Osteosarcoma - historical
The purpose of this page is to provide references to regimens that are obsolete, outdated, or of historical interest only. As a general rule, this includes the inferior arm(s) of a randomized study, unless said regimens continue to be recommended by trustworthy sources such as the NCCN Guidelines. Is there a regimen missing from this list? See the main osteosarcoma page for current regimens.
8 regimens on this page
8 variants on this page
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Neoadjuvant therapy
MA-BCD
MA-BCD: High-dose Methotrexate, Adriamycin (Doxorubicin), Bleomycin, Cyclophosphamide, Dactinomycin
Protocol
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Winkler et al. 1984 (COSS-80) | 1979-1982 | Phase 3 (C) | MAP | Did not meet primary endpoint of CDF rate |
Note: The exact schedule is unclear based on limited/conflicting information in the reference. For example, Figure 1 appears to depict high-dose methotrexate starting 2 weeks after adriamycin, but the text says that methotrexate begins after a 3-week rest period. Additionally, the diagram in Figure 1 implies that the later therapies are given 4 times (once, then repeated x 3 cycles), but based on the cumulative doses listed, they are only given for a total of 3 cycles. The optional interferon arm is omitted given lack of benefit seen in the study.
Chemotherapy, part 1
- Doxorubicin (Adriamycin) 45 mg/m2 IV bolus once per day on days 1 & 2
21-day course, then
Chemotherapy, part 2
See note above about uncertainty about the exact schedule.
- Methotrexate (MTX) 12,000 mg/m2 (maximum dose of 20,000 mg) IV over 4 hours once per day on days 1 & 8
- MTX is dissolved at a concentration of 20,000 mg/L in a solution containing 5% glucose
- Bleomycin (Blenoxane) 12 mg/m2 IV bolus once per day on days 15 & 16
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV bolus once per day on days 15 & 16
- Dactinomycin (Cosmegen) 0.45 mg/m2 IV bolus once per day on days 15 & 16
Supportive therapy
- Folinic acid (Leucovorin) 15 mg/m2 PO every 6 hours x 12 hours once per day on days 2 & 9, starting 24 hours after the completion of methotrexate infusion; additional leucovorin used for delayed methotrexate elimination
- Sodium bicarbonate urine alkalinization prior to high-dose methotrexate
- Normal saline 4.5 L/m2 on day 1 after methotrexate; NS 3 L/m2 on day 2, with adjustments made to keep urine pH greater than 7.4
35-day course, followed by:
Chemotherapy, part 3
See note above about uncertainty about the exact schedule.
- Methotrexate (MTX) 12,000 mg/m2 (maximum dose of 20,000 mg) IV over 4 hours once per day on days 1, 8, 29, 36
- MTX is dissolved at a concentration of 20,000 mg/L in a solution containing 5% glucose
- Doxorubicin (Adriamycin) 45 mg/m2 IV bolus once per day on days 15 & 16 (delayed during cycle 1 until after surgery)
- Bleomycin (Blenoxane) 12 mg/m2 IV bolus once per day on days 43 & 44
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV bolus once per day on days 43 & 44
- Dactinomycin (Cosmegen) 0.45 mg/m2 IV bolus once per day on days 43 & 44
Supportive therapy
- Folinic acid (Leucovorin) 15 mg/m2 PO every 6 hours x 12 hours once per day on days 2, 9, 30, 37, starting 24 hours after the completion of methotrexate infusion; additional leucovorin used for delayed methotrexate elimination
- Sodium bicarbonate urine alkalinization prior to high-dose methotrexate
- Normal saline 4.5 L/m2 on day 1 after methotrexate; NS 3 L/m2 on day 2, with adjustments made to keep urine pH greater than 7.4
8-week cycle for 3 cycles, with surgery done during cycle 1 before doxorubicin; surgery is done 9 to 18 weeks after the start of chemotherapy
References
- 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
M-BCD
M-BCD: High-dose Methotrexate, Bleomycin, Cyclophosphamide, Dactinomycin
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Winkler et al. 1988 (COSS-82) | 1982-1984 | Phase 3 (C) | MAP | Inferior ORR |
Note: The exact schedule is unclear based on limited information in the reference, as schedule of doses is primarily extrapolated from Figure 1, which does not contain clear delineations in time.
Chemotherapy
- Methotrexate (MTX) 12,000 mg/m2 (maximum dose of 20,000 mg) IV over 4 hours once per day on days 15 & 22
- MTX is dissolved at a concentration of 20,000 mg/L in a solution containing 5% glucose
- Bleomycin (Blenoxane) 15 mg/m2 IV bolus once per day on days 1 & 2
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV bolus once per day on days 1 & 2
- Dactinomycin (Cosmegen) 0.6 mg/m2 IV bolus once per day on days 1 & 2
Supportive therapy
- Folinic acid (Leucovorin) 15 mg/m2 PO every 6 hours x 12 hours once per day on days 16 & 23, starting 24 hours after the completion of methotrexate infusion; additional leucovorin used for delayed methotrexate elimination
- Sodium bicarbonate urine alkalinization prior to high-dose methotrexate
- Normal saline 4.5 L/m2 on day 1 after methotrexate; NS 3 L/m2 on day 2, with adjustments made to keep urine pH greater than 7.4
35-day cycle for 2 cycles
References
- 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
Adjuvant therapy
Doxorubicin monotherapy
Regimen
Study | Evidence |
---|---|
Cortes et al. 1974 | Non-randomized |
Preceding treatment
Chemotherapy
- Doxorubicin (Adriamycin) 30 mg/m2 IV once per day on days 1 to 3
4- to 6-week cycle for 6 cycles
References
- Cortes EP, Holland JF, Wang JJ, Sinks LF, Blom J, Senn H, Bank A, Glidewell O. Amputation and adriamycin in primary osteosarcoma. N Engl J Med. 1974 Nov 7;291(19):998-1000. link to original article contains dosing details in abstract PubMed
IP-BCD
IP-BCD: Ifosfamide, Platinol (Cisplatin), Bleomycin, Cyclophosphamide, Dactinomycin
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Winkler et al. 1988 (COSS-82) | 1982-1984 | Non-randomized part of phase 3 RCT |
Preceding treatment
- Neoadjuvant MAP, then surgery, with poor response
Chemotherapy
- Ifosfamide (Ifex) 2000 mg/m2 IV over 23.5 hours once per day on days 1 to 5, given second, with mesna
- Cisplatin (Platinol) 20 mg/m2 IV over 30 minutes once per day on days 1 to 5, given first
- Bleomycin (Blenoxane) 15 mg/m2 IV bolus once per day on days 22 & 23
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV bolus once per day on days 22 & 23
- Dactinomycin (Cosmegen) 0.6 mg/m2 IV bolus once per day on days 22 & 23
Supportive therapy
- Mesna (Mesnex) 2000 mg/m2 IV over 23.5 hours once per day on days 1 to 5, given second, with ifosfamide, then 2000 mg/m2/day IV continuous infusion over 48 hours, started on day 6 (total dose: 14,000 mg/m2)
- Mannitol given with cisplatin; no further details provided
35-day cycle for 3 cycles
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
MA-BCD/AP
MA-BCD/AP: High-dose Methotrexate, Adriamycin (Doxorubicin), Bleomycin, Cyclophosphamide, Dactinomycin alternating with Adriamycin (Doxorubicin) & Platinol (Cisplatin)
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Link et al. 1986 | 1982-1984 | Phase 3 (E-esc) | No further treatment | Superior RFS |
Preceding treatment
References
- Link MP, Goorin AM, Miser AW, Green AA, Pratt CB, Belasco JB, Pritchard J, Malpas JS, Baker AR, Kirkpatrick JA, Ayala AG, Shuster JJ, Abelson HT, Simone JV, Vietti TJ. The effect of adjuvant chemotherapy on relapse-free survival in patients with osteosarcoma of the extremity. N Engl J Med. 1986 Jun 19;314(25):1600-6. link to original article PubMed
M-BCD
M-BCD: High-dose Methotrexate, Bleomycin, Cyclophosphamide, Dactinomycin
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Eilber et al. 1987 | 1981-1984 | Randomized (E-esc) | Observation | Seems to have superior OS |
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 references; schedule of doses is primarily extrapolated from Figure 1 of Winkler et al. 1988, which does not contain clear delineations in time.
Preceding treatment
- Neoadjuvant M-BCD, then surgery, with good response
Chemotherapy
- Methotrexate (MTX) 12,000 mg/m2 (maximum dose of 20,000 mg) IV over 4 hours once per day on days 15 & 22
- MTX is dissolved at a concentration of 20,000 mg/L in a solution containing 5% glucose
- Bleomycin (Blenoxane) 15 mg/m2 IV bolus once per day on days 1 & 2
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV bolus once per day on days 1 & 2
- Dactinomycin (Cosmegen) 0.6 mg/m2 IV bolus once per day on days 1 & 2
Supportive therapy
- Folinic acid (Leucovorin) 15 mg/m2 PO every 6 hours x 12 hours once per day on days 16 & 23, starting 24 hours after the completion of methotrexate infusion; additional leucovorin used for delayed methotrexate elimination
- Sodium bicarbonate urine alkalinization prior to high-dose methotrexate
- Normal saline 4.5 L/m2 on day 1 after methotrexate; NS 3 L/m2 on day 2, with adjustments made to keep urine pH greater than 7.4
35-day cycle for 2 cycles
References
- Eilber F, Giuliano A, Eckardt J, Patterson K, Moseley S, Goodnight J. Adjuvant chemotherapy for osteosarcoma: a randomized prospective trial. J Clin Oncol. 1987 Jan;5(1):21-6. link to original article PubMed
- Update: Bernthal NM, Federman N, Eilber FR, Nelson SD, Eckardt JJ, Eilber FC, Tap WD. Long-term results (>25 years) of a randomized, prospective clinical trial evaluating chemotherapy in patients with high-grade, operable osteosarcoma. Cancer. 2012 Dec 1;118(23):5888-93. Epub 2012 May 30. link to original article 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
Methotrexate & Vincristine
Regimen
Study | Evidence |
---|---|
Jaffe et al. 1974 | Non-randomized |
Preceding treatment
Chemotherapy
Supportive therapy
21-day cycle for up to 35 cycles (2 years)
References
- Jaffe N, Frei E 3rd, Traggis D, Bishop Y. Adjuvant methotrexate and citrovorum-factor treatment of osteogenic sarcoma. N Engl J Med. 1974 Nov 7;291(19):994-7. link to original article PubMed
Relapsed, refractory, or metastatic
Doxorubicin monotherapy
References
- Cortes EP, Holland JF, Wang JJ, Sinks LF. Doxorubicin in disseminated osteosarcoma. JAMA. 1972 Sep 4;221(10):1132-8. link to original article PubMed
MAPifn [COG AOST0331]
Note: Induction is received by all patients and consists of 2 cycles of MAP. The remainder of this protocol is for good responders.
Induction
Chemotherapy
- Cisplatin (Platinol) 60 mg/m2 IV infusion over 4 hours, started on day 1 of weeks 1 and 6
- Doxorubicin (Adriamycin) 37.5 mg/m2/day (total dose is 75 mg/m2 given as a 48 hour infusion) on days 1 to 2 of Weeks 1 and 6
- Methotrexate (MTX) 12,000 mg/m2 (maximum dose of 20,000 mg) IV over 4 hours once on day 1 of weeks 4, 5, 9, and 10.
Supportive therapy
- Folinic acid (Leucovorin) 15 mg/m2 PO or IV every 6 hours beginning 24 hours after the beginning of the methotrexate infusion and continuing until the serum methotrexate level is less than 0.1 μM.
10 Week course
Consolidation, Cycles 3-4
Chemotherapy
- Cisplatin (Platinol) 60 mg/m2 IV infusion over 4 hours, started on day 1 of weeks 12 and 17
- Doxorubicin (Adriamycin) 37.5 mg/m2/day (total dose is 75 mg/m2 given as a 48 hour infusion) on days 1 to 2 of Weeks 12 and 17.
- Methotrexate (MTX) 12,000 mg/m2 (maximum dose of 20,000 mg) IV over 4 hours once on day 1 of weeks 15, 16, 20, and 21.
Supportive therapy
- Folinic acid (Leucovorin) 15 mg/m2 PO or IV every 6 hours beginning 24 hours after the beginning of the methotrexate infusion and continuing until the serum methotrexate level is less than 0.1 μM.
10 Week course
Consolidation, Cycles 5-6
Chemotherapy
- Doxorubicin (Adriamycin) 37.5 mg/m2/day (total dose is 75 mg/m2 given as a 48 hour infusion) on days 1 to 2 of Weeks 22 and 26.
- Methotrexate (MTX) 12,000 mg/m2 (maximum dose of 20,000 mg) IV over 4 hours once on day 1 of weeks 24, 25, 28, and 29
Supportive therapy
- Folinic acid (Leucovorin) 15 mg/m2 PO or IV every 6 hours beginning 24 hours after the beginning of the methotrexate infusion and continuing until the serum methotrexate level is less than 0.1 μM.
10 Week course
Maintenance, Weeks 30-104
Immunotherapy
- Peginterferon alfa-2b (Sylatron) 0.5 mcg/kg/day (MAX DOSE = 50 mcg) subcutaneously on day 1 of Weeks 30, 31, 32, and 33.
- If well tolerated during first 4 weeks of therapy, escalate dose.
- Peginterferon alfa-2b (Sylatron) 1 mcg/kg/day (MAX DOSE = 100 mcg) subcutaneously on day 1 of Weeks 34 through 104.
75 Week course
References
- COG AOST0331: Marina NM, Smeland S, Bielack SS, Bernstein M, Jovic G, Krailo MD, Hook JM, Arndt C, Berg H, Brennan B, Brichard B, Brown KLB, Butterfass-Bahloul T, Calaminus G, Daldrup-Link HE, Eriksson M, Gebhardt MC, Gelderblom H, Gerss J, Goldsby R, Goorin A, Gorlick R, Grier H, Hale JP, Hall KS, Hardes J, Hawkins DS, Helmke K, Hogendoorn PCW, Isakoff MS, JAneway KA, Jurgens H, Kager L, Kuhne T, Lau CC, Leavey PJ, Lessnick SL, Mascarenhas L, Meyers PA, Mottl H, Nathrath M, Papai Z, Randall RL, Reichardt P, Renard M, Safwat AA, Schwartz CL, Stevens MCG, Strauss SJ, Teot L, Werner M, Sydes MR, Whelan JS. Comparison of MAPIE versus MAP in patients with a poor response to preoperative chemotherapy for newly diagnosed high-grade osteosarcoma (EURAMOS-1): an open-label, international randomized controlled trial. J Clin Oncol. 2020 Feb 20;38(6):602-612. Epub 2019 Dec 11. link to original article link to PMC article contains dosing details in manuscript PubMed Clinical Trials Registry
MAPIE [COG AOST0331]
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Marina et al. 2016 (EURAMOS-1 poor response) | 2005-2011 | Phase 3 (E-esc) | MAP | Did not meet primary endpoint of EFS |
Note: Induction is received by all patients and consists of 2 cycles of MAP; subsequent treatments in this protocol are for poor responders.
Induction
Chemotherapy
- Cisplatin (Platinol) 60 mg/m2 IV infusion over 4 hours, started on day 1 of weeks 1 and 6
- Doxorubicin (Adriamycin) 37.5 mg/m2/day (total dose is 75 mg/m2 given as a 48 hour infusion) on days 1 to 2 of Weeks 1 and 6
- Methotrexate (MTX) 12,000 mg/m2 (maximum dose of 20,000 mg) IV over 4 hours once on day 1 of weeks 4, 5, 9, and 10.
Supportive therapy
- Folinic acid (Leucovorin) 15 mg/m2 PO or IV every 6 hours beginning 24 hours after the beginning of the methotrexate infusion and continuing until the serum methotrexate level is less than 0.1 μM.
10 Week course
Consolidation, MAPIE Cycles 3 and 7
Chemotherapy
- Cisplatin (Platinol) 60 mg/m2 IV infusion over 4 hours, started on day 1 of weeks 12 and 28
- Doxorubicin (Adriamycin) 37.5 mg/m2/day (total dose is 75 mg/m2 given as a 48 hour infusion) on days 1 to 2 of Weeks 12 and 28.
- Methotrexate (MTX) 12,000 mg/m2 (maximum dose of 20,000 mg) IV over 4 hours once on day 1 of weeks 15 and 31.
Supportive therapy
- Folinic acid (Leucovorin) 15 mg/m2 PO or IV every 6 hours beginning 24 hours after the beginning of the methotrexate infusion and continuing until the serum methotrexate level is less than 0.1 μM.
5-Week Courses
Consolidation, MAP Cycles 4, 6, and 8
Chemotherapy
- Ifosfamide (Ifex) 2.8 g/m2/dose IV over 4 hours once per day on days 1 through 5 of weeks 16, 24, and 32.
- Etoposide (Vepesid) 100 mg/m2/dose IV over 60 minutes once per day on days 1 through 5 of weeks 16, 24, and 32.
- Methotrexate (MTX) 12,000 mg/m2 (maximum dose of 20,000 mg) IV over 4 hours once on day 1 of weeks 19, 27, and 35.
Supportive therapy
- Mesna (Mesnex) 2.8 g/m2/24 hours IV continuous infusion over 24 hours on days 1 through 5 of weeks 16, 24, and 32.
- Folinic acid (Leucovorin) 15 mg/m2 PO or IV every 6 hours beginning 24 hours after the beginning of the methotrexate infusion and continuing until the serum methotrexate level is less than 0.1 μM.
5-Week Courses
Consolidation, MAP Cycle 5
Chemotherapy
- Doxorubicin (Adriamycin) 37.5 mg/m2/day (total dose is 75 mg/m2 given as a 48 hour infusion) on days 1 to 2 of Week 20.
- Ifosfamide (Ifex) 3 g/m2/dose IV over 4 hours once per day on days 1, 2, and 3 of weeks 20.
- Methotrexate (MTX) 12,000 mg/m2 (maximum dose of 20,000 mg) IV over 4 hours once on day 1 of weeks 23.
Supportive therapy
- Mesna (Mesnex) 3 g/m2/24 hours IV continuous infusion over 24 hours on days 1, 2, and 3 of weeks 20.
- Folinic acid (Leucovorin) 15 mg/m2 PO or IV every 6 hours beginning 24 hours after the beginning of the methotrexate infusion and continuing until the serum methotrexate level is less than 0.1 μM.
5-Week Courses
Consolidation, MAP Cycle 9
Chemotherapy
- Doxorubicin (Adriamycin) 37.5 mg/m2/day (total dose is 75 mg/m2 given as a 48 hour infusion) on days 1 to 2 of Week 36.
- Ifosfamide (Ifex) 3 g/m2/dose IV over 4 hours once per day on days 1, 2, and 3 of weeks 36.
- Methotrexate (MTX) 12,000 mg/m2 (maximum dose of 20,000 mg) IV over 4 hours once on day 1 of weeks 39 and 40.
Supportive therapy
- Mesna (Mesnex) 3 g/m2/24 hours IV continuous infusion over 24 hours on days 1, 2, and 3 of weeks 36.
- Folinic acid (Leucovorin) 15 mg/m2 PO or IV every 6 hours beginning 24 hours after the beginning of the methotrexate infusion and continuing until the serum methotrexate level is less than 0.1 μM.
5-Week Courses
References
- EURAMOS-1 poor response: Marina NM, Smeland S, Bielack SS, Bernstein M, Jovic G, Krailo MD, Hook JM, Arndt C, Berg H, Brennan B, Brichard B, Brown KLB, Butterfass-Bahloul T, Calaminus G, Daldrup-Link HE, Eriksson M, Gebhardt MC, Gelderblom H, Gerss J, Goldsby R, Goorin A, Gorlick R, Grier H, Hale JP, Hall KS, Hardes J, Hawkins DS, Helmke K, Hogendoorn PCW, Isakoff MS, JAneway KA, Jurgens H, Kager L, Kuhne T, Lau CC, Leavey PJ, Lessnick SL, Mascarenhas L, Meyers PA, Mottl H, Nathrath M, Papai Z, Randall RL, Reichardt P, Renard M, Safwat AA, Schwartz CL, Stevens MCG, Strauss SJ, Teot L, Werner M, Sydes MR, Whelan JS. Comparison of MAPIE versus MAP in patients with a poor response to preoperative chemotherapy for newly diagnosed high-grade osteosarcoma (EURAMOS-1): an open-label, international randomized controlled trial. J Clin Oncol. 2020 Feb 20;38(6):602-612. Epub 2019 Dec 11. link to original article link to PMC article contains dosing details in manuscript PubMed Clinical Trials Registry