wall DA, Bernstein ML, Harris MB, Hayashi R, Vietti TJ; Pediatric Oncology Group. Cyclophosphamide plus topotecan in children with recurrent or refractory solid tumors: a Pediatric Oncology Group phase II study. J Clin Oncol. 2001 Aug 1;19(15):3463-9. link to original article contains verified protocol PubMed

Docetaxel & Gemcitabine

back to top

Regimen

Study Evidence
Navid et al. 2008 Retrospective

17 of the 22 patients in this retrospective review had osteosarcoma.

Chemotherapy

Supportive medications

21-day cycles

References

  1. Retrospective: Navid F, Willert JR, McCarville MB, Furman W, Watkins A, Roberts W, Daw NC. Combination of gemcitabine and docetaxel in the treatment of children and young adults with refractory bone sarcoma. Cancer. 2008 Jul 15;113(2):419-25. link to original article contains verified protocol PubMed

Gemcitabine monotherapy

back to top

Regimen

Study Evidence
Merimsky et al. 2000 Phase II

Chemotherapy

28-day cycles

References

  1. Merimsky O, Meller I, Flusser G, Kollender Y, Issakov J, Weil-Ben-Arush M, Fenig E, Neuman G, Sapir D, Ariad S, Inbar M. Gemcitabine in soft tissue or bone sarcoma resistant to standard chemotherapy: a phase II study. Cancer Chemother Pharmacol. 2000;45(2):177-81. link to original article contains verified protocol PubMed

ICE

back to top

ICE: Ifosfamide, Carboplatin, Etoposide

Regimen

Study Evidence
Van Winkle et al. 2005 Phase II

Note: the reference did not mention Mesna (Mesnex) being used.

Chemotherapy

Supportive medications

  • Depending on the study the patients were enrolled on, they received one of the following:
    • CCG-0894: Filgrastim (Neupogen) 5 or 10 mcg/kg SC once per day, starting 24 hours after completing ICE, and to continue until day 18 if ANC is at least 1000/uL, or until ANC is at least 1000/uL above nadir, whichever comes later
    • CCG-0924: PIXY 321 at doses of 500/750/1000 mcg/m2 SC once per day or 500 mcg/m2 SC twice per day, starting on day 5 and to continue until day 18 unless ANC reached 20,000/uL or platelet count is at least 900 x 109/L for 2 days between days 13 to 18, or until ANC is at least 1000/uL and platelet count is at least 100 x 109/L, whichever comes later
    • CCG-0931: Filgrastim (Neupogen) 5 mcg/kg SC once per day and IL-6 at 2.5, 3.75, or 5 mcg/kg SC twice per day, starting 24 hours after completing ICE. Filgrastim is continued until ANC is at least 1000/uL, and IL-6 is continued until platelets are at least 100 x 109/L for 2 consecutive days or until day 35, whichever comes sooner.

21-day cycles, with next cycle starting as soon as ANC is at least 1000/uL and platelet count is at least 100 x 109/L

Subsequent treatment

  • Resection of disease was allowed after 4 cycles based on patient's response to ICE

References

  1. Van Winkle P, Angiolillo A, Krailo M, Cheung YK, Anderson B, Davenport V, Reaman G, Cairo MS; Children's Cancer Group. Ifosfamide, carboplatin, and etoposide (ICE) reinduction chemotherapy in a large cohort of children and adolescents with recurrent/refractory sarcoma: the Children's Cancer Group (CCG) experience. Pediatr Blood Cancer. 2005 Apr;44(4):338-47. link to original article contains verified protocol PubMed

IE

back to top

IE: Ifosfamide & Etoposide

Regimen

Study Evidence
Gentet et al. 1997 Phase II

Chemotherapy

  • Ifosfamide (Ifex) 3000 mg/m2 IV over 3 hours once per day on days 1 to 4
    • Given in D5W 250 to 500 mL
  • Etoposide (Vepesid) 75 mg/m2 IV over 60 minutes once per day on days 1 to 4
    • Given in D5W 250 to 500 mL

Supportive medications

  • Mesna (Mesnex) 3600 mg/m2/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 14,400 mg/m2)
  • At least 2000 mL/m2/day of hydration with chemotherapy

21- to 28-day cycle for 2 cycles, with next cycle starting when ANC greater than 1500/uL and platelet count greater than 100 x 109/L

References

  1. Gentet JC, Brunat-Mentigny M, Demaille MC, Pein F, Avet-Loiseau H, Berger C, De Lumley L, Pacquement H, Schmitt C, Sariban E, Pillon P, Bernard JL, Kalifa C. Ifosfamide and etoposide in childhood osteosarcoma: a phase II study of the French Society of Paediatric Oncology. Eur J Cancer. 1997 Feb;33(2):232-7. link to original article contains verified protocol PubMed

Regorafenib monotherapy

back to top

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Davis et al. 2019 (SARC024) 2014-2018 Randomized Phase II (E-esc) Placebo Superior PFS
Median PFS: 3.6 vs 1.7 mo
(HR 0.42, 95% CI 0.21-0.85)

Targeted therapy

28-day cycles

References

  1. SARC024: Davis LE, Bolejack V, Ryan CW, Ganjoo KN, Loggers ET, Chawla S, Agulnik M, Livingston MB, Reed D, Keedy V, Rushing D, Okuno S, Reinke DK, Riedel RF, Attia S, Mascarenhas L, Maki RG. Randomized Double-Blind Phase II Study of Regorafenib in Patients With Metastatic Osteosarcoma. J Clin Oncol. 2019 Jun 1;37(16):1424-1431. Epub 2019 Apr 23. link to original article link to PMC article contains verified protocol PubMed NCT02048371

Samarium-153 with stem cell support

back to top

Regimen

Study Evidence
Anderson et al. 2002 Phase I
  • Peripheral blood progenetor cell (PBPC) or bone marrow harvest and cryopreservation of at least 2 x 106 CD34+ cells/kg

Radiotherapy

Supportive medications

On day +14, infuse peripheral blood progenetor cell (PBPC) or bone marrow cells

References

  1. Phase 1: Anderson PM, Wiseman GA, Dispenzieri A, Arndt CA, Hartmann LC, Smithson WA, Mullan BP, Bruland OS. High-dose samarium-153 ethylene diamine tetramethylene phosphonate: low toxicity of skeletal irradiation in patients with osteosarcoma and bone metastases. J Clin Oncol. 2002 Jan 1;20(1):189-96. link to original article contains verified protocol PubMed

Sorafenib monotherapy

back to top

Regimen

Study Years of enrollment Evidence
Grignani et al. 2011 2008-2009 Phase II

Targeted therapy

28-day cycles

References

  1. Grignani G, Palmerini E, Dileo P, Asaftei SD, D'Ambrosio L, Pignochino Y, Mercuri M, Picci P, Fagioli F, Casali PG, Ferrari S, Aglietta M. A phase II trial of sorafenib in relapsed and unresectable high-grade osteosarcoma after failure of standard multimodal therapy: an Italian Sarcoma Group study. Ann Oncol. 2012 Feb;23(2):508-16. Epub 2011 Apr 28. link to original article contains verified protocol PubMed EudraCT 2007-004396-19