Osteosarcoma

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

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!

• Pediatric osteosarcoma regimens can be found here.

26 regimens on this page 37 variants on this page

Guidelines

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

ESMO

• 2009: Bielack et al. Osteosarcoma: ESMO clinical recommendations for diagnosis, treatment and follow-up PubMed
  • 2008: Bielack et al. Osteosarcoma: ESMO clinical recommendations for diagnosis, treatment and follow-up PubMed
  • 2003: Saeter. ESMO Minimum Clinical Recommendations for diagnosis, treatment and follow-up of osteosarcoma PubMed

NCCN

• NCCN does not currently have guidelines at this granular level; please see NCCN Guidelines - Bone Cancer.

Neoadjuvant therapy

Cisplatin & Doxorubicin

AP: Adriamycin (Doxorubicin) & Platinol (Cisplatin)

Regimen variant #1

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Bramwell et al. 1992	1983-1986	Phase 3 (E-switch-ic)	MAP	Seems to have superior DFS
Souhami et al. 1997	1986-1991	Phase 3 (E-de-esc)	Multi-drug T10 protocol	Did not meet co-primary endpoints of PFS/OS

Chemotherapy

• Cisplatin (Platinol) 100 mg/m² IV continuous infusion over 24 hours, started on day 1
• Doxorubicin (Adriamycin) 25 mg/m² IV bolus once per day on days 1 to 3

Supportive therapy

• Prehydration: normal saline 400 mL/m² and D5W 400 mL/m² IV 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

• Definitive surgery on week 9, then adjuvant AP that starts 14 to 28 days after surgery

Regimen variant #2

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Lewis et al. 2007 (EORTC 80931)	1993-2002	Phase 3 (C)	Cisplatin & Doxorubicin; dose-intense	Did not meet primary endpoint of OS

Chemotherapy

• Cisplatin (Platinol) 100 mg/m² IV continuous infusion over 24 hours, started on day 1
• Doxorubicin (Adriamycin) 25 mg/m² IV over 4 hours once per day on days 1 to 3

Supportive therapy

• 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

• Definitive surgery in a 14-day window between cycles 2 & 3, then adjuvant AP

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 dosing details in manuscript 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 dosing details in manuscript PubMed NCT00002539

Cisplatin, Epirubicin, Ifosfamide

Regimen

Study	Evidence
Basaran et al. 2007	Phase 2

Chemotherapy

• Cisplatin (Platinol) 100 mg/m² IV over 2 hours once on day 1
• Epirubicin (Ellence) 90 mg/m² IV over 15 minutes once on day 1
• Ifosfamide (Ifex) 2000 mg/m² IV over 4 hours once per day on days 2 to 4, given with mesna

Supportive therapy

• Mesna (Mesnex) 2000 mg/m² IV over 4 hours once per day on days 2 to 4, given with ifosfamide
• Pre- and post-hydration with mannitol diuresis for cisplatin

21-day cycle for 3 cycles

Subsequent treatment

• Surgery, then adjuvant cisplatin, epirubicin, ifosfamide

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 dosing details in manuscript PubMed

MA

MA: High-dose Methotrexate, Adriamycin (Doxorubicin)

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Le Deley et al. 2007 (SFOP OS94)	1994-2001	Phase 3 (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 therapy

• Leucovorin (Folinic acid) 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 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 by the following response-based criteria:
  • SFOP OS94, patients with good response: Adjuvant MA
  • SFOP OS94, patients with poor response: Adjuvant IE

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 dosing details in manuscript PubMed NCT00180908

MAP

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

Regimen variant #1

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Bramwell et al. 1992	1983-1986	Phase 3 (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

• Methotrexate (MTX) 8000 mg/m² IV over 4 to 6 hours once on day 1
• Doxorubicin (Adriamycin) 25 mg/m² IV bolus once per day on days 11 to 13
• Cisplatin (Platinol) 100 mg/m² IV continuous infusion over 24 hours, started on day 11

Supportive therapy

• Leucovorin (Folinic acid) 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 IV 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.
• Furosemide (Lasix) 20 to 40 mg IV if urine output is less than 400 mL/m² over 6 hours during cisplatin

21-day cycle for 2 cycles

Subsequent treatment

• Definitive surgery on week 9, then adjuvant MAP that starts 14 to 28 days after surgery

Regimen variant #2

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

Chemotherapy

• Methotrexate (MTX) 8000 mg/m² IV over 6 hours once on day 1
• Doxorubicin (Adriamycin) 60 mg/m² IV over 8 hours once on day 9, starting 48 hours after the start of cisplatin
• Cisplatin (Platinol) 40 mg/m²/day IA continuous infusion over 72 hours, started on day 7 (total dose per cycle: 120 mg/m²)

Supportive therapy

• Leucovorin (Folinic acid) 15 mg IV every 6 hours x 11 doses on days 2 to 4, starting 24 hours after the start of methotrexate infusion
• Hydration during and after methotrexate infusion

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.
  • IOR/OS-2, at least 90% tumor necrosis in the surgically removed specimen: Adjuvant MAP
  • IOR/OS-2, less than 90% tumor necrosis in the surgically removed specimen: Adjuvant MAPIE

Regimen variant #3

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Winkler et al. 1988 (COSS-82)	1982-1984	Phase 3 (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 therapy

• Leucovorin (Folinic acid) 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

Subsequent treatment

• Surgery, then risk-adapted treatment:
  • COSS-82, good response: Adjuvant MAP
  • COSS-82, poor response: Adjuvant IP-BCD

Regimen variant #4

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Winkler et al. 1984 (COSS-80)	1979-1982	Phase 3 (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

• Methotrexate (MTX) as follows:
  • Cycle 1: 12,000 mg/m² (maximum dose of 20,000 mg) IV over 4 hours once per day on days 29 & 36
  • Cycles 2 to 4: 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) as follows:
  • Cycles 1, 3, 4: 45 mg/m² IV bolus once per day on days 1 & 2
  • Cycle 2: 45 mg/m² IV bolus once per day on days 15 & 16 (delayed during cycle 2 until after surgery)
• Cisplatin (Platinol) 120 mg/m² IV over 5 hours once on day 43

Supportive therapy

• Leucovorin (Folinic acid) 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 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
• 3 hours of hydration prior to cisplatin & 3 hours of hydration after cisplatin; 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

8-week cycle for 4 cycles, with surgery done during cycle 2 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 dosing details in manuscript 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 dosing details in manuscript 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 dosing details in manuscript 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 dosing details in manuscript PubMed

MAPI

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

Regimen

Study	Evidence
Bacci et al. 2003	Phase 2

Chemotherapy

• Methotrexate (MTX) 12,000 mg/m² IV over 4 hours once on day 1
• 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 (total dose per cycle: 15,000 mg/m²)

Supportive therapy

• Leucovorin (Folinic acid) 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
• 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 (total dose: 15,000 mg/m²)

42-day cycle for 2 cycles

Subsequent treatment

• Surgery, then adjuvant MAPI

Dose and schedule modifications

• If 4-hour methotrexate level is less than 10,000 nmol/L, the next cycle's methotrexate dose is increased by 2000 mg/m²

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 dosing details in manuscript PubMed

M-EI

M-EI: Methotrexate, Etoposide, Ifosfamide

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Le Deley et al. 2007 (SFOP OS94)	1994-2001	Phase 3 (E-switch-ic)	MA	Might have superior EFS
Piperno-Neumann et al. 2016 (OS2006)	2007-2014	Phase 3 (C)	M-EI & Zoledronic acid	Might have superior EFS EFS36: 63.4% vs 57.1% (HR 0.74, 95% CI 0.51-1.05)

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
    • Given in NS 250 to 500 mL

Supportive therapy

• Leucovorin (Folinic acid) 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 (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:
  • SFOP OS94, patients with good response: Adjuvant M-EI
  • SFOP OS94, patients with poor response: Adjuvant AP

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 dosing details in manuscript 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

AP: Adriamycin (Doxorubicin) & Platinol (Cisplatin)

Regimen variant #1

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Bramwell et al. 1992	1983-1986	Phase 3 (E-esc)	MAP	Seems to have superior DFS
Souhami et al. 1997	1986-1991	Phase 3 (E-de-esc)	Multi-drug T10 protocol	Did not meet co-primary endpoints of PFS/OS

Preceding treatment

• Neoadjuvant AP, then surgery

Chemotherapy

• Cisplatin (Platinol) 100 mg/m² IV continuous infusion over 24 hours, started on day 1
• Doxorubicin (Adriamycin) 25 mg/m² IV bolus once per day on days 1 to 3

Supportive therapy

• Prehydration: normal saline 400 mL/m² and D5W 400 mL/m² IV 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	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Lewis et al. 2007 (EORTC 80931)	1993-2002	Phase 3 (C)	Cisplatin & Doxorubicin; dose-intense	Did not meet primary endpoint of OS

Preceding treatment

• Neoadjuvant AP, then surgery

Chemotherapy

• Cisplatin (Platinol) 100 mg/m² IV continuous infusion over 24 hours, started on day 1
• Doxorubicin (Adriamycin) 25 mg/m² IV over 4 hours once per day on days 1 to 3

Supportive therapy

• 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	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Lewis et al. 2007 (EORTC 80931)	1993-2002	Phase 3 (E-esc)	Cisplatin & Doxorubicin; conventional	Did not meet primary endpoint of OS

Preceding treatment

• Neoadjuvant AP, then surgery

Chemotherapy

• Cisplatin (Platinol) 100 mg/m² IV continuous infusion over 24 hours, started on day 1
• Doxorubicin (Adriamycin) 25 mg/m² IV over 4 hours once per day on days 1 to 3

Supportive therapy

• Growth factor suppor with ONE of the following:
  • Filgrastim (Neupogen) 5 mcg/kg SC once per day on days 4 to 13
  • Lenograstim (Granocyte) 5 mcg/kg SC once per day on days 4 to 13
• 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

14-day cycle for 3 cycles

Regimen variant #4

Study	Dates of enrollment	Evidence
Winkler et al. 1988 (COSS-82)	1982-1984	Non-randomized part of phase 3 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

• Neoadjuvant M-BCD, then surgery, with poor response

Chemotherapy

• Cisplatin (Platinol) 90 mg/m² IV over 4 hours once on day 3
• Doxorubicin (Adriamycin) 30 mg/m² IV bolus once per day on days 1 & 2

Supportive therapy

• 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	Dates of enrollment	Evidence
Le Deley et al. 2007 (SFOP OS94)	1994-2001	Non-randomized part of phase 3 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

• Neoadjuvant M-EI, then surgery, with poor response

Chemotherapy

• Cisplatin (Platinol) 120 mg/m² IV (schedule not specified)
• Doxorubicin (Adriamycin) 70 mg/m² IV over 6 hours (schedule not specified)

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 dosing details in manuscript 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 dosing details in manuscript 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 dosing details in manuscript 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 dosing details in manuscript PubMed NCT00180908

Cisplatin, Epirubicin, Ifosfamide

Regimen

Study	Evidence
Basaran et al. 2007	Phase 2

Preceding treatment

• Neoadjuvant cisplatin, epirubicin, ifosfamide, then surgery

Chemotherapy

• Cisplatin (Platinol) 100 mg/m² IV over 2 hours once on day 1
• Epirubicin (Ellence) 90 mg/m² IV over 15 minutes once on day 1
• Ifosfamide (Ifex) 2000 mg/m² IV over 4 hours once per day on days 2 to 4, given with mesna

Supportive therapy

• Mesna (Mesnex) 2000 mg/m² IV over 4 hours once per day on days 2 to 4, given with ifosfamide
• Pre- and post-hydration with mannitol diuresis for cisplatin

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 dosing details in abstract PubMed

IE

IE: Ifosfamide, Etoposide

Regimen

Study	Dates of enrollment	Evidence
Le Deley et al. 2007 (SFOP OS94)	1994-2001	Non-randomized part of phase 3 RCT

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

Preceding treatment

• Neoadjuvant MA, then surgery, with poor response

Chemotherapy

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

Supportive therapy

• 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 dosing details in manuscript PubMed NCT00180908

MA

MA: High-dose Methotrexate, Adriamycin (Doxorubicin)

Regimen

Study	Dates of enrollment	Evidence
Le Deley et al. 2007 (SFOP OS94)	1994-2001	Non-randomized part of phase 3 RCT

Preceding treatment

• Neoadjuvant MA, then surgery, with good response

Chemotherapy

• 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
• Doxorubicin (Adriamycin) as follows:
  • Cycles 1 to 3: 70 mg/m² IV over 6 hours once on day 22

Supportive therapy

• Leucovorin (Folinic acid) 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 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 4 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 dosing details in manuscript PubMed NCT00180908

MAP

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

Regimen variant #1, 8000/75/100

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Bramwell et al. 1992	1983-1986	Phase 3 (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

• Neoadjuvant MAP, then surgery

Chemotherapy

• Methotrexate (MTX) 8000 mg/m² IV over 4 to 6 hours once on day 1
• Doxorubicin (Adriamycin) 25 mg/m² IV bolus once per day on days 11 to 13
• Cisplatin (Platinol) 100 mg/m² IV continuous infusion over 24 hours, started on day 11

Supportive therapy

• Leucovorin (Folinic acid) 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 IV 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

Regimen variant #2, 8000/90/120

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

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

Preceding treatment

• Neoadjuvant MAP, then surgery, with at least 90% tumor necrosis in the surgically removed specimen

Chemotherapy

• Methotrexate (MTX) as follows:
  • Cycles 1 to 3: 8000 mg/m² IV over 6 hours once on day 21
• Doxorubicin (Adriamycin) 45 mg/m² IV over 4 hours once per day on days 1 & 2
• Cisplatin (Platinol) as follows:
  • Cycles 1 to 3: 40 mg/m²/day IV continuous infusion over 72 hours, started on day 27 (total dose per cycle: 120 mg/m²)

Supportive therapy

• Leucovorin (Folinic acid) as follows:
  • Cycles 1 to 3: 15 mg IV every 6 hours x 11 doses on days 22 to 24, starting 24 hours after the start of methotrexate infusion
• Hydration during and after methotrexate infusion

48-day cycle for 4 cycles

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

Study	Dates of enrollment	Evidence
Winkler et al. 1988 (COSS-82)	1982-1984	Non-randomized part of phase 3 RCT

Preceding treatment

• Neoadjuvant MAP, then surgery, with good response

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 therapy

• Leucovorin (Folinic acid) 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	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Marina et al. 2016 (EURAMOS-1 poor response)	2005-2011	Phase 3 (C)	MAPIE	Did not meet primary endpoint of EFS

Preceding treatment

• Neoadjuvant MAP x 2, then surgery

Chemotherapy

• Methotrexate (MTX) by the following site-based criteria:
  • 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) by the following site-based criteria:
  • Non-COG sites: 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 therapy

• Leucovorin (Folinic acid) 15 mg/m² (route/schedule not specified), starting 24 to 48 hours after methotrexate infusion, continued until MTX level less than 100 nmol/L

35-day cycle for 2 cycles

Subsequent treatment

• Adjuvant MA x 2

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 dosing details in manuscript 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 dosing details in manuscript 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 dosing details in manuscript 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 dosing details in manuscript PubMed NCT00134030

MAPI

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

Regimen

Study	Evidence
Bacci et al. 2003	Phase 2

Preceding treatment

• Neoadjuvant MAPI, then surgery

Chemotherapy

• Methotrexate (MTX) 12,000 mg/m² IV over 4 hours once on day 36
• 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 (total dose per cycle: 15,000 mg/m²)

Supportive therapy

• Mesna (Mesnex) 3000 mg/m²/day IV continuous infusion over 120 hours, started on day 22, given with ifosfamide (total dose per cycle: 15,000 mg/m²)
• Leucovorin (Folinic acid) 15 mg (route not specified) every 6 hours x 11 doses, starting day 36, 24 hours after the start of methotrexate
• 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

9-week cycle for 3 cycles

Dose and schedule modifications

• If 4-hour methotrexate level is less than 10,000 nmol/L, the next cycle's methotrexate dose is increased by 2000 mg/m²

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 dosing details in manuscript PubMed

MAPIE

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

Regimen

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

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

Preceding treatment

• Neoadjuvant MAP, then surgery, with less than 90% tumor necrosis in the surgically removed specimen

Chemotherapy

• Methotrexate (MTX) as follows:
  • Cycles 1 to 3: 8000 mg/m² IV over 6 hours once on day 42
• Doxorubicin (Adriamycin) 45 mg/m² IV over 4 hours once per day on days 1 & 2
• Cisplatin (Platinol) as follows:
  • Cycles 1 to 3: 40 mg/m²/day IV continuous infusion over 72 hours, started on day 48 (total dose per cycle: 120 mg/m²)
• Ifosfamide (Ifex) as follows:
  • Cycles 1 to 3: 2000 mg/m² IV over 90 minutes once per day on days 21 to 25, with mesna
• Etoposide (Vepesid) as follows:
  • Cycles 1 to 3: 120 mg/m² IV over 60 minutes once per day on days 48 to 50

Supportive therapy

• Mesna (Mesnex) as follows:
  • Cycles 1 to 3: with ifosfamide; no actual dose is listed in the reference
• Leucovorin (Folinic acid) as follows:
  • Cycles 1 to 3: 15 mg IV every 6 hours x 11 doses on days 43 to 45, starting 24 hours after the start of methotrexate infusion
• Hydration during and after methotrexate infusion

69-day cycle for 4 cycles

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 dosing details in manuscript 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

M-EI: Methotrexate, Etoposide, Ifosfamide

Regimen

Study	Dates of enrollment	Evidence
Le Deley et al. 2007 (SFOP OS94)	1994-2001	Non-randomized part of phase 3 RCT

Preceding treatment

• Neoadjuvant M-EI, then surgery, with good response

Chemotherapy

• 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) as follows:
  • Cycles 1 to 3: 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) as follows:
  • Cycles 1 to 3: 3000 mg/m² IV over 3 hours once per day on days 22 to 25 (week 4), given during mesna infusion (total dose per cycle: 12,000 mg/m²)
    • Given in NS 250 to 500 mL

Supportive therapy

• Leucovorin (Folinic acid) 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 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) as follows:
  • Cycles 1 to 3: 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 4 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 dosing details in manuscript 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

Relapsed, refractory, or metastatic, first-line

Cisplatin & Doxorubicin

AP: Adriamycin (Doxorubicin) & Platinol (Cisplatin)

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Bramwell et al. 1997 (EOI 80831/MRC B002)	1983-1986	Phase 3 (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

• Cisplatin (Platinol) 100 mg/m² IV continuous infusion over 24 hours, started on day 1
• Doxorubicin (Adriamycin) 25 mg/m² IV bolus once per day on days 1 to 3

Supportive therapy

• Prehydration: normal saline 400 mL/m² and D5W 400 mL/m² IV 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 dosing details in manuscript link to PMC article PubMed

MAP

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

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Bramwell et al. 1997 (EOI 80831/MRC B002)	1983-1986	Phase 3 (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

• Methotrexate (MTX) 8000 mg/m² IV over 4 hours once on day 1
• Doxorubicin (Adriamycin) 25 mg/m² IV bolus once per day on days 11 to 13
• Cisplatin (Platinol) 100 mg/m² IV continuous infusion over 24 hours, started on day 11

Supportive therapy

• Leucovorin (Folinic acid) 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 IV 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 dosing details in manuscript link to PMC article PubMed

Relapsed, refractory, or metastatic, subsequent lines

Cabozantinib monotherapy

Regimen variant #1, adult dosing

Study	Dates of enrollment	Evidence
Italiano et al. 2020 (CABONE)	2015-2018	Phase 2

Targeted therapy

• Cabozantinib (Cometriq) 60 mg PO once per day on day 1 to 28

28-day cycles

Regimen variant #2, pediatric dosing

Study	Dates of enrollment	Evidence
Italiano et al. 2020 (CABONE)	2015-2018	Phase 2

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

Targeted therapy

• Cabozantinib (Cometriq) 40 mg/m² PO once per day on days 1 to 28

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 dosing details in abstract link to PMC article PubMed NCT02243605

Cyclophosphamide & Etoposide

Regimen

Study	Dates of enrollment	Evidence
Berger et al. 2009	2002-07 to 2006-09	Phase 2

Chemotherapy

• Cyclophosphamide (Cytoxan) 4000 mg/m² IV over 3 hours once on day 1
• Etoposide (Vepesid) 100 mg/m² IV over 60 minutes twice per day on days 2 to 4 (total dose: 600 mg/m²)

Supportive therapy

• Mesna (Mesnex) 1400 mg/m² IV three times per day on day 1, given prior to, 4 hours after, and 8 hours after cyclophosphamide
  • With mesna, 3000 mL/m² hydration

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 dosing details in manuscript PubMed

Cyclophosphamide & Topotecan

Regimen

Study	Evidence
Saylors et al. 2001	Phase 2

Chemotherapy

• Cyclophosphamide (Cytoxan) 250 mg/m² IV over 30 minutes once per day on days 1 to 5, given first
• Topotecan (Hycamtin) 0.75 mg/m² IV over 30 minutes once per day on days 1 to 5, given second

Supportive therapy

• 500 mL/m/2 fluids IV or PO once per day on days 1 to 5; 2 to 4 hours prior to chemotherapy
• 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/μL

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 dosing details in manuscript PubMed

Docetaxel & Gemcitabine

Regimen

Study	Evidence
Navid et al. 2008	Retrospective

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

Chemotherapy

• Docetaxel (Taxotere) 75 to 100 mg/m² IV over 60 minutes once on day 8, given second
• Gemcitabine (Gemzar) 675 mg/m² IV over 90 minutes once per day on days 1 & 8, given first

Supportive therapy

• Ondansetron (Zofran) (dose/route not specified) once per day on days 1 & 8, prior to chemotherapy
• Dexamethasone (Decadron) starting either the day before or the day of docetaxel, and continued for 2 days after docetaxel
• Per physician discretion: H1 or H2 blockers such as Diphenhydramine (Benadryl) and Ranitidine (Zantac) once per day on days 1 & 8
• Some patients received Filgrastim (Neupogen) starting on day 9

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 dosing details in manuscript PubMed

Gemcitabine monotherapy

Regimen

Study	Evidence
Merimsky et al. 2000	Phase 2

Chemotherapy

• Gemcitabine (Gemzar) as follows:
  • Cycle 1: 1000 mg/m² IV once per day on days 1, 8, 15, 22
  • Cycle 2 onwards: 1000 mg/m² IV once per day on days 1, 8, 15

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 dosing details in manuscript PubMed

ICE

ICE: Ifosfamide, Carboplatin, Etoposide

Regimen

Study	Evidence
Van Winkle et al. 2005	Phase 2

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

Chemotherapy

• Ifosfamide (Ifex) 1800 mg/m² IV once per day on days 1 to 5
• Carboplatin (Paraplatin) 400 mg/m² IV "for 2 days"
  • Note: the reference did not explicitly say which 2 days carboplatin should be given on
• Etoposide (Vepesid) 100 mg/m² IV once per day on days 1 to 5

Supportive therapy

• Depending on the study the patients were enrolled on, they received one of the following:
  • CCG-0894: Filgrastim (Neupogen) 5 or 10 mcg/kg SC once per day, starting 24 hours after completing ICE, and to continue until day 18 if ANC is at least 1000/μL, or until ANC is at least 1000/μL 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/μL 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/μL 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/μL, 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/μL 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 dosing details in manuscript PubMed

IE

IE: Ifosfamide & Etoposide

Regimen

Study	Dates of enrollment	Evidence
Gentet et al. 1997	1992-01 to 1995-01	Phase 2

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 therapy

• 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; next cycle starting when ANC greater than 1500/μL 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 dosing details in manuscript PubMed

Regorafenib monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Davis et al. 2019 (SARC024)	2014-2018	Randomized Phase 2 (E-esc)	Placebo	Superior PFS (primary endpoint) Median PFS: 3.6 vs 1.7 mo (HR 0.42, 95% CI 0.21-0.85)

Targeted therapy

• Regorafenib (Stivarga) 160 mg PO once per day on days 1 to 28

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 dosing details in manuscript PubMed NCT02048371

Samarium-153 with stem cell support

Regimen

Study	Dates of enrollment	Evidence
Anderson et al. 2002	NR	Phase 1

• Peripheral blood progenitor cell (PBPC) or bone marrow harvest and cryopreservation of at least 2 x 10⁶ CD34+ cells/kg

Radiotherapy

• Samarium-153 (Quadramet) 30 mCi/kg IV once on day 0

Supportive therapy

• Autologous stem cells (peripheral blood progenitor cell (PBPC) or bone marrow cells) re-infused on day +14
• Growth factor support with ONE of the following started when ANC less than 1000/μL:
  • Filgrastim (Neupogen)
  • Sargramostim (Leukine)

One course

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 dosing details in manuscript PubMed

Sorafenib monotherapy

Regimen

Study	Dates of enrollment	Evidence
Grignani et al. 2011	2008-2009	Phase 2

Targeted therapy

• Sorafenib (Nexavar) 400 mg PO twice per day on days 1 to 28

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 dosing details in manuscript PubMed EudraCT 2007-004396-19