Difference between revisions of "Osteosarcoma"
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− | < | + | <span id="BackToTop"></span> |
− | + | <div class="noprint" style="background-color:LightGray; position:fixed; bottom:2%; right:0.25%; padding-left:5px; padding-right:5px; margin: 15px; opacity:0.8; border-style: solid; border-color:DarkGray; border-width: 1px"> | |
− | < | + | [[#top|Back to Top]] |
− | + | </div> | |
− | + | {{#lst:Editorial board transclusions|sarcoma}} | |
− | + | ''Are you looking for a regimen but can't find it here? It is possible that we've moved it to the [[Osteosarcoma_-_historical|historical regimens page]]. For placebo or observational studies in this condition, please visit [[Osteosarcoma - null regimens|this page]]. If you still can't find it, please let us know so we can add it!'' | |
− | + | <big> | |
− | + | *'''[[Osteosarcoma, pediatric|Pediatric osteosarcoma]] regimens can be found here.'''</big> | |
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{| class="wikitable" style="float:right; margin-right: 5px;" | {| class="wikitable" style="float:right; margin-right: 5px;" | ||
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{{TOC limit|limit=3}} | {{TOC limit|limit=3}} | ||
+ | =Guidelines= | ||
+ | '''Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.''' | ||
+ | ==[https://www.esmo.org/ ESMO]== | ||
+ | *'''2009:''' Bielack et al. [https://doi.org/10.1093/annonc/mdp154 Osteosarcoma: ESMO clinical recommendations for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/19454435/ PubMed] | ||
+ | **'''2008:''' Bielack et al. [https://doi.org/10.1093/annonc/mdn102 Osteosarcoma: ESMO clinical recommendations for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/18456784/ PubMed] | ||
+ | **'''2003:''' Saeter. [https://doi.org/10.1093/annonc/mdg336 ESMO Minimum Clinical Recommendations for diagnosis, treatment and follow-up of osteosarcoma] [https://pubmed.ncbi.nlm.nih.gov/12881369/ PubMed] | ||
− | = | + | ==NCCN== |
− | + | *''NCCN does not currently have guidelines at this granular level; please see [https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1418 NCCN Guidelines - Bone Cancer].'' | |
− | *'' | ||
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=Neoadjuvant therapy= | =Neoadjuvant therapy= | ||
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==Cisplatin & Doxorubicin {{#subobject:ae685c|Regimen=1}}== | ==Cisplatin & Doxorubicin {{#subobject:ae685c|Regimen=1}}== | ||
− | + | AP: '''<u>A</u>'''driamycin (Doxorubicin) & '''<u>P</u>'''latinol (Cisplatin) | |
− | + | <div class="toccolours" style="background-color:#eeeeee"> | |
− | + | ===Regimen variant #1 {{#subobject:248bc1|Variant=1}}=== | |
− | + | {| class="wikitable sortable" style="width: 100%; text-align:center;" | |
− | === | + | !style="width: 20%"|Study |
− | {| class="wikitable" style="width: 100%; text-align:center;" | + | !style="width: 20%"|Dates of enrollment |
− | !Study | + | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] |
− | ![[Levels_of_Evidence#Evidence|Evidence]] | + | !style="width: 20%"|Comparator |
− | !Comparator | + | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] |
− | ![[Levels_of_Evidence# | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1200/jco.1992.10.10.1579 Bramwell et al. 1992] |
− | |style="background-color:#1a9851"|Phase | + | |1983-1986 |
+ | |style="background-color:#1a9851"|Phase 3 (E-switch-ic) | ||
|[[#MAP|MAP]] | |[[#MAP|MAP]] | ||
|style="background-color:#91cf60"|Seems to have superior DFS | |style="background-color:#91cf60"|Seems to have superior DFS | ||
|- | |- | ||
− | |[https:// | + | |[https://doi.org/10.1016/S0140-6736(97)02307-6 Souhami et al. 1997] |
− | |style="background-color:#1a9851"|Phase | + | |1986-1991 |
− | |Multi-drug | + | |style="background-color:#1a9851"|Phase 3 (E-de-esc) |
− | |style="background-color:#ffffbf"| | + | |[[#T10_protocol_888|Multi-drug T10 protocol]] |
+ | |style="background-color:#ffffbf"|Did not meet co-primary endpoints of PFS/OS | ||
|- | |- | ||
|} | |} | ||
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
− | *[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV continuous 24 | + | *[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV continuous infusion over 24 hours, started on day 1 |
*[[Doxorubicin (Adriamycin)]] 25 mg/m<sup>2</sup> IV bolus once per day on days 1 to 3 | *[[Doxorubicin (Adriamycin)]] 25 mg/m<sup>2</sup> IV bolus once per day on days 1 to 3 | ||
− | + | ====Supportive therapy==== | |
− | ====Supportive | + | *Prehydration: normal saline 400 mL/m<sup>2</sup> and D5W 400 mL/m<sup>2</sup> IV over 2 hours--the reference did not clarify if these two solutions are given at the same time |
− | *Prehydration: normal saline 400 mL/m<sup>2</sup> and D5W 400 mL/m<sup>2</sup> 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/m<sup>2</sup> NS, with KCl 80 mEq/L and mannitol 32,000 mg/m<sup>2</sup> |
− | *The volume of fluid for cisplatin continuous infusion is 2400 mL/m<sup>2</sup> NS, with KCl 80 mEq/L and mannitol 32 | + | *Posthydration: D5W 600 mL/m<sup>2</sup> over 6 hours, with KCl 20 mEq/L and mannitol 8000 mg/m<sup>2</sup>; and NS 600 mL/m<sup>2</sup> 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/m<sup>2</sup> over 12 hours, with KCl 20 mEq/L and mannitol 8000 mg/m<sup>2</sup>. |
− | *Posthydration: D5W 600 mL/m<sup>2</sup> over 6 hours, with KCl 20 mEq/L and mannitol | ||
*[[Furosemide (Lasix)]] 20 to 40 mg IV if urine output is less than 400 mL/m<sup>2</sup> over 6 hours | *[[Furosemide (Lasix)]] 20 to 40 mg IV if urine output is less than 400 mL/m<sup>2</sup> over 6 hours | ||
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'''21-day cycle for 3 cycles''' | '''21-day cycle for 3 cycles''' | ||
− | + | </div> | |
− | + | <div class="toccolours" style="background-color:#cbd5e7"> | |
− | + | ====Subsequent treatment==== | |
− | === | + | *Definitive [[Surgery#Surgical_resection|surgery]] on week 9, then adjuvant [[#Cisplatin_.26_Doxorubicin_2|AP]] that starts 14 to 28 days after surgery |
− | {| class="wikitable" style="width: 100%; text-align:center;" | + | </div></div><br> |
− | !Study | + | <div class="toccolours" style="background-color:#eeeeee"> |
− | ![[Levels_of_Evidence#Evidence|Evidence]] | + | ===Regimen variant #2 {{#subobject:33e180|Variant=1}}=== |
− | !Comparator | + | {| class="wikitable sortable" style="width: 100%; text-align:center;" |
− | ![[Levels_of_Evidence# | + | !style="width: 20%"|Study |
+ | !style="width: 20%"|Dates of enrollment | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | !style="width: 20%"|Comparator | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1093/jnci/djk015 Lewis et al. 2007 (EORTC 80931)] |
− | |style="background-color:#1a9851"|Phase | + | |1993-2002 |
− | | | + | |style="background-color:#1a9851"|Phase 3 (C) |
− | |style="background-color:# | + | |[[#Cisplatin_.26_Doxorubicin|Cisplatin & Doxorubicin]]; dose-intense |
+ | |style="background-color:#ffffbf"|Did not meet primary endpoint of OS | ||
|- | |- | ||
|} | |} | ||
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
− | *[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV continuous 24 | + | *[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV continuous infusion over 24 hours, started on day 1 |
*[[Doxorubicin (Adriamycin)]] 25 mg/m<sup>2</sup> IV over 4 hours once per day on days 1 to 3 | *[[Doxorubicin (Adriamycin)]] 25 mg/m<sup>2</sup> IV over 4 hours once per day on days 1 to 3 | ||
− | + | ====Supportive therapy==== | |
− | ====Supportive | ||
*4 hours of prehydration prior to cisplatin | *4 hours of prehydration prior to cisplatin | ||
*24 hours of posthydration & mannitol after cisplatin | *24 hours of posthydration & mannitol after cisplatin | ||
*Recommended that fluid for cisplatin is isotonic saline with potassium chloride and mannitol | *Recommended that fluid for cisplatin is isotonic saline with potassium chloride and mannitol | ||
− | |||
'''21-day cycle for 2 cycles''' | '''21-day cycle for 2 cycles''' | ||
− | + | </div> | |
− | + | <div class="toccolours" style="background-color:#cbd5e7"> | |
− | + | ====Subsequent treatment==== | |
− | + | *Definitive [[Surgery#Surgical_resection|surgery]] in a 14-day window between cycles 2 & 3, then adjuvant [[#Cisplatin_.26_Doxorubicin_2|AP]] | |
− | + | </div></div> | |
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− | ==== | ||
− | * | ||
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===References=== | ===References=== | ||
− | # 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. [ | + | # Bramwell VH, Burgers M, Sneath R, Souhami R, van Oosterom AT, Voûte PA, Rouesse J, Spooner D, Craft AW, Somers R, Pringle J, Malcolm AJ, van der Eiiken J, Thomas D, Uscinska B, Machin D, van Glabbeke M; European Osteosarcoma Intergroup. A comparison of two short intensive adjuvant chemotherapy regimens in operable osteosarcoma of limbs in children and young adults: the first study of the European Osteosarcoma Intergroup. J Clin Oncol. 1992 Oct;10(10):1579-91. [https://doi.org/10.1200/jco.1992.10.10.1579 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/1403038/ 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. [https:// | + | # Souhami RL, Craft AW, Van der Eijken JW, Nooij M, Spooner D, Bramwell VH, Wierzbicki R, Malcolm AJ, Kirkpatrick A, Uscinska BM, Van Glabbeke M, Machin D; European Osteosarcoma Intergroup. Randomised trial of two regimens of chemotherapy in operable osteosarcoma: a study of the European Osteosarcoma Intergroup. Lancet. 1997 Sep 27;350(9082):911-7. [https://doi.org/10.1016/S0140-6736(97)02307-6 link to original article] [https://pubmed.ncbi.nlm.nih.gov/9314869/ 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. [ | + | # '''EORTC 80931:''' Lewis IJ, Nooij MA, Whelan J, Sydes MR, Grimer R, Hogendoorn PC, Memon MA, Weeden S, Uscinska BM, van Glabbeke M, Kirkpatrick A, Hauben EI, Craft AW, Taminiau AH; MRC BO06 and EORTC 80931 collaborators; European Osteosarcoma Intergroup. Improvement in histologic response but not survival in osteosarcoma patients treated with intensified chemotherapy: a randomized phase III trial of the European Osteosarcoma Intergroup. J Natl Cancer Inst. 2007 Jan 17;99(2):112-28. [https://doi.org/10.1093/jnci/djk015 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17227995/ PubMed] [https://clinicaltrials.gov/study/NCT00002539 NCT00002539] |
− | |||
==Cisplatin, Epirubicin, Ifosfamide {{#subobject:57c6cd|Regimen=1}}== | ==Cisplatin, Epirubicin, Ifosfamide {{#subobject:57c6cd|Regimen=1}}== | ||
− | + | <div class="toccolours" style="background-color:#eeeeee"> | |
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===Regimen {{#subobject:f6b024|Variant=1}}=== | ===Regimen {{#subobject:f6b024|Variant=1}}=== | ||
− | {| class="wikitable" style="width: | + | {| class="wikitable sortable" style="width: 60%; text-align:center;" |
− | !Study | + | !style="width: 33%"|Study |
− | ![[Levels_of_Evidence#Evidence|Evidence]] | + | !style="width: 33%"|Dates of enrollment |
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1159/000113017 Basaran et al. 2007] |
− | |style="background-color:#91cf61"|Phase | + | |1993-2002 |
+ | |style="background-color:#91cf61"|Phase 2 | ||
|- | |- | ||
|} | |} | ||
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
*[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV over 2 hours once on day 1 | *[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV over 2 hours once on day 1 | ||
*[[Epirubicin (Ellence)]] 90 mg/m<sup>2</sup> IV over 15 minutes once on day 1 | *[[Epirubicin (Ellence)]] 90 mg/m<sup>2</sup> IV over 15 minutes once on day 1 | ||
− | *[[Ifosfamide (Ifex)]] 2000 mg/m<sup>2</sup> | + | *[[Ifosfamide (Ifex)]] 2000 mg/m<sup>2</sup> IV over 4 hours once per day on days 2 to 4, '''given with mesna''' |
− | + | ====Supportive therapy==== | |
− | ====Supportive | + | *[[Mesna (Mesnex)]] 2000 mg/m<sup>2</sup> IV over 4 hours once per day on days 2 to 4, '''given with ifosfamide''' |
− | *[[Mesna (Mesnex)]] 2000 mg/m<sup>2</sup> | + | *Pre- and post-[[:Category:Hydration|hydration]] with mannitol diuresis for cisplatin |
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'''21-day cycle for 3 cycles''' | '''21-day cycle for 3 cycles''' | ||
− | + | </div> | |
− | + | <div class="toccolours" style="background-color:#cbd5e7"> | |
− | + | ====Subsequent treatment==== | |
+ | *[[Surgery#Surgical_resection|Surgery]], then adjuvant [[#Cisplatin.2C_Epirubicin.2C_Ifosfamide_2|cisplatin, epirubicin, ifosfamide]] | ||
+ | </div></div> | ||
===References=== | ===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. [ | + | # 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. [https://doi.org/10.1159/000113017 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18185020/ PubMed] |
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==MA {{#subobject:770fb2|Regimen=1}}== | ==MA {{#subobject:770fb2|Regimen=1}}== | ||
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MA: High-dose '''<u>M</u>'''ethotrexate, '''<u>A</u>'''driamycin (Doxorubicin) | MA: High-dose '''<u>M</u>'''ethotrexate, '''<u>A</u>'''driamycin (Doxorubicin) | ||
− | + | <div class="toccolours" style="background-color:#eeeeee"> | |
===Regimen {{#subobject:216b6e|Variant=1}}=== | ===Regimen {{#subobject:216b6e|Variant=1}}=== | ||
− | {| class="wikitable" style="width: 100%; text-align:center;" | + | {| class="wikitable sortable" style="width: 100%; text-align:center;" |
− | !Study | + | !style="width: 20%"|Study |
− | ![[Levels_of_Evidence#Evidence|Evidence]] | + | !style="width: 20%"|Dates of enrollment |
− | !Comparator | + | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] |
− | ![[Levels_of_Evidence# | + | !style="width: 20%"|Comparator |
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
|- | |- | ||
− | |[https:// | + | |[https://doi.org/10.1016/j.ejca.2006.10.023 Le Deley et al. 2007 (SFOP OS94)] |
− | |style="background-color:#1a9851"|Phase | + | |1994-2001 |
− | |[[# | + | |style="background-color:#1a9851"|Phase 3 (C) |
+ | |[[#M-EI|M-EI]] | ||
|style="background-color:#fee08b"|Might have inferior EFS | |style="background-color:#fee08b"|Might have inferior EFS | ||
|- | |- | ||
|} | |} | ||
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
− | *[[Methotrexate (MTX)]] 12,000 mg/m<sup>2</sup> IV over 4 hours once | + | *[[Methotrexate (MTX)]] as follows: |
− | **Given in D5W 1L with sodium bicarbonate 1 mEq/kg | + | **Cycles 1, 2, 3, 6, 7, 10, 11: 12,000 mg/m<sup>2</sup> IV over 4 hours once on day 1 |
− | *[[Doxorubicin (Adriamycin)]] 70 mg/m<sup>2</sup> IV over 6 hours once | + | ***Given in D5W 1L with sodium bicarbonate 1 mEq/kg |
− | + | *[[Doxorubicin (Adriamycin)]] as follows: | |
− | ====Supportive | + | **Cycles 4 & 8: 70 mg/m<sup>2</sup> IV over 6 hours once on day 1 |
− | *[[Folinic acid | + | ====Supportive therapy==== |
+ | *[[Leucovorin (Folinic acid)]] 15 mg PO every 6 hours for up to 11 doses on weeks 1, 2, 3, 6, 7, 10, 11, starting 20 hours after the completion of methotrexate infusion | ||
*For methotrexate: hydration & urine alkalinization by PO and IV routes to maintain 1.6 L/m<sup>2</sup> urine output over the first 24 hours and 2 L/m<sup>2</sup> on days 2 & 3, with urine pH greater than 7 | *For methotrexate: hydration & urine alkalinization by PO and IV routes to maintain 1.6 L/m<sup>2</sup> urine output over the first 24 hours and 2 L/m<sup>2</sup> on days 2 & 3, with urine pH greater than 7 | ||
*Daily monitoring of methotrexate levels and creatinine | *Daily monitoring of methotrexate levels and creatinine | ||
− | + | '''7-day cycle for 11 cycles''' | |
− | '''11 | + | </div> |
− | + | <div class="toccolours" style="background-color:#cbd5e7"> | |
− | + | ====Subsequent treatment==== | |
− | + | *[[Surgery#Surgical_resection|Surgery]] occurs during week 12, with risk-adapted treatment by the following response-based criteria: | |
− | + | **SFOP OS94, patients with good response: Adjuvant [[#MA|MA]] | |
− | + | **SFOP OS94, patients with poor response: Adjuvant [[#IE|IE]] | |
− | + | </div></div> | |
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− | *[[ | ||
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===References=== | ===References=== | ||
− | # ''' | + | # '''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. [https://doi.org/10.1016/j.ejca.2006.10.023 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17267204/ PubMed] [https://clinicaltrials.gov/study/NCT00180908 NCT00180908] |
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==MAP {{#subobject:c479f6|Regimen=1}}== | ==MAP {{#subobject:c479f6|Regimen=1}}== | ||
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MAP: High-dose '''<u>M</u>'''ethotrexate, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>P</u>'''latinol (Cisplatin) | MAP: High-dose '''<u>M</u>'''ethotrexate, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>P</u>'''latinol (Cisplatin) | ||
− | === | + | <div class="toccolours" style="background-color:#eeeeee"> |
− | {| class="wikitable" style="width: 100%; text-align:center;" | + | ===Regimen variant #1 {{#subobject:726dd7|Variant=1}}=== |
− | !Study | + | {| class="wikitable sortable" style="width: 100%; text-align:center;" |
− | ![[Levels_of_Evidence#Evidence|Evidence]] | + | !style="width: 20%"|Study |
− | !Comparator | + | !style="width: 20%"|Dates of enrollment |
− | ![[Levels_of_Evidence# | + | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] |
+ | !style="width: 20%"|Comparator | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1200/jco.1992.10.10.1579 Bramwell et al. 1992] |
− | |style="background-color:#1a9851"|Phase | + | |1983-1986 |
+ | |style="background-color:#1a9851"|Phase 3 (E-esc) | ||
|[[#Cisplatin_.26_Doxorubicin|Cisplatin & Doxorubicin]] | |[[#Cisplatin_.26_Doxorubicin|Cisplatin & Doxorubicin]] | ||
|style="background-color:#fc8d59"|Seems to have inferior DFS | |style="background-color:#fc8d59"|Seems to have inferior DFS | ||
Line 306: | Line 184: | ||
|} | |} | ||
''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.'' | ''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.'' | ||
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
*[[Methotrexate (MTX)]] 8000 mg/m<sup>2</sup> IV over 4 to 6 hours once on day 1 | *[[Methotrexate (MTX)]] 8000 mg/m<sup>2</sup> IV over 4 to 6 hours once on day 1 | ||
*[[Doxorubicin (Adriamycin)]] 25 mg/m<sup>2</sup> IV bolus once per day on days 11 to 13 | *[[Doxorubicin (Adriamycin)]] 25 mg/m<sup>2</sup> IV bolus once per day on days 11 to 13 | ||
− | *[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV continuous 24 | + | *[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV continuous infusion over 24 hours, started on day 11 |
− | + | ====Supportive therapy==== | |
− | ====Supportive | + | *[[Leucovorin (Folinic acid)]] 12 mg/m<sup>2</sup> IV every 6 hours x 10 doses or 15 mg/m<sup>2</sup> PO every 6 hours x 10 doses, starting 24 hours after the start of methotrexate infusion |
− | *[[Folinic acid | ||
**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 | **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 | **Methotrexate levels higher than 100 nmol/L at 48 hours required additional leucovorin rescue | ||
Line 319: | Line 197: | ||
*Posthydration for methotrexate: Alternating liters of D5W and NS 3000 mL/m<sup>2</sup> over 24 hours, with KCl 60 mEq/L. | *Posthydration for methotrexate: Alternating liters of D5W and NS 3000 mL/m<sup>2</sup> 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. | *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 [[ | + | *Prehydration for cisplatin: [[normal saline]] 400 mL/m<sup>2</sup> and D5W 400 mL/m<sup>2</sup> IV over 2 hours--the reference did not clarify if these two solutions are given at the same time |
− | *The volume of fluid for cisplatin continuous infusion is 2400 mL/m<sup>2</sup> NS, with KCl 80 mEq/L and mannitol 32 | + | *The volume of fluid for cisplatin continuous infusion is 2400 mL/m<sup>2</sup> NS, with KCl 80 mEq/L and mannitol 32,000 mg/m<sup>2</sup> |
− | *Posthydration for | + | *Posthydration for cisplatin: D5W 600 mL/m<sup>2</sup> over 6 hours, with KCl 20 mEq/L and mannitol 8000 mg/m<sup>2</sup>; and NS 600 mL/m<sup>2</sup> 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/m<sup>2</sup> over 12 hours, with KCl 20 mEq/L and mannitol 8000 mg/m<sup>2</sup>. |
− | *[[Furosemide (Lasix)]] 20 to 40 mg IV if urine output is less than 400 mL/m<sup>2</sup> over 6 hours during | + | *[[Furosemide (Lasix)]] 20 to 40 mg IV if urine output is less than 400 mL/m<sup>2</sup> over 6 hours during cisplatin |
− | |||
'''21-day cycle for 2 cycles''' | '''21-day cycle for 2 cycles''' | ||
+ | </div> | ||
+ | <div class="toccolours" style="background-color:#cbd5e7"> | ||
====Subsequent treatment==== | ====Subsequent treatment==== | ||
− | *Definitive surgery on week 9, then [[#MAP_2| | + | *Definitive [[Surgery#Surgical_resection|surgery]] on week 9, then adjuvant [[#MAP_2|MAP]] that starts 14 to 28 days after surgery |
− | + | </div></div><br> | |
− | === | + | <div class="toccolours" style="background-color:#eeeeee"> |
− | {| class="wikitable" style="width: | + | ===Regimen variant #2 {{#subobject:9f5a4e|Variant=1}}=== |
− | !Study | + | {| class="wikitable sortable" style="width: 60%; text-align:center;" |
− | ![[Levels_of_Evidence#Evidence|Evidence]] | + | !style="width: 33%"|Study |
+ | !style="width: 33%"|Dates of enrollment | ||
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
|- | |- | ||
− | |[https:// | + | |[https://doi.org/10.1002/1097-0142(19931201)72:11%3C3227::AID-CNCR2820721116%3E3.0.CO;2-C Bacci et al. 1993 (IOR/OS-2)] |
− | |style="background-color:#91cf61"|Phase | + | |1986-09 to 1989-12 |
+ | |style="background-color:#91cf61"|Phase 2 | ||
|- | |- | ||
|} | |} | ||
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
*[[Methotrexate (MTX)]] 8000 mg/m<sup>2</sup> IV over 6 hours once on day 1 | *[[Methotrexate (MTX)]] 8000 mg/m<sup>2</sup> IV over 6 hours once on day 1 | ||
*[[Doxorubicin (Adriamycin)]] 60 mg/m<sup>2</sup> IV over 8 hours once on day 9, '''starting 48 hours after the start of cisplatin''' | *[[Doxorubicin (Adriamycin)]] 60 mg/m<sup>2</sup> IV over 8 hours once on day 9, '''starting 48 hours after the start of cisplatin''' | ||
− | *[[Cisplatin (Platinol)]] 40 mg/m<sup>2</sup>/day | + | *[[Cisplatin (Platinol)]] 40 mg/m<sup>2</sup>/day IA continuous infusion over 72 hours, started on day 7 (total dose per cycle: 120 mg/m<sup>2</sup>) |
− | + | ====Supportive therapy==== | |
− | ====Supportive | + | *[[Leucovorin (Folinic acid)]] 15 mg IV every 6 hours x 11 doses on days 2 to 4, starting 24 hours after the start of methotrexate infusion |
− | *[[Folinic acid | + | *Hydration during and after methotrexate infusion |
− | *Hydration during and after | ||
− | |||
'''27-day cycle for 2 cycles''' | '''27-day cycle for 2 cycles''' | ||
+ | </div> | ||
+ | <div class="toccolours" style="background-color:#cbd5e7"> | ||
====Subsequent treatment==== | ====Subsequent treatment==== | ||
− | *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. | + | *Definitive [[Surgery#Surgical_resection|surgery]], then risk-adapted therapy. Amputated patients restart chemotherapy 3 to 5 days after surgery; patients who undergo limb salvage or rotation plasty restart chemotherapy 10 to 21 days after surgery. |
− | + | **IOR/OS-2, at least 90% tumor necrosis in the surgically removed specimen: Adjuvant [[#MAP_2|MAP]] | |
− | === | + | **IOR/OS-2, less than 90% tumor necrosis in the surgically removed specimen: Adjuvant [[#MAPIE|MAPIE]] |
− | {| class="wikitable" style="width: 100%; text-align:center;" | + | </div></div><br> |
− | !Study | + | <div class="toccolours" style="background-color:#eeeeee"> |
− | ![[Levels_of_Evidence#Evidence|Evidence]] | + | ===Regimen variant #3 {{#subobject:727eb0|Variant=1}}=== |
− | !Comparator | + | {| class="wikitable sortable" style="width: 100%; text-align:center;" |
− | ![[Levels_of_Evidence# | + | !style="width: 20%"|Study |
+ | !style="width: 20%"|Dates of enrollment | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | !style="width: 20%"|Comparator | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1200/jco.1988.6.2.329 Winkler et al. 1988 (COSS-82)] |
− | |style="background-color:#1a9851"|Phase | + | |1982-1984 |
− | |[[#M-BCD|M-BCD]] | + | |style="background-color:#1a9851"|Phase 3 (E-switch-ic) |
+ | |[[Osteosarcoma_-_historical#M-BCD|M-BCD]] | ||
|style="background-color:#1a9850"|Superior ORR | |style="background-color:#1a9850"|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.'' | ''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.'' | ||
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
− | *[[Methotrexate (MTX)]] 12,000 mg/m<sup>2</sup> (maximum dose of 20,000 mg | + | *[[Methotrexate (MTX)]] 12,000 mg/m<sup>2</sup> (maximum dose of 20,000 mg) IV over 4 hours once per day on days 22 & 29 |
**MTX is dissolved at a concentration of 20,000 mg/L in a solution containing 5% glucose | **MTX is dissolved at a concentration of 20,000 mg/L in a solution containing 5% glucose | ||
*[[Doxorubicin (Adriamycin)]] 30 mg/m<sup>2</sup> IV bolus once per day on days 1 & 2 | *[[Doxorubicin (Adriamycin)]] 30 mg/m<sup>2</sup> IV bolus once per day on days 1 & 2 | ||
− | *[[Cisplatin (Platinol)]] 90 mg/m<sup>2</sup> | + | *[[Cisplatin (Platinol)]] 90 mg/m<sup>2</sup> IV over 4 hours once on day 3 |
− | + | ====Supportive therapy==== | |
− | ====Supportive | + | *[[Leucovorin (Folinic acid)]] 15 mg/m<sup>2</sup> PO every 6 hours x 12 hours once per day on days 23 & 30, starting 24 hours after the completion of methotrexate infusion; additional leucovorin used for delayed methotrexate elimination |
− | *[[Folinic acid | + | *[[Sodium bicarbonate]] urine alkalinization prior to high-dose methotrexate |
− | *Sodium bicarbonate urine alkalinization prior to high-dose [[ | + | *[[Normal saline|NS]] 4.5 L/m<sup>2</sup> on day 1 after methotrexate; NS 3 L/m<sup>2</sup> on day 2, with adjustments made to keep urine pH greater than 7.4 |
− | + | *12 hours of [[:Category:Hydration|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/m<sup>2</sup> with mannitol 8 g/L and potassium 20 mval/L. | |
− | *12 hours of | + | *Magnesium 180 mg/m<sup>2</sup> PO "per day throughout the whole chemotherapy time"--as described in COSS-80 |
− | *Magnesium 180 mg/m<sup>2</sup> PO "per day throughout the whole chemotherapy time"--as described in | ||
− | |||
'''35-day cycle for 2 cycles''' | '''35-day cycle for 2 cycles''' | ||
+ | </div> | ||
+ | <div class="toccolours" style="background-color:#cbd5e7"> | ||
====Subsequent treatment==== | ====Subsequent treatment==== | ||
− | *Surgery, then [[#MAP_2| | + | *[[Surgery#Surgical_resection|Surgery]], then risk-adapted treatment: |
− | + | **COSS-82, good response: Adjuvant [[#MAP_2|MAP]] | |
− | === | + | **COSS-82, poor response: Adjuvant [[Osteosarcoma_-_historical#IP-BCD|IP-BCD]] |
− | {| class="wikitable" style="width: 100%; text-align:center;" | + | </div></div><br> |
− | !Study | + | <div class="toccolours" style="background-color:#eeeeee"> |
− | ![[Levels_of_Evidence#Evidence|Evidence]] | + | ===Regimen variant #4 {{#subobject:267572|Variant=1}}=== |
− | !Comparator | + | {| class="wikitable sortable" style="width: 100%; text-align:center;" |
− | ![[Levels_of_Evidence# | + | !style="width: 20%"|Study |
+ | !style="width: 20%"|Dates of enrollment | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | !style="width: 20%"|Comparator | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1200/jco.1984.2.6.617 Winkler et al. 1984 (COSS-80)] |
− | |style="background-color:#1a9851"|Phase | + | |1979-1982 |
− | |MA-BCD | + | |style="background-color:#1a9851"|Phase 3 (E-switch-ic) |
− | |style="background-color:#ffffbf"| | + | |[[#Osteosarcoma_-_historical#MA-BCD|MA-BCD]] |
+ | |style="background-color:#ffffbf"|Did not meet primary endpoint of CDF rate | ||
|- | |- | ||
|} | |} | ||
''Note: The exact schedule is unclear based on limited/conflicting information in the reference. For example, Figure 1 appears to depict high-dose methotrexate starting 2 weeks after adriamycin, but the text says that methotrexate begins after a 3-week rest period. Additionally, the diagram in Figure 1 implies that the later therapies are given 4 times (once, then repeated x 3 cycles), but based on the cumulative doses listed, they are only given for a total of 3 cycles. The optional interferon arm is omitted given lack of benefit seen in the study.'' | ''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.'' | ||
− | == | + | <div class="toccolours" style="background-color:#b3e2cd"> |
− | + | ====Chemotherapy==== | |
− | + | *[[Methotrexate (MTX)]] as follows: | |
− | + | **Cycle 1: 12,000 mg/m<sup>2</sup> (maximum dose of 20,000 mg) IV over 4 hours once per day on days 29 & 36 | |
− | + | **Cycles 2 to 4: 12,000 mg/m<sup>2</sup> (maximum dose of 20,000 mg) IV over 4 hours once per day on days 1, 8, 29, 36 | |
− | ====Chemotherapy | ||
− | |||
− | *[[Methotrexate (MTX)]] 12,000 mg/m<sup>2</sup> (maximum dose of 20,000 mg | ||
− | |||
− | |||
− | |||
− | |||
− | |||
− | * | ||
− | * | ||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
**MTX is dissolved at a concentration of 20,000 mg/L in a solution containing 5% glucose | **MTX is dissolved at a concentration of 20,000 mg/L in a solution containing 5% glucose | ||
− | *[[Doxorubicin (Adriamycin)]] 45 mg/m<sup>2</sup> IV bolus once per day on days 15 & 16 (delayed during cycle | + | *[[Doxorubicin (Adriamycin)]] as follows: |
+ | **Cycles 1, 3, 4: 45 mg/m<sup>2</sup> IV bolus once per day on days 1 & 2 | ||
+ | **Cycle 2: 45 mg/m<sup>2</sup> IV bolus once per day on days 15 & 16 (delayed during cycle 2 until after surgery) | ||
*[[Cisplatin (Platinol)]] 120 mg/m<sup>2</sup> IV over 5 hours once on day 43 | *[[Cisplatin (Platinol)]] 120 mg/m<sup>2</sup> IV over 5 hours once on day 43 | ||
− | + | ====Supportive therapy==== | |
− | ====Supportive | + | *[[Leucovorin (Folinic acid)]] 15 mg/m<sup>2</sup> PO every 6 hours x 12 hours once per day on days 2, 9, 30, 37, starting 24 hours after the completion of methotrexate infusion; additional leucovorin used for delayed methotrexate elimination |
− | *[[Folinic acid | + | *[[Sodium bicarbonate]] urine alkalinization prior to high-dose methotrexate |
− | *Sodium bicarbonate urine alkalinization prior to high-dose [[ | + | *[[Normal saline|NS]] 4.5 L/m<sup>2</sup> on day 1 after methotrexate; NS 3 L/m<sup>2</sup> on day 2, with adjustments made to keep urine pH greater than 7.4 |
− | + | *3 hours of [[:Category:Hydration|hydration]] prior to cisplatin & 3 hours of [[:Category:Hydration|hydration]] after cisplatin; total amount of fluid given over 11 hours of prehydration, cisplatin, and posthydration is NS 2.5 L/m<sup>2</sup> with mannitol 8 g/L and potassium 20 mval/L. | |
− | *3 hours of | + | *Magnesium 180 mg/m<sup>2</sup> PO "per day throughout the whole chemotherapy time" with cisplatin |
− | *Magnesium 180 mg/m<sup>2</sup> PO "per day throughout the whole chemotherapy time" with | + | '''8-week cycle for 4 cycles, with surgery done during cycle 2 before doxorubicin'''; surgery is done 9 to 18 weeks after the start of chemotherapy |
− | + | </div></div> | |
− | '''8-week cycle for | ||
===References=== | ===References=== | ||
− | # '''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. [ | + | # '''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. [https://doi.org/10.1200/jco.1984.2.6.617 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/6202851/ PubMed] |
− | # '''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. [ | + | # '''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. [https://doi.org/10.1200/jco.1988.6.2.329 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/2448428/ PubMed] |
− | # 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. [ | + | # Bramwell VH, Burgers M, Sneath R, Souhami R, van Oosterom AT, Voûte PA, Rouesse J, Spooner D, Craft AW, Somers R, Pringle J, Malcolm AJ, van der Eiiken J, Thomas D, Uscinska B, Machin D, van Glabbeke M; European Osteosarcoma Intergroup. A comparison of two short intensive adjuvant chemotherapy regimens in operable osteosarcoma of limbs in children and young adults: the first study of the European Osteosarcoma Intergroup. J Clin Oncol. 1992 Oct;10(10):1579-91. [https://doi.org/10.1200/jco.1992.10.10.1579 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/1403038/ PubMed] content property of [https://hemonc.org HemOnc.org] |
− | # '''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. [https:// | + | # '''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. [https://doi.org/10.1002/1097-0142(19931201)72:11%3C3227::AID-CNCR2820721116%3E3.0.CO;2-C link to original article] [https://pubmed.ncbi.nlm.nih.gov/8242546/ 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. [ | + | ## '''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. [https://doi.org/10.1200/jco.2000.18.24.4016 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/11118462/ PubMed] |
− | + | ==MAPI {{#subobject:8fa44|Regimen=1}}== | |
− | == | + | MAPI: High-dose '''<u>M</u>'''ethotrexate, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>P</u>'''latinol (Cisplatin), '''<u>I</u>'''fosfamide |
− | + | <div class="toccolours" style="background-color:#eeeeee"> | |
− | + | ===Regimen {{#subobject:ad261e|Variant=1}}=== | |
− | + | {| class="wikitable sortable" style="width: 60%; text-align:center;" | |
− | + | !style="width: 33%"|Study | |
− | + | !style="width: 33%"|Dates of enrollment | |
− | + | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | |
− | ===Regimen {{#subobject: | ||
− | {| class="wikitable" style="width: | ||
− | !Study | ||
− | ! | ||
− | |||
− | ![[Levels_of_Evidence# | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1093/annonc/mdg286 Bacci et al. 2003] |
− | | | + | |1995-05 to 2000-05 |
− | + | |style="background-color:#91cf61"|Phase 2 | |
− | |style="background-color:# | ||
|- | |- | ||
|} | |} | ||
− | + | <div class="toccolours" style="background-color:#b3e2cd"> | |
====Chemotherapy==== | ====Chemotherapy==== | ||
− | *[[Methotrexate (MTX)]] 12,000 mg/m<sup>2</sup> | + | *[[Methotrexate (MTX)]] 12,000 mg/m<sup>2</sup> IV over 4 hours once on day 1 |
− | + | *[[Cisplatin (Platinol)]] 60 mg/m<sup>2</sup>/day IV continuous infusion over 48 hours, started on day 8 (total dose per cycle: 120 mg/m<sup>2</sup>) | |
− | *[[ | + | *[[Doxorubicin (Adriamycin)]] 75 mg/m<sup>2</sup> IV continuous infusion over 24 hours, started on day 10 |
− | *[[ | + | *[[Ifosfamide (Ifex)]] 3000 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on day 29, '''given with mesna''' (total dose per cycle: 15,000 mg/m<sup>2</sup>) |
− | *[[ | + | ====Supportive therapy==== |
− | + | *[[Leucovorin (Folinic acid)]] 15 mg (route not specified) every 6 hours x 11 doses (note: the reference says "11 cycles," but it is assumed this is the intended meaning), starting day 2, 24 hours after the start of methotrexate | |
− | ====Supportive | + | *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. [https://pubmed.ncbi.nlm.nih.gov/6981454/ PubMed] |
− | *[[Folinic acid | + | *[[Mesna (Mesnex)]] 3000 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on day 29, '''given with ifosfamide''' (total dose: 15,000 mg/m<sup>2</sup>) |
− | * | + | '''42-day cycle for 2 cycles''' |
− | + | </div> | |
− | + | <div class="toccolours" style="background-color:#cbd5e7"> | |
− | ''' | + | ====Subsequent treatment==== |
− | + | *[[Surgery#Surgical_resection|Surgery]], then adjuvant [[#MAPI_2|MAPI]] | |
− | + | </div> | |
− | + | <div class="toccolours" style="background-color:#fff2ae"> | |
+ | ====Dose and schedule modifications==== | ||
+ | *If 4-hour methotrexate level is less than 10,000 nmol/L, the next cycle's methotrexate dose is increased by 2000 mg/m<sup>2</sup> | ||
+ | </div></div> | ||
===References=== | ===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. [https://doi.org/10.1093/annonc/mdg286 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/12853357/ PubMed] |
− | + | ==M-EI {{#subobject:ac6075|Regimen=1}}== | |
− | == | + | M-EI: '''<u>M</u>'''ethotrexate, '''<u>E</u>'''toposide, '''<u>I</u>'''fosfamide |
− | {| class="wikitable" style=" | + | <div class="toccolours" style="background-color:#eeeeee"> |
+ | ===Regimen {{#subobject:9ed88a|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 100%; text-align:center;" | ||
+ | !style="width: 20%"|Study | ||
+ | !style="width: 20%"|Dates of enrollment | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | !style="width: 20%"|Comparator | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1016/j.ejca.2006.10.023 Le Deley et al. 2007 (SFOP OS94)] |
− | + | |1994-2001 | |
− | + | |style="background-color:#1a9851"|Phase 3 (E-switch-ic) | |
− | + | |[[#MA|MA]] | |
− | + | |style="background-color:#d9ef8b"|Might have superior EFS | |
− | |||
− | |||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1016/S1470-2045(16)30096-1 Piperno-Neumann et al. 2016 (OS2006)] |
− | |style="background-color:# | + | |2007-2014 |
+ | |style="background-color:#1a9851"|Phase 3 (C) | ||
+ | |[[#M-EI_.26_Zoledronic_acid_999|M-EI & Zoledronic acid]] | ||
+ | |style="background-color:#d9ef8b"|Might have superior EFS<br>EFS36: 63.4% vs 57.1%<br>(HR 0.74, 95% CI 0.51-1.05) | ||
|- | |- | ||
|} | |} | ||
+ | ''Note: this regimen information is from SFOP OS94.'' | ||
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
− | *[[Methotrexate (MTX)]] 12,000 mg/m<sup>2</sup> IV over 4 hours once on day 1 | + | *[[Methotrexate (MTX)]] as follows: |
− | ** | + | **Cycles 1, 2, 3, 7, 8, 12, 13: 12,000 mg/m<sup>2</sup> IV over 4 hours once on day 1 |
− | *[[ | + | ***Given in D5W 1L with sodium bicarbonate 1 mEq/kg |
− | + | *[[Etoposide (Vepesid)]] as follows: | |
− | *[[Ifosfamide (Ifex)]] 3000 mg/m<sup>2</sup> | + | **Cycles 4 & 9: 75 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 4 |
− | + | ***Given in NS 250 to 500 mL | |
− | ====Supportive | + | *[[Ifosfamide (Ifex)]] as follows: |
− | *[[Folinic acid | + | **Cycles 4 & 9: 3000 mg/m<sup>2</sup> IV over 3 hours once per day on days 1 to 4, '''given with mesna''' |
− | * | + | ***Given in NS 250 to 500 mL |
− | *[[Mesna (Mesnex)]] | + | ====Supportive therapy==== |
− | + | *[[Leucovorin (Folinic acid)]] 15 mg PO every 6 hours for up to 11 doses on weeks 1, 2, 3, 7, 8, 12, 13, starting 20 hours after the completion of methotrexate infusion | |
− | ''' | + | *For methotrexate: hydration & urine alkalinization by PO and IV routes to maintain 1.6 L/m<sup>2</sup> urine output over the first 24 hours and 2 L/m<sup>2</sup> on days 2 & 3, with urine pH greater than 7 |
− | + | *Daily monitoring of methotrexate levels and creatinine | |
− | + | *[[Mesna (Mesnex)]] 3600 mg/m<sup>2</sup>/day IV continuous infusion over 96 hours, started on day 22 (week 4) and 57 (week 9), '''given with ifosfamide''' (total dose: 14,400 mg/m<sup>2</sup>) | |
− | + | *Up to 2 L/day hydration with ifosfamide & mesna | |
+ | '''7-day cycle for 13 cycles''' | ||
+ | </div> | ||
+ | <div class="toccolours" style="background-color:#cbd5e7"> | ||
+ | ====Subsequent treatment==== | ||
+ | *[[Surgery#Surgical_resection|Surgery]] occurs during week 14, with further treatment based on pathologic response: | ||
+ | **SFOP OS94, patients with good response: Adjuvant [[#M-EI_2|M-EI]] | ||
+ | **SFOP OS94, patients with poor response: Adjuvant [[#Cisplatin_.26_Doxorubicin_2|AP]] | ||
+ | </div></div> | ||
===References=== | ===References=== | ||
− | # | + | # '''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. [https://doi.org/10.1016/j.ejca.2006.10.023 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17267204/ PubMed] [https://clinicaltrials.gov/study/NCT00180908 NCT00180908] |
− | + | # '''OS2006:''' Piperno-Neumann S, Le Deley MC, Rédini F, Pacquement H, Marec-Bérard P, Petit P, Brisse H, Lervat C, Gentet JC, Entz-Werlé N, Italiano A, Corradini N, Bompas E, Penel N, Tabone MD, Gomez-Brouchet A, Guinebretière JM, Mascard E, Gouin F, Chevance A, Bonnet N, Blay JY, Brugières L; Sarcoma Group of UNICANCER; SFCE; GSF-GETO. Zoledronate in combination with chemotherapy and surgery to treat osteosarcoma (OS2006): a randomised, multicentre, open-label, phase 3 trial. Lancet Oncol. 2016 Aug;17(8):1070-1080. Epub 2016 Jun 17. [https://doi.org/10.1016/S1470-2045(16)30096-1 link to original article] [https://pubmed.ncbi.nlm.nih.gov/27324280/ PubMed] [https://clinicaltrials.gov/study/NCT00470223 NCT00470223] | |
+ | ## '''Update:''' Gaspar N, Occean BV, Pacquement H, Bompas E, Bouvier C, Brisse HJ, Castex MP, Cheurfa N, Corradini N, Delaye J, Entz-Werlé N, Gentet JC, Italiano A, Lervat C, Marec-Berard P, Mascard E, Redini F, Saumet L, Schmitt C, Tabone MD, Verite-Goulard C, Le Deley MC, Piperno-Neumann S, Brugieres L; SFCE; GSF-GETO; UNICANCER sarcoma group. Results of methotrexate-etoposide-ifosfamide based regimen (M-EI) in osteosarcoma patients included in the French OS2006/sarcome-09 study. Eur J Cancer. 2018 Jan;88:57-66. Epub 2017 Nov 28. [https://doi.org/10.1016/j.ejca.2017.09.036 link to original article] [https://pubmed.ncbi.nlm.nih.gov/29190507/ PubMed] | ||
=Adjuvant therapy= | =Adjuvant therapy= | ||
− | |||
==Cisplatin & Doxorubicin {{#subobject:267127|Regimen=1}}== | ==Cisplatin & Doxorubicin {{#subobject:267127|Regimen=1}}== | ||
− | {| class="wikitable" style=" | + | AP: '''<u>A</u>'''driamycin (Doxorubicin) & '''<u>P</u>'''latinol (Cisplatin) |
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
+ | ===Regimen variant #1 {{#subobject:602292|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 100%; text-align:center;" | ||
+ | !style="width: 20%"|Study | ||
+ | !style="width: 20%"|Dates of enrollment | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | !style="width: 20%"|Comparator | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1200/jco.1992.10.10.1579 Bramwell et al. 1992] |
− | + | |1983-1986 | |
− | + | |style="background-color:#1a9851"|Phase 3 (E-esc) | |
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |style="background-color:#1a9851"|Phase | ||
|[[#MAP|MAP]] | |[[#MAP|MAP]] | ||
|style="background-color:#91cf60"|Seems to have superior DFS | |style="background-color:#91cf60"|Seems to have superior DFS | ||
|- | |- | ||
− | |[https:// | + | |[https://doi.org/10.1016/S0140-6736(97)02307-6 Souhami et al. 1997] |
− | |style="background-color:#1a9851"|Phase | + | |1986-1991 |
− | |Multi-drug | + | |style="background-color:#1a9851"|Phase 3 (E-de-esc) |
− | |style="background-color:#ffffbf"| | + | |[[#T10_protocol_888|Multi-drug T10 protocol]] |
+ | |style="background-color:#ffffbf"|Did not meet co-primary endpoints of PFS/OS | ||
|- | |- | ||
|} | |} | ||
+ | <div class="toccolours" style="background-color:#cbd5e8"> | ||
====Preceding treatment==== | ====Preceding treatment==== | ||
− | *[[#Cisplatin_.26_Doxorubicin| | + | *Neoadjuvant [[#Cisplatin_.26_Doxorubicin|AP]], then [[Surgery#Surgical_resection|surgery]] |
+ | </div> | ||
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
− | *[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV continuous 24 | + | *[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV continuous infusion over 24 hours, started on day 1 |
*[[Doxorubicin (Adriamycin)]] 25 mg/m<sup>2</sup> IV bolus once per day on days 1 to 3 | *[[Doxorubicin (Adriamycin)]] 25 mg/m<sup>2</sup> IV bolus once per day on days 1 to 3 | ||
− | + | ====Supportive therapy==== | |
− | ====Supportive | + | *Prehydration: normal saline 400 mL/m<sup>2</sup> and D5W 400 mL/m<sup>2</sup> IV over 2 hours--the reference did not clarify if these two solutions are given at the same time |
− | *Prehydration: normal saline 400 mL/m<sup>2</sup> and D5W 400 mL/m<sup>2</sup> 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/m<sup>2</sup> NS, with KCl 80 mEq/L and mannitol 32,000 mg/m<sup>2</sup> |
− | *The volume of fluid for cisplatin continuous infusion is 2400 mL/m<sup>2</sup> NS, with KCl 80 mEq/L and mannitol 32 | + | *Posthydration: D5W 600 mL/m<sup>2</sup> over 6 hours, with KCl 20 mEq/L and mannitol 8000 mg/m<sup>2</sup>; and NS 600 mL/m<sup>2</sup> 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/m<sup>2</sup> over 12 hours, with KCl 20 mEq/L and mannitol 8000 mg/m<sup>2</sup>. |
− | *Posthydration: D5W 600 mL/m<sup>2</sup> over 6 hours, with KCl 20 mEq/L and mannitol | ||
*[[Furosemide (Lasix)]] 20 to 40 mg IV if urine output is less than 400 mL/m<sup>2</sup> over 6 hours | *[[Furosemide (Lasix)]] 20 to 40 mg IV if urine output is less than 400 mL/m<sup>2</sup> over 6 hours | ||
− | |||
'''21-day cycle for 3 cycles''' | '''21-day cycle for 3 cycles''' | ||
− | + | </div></div><br> | |
− | === | + | <div class="toccolours" style="background-color:#eeeeee"> |
− | {| class="wikitable" style="width: 100%; text-align:center;" | + | ===Regimen variant #2 {{#subobject:32db86|Variant=1}}=== |
− | !Study | + | {| class="wikitable sortable" style="width: 100%; text-align:center;" |
− | ![[Levels_of_Evidence#Evidence|Evidence]] | + | !style="width: 20%"|Study |
− | !Comparator | + | !style="width: 20%"|Dates of enrollment |
− | ![[Levels_of_Evidence# | + | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] |
+ | !style="width: 20%"|Comparator | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1093/jnci/djk015 Lewis et al. 2007 (EORTC 80931)] |
− | |style="background-color:#1a9851"|Phase | + | |1993-2002 |
− | | | + | |style="background-color:#1a9851"|Phase 3 (C) |
− | |style="background-color:# | + | |[[#Cisplatin_.26_Doxorubicin_2|Cisplatin & Doxorubicin]]; dose-intense |
+ | |style="background-color:#ffffbf"|Did not meet primary endpoint of OS | ||
|- | |- | ||
|} | |} | ||
+ | <div class="toccolours" style="background-color:#cbd5e8"> | ||
====Preceding treatment==== | ====Preceding treatment==== | ||
− | *[[#Cisplatin_.26_Doxorubicin| | + | *Neoadjuvant [[#Cisplatin_.26_Doxorubicin|AP]], then [[Surgery#Surgical_resection|surgery]] |
+ | </div> | ||
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
− | *[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV continuous 24 | + | *[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV continuous infusion over 24 hours, started on day 1 |
*[[Doxorubicin (Adriamycin)]] 25 mg/m<sup>2</sup> IV over 4 hours once per day on days 1 to 3 | *[[Doxorubicin (Adriamycin)]] 25 mg/m<sup>2</sup> IV over 4 hours once per day on days 1 to 3 | ||
− | + | ====Supportive therapy==== | |
− | ====Supportive | ||
*4 hours of prehydration prior to cisplatin | *4 hours of prehydration prior to cisplatin | ||
*24 hours of posthydration & mannitol after cisplatin | *24 hours of posthydration & mannitol after cisplatin | ||
*Recommended that fluid for cisplatin is isotonic saline with potassium chloride and mannitol | *Recommended that fluid for cisplatin is isotonic saline with potassium chloride and mannitol | ||
− | |||
'''21-day cycle for 4 cycles''' | '''21-day cycle for 4 cycles''' | ||
− | + | </div></div><br> | |
− | === | + | <div class="toccolours" style="background-color:#eeeeee"> |
− | {| class="wikitable" style="width: 100%; text-align:center;" | + | ===Regimen variant #3, dose intense {{#subobject:d1ecd3|Variant=1}}=== |
− | !Study | + | {| class="wikitable sortable" style="width: 100%; text-align:center;" |
− | ![[Levels_of_Evidence#Evidence|Evidence]] | + | !style="width: 20%"|Study |
− | !Comparator | + | !style="width: 20%"|Dates of enrollment |
− | ![[Levels_of_Evidence# | + | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] |
+ | !style="width: 20%"|Comparator | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1093/jnci/djk015 Lewis et al. 2007 (EORTC 80931)] |
− | |style="background-color:#1a9851"|Phase | + | |1993-2002 |
− | | | + | |style="background-color:#1a9851"|Phase 3 (E-esc) |
− | |style="background-color:# | + | |[[#Cisplatin_.26_Doxorubicin|Cisplatin & Doxorubicin]]; conventional |
+ | |style="background-color:#ffffbf"|Did not meet primary endpoint of OS | ||
|- | |- | ||
|} | |} | ||
+ | <div class="toccolours" style="background-color:#cbd5e8"> | ||
====Preceding treatment==== | ====Preceding treatment==== | ||
− | *[[#Cisplatin_.26_Doxorubicin| | + | *Neoadjuvant [[#Cisplatin_.26_Doxorubicin|AP]], then [[Surgery#Surgical_resection|surgery]] |
+ | </div> | ||
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
− | *[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV continuous 24 | + | *[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV continuous infusion over 24 hours, started on day 1 |
*[[Doxorubicin (Adriamycin)]] 25 mg/m<sup>2</sup> IV over 4 hours once per day on days 1 to 3 | *[[Doxorubicin (Adriamycin)]] 25 mg/m<sup>2</sup> IV over 4 hours once per day on days 1 to 3 | ||
− | + | ====Supportive therapy==== | |
− | ====Supportive | ||
*Growth factor suppor with ONE of the following: | *Growth factor suppor with ONE of the following: | ||
**[[Filgrastim (Neupogen)]] 5 mcg/kg SC once per day on days 4 to 13 | **[[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 | **[[Lenograstim (Granocyte)]] 5 mcg/kg SC once per day on days 4 to 13 | ||
− | *4 hours of prehydration prior to | + | *4 hours of prehydration prior to cisplatin |
− | *24 hours of posthydration & mannitol after | + | *24 hours of posthydration & mannitol after cisplatin |
*Recommended that fluid for cisplatin is isotonic saline with potassium chloride and mannitol | *Recommended that fluid for cisplatin is isotonic saline with potassium chloride and mannitol | ||
− | |||
'''14-day cycle for 3 cycles''' | '''14-day cycle for 3 cycles''' | ||
− | + | </div></div><br> | |
− | === | + | <div class="toccolours" style="background-color:#eeeeee"> |
− | {| class="wikitable" style="width: | + | ===Regimen variant #4 {{#subobject:44bba3|Variant=1}}=== |
− | !Study | + | {| class="wikitable sortable" style="width: 60%; text-align:center;" |
− | ![[Levels_of_Evidence#Evidence|Evidence]] | + | !style="width: 33%"|Study |
+ | !style="width: 33%"|Dates of enrollment | ||
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1200/jco.1988.6.2.329 Winkler et al. 1988 (COSS-82)] |
− | |style="background-color:#91cf61"|Non-randomized | + | |1982-1984 |
+ | |style="background-color:#91cf61"|Non-randomized part of phase 3 RCT | ||
|- | |- | ||
|} | |} | ||
− | ''Note: The exact schedule is unclear based on limited information in the reference, as schedule of doses is primarily extrapolated from Figure 1, which does not contain clear delineations in time | + | ''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.'' |
+ | <div class="toccolours" style="background-color:#cbd5e8"> | ||
====Preceding treatment==== | ====Preceding treatment==== | ||
− | *[[#M-BCD| | + | *Neoadjuvant [[Osteosarcoma_-_historical#M-BCD|M-BCD]], then [[Surgery#Surgical_resection|surgery]], with poor response |
+ | </div> | ||
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
− | *[[Cisplatin (Platinol)]] 90 mg/m<sup>2</sup> | + | *[[Cisplatin (Platinol)]] 90 mg/m<sup>2</sup> IV over 4 hours once on day 3 |
*[[Doxorubicin (Adriamycin)]] 30 mg/m<sup>2</sup> IV bolus once per day on days 1 & 2 | *[[Doxorubicin (Adriamycin)]] 30 mg/m<sup>2</sup> IV bolus once per day on days 1 & 2 | ||
− | + | ====Supportive therapy==== | |
− | ====Supportive | ||
*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/m<sup>2</sup> with mannitol 8 g/L and potassium 20 mval/L. | *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/m<sup>2</sup> with mannitol 8 g/L and potassium 20 mval/L. | ||
− | *Magnesium 180 mg/m<sup>2</sup> PO "per day throughout the whole chemotherapy time"--as described in | + | *Magnesium 180 mg/m<sup>2</sup> PO "per day throughout the whole chemotherapy time"--as described in COSS-80 |
− | |||
'''21-day cycle for 6 cycles''' | '''21-day cycle for 6 cycles''' | ||
− | + | </div></div><br> | |
− | === | + | <div class="toccolours" style="background-color:#eeeeee"> |
− | {| class="wikitable" style="width: | + | ===Regimen variant #5 {{#subobject:7fc4e3|Variant=1}}=== |
− | !Study | + | {| class="wikitable sortable" style="width: 60%; text-align:center;" |
− | ![[Levels_of_Evidence#Evidence|Evidence]] | + | !style="width: 33%"|Study |
+ | !style="width: 33%"|Dates of enrollment | ||
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
|- | |- | ||
− | |[https:// | + | |[https://doi.org/10.1016/j.ejca.2006.10.023 Le Deley et al. 2007 (SFOP OS94)] |
− | |style="background-color:#91cf61"|Non-randomized | + | |1994-2001 |
+ | |style="background-color:#91cf61"|Non-randomized part of phase 3 RCT | ||
|- | |- | ||
|} | |} | ||
− | '' | + | ''Details were not listed about the precise schedule. Other regimens have used both medications both on day 1, with 21-day cycles.'' |
+ | <div class="toccolours" style="background-color:#cbd5e8"> | ||
====Preceding treatment==== | ====Preceding treatment==== | ||
− | *[[# | + | *Neoadjuvant [[#M-EI|M-EI]], then [[Surgery#Surgical_resection|surgery]], with poor response |
+ | </div> | ||
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
− | *[[Cisplatin (Platinol)]] 120 mg/m<sup>2</sup> | + | *[[Cisplatin (Platinol)]] 120 mg/m<sup>2</sup> IV (schedule not specified) |
− | *[[Doxorubicin (Adriamycin)]] 70 mg/m<sup>2</sup> IV over 6 hours | + | *[[Doxorubicin (Adriamycin)]] 70 mg/m<sup>2</sup> IV over 6 hours (schedule not specified) |
− | '''5 cycles''' | + | '''5 cycles (length not specified)''' |
+ | </div></div> | ||
===References=== | ===References=== | ||
− | # '''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. [ | + | # '''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. [https://doi.org/10.1200/jco.1988.6.2.329 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/2448428/ PubMed] |
− | # 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. [ | + | # Bramwell VH, Burgers M, Sneath R, Souhami R, van Oosterom AT, Voûte PA, Rouesse J, Spooner D, Craft AW, Somers R, Pringle J, Malcolm AJ, van der Eiiken J, Thomas D, Uscinska B, Machin D, van Glabbeke M; European Osteosarcoma Intergroup. A comparison of two short intensive adjuvant chemotherapy regimens in operable osteosarcoma of limbs in children and young adults: the first study of the European Osteosarcoma Intergroup. J Clin Oncol. 1992 Oct;10(10):1579-91. [https://doi.org/10.1200/jco.1992.10.10.1579 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/1403038/ 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. [https:// | + | # Souhami RL, Craft AW, Van der Eijken JW, Nooij M, Spooner D, Bramwell VH, Wierzbicki R, Malcolm AJ, Kirkpatrick A, Uscinska BM, Van Glabbeke M, Machin D; European Osteosarcoma Intergroup. Randomised trial of two regimens of chemotherapy in operable osteosarcoma: a study of the European Osteosarcoma Intergroup. Lancet. 1997 Sep 27;350(9082):911-7. [https://doi.org/10.1016/S0140-6736(97)02307-6 link to original article] [https://pubmed.ncbi.nlm.nih.gov/9314869/ 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. [ | + | # '''EORTC 80931:''' Lewis IJ, Nooij MA, Whelan J, Sydes MR, Grimer R, Hogendoorn PC, Memon MA, Weeden S, Uscinska BM, van Glabbeke M, Kirkpatrick A, Hauben EI, Craft AW, Taminiau AH; MRC BO06 and EORTC 80931 collaborators; European Osteosarcoma Intergroup. Improvement in histologic response but not survival in osteosarcoma patients treated with intensified chemotherapy: a randomized phase III trial of the European Osteosarcoma Intergroup. J Natl Cancer Inst. 2007 Jan 17;99(2):112-28. [https://doi.org/10.1093/jnci/djk015 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17227995/ PubMed] [https://clinicaltrials.gov/study/NCT00002539 NCT00002539] |
− | # '''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. [https:// | + | # '''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. [https://doi.org/10.1016/j.ejca.2006.10.023 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17267204/ PubMed] [https://clinicaltrials.gov/study/NCT00180908 NCT00180908] |
− | |||
==Cisplatin, Epirubicin, Ifosfamide {{#subobject:cd0e26|Regimen=1}}== | ==Cisplatin, Epirubicin, Ifosfamide {{#subobject:cd0e26|Regimen=1}}== | ||
− | + | <div class="toccolours" style="background-color:#eeeeee"> | |
− | |||
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===Regimen {{#subobject:320a96|Variant=1}}=== | ===Regimen {{#subobject:320a96|Variant=1}}=== | ||
− | {| class="wikitable" style="width: | + | {| class="wikitable sortable" style="width: 60%; text-align:center;" |
− | !Study | + | !style="width: 33%"|Study |
− | ![[Levels_of_Evidence#Evidence|Evidence]] | + | !style="width: 33%"|Dates of enrollment |
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1159/000113017 Basaran et al. 2007] |
− | |style="background-color:#91cf61"|Phase | + | |1993-2002 |
+ | |style="background-color:#91cf61"|Phase 2 | ||
|- | |- | ||
|} | |} | ||
+ | <div class="toccolours" style="background-color:#cbd5e8"> | ||
====Preceding treatment==== | ====Preceding treatment==== | ||
− | *[[#Cisplatin.2C_Epirubicin.2C_Ifosfamide| | + | *Neoadjuvant [[#Cisplatin.2C_Epirubicin.2C_Ifosfamide|cisplatin, epirubicin, ifosfamide]], then [[Surgery#Surgical_resection|surgery]] |
+ | </div> | ||
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
− | *[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV over 2 hours | + | *[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV over 2 hours once on day 1 |
*[[Epirubicin (Ellence)]] 90 mg/m<sup>2</sup> IV over 15 minutes once on day 1 | *[[Epirubicin (Ellence)]] 90 mg/m<sup>2</sup> IV over 15 minutes once on day 1 | ||
− | *[[Ifosfamide (Ifex)]] 2000 mg/m<sup>2</sup> | + | *[[Ifosfamide (Ifex)]] 2000 mg/m<sup>2</sup> IV over 4 hours once per day on days 2 to 4, '''given with mesna''' |
− | + | ====Supportive therapy==== | |
− | ====Supportive | + | *[[Mesna (Mesnex)]] 2000 mg/m<sup>2</sup> IV over 4 hours once per day on days 2 to 4, '''given with ifosfamide''' |
− | *[[Mesna (Mesnex)]] 2000 mg/m<sup>2</sup> | + | *Pre- and post-[[:Category:Hydration|hydration]] with mannitol diuresis for cisplatin |
− | |||
− | |||
'''28-day cycle for 3 cycles''' | '''28-day cycle for 3 cycles''' | ||
− | + | </div></div> | |
===References=== | ===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. [ | + | # 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. [https://doi.org/10.1159/000113017 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/18185020/ PubMed] |
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==IE {{#subobject:777bc8|Regimen=1}}== | ==IE {{#subobject:777bc8|Regimen=1}}== | ||
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IE: '''<u>I</u>'''fosfamide, '''<u>E</u>'''toposide | IE: '''<u>I</u>'''fosfamide, '''<u>E</u>'''toposide | ||
− | + | <div class="toccolours" style="background-color:#eeeeee"> | |
===Regimen {{#subobject:7d60b5|Variant=1}}=== | ===Regimen {{#subobject:7d60b5|Variant=1}}=== | ||
− | {| class="wikitable" style="width: | + | {| class="wikitable sortable" style="width: 60%; text-align:center;" |
− | !Study | + | !style="width: 33%"|Study |
− | ![[Levels_of_Evidence#Evidence|Evidence]] | + | !style="width: 33%"|Dates of enrollment |
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
|- | |- | ||
− | |[https:// | + | |[https://doi.org/10.1016/j.ejca.2006.10.023 Le Deley et al. 2007 (SFOP OS94)] |
− | |style="background-color:#91cf61"|Non-randomized | + | |1994-2001 |
+ | |style="background-color:#91cf61"|Non-randomized part of phase 3 RCT | ||
|- | |- | ||
|} | |} | ||
− | '' | + | ''Details were not listed about the length of each cycle. Other regimens have used 21 to 28-day cycles.'' |
+ | <div class="toccolours" style="background-color:#cbd5e8"> | ||
====Preceding treatment==== | ====Preceding treatment==== | ||
− | *[[#MA| | + | *Neoadjuvant [[#MA|MA]], then [[Surgery#Surgical_resection|surgery]], with poor response |
+ | </div> | ||
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
− | *[[Ifosfamide (Ifex)]] 3000 mg/m<sup>2</sup> | + | *[[Ifosfamide (Ifex)]] 3000 mg/m<sup>2</sup> IV over 3 hours once per day on days 1 to 4, '''given during mesna infusion''' |
**Given in NS 250 to 500 mL | **Given in NS 250 to 500 mL | ||
*[[Etoposide (Vepesid)]] 75 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 4 | *[[Etoposide (Vepesid)]] 75 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 4 | ||
**Given in NS 250 to 500 mL | **Given in NS 250 to 500 mL | ||
− | + | ====Supportive therapy==== | |
− | ====Supportive | + | *[[Mesna (Mesnex)]] 3600 mg/m<sup>2</sup>/day IV continuous infusion over 96 hours, started on day 1 (total dose: 14,400 mg/m<sup>2</sup>) |
− | *[[Mesna (Mesnex)]] 3600 mg/m<sup>2</sup>/day IV continuous 96 | ||
*Up to 2 L/day hydration with ifosfamide & mesna | *Up to 2 L/day hydration with ifosfamide & mesna | ||
− | |||
'''5 cycles''' | '''5 cycles''' | ||
− | + | </div></div> | |
===References=== | ===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. [https:// | + | # '''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. [https://doi.org/10.1016/j.ejca.2006.10.023 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17267204/ PubMed] [https://clinicaltrials.gov/study/NCT00180908 NCT00180908] |
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==MA {{#subobject:cf86ac|Regimen=1}}== | ==MA {{#subobject:cf86ac|Regimen=1}}== | ||
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MA: High-dose '''<u>M</u>'''ethotrexate, '''<u>A</u>'''driamycin (Doxorubicin) | MA: High-dose '''<u>M</u>'''ethotrexate, '''<u>A</u>'''driamycin (Doxorubicin) | ||
− | + | <div class="toccolours" style="background-color:#eeeeee"> | |
===Regimen {{#subobject:243248|Variant=1}}=== | ===Regimen {{#subobject:243248|Variant=1}}=== | ||
− | {| class="wikitable" style="width: | + | {| class="wikitable sortable" style="width: 60%; text-align:center;" |
− | !Study | + | !style="width: 33%"|Study |
− | ![[Levels_of_Evidence#Evidence|Evidence]] | + | !style="width: 33%"|Dates of enrollment |
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
|- | |- | ||
− | |[https:// | + | |[https://doi.org/10.1016/j.ejca.2006.10.023 Le Deley et al. 2007 (SFOP OS94)] |
− | |style="background-color:#91cf61"|Non-randomized | + | |1994-2001 |
+ | |style="background-color:#91cf61"|Non-randomized part of phase 3 RCT | ||
|- | |- | ||
|} | |} | ||
− | + | <div class="toccolours" style="background-color:#cbd5e8"> | |
====Preceding treatment==== | ====Preceding treatment==== | ||
− | *[[#MA| | + | *Neoadjuvant [[#MA|MA]], then [[Surgery#Surgical_resection|surgery]], with good response |
− | + | </div> | |
− | + | <div class="toccolours" style="background-color:#b3e2cd"> | |
− | + | ====Chemotherapy==== | |
− | |||
− | |||
− | == | ||
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− | ====Chemotherapy | ||
*[[Methotrexate (MTX)]] 12,000 mg/m<sup>2</sup> IV over 4 hours once per day on days 1, 8, 15 | *[[Methotrexate (MTX)]] 12,000 mg/m<sup>2</sup> IV over 4 hours once per day on days 1, 8, 15 | ||
**Given in D5W 1L with sodium bicarbonate 1 mEq/kg | **Given in D5W 1L with sodium bicarbonate 1 mEq/kg | ||
− | + | *[[Doxorubicin (Adriamycin)]] as follows: | |
− | ====Supportive | + | **Cycles 1 to 3: 70 mg/m<sup>2</sup> IV over 6 hours once on day 22 |
− | *[[Folinic acid | + | ====Supportive therapy==== |
+ | *[[Leucovorin (Folinic acid)]] 15 mg PO every 6 hours for up to 11 doses, starting on days 1, 8, 15, starting 20 hours after the completion of methotrexate infusion | ||
*For methotrexate: hydration & urine alkalinization by PO and IV routes to maintain 1.6 L/m<sup>2</sup> urine output over the first 24 hours and 2 L/m<sup>2</sup> on days 2 & 3, with urine pH greater than 7 | *For methotrexate: hydration & urine alkalinization by PO and IV routes to maintain 1.6 L/m<sup>2</sup> urine output over the first 24 hours and 2 L/m<sup>2</sup> on days 2 & 3, with urine pH greater than 7 | ||
*Daily monitoring of methotrexate levels and creatinine | *Daily monitoring of methotrexate levels and creatinine | ||
− | + | '''28-day cycle for 4 cycles''' | |
− | ''' | + | </div></div> |
− | |||
===References=== | ===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. [https:// | + | # '''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. [https://doi.org/10.1016/j.ejca.2006.10.023 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17267204/ PubMed] [https://clinicaltrials.gov/study/NCT00180908 NCT00180908] |
==MAP {{#subobject:3b095e|Regimen=1}}== | ==MAP {{#subobject:3b095e|Regimen=1}}== | ||
− | |||
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MAP: High-dose '''<u>M</u>'''ethotrexate, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>P</u>'''latinol (Cisplatin) | MAP: High-dose '''<u>M</u>'''ethotrexate, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>P</u>'''latinol (Cisplatin) | ||
− | + | <div class="toccolours" style="background-color:#eeeeee"> | |
− | === | + | ===Regimen variant #1, 8000/75/100 {{#subobject:6db034|Variant=1}}=== |
− | {| class="wikitable" style="width: 100%; text-align:center;" | + | {| class="wikitable sortable" style="width: 100%; text-align:center;" |
− | !Study | + | !style="width: 20%"|Study |
− | ![[Levels_of_Evidence#Evidence|Evidence]] | + | !style="width: 20%"|Dates of enrollment |
− | !Comparator | + | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] |
− | ![[Levels_of_Evidence# | + | !style="width: 20%"|Comparator |
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1200/jco.1992.10.10.1579 Bramwell et al. 1992] |
− | |style="background-color:#1a9851"|Phase | + | |1983-1986 |
+ | |style="background-color:#1a9851"|Phase 3 (E-esc) | ||
|[[#Cisplatin_.26_Doxorubicin_2|Cisplatin & Doxorubicin]] | |[[#Cisplatin_.26_Doxorubicin_2|Cisplatin & Doxorubicin]] | ||
|style="background-color:#fc8d59"|Seems to have inferior DFS | |style="background-color:#fc8d59"|Seems to have inferior DFS | ||
Line 865: | Line 677: | ||
|} | |} | ||
''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.'' | ''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.'' | ||
+ | <div class="toccolours" style="background-color:#cbd5e8"> | ||
====Preceding treatment==== | ====Preceding treatment==== | ||
− | *[[#MAP| | + | *Neoadjuvant [[#MAP|MAP]], then [[Surgery#Surgical_resection|surgery]] |
+ | </div> | ||
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
*[[Methotrexate (MTX)]] 8000 mg/m<sup>2</sup> IV over 4 to 6 hours once on day 1 | *[[Methotrexate (MTX)]] 8000 mg/m<sup>2</sup> IV over 4 to 6 hours once on day 1 | ||
*[[Doxorubicin (Adriamycin)]] 25 mg/m<sup>2</sup> IV bolus once per day on days 11 to 13 | *[[Doxorubicin (Adriamycin)]] 25 mg/m<sup>2</sup> IV bolus once per day on days 11 to 13 | ||
− | *[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV continuous 24 | + | *[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV continuous infusion over 24 hours, started on day 11 |
− | + | ====Supportive therapy==== | |
− | ====Supportive | + | *[[Leucovorin (Folinic acid)]] 12 mg/m<sup>2</sup> IV every 6 hours x 10 doses or 15 mg/m<sup>2</sup> PO every 6 hours x 10 doses, starting 24 hours after the start of methotrexate infusion |
− | *[[Folinic acid | ||
**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 | **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 | **Methotrexate levels higher than 100 nmol/L at 48 hours required additional leucovorin rescue | ||
Line 880: | Line 694: | ||
*Posthydration for methotrexate: Alternating liters of D5W and NS 3000 mL/m<sup>2</sup> over 24 hours, with KCl 60 mEq/L. | *Posthydration for methotrexate: Alternating liters of D5W and NS 3000 mL/m<sup>2</sup> 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. | *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/m<sup>2</sup> and D5W 400 mL/m<sup>2</sup> over 2 hours--the reference did not clarify if these two solutions are given at the same time | + | *Prehydration for cisplatin: normal saline 400 mL/m<sup>2</sup> and D5W 400 mL/m<sup>2</sup> IV over 2 hours--the reference did not clarify if these two solutions are given at the same time |
− | *The volume of fluid for cisplatin continuous infusion is 2400 mL/m<sup>2</sup> NS, with KCl 80 mEq/L and mannitol 32 | + | *The volume of fluid for cisplatin continuous infusion is 2400 mL/m<sup>2</sup> NS, with KCl 80 mEq/L and mannitol 32,000 mg/m<sup>2</sup> |
− | *Posthydration for cisplatin: D5W 600 mL/m<sup>2</sup> over 6 hours, with KCl 20 mEq/L and mannitol | + | *Posthydration for cisplatin: D5W 600 mL/m<sup>2</sup> over 6 hours, with KCl 20 mEq/L and mannitol 8000 mg/m<sup>2</sup>; and NS 600 mL/m<sup>2</sup> 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/m<sup>2</sup> over 12 hours, with KCl 20 mEq/L and mannitol 8000 mg/m<sup>2</sup>. |
*With cisplatin, [[Furosemide (Lasix)]] 20 to 40 mg IV if urine output is less than 400 mL/m<sup>2</sup> over 6 hours | *With cisplatin, [[Furosemide (Lasix)]] 20 to 40 mg IV if urine output is less than 400 mL/m<sup>2</sup> over 6 hours | ||
− | |||
'''21-day cycle for 2 cycles''' | '''21-day cycle for 2 cycles''' | ||
− | + | </div></div><br> | |
− | === | + | <div class="toccolours" style="background-color:#eeeeee"> |
− | {| class="wikitable" style="width: | + | ===Regimen variant #2, 8000/90/120 {{#subobject:85bced|Variant=1}}=== |
− | !Study | + | {| class="wikitable" style="width: 40%; text-align:center;" |
− | ![[Levels_of_Evidence#Evidence|Evidence]] | + | !style="width: 25%"|Study |
+ | !style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
|- | |- | ||
− | |[https:// | + | |[https://doi.org/10.1002/1097-0142(19931201)72:11%3C3227::AID-CNCR2820721116%3E3.0.CO;2-C Bacci et al. 1993 (IOR/OS-2)] |
− | |style="background-color:#91cf61"|Phase | + | |style="background-color:#91cf61"|Phase 2 |
|- | |- | ||
|} | |} | ||
− | '' | + | ''Note: Figure 1 of Bacci et al. 2000 actually depicted the first cycle as being 47 days, and cycles 2 & 3 being 48 days.'' |
+ | <div class="toccolours" style="background-color:#cbd5e8"> | ||
====Preceding treatment==== | ====Preceding treatment==== | ||
− | *[[#MAP| | + | *Neoadjuvant [[#MAP|MAP]], then [[Surgery#Surgical_resection|surgery]], with at least 90% tumor necrosis in the surgically removed specimen |
− | ====Chemotherapy | + | </div> |
− | *[[Methotrexate (MTX)]] 8000 mg/m<sup>2</sup> IV over 6 hours once on day 21 | + | <div class="toccolours" style="background-color:#b3e2cd"> |
− | *[[Doxorubicin (Adriamycin)]] 45 mg/m<sup>2</sup> | + | ====Chemotherapy==== |
− | *[[Cisplatin (Platinol)]] 40 mg/m<sup>2</sup>/day IV continuous 72 | + | *[[Methotrexate (MTX)]] as follows: |
+ | **Cycles 1 to 3: 8000 mg/m<sup>2</sup> IV over 6 hours once on day 21 | ||
+ | *[[Doxorubicin (Adriamycin)]] 45 mg/m<sup>2</sup> IV over 4 hours once per day on days 1 & 2 | ||
+ | *[[Cisplatin (Platinol)]] as follows: | ||
+ | **Cycles 1 to 3: 40 mg/m<sup>2</sup>/day IV continuous infusion over 72 hours, started on day 27 (total dose per cycle: 120 mg/m<sup>2</sup>) | ||
+ | ====Supportive therapy==== | ||
+ | *[[Leucovorin (Folinic acid)]] as follows: | ||
+ | **Cycles 1 to 3: 15 mg IV every 6 hours x 11 doses on days 22 to 24, starting 24 hours after the start of methotrexate infusion | ||
+ | *Hydration during and after methotrexate infusion | ||
+ | '''48-day cycle for 4 cycles''' | ||
+ | </div></div><br> | ||
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
− | === | + | ===Regimen variant #3, 12,000/60/90 {{#subobject:03bb56|Variant=1}}=== |
− | + | {| class="wikitable sortable" style="width: 60%; text-align:center;" | |
− | + | !style="width: 33%"|Study | |
− | + | !style="width: 33%"|Dates of enrollment | |
− | + | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | |
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | {| class="wikitable" style="width: | ||
− | !Study | ||
− | ![[Levels_of_Evidence#Evidence|Evidence]] | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1200/jco.1988.6.2.329 Winkler et al. 1988 (COSS-82)] |
− | |style="background-color:#91cf61"|Non-randomized | + | |1982-1984 |
+ | |style="background-color:#91cf61"|Non-randomized part of phase 3 RCT | ||
|- | |- | ||
|} | |} | ||
− | + | <div class="toccolours" style="background-color:#cbd5e8"> | |
====Preceding treatment==== | ====Preceding treatment==== | ||
− | *[[#MAP| | + | *Neoadjuvant [[#MAP|MAP]], then [[Surgery#Surgical_resection|surgery]], with good response |
+ | </div> | ||
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
− | *[[Methotrexate (MTX)]] 12,000 mg/m<sup>2</sup> (maximum dose of 20,000 mg | + | *[[Methotrexate (MTX)]] 12,000 mg/m<sup>2</sup> (maximum dose of 20,000 mg) IV over 4 hours once per day on days 22 & 29 |
**MTX is dissolved at a concentration of 20,000 mg/L in a solution containing 5% glucose | **MTX is dissolved at a concentration of 20,000 mg/L in a solution containing 5% glucose | ||
*[[Doxorubicin (Adriamycin)]] 30 mg/m<sup>2</sup> IV bolus once per day on days 1 & 2 | *[[Doxorubicin (Adriamycin)]] 30 mg/m<sup>2</sup> IV bolus once per day on days 1 & 2 | ||
− | *[[Cisplatin (Platinol)]] 90 mg/m<sup>2</sup> | + | *[[Cisplatin (Platinol)]] 90 mg/m<sup>2</sup> IV over 4 hours once on day 3 |
− | + | ====Supportive therapy==== | |
− | ====Supportive | + | *[[Leucovorin (Folinic acid)]] 15 mg/m<sup>2</sup> PO every 6 hours x 12 hours once per day on days 23 & 30, starting 24 hours after the completion of methotrexate infusion; additional leucovorin used for delayed methotrexate elimination |
− | *[[Folinic acid | ||
*Sodium bicarbonate urine alkalinization prior to high-dose methotrexate | *Sodium bicarbonate urine alkalinization prior to high-dose methotrexate | ||
*NS 4.5 L/m<sup>2</sup> on day 1 after methotrexate; NS 3 L/m<sup>2</sup> on day 2, with adjustments made to keep urine pH greater than 7.4 | *NS 4.5 L/m<sup>2</sup> on day 1 after methotrexate; NS 3 L/m<sup>2</sup> 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/m<sup>2</sup> with mannitol 8 g/L and potassium 20 mval/L. | *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/m<sup>2</sup> with mannitol 8 g/L and potassium 20 mval/L. | ||
− | *Magnesium 180 mg/m<sup>2</sup> PO "per day throughout the whole chemotherapy time"--as described in | + | *Magnesium 180 mg/m<sup>2</sup> PO "per day throughout the whole chemotherapy time"--as described in COSS-80 |
− | + | '''35-day cycle for 2 cycles''' | |
+ | </div></div><br> | ||
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
+ | ===Regimen variant #4, 12,000/75/120 {{#subobject:11a698|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 100%; text-align:center;" | ||
+ | !style="width: 20%"|Study | ||
+ | !style="width: 20%"|Dates of enrollment | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | !style="width: 20%"|Comparator | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
+ | |- | ||
+ | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5052459/ Marina et al. 2016 (EURAMOS-1 poor response)] | ||
+ | |2005-2011 | ||
+ | |style="background-color:#1a9851"|Phase 3 (C) | ||
+ | |[[#MAPIE|MAPIE]] | ||
+ | | style="background-color:#ffffbf" |Did not meet primary endpoint of EFS | ||
+ | |- | ||
+ | |} | ||
+ | <div class="toccolours" style="background-color:#cbd5e8"> | ||
+ | ====Preceding treatment==== | ||
+ | *Neoadjuvant [[#MAP|MAP]] x 2, then [[Surgery#Surgical_resection|surgery]] | ||
+ | </div> | ||
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
+ | ====Chemotherapy==== | ||
+ | *[[Methotrexate (MTX)]] by the following site-based criteria: | ||
+ | **Non-COG sites: 12,000 mg/m<sup>2</sup> IV over 4 hours once per day on days 22 & 29 | ||
+ | **COG sites: 12,000 mg/m<sup>2</sup> (maximum dose of 20,000 mg) IV over 4 hours once per day on days 22 & 29 | ||
+ | *[[Doxorubicin (Adriamycin)]] 37.5 mg/m<sup>2</sup> IV once per day on days 1 & 2 | ||
+ | *[[Cisplatin (Platinol)]] by the following site-based criteria: | ||
+ | **Non-COG sites: 40 mg/m<sup>2</sup>/day IV continuous infusion over 72 hours, started on day 1 (total dose per cycle: 120 mg/m<sup>2</sup>) | ||
+ | **COG sites: 60 mg/m<sup>2</sup> IV once per day on days 1 & 2 | ||
+ | ====Supportive therapy==== | ||
+ | *[[Leucovorin (Folinic acid)]] 15 mg/m<sup>2</sup> (route/schedule not specified), starting 24 to 48 hours after methotrexate infusion, continued until MTX level less than 100 nmol/L | ||
'''35-day cycle for 2 cycles''' | '''35-day cycle for 2 cycles''' | ||
− | + | </div> | |
+ | <div class="toccolours" style="background-color:#cbd5e7"> | ||
+ | ====Subsequent treatment==== | ||
+ | *Adjuvant [[#MA_2|MA]] x 2 | ||
+ | </div></div> | ||
===References=== | ===References=== | ||
− | # '''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. [ | + | # '''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. [https://doi.org/10.1200/jco.1988.6.2.329 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/2448428/ PubMed] |
− | # 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. [ | + | # Bramwell VH, Burgers M, Sneath R, Souhami R, van Oosterom AT, Voûte PA, Rouesse J, Spooner D, Craft AW, Somers R, Pringle J, Malcolm AJ, van der Eiiken J, Thomas D, Uscinska B, Machin D, van Glabbeke M; European Osteosarcoma Intergroup. A comparison of two short intensive adjuvant chemotherapy regimens in operable osteosarcoma of limbs in children and young adults: the first study of the European Osteosarcoma Intergroup. J Clin Oncol. 1992 Oct;10(10):1579-91. [https://doi.org/10.1200/jco.1992.10.10.1579 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/1403038/ PubMed] |
− | # '''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. [https:// | + | # '''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. [https://doi.org/10.1002/1097-0142(19931201)72:11%3C3227::AID-CNCR2820721116%3E3.0.CO;2-C link to original article] [https://pubmed.ncbi.nlm.nih.gov/8242546/ 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 | + | ## '''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. [https://doi.org/10.1200/jco.2000.18.24.4016 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/11118462/ PubMed] |
− | # '''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. [ | + | # '''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. [https://doi.org/10.1200/JCO.2014.60.0734 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4486345/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26033801/ PubMed] |
− | # '''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. [https:// | + | # '''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. [https://doi.org/10.1016/S1470-2045(16)30214-5 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5052459/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/27569442/ PubMed] [https://clinicaltrials.gov/study/NCT00134030 NCT00134030] |
− | |||
==MAPI {{#subobject:909a14|Regimen=1}}== | ==MAPI {{#subobject:909a14|Regimen=1}}== | ||
− | |||
− | |||
− | |||
− | |||
MAPI: High-dose '''<u>M</u>'''ethotrexate, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>P</u>'''latinol (Cisplatin), '''<u>I</u>'''fosfamide | MAPI: High-dose '''<u>M</u>'''ethotrexate, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>P</u>'''latinol (Cisplatin), '''<u>I</u>'''fosfamide | ||
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
===Regimen {{#subobject:61db3e|Variant=1}}=== | ===Regimen {{#subobject:61db3e|Variant=1}}=== | ||
− | {| class="wikitable" style="width: | + | {| class="wikitable sortable" style="width: 60%; text-align:center;" |
− | !Study | + | !style="width: 33%"|Study |
− | ![[Levels_of_Evidence#Evidence|Evidence]] | + | !style="width: 33%"|Dates of enrollment |
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1093/annonc/mdg286 Bacci et al. 2003] |
− | |style="background-color:#91cf61"|Phase | + | |1995-05 to 2000-05 |
+ | |style="background-color:#91cf61"|Phase 2 | ||
|- | |- | ||
|} | |} | ||
+ | <div class="toccolours" style="background-color:#cbd5e8"> | ||
====Preceding treatment==== | ====Preceding treatment==== | ||
− | *[[#MAPI| | + | *Neoadjuvant [[#MAPI|MAPI]], then [[Surgery#Surgical_resection|surgery]] |
+ | </div> | ||
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
*[[Methotrexate (MTX)]] 12,000 mg/m<sup>2</sup> IV over 4 hours once on day 36 | *[[Methotrexate (MTX)]] 12,000 mg/m<sup>2</sup> IV over 4 hours once on day 36 | ||
− | + | *[[Doxorubicin (Adriamycin)]] 90 mg/m<sup>2</sup> IV continuous infusion over 24 hours, started on day 1 | |
− | *[[Doxorubicin (Adriamycin)]] 90 mg/m<sup>2</sup> IV continuous 24 | + | *[[Cisplatin (Platinol)]] 60 mg/m<sup>2</sup>/day IV continuous infusion over 48 hours, started on day 43 (total dose per cycle: 120 mg/m<sup>2</sup>) |
− | *[[Cisplatin (Platinol)]] 60 mg/m<sup>2</sup>/day IV continuous 48 | + | *[[Ifosfamide (Ifex)]] 3000 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on day 22, '''given with mesna''' (total dose per cycle: 15,000 mg/m<sup>2</sup>) |
− | *[[Ifosfamide (Ifex)]] 3000 mg/m<sup>2</sup>/day IV continuous 120 | + | ====Supportive therapy==== |
− | + | *[[Mesna (Mesnex)]] 3000 mg/m<sup>2</sup>/day IV continuous infusion over 120 hours, started on day 22, '''given with ifosfamide''' (total dose per cycle: 15,000 mg/m<sup>2</sup>) | |
− | ====Supportive | + | *[[Leucovorin (Folinic acid)]] 15 mg (route not specified) every 6 hours x 11 doses, starting day 36, 24 hours after the start of methotrexate |
− | *[[Mesna (Mesnex)]] 3000 mg/m<sup>2</sup>/day IV continuous 120 | + | *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. [https://pubmed.ncbi.nlm.nih.gov/6981454/ PubMed] |
− | *[[Folinic acid | ||
− | *Hydration during and after | ||
− | |||
'''9-week cycle for 3 cycles''' | '''9-week cycle for 3 cycles''' | ||
− | + | </div> | |
+ | <div class="toccolours" style="background-color:#fff2ae"> | ||
+ | ====Dose and schedule modifications==== | ||
+ | *If 4-hour methotrexate level is less than 10,000 nmol/L, the next cycle's methotrexate dose is increased by 2000 mg/m<sup>2</sup> | ||
+ | </div></div> | ||
===References=== | ===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. [ | + | # 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. [https://doi.org/10.1093/annonc/mdg286 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/12853357/ PubMed] |
− | |||
==MAPIE {{#subobject:d9962f|Regimen=1}}== | ==MAPIE {{#subobject:d9962f|Regimen=1}}== | ||
− | |||
− | |||
− | |||
− | |||
MAPIE: High-dose '''<u>M</u>'''ethotrexate, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>P</u>'''latinol (Cisplatin), '''<u>I</u>'''fosfamide, '''<u>E</u>'''toposide | MAPIE: High-dose '''<u>M</u>'''ethotrexate, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>P</u>'''latinol (Cisplatin), '''<u>I</u>'''fosfamide, '''<u>E</u>'''toposide | ||
− | + | <div class="toccolours" style="background-color:#eeeeee"> | |
===Regimen {{#subobject:97ec7e|Variant=1}}=== | ===Regimen {{#subobject:97ec7e|Variant=1}}=== | ||
− | {| class="wikitable" style="width: | + | {| class="wikitable sortable" style="width: 60%; text-align:center;" |
− | !Study | + | !style="width: 33%"|Study |
− | ![[Levels_of_Evidence#Evidence|Evidence]] | + | !style="width: 33%"|Dates of enrollment |
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
|- | |- | ||
− | |[https:// | + | |[https://doi.org/10.1002/1097-0142(19931201)72:11%3C3227::AID-CNCR2820721116%3E3.0.CO;2-C Bacci et al. 1993 (IOR/OS-2)] |
− | |style="background-color:#91cf61"|Phase | + | |1986-09 to 1989-12 |
+ | |style="background-color:#91cf61"|Phase 2 | ||
|- | |- | ||
|} | |} | ||
− | '' | + | ''Note: Figure 1 of Bacci et al. 2000 actually depicted the first cycle as being 68 days, and cycles 2 & 3 being 69 days.'' |
+ | <div class="toccolours" style="background-color:#cbd5e8"> | ||
====Preceding treatment==== | ====Preceding treatment==== | ||
− | *[[#MAP| | + | *Neoadjuvant [[#MAP|MAP]], then [[Surgery#Surgical_resection|surgery]], with less than 90% tumor necrosis in the surgically removed specimen |
− | ====Chemotherapy | + | </div> |
− | *[[Methotrexate (MTX)]] 8000 mg/m<sup>2</sup> IV over 6 hours once on day 42 | + | <div class="toccolours" style="background-color:#b3e2cd"> |
− | *[[Doxorubicin (Adriamycin)]] 45 mg/m<sup>2</sup> | + | ====Chemotherapy==== |
− | *[[Cisplatin (Platinol)]] 40 mg/m<sup>2</sup>/day IV continuous 72 | + | *[[Methotrexate (MTX)]] as follows: |
− | *[[Ifosfamide (Ifex)]] 2000 mg/m<sup>2</sup> IV over 90 minutes once per day on days 21 to 25 | + | **Cycles 1 to 3: 8000 mg/m<sup>2</sup> IV over 6 hours once on day 42 |
− | *[[Etoposide (Vepesid)]] 120 mg/m<sup>2</sup> IV over 60 minutes once per day on days 48 to 50 | + | *[[Doxorubicin (Adriamycin)]] 45 mg/m<sup>2</sup> IV over 4 hours once per day on days 1 & 2 |
− | + | *[[Cisplatin (Platinol)]] as follows: | |
− | ====Supportive | + | **Cycles 1 to 3: 40 mg/m<sup>2</sup>/day IV continuous infusion over 72 hours, started on day 48 (total dose per cycle: 120 mg/m<sup>2</sup>) |
− | *[[Mesna (Mesnex)]] with | + | *[[Ifosfamide (Ifex)]] as follows: |
− | *[[Folinic acid | + | **Cycles 1 to 3: 2000 mg/m<sup>2</sup> IV over 90 minutes once per day on days 21 to 25, with mesna |
− | *Hydration during and after | + | *[[Etoposide (Vepesid)]] as follows: |
− | + | **Cycles 1 to 3: 120 mg/m<sup>2</sup> IV over 60 minutes once per day on days 48 to 50 | |
− | '''69-day cycle for | + | ====Supportive therapy==== |
− | + | *[[Mesna (Mesnex)]] as follows: | |
− | + | **Cycles 1 to 3: with ifosfamide; no actual dose is listed in the reference | |
− | + | *[[Leucovorin (Folinic acid)]] as follows: | |
− | + | **Cycles 1 to 3: 15 mg IV every 6 hours x 11 doses on days 43 to 45, starting 24 hours after the start of methotrexate infusion | |
− | + | *Hydration during and after methotrexate infusion | |
− | + | '''69-day cycle for 4 cycles''' | |
+ | </div></div> | ||
===References=== | ===References=== | ||
− | # '''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. [https:// | + | # '''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. [https://doi.org/10.1002/1097-0142(19931201)72:11%3C3227::AID-CNCR2820721116%3E3.0.CO;2-C link to original article] [https://pubmed.ncbi.nlm.nih.gov/8242546/ 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 | + | ## '''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. [https://doi.org/10.1200/jco.2000.18.24.4016 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/11118462/ 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 | + | # '''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. [https://doi.org/10.1016/S1470-2045(16)30214-5 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5052459/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/27569442/ PubMed] [https://clinicaltrials.gov/study/NCT00134030 NCT00134030] |
− | ==M- | + | ==M-EI {{#subobject:79b8f9|Regimen=1}}== |
− | + | M-EI: '''<u>M</u>'''ethotrexate, '''<u>E</u>'''toposide, '''<u>I</u>'''fosfamide | |
− | + | <div class="toccolours" style="background-color:#eeeeee"> | |
− | + | ===Regimen {{#subobject:7fc4e3|Variant=1}}=== | |
− | + | {| class="wikitable sortable" style="width: 60%; text-align:center;" | |
− | M- | + | !style="width: 33%"|Study |
− | + | !style="width: 33%"|Dates of enrollment | |
− | ===Regimen {{#subobject: | + | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] |
− | {| class="wikitable" style="width: | ||
− | !Study | ||
− | ![[Levels_of_Evidence#Evidence|Evidence]] | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1016/j.ejca.2006.10.023 Le Deley et al. 2007 (SFOP OS94)] |
− | |style="background-color:#91cf61"|Non-randomized | + | |1994-2001 |
+ | |style="background-color:#91cf61"|Non-randomized part of phase 3 RCT | ||
|- | |- | ||
|} | |} | ||
− | + | <div class="toccolours" style="background-color:#cbd5e8"> | |
====Preceding treatment==== | ====Preceding treatment==== | ||
− | *[[#M- | + | *Neoadjuvant [[#M-EI|M-EI]], then [[Surgery#Surgical_resection|surgery]], with good response |
+ | </div> | ||
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
− | *[[Methotrexate (MTX)]] 12,000 mg/m<sup>2</sup> | + | *[[Methotrexate (MTX)]] 12,000 mg/m<sup>2</sup> IV over 4 hours once per day on days 1, 8, 15 |
− | ** | + | **Given in D5W 1L with sodium bicarbonate 1 mEq/kg |
− | *[[ | + | *[[Etoposide (Vepesid)]] as follows: |
− | *[[ | + | **Cycles 1 to 3: 75 mg/m<sup>2</sup> IV over 60 minutes once per day on days 22 to 25 (week 4) |
− | + | ***Given in NS 250 to 500 mL | |
− | + | *[[Ifosfamide (Ifex)]] as follows: | |
− | ====Supportive | + | **Cycles 1 to 3: 3000 mg/m<sup>2</sup> IV over 3 hours once per day on days 22 to 25 (week 4), '''given during mesna infusion''' (total dose per cycle: 12,000 mg/m<sup>2</sup>) |
− | *[[Folinic acid | + | ***Given in NS 250 to 500 mL |
− | * | + | ====Supportive therapy==== |
− | + | *[[Leucovorin (Folinic acid)]] 15 mg PO every 6 hours for up to 11 doses, starting on days 1, 8, 15, starting 20 hours after the completion of methotrexate infusion | |
− | + | *For methotrexate: hydration & urine alkalinization by PO and IV routes to maintain 1.6 L/m<sup>2</sup> urine output over the first 24 hours and 2 L/m<sup>2</sup> on days 2 & 3, with urine pH greater than 7 | |
− | ''' | + | *Daily monitoring of methotrexate levels and creatinine |
− | + | *[[Mesna (Mesnex)]] as follows: | |
+ | **Cycles 1 to 3: 3600 mg/m<sup>2</sup>/day IV continuous infusion over 96 hours, started on day 22 (week 4) (total dose per cycle: 14,400 mg/m<sup>2</sup>) | ||
+ | *Up to 2 L/day hydration with ifosfamide & mesna | ||
+ | '''28-day cycle for 4 cycles''' | ||
+ | </div></div> | ||
===References=== | ===References=== | ||
− | # ''' | + | # '''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. [https://doi.org/10.1016/j.ejca.2006.10.023 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17267204/ PubMed] [https://clinicaltrials.gov/study/NCT00180908 NCT00180908] |
+ | # '''OS2006:''' Piperno-Neumann S, Le Deley MC, Rédini F, Pacquement H, Marec-Bérard P, Petit P, Brisse H, Lervat C, Gentet JC, Entz-Werlé N, Italiano A, Corradini N, Bompas E, Penel N, Tabone MD, Gomez-Brouchet A, Guinebretière JM, Mascard E, Gouin F, Chevance A, Bonnet N, Blay JY, Brugières L; Sarcoma Group of UNICANCER; SFCE; GSF-GETO. Zoledronate in combination with chemotherapy and surgery to treat osteosarcoma (OS2006): a randomised, multicentre, open-label, phase 3 trial. Lancet Oncol. 2016 Aug;17(8):1070-1080. Epub 2016 Jun 17. [https://doi.org/10.1016/S1470-2045(16)30096-1 link to original article] [https://pubmed.ncbi.nlm.nih.gov/27324280/ PubMed] [https://clinicaltrials.gov/study/NCT00470223 NCT00470223] | ||
+ | ## '''Update:''' Gaspar N, Occean BV, Pacquement H, Bompas E, Bouvier C, Brisse HJ, Castex MP, Cheurfa N, Corradini N, Delaye J, Entz-Werlé N, Gentet JC, Italiano A, Lervat C, Marec-Berard P, Mascard E, Redini F, Saumet L, Schmitt C, Tabone MD, Verite-Goulard C, Le Deley MC, Piperno-Neumann S, Brugieres L; SFCE; GSF-GETO; UNICANCER sarcoma group. Results of methotrexate-etoposide-ifosfamide based regimen (M-EI) in osteosarcoma patients included in the French OS2006/sarcome-09 study. Eur J Cancer. 2018 Jan;88:57-66. Epub 2017 Nov 28. [https://doi.org/10.1016/j.ejca.2017.09.036 link to original article] [https://pubmed.ncbi.nlm.nih.gov/29190507/ PubMed] | ||
=Relapsed, refractory, or metastatic, first-line= | =Relapsed, refractory, or metastatic, first-line= | ||
− | |||
==Cisplatin & Doxorubicin {{#subobject:418c69|Regimen=1}}== | ==Cisplatin & Doxorubicin {{#subobject:418c69|Regimen=1}}== | ||
− | + | AP: '''<u>A</u>'''driamycin (Doxorubicin) & '''<u>P</u>'''latinol (Cisplatin) | |
− | + | <div class="toccolours" style="background-color:#eeeeee"> | |
− | |||
− | |||
===Regimen {{#subobject:60d18a|Variant=1}}=== | ===Regimen {{#subobject:60d18a|Variant=1}}=== | ||
− | {| class="wikitable" style="width: 100%; text-align:center;" | + | {| class="wikitable sortable" style="width: 100%; text-align:center;" |
− | !Study | + | !style="width: 20%"|Study |
− | ![[Levels_of_Evidence#Evidence|Evidence]] | + | !style="width: 20%"|Dates of enrollment |
− | !Comparator | + | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] |
− | ![[Levels_of_Evidence# | + | !style="width: 20%"|Comparator |
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
|- | |- | ||
− | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2395371/ Bramwell et al. 1997] | + | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2395371/ Bramwell et al. 1997 (EOI 80831/MRC B002)] |
− | |style="background-color:#1a9851"|Phase | + | |1983-1986 |
+ | |style="background-color:#1a9851"|Phase 3 (E-de-esc) | ||
|[[#MAP_3|MAP]] | |[[#MAP_3|MAP]] | ||
|style="background-color:#d73027"|Inferior OS | |style="background-color:#d73027"|Inferior OS | ||
Line 1,084: | Line 944: | ||
|} | |} | ||
''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."'' | ''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."'' | ||
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
− | *[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV continuous 24 | + | *[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV continuous infusion over 24 hours, started on day 1 |
*[[Doxorubicin (Adriamycin)]] 25 mg/m<sup>2</sup> IV bolus once per day on days 1 to 3 | *[[Doxorubicin (Adriamycin)]] 25 mg/m<sup>2</sup> IV bolus once per day on days 1 to 3 | ||
− | + | ====Supportive therapy==== | |
− | ====Supportive | + | *Prehydration: normal saline 400 mL/m<sup>2</sup> and D5W 400 mL/m<sup>2</sup> IV over 2 hours--the reference did not clarify if these two solutions are given at the same time |
− | *Prehydration: normal saline 400 mL/m<sup>2</sup> and D5W 400 mL/m<sup>2</sup> 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/m<sup>2</sup> NS, with KCl 80 mEq/L and mannitol 32,000 mg/m<sup>2</sup> |
− | *The volume of fluid for cisplatin continuous infusion is 2400 mL/m<sup>2</sup> NS, with KCl 80 mEq/L and mannitol 32 | + | *Posthydration: D5W 600 mL/m<sup>2</sup> over 6 hours, with KCl 20 mEq/L and mannitol 8000 mg/m<sup>2</sup>; and NS 600 mL/m<sup>2</sup> 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/m<sup>2</sup> over 12 hours, with KCl 20 mEq/L and mannitol 8000 mg/m<sup>2</sup>. |
− | *Posthydration: D5W 600 mL/m<sup>2</sup> over 6 hours, with KCl 20 mEq/L and mannitol | ||
*[[Furosemide (Lasix)]] 20 to 40 mg IV if urine output is less than 400 mL/m<sup>2</sup> over 6 hours | *[[Furosemide (Lasix)]] 20 to 40 mg IV if urine output is less than 400 mL/m<sup>2</sup> over 6 hours | ||
− | |||
'''21-day cycle for 6 cycles''' | '''21-day cycle for 6 cycles''' | ||
− | + | </div></div> | |
===References=== | ===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. [https:// | + | # '''EOI 80831/MRC B002:''' Bramwell VH, Burgers MV, Souhami RL, Taminiau AH, Van Der Eijken JW, Craft AW, Malcolm AJ, Uscinska B, Kirkpatrick AL, Machin D, Van Glabbeke MM; European Osteosarcoma Intergroup. A randomized comparison of two short intensive chemotherapy regimens in children and young adults with osteosarcoma: results in patients with metastases: a study of the European Osteosarcoma Intergroup. Sarcoma. 1997;1(3-4):155-60. [https://doi.org/10.1080/13577149778245 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2395371/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/18521218/ PubMed] |
− | |||
==MAP {{#subobject:ed2dcf|Regimen=1}}== | ==MAP {{#subobject:ed2dcf|Regimen=1}}== | ||
− | |||
− | |||
− | |||
− | |||
MAP: High-dose '''<u>M</u>'''ethotrexate, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>P</u>'''latinol (Cisplatin) | MAP: High-dose '''<u>M</u>'''ethotrexate, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>P</u>'''latinol (Cisplatin) | ||
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
===Regimen {{#subobject:d359c6|Variant=1}}=== | ===Regimen {{#subobject:d359c6|Variant=1}}=== | ||
− | {| class="wikitable" style="width: 100%; text-align:center;" | + | {| class="wikitable sortable" style="width: 100%; text-align:center;" |
− | !Study | + | !style="width: 20%"|Study |
− | ![[Levels_of_Evidence#Evidence|Evidence]] | + | !style="width: 20%"|Dates of enrollment |
− | !Comparator | + | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] |
− | ![[Levels_of_Evidence# | + | !style="width: 20%"|Comparator |
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
|- | |- | ||
− | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2395371/ Bramwell et al. 1997] | + | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2395371/ Bramwell et al. 1997 (EOI 80831/MRC B002)] |
− | |style="background-color:#1a9851"|Phase | + | |1983-1986 |
+ | |style="background-color:#1a9851"|Phase 3 (E-esc) | ||
|[[#Cisplatin_.26_Doxorubicin_3|Cisplatin & Doxorubicin]] | |[[#Cisplatin_.26_Doxorubicin_3|Cisplatin & Doxorubicin]] | ||
|style="background-color:#1a9850"|Superior OS | |style="background-color:#1a9850"|Superior OS | ||
Line 1,119: | Line 976: | ||
|} | |} | ||
''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."'' | ''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."'' | ||
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
*[[Methotrexate (MTX)]] 8000 mg/m<sup>2</sup> IV over 4 hours once on day 1 | *[[Methotrexate (MTX)]] 8000 mg/m<sup>2</sup> IV over 4 hours once on day 1 | ||
*[[Doxorubicin (Adriamycin)]] 25 mg/m<sup>2</sup> IV bolus once per day on days 11 to 13 | *[[Doxorubicin (Adriamycin)]] 25 mg/m<sup>2</sup> IV bolus once per day on days 11 to 13 | ||
− | *[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV continuous 24 | + | *[[Cisplatin (Platinol)]] 100 mg/m<sup>2</sup> IV continuous infusion over 24 hours, started on day 11 |
− | + | ====Supportive therapy==== | |
− | ====Supportive | + | *[[Leucovorin (Folinic acid)]] 12 mg/m<sup>2</sup> IV every 6 hours x 10 doses or 15 mg/m<sup>2</sup> PO every 6 hours x 10 doses, starting 24 hours after the start of methotrexate infusion |
− | *[[Folinic acid | ||
**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 | **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 | **Methotrexate levels higher than 100 nmol/L at 48 hours required additional leucovorin rescue | ||
Line 1,132: | Line 989: | ||
*Posthydration for methotrexate: Alternating liters of D5W and NS 3000 mL/m<sup>2</sup> over 24 hours, with KCl 60 mEq/L. | *Posthydration for methotrexate: Alternating liters of D5W and NS 3000 mL/m<sup>2</sup> 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. | *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/m<sup>2</sup> and D5W 400 mL/m<sup>2</sup> over 2 hours--the reference did not clarify if these two solutions are given at the same time | + | *Prehydration for cisplatin: normal saline 400 mL/m<sup>2</sup> and D5W 400 mL/m<sup>2</sup> IV over 2 hours--the reference did not clarify if these two solutions are given at the same time |
− | *The volume of fluid for cisplatin continuous infusion is 2400 mL/m<sup>2</sup> NS, with KCl 80 mEq/L and mannitol 32 | + | *The volume of fluid for cisplatin continuous infusion is 2400 mL/m<sup>2</sup> NS, with KCl 80 mEq/L and mannitol 32,000 mg/m<sup>2</sup> |
− | *Posthydration for cisplatin: D5W 600 mL/m<sup>2</sup> over 6 hours, with KCl 20 mEq/L and mannitol | + | *Posthydration for cisplatin: D5W 600 mL/m<sup>2</sup> over 6 hours, with KCl 20 mEq/L and mannitol 8000 mg/m<sup>2</sup>; and NS 600 mL/m<sup>2</sup> 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/m<sup>2</sup> over 12 hours, with KCl 20 mEq/L and mannitol 8000 mg/m<sup>2</sup>. |
*With cisplatin, [[Furosemide (Lasix)]] 20 to 40 mg IV if urine output is less than 400 mL/m<sup>2</sup> over 6 hours | *With cisplatin, [[Furosemide (Lasix)]] 20 to 40 mg IV if urine output is less than 400 mL/m<sup>2</sup> over 6 hours | ||
− | |||
'''21-day cycle for 4 cycles''' | '''21-day cycle for 4 cycles''' | ||
− | + | </div></div> | |
===References=== | ===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 | + | # '''EOI 80831/MRC B002:''' Bramwell VH, Burgers MV, Souhami RL, Taminiau AH, Van Der Eijken JW, Craft AW, Malcolm AJ, Uscinska B, Kirkpatrick AL, Machin D, Van Glabbeke MM; European Osteosarcoma Intergroup. A randomized comparison of two short intensive chemotherapy regimens in children and young adults with osteosarcoma: results in patients with metastases: a study of the European Osteosarcoma Intergroup. Sarcoma. 1997;1(3-4):155-60. [https://doi.org/10.1080/13577149778245 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2395371/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/18521218/ PubMed] |
− | |||
=Relapsed, refractory, or metastatic, subsequent lines= | =Relapsed, refractory, or metastatic, subsequent lines= | ||
− | + | ==Cabozantinib monotherapy {{#subobject:s9nxm1|Regimen=1}}== | |
− | == | + | <div class="toccolours" style="background-color:#eeeeee"> |
− | {| class="wikitable" style=" | + | ===Regimen variant #1, adult dosing {{#subobject:8c0u8g|Variant=1}}=== |
+ | {| class="wikitable sortable" style="width: 60%; text-align:center;" | ||
+ | !style="width: 33%"|Study | ||
+ | !style="width: 33%"|Dates of enrollment | ||
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | |- | ||
+ | |[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8763616/ Italiano et al. 2020 (CABONE)] | ||
+ | |2015-2018 | ||
+ | | style="background-color:#91cf61" |Phase 2 | ||
+ | |- | ||
+ | |} | ||
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
+ | ====Targeted therapy==== | ||
+ | *[[Cabozantinib (Cometriq)]] 60 mg PO once per day on day 1 to 28 | ||
+ | '''28-day cycles''' | ||
+ | </div></div><br> | ||
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
+ | ===Regimen variant #2, pediatric dosing {{#subobject:yr1u8g|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 60%; text-align:center;" | ||
+ | !style="width: 33%"|Study | ||
+ | !style="width: 33%"|Dates of enrollment | ||
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | |- | ||
+ | |[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8763616/ Italiano et al. 2020 (CABONE)] | ||
+ | |2015-2018 | ||
+ | | style="background-color:#91cf61" |Phase 2 | ||
|- | |- | ||
− | |||
|} | |} | ||
+ | ''Note: this dosing was for children aged less than 16 years.'' | ||
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
+ | ====Targeted therapy==== | ||
+ | *[[Cabozantinib (Cometriq)]] 40 mg/m<sup>2</sup> PO once per day on days 1 to 28 | ||
+ | '''28-day cycles''' | ||
+ | </div></div> | ||
+ | ===References=== | ||
+ | #'''CABONE:''' Italiano A, Mir O, Mathoulin-Pelissier S, Penel N, Piperno-Neumann S, Bompas E, Chevreau C, Duffaud F, Entz-Werlé N, Saada E, Ray-Coquard I, Lervat C, Gaspar N, Marec-Berard P, Pacquement H, Wright J, Toulmonde M, Bessede A, Crombe A, Kind M, Bellera C, Blay JY. Cabozantinib in patients with advanced Ewing sarcoma or osteosarcoma (CABONE): a multicentre, single-arm, phase 2 trial. Lancet Oncol. 2020 Mar;21(3):446-455. Epub 2020 Feb 17. [https://doi.org/10.1016/s1470-2045(19)30825-3 link to original article] '''contains dosing details in abstract''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8763616/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/32078813/ PubMed] [https://clinicaltrials.gov/study/NCT02243605 NCT02243605] | ||
+ | ==Cyclophosphamide & Etoposide {{#subobject:7bb7cb|Regimen=1}}== | ||
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
===Regimen {{#subobject:1d31a0|Variant=1}}=== | ===Regimen {{#subobject:1d31a0|Variant=1}}=== | ||
− | {| class="wikitable" style="width: | + | {| class="wikitable sortable" style="width: 60%; text-align:center;" |
− | !Study | + | !style="width: 33%"|Study |
− | ![[Levels_of_Evidence#Evidence|Evidence]] | + | !style="width: 33%"|Dates of enrollment |
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
|- | |- | ||
− | |[https:// | + | |[https://doi.org/10.1002/cncr.24368 Berger et al. 2009] |
− | |style="background-color:#91cf61"|Phase | + | |2002-07 to 2006-09 |
+ | |style="background-color:#91cf61"|Phase 2 | ||
|- | |- | ||
|} | |} | ||
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
*[[Cyclophosphamide (Cytoxan)]] 4000 mg/m<sup>2</sup> IV over 3 hours once on day 1 | *[[Cyclophosphamide (Cytoxan)]] 4000 mg/m<sup>2</sup> IV over 3 hours once on day 1 | ||
− | *[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV over 60 minutes | + | *[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV over 60 minutes twice per day on days 2 to 4 (total dose: 600 mg/m<sup>2</sup>) |
− | + | ====Supportive therapy==== | |
− | ====Supportive | + | *[[Mesna (Mesnex)]] 1400 mg/m<sup>2</sup> IV three times per day on day 1, given prior to, 4 hours after, and 8 hours after cyclophosphamide |
− | *[[Mesna (Mesnex)]] 1400 mg/m<sup>2</sup> IV | ||
**With mesna, 3000 mL/m<sup>2</sup> hydration | **With mesna, 3000 mL/m<sup>2</sup> hydration | ||
− | |||
'''At least 21-day cycle for 2 cycles, then restaging''' | '''At least 21-day cycle for 2 cycles, then restaging''' | ||
+ | </div> | ||
+ | <div class="toccolours" style="background-color:#cbd5e7"> | ||
====Subsequent treatment==== | ====Subsequent treatment==== | ||
− | Patients with no progression received an experimental protocol with: | + | *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)) | + | **Progression-free patients received reduced intensity stem cell transplant (preferably from a matched sibling donor (MSD)) |
− | *Patients with no MSD received | + | **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) |
− | + | </div></div> | |
===References=== | ===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. [https:// | + | # 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. [https://doi.org/10.1002/cncr.24368 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19452540/ PubMed] |
==Cyclophosphamide & Topotecan {{#subobject:533aef|Regimen=1}}== | ==Cyclophosphamide & Topotecan {{#subobject:533aef|Regimen=1}}== | ||
− | + | <div class="toccolours" style="background-color:#eeeeee"> | |
− | |||
− | |||
− | |||
===Regimen {{#subobject:950899|Variant=1}}=== | ===Regimen {{#subobject:950899|Variant=1}}=== | ||
− | {| class="wikitable" style="width: | + | {| class="wikitable" style="width: 40%; text-align:center;" |
− | !Study | + | !style="width: 25%"|Study |
− | ![[Levels_of_Evidence#Evidence|Evidence]] | + | !style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]] |
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1200/jco.2001.19.15.3463 Saylors et al. 2001] |
− | |style="background-color:#91cf61"|Phase | + | |style="background-color:#91cf61"|Phase 2 |
|- | |- | ||
|} | |} | ||
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
*[[Cyclophosphamide (Cytoxan)]] 250 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 to 5, '''given first''' | *[[Cyclophosphamide (Cytoxan)]] 250 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 to 5, '''given first''' | ||
*[[Topotecan (Hycamtin)]] 0.75 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 to 5, '''given second''' | *[[Topotecan (Hycamtin)]] 0.75 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 to 5, '''given second''' | ||
− | + | ====Supportive therapy==== | |
− | ====Supportive | + | *500 mL/m/2 fluids IV or PO once per day on days 1 to 5; 2 to 4 hours prior to chemotherapy |
− | *500 mL/m/2 fluids PO | + | *[[:Category:Emesis_prevention|Antiemetics]] once per day on days 1 to 5, prior to chemotherapy |
− | *Antiemetics | + | *3 liters/m<sup>2</sup> fluids IV or PO over 24 hours after chemotherapy |
− | *3 liters/m<sup>2</sup> PO | + | *[[Filgrastim (Neupogen)]] 5 mcg/kg SC once per day, starting on day 6, to continue until post-nadir ANC is at least 1500/μL |
− | *[[Filgrastim (Neupogen)]] 5 mcg/kg SC once per day starting on day 6, to continue until ANC is at least 1500/ | ||
− | |||
'''21-day cycle for 12 to 14 cycles''' | '''21-day cycle for 12 to 14 cycles''' | ||
− | + | </div></div> | |
===References=== | ===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. [ | + | # 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. [https://doi.org/10.1200/jco.2001.19.15.3463 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/11481351/ PubMed] |
− | |||
==Docetaxel & Gemcitabine {{#subobject:55d598|Regimen=1}}== | ==Docetaxel & Gemcitabine {{#subobject:55d598|Regimen=1}}== | ||
− | + | <div class="toccolours" style="background-color:#eeeeee"> | |
− | |||
− | |||
− | |||
===Regimen {{#subobject:c3c88e|Variant=1}}=== | ===Regimen {{#subobject:c3c88e|Variant=1}}=== | ||
− | {| class="wikitable" style="width: | + | {| class="wikitable sortable" style="width: 60%; text-align:center;" |
− | !Study | + | !style="width: 33%"|Study |
− | ![[Levels_of_Evidence#Evidence|Evidence]] | + | !style="width: 33%"|Dates of enrollment |
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
|- | |- | ||
− | |[https:// | + | |[https://doi.org/10.1002/cncr.23586 Navid et al. 2008] |
+ | |NR | ||
|style="background-color:#ffffbe"|Retrospective | |style="background-color:#ffffbe"|Retrospective | ||
|- | |- | ||
|} | |} | ||
− | ''17 of the 22 patients in this retrospective review had osteosarcoma.'' | + | ''Note: 17 of the 22 patients in this retrospective review had osteosarcoma.'' |
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
− | *[[Docetaxel (Taxotere)]] 75 to 100 mg/m<sup>2</sup> IV over 60 minutes once on day 8, '''given | + | *[[Docetaxel (Taxotere)]] 75 to 100 mg/m<sup>2</sup> IV over 60 minutes once on day 8, '''given second''' |
*[[Gemcitabine (Gemzar)]] 675 mg/m<sup>2</sup> IV over 90 minutes once per day on days 1 & 8, '''given first''' | *[[Gemcitabine (Gemzar)]] 675 mg/m<sup>2</sup> IV over 90 minutes once per day on days 1 & 8, '''given first''' | ||
− | + | ====Supportive therapy==== | |
− | ====Supportive | + | *[[Ondansetron (Zofran)]] (dose/route not specified) once per day on days 1 & 8, prior to chemotherapy |
− | *[[Ondansetron (Zofran)]] | + | *[[Dexamethasone (Decadron)]] starting either the day before or the day of docetaxel, and continued for 2 days after docetaxel |
− | *[[Dexamethasone (Decadron)]] starting either the day before or the day of | + | *Per physician discretion: H1 or H2 blockers such as [[Diphenhydramine (Benadryl)]] and [[Ranitidine (Zantac)]] once per day on days 1 & 8 |
− | *H1 or H2 blockers such as [[Diphenhydramine (Benadryl)]] and [[Ranitidine (Zantac)]] | ||
*Some patients received [[Filgrastim (Neupogen)]] starting on day 9 | *Some patients received [[Filgrastim (Neupogen)]] starting on day 9 | ||
− | |||
'''21-day cycles''' | '''21-day cycles''' | ||
− | + | </div></div> | |
===References=== | ===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. [https:// | + | # '''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. [https://doi.org/10.1002/cncr.23586 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18484657/ PubMed] |
− | |||
==Gemcitabine monotherapy {{#subobject:2a9006|Regimen=1}}== | ==Gemcitabine monotherapy {{#subobject:2a9006|Regimen=1}}== | ||
− | + | <div class="toccolours" style="background-color:#eeeeee"> | |
− | |||
− | |||
− | |||
===Regimen {{#subobject:fb0d84|Variant=1}}=== | ===Regimen {{#subobject:fb0d84|Variant=1}}=== | ||
− | {| class="wikitable" style="width: | + | {| class="wikitable sortable" style="width: 60%; text-align:center;" |
− | !Study | + | !style="width: 33%"|Study |
− | ![[Levels_of_Evidence#Evidence|Evidence]] | + | !style="width: 33%"|Dates of enrollment |
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1007/s002800050027 Merimsky et al. 2000] |
− | |style="background-color:# | + | |1996-12 to 1998-08 |
+ | | style="background-color:#ffffbe" |Phase 2, fewer than 20 pts | ||
|- | |- | ||
|} | |} | ||
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
*[[Gemcitabine (Gemzar)]] as follows: | *[[Gemcitabine (Gemzar)]] as follows: | ||
**Cycle 1: 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22 | **Cycle 1: 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22 | ||
− | **Cycle 2 onwards: | + | **Cycle 2 onwards: 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15 |
− | |||
'''28-day cycles''' | '''28-day cycles''' | ||
− | + | </div></div> | |
===References=== | ===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. [ | + | # 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. [https://doi.org/10.1007/s002800050027 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/10663634/ PubMed] |
− | |||
==ICE {{#subobject:3fe1fa|Regimen=1}}== | ==ICE {{#subobject:3fe1fa|Regimen=1}}== | ||
− | |||
− | |||
− | |||
− | |||
ICE: '''<u>I</u>'''fosfamide, '''<u>C</u>'''arboplatin, '''<u>E</u>'''toposide | ICE: '''<u>I</u>'''fosfamide, '''<u>C</u>'''arboplatin, '''<u>E</u>'''toposide | ||
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
===Regimen {{#subobject:61c68a|Variant=1}}=== | ===Regimen {{#subobject:61c68a|Variant=1}}=== | ||
− | {| class="wikitable" style="width: | + | {| class="wikitable sortable" style="width: 60%; text-align:center;" |
− | !Study | + | !style="width: 33%"|Study |
− | ![[Levels_of_Evidence#Evidence|Evidence]] | + | !style="width: 33%"|Dates of enrollment |
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
|- | |- | ||
− | |[https:// | + | |[https://doi.org/10.1002/pbc.20227 Van Winkle et al. 2005 (CCG-0894)] |
− | |style="background-color:#91cf61"|Phase | + | |1992-06 to 1994-11 |
+ | |style="background-color:#91cf61"|Phase 2 | ||
+ | |- | ||
+ | |[https://doi.org/10.1002/pbc.20227 Van Winkle et al. 2005 (CCG-0924)] | ||
+ | |1993-07 to 1995-04 | ||
+ | |style="background-color:#91cf61"|Phase 1, >20 pts | ||
+ | |- | ||
+ | |[https://doi.org/10.1002/pbc.20227 Van Winkle et al. 2005 (CCG-0931)] | ||
+ | |1994-05 to 1996-12 | ||
+ | | style="background-color:#ffffbe" |Non-randomized, <20 pts | ||
|- | |- | ||
|} | |} | ||
''Note: the reference did not mention [[Mesna (Mesnex)]] being used.'' | ''Note: the reference did not mention [[Mesna (Mesnex)]] being used.'' | ||
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
*[[Ifosfamide (Ifex)]] 1800 mg/m<sup>2</sup> IV once per day on days 1 to 5 | *[[Ifosfamide (Ifex)]] 1800 mg/m<sup>2</sup> IV once per day on days 1 to 5 | ||
Line 1,280: | Line 1,170: | ||
**Note: the reference did not explicitly say which 2 days carboplatin should be given on | **Note: the reference did not explicitly say which 2 days carboplatin should be given on | ||
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV once per day on days 1 to 5 | *[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV once per day on days 1 to 5 | ||
− | + | ====Supportive therapy==== | |
− | ====Supportive | ||
*Depending on the study the patients were enrolled on, they received one of the following: | *Depending on the study the patients were enrolled on, they received one of the following: | ||
− | **CCG-0894: [[Filgrastim (Neupogen)]] 5 or 10 mcg/kg | + | **CCG-0894: [[Filgrastim (Neupogen)]] 5 or 10 mcg/kg SC once per day, starting 24 hours after completing ICE, and to continue until day 18 if ANC is at least 1000/μL, or until ANC is at least 1000/μL above nadir, whichever comes later |
− | **CCG-0924: PIXY 321 at doses of 500/750/1000 mcg/m<sup>2</sup> once per day or 500 mcg/m<sup>2</sup> | + | **CCG-0924: PIXY 321 at doses of 500/750/1000 mcg/m<sup>2</sup> SC once per day or 500 mcg/m<sup>2</sup> SC twice per day, starting on day 5 and to continue until day 18 unless ANC reached 20,000/μL or platelet count is at least 900 x 10<sup>9</sup>/L for 2 days between days 13 to 18, or until ANC is at least 1000/μL and platelet count is at least 100 x 10<sup>9</sup>/L, whichever comes later |
− | **CCG-0931: [[Filgrastim (Neupogen)]] 5 mcg/kg | + | **CCG-0931: [[Filgrastim (Neupogen)]] 5 mcg/kg SC once per day and IL-6 at 2.5, 3.75, or 5 mcg/kg SC twice per day, starting 24 hours after completing ICE. Filgrastim is continued until ANC is at least 1000/μL, and IL-6 is continued until platelets are at least 100 x 10<sup>9</sup>/L for 2 consecutive days or until day 35, whichever comes sooner. |
− | + | '''21-day cycles''', with next cycle starting as soon as ANC is at least 1000/μL and platelet count is at least 100 x 10<sup>9</sup>/L | |
− | '''21-day cycles''', with next cycle starting as soon as ANC is at least 1000/ | + | </div> |
+ | <div class="toccolours" style="background-color:#cbd5e7"> | ||
====Subsequent treatment==== | ====Subsequent treatment==== | ||
*Resection of disease was allowed after 4 cycles based on patient's response to ICE | *Resection of disease was allowed after 4 cycles based on patient's response to ICE | ||
− | + | </div></div> | |
===References=== | ===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. [https:// | + | # '''CCG-0894:''' Van Winkle P, Angiolillo A, Krailo M, Cheung YK, Anderson B, Davenport V, Reaman G, Cairo MS; Children's Cancer Group. Ifosfamide, carboplatin, and etoposide (ICE) reinduction chemotherapy in a large cohort of children and adolescents with recurrent/refractory sarcoma: the Children's Cancer Group (CCG) experience. Pediatr Blood Cancer. 2005 Apr;44(4):338-47. [https://doi.org/10.1002/pbc.20227 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/15503297/ PubMed] |
− | + | # '''CCG-0924:''' Van Winkle P, Angiolillo A, Krailo M, Cheung YK, Anderson B, Davenport V, Reaman G, Cairo MS; Children's Cancer Group. Ifosfamide, carboplatin, and etoposide (ICE) reinduction chemotherapy in a large cohort of children and adolescents with recurrent/refractory sarcoma: the Children's Cancer Group (CCG) experience. Pediatr Blood Cancer. 2005 Apr;44(4):338-47. [https://doi.org/10.1002/pbc.20227 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/15503297/ PubMed] | |
+ | # '''CCG-0931:''' Van Winkle P, Angiolillo A, Krailo M, Cheung YK, Anderson B, Davenport V, Reaman G, Cairo MS; Children's Cancer Group. Ifosfamide, carboplatin, and etoposide (ICE) reinduction chemotherapy in a large cohort of children and adolescents with recurrent/refractory sarcoma: the Children's Cancer Group (CCG) experience. Pediatr Blood Cancer. 2005 Apr;44(4):338-47. [https://doi.org/10.1002/pbc.20227 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/15503297/ PubMed] | ||
==IE {{#subobject:29f233|Regimen=1}}== | ==IE {{#subobject:29f233|Regimen=1}}== | ||
− | |||
− | |||
− | |||
− | |||
IE: '''<u>I</u>'''fosfamide & '''<u>E</u>'''toposide | IE: '''<u>I</u>'''fosfamide & '''<u>E</u>'''toposide | ||
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
===Regimen {{#subobject:659e8c|Variant=1}}=== | ===Regimen {{#subobject:659e8c|Variant=1}}=== | ||
− | {| class="wikitable" style="width: | + | {| class="wikitable sortable" style="width: 60%; text-align:center;" |
− | !Study | + | !style="width: 33%"|Study |
− | ![[Levels_of_Evidence#Evidence|Evidence]] | + | !style="width: 33%"|Dates of enrollment |
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
|- | |- | ||
− | |[https:// | + | |[https://doi.org/10.1016/s0959-8049(96)00439-x Gentet et al. 1997] |
− | |style="background-color:#91cf61"|Phase | + | |1992-01 to 1995-01 |
+ | |style="background-color:#91cf61"|Phase 2 | ||
|- | |- | ||
|} | |} | ||
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
*[[Ifosfamide (Ifex)]] 3000 mg/m<sup>2</sup> IV over 3 hours once per day on days 1 to 4 | *[[Ifosfamide (Ifex)]] 3000 mg/m<sup>2</sup> IV over 3 hours once per day on days 1 to 4 | ||
Line 1,314: | Line 1,205: | ||
*[[Etoposide (Vepesid)]] 75 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 4 | *[[Etoposide (Vepesid)]] 75 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 4 | ||
**Given in D5W 250 to 500 mL | **Given in D5W 250 to 500 mL | ||
− | + | ====Supportive therapy==== | |
− | ====Supportive | + | *[[Mesna (Mesnex)]] 3600 mg/m<sup>2</sup>/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 14,400 mg/m<sup>2</sup>) |
− | *[[Mesna (Mesnex)]] 3600 mg/m<sup>2</sup>/day IV continuous infusion on | ||
*At least 2000 mL/m<sup>2</sup>/day of hydration with chemotherapy | *At least 2000 mL/m<sup>2</sup>/day of hydration with chemotherapy | ||
+ | '''21- to 28-day cycle for 2 cycles; next cycle starting when ANC greater than 1500/μL and platelet count greater than 100 x 10<sup>9</sup>/L''' | ||
+ | </div></div> | ||
+ | ===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. [https://doi.org/10.1016/s0959-8049(96)00439-x link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/9135494/ PubMed] | ||
− | ''' | + | ==Regorafenib monotherapy {{#subobject:267gu1|Regimen=1}}== |
− | + | <div class="toccolours" style="background-color:#eeeeee"> | |
+ | ===Regimen {{#subobject:8c0b71|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 100%; text-align:center;" | ||
+ | !style="width: 20%"|Study | ||
+ | !style="width: 20%"|Dates of enrollment | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | !style="width: 20%"|Comparator | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
+ | |- | ||
+ | |[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7799443/ Davis et al. 2019 (SARC024)] | ||
+ | |2014-2018 | ||
+ | | style="background-color:#1a9851" |Randomized Phase 2 (E-esc) | ||
+ | |[[Osteosarcoma_-_null_regimens#Placebo|Placebo]] | ||
+ | | style="background-color:#1a9850" |Superior PFS (primary endpoint)<br>Median PFS: 3.6 vs 1.7 mo<br>(HR 0.42, 95% CI 0.21-0.85) | ||
+ | |- | ||
+ | |} | ||
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
+ | ====Targeted therapy==== | ||
+ | *[[Regorafenib (Stivarga)]] 160 mg PO once per day on days 1 to 28 | ||
+ | '''28-day cycles''' | ||
+ | </div></div> | ||
===References=== | ===References=== | ||
− | # | + | #'''SARC024:''' Davis LE, Bolejack V, Ryan CW, Ganjoo KN, Loggers ET, Chawla S, Agulnik M, Livingston MB, Reed D, Keedy V, Rushing D, Okuno S, Reinke DK, Riedel RF, Attia S, Mascarenhas L, Maki RG. Randomized Double-Blind Phase II Study of Regorafenib in Patients With Metastatic Osteosarcoma. J Clin Oncol. 2019 Jun 1;37(16):1424-1431. Epub 2019 Apr 23. [https://doi.org/10.1200/jco.18.02374 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7799443/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/31013172/ PubMed] [https://clinicaltrials.gov/study/NCT02048371 NCT02048371] |
==Samarium-153 with stem cell support {{#subobject:26224a|Regimen=1}}== | ==Samarium-153 with stem cell support {{#subobject:26224a|Regimen=1}}== | ||
− | + | <div class="toccolours" style="background-color:#eeeeee"> | |
− | |||
− | |||
− | |||
===Regimen {{#subobject:8c0a7f|Variant=1}}=== | ===Regimen {{#subobject:8c0a7f|Variant=1}}=== | ||
− | {| class="wikitable" style="width: | + | {| class="wikitable sortable" style="width: 60%; text-align:center;" |
− | !Study | + | !style="width: 33%"|Study |
− | ![[Levels_of_Evidence#Evidence|Evidence]] | + | !style="width: 33%"|Dates of enrollment |
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1200/jco.2002.20.1.189 Anderson et al. 2002] |
− | |style="background-color:#ffffbe"|Phase | + | |NR |
+ | |style="background-color:#ffffbe"|Phase 1 | ||
|- | |- | ||
|} | |} | ||
− | + | *Peripheral blood progenitor cell (PBPC) or bone marrow harvest and cryopreservation of at least 2 x 10<sup>6</sup> CD34+ cells/kg | |
− | *Peripheral blood | + | <div class="toccolours" style="background-color:#b3e2cd"> |
====Radiotherapy==== | ====Radiotherapy==== | ||
*[[Samarium-153 (Quadramet)]] 30 mCi/kg IV once on day 0 | *[[Samarium-153 (Quadramet)]] 30 mCi/kg IV once on day 0 | ||
− | + | ====Supportive therapy==== | |
− | ====Supportive | + | *[[Autologous stem cells]] (peripheral blood progenitor cell (PBPC) or bone marrow cells) re-infused on day +14 |
− | *Growth factor support with ONE of the following started when ANC less than 1000/ | + | *Growth factor support with ONE of the following started when ANC less than 1000/μL: |
**[[Filgrastim (Neupogen)]] | **[[Filgrastim (Neupogen)]] | ||
**[[Sargramostim (Leukine)]] | **[[Sargramostim (Leukine)]] | ||
+ | '''One course''' | ||
+ | </div></div> | ||
+ | ===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. [https://doi.org/10.1200/jco.2002.20.1.189 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/11773169/ PubMed] | ||
− | ''' | + | ==Sorafenib monotherapy {{#subobject:s9ggu1|Regimen=1}}== |
− | + | <div class="toccolours" style="background-color:#eeeeee"> | |
+ | ===Regimen {{#subobject:8c0hcs|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 60%; text-align:center;" | ||
+ | !style="width: 33%"|Study | ||
+ | !style="width: 33%"|Dates of enrollment | ||
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | |- | ||
+ | |[https://doi.org/10.1093/annonc/mdr151 Grignani et al. 2011] | ||
+ | |2008-2009 | ||
+ | | style="background-color:#91cf61" |Phase 2 | ||
+ | |- | ||
+ | |} | ||
+ | <div class="toccolours" style="background-color:#b3e2cd"> | ||
+ | ====Targeted therapy==== | ||
+ | *[[Sorafenib (Nexavar)]] 400 mg PO twice per day on days 1 to 28 | ||
+ | '''28-day cycles''' | ||
+ | </div></div> | ||
===References=== | ===References=== | ||
− | # ' | + | # Grignani G, Palmerini E, Dileo P, Asaftei SD, D'Ambrosio L, Pignochino Y, Mercuri M, Picci P, Fagioli F, Casali PG, Ferrari S, Aglietta M. A phase II trial of sorafenib in relapsed and unresectable high-grade osteosarcoma after failure of standard multimodal therapy: an Italian Sarcoma Group study. Ann Oncol. 2012 Feb;23(2):508-16. Epub 2011 Apr 28. [https://doi.org/10.1093/annonc/mdr151 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/21527590/ PubMed] EudraCT 2007-004396-19 |
− | |||
[[Category:Osteosarcoma regimens]] | [[Category:Osteosarcoma regimens]] | ||
[[Category:Disease-specific pages]] | [[Category:Disease-specific pages]] | ||
− | [[Category: | + | [[Category:Bone sarcomas]] |
− |
Latest revision as of 10:05, 2 July 2024
Section editor | |
---|---|
Elizabeth J. Davis, MD Vanderbilt University Nashville, TN, USA |
Are you looking for a regimen but can't find it here? It is possible that we've moved it to the historical regimens page. For placebo or observational studies in this condition, please visit this page. If you still can't find it, please let us know so we can add it!
- Pediatric osteosarcoma regimens can be found here.
26 regimens on this page
37 variants on this page
|
Guidelines
Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.
ESMO
- 2009: Bielack et al. Osteosarcoma: ESMO clinical recommendations for diagnosis, treatment and follow-up PubMed
NCCN
- NCCN does not currently have guidelines at this granular level; please see NCCN Guidelines - Bone Cancer.
Neoadjuvant therapy
Cisplatin & Doxorubicin
AP: Adriamycin (Doxorubicin) & Platinol (Cisplatin)
Regimen variant #1
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Bramwell et al. 1992 | 1983-1986 | Phase 3 (E-switch-ic) | MAP | Seems to have superior DFS |
Souhami et al. 1997 | 1986-1991 | Phase 3 (E-de-esc) | Multi-drug T10 protocol | Did not meet co-primary endpoints of PFS/OS |
Chemotherapy
- Cisplatin (Platinol) 100 mg/m2 IV continuous infusion over 24 hours, started on day 1
- Doxorubicin (Adriamycin) 25 mg/m2 IV bolus once per day on days 1 to 3
Supportive therapy
- Prehydration: normal saline 400 mL/m2 and D5W 400 mL/m2 IV over 2 hours--the reference did not clarify if these two solutions are given at the same time
- The volume of fluid for cisplatin continuous infusion is 2400 mL/m2 NS, with KCl 80 mEq/L and mannitol 32,000 mg/m2
- Posthydration: D5W 600 mL/m2 over 6 hours, with KCl 20 mEq/L and mannitol 8000 mg/m2; and NS 600 mL/m2 over 6 hours, with KCl 20 mEq/L, magnesium sulfate 2 mmol/L, and calcium gluconate 0.6 mmol/L--the reference did not clarify if these two solutions are given at the same time. Then D5W 600 mL/m2 over 12 hours, with KCl 20 mEq/L and mannitol 8000 mg/m2.
- Furosemide (Lasix) 20 to 40 mg IV if urine output is less than 400 mL/m2 over 6 hours
21-day cycle for 3 cycles
Regimen variant #2
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Lewis et al. 2007 (EORTC 80931) | 1993-2002 | Phase 3 (C) | Cisplatin & Doxorubicin; dose-intense | Did not meet primary endpoint of OS |
Chemotherapy
- Cisplatin (Platinol) 100 mg/m2 IV continuous infusion over 24 hours, started on day 1
- Doxorubicin (Adriamycin) 25 mg/m2 IV over 4 hours once per day on days 1 to 3
Supportive therapy
- 4 hours of prehydration prior to cisplatin
- 24 hours of posthydration & mannitol after cisplatin
- Recommended that fluid for cisplatin is isotonic saline with potassium chloride and mannitol
21-day cycle for 2 cycles
References
- Bramwell VH, Burgers M, Sneath R, Souhami R, van Oosterom AT, Voûte PA, Rouesse J, Spooner D, Craft AW, Somers R, Pringle J, Malcolm AJ, van der Eiiken J, Thomas D, Uscinska B, Machin D, van Glabbeke M; European Osteosarcoma Intergroup. A comparison of two short intensive adjuvant chemotherapy regimens in operable osteosarcoma of limbs in children and young adults: the first study of the European Osteosarcoma Intergroup. J Clin Oncol. 1992 Oct;10(10):1579-91. link to original article contains dosing details in manuscript PubMed
- Souhami RL, Craft AW, Van der Eijken JW, Nooij M, Spooner D, Bramwell VH, Wierzbicki R, Malcolm AJ, Kirkpatrick A, Uscinska BM, Van Glabbeke M, Machin D; European Osteosarcoma Intergroup. Randomised trial of two regimens of chemotherapy in operable osteosarcoma: a study of the European Osteosarcoma Intergroup. Lancet. 1997 Sep 27;350(9082):911-7. link to original article PubMed
- EORTC 80931: Lewis IJ, Nooij MA, Whelan J, Sydes MR, Grimer R, Hogendoorn PC, Memon MA, Weeden S, Uscinska BM, van Glabbeke M, Kirkpatrick A, Hauben EI, Craft AW, Taminiau AH; MRC BO06 and EORTC 80931 collaborators; European Osteosarcoma Intergroup. Improvement in histologic response but not survival in osteosarcoma patients treated with intensified chemotherapy: a randomized phase III trial of the European Osteosarcoma Intergroup. J Natl Cancer Inst. 2007 Jan 17;99(2):112-28. link to original article contains dosing details in manuscript PubMed NCT00002539
Cisplatin, Epirubicin, Ifosfamide
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Basaran et al. 2007 | 1993-2002 | Phase 2 |
Chemotherapy
- Cisplatin (Platinol) 100 mg/m2 IV over 2 hours once on day 1
- Epirubicin (Ellence) 90 mg/m2 IV over 15 minutes once on day 1
- Ifosfamide (Ifex) 2000 mg/m2 IV over 4 hours once per day on days 2 to 4, given with mesna
Supportive therapy
- Mesna (Mesnex) 2000 mg/m2 IV over 4 hours once per day on days 2 to 4, given with ifosfamide
- Pre- and post-hydration with mannitol diuresis for cisplatin
21-day cycle for 3 cycles
Subsequent treatment
- Surgery, then adjuvant cisplatin, epirubicin, ifosfamide
References
- Basaran M, Bavbek ES, Saglam S, Eralp L, Sakar B, Atalar AC, Bilgic B, Ozger H, Onat H. A phase II study of cisplatin, ifosfamide and epirubicin combination chemotherapy in adults with nonmetastatic and extremity osteosarcomas. Oncology. 2007;72(3-4):255-60. Epub 2008 Jan 10. link to original article contains dosing details in manuscript PubMed
MA
MA: High-dose Methotrexate, Adriamycin (Doxorubicin)
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Le Deley et al. 2007 (SFOP OS94) | 1994-2001 | Phase 3 (C) | M-EI | Might have inferior EFS |
Chemotherapy
- Methotrexate (MTX) as follows:
- Cycles 1, 2, 3, 6, 7, 10, 11: 12,000 mg/m2 IV over 4 hours once on day 1
- Given in D5W 1L with sodium bicarbonate 1 mEq/kg
- Cycles 1, 2, 3, 6, 7, 10, 11: 12,000 mg/m2 IV over 4 hours once on day 1
- Doxorubicin (Adriamycin) as follows:
- Cycles 4 & 8: 70 mg/m2 IV over 6 hours once on day 1
Supportive therapy
- Leucovorin (Folinic acid) 15 mg PO every 6 hours for up to 11 doses on weeks 1, 2, 3, 6, 7, 10, 11, starting 20 hours after the completion of methotrexate infusion
- For methotrexate: hydration & urine alkalinization by PO and IV routes to maintain 1.6 L/m2 urine output over the first 24 hours and 2 L/m2 on days 2 & 3, with urine pH greater than 7
- Daily monitoring of methotrexate levels and creatinine
7-day cycle for 11 cycles
References
- SFOP OS94: Le Deley MC, Guinebretière JM, Gentet JC, Pacquement H, Pichon F, Marec-Bérard P, Entz-Werlé N, Schmitt C, Brugières L, Vanel D, Dupoüy N, Tabone MD, Kalifa C; Société Française d'Oncologie Pédiatrique (SFOP). SFOP OS94: a randomised trial comparing preoperative high-dose methotrexate plus doxorubicin to high-dose methotrexate plus etoposide and ifosfamide in osteosarcoma patients. Eur J Cancer. 2007 Mar;43(4):752-61. Epub 2007 Jan 30. link to original article contains dosing details in manuscript PubMed NCT00180908
MAP
MAP: High-dose Methotrexate, Adriamycin (Doxorubicin), Platinol (Cisplatin)
Regimen variant #1
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Bramwell et al. 1992 | 1983-1986 | Phase 3 (E-esc) | Cisplatin & Doxorubicin | Seems to have inferior DFS |
Note: The body of Bramwell et al. 1992 says that methotrexate is given over 4 hours, whereas Bramwell et al. 1992 figure 1's text says that methotrexate is given over 6 hours.
Chemotherapy
- Methotrexate (MTX) 8000 mg/m2 IV over 4 to 6 hours once on day 1
- Doxorubicin (Adriamycin) 25 mg/m2 IV bolus once per day on days 11 to 13
- Cisplatin (Platinol) 100 mg/m2 IV continuous infusion over 24 hours, started on day 11
Supportive therapy
- Leucovorin (Folinic acid) 12 mg/m2 IV every 6 hours x 10 doses or 15 mg/m2 PO every 6 hours x 10 doses, starting 24 hours after the start of methotrexate infusion
- Monitor methotrexate level at "24 hours and 48 hours"--it is unclear in the reference if this is time after the start/end of methotrexate, beginning of leucovorin, or something else
- Methotrexate levels higher than 100 nmol/L at 48 hours required additional leucovorin rescue
- Prehydration for methotrexate: "0.9 NaCl:D5W"--unclear if this means either normal saline or D5W can be used--750 mL/m2 over 6 hours, with KCl 20 mEq/L
- The volume of fluid for methotrexate is D5W 1000 mL, to be given over 6 hours
- Posthydration for methotrexate: Alternating liters of D5W and NS 3000 mL/m2 over 24 hours, with KCl 60 mEq/L.
- Sodium bicarbonate 3 g PO Q6H, starting 12 hours before methotrexate, and sodium bicarbonate 167 mmol/L IV until serum methotrexate level is less than 8000 to 10,000 nmol/L. Note: the reference is not clear about when/if PO sodium bicarbonate is stopped, when IV sodium bicarbonate is started, or the administration rate of IV sodium bicarbonate.
- Prehydration for cisplatin: normal saline 400 mL/m2 and D5W 400 mL/m2 IV over 2 hours--the reference did not clarify if these two solutions are given at the same time
- The volume of fluid for cisplatin continuous infusion is 2400 mL/m2 NS, with KCl 80 mEq/L and mannitol 32,000 mg/m2
- Posthydration for cisplatin: D5W 600 mL/m2 over 6 hours, with KCl 20 mEq/L and mannitol 8000 mg/m2; and NS 600 mL/m2 over 6 hours, with KCl 20 mEq/L, magnesium sulfate 2 mmol/L, and calcium gluconate 0.6 mmol/L--the reference did not clarify if these two solutions are given at the same time. Then D5W 600 mL/m2 over 12 hours, with KCl 20 mEq/L and mannitol 8000 mg/m2.
- Furosemide (Lasix) 20 to 40 mg IV if urine output is less than 400 mL/m2 over 6 hours during cisplatin
21-day cycle for 2 cycles
Regimen variant #2
Study | Dates of enrollment | Evidence |
---|---|---|
Bacci et al. 1993 (IOR/OS-2) | 1986-09 to 1989-12 | Phase 2 |
Chemotherapy
- Methotrexate (MTX) 8000 mg/m2 IV over 6 hours once on day 1
- Doxorubicin (Adriamycin) 60 mg/m2 IV over 8 hours once on day 9, starting 48 hours after the start of cisplatin
- Cisplatin (Platinol) 40 mg/m2/day IA continuous infusion over 72 hours, started on day 7 (total dose per cycle: 120 mg/m2)
Supportive therapy
- Leucovorin (Folinic acid) 15 mg IV every 6 hours x 11 doses on days 2 to 4, starting 24 hours after the start of methotrexate infusion
- Hydration during and after methotrexate infusion
27-day cycle for 2 cycles
Subsequent treatment
- Definitive surgery, then risk-adapted therapy. Amputated patients restart chemotherapy 3 to 5 days after surgery; patients who undergo limb salvage or rotation plasty restart chemotherapy 10 to 21 days after surgery.
Regimen variant #3
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Winkler et al. 1988 (COSS-82) | 1982-1984 | Phase 3 (E-switch-ic) | M-BCD | Superior ORR |
Note: The exact schedule is unclear based on limited information in the reference, as schedule of doses is primarily extrapolated from Figure 1, which does not contain clear delineations in time. The dose/schedule of cisplatin reflects the protocol amendment that was done because of nephrotoxicity.
Chemotherapy
- Methotrexate (MTX) 12,000 mg/m2 (maximum dose of 20,000 mg) IV over 4 hours once per day on days 22 & 29
- MTX is dissolved at a concentration of 20,000 mg/L in a solution containing 5% glucose
- Doxorubicin (Adriamycin) 30 mg/m2 IV bolus once per day on days 1 & 2
- Cisplatin (Platinol) 90 mg/m2 IV over 4 hours once on day 3
Supportive therapy
- Leucovorin (Folinic acid) 15 mg/m2 PO every 6 hours x 12 hours once per day on days 23 & 30, starting 24 hours after the completion of methotrexate infusion; additional leucovorin used for delayed methotrexate elimination
- Sodium bicarbonate urine alkalinization prior to high-dose methotrexate
- NS 4.5 L/m2 on day 1 after methotrexate; NS 3 L/m2 on day 2, with adjustments made to keep urine pH greater than 7.4
- 12 hours of hydration prior to cisplatin & 20 hours of hydration after cisplatin; total amount of fluid given over 36hours of prehydration, cisplatin, and posthydration is NS 6 L/m2 with mannitol 8 g/L and potassium 20 mval/L.
- Magnesium 180 mg/m2 PO "per day throughout the whole chemotherapy time"--as described in COSS-80
35-day cycle for 2 cycles
Regimen variant #4
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Winkler et al. 1984 (COSS-80) | 1979-1982 | Phase 3 (E-switch-ic) | MA-BCD | Did not meet primary endpoint of CDF rate |
Note: The exact schedule is unclear based on limited/conflicting information in the reference. For example, Figure 1 appears to depict high-dose methotrexate starting 2 weeks after adriamycin, but the text says that methotrexate begins after a 3-week rest period. Additionally, the diagram in Figure 1 implies that the later therapies are given 4 times (once, then repeated x 3 cycles), but based on the cumulative doses listed, they are only given for a total of 3 cycles. The optional interferon arm is omitted given lack of benefit seen in the study.
Chemotherapy
- Methotrexate (MTX) as follows:
- Cycle 1: 12,000 mg/m2 (maximum dose of 20,000 mg) IV over 4 hours once per day on days 29 & 36
- Cycles 2 to 4: 12,000 mg/m2 (maximum dose of 20,000 mg) IV over 4 hours once per day on days 1, 8, 29, 36
- MTX is dissolved at a concentration of 20,000 mg/L in a solution containing 5% glucose
- Doxorubicin (Adriamycin) as follows:
- Cycles 1, 3, 4: 45 mg/m2 IV bolus once per day on days 1 & 2
- Cycle 2: 45 mg/m2 IV bolus once per day on days 15 & 16 (delayed during cycle 2 until after surgery)
- Cisplatin (Platinol) 120 mg/m2 IV over 5 hours once on day 43
Supportive therapy
- Leucovorin (Folinic acid) 15 mg/m2 PO every 6 hours x 12 hours once per day on days 2, 9, 30, 37, starting 24 hours after the completion of methotrexate infusion; additional leucovorin used for delayed methotrexate elimination
- Sodium bicarbonate urine alkalinization prior to high-dose methotrexate
- NS 4.5 L/m2 on day 1 after methotrexate; NS 3 L/m2 on day 2, with adjustments made to keep urine pH greater than 7.4
- 3 hours of hydration prior to cisplatin & 3 hours of hydration after cisplatin; total amount of fluid given over 11 hours of prehydration, cisplatin, and posthydration is NS 2.5 L/m2 with mannitol 8 g/L and potassium 20 mval/L.
- Magnesium 180 mg/m2 PO "per day throughout the whole chemotherapy time" with cisplatin
8-week cycle for 4 cycles, with surgery done during cycle 2 before doxorubicin; surgery is done 9 to 18 weeks after the start of chemotherapy
References
- COSS-80: Winkler K, Beron G, Kotz R, Salzer-Kuntschik M, Beck J, Beck W, Brandeis W, Ebell W, Erttmann R, Göbel U, Havers W, Henze G, Hinderfeld L, Höcker P, Jobke A, Jürgens H, Kabisch H, Preusser P, Prindull G, Ramach W, Ritter J, Sekera J, Treuner J, Wist G, Landbeck G. Neoadjuvant chemotherapy for osteogenic sarcoma: results of a Cooperative German/Austrian study. J Clin Oncol. 1984 Jun;2(6):617-24. link to original article contains dosing details in manuscript PubMed
- COSS-82: Winkler K, Beron G, Delling G, Heise U, Kabisch H, Purfürst C, Berger J, Ritter J, Jürgens H, Gerein V, Graf N, Russe W, Gruemayer ER, Ertelt W, Kotz R, Preuzzer P, Prindull G, Brandeis W, Landbeck G. Neoadjuvant chemotherapy of osteosarcoma: results of a randomized cooperative trial (COSS-82) with salvage chemotherapy based on histological tumor response. J Clin Oncol. 1988 Feb;6(2):329-37. link to original article contains dosing details in manuscript PubMed
- Bramwell VH, Burgers M, Sneath R, Souhami R, van Oosterom AT, Voûte PA, Rouesse J, Spooner D, Craft AW, Somers R, Pringle J, Malcolm AJ, van der Eiiken J, Thomas D, Uscinska B, Machin D, van Glabbeke M; European Osteosarcoma Intergroup. A comparison of two short intensive adjuvant chemotherapy regimens in operable osteosarcoma of limbs in children and young adults: the first study of the European Osteosarcoma Intergroup. J Clin Oncol. 1992 Oct;10(10):1579-91. link to original article contains dosing details in manuscript PubMed content property of HemOnc.org
- 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
- Update: Bacci G, Ferrari S, Bertoni F, Ruggieri P, Picci P, Longhi A, Casadei R, Fabbri N, Forni C, Versari M, Campanacci M. Long-term outcome for patients with nonmetastatic osteosarcoma of the extremity treated at the Istituto Ortopedico Rizzoli according to the Istituto Ortopedico Rizzoli/Osteosarcoma-2 protocol: an updated report. J Clin Oncol. 2000 Dec 15;18(24):4016-27. link to original article contains dosing details in manuscript PubMed
MAPI
MAPI: High-dose Methotrexate, Adriamycin (Doxorubicin), Platinol (Cisplatin), Ifosfamide
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Bacci et al. 2003 | 1995-05 to 2000-05 | Phase 2 |
Chemotherapy
- Methotrexate (MTX) 12,000 mg/m2 IV over 4 hours once on day 1
- Cisplatin (Platinol) 60 mg/m2/day IV continuous infusion over 48 hours, started on day 8 (total dose per cycle: 120 mg/m2)
- Doxorubicin (Adriamycin) 75 mg/m2 IV continuous infusion over 24 hours, started on day 10
- Ifosfamide (Ifex) 3000 mg/m2/day IV continuous infusion over 120 hours, started on day 29, given with mesna (total dose per cycle: 15,000 mg/m2)
Supportive therapy
- Leucovorin (Folinic acid) 15 mg (route not specified) every 6 hours x 11 doses (note: the reference says "11 cycles," but it is assumed this is the intended meaning), starting day 2, 24 hours after the start of methotrexate
- Hydration during and after methotrexate as described by: Rosen G, Nirenberg A. Chemotherapy for osteogenic sarcoma: an investigative method, not a recipe. Cancer Treat Rep. 1982 Sep;66(9):1687-97. PubMed
- Mesna (Mesnex) 3000 mg/m2/day IV continuous infusion over 120 hours, started on day 29, given with ifosfamide (total dose: 15,000 mg/m2)
42-day cycle for 2 cycles
Dose and schedule modifications
- If 4-hour methotrexate level is less than 10,000 nmol/L, the next cycle's methotrexate dose is increased by 2000 mg/m2
References
- Bacci G, Briccoli A, Rocca M, Ferrari S, Donati D, Longhi A, Bertoni F, Bacchini P, Giacomini S, Forni C, Manfrini M, Galletti S. Neoadjuvant chemotherapy for osteosarcoma of the extremities with metastases at presentation: recent experience at the Rizzoli Institute in 57 patients treated with cisplatin, doxorubicin, and a high dose of methotrexate and ifosfamide. Ann Oncol. 2003 Jul;14(7):1126-34. link to original article contains dosing details in manuscript PubMed
M-EI
M-EI: Methotrexate, Etoposide, Ifosfamide
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Le Deley et al. 2007 (SFOP OS94) | 1994-2001 | Phase 3 (E-switch-ic) | MA | Might have superior EFS |
Piperno-Neumann et al. 2016 (OS2006) | 2007-2014 | Phase 3 (C) | M-EI & Zoledronic acid | Might have superior EFS EFS36: 63.4% vs 57.1% (HR 0.74, 95% CI 0.51-1.05) |
Note: this regimen information is from SFOP OS94.
Chemotherapy
- Methotrexate (MTX) as follows:
- Cycles 1, 2, 3, 7, 8, 12, 13: 12,000 mg/m2 IV over 4 hours once on day 1
- Given in D5W 1L with sodium bicarbonate 1 mEq/kg
- Cycles 1, 2, 3, 7, 8, 12, 13: 12,000 mg/m2 IV over 4 hours once on day 1
- Etoposide (Vepesid) as follows:
- Cycles 4 & 9: 75 mg/m2 IV over 60 minutes once per day on days 1 to 4
- Given in NS 250 to 500 mL
- Cycles 4 & 9: 75 mg/m2 IV over 60 minutes once per day on days 1 to 4
- Ifosfamide (Ifex) as follows:
- Cycles 4 & 9: 3000 mg/m2 IV over 3 hours once per day on days 1 to 4, given with mesna
- Given in NS 250 to 500 mL
- Cycles 4 & 9: 3000 mg/m2 IV over 3 hours once per day on days 1 to 4, given with mesna
Supportive therapy
- Leucovorin (Folinic acid) 15 mg PO every 6 hours for up to 11 doses on weeks 1, 2, 3, 7, 8, 12, 13, starting 20 hours after the completion of methotrexate infusion
- For methotrexate: hydration & urine alkalinization by PO and IV routes to maintain 1.6 L/m2 urine output over the first 24 hours and 2 L/m2 on days 2 & 3, with urine pH greater than 7
- Daily monitoring of methotrexate levels and creatinine
- Mesna (Mesnex) 3600 mg/m2/day IV continuous infusion over 96 hours, started on day 22 (week 4) and 57 (week 9), given with ifosfamide (total dose: 14,400 mg/m2)
- Up to 2 L/day hydration with ifosfamide & mesna
7-day cycle for 13 cycles
References
- SFOP OS94: Le Deley MC, Guinebretière JM, Gentet JC, Pacquement H, Pichon F, Marec-Bérard P, Entz-Werlé N, Schmitt C, Brugières L, Vanel D, Dupoüy N, Tabone MD, Kalifa C; Société Française d'Oncologie Pédiatrique (SFOP). SFOP OS94: a randomised trial comparing preoperative high-dose methotrexate plus doxorubicin to high-dose methotrexate plus etoposide and ifosfamide in osteosarcoma patients. Eur J Cancer. 2007 Mar;43(4):752-61. Epub 2007 Jan 30. link to original article contains dosing details in manuscript PubMed NCT00180908
- OS2006: Piperno-Neumann S, Le Deley MC, Rédini F, Pacquement H, Marec-Bérard P, Petit P, Brisse H, Lervat C, Gentet JC, Entz-Werlé N, Italiano A, Corradini N, Bompas E, Penel N, Tabone MD, Gomez-Brouchet A, Guinebretière JM, Mascard E, Gouin F, Chevance A, Bonnet N, Blay JY, Brugières L; Sarcoma Group of UNICANCER; SFCE; GSF-GETO. Zoledronate in combination with chemotherapy and surgery to treat osteosarcoma (OS2006): a randomised, multicentre, open-label, phase 3 trial. Lancet Oncol. 2016 Aug;17(8):1070-1080. Epub 2016 Jun 17. link to original article PubMed NCT00470223
- Update: Gaspar N, Occean BV, Pacquement H, Bompas E, Bouvier C, Brisse HJ, Castex MP, Cheurfa N, Corradini N, Delaye J, Entz-Werlé N, Gentet JC, Italiano A, Lervat C, Marec-Berard P, Mascard E, Redini F, Saumet L, Schmitt C, Tabone MD, Verite-Goulard C, Le Deley MC, Piperno-Neumann S, Brugieres L; SFCE; GSF-GETO; UNICANCER sarcoma group. Results of methotrexate-etoposide-ifosfamide based regimen (M-EI) in osteosarcoma patients included in the French OS2006/sarcome-09 study. Eur J Cancer. 2018 Jan;88:57-66. Epub 2017 Nov 28. link to original article PubMed
Adjuvant therapy
Cisplatin & Doxorubicin
AP: Adriamycin (Doxorubicin) & Platinol (Cisplatin)
Regimen variant #1
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Bramwell et al. 1992 | 1983-1986 | Phase 3 (E-esc) | MAP | Seems to have superior DFS |
Souhami et al. 1997 | 1986-1991 | Phase 3 (E-de-esc) | Multi-drug T10 protocol | Did not meet co-primary endpoints of PFS/OS |
Chemotherapy
- Cisplatin (Platinol) 100 mg/m2 IV continuous infusion over 24 hours, started on day 1
- Doxorubicin (Adriamycin) 25 mg/m2 IV bolus once per day on days 1 to 3
Supportive therapy
- Prehydration: normal saline 400 mL/m2 and D5W 400 mL/m2 IV over 2 hours--the reference did not clarify if these two solutions are given at the same time
- The volume of fluid for cisplatin continuous infusion is 2400 mL/m2 NS, with KCl 80 mEq/L and mannitol 32,000 mg/m2
- Posthydration: D5W 600 mL/m2 over 6 hours, with KCl 20 mEq/L and mannitol 8000 mg/m2; and NS 600 mL/m2 over 6 hours, with KCl 20 mEq/L, magnesium sulfate 2 mmol/L, and calcium gluconate 0.6 mmol/L--the reference did not clarify if these two solutions are given at the same time. Then D5W 600 mL/m2 over 12 hours, with KCl 20 mEq/L and mannitol 8000 mg/m2.
- Furosemide (Lasix) 20 to 40 mg IV if urine output is less than 400 mL/m2 over 6 hours
21-day cycle for 3 cycles
Regimen variant #2
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Lewis et al. 2007 (EORTC 80931) | 1993-2002 | Phase 3 (C) | Cisplatin & Doxorubicin; dose-intense | Did not meet primary endpoint of OS |
Chemotherapy
- Cisplatin (Platinol) 100 mg/m2 IV continuous infusion over 24 hours, started on day 1
- Doxorubicin (Adriamycin) 25 mg/m2 IV over 4 hours once per day on days 1 to 3
Supportive therapy
- 4 hours of prehydration prior to cisplatin
- 24 hours of posthydration & mannitol after cisplatin
- Recommended that fluid for cisplatin is isotonic saline with potassium chloride and mannitol
21-day cycle for 4 cycles
Regimen variant #3, dose intense
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Lewis et al. 2007 (EORTC 80931) | 1993-2002 | Phase 3 (E-esc) | Cisplatin & Doxorubicin; conventional | Did not meet primary endpoint of OS |
Chemotherapy
- Cisplatin (Platinol) 100 mg/m2 IV continuous infusion over 24 hours, started on day 1
- Doxorubicin (Adriamycin) 25 mg/m2 IV over 4 hours once per day on days 1 to 3
Supportive therapy
- Growth factor suppor with ONE of the following:
- Filgrastim (Neupogen) 5 mcg/kg SC once per day on days 4 to 13
- Lenograstim (Granocyte) 5 mcg/kg SC once per day on days 4 to 13
- 4 hours of prehydration prior to cisplatin
- 24 hours of posthydration & mannitol after cisplatin
- Recommended that fluid for cisplatin is isotonic saline with potassium chloride and mannitol
14-day cycle for 3 cycles
Regimen variant #4
Study | Dates of enrollment | Evidence |
---|---|---|
Winkler et al. 1988 (COSS-82) | 1982-1984 | Non-randomized part of phase 3 RCT |
Note: The exact schedule is unclear based on limited information in the reference, as schedule of doses is primarily extrapolated from Figure 1, which does not contain clear delineations in time.
Chemotherapy
- Cisplatin (Platinol) 90 mg/m2 IV over 4 hours once on day 3
- Doxorubicin (Adriamycin) 30 mg/m2 IV bolus once per day on days 1 & 2
Supportive therapy
- 12 hours of hydration prior to cisplatin & 20 hours of hydration after cisplatin; total amount of fluid given over 36hours of prehydration, cisplatin, and posthydration is NS 6 L/m2 with mannitol 8 g/L and potassium 20 mval/L.
- Magnesium 180 mg/m2 PO "per day throughout the whole chemotherapy time"--as described in COSS-80
21-day cycle for 6 cycles
Regimen variant #5
Study | Dates of enrollment | Evidence |
---|---|---|
Le Deley et al. 2007 (SFOP OS94) | 1994-2001 | Non-randomized part of phase 3 RCT |
Details were not listed about the precise schedule. Other regimens have used both medications both on day 1, with 21-day cycles.
Chemotherapy
- Cisplatin (Platinol) 120 mg/m2 IV (schedule not specified)
- Doxorubicin (Adriamycin) 70 mg/m2 IV over 6 hours (schedule not specified)
5 cycles (length not specified)
References
- COSS-82: Winkler K, Beron G, Delling G, Heise U, Kabisch H, Purfürst C, Berger J, Ritter J, Jürgens H, Gerein V, Graf N, Russe W, Gruemayer ER, Ertelt W, Kotz R, Preuzzer P, Prindull G, Brandeis W, Landbeck G. Neoadjuvant chemotherapy of osteosarcoma: results of a randomized cooperative trial (COSS-82) with salvage chemotherapy based on histological tumor response. J Clin Oncol. 1988 Feb;6(2):329-37. link to original article contains dosing details in manuscript PubMed
- Bramwell VH, Burgers M, Sneath R, Souhami R, van Oosterom AT, Voûte PA, Rouesse J, Spooner D, Craft AW, Somers R, Pringle J, Malcolm AJ, van der Eiiken J, Thomas D, Uscinska B, Machin D, van Glabbeke M; European Osteosarcoma Intergroup. A comparison of two short intensive adjuvant chemotherapy regimens in operable osteosarcoma of limbs in children and young adults: the first study of the European Osteosarcoma Intergroup. J Clin Oncol. 1992 Oct;10(10):1579-91. link to original article contains dosing details in manuscript PubMed
- Souhami RL, Craft AW, Van der Eijken JW, Nooij M, Spooner D, Bramwell VH, Wierzbicki R, Malcolm AJ, Kirkpatrick A, Uscinska BM, Van Glabbeke M, Machin D; European Osteosarcoma Intergroup. Randomised trial of two regimens of chemotherapy in operable osteosarcoma: a study of the European Osteosarcoma Intergroup. Lancet. 1997 Sep 27;350(9082):911-7. link to original article PubMed
- EORTC 80931: Lewis IJ, Nooij MA, Whelan J, Sydes MR, Grimer R, Hogendoorn PC, Memon MA, Weeden S, Uscinska BM, van Glabbeke M, Kirkpatrick A, Hauben EI, Craft AW, Taminiau AH; MRC BO06 and EORTC 80931 collaborators; European Osteosarcoma Intergroup. Improvement in histologic response but not survival in osteosarcoma patients treated with intensified chemotherapy: a randomized phase III trial of the European Osteosarcoma Intergroup. J Natl Cancer Inst. 2007 Jan 17;99(2):112-28. link to original article contains dosing details in manuscript PubMed NCT00002539
- SFOP OS94: Le Deley MC, Guinebretière JM, Gentet JC, Pacquement H, Pichon F, Marec-Bérard P, Entz-Werlé N, Schmitt C, Brugières L, Vanel D, Dupoüy N, Tabone MD, Kalifa C; Société Française d'Oncologie Pédiatrique (SFOP). SFOP OS94: a randomised trial comparing preoperative high-dose methotrexate plus doxorubicin to high-dose methotrexate plus etoposide and ifosfamide in osteosarcoma patients. Eur J Cancer. 2007 Mar;43(4):752-61. Epub 2007 Jan 30. link to original article contains dosing details in manuscript PubMed NCT00180908
Cisplatin, Epirubicin, Ifosfamide
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Basaran et al. 2007 | 1993-2002 | Phase 2 |
Preceding treatment
- Neoadjuvant cisplatin, epirubicin, ifosfamide, then surgery
Chemotherapy
- Cisplatin (Platinol) 100 mg/m2 IV over 2 hours once on day 1
- Epirubicin (Ellence) 90 mg/m2 IV over 15 minutes once on day 1
- Ifosfamide (Ifex) 2000 mg/m2 IV over 4 hours once per day on days 2 to 4, given with mesna
Supportive therapy
- Mesna (Mesnex) 2000 mg/m2 IV over 4 hours once per day on days 2 to 4, given with ifosfamide
- Pre- and post-hydration with mannitol diuresis for cisplatin
28-day cycle for 3 cycles
References
- Basaran M, Bavbek ES, Saglam S, Eralp L, Sakar B, Atalar AC, Bilgic B, Ozger H, Onat H. A phase II study of cisplatin, ifosfamide and epirubicin combination chemotherapy in adults with nonmetastatic and extremity osteosarcomas. Oncology. 2007;72(3-4):255-60. Epub 2008 Jan 10. link to original article contains dosing details in abstract PubMed
IE
IE: Ifosfamide, Etoposide
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Le Deley et al. 2007 (SFOP OS94) | 1994-2001 | Non-randomized part of phase 3 RCT |
Details were not listed about the length of each cycle. Other regimens have used 21 to 28-day cycles.
Chemotherapy
- Ifosfamide (Ifex) 3000 mg/m2 IV over 3 hours once per day on days 1 to 4, given during mesna infusion
- Given in NS 250 to 500 mL
- Etoposide (Vepesid) 75 mg/m2 IV over 60 minutes once per day on days 1 to 4
- Given in NS 250 to 500 mL
Supportive therapy
- Mesna (Mesnex) 3600 mg/m2/day IV continuous infusion over 96 hours, started on day 1 (total dose: 14,400 mg/m2)
- Up to 2 L/day hydration with ifosfamide & mesna
5 cycles
References
- SFOP OS94: Le Deley MC, Guinebretière JM, Gentet JC, Pacquement H, Pichon F, Marec-Bérard P, Entz-Werlé N, Schmitt C, Brugières L, Vanel D, Dupoüy N, Tabone MD, Kalifa C; Société Française d'Oncologie Pédiatrique (SFOP). SFOP OS94: a randomised trial comparing preoperative high-dose methotrexate plus doxorubicin to high-dose methotrexate plus etoposide and ifosfamide in osteosarcoma patients. Eur J Cancer. 2007 Mar;43(4):752-61. Epub 2007 Jan 30. link to original article contains dosing details in manuscript PubMed NCT00180908
MA
MA: High-dose Methotrexate, Adriamycin (Doxorubicin)
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Le Deley et al. 2007 (SFOP OS94) | 1994-2001 | Non-randomized part of phase 3 RCT |
Chemotherapy
- Methotrexate (MTX) 12,000 mg/m2 IV over 4 hours once per day on days 1, 8, 15
- Given in D5W 1L with sodium bicarbonate 1 mEq/kg
- Doxorubicin (Adriamycin) as follows:
- Cycles 1 to 3: 70 mg/m2 IV over 6 hours once on day 22
Supportive therapy
- Leucovorin (Folinic acid) 15 mg PO every 6 hours for up to 11 doses, starting on days 1, 8, 15, starting 20 hours after the completion of methotrexate infusion
- For methotrexate: hydration & urine alkalinization by PO and IV routes to maintain 1.6 L/m2 urine output over the first 24 hours and 2 L/m2 on days 2 & 3, with urine pH greater than 7
- Daily monitoring of methotrexate levels and creatinine
28-day cycle for 4 cycles
References
- SFOP OS94: Le Deley MC, Guinebretière JM, Gentet JC, Pacquement H, Pichon F, Marec-Bérard P, Entz-Werlé N, Schmitt C, Brugières L, Vanel D, Dupoüy N, Tabone MD, Kalifa C; Société Française d'Oncologie Pédiatrique (SFOP). SFOP OS94: a randomised trial comparing preoperative high-dose methotrexate plus doxorubicin to high-dose methotrexate plus etoposide and ifosfamide in osteosarcoma patients. Eur J Cancer. 2007 Mar;43(4):752-61. Epub 2007 Jan 30. link to original article contains dosing details in manuscript PubMed NCT00180908
MAP
MAP: High-dose Methotrexate, Adriamycin (Doxorubicin), Platinol (Cisplatin)
Regimen variant #1, 8000/75/100
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Bramwell et al. 1992 | 1983-1986 | Phase 3 (E-esc) | Cisplatin & Doxorubicin | Seems to have inferior DFS |
Note: The body of Bramwell et al. 1992 says that methotrexate is given over 4 hours, whereas Bramwell et al. 1992 figure 1's text says that methotrexate is given over 6 hours.
Chemotherapy
- Methotrexate (MTX) 8000 mg/m2 IV over 4 to 6 hours once on day 1
- Doxorubicin (Adriamycin) 25 mg/m2 IV bolus once per day on days 11 to 13
- Cisplatin (Platinol) 100 mg/m2 IV continuous infusion over 24 hours, started on day 11
Supportive therapy
- Leucovorin (Folinic acid) 12 mg/m2 IV every 6 hours x 10 doses or 15 mg/m2 PO every 6 hours x 10 doses, starting 24 hours after the start of methotrexate infusion
- Monitor methotrexate level at "24 hours and 48 hours"--it is unclear in the reference if this is time after the start/end of methotrexate, beginning of leucovorin, or something else
- Methotrexate levels higher than 100 nmol/L at 48 hours required additional leucovorin rescue
- Prehydration for methotrexate: "0.9 NaCl:D5W"--unclear if this means either normal saline or D5W can be used--750 mL/m2 over 6 hours, with KCl 20 mEq/L
- The volume of fluid for methotrexate is D5W 1000 mL, to be given over 6 hours
- Posthydration for methotrexate: Alternating liters of D5W and NS 3000 mL/m2 over 24 hours, with KCl 60 mEq/L.
- Sodium bicarbonate 3 g PO Q6H, starting 12 hours before methotrexate, and sodium bicarbonate 167 mmol/L IV until serum methotrexate level is less than 8000 to 10,000 nmol/L. Note: the reference is not clear about when/if PO sodium bicarbonate is stopped, when IV sodium bicarbonate is started, or the administration rate of IV sodium bicarbonate.
- Prehydration for cisplatin: normal saline 400 mL/m2 and D5W 400 mL/m2 IV over 2 hours--the reference did not clarify if these two solutions are given at the same time
- The volume of fluid for cisplatin continuous infusion is 2400 mL/m2 NS, with KCl 80 mEq/L and mannitol 32,000 mg/m2
- Posthydration for cisplatin: D5W 600 mL/m2 over 6 hours, with KCl 20 mEq/L and mannitol 8000 mg/m2; and NS 600 mL/m2 over 6 hours, with KCl 20 mEq/L, magnesium sulfate 2 mmol/L, and calcium gluconate 0.6 mmol/L--the reference did not clarify if these two solutions are given at the same time. Then D5W 600 mL/m2 over 12 hours, with KCl 20 mEq/L and mannitol 8000 mg/m2.
- With cisplatin, Furosemide (Lasix) 20 to 40 mg IV if urine output is less than 400 mL/m2 over 6 hours
21-day cycle for 2 cycles
Regimen variant #2, 8000/90/120
Study | Evidence |
---|---|
Bacci et al. 1993 (IOR/OS-2) | Phase 2 |
Note: Figure 1 of Bacci et al. 2000 actually depicted the first cycle as being 47 days, and cycles 2 & 3 being 48 days.
Preceding treatment
Chemotherapy
- Methotrexate (MTX) as follows:
- Cycles 1 to 3: 8000 mg/m2 IV over 6 hours once on day 21
- Doxorubicin (Adriamycin) 45 mg/m2 IV over 4 hours once per day on days 1 & 2
- Cisplatin (Platinol) as follows:
- Cycles 1 to 3: 40 mg/m2/day IV continuous infusion over 72 hours, started on day 27 (total dose per cycle: 120 mg/m2)
Supportive therapy
- Leucovorin (Folinic acid) as follows:
- Cycles 1 to 3: 15 mg IV every 6 hours x 11 doses on days 22 to 24, starting 24 hours after the start of methotrexate infusion
- Hydration during and after methotrexate infusion
48-day cycle for 4 cycles
Regimen variant #3, 12,000/60/90
Study | Dates of enrollment | Evidence |
---|---|---|
Winkler et al. 1988 (COSS-82) | 1982-1984 | Non-randomized part of phase 3 RCT |
Chemotherapy
- Methotrexate (MTX) 12,000 mg/m2 (maximum dose of 20,000 mg) IV over 4 hours once per day on days 22 & 29
- MTX is dissolved at a concentration of 20,000 mg/L in a solution containing 5% glucose
- Doxorubicin (Adriamycin) 30 mg/m2 IV bolus once per day on days 1 & 2
- Cisplatin (Platinol) 90 mg/m2 IV over 4 hours once on day 3
Supportive therapy
- Leucovorin (Folinic acid) 15 mg/m2 PO every 6 hours x 12 hours once per day on days 23 & 30, starting 24 hours after the completion of methotrexate infusion; additional leucovorin used for delayed methotrexate elimination
- Sodium bicarbonate urine alkalinization prior to high-dose methotrexate
- NS 4.5 L/m2 on day 1 after methotrexate; NS 3 L/m2 on day 2, with adjustments made to keep urine pH greater than 7.4
- 12 hours of hydration prior to cisplatin & 20 hours of hydration after cisplatin; total amount of fluid given over 36hours of prehydration, cisplatin, and posthydration is NS 6 L/m2 with mannitol 8 g/L and potassium 20 mval/L.
- Magnesium 180 mg/m2 PO "per day throughout the whole chemotherapy time"--as described in COSS-80
35-day cycle for 2 cycles
Regimen variant #4, 12,000/75/120
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Marina et al. 2016 (EURAMOS-1 poor response) | 2005-2011 | Phase 3 (C) | MAPIE | Did not meet primary endpoint of EFS |
Chemotherapy
- Methotrexate (MTX) by the following site-based criteria:
- Non-COG sites: 12,000 mg/m2 IV over 4 hours once per day on days 22 & 29
- COG sites: 12,000 mg/m2 (maximum dose of 20,000 mg) IV over 4 hours once per day on days 22 & 29
- Doxorubicin (Adriamycin) 37.5 mg/m2 IV once per day on days 1 & 2
- Cisplatin (Platinol) by the following site-based criteria:
- Non-COG sites: 40 mg/m2/day IV continuous infusion over 72 hours, started on day 1 (total dose per cycle: 120 mg/m2)
- COG sites: 60 mg/m2 IV once per day on days 1 & 2
Supportive therapy
- Leucovorin (Folinic acid) 15 mg/m2 (route/schedule not specified), starting 24 to 48 hours after methotrexate infusion, continued until MTX level less than 100 nmol/L
35-day cycle for 2 cycles
Subsequent treatment
- Adjuvant MA x 2
References
- COSS-82: Winkler K, Beron G, Delling G, Heise U, Kabisch H, Purfürst C, Berger J, Ritter J, Jürgens H, Gerein V, Graf N, Russe W, Gruemayer ER, Ertelt W, Kotz R, Preuzzer P, Prindull G, Brandeis W, Landbeck G. Neoadjuvant chemotherapy of osteosarcoma: results of a randomized cooperative trial (COSS-82) with salvage chemotherapy based on histological tumor response. J Clin Oncol. 1988 Feb;6(2):329-37. link to original article contains dosing details in manuscript PubMed
- Bramwell VH, Burgers M, Sneath R, Souhami R, van Oosterom AT, Voûte PA, Rouesse J, Spooner D, Craft AW, Somers R, Pringle J, Malcolm AJ, van der Eiiken J, Thomas D, Uscinska B, Machin D, van Glabbeke M; European Osteosarcoma Intergroup. A comparison of two short intensive adjuvant chemotherapy regimens in operable osteosarcoma of limbs in children and young adults: the first study of the European Osteosarcoma Intergroup. J Clin Oncol. 1992 Oct;10(10):1579-91. link to original article contains dosing details in manuscript PubMed
- 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
- Update: Bacci G, Ferrari S, Bertoni F, Ruggieri P, Picci P, Longhi A, Casadei R, Fabbri N, Forni C, Versari M, Campanacci M. Long-term outcome for patients with nonmetastatic osteosarcoma of the extremity treated at the Istituto Ortopedico Rizzoli according to the Istituto Ortopedico Rizzoli/Osteosarcoma-2 protocol: an updated report. J Clin Oncol. 2000 Dec 15;18(24):4016-27. link to original article contains dosing details in manuscript PubMed
- 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
- EURAMOS-1 poor response: Marina NM, Smeland S, Bielack SS, Bernstein M, Jovic G, Krailo MD, Hook JM, Arndt C, van den Berg H, Brennan B, Brichard B, Brown KL, Butterfass-Bahloul T, Calaminus G, Daldrup-Link HE, Eriksson M, Gebhardt MC, Gelderblom H, Gerss J, Goldsby R, Goorin A, Gorlick R, Grier HE, Hale JP, Hall KS, Hardes J, Hawkins DS, Helmke K, Hogendoorn PC, Isakoff MS, Janeway KA, Jürgens H, Kager L, Kühne T, Lau CC, Leavey PJ, Lessnick SL, Mascarenhas L, Meyers PA, Mottl H, Nathrath M, Papai Z, Randall RL, Reichardt P, Renard M, Safwat AA, Schwartz CL, Stevens MC, Strauss SJ, Teot L, Werner M, Sydes MR, Whelan JS. Comparison of MAPIE versus MAP in patients with a poor response to preoperative chemotherapy for newly diagnosed high-grade osteosarcoma (EURAMOS-1): an open-label, international, randomised controlled trial. Lancet Oncol. 2016 Oct;17(10):1396-1408. Epub 2016 Aug 25. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00134030
MAPI
MAPI: High-dose Methotrexate, Adriamycin (Doxorubicin), Platinol (Cisplatin), Ifosfamide
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Bacci et al. 2003 | 1995-05 to 2000-05 | Phase 2 |
Chemotherapy
- Methotrexate (MTX) 12,000 mg/m2 IV over 4 hours once on day 36
- Doxorubicin (Adriamycin) 90 mg/m2 IV continuous infusion over 24 hours, started on day 1
- Cisplatin (Platinol) 60 mg/m2/day IV continuous infusion over 48 hours, started on day 43 (total dose per cycle: 120 mg/m2)
- Ifosfamide (Ifex) 3000 mg/m2/day IV continuous infusion over 120 hours, started on day 22, given with mesna (total dose per cycle: 15,000 mg/m2)
Supportive therapy
- Mesna (Mesnex) 3000 mg/m2/day IV continuous infusion over 120 hours, started on day 22, given with ifosfamide (total dose per cycle: 15,000 mg/m2)
- Leucovorin (Folinic acid) 15 mg (route not specified) every 6 hours x 11 doses, starting day 36, 24 hours after the start of methotrexate
- Hydration during and after methotrexate as described by: Rosen G, Nirenberg A. Chemotherapy for osteogenic sarcoma: an investigative method, not a recipe. Cancer Treat Rep. 1982 Sep;66(9):1687-97. PubMed
9-week cycle for 3 cycles
Dose and schedule modifications
- If 4-hour methotrexate level is less than 10,000 nmol/L, the next cycle's methotrexate dose is increased by 2000 mg/m2
References
- Bacci G, Briccoli A, Rocca M, Ferrari S, Donati D, Longhi A, Bertoni F, Bacchini P, Giacomini S, Forni C, Manfrini M, Galletti S. Neoadjuvant chemotherapy for osteosarcoma of the extremities with metastases at presentation: recent experience at the Rizzoli Institute in 57 patients treated with cisplatin, doxorubicin, and a high dose of methotrexate and ifosfamide. Ann Oncol. 2003 Jul;14(7):1126-34. link to original article contains dosing details in manuscript PubMed
MAPIE
MAPIE: High-dose Methotrexate, Adriamycin (Doxorubicin), Platinol (Cisplatin), Ifosfamide, Etoposide
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Bacci et al. 1993 (IOR/OS-2) | 1986-09 to 1989-12 | Phase 2 |
Note: Figure 1 of Bacci et al. 2000 actually depicted the first cycle as being 68 days, and cycles 2 & 3 being 69 days.
Preceding treatment
Chemotherapy
- Methotrexate (MTX) as follows:
- Cycles 1 to 3: 8000 mg/m2 IV over 6 hours once on day 42
- Doxorubicin (Adriamycin) 45 mg/m2 IV over 4 hours once per day on days 1 & 2
- Cisplatin (Platinol) as follows:
- Cycles 1 to 3: 40 mg/m2/day IV continuous infusion over 72 hours, started on day 48 (total dose per cycle: 120 mg/m2)
- Ifosfamide (Ifex) as follows:
- Cycles 1 to 3: 2000 mg/m2 IV over 90 minutes once per day on days 21 to 25, with mesna
- Etoposide (Vepesid) as follows:
- Cycles 1 to 3: 120 mg/m2 IV over 60 minutes once per day on days 48 to 50
Supportive therapy
- Mesna (Mesnex) as follows:
- Cycles 1 to 3: with ifosfamide; no actual dose is listed in the reference
- Leucovorin (Folinic acid) as follows:
- Cycles 1 to 3: 15 mg IV every 6 hours x 11 doses on days 43 to 45, starting 24 hours after the start of methotrexate infusion
- Hydration during and after methotrexate infusion
69-day cycle for 4 cycles
References
- 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
- Update: Bacci G, Ferrari S, Bertoni F, Ruggieri P, Picci P, Longhi A, Casadei R, Fabbri N, Forni C, Versari M, Campanacci M. Long-term outcome for patients with nonmetastatic osteosarcoma of the extremity treated at the Istituto Ortopedico Rizzoli according to the Istituto Ortopedico Rizzoli/Osteosarcoma-2 protocol: an updated report. J Clin Oncol. 2000 Dec 15;18(24):4016-27. link to original article contains dosing details in manuscript PubMed
- EURAMOS-1 poor response: Marina NM, Smeland S, Bielack SS, Bernstein M, Jovic G, Krailo MD, Hook JM, Arndt C, van den Berg H, Brennan B, Brichard B, Brown KL, Butterfass-Bahloul T, Calaminus G, Daldrup-Link HE, Eriksson M, Gebhardt MC, Gelderblom H, Gerss J, Goldsby R, Goorin A, Gorlick R, Grier HE, Hale JP, Hall KS, Hardes J, Hawkins DS, Helmke K, Hogendoorn PC, Isakoff MS, Janeway KA, Jürgens H, Kager L, Kühne T, Lau CC, Leavey PJ, Lessnick SL, Mascarenhas L, Meyers PA, Mottl H, Nathrath M, Papai Z, Randall RL, Reichardt P, Renard M, Safwat AA, Schwartz CL, Stevens MC, Strauss SJ, Teot L, Werner M, Sydes MR, Whelan JS. Comparison of MAPIE versus MAP in patients with a poor response to preoperative chemotherapy for newly diagnosed high-grade osteosarcoma (EURAMOS-1): an open-label, international, randomised controlled trial. Lancet Oncol. 2016 Oct;17(10):1396-1408. Epub 2016 Aug 25. link to original article link to PMC article PubMed NCT00134030
M-EI
M-EI: Methotrexate, Etoposide, Ifosfamide
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Le Deley et al. 2007 (SFOP OS94) | 1994-2001 | Non-randomized part of phase 3 RCT |
Chemotherapy
- Methotrexate (MTX) 12,000 mg/m2 IV over 4 hours once per day on days 1, 8, 15
- Given in D5W 1L with sodium bicarbonate 1 mEq/kg
- Etoposide (Vepesid) as follows:
- Cycles 1 to 3: 75 mg/m2 IV over 60 minutes once per day on days 22 to 25 (week 4)
- Given in NS 250 to 500 mL
- Cycles 1 to 3: 75 mg/m2 IV over 60 minutes once per day on days 22 to 25 (week 4)
- Ifosfamide (Ifex) as follows:
- Cycles 1 to 3: 3000 mg/m2 IV over 3 hours once per day on days 22 to 25 (week 4), given during mesna infusion (total dose per cycle: 12,000 mg/m2)
- Given in NS 250 to 500 mL
- Cycles 1 to 3: 3000 mg/m2 IV over 3 hours once per day on days 22 to 25 (week 4), given during mesna infusion (total dose per cycle: 12,000 mg/m2)
Supportive therapy
- Leucovorin (Folinic acid) 15 mg PO every 6 hours for up to 11 doses, starting on days 1, 8, 15, starting 20 hours after the completion of methotrexate infusion
- For methotrexate: hydration & urine alkalinization by PO and IV routes to maintain 1.6 L/m2 urine output over the first 24 hours and 2 L/m2 on days 2 & 3, with urine pH greater than 7
- Daily monitoring of methotrexate levels and creatinine
- Mesna (Mesnex) as follows:
- Cycles 1 to 3: 3600 mg/m2/day IV continuous infusion over 96 hours, started on day 22 (week 4) (total dose per cycle: 14,400 mg/m2)
- Up to 2 L/day hydration with ifosfamide & mesna
28-day cycle for 4 cycles
References
- SFOP OS94: Le Deley MC, Guinebretière JM, Gentet JC, Pacquement H, Pichon F, Marec-Bérard P, Entz-Werlé N, Schmitt C, Brugières L, Vanel D, Dupoüy N, Tabone MD, Kalifa C; Société Française d'Oncologie Pédiatrique (SFOP). SFOP OS94: a randomised trial comparing preoperative high-dose methotrexate plus doxorubicin to high-dose methotrexate plus etoposide and ifosfamide in osteosarcoma patients. Eur J Cancer. 2007 Mar;43(4):752-61. Epub 2007 Jan 30. link to original article contains dosing details in manuscript PubMed NCT00180908
- OS2006: Piperno-Neumann S, Le Deley MC, Rédini F, Pacquement H, Marec-Bérard P, Petit P, Brisse H, Lervat C, Gentet JC, Entz-Werlé N, Italiano A, Corradini N, Bompas E, Penel N, Tabone MD, Gomez-Brouchet A, Guinebretière JM, Mascard E, Gouin F, Chevance A, Bonnet N, Blay JY, Brugières L; Sarcoma Group of UNICANCER; SFCE; GSF-GETO. Zoledronate in combination with chemotherapy and surgery to treat osteosarcoma (OS2006): a randomised, multicentre, open-label, phase 3 trial. Lancet Oncol. 2016 Aug;17(8):1070-1080. Epub 2016 Jun 17. link to original article PubMed NCT00470223
- Update: Gaspar N, Occean BV, Pacquement H, Bompas E, Bouvier C, Brisse HJ, Castex MP, Cheurfa N, Corradini N, Delaye J, Entz-Werlé N, Gentet JC, Italiano A, Lervat C, Marec-Berard P, Mascard E, Redini F, Saumet L, Schmitt C, Tabone MD, Verite-Goulard C, Le Deley MC, Piperno-Neumann S, Brugieres L; SFCE; GSF-GETO; UNICANCER sarcoma group. Results of methotrexate-etoposide-ifosfamide based regimen (M-EI) in osteosarcoma patients included in the French OS2006/sarcome-09 study. Eur J Cancer. 2018 Jan;88:57-66. Epub 2017 Nov 28. link to original article PubMed
Relapsed, refractory, or metastatic, first-line
Cisplatin & Doxorubicin
AP: Adriamycin (Doxorubicin) & Platinol (Cisplatin)
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Bramwell et al. 1997 (EOI 80831/MRC B002) | 1983-1986 | Phase 3 (E-de-esc) | MAP | Inferior OS |
Note: the authors state that "[i]t is likely that random bias in the population..accounts for the difference in outcome favoring the three-drug treatment in patients with metastatic disease."
Chemotherapy
- Cisplatin (Platinol) 100 mg/m2 IV continuous infusion over 24 hours, started on day 1
- Doxorubicin (Adriamycin) 25 mg/m2 IV bolus once per day on days 1 to 3
Supportive therapy
- Prehydration: normal saline 400 mL/m2 and D5W 400 mL/m2 IV over 2 hours--the reference did not clarify if these two solutions are given at the same time
- The volume of fluid for cisplatin continuous infusion is 2400 mL/m2 NS, with KCl 80 mEq/L and mannitol 32,000 mg/m2
- Posthydration: D5W 600 mL/m2 over 6 hours, with KCl 20 mEq/L and mannitol 8000 mg/m2; and NS 600 mL/m2 over 6 hours, with KCl 20 mEq/L, magnesium sulfate 2 mmol/L, and calcium gluconate 0.6 mmol/L--the reference did not clarify if these two solutions are given at the same time. Then D5W 600 mL/m2 over 12 hours, with KCl 20 mEq/L and mannitol 8000 mg/m2.
- Furosemide (Lasix) 20 to 40 mg IV if urine output is less than 400 mL/m2 over 6 hours
21-day cycle for 6 cycles
References
- EOI 80831/MRC B002: Bramwell VH, Burgers MV, Souhami RL, Taminiau AH, Van Der Eijken JW, Craft AW, Malcolm AJ, Uscinska B, Kirkpatrick AL, Machin D, Van Glabbeke MM; European Osteosarcoma Intergroup. A randomized comparison of two short intensive chemotherapy regimens in children and young adults with osteosarcoma: results in patients with metastases: a study of the European Osteosarcoma Intergroup. Sarcoma. 1997;1(3-4):155-60. link to original article contains dosing details in manuscript link to PMC article PubMed
MAP
MAP: High-dose Methotrexate, Adriamycin (Doxorubicin), Platinol (Cisplatin)
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Bramwell et al. 1997 (EOI 80831/MRC B002) | 1983-1986 | Phase 3 (E-esc) | Cisplatin & Doxorubicin | Superior OS |
Note: the authors state that "[i]t is likely that random bias in the population..accounts for the difference in outcome favoring the three-drug treatment in patients with metastatic disease."
Chemotherapy
- Methotrexate (MTX) 8000 mg/m2 IV over 4 hours once on day 1
- Doxorubicin (Adriamycin) 25 mg/m2 IV bolus once per day on days 11 to 13
- Cisplatin (Platinol) 100 mg/m2 IV continuous infusion over 24 hours, started on day 11
Supportive therapy
- Leucovorin (Folinic acid) 12 mg/m2 IV every 6 hours x 10 doses or 15 mg/m2 PO every 6 hours x 10 doses, starting 24 hours after the start of methotrexate infusion
- Monitor methotrexate level at "24 hours and 48 hours"--it is unclear in the reference if this is time after the start/end of methotrexate, beginning of leucovorin, or something else
- Methotrexate levels higher than 100 nmol/L at 48 hours required additional leucovorin rescue
- Prehydration for methotrexate: "0.9 NaCl:D5W"--unclear if this means either normal saline or D5W can be used--750 mL/m2 over 6 hours, with KCl 20 mEq/L
- The volume of fluid for methotrexate is D5W 1000 mL, to be given over 6 hours
- Posthydration for methotrexate: Alternating liters of D5W and NS 3000 mL/m2 over 24 hours, with KCl 60 mEq/L.
- Sodium bicarbonate 3 g PO Q6H, starting 12 hours before methotrexate, and sodium bicarbonate 167 mmol/L IV until serum methotrexate level is less than 8000 to 10,000 nmol/L. Note: the reference is not clear about when/if PO sodium bicarbonate is stopped, when IV sodium bicarbonate is started, or the administration rate of IV sodium bicarbonate.
- Prehydration for cisplatin: normal saline 400 mL/m2 and D5W 400 mL/m2 IV over 2 hours--the reference did not clarify if these two solutions are given at the same time
- The volume of fluid for cisplatin continuous infusion is 2400 mL/m2 NS, with KCl 80 mEq/L and mannitol 32,000 mg/m2
- Posthydration for cisplatin: D5W 600 mL/m2 over 6 hours, with KCl 20 mEq/L and mannitol 8000 mg/m2; and NS 600 mL/m2 over 6 hours, with KCl 20 mEq/L, magnesium sulfate 2 mmol/L, and calcium gluconate 0.6 mmol/L--the reference did not clarify if these two solutions are given at the same time. Then D5W 600 mL/m2 over 12 hours, with KCl 20 mEq/L and mannitol 8000 mg/m2.
- With cisplatin, Furosemide (Lasix) 20 to 40 mg IV if urine output is less than 400 mL/m2 over 6 hours
21-day cycle for 4 cycles
References
- EOI 80831/MRC B002: Bramwell VH, Burgers MV, Souhami RL, Taminiau AH, Van Der Eijken JW, Craft AW, Malcolm AJ, Uscinska B, Kirkpatrick AL, Machin D, Van Glabbeke MM; European Osteosarcoma Intergroup. A randomized comparison of two short intensive chemotherapy regimens in children and young adults with osteosarcoma: results in patients with metastases: a study of the European Osteosarcoma Intergroup. Sarcoma. 1997;1(3-4):155-60. link to original article contains dosing details in manuscript link to PMC article PubMed
Relapsed, refractory, or metastatic, subsequent lines
Cabozantinib monotherapy
Regimen variant #1, adult dosing
Study | Dates of enrollment | Evidence |
---|---|---|
Italiano et al. 2020 (CABONE) | 2015-2018 | Phase 2 |
Regimen variant #2, pediatric dosing
Study | Dates of enrollment | Evidence |
---|---|---|
Italiano et al. 2020 (CABONE) | 2015-2018 | Phase 2 |
Note: this dosing was for children aged less than 16 years.
References
- CABONE: Italiano A, Mir O, Mathoulin-Pelissier S, Penel N, Piperno-Neumann S, Bompas E, Chevreau C, Duffaud F, Entz-Werlé N, Saada E, Ray-Coquard I, Lervat C, Gaspar N, Marec-Berard P, Pacquement H, Wright J, Toulmonde M, Bessede A, Crombe A, Kind M, Bellera C, Blay JY. Cabozantinib in patients with advanced Ewing sarcoma or osteosarcoma (CABONE): a multicentre, single-arm, phase 2 trial. Lancet Oncol. 2020 Mar;21(3):446-455. Epub 2020 Feb 17. link to original article contains dosing details in abstract link to PMC article PubMed NCT02243605
Cyclophosphamide & Etoposide
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Berger et al. 2009 | 2002-07 to 2006-09 | Phase 2 |
Chemotherapy
- Cyclophosphamide (Cytoxan) 4000 mg/m2 IV over 3 hours once on day 1
- Etoposide (Vepesid) 100 mg/m2 IV over 60 minutes twice per day on days 2 to 4 (total dose: 600 mg/m2)
Supportive therapy
- Mesna (Mesnex) 1400 mg/m2 IV three times per day on day 1, given prior to, 4 hours after, and 8 hours after cyclophosphamide
- With mesna, 3000 mL/m2 hydration
At least 21-day cycle for 2 cycles, then restaging
Subsequent treatment
- Patients with no progression received an experimental protocol with:
- Samarium-153 10 mCi/kg and/or carboplatin & etoposide based on status of bone metastases (no further details about dose/schedule given)
- Progression-free patients received reduced intensity stem cell transplant (preferably from a matched sibling donor (MSD))
- Patients with no MSD received IL-2 maintenance, 5 days a week every 2 weeks x 12 cycles (reference did not specify if a cycle was 2 weeks, 4 weeks, or another length)
References
- Berger M, Grignani G, Ferrari S, Biasin E, Brach del Prever A, Aliberti S, Saglio F, Aglietta M, Fagioli F. Phase 2 trial of two courses of cyclophosphamide and etoposide for relapsed high-risk osteosarcoma patients. Cancer. 2009 Jul 1;115(13):2980-7. link to original article contains dosing details in manuscript PubMed
Cyclophosphamide & Topotecan
Regimen
Study | Evidence |
---|---|
Saylors et al. 2001 | Phase 2 |
Chemotherapy
- Cyclophosphamide (Cytoxan) 250 mg/m2 IV over 30 minutes once per day on days 1 to 5, given first
- Topotecan (Hycamtin) 0.75 mg/m2 IV over 30 minutes once per day on days 1 to 5, given second
Supportive therapy
- 500 mL/m/2 fluids IV or PO once per day on days 1 to 5; 2 to 4 hours prior to chemotherapy
- Antiemetics once per day on days 1 to 5, prior to chemotherapy
- 3 liters/m2 fluids IV or PO over 24 hours after chemotherapy
- Filgrastim (Neupogen) 5 mcg/kg SC once per day, starting on day 6, to continue until post-nadir ANC is at least 1500/μL
21-day cycle for 12 to 14 cycles
References
- Saylors RL 3rd, Stine KC, Sullivan J, Kepner JL, Wall DA, Bernstein ML, Harris MB, Hayashi R, Vietti TJ; Pediatric Oncology Group. Cyclophosphamide plus topotecan in children with recurrent or refractory solid tumors: a Pediatric Oncology Group phase II study. J Clin Oncol. 2001 Aug 1;19(15):3463-9. link to original article contains dosing details in manuscript PubMed
Docetaxel & Gemcitabine
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Navid et al. 2008 | NR | Retrospective |
Note: 17 of the 22 patients in this retrospective review had osteosarcoma.
Chemotherapy
- Docetaxel (Taxotere) 75 to 100 mg/m2 IV over 60 minutes once on day 8, given second
- Gemcitabine (Gemzar) 675 mg/m2 IV over 90 minutes once per day on days 1 & 8, given first
Supportive therapy
- Ondansetron (Zofran) (dose/route not specified) once per day on days 1 & 8, prior to chemotherapy
- Dexamethasone (Decadron) starting either the day before or the day of docetaxel, and continued for 2 days after docetaxel
- Per physician discretion: H1 or H2 blockers such as Diphenhydramine (Benadryl) and Ranitidine (Zantac) once per day on days 1 & 8
- Some patients received Filgrastim (Neupogen) starting on day 9
21-day cycles
References
- Retrospective: Navid F, Willert JR, McCarville MB, Furman W, Watkins A, Roberts W, Daw NC. Combination of gemcitabine and docetaxel in the treatment of children and young adults with refractory bone sarcoma. Cancer. 2008 Jul 15;113(2):419-25. link to original article contains dosing details in manuscript PubMed
Gemcitabine monotherapy
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Merimsky et al. 2000 | 1996-12 to 1998-08 | Phase 2, fewer than 20 pts |
Chemotherapy
- Gemcitabine (Gemzar) as follows:
- Cycle 1: 1000 mg/m2 IV once per day on days 1, 8, 15, 22
- Cycle 2 onwards: 1000 mg/m2 IV once per day on days 1, 8, 15
28-day cycles
References
- Merimsky O, Meller I, Flusser G, Kollender Y, Issakov J, Weil-Ben-Arush M, Fenig E, Neuman G, Sapir D, Ariad S, Inbar M. Gemcitabine in soft tissue or bone sarcoma resistant to standard chemotherapy: a phase II study. Cancer Chemother Pharmacol. 2000;45(2):177-81. link to original article contains dosing details in manuscript PubMed
ICE
ICE: Ifosfamide, Carboplatin, Etoposide
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Van Winkle et al. 2005 (CCG-0894) | 1992-06 to 1994-11 | Phase 2 |
Van Winkle et al. 2005 (CCG-0924) | 1993-07 to 1995-04 | Phase 1, >20 pts |
Van Winkle et al. 2005 (CCG-0931) | 1994-05 to 1996-12 | Non-randomized, <20 pts |
Note: the reference did not mention Mesna (Mesnex) being used.
Chemotherapy
- Ifosfamide (Ifex) 1800 mg/m2 IV once per day on days 1 to 5
- Carboplatin (Paraplatin) 400 mg/m2 IV "for 2 days"
- Note: the reference did not explicitly say which 2 days carboplatin should be given on
- Etoposide (Vepesid) 100 mg/m2 IV once per day on days 1 to 5
Supportive therapy
- Depending on the study the patients were enrolled on, they received one of the following:
- CCG-0894: Filgrastim (Neupogen) 5 or 10 mcg/kg SC once per day, starting 24 hours after completing ICE, and to continue until day 18 if ANC is at least 1000/μL, or until ANC is at least 1000/μL above nadir, whichever comes later
- CCG-0924: PIXY 321 at doses of 500/750/1000 mcg/m2 SC once per day or 500 mcg/m2 SC twice per day, starting on day 5 and to continue until day 18 unless ANC reached 20,000/μL or platelet count is at least 900 x 109/L for 2 days between days 13 to 18, or until ANC is at least 1000/μL and platelet count is at least 100 x 109/L, whichever comes later
- CCG-0931: Filgrastim (Neupogen) 5 mcg/kg SC once per day and IL-6 at 2.5, 3.75, or 5 mcg/kg SC twice per day, starting 24 hours after completing ICE. Filgrastim is continued until ANC is at least 1000/μL, and IL-6 is continued until platelets are at least 100 x 109/L for 2 consecutive days or until day 35, whichever comes sooner.
21-day cycles, with next cycle starting as soon as ANC is at least 1000/μL and platelet count is at least 100 x 109/L
Subsequent treatment
- Resection of disease was allowed after 4 cycles based on patient's response to ICE
References
- CCG-0894: Van Winkle P, Angiolillo A, Krailo M, Cheung YK, Anderson B, Davenport V, Reaman G, Cairo MS; Children's Cancer Group. Ifosfamide, carboplatin, and etoposide (ICE) reinduction chemotherapy in a large cohort of children and adolescents with recurrent/refractory sarcoma: the Children's Cancer Group (CCG) experience. Pediatr Blood Cancer. 2005 Apr;44(4):338-47. link to original article contains dosing details in manuscript PubMed
- CCG-0924: Van Winkle P, Angiolillo A, Krailo M, Cheung YK, Anderson B, Davenport V, Reaman G, Cairo MS; Children's Cancer Group. Ifosfamide, carboplatin, and etoposide (ICE) reinduction chemotherapy in a large cohort of children and adolescents with recurrent/refractory sarcoma: the Children's Cancer Group (CCG) experience. Pediatr Blood Cancer. 2005 Apr;44(4):338-47. link to original article contains dosing details in manuscript PubMed
- CCG-0931: Van Winkle P, Angiolillo A, Krailo M, Cheung YK, Anderson B, Davenport V, Reaman G, Cairo MS; Children's Cancer Group. Ifosfamide, carboplatin, and etoposide (ICE) reinduction chemotherapy in a large cohort of children and adolescents with recurrent/refractory sarcoma: the Children's Cancer Group (CCG) experience. Pediatr Blood Cancer. 2005 Apr;44(4):338-47. link to original article contains dosing details in manuscript PubMed
IE
IE: Ifosfamide & Etoposide
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Gentet et al. 1997 | 1992-01 to 1995-01 | Phase 2 |
Chemotherapy
- Ifosfamide (Ifex) 3000 mg/m2 IV over 3 hours once per day on days 1 to 4
- Given in D5W 250 to 500 mL
- Etoposide (Vepesid) 75 mg/m2 IV over 60 minutes once per day on days 1 to 4
- Given in D5W 250 to 500 mL
Supportive therapy
- Mesna (Mesnex) 3600 mg/m2/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 14,400 mg/m2)
- At least 2000 mL/m2/day of hydration with chemotherapy
21- to 28-day cycle for 2 cycles; next cycle starting when ANC greater than 1500/μL and platelet count greater than 100 x 109/L
References
- Gentet JC, Brunat-Mentigny M, Demaille MC, Pein F, Avet-Loiseau H, Berger C, De Lumley L, Pacquement H, Schmitt C, Sariban E, Pillon P, Bernard JL, Kalifa C. Ifosfamide and etoposide in childhood osteosarcoma: a phase II study of the French Society of Paediatric Oncology. Eur J Cancer. 1997 Feb;33(2):232-7. link to original article contains dosing details in manuscript PubMed
Regorafenib monotherapy
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Davis et al. 2019 (SARC024) | 2014-2018 | Randomized Phase 2 (E-esc) | Placebo | Superior PFS (primary endpoint) Median PFS: 3.6 vs 1.7 mo (HR 0.42, 95% CI 0.21-0.85) |
References
- SARC024: Davis LE, Bolejack V, Ryan CW, Ganjoo KN, Loggers ET, Chawla S, Agulnik M, Livingston MB, Reed D, Keedy V, Rushing D, Okuno S, Reinke DK, Riedel RF, Attia S, Mascarenhas L, Maki RG. Randomized Double-Blind Phase II Study of Regorafenib in Patients With Metastatic Osteosarcoma. J Clin Oncol. 2019 Jun 1;37(16):1424-1431. Epub 2019 Apr 23. link to original article link to PMC article contains dosing details in manuscript PubMed NCT02048371
Samarium-153 with stem cell support
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Anderson et al. 2002 | NR | Phase 1 |
- Peripheral blood progenitor cell (PBPC) or bone marrow harvest and cryopreservation of at least 2 x 106 CD34+ cells/kg
Radiotherapy
- Samarium-153 (Quadramet) 30 mCi/kg IV once on day 0
Supportive therapy
- Autologous stem cells (peripheral blood progenitor cell (PBPC) or bone marrow cells) re-infused on day +14
- Growth factor support with ONE of the following started when ANC less than 1000/μL:
One course
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 dosing details in manuscript PubMed
Sorafenib monotherapy
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Grignani et al. 2011 | 2008-2009 | Phase 2 |
References
- Grignani G, Palmerini E, Dileo P, Asaftei SD, D'Ambrosio L, Pignochino Y, Mercuri M, Picci P, Fagioli F, Casali PG, Ferrari S, Aglietta M. A phase II trial of sorafenib in relapsed and unresectable high-grade osteosarcoma after failure of standard multimodal therapy: an Italian Sarcoma Group study. Ann Oncol. 2012 Feb;23(2):508-16. Epub 2011 Apr 28. link to original article contains dosing details in manuscript PubMed EudraCT 2007-004396-19