Difference between revisions of "Osteosarcoma"
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Is there a regimen missing from this list? Would you like to share a different dosage/schedule or an additional reference for a regimen? Have you noticed an error? Do you have an idea that will help the site grow to better meet your needs and the needs of many others? You are [[How_to_contribute|invited to contribute to the site]]. | Is there a regimen missing from this list? Would you like to share a different dosage/schedule or an additional reference for a regimen? Have you noticed an error? Do you have an idea that will help the site grow to better meet your needs and the needs of many others? You are [[How_to_contribute|invited to contribute to the site]]. |
Revision as of 16:24, 11 December 2017
Use of this site is subject to you reading and agreeing with the terms set forth in the disclaimer. If this is your first time visiting, we suggest you read the tutorial.
Is there a regimen missing from this list? Would you like to share a different dosage/schedule or an additional reference for a regimen? Have you noticed an error? Do you have an idea that will help the site grow to better meet your needs and the needs of many others? You are invited to contribute to the site.
26 regimens on this page
37 variants on this page
|
Guidelines
ESMO
- 2014: Bone sarcomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. PubMed
NCCN
Neoadjuvant therapy
Cisplatin & Doxorubicin
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Regimen #1
Study | Evidence | Comparator | Efficacy |
Bramwell et al. 1992 | Phase III | MAP | Seems to have superior DFS |
Souhami et al. 1997 | Phase III | Multi-drug regimen | Seems not superior |
Chemotherapy
- Cisplatin (Platinol) 100 mg/m2 IV continuous 24-hour infusion on day 1
- Doxorubicin (Adriamycin) 25 mg/m2 IV bolus once per day on days 1 to 3
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
Treatment followed by definitive surgery on week 9, then adjuvant cisplatin & doxorubicin that starts 14 to 28 days after surgery.
Regimen #2
Study | Evidence | Comparator | Efficacy |
Lewis et al. 2007 | Phase III | Dose-intense Cisplatin & Doxorubicin | Inferior good histologic response rate |
Chemotherapy
- Cisplatin (Platinol) 100 mg/m2 IV continuous 24-hour infusion on day 1
- Doxorubicin (Adriamycin) 25 mg/m2 IV over 4 hours once per day on days 1 to 3
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
Treatment followed by definitive surgery in a 14-day window between cycles 2 & 3, then adjuvant cisplatin & doxorubicin.
Regimen #3, dose-intense
Study | Evidence | Comparator | Efficacy |
Lewis et al. 2007 | Phase III | Conventional Cisplatin & Doxorubicin | Superior good histologic response rate |
Chemotherapy
- Cisplatin (Platinol) 100 mg/m2 IV continuous 24-hour infusion on day 1
- Doxorubicin (Adriamycin) 25 mg/m2 IV over 4 hours once per day on days 1 to 3
Supportive medications
- 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 (Platinol)
- 24 hours of posthydration & mannitol after Cisplatin (Platinol)
- Recommended that fluid for cisplatin is isotonic saline with potassium chloride and mannitol
14-day cycle for 3 cycles
Treatment followed by definitive surgery in a 14-day window between cycles 3 & 4, then adjuvant cisplatin & doxorubicin.
References
- Bramwell VH, Burgers M, Sneath R, Souhami R, van Oosterom AT, Voûte PA, Rouesse J, Spooner D, Craft AW, Somers R et al. 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
- 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
- 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
- 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/day IV over 4 hours once per day on days 2 to 4, given with Mesna (Mesnex) (total dose: 6000 mg/m2)
Supportive medications
- Mesna (Mesnex) 2000 mg/m2/day IV over 4 hours once per day on days 2 to 4, given together with Ifosfamide (Ifex) (total dose: 6000 mg/m2)
- Prehydration and posthydration with mannitol diuresis for Cisplatin (Platinol)
21-day cycle for 3 cycles
Treatment followed by surgery and adjuvant cisplatin, epirubicin, ifosfamide.
References
- 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
Etoposide, Ifosfamide, Methotrexate
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Regimen
Study | Evidence | Comparator | Efficacy |
Le Deley et al. 2007 (SFOP OS94) | Phase III | MA | Might have superior EFS |
Chemotherapy
- Etoposide (Vepesid) 75 mg/m2 IV over 1 hour 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
- 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
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
Surgery occurs during week 14, with further treatment based on pathologic response. Patients with good response receive adjuvant etoposide, ifosfamide, methotrexate, whereas patients with poor response receive adjuvant cisplatin & doxorubicin.
References
- 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
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MA: High-dose Methotrexate, Adriamycin (Doxorubicin)
Regimen
Study | Evidence | Comparator | Efficacy |
Le Deley et al. 2007 (SFOP OS94) | Phase III | 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
Surgery occurs during week 12, with further treatment based on pathologic response. Patients with good response receive adjuvant MA, whereas patients with poor response receive adjuvant IE.
References
- 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 | 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
- Doxorubicin (Adriamycin) 45 mg/m2 IV bolus once per day on days 1 & 2
21-day course, then
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
- Bleomycin (Blenoxane) 12 mg/m2 IV bolus once per day on days 15 & 16
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV bolus once per day on days 15 & 16
- Dactinomycin (Cosmegen) 0.45 mg/m2 IV bolus once per day on days 15 & 16
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.
- 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)
- Bleomycin (Blenoxane) 12 mg/m2 IV bolus once per day on days 43 & 44
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV bolus once per day on days 43 & 44
- Dactinomycin (Cosmegen) 0.45 mg/m2 IV bolus once per day on days 43 & 44
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
- Winkler K, Beron G, Kotz R, Salzer-Kuntschik M, Beck J, Beck W, Brandeis W, Ebell W, Erttmann R, Göbel U et al. 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)
Regimen #1
Study | Evidence | Comparator | Efficacy |
Bramwell et al. 1992 | Phase III | 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 24-hour infusion on day 11
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
Treatment followed by definitive surgery on week 9, then adjuvant MAP that starts 14 to 28 days after surgery'
Regimen #2
Study | Evidence |
Bacci et al. 1993 | Phase II |
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 intraarterial continuous 72-hour infusion on days 7 to 9 (total dose: 120 mg/m2)
Supportive medications
- Folinic acid (Leucovorin) 15 mg IV Q6H x 11 doses on days 2 to 4, starting 24 hours after the start of Methotrexate (MTX) infusion
- Hydration during and after Methotrexate (MTX) infusion
27-day cycle for 2 cycles
Treatment followed by definitive surgery. 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. If there is at least 90% tumor necrosis in the surgically removed specimen, surgery is followed by adjuvant MAP. If there is less than 90% tumor necrosis in the surgically removed specimen, surgery is followed by adjuvant MAPIE.
Regimen #3
Study | Evidence | Comparator | Efficacy |
Winkler et al. 1988 (COSS-82) | Phase III | 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 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
Followed by surgery. Patients who had a good response based on surgical pathology received adjuvant MAP. Patients who had a poor response based on surgical pathology received adjuvant IP-BCD.
Regimen #4
Study | Evidence | Comparator | Efficacy |
Winkler et al. 1984 (COSS-80) | Phase III | 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
- Doxorubicin (Adriamycin) 45 mg/m2 IV bolus once per day on days 1 & 2
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 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
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 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 3 cycles, with surgery done during cycle 1 before doxorubicin; surgery is done 9 to 18 weeks after the start of chemotherapy
References
- Winkler K, Beron G, Kotz R, Salzer-Kuntschik M, Beck J, Beck W, Brandeis W, Ebell W, Erttmann R, Göbel U et al. 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
- Winkler K, Beron G, Delling G, Heise U, Kabisch H, Purfürst C, Berger J, Ritter J, Jürgens H, Gerein V et al. 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
- Bramwell VH, Burgers M, Sneath R, Souhami R, van Oosterom AT, Voûte PA, Rouesse J, Spooner D, Craft AW, Somers R et al. 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
- 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
- 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
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 | 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
- Methotrexate (MTX) 12,000 mg/m2 (maximum dose of 20,000 mg per cycle) IV over 4 hours once per day on days 15 & 22
- MTX is dissolved at a concentration of 20,000 mg/L in a solution containing 5% glucose
- Bleomycin (Blenoxane) 15 mg/m2 IV bolus once per day on days 1 & 2
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV bolus once per day on days 1 & 2
- Dactinomycin (Cosmegen) 0.6 mg/m2 IV bolus once per day on days 1 & 2
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
Followed by surgery. Patients who had a good response based on surgical pathology received adjuvant M-BCD. Patients who had a poor response based on surgical pathology received adjuvant cisplatin & doxorubicin.
References
- Winkler K, Beron G, Delling G, Heise U, Kabisch H, Purfürst C, Berger J, Ritter J, Jürgens H, Gerein V et al. 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
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
Treatment followed by surgery, followed by adjuvant MAPI.
References
- 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
Adjuvant therapy
Cisplatin & Doxorubicin
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Regimen #1
Study | Evidence | Comparator | Efficacy |
Bramwell et al. 1992 | Phase III | MAP | Seems to have superior DFS |
Souhami et al. 1997 | Phase III | Multi-drug regimen | Seems not superior |
Preceding treatment
- Neoadjuvant cisplatin & doxorubicin and surgery
Chemotherapy
- Cisplatin (Platinol) 100 mg/m2 IV continuous 24-hour infusion on day 1
- Doxorubicin (Adriamycin) 25 mg/m2 IV bolus once per day on days 1 to 3
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
Regimen #2
Study | Evidence | Comparator | Efficacy |
Lewis et al. 2007 | Phase III | Dose-intense Cisplatin & Doxorubicin | Inferior good histologic response rate |
Preceding treatment
- Neoadjuvant cisplatin & doxorubicin and surgery
Chemotherapy
- Cisplatin (Platinol) 100 mg/m2 IV continuous 24-hour infusion on day 1
- Doxorubicin (Adriamycin) 25 mg/m2 IV over 4 hours once per day on days 1 to 3
Supportive medications
- 4 hours of prehydration prior to cisplatin
- 24 hours of posthydration & mannitol after cisplatin
- Recommended that fluid for cisplatin is isotonic saline with potassium chloride and mannitol
21-day cycle for 4 cycles
Regimen #3, dose intense
Study | Evidence | Comparator | Efficacy |
Lewis et al. 2007 | Phase III | Conventional Cisplatin & Doxorubicin | Superior good histologic response rate |
Preceding treatment
- Neoadjuvant cisplatin & doxorubicin and surgery
Chemotherapy
- Cisplatin (Platinol) 100 mg/m2 IV continuous 24-hour infusion on day 1
- Doxorubicin (Adriamycin) 25 mg/m2 IV over 4 hours once per day on days 1 to 3
Supportive medications
- 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 (Platinol)
- 24 hours of posthydration & mannitol after Cisplatin (Platinol)
- Recommended that fluid for cisplatin is isotonic saline with potassium chloride and mannitol
14-day cycle for 3 cycles
Regimen #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
- Neoadjuvant M-BCD and surgery
Chemotherapy
- Cisplatin (Platinol) 90 mg/m2/day IV over 4 hours once on day 3
- Doxorubicin (Adriamycin) 30 mg/m2 IV bolus once per day on days 1 & 2
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
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 precise schedule. Other regimens have used both medications both on day 1, with 21-day cycles.
Preceding treatment
Chemotherapy
- Cisplatin (Platinol) 120 mg/m2
- Doxorubicin (Adriamycin) 70 mg/m2 IV over 6 hours
5 cycles
References
- Winkler K, Beron G, Delling G, Heise U, Kabisch H, Purfürst C, Berger J, Ritter J, Jürgens H, Gerein V et al. 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
- Bramwell VH, Burgers M, Sneath R, Souhami R, van Oosterom AT, Voûte PA, Rouesse J, Spooner D, Craft AW, Somers R et al. 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
- 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
- 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
- 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
- Neoadjuvant cisplatin, epirubicin, ifosfamide and surgery
Chemotherapy
- Cisplatin (Platinol) 100 mg/m2 IV over 2 hours
- Epirubicin (Ellence) 90 mg/m2 IV over 15 minutes once on day 1
- Ifosfamide (Ifex) 2000 mg/m2/day IV over 4 hours once per day on days 2 to 4, given with Mesna (Mesnex) (total dose: 6000 mg/m2)
Supportive medications
- Mesna (Mesnex) 2000 mg/m2/day IV over 4 hours once per day on days 2 to 4, given together with Ifosfamide (Ifex) (total dose: 6000 mg/m2)
- Prehydration and posthydration with mannitol diuresis for Cisplatin (Platinol)
28-day cycle for 3 cycles
References
- 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
Etoposide, Ifosfamide, Methotrexate
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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
- 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
- Etoposide (Vepesid) 75 mg/m2 IV over 1 hour once per day on days 22 to 25 (week 4)
- 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
- 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
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
- Neoadjuvant MA and surgery
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 1 hour 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
- 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
- Neoadjuvant MAP and surgery
Chemotherapy
- Ifosfamide (Ifex) 2000 mg/m2/day IV over 23.5 hours once per day on days 1 to 5, given after cisplatin (total dose: 10,000 mg/m2)
- Cisplatin (Platinol) 20 mg/m2/day IV over 30 minutes once per day on days 1 to 5, given before ifosfamide (total dose: 100 mg/m2)
- Bleomycin (Blenoxane) 15 mg/m2 IV bolus once per day on days 22 & 23
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV bolus once per day on days 22 & 23
- Dactinomycin (Cosmegen) 0.6 mg/m2 IV bolus once per day on days 22 & 23
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
- Winkler K, Beron G, Delling G, Heise U, Kabisch H, Purfürst C, Berger J, Ritter J, Jürgens H, Gerein V et al. 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
- Neoadjuvant MA and surgery
Chemotherapy, part 1
- Methotrexate (MTX) 12,000 mg/m2 IV over 4 hours once per day on days 1, 8, 15
- Given in D5W 1L with sodium bicarbonate 1 mEq/kg
- Doxorubicin (Adriamycin) 70 mg/m2 IV over 6 hours once on day 22
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
- 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)
Regimen #1
Study | Evidence | Comparator | Efficacy |
Bramwell et al. 1992 | Phase III | 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 and 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 24-hour infusion on day 11
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
Regimen #2
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
- Neoadjuvant MAP and surgery
Chemotherapy, part 1
- Methotrexate (MTX) 8000 mg/m2 IV over 6 hours once on day 21
- Doxorubicin (Adriamycin) 45 mg/m2/day IV over 4 hours once per day on days 1 & 2
- Cisplatin (Platinol) 40 mg/m2/day IV continuous 72-hour infusion on days 27 to 29 (total dose: 120 mg/m2)
Supportive medications
- Folinic acid (Leucovorin) 15 mg IV Q6H x 11 doses on days 22 to 24, starting 24 hours after the start of Methotrexate (MTX) infusion
- Hydration during and after Methotrexate (MTX) infusion
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
- Doxorubicin (Adriamycin) 45 mg/m2/day IV over 4 hours once per day on days 1 & 2
Given once after cycle 3
Regimen #3
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
- Neoadjuvant MAP and surgery
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
References
- Winkler K, Beron G, Delling G, Heise U, Kabisch H, Purfürst C, Berger J, Ritter J, Jürgens H, Gerein V et al. 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
- Bramwell VH, Burgers M, Sneath R, Souhami R, van Oosterom AT, Voûte PA, Rouesse J, Spooner D, Craft AW, Somers R et al. 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
- 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
- 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
- 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
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
- Neoadjuvant MAPI and surgery
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
- 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
- Neoadjuvant MAP and surgery
Chemotherapy, part 1
- Methotrexate (MTX) 8000 mg/m2 IV over 6 hours once on day 42
- Doxorubicin (Adriamycin) 45 mg/m2/day IV over 4 hours once per day on days 1 & 2
- Cisplatin (Platinol) 40 mg/m2/day IV continuous 72-hour infusion on days 48 to 50 (total dose: 120 mg/m2)
- Ifosfamide (Ifex) 2000 mg/m2 IV over 90 minutes once per day on days 21 to 25
- Etoposide (Vepesid) 120 mg/m2 IV over 1 hour once per day on days 48 to 50
Supportive medications
- Mesna (Mesnex) with Ifosfamide (Ifex); no actual dose is listed in the reference
- Folinic acid (Leucovorin) 15 mg IV Q6H x 11 doses on days 43-45, starting 24 hours after the start of Methotrexate (MTX) infusion
- Hydration during and after Methotrexate (MTX) infusion
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
- Doxorubicin (Adriamycin) 45 mg/m2/day IV over 4 hours once per day on days 1 & 2
Given once after postoperative chemotherapy cycle 3
References
- 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
- 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
- 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 Aug 25. pii: S1470-2045(16)30214-5. [Epub ahead of print] 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. This regimen is for patients who had a good response based on surgical pathology.
Preceding treatment
- Neoadjuvant M-BCD and surgery
Chemotherapy
- Methotrexate (MTX) 12,000 mg/m2 (maximum dose of 20,000 mg per cycle) IV over 4 hours once per day on days 15 & 22
- MTX is dissolved at a concentration of 20,000 mg/L in a solution containing 5% glucose
- Bleomycin (Blenoxane) 15 mg/m2 IV bolus once per day on days 1 & 2
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV bolus once per day on days 1 & 2
- Dactinomycin (Cosmegen) 0.6 mg/m2 IV bolus once per day on days 1 & 2
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
- Winkler K, Beron G, Delling G, Heise U, Kabisch H, Purfürst C, Berger J, Ritter J, Jürgens H, Gerein V et al. 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
Relapsed or refractory or metastatic
Cisplatin & Doxorubicin
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Regimen
Study | Evidence | Comparator | Efficacy |
Bramwell et al. 1997 | Phase III | 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 24-hour infusion on day 1
- Doxorubicin (Adriamycin) 25 mg/m2 IV bolus once per day on days 1 to 3
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
- 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
Cyclophosphamide & Etoposide
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Regimen
Study | Evidence |
Berger et al. 2009 | Phase II |
Chemotherapy
- Cyclophosphamide (Cytoxan) 4000 mg/m2 IV over 3 hours once on day 1
- Etoposide (Vepesid) 100 mg/m2 IV over 1 hour BID on days 2 to 4 (total dose: 600 mg/m2)
Supportive medications
- Mesna (Mesnex) 1400 mg/m2 IV TID on day 1: before, 4 hours after, and 8 hours after Cyclophosphamide (Cytoxan)
- With mesna, 3000 mL/m2 hydration
At least 21-day cycle for 2 cycles, then restaging
Patients with no progression received an experimental protocol with:
- Samarium-153 (Quadramet) 10 mCi/kg and/or Carboplatin (Paraplatin) and Etoposide (Vepesid) 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 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
- 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
- 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 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
- 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
- Docetaxel (Taxotere) 75 to 100 mg/m2 IV over 60 minutes once on day 8, given after gemcitabine
- Gemcitabine (Gemzar) 675 mg/m2 IV over 90 minutes once per day on days 1 & 8, given first
Supportive medications
- Ondansetron (Zofran) prior to chemotherapy on days 1 & 8
- Dexamethasone (Decadron) starting either the day before or the day of Docetaxel (Taxotere), and continued for 2 days after Docetaxel (Taxotere)
- H1 or H2 blockers such as Diphenhydramine (Benadryl) and Ranitidine (Zantac) prior to chemotherapy on days 1 & 8 per physician discretion
- Some patients received Filgrastim (Neupogen) starting on day 9
21-day cycles
References
- 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
- Gemcitabine (Gemzar) 1000 mg/m2 IV once per day on days 1, 8, 15, 22, 29, 36, 43
8-week course, then
Maintenance therapy if patient does not have progressive disease:
- Gemcitabine (Gemzar) 1000 mg/m2 IV once per day on days 1, 8, 15
28-day cycles
References
- 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
- 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 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
Resection of disease was allowed after 4 cycles based on patient's response to ICE.
References
- 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 1 hour 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
- 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
MAP
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MAP: High-dose Methotrexate, Adriamycin (Doxorubicin), Platinol (Cisplatin)
Regimen
Study | Evidence | Comparator | Efficacy |
Bramwell et al. 1997 | Phase III | 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 24-hour infusion on day 11
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
- 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
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
- Samarium-153 (Quadramet) 30 mCi/kg IV once on day 0
Supportive medications
- Growth factor support with ONE of the following started when ANC less than 1000/uL:
On day +14, infuse peripheral blood progenetor cell (PBPC) or bone marrow cells
References
- 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