Osteosarcoma

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 James L. Chen, MD, MS
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26 regimens on this page
37 variants on this page


Guidelines

ESMO

NCCN

Neoadjuvant therapy

Cisplatin & Doxorubicin

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AP: Adriamycin (Doxorubicin) & Platinol (Cisplatin)

Variant #1

Study Evidence Comparator Efficacy
Bramwell et al. 1992 Phase III (E) MAP Seems to have superior DFS
Souhami et al. 1997 Phase III (E) Multi-drug T10 protocol Seems not superior

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 g/m2
  • Posthydration: D5W 600 mL/m2 over 6 hours, with KCl 20 mEq/L and mannitol 8 g/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 8 g/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

Variant #2

Study Evidence Comparator Efficacy
Lewis et al. 2007 Phase III (C) Dose-intense Cisplatin & Doxorubicin Inferior good histologic response rate

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

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

Variant #3, dose-intense

Study Evidence Comparator Efficacy
Lewis et al. 2007 Phase III (E) Conventional Cisplatin & Doxorubicin Superior good histologic response rate

Chemotherapy

Supportive medications

14-day cycle for 3 cycles

Subsequent treatment

  • Definitive surgery in a 14-day window between cycles 3 & 4, 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. 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. 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. 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

Cisplatin, Epirubicin, Ifosfamide

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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

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MA: High-dose Methotrexate, Adriamycin (Doxorubicin)

Regimen

Study Evidence Comparator Efficacy
Le Deley et al. 2007 (SFOP OS94) Phase III (C) Methotrexate, Etoposide, Ifosfamide Might have inferior EFS

Chemotherapy

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

Supportive medications

  • Folinic acid (Leucovorin) 15 mg PO Q6H x 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

11-week course

Subsequent treatment

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

References

  1. 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

MA-BCD

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MA-BCD: High-dose Methotrexate, Adriamycin (Doxorubicin), Bleomycin, Ccyclophosphamide, Dactinomycin

Regimen

Study Evidence Comparator Efficacy
Winkler et al. 1984 (COSS-80) Phase III (C) MAP Seems not superior

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, then

Chemotherapy, part 2

See note above about uncertainty about the exact schedule.

Supportive medications

  • Folinic acid (Leucovorin) 15 mg/m2 PO Q6H x 12 hours once per day on days 2 & 9, 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

35-day course, followed by:

Chemotherapy, part 3

See note above about uncertainty about the exact schedule.

Supportive medications

  • Folinic acid (Leucovorin) 15 mg/m2 PO Q6H 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

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

MAP

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

Variant #1

Study Evidence Comparator Efficacy
Bramwell et al. 1992 Phase III (E) 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 Q6H x 10 doses or 15 mg/m2 PO Q6H 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 g/m2
  • Posthydration for Cisplatin (Platinol): D5W 600 mL/m2 over 6 hours, with KCl 20 mEq/L and mannitol 8 g/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 8 g/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

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

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

Variant #3

Study Evidence Comparator Efficacy
Winkler et al. 1988 (COSS-82) Phase III (E) 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 per cycle) 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/day IV over 4 hours once on day 3

Supportive medications

  • Folinic acid (Leucovorin) 15 mg/m2 PO Q6H 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 the cited reference Winkler et al. 1984

35-day cycle for 2 cycles

Subsequent treatment

Variant #4

Study Evidence Comparator Efficacy
Winkler et al. 1984 (COSS-80) Phase III (E) MA-BCD Seems not superior

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 per cycle) 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 Q6H 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 per cycle) 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 Q6H 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. 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

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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 48-hour infusion on days 8 & 9 (total dose: 120 mg/m2)
  • Doxorubicin (Adriamycin) 75 mg/m2 IV continuous 24-hour infusion on day 10
  • Ifosfamide (Ifex) 3000 mg/m2/day IV continuous 120-hour (5-day) infusion on days 29 to 33, given together with Mesna (Mesnex) (total dose per cycle: 15,000 mg/m2)

Supportive medications

  • Folinic acid (Leucovorin) 15 mg (route not specified) Q6H 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 120-hour (5-day) infusion on days 29 to 33, given together 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-BCD

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M-BCD: High-dose Methotrexate, Bleomycin, Ccyclophosphamide, Dactinomycin

Regimen

Study Evidence Comparator Efficacy
Winkler et al. 1988 (COSS-82) Phase III (C) MAP Inferior 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.

Chemotherapy

Supportive medications

  • Folinic acid (Leucovorin) 15 mg/m2 PO Q6H x 12 hours once per day on days 16 & 23, 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 (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

35-day cycle for 2 cycles

Subsequent treatment

  • Surgery, then risk-adapted 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

M-EI

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M-EI: ethotrexate, Etoposide, Ifosfamide

Regimen

Study Evidence Comparator Efficacy
Le Deley et al. 2007 (SFOP OS94) Phase III (E) MA Might have superior EFS

Chemotherapy

  • Methotrexate (MTX) 12,000 mg/m2 IV over 4 hours on weeks 1, 2, 3, 7, 8, 12, 13
    • 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), 57 to 60 (week 9)
    • Given in NS 250 to 500 mL
  • Ifosfamide (Ifex) 3000 mg/m2/day (total dose: 12,000 mg/m2) IV over 3 hours once per day on days 22 to 25 (week 4), 57 to 60 (week 9), given together with Mesna (Mesnex)
    • Given in NS 250 to 500 mL

Supportive medications

  • Folinic acid (Leucovorin) 15 mg PO Q6H x 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 (total dose: 14,400 mg/m2) IV continuous 96-hour (4-day) infusion on days 22 to 25 (week 4), 57 to 60 (week 9), given together with ifosfamide
  • Up to 2 L/day hydration with ifosfamide & mesna

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
  2. French OS2006: 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 (Société Française des Cancers de l'Enfant et l'adolescent); GSF-GETO (Groupe Sarcome Français); 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 SD article PubMed

Adjuvant therapy

Cisplatin & Doxorubicin

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AP: Adriamycin (Doxorubicin) & Platinol (Cisplatin)

Variant #1

Study Evidence Comparator Efficacy
Bramwell et al. 1992 Phase III (E) MAP Seems to have superior DFS
Souhami et al. 1997 Phase III (E) Multi-drug T10 protocol Seems not superior

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 g/m2
  • Posthydration: D5W 600 mL/m2 over 6 hours, with KCl 20 mEq/L and mannitol 8 g/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 8 g/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

Variant #2

Study Evidence Comparator Efficacy
Lewis et al. 2007 Phase III (C) Dose-intense Cisplatin & Doxorubicin 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

Variant #3, dose intense

Study Evidence Comparator Efficacy
Lewis et al. 2007 Phase III (E) Conventional Cisplatin & Doxorubicin Superior good histologic response rate

Preceding treatment

Chemotherapy

Supportive medications

14-day cycle for 3 cycles

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. This regimen is for patients who had a poor response based on surgical pathology.

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 the cited reference Winkler et al. 1984

21-day cycle for 6 cycles

Variant #5

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

This regimen is for poor responders. 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

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. 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. 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. 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
  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

Cisplatin, Epirubicin, Ifosfamide

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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

IE

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IE: Ifosfamide, Etoposide

Regimen

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

This regimen is for poor responders. Details were not listed about the length of each cycle. Other regimens have used 21 to 28-day cycles.

Preceding treatment

Chemotherapy

  • Ifosfamide (Ifex) 3000 mg/m2/day IV over 3 hours once per day on days 1 to 4, given together with Mesna (Mesnex) (total dose: 12,000 mg/m2)
    • 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 medications

  • Mesna (Mesnex) 3600 mg/m2/day IV continuous 96-hour (4-day) infusion on days 1 to 4, given together with Ifosfamide (Ifex) (total dose: 14,400 mg/m2)
  • Up to 2 L/day hydration with ifosfamide & mesna

5 cycles

References

  1. 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

IP-BCD

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IP-BCD: Ifosfamide, Platinol (Cisplatin), Bleomycin, Ccyclophosphamide, Dactinomycin

Regimen

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

This regimen is for patients with a poor response based on surgical pathology.

Preceding treatment

Chemotherapy

Supportive medications

  • Mesna (Mesnex) 2000 mg/m2/day IV over 23.5 hours once per day on days 1 to 5, given together with Ifosfamide (Ifex), then 2000 mg/m2/day IV continuous infusion over 48 hours on days 6 to 7 (total dose: 10,000 mg/m2)
  • Mannitol given together with Cisplatin (Platinol); no further details provided

35-day cycle for 3 cycles

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

MA

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MA: High-dose Methotrexate, Adriamycin (Doxorubicin)

Regimen

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

This regimen is for good responders.

Preceding treatment

Chemotherapy, part 1

Supportive medications

  • Folinic acid (Leucovorin) 15 mg PO Q6H x 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 Q6H x up to 11 doses starting on days 1, 8, 15, 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

21-day course

References

  1. 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

MAP

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

Variant #1, 8000/75/100

Study Evidence Comparator Efficacy
Bramwell et al. 1992 Phase III (E) 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 Q6H x 10 doses or 15 mg/m2 PO Q6H 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 g/m2
  • Posthydration for cisplatin: D5W 600 mL/m2 over 6 hours, with KCl 20 mEq/L and mannitol 8 g/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 8 g/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

Variant #2, 8000/90/120

Study Evidence
Bacci et al. 1993 Phase II

This regimen is for patients with at least 90% tumor necrosis in the surgically removed specimen.

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

Variant #3, 12,000/60/90

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

This regimen is for patients with a good response based on surgical pathology.

Preceding treatment

Chemotherapy

  • Methotrexate (MTX) 12,000 mg/m2 (maximum dose of 20,000 mg per cycle) 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/day IV over 4 hours once on day 3

Supportive medications

  • Folinic acid (Leucovorin) 15 mg/m2 PO Q6H 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 the cited reference Winkler et al. 1984

35-day cycle for 2 cycles

Variant #4, 12,000/75/120

Study Evidence Comparator Efficacy
Marina et al. 2016 (EURAMOS-1 poor response) Phase III (C) MAPIE Seems not superior

Preceding treatment

Chemotherapy

  • Methotrexate (MTX) 12,000 mg/m2 (maximum dose of 20,000 mg at COG sites) IV over 4 hours once per week in weeks 4 & 5
  • Doxorubicin (Adriamycin) 37.5 mg/m2 IV once per day on days 1 & 2
  • Cisplatin (Platinol) 120 mg/m2 IV continuous 72-hour infusion on days 1 to 3
    • 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. 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

MAPI

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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 24-hour infusion on day 1
  • Cisplatin (Platinol) 60 mg/m2/day IV continuous 48-hour infusion on days 43 & 44 (total dose: 120 mg/m2)
  • Ifosfamide (Ifex) 3000 mg/m2/day IV continuous 120-hour (5-day) infusion on days 22 to 26, given together with Mesna (Mesnex) (total dose: 15,000 mg/m2)

Supportive medications

  • Mesna (Mesnex) 3000 mg/m2/day IV continuous 120-hour (5-day) infusion on days 22 to 26, given together with Ifosfamide (Ifex) (total dose: 15,000 mg/m2)
  • Folinic acid (Leucovorin) 15 mg (route not specified) Q6H 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

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

Regimen

Study Evidence
Bacci et al. 1993 Phase II

This regimen is for patients with less than 90% tumor necrosis in the surgically removed specimen.

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

M-BCD

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M-BCD: High-dose Methotrexate, Bleomycin, Ccyclophosphamide, Dactinomycin

Regimen

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

  • Folinic acid (Leucovorin) 15 mg/m2 PO Q6H x 12 hours once per day on days 16 & 23, 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

35-day cycle for 2 cycles

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

M-EI

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M-EI: ethotrexate, Etoposide, Ifosfamide

Regimen

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

This regimen is for good responders.

Preceding treatment

Chemotherapy, part 1

  • Methotrexate (MTX) 12,000 mg/m2 IV over 4 hours on weeks 1, 2, 3
    • 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/day IV over 3 hours once per day on days 22 to 25 (week 4), given together withMesna (Mesnex) (total dose: 12,000 mg/m2)
    • Given in NS 250 to 500 mL

Supportive medications

  • Folinic acid (Leucovorin) 15 mg PO Q6H x up to 11 doses on weeks 1, 2, 3, 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 96-hour (4-day) infusion on days 22 to 25 (week 4), given together with Ifosfamide (Ifex) (total dose: 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 Q6H x up to 11 doses starting on days 1, 8, 15, 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

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
  2. French OS2006: 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 (Société Française des Cancers de l'Enfant et l'adolescent); GSF-GETO (Groupe Sarcome Français); 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 SD article PubMed

Maintenance after upfront therapy

Observation

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Regimen

Study Evidence Comparator Efficacy
Bielack et al. 2015 (EURAMOS-1 good response) Phase III (C) Interferon alfa-2B Seems not superior

No further treatment.

Preceding treatment

References

  1. 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

Relapsed, refractory, or metastatic, first-line

Cisplatin & Doxorubicin

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AP: Adriamycin (Doxorubicin) & Platinol (Cisplatin)

Regimen

Study Evidence Comparator Efficacy
Bramwell et al. 1997 (EOI 80831/MRC B002) Phase III (E) 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 g/m2
  • Posthydration: D5W 600 mL/m2 over 6 hours, with KCl 20 mEq/L and mannitol 8 g/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 8 g/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. 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

MAP

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

Regimen

Study Evidence Comparator Efficacy
Bramwell et al. 1997 (EOI 80831/MRC B002) Phase III (E) 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 Q6H x 10 doses or 15 mg/m2 PO Q6H 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 g/m2
  • Posthydration for cisplatin: D5W 600 mL/m2 over 6 hours, with KCl 20 mEq/L and mannitol 8 g/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 8 g/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. 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. contains verified partial protocol link to PMC article PubMed

Relapsed, refractory, or metastatic, subsequent lines

Cyclophosphamide & Etoposide

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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

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Regimen

Study Evidence
Saylors et al. 2001 Phase II

Chemotherapy

Supportive medications

  • 500 mL/m/2 fluids PO/IV 2 to 4 hours before chemotherapy
  • Antiemetics as premedication before chemotherapy
  • 3 liters/m2 PO/IV over 24 hours after chemotherapy
  • Filgrastim (Neupogen) 5 mcg/kg SC once per day starting on day 6, to continue until ANC is at least 1500/uL after the nadir period

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

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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

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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

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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/day 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 once per day or 500 mcg/m2 BID SQ, 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/day SC once per day and IL-6 at 2.5, 3.75, or 5.0 mcg/kg SC BID, 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. 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

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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 on days 1 to 4 (total dose: 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

Samarium-153 with stem cell support

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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
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