Bone sarcoma

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Chondrosarcoma

Ewing's sarcoma

Cyclophosphamide & Topotecan

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Regimen #1, Saylors et al. 2001

Level of Evidence: Phase II

The NCCN, Bone Cancer version 2.2012, also says that Vincristine (Oncovin) can be added to this regimen. No primary reference for this is available.

21-day cycles x 12 to 14 cycles

Supportive medications:

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

Regimen #2, Hunold et al. 2006

Level of Evidence: Phase II

The NCCN, Bone Cancer version 2.2012, also says that Vincristine (Oncovin) can be added to this regimen. No primary reference for this is available.

21-day cycles x 12 to 14 cycles

Supportive medications:

Local therapy:

  • Surgical removal of tumors is done when possible.
  • Radiation therapy for all other lesions.

References

  1. Saylors RL 3rd, Stine KC, Sullivan J, Kepner JL, Wall DA, Bernstein ML, Harris MB, Hayashi R, Vietti TJ; Pediatric Oncology Group. Cyclophosphamide plus topotecan in children with recurrent or refractory solid tumors: a Pediatric Oncology Group phase II study. J Clin Oncol. 2001 Aug 1;19(15):3463-9. link to original article contains verified protocol PubMed
  2. Hunold A, Weddeling N, Paulussen M, Ranft A, Liebscher C, Jürgens H. Topotecan and cyclophosphamide in patients with refractory or relapsed Ewing tumors. Pediatr Blood Cancer. 2006 Nov;47(6):795-800. link to original article contains verified protocol PubMed

Cyclophosphamide & Topotecan - high dose

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Regimen

Level of Evidence: Non-randomized

The NCCN, Bone Cancer version 2.2012, also says that Vincristine (Oncovin) can be added to this regimen. No primary reference for this is available.

  • Cyclophosphamide (Cytoxan) 2100 mg/m2/day (4200 mg/m2 total dose) IV continuous 24-hour infusion on days 1 & 2; infusion starts second after mesna has started
    • Children 10 years or younger received Cyclophosphamide (Cytoxan) 70 mg/kg/day (140 mg/kg total dose) IV continuous 24-hour infusion on days 1 & 2
    • Cyclophosphamide is given in D5NS with 10 mEq potassium chloride (KCl) and 5 mg Furosemide (Lasix) per 500 mL fluid. 500 mL total volume is used for patients with body surface area <1 m2; 1000 mL total volume is used for patients with BSA of at least 1 m2
  • Mesna (Mesnex) 2100 mg/m2/day (6300 mg/m2 total dose) IV continuous 24-hour infusion on days 1 to 3; infusion starts first
    • Children 10 years or younger received Mesna (Mesnex) 70 mg/kg/day (210 mg/kg total dose) IV continuous 24-hour infusion on days 1 to 3
      • If body surface area <1 m2, mesna is given in 500 mL NS over 24 hours
      • If body surface area is at least 1 m2, mesna is given in 1000 mL NS over 24 hours
  • Topotecan (Hycamtin) 2 mg/m2/day (6 mg/m2 total dose) IV continuous 24-hour infusion on days 1 to 3; suspended in D5W; infusion starts third after mesna and cyclophosphamide have started

subsequent cycles to start when ANC >1000 and platelets >75,000

Supportive medications:

  • On day 1, prior to chemotherapy, 20 mL/kg normal saline IV bolus over 30 minutes, then D5 1/2 NS with 15 mEq KCl per 500 mL at 200 mL/m2/H until urine specific gravity <1.010, then start mesna & cyclophosphamide
  • Additional hydration fluid on days 1 & 2 so that, when added to volumes of cyclophosphamide, mesna, and topotecan, total volume of fluids is 3000 mL/m2/24 hours
  • Additional hydration fluid on day 3 at 150 mL/m2/hour for 6-12 hours after completion of cyclophosphamide infusion
  • Filgrastim (Neupogen) 5 mcg/kg SC daily starting one day after completion of chemotherapy, to continue until ANC is at least 1000

References

  1. Kushner BH, Kramer K, Meyers PA, Wollner N, Cheung NK. Pilot study of topotecan and high-dose cyclophosphamide for resistant pediatric solid tumors. Med Pediatr Oncol. 2000 Nov;35(5):468-74. link to original article contains verified protocol PubMed

Docetaxel & Gemcitabine

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Regimen

Level of Evidence: Retrospective

The NCCN, Bone Cancer version 2.2012, also says that Vincristine (Oncovin) can be added to this regimen. No primary reference for this is available.
Only 2 of the 22 patients in this retrospective review had Ewing sarcoma.

21-day cycles

Supportive medications:

  • Ondansetron (Zofran) prior to chemotherapy on days 1 & 8
  • Dexamethasone (Decadron) starting either the day before or the day of docetaxel, and continued for 2 days after docetaxel
  • H1 or H2 blockers such as Diphenhydramine (Benadryl) and Ranitidine (Zantac) prior to chemotherapy on days 1 & 8 per physician discretion
  • Some patients received Filgrastim (Neupogen) starting on day 9

References

  1. Navid F, Willert JR, McCarville MB, Furman W, Watkins A, Roberts W, Daw NC. Combination of gemcitabine and docetaxel in the treatment of children and young adults with refractory bone sarcoma. Cancer. 2008 Jul 15;113(2):419-25. link to original article contains verified protocol PubMed

EVAIA

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EVAIA: Etoposide, Vincristine, Adriamycin (Doxorubicin), Ifosfamide, DActinomycin

Regimen

Study Evidence Comparator
Paulussen et al. 2008 (EICESS-92) Phase III VAIA

This regimen is intended for high-risk patients.

Initial therapy

21-day cycle x 4 cycles, then proceed to local therapy:

Local therapy

  • Surgical removal of tumors is done when possible.
  • For patients not undergoing surgery, with incomplete surgical resection, or poor histologic response, 54.4 Gy of radiation is administered
  • For patients with a good histologic response, 44.8 Gy of radiation is administered
  • Additional details about particular clinical scenarios can be found in the original reference

Chemotherapy after local therapy

  • 10 additional cycles of EVAIA as described above

References

  1. Paulussen M, Craft AW, Lewis I, Hackshaw A, Douglas C, Dunst J, Schuck A, Winkelmann W, Köhler G, Poremba C, Zoubek A, Ladenstein R, van den Berg H, Hunold A, Cassoni A, Spooner D, Grimer R, Whelan J, McTiernan A, Jürgens H; European Intergroup Cooperative Ewing's Sarcoma Study-92. Results of the EICESS-92 Study: two randomized trials of Ewing's sarcoma treatment--cyclophosphamide compared with ifosfamide in standard-risk patients and assessment of benefit of etoposide added to standard treatment in high-risk patients. J Clin Oncol. 2008 Sep 20;26(27):4385-93. link to original article contains verified protocol PubMed

ICE - Ifosfamide, Carboplatin, Etoposide

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ICE: Ifosfamide, Carboplatin, Etoposide

Regimen

Level of Evidence: Phase II

The NCCN, Bone Cancer version 2.2012, also says that Vincristine (Oncovin) can be added to this regimen. No primary reference for this is available.
The reference did not mention Mesna (Mesnex) being used.

  • Ifosfamide (Ifex) 1800 mg/m2 IV once per day on days 1 to 5
  • Carboplatin (Paraplatin) 400 mg/m2 IV "for 2 days"--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
  • Resection of disease was allowed after 4 cycles based on patient's response to ICE

21-day cycles, with next cycle starting as soon as ANC is at least 1000 and platelet count is at least 100,000

Supportive medications:

  • Depending on the study the patients were enrolled on, they received one of the following:
    • CCG-0894: Filgrastim (Neupogen) 5 or 10 mcg/kg/day SC daily, starting 24 hours after completing ICE, and to continue until day 18 if ANC is at least 1000, or until ANC is at least 1000 post nadir, whichever comes later
    • CCG-0924: PIXY 321 at doses of 500/750/1000 mcg/m2 daily or 500 mcg/m2 BID SQ, starting on day 5 and to continue until day 18 unless ANC reached 20,000 or platelet count is at least 900,000 for 2 days between days 13-18, or until ANC is at least 1000 and platelet count is at least 100,000, whichever comes later
    • CCG-0931: Filgrastim (Neupogen) 5 mcg/kg/day SC daily and IL-6 at 2.5, 3.75, or 5.0 mcg/kg SC BID, starting 24 hours after completing ICE. Filgrastim is continued until ANC is at least 1000, and IL-6 is continued until platelets are at least 100,000 for 2 consecutive days or until day 35, whichever comes sooner.

References

  1. Van Winkle P, Angiolillo A, Krailo M, Cheung YK, Anderson B, Davenport V, Reaman G, Cairo MS. Ifosfamide, carboplatin, and etoposide (ICE) reinduction chemotherapy in a large cohort of children and adolescents with recurrent/refractory sarcoma: the Children's Cancer Group (CCG) experience. Pediatr Blood Cancer. 2005 Apr;44(4):338-47. link to original article contains verified protocol PubMed

IE - Ifosfamide & Etoposide

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IE: Ifosfamide, Etoposide

Regimen

Level of Evidence: Phase II

The NCCN, Bone Cancer version 2.2012, also says that Vincristine (Oncovin) can be added to this regimen. No primary reference for this is available.

  • Ifosfamide (Ifex) 1800 mg/m2 IV once per day on days 1 to 5, given second, together with loading dose of mesna
  • Mesna (Mesnex) 2880 mg/m2 total dose on days 1 to 5, given second with irinotecan as follows
    • Mesna 360 mg/m2 IV loading dose over 1 hour
    • Then Mesna 120 mg/m2/hour IV continuous infusion x 3 hours
    • Then Mesna 360 mg/m2 over 15 minutes Q3hours (given at hours 5, 8, 11, 14, 17, 20) x 6 doses; doses after hour 5 can be given PO or IV
  • Etoposide (Vepesid) 100 mg/m2 IV over 1 hour on days 1 to 5, given first
  • For patients responding to therapy after 4 cycles, local therapy with surgery or radiation is used to try to achieve a complete remission
    • Radiation therapy consisted of 1.8 Gy fractions given for a total dose of 50-55 Gy

21-day cycles x 12 cycles

References

  1. Miser JS, Kinsella TJ, Triche TJ, Tsokos M, Jarosinski P, Forquer R, Wesley R, Magrath I. Ifosfamide with mesna uroprotection and etoposide: an effective regimen in the treatment of recurrent sarcomas and other tumors of children and young adults. J Clin Oncol. 1987 Aug;5(8):1191-8. link to original article contains verified protocol PubMed

TC -> IE, VDoxoC, VEC - POG 9457

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TC -> IE, VDoxoC, VEC: Topotecan, Cyclophosphamide -> Ifosfamide, Etoposide; Vincristine, Doxorubicin, Cyclophosphamide; Vincristine, Etoposide, Cyclophosphamide
POG: Pediatric Oncology Group

Regimen

Level of Evidence: Phase II

This is a complex regimen, and it is suggested to refer to the primary reference and figure 1 for the protocol schema. One arm of patients in this trial received Amifostine (Ethyol), but its usage is not described below since it did not result in improved outcomes.
Optional initial window for stable patients without significantly impaired function or life-threatening disease:

Supportive medications:

  • Filgrastim (Neupogen) 5 mcg/kg SC daily starting on day 6, to continue until ANC is at least 5000 after nadir

5-day course

TC upfront window (starts at week 0):

Supportive medications:

  • Prehydration with 500 mL/m2 D5 1/4 NS
  • 1500 mL/m2 PO/IV hydration continuous for 24 hours after chemotherapy
  • Filgrastim (Neupogen) 5 mcg/kg SC daily starting on day 6, to continue until ANC is at least 5000 after nadir

21-day cycles x up to 2 cycles--patients with progression after the first cycle moved immediately to induction therapy

High-dose induction therapy (starts at week 6):
IE for cycles 1, 3, 5 (starts at week 6):

  • Ifosfamide (Ifex) 3600 mg/m2 IV over 2 hours on days 1 to 5, given second, after etoposide; administered in 200 mL/m2 D5 1/2 NS
  • Mesna (Mesnex) 4000 mg/m2 IV once per day on days 1 to 5
  • Etoposide (Vepesid) 100 mg/m2 IV over 45 minutes on days 1 to 5, given first, before ifosfamide; administered in 250 mL/m2 of D5 1/2 NS

Supportive medications:

  • "Vigorous hydration," antiemetics
  • Filgrastim (Neupogen) 5 mcg/kg SC daily starting 24-48 hours after completion of chemotherapy

21-day cycles x a total of 3 cycles of IE, alternating with VDoxoC

VDoxoC for cycles 2 & 4 (starts at week 9):

  • Vincristine (Oncovin) 2 mg/m2 (maximum dose per cycle is 2mg) IV bolus on days 1, 8, 15, given first, prior to cyclophosphamide
  • Doxorubicin (Adriamycin) 37.5 mg/m2/day (75 mg/m2 total dose) IV continuous 24-hour infusion on days 1 & 2, given third; administered in 2400 mL/m2/day (4800 mL/m2 total volume) of D5 1/2 NS
  • Cyclophosphamide (Cytoxan) 2100 mg/m2/day (4200 mg/m2 total dose) IV over 30 minutes on days 1 & 2, given second after vincristine; administered in 200 mL/m2 D5 1/2 NS
  • Mesna (Mesnex) 2400 mg/m2 total dose IV; exact schedule not specified by reference

Supportive medications:

21-day cycles x a total of 2 cycles of VDoxoC, alternating with IE

Local therapy for primary disease and ongoing chemotherapy (starts at week 21):
VDoxoC:

Supportive medications:

21-day cycle x 1 cycle, followed by local control

Local control (after week 21):

  • Choice of modality between surgical and radiation therapy options is at the discretion of the provider
  • Patients treated with radiation along received 45 Gy in 1.8 Gy fractions to the initial tumor volume; additional treatment up to a total of 55.8 Gy was administered to original bony tumors and the postinduction chemotherapy soft tissue volumes plus a 2 cm margin
  • See primary reference for details about radiation therapy in a variety of clinical scenarios

Further VEC chemotherapy after local control (starts at "week 24," but depending on what local therapy precedes it, may be at a different point in the schedule):

Supportive medications:

21-day cycles x 2 cycles

Continuation therapy (starts at week 30):
IE:

Supportive medications:

21-day cycle x 1 cycle

VDoxoC:

Supportive medications:

21-day cycle x 1 cycle

IE:

Supportive medications:

21-day cycle x 1 cycle

Local therapy for metastatic disease and ongoing chemotherapy (starts at week 39):
VDoxoC (starts at week 39):

  • Vincristine (Oncovin) 2 mg/m2 (maximum dose per cycle is 2mg) IV once per day on days 1 & 8; note: the day 8 dose is not described in the text but is described in figure 1
  • Doxorubicin (Adriamycin) 37.5 mg/m2/day (75 mg/m2 total dose) IV continuous 24-hour infusion on days 1 & 2
  • Cyclophosphamide (Cytoxan) 2100 mg/m2/day (4200 mg/m2 total dose) IV once per day on days 1 & 2
  • Mesna (Mesnex) dosage & schedule not specified by reference

Supportive medications:

21-day cycle x 1 cycle, then local control of metastatic disease

Local control of metastatic disease (after week 39):

  • Choice of modality between surgical and radiation therapy options is at the discretion of the provider
  • Radiation therapy could be used to treat up to three sites of metastatic disease
  • See primary reference for details about radiation therapy in a variety of clinical scenarios

Further VEC chemotherapy after local control (starts at "week 42," but depending on what local therapy precedes it, may be at a different point in the schedule):

Supportive medications:

21-day cycles x 2 cycles

References

  1. Bernstein ML, Devidas M, Lafreniere D, Souid AK, Meyers PA, Gebhardt M, Stine K, Nicholas R, Perlman EJ, Dubowy R, Wainer IW, Dickman PS, Link MP, Goorin A, Grier HE; Pediatric Oncology Group; Children's Cancer Group Phase II Study 9457; Children's Oncology Group. Intensive therapy with growth factor support for patients with Ewing tumor metastatic at diagnosis: Pediatric Oncology Group/Children's Cancer Group Phase II Study 9457--a report from the Children's Oncology Group. J Clin Oncol. 2006 Jan 1;24(1):152-9. link to original article contains verified protocol PubMed

Temozolomide & Irinotecan

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Regimen #1, Casey, et al., 2009

Level of Evidence: Retrospective

The NCCN, Bone Cancer version 2.2012, also says that Vincristine (Oncovin) can be added to this regimen. No primary reference for this is available.

21-day cycles, given until progression of disease or unacceptable toxicity

Supportive medications:

  • Cefixime (Suprax) prophylaxis starting 1 to 2 days prior to irinotecan, continuing until the completion of each cycle
  • Activated charcoal, with 5x the dose in mg of the irinotecan dose, maximum of 260 mg PO TID during irinotecan therapy
  • Loperamide (Imodium) prn diarrhea
  • Patient "advised to maintain hydration"

Regimen #2, Wagner, et al., 2004 & Wagner, et al., 2007

Level of Evidence: Pilot, <20 patients reported

The NCCN, Bone Cancer version 2.2012, also says that Vincristine (Oncovin) can be added to this regimen. No primary reference for this is available.

28-day cycles

Supportive medications:

  • Loperamide (Imodium) prn diarrhea

References

  1. Wagner LM, Crews KR, Iacono LC, Houghton PJ, Fuller CE, McCarville MB, Goldsby RE, Albritton K, Stewart CF, Santana VM. Phase I trial of temozolomide and protracted irinotecan in pediatric patients with refractory solid tumors. Clin Cancer Res. 2004 Feb 1;10(3):840-8. link to original article contains verified protocol PubMed
  2. Wagner LM, McAllister N, Goldsby RE, Rausen AR, McNall-Knapp RY, McCarville MB, Albritton K. Temozolomide and intravenous irinotecan for treatment of advanced Ewing sarcoma. Pediatr Blood Cancer. 2007 Feb;48(2):132-9. link to original article PubMed
  3. Casey DA, Wexler LH, Merchant MS, Chou AJ, Merola PR, Price AP, Meyers PA. Irinotecan and temozolomide for Ewing sarcoma: the Memorial Sloan-Kettering experience. Pediatr Blood Cancer. 2009 Dec;53(6):1029-34. link to original article contains verified protocol PubMed

VAC, CVD

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VAC: Vincristine, Adriamycin, Cyclophosphamide
CVD: Cyclophosphamide, Vincristine, Doxorubicin or Dactinomycin

Regimen

21-day cycles x 3 cycles, then local therapy

Local therapy:

  • Surgical removal of tumors is done when possible.
  • Radiation therapy to all metastatic sites of disease in addition to any radiation planned for primary tumor.
  • If only radiation therapy is used, 4500 cGy of radiation is administered to the tumor volume plus a 3 cm margin, followed by 1080 cGy to only the preradiation tumor volume, for a total dose of 5580 cGy
  • Residual tumor after surgery and lung metastases are treated with "dose-volume guidelines for gross residual disease"

After local therapy is complete, 2 more cycles of VAC as above are given, for a total of 5 cycles. This is then followed by:

21-day cycles x 12 additional cycles

References

  1. Miser JS, Krailo MD, Tarbell NJ, Link MP, Fryer CJ, Pritchard DJ, Gebhardt MC, Dickman PS, Perlman EJ, Meyers PA, Donaldson SS, Moore S, Rausen AR, Vietti TJ, Grier HE. Treatment of metastatic Ewing's sarcoma or primitive neuroectodermal tumor of bone: evaluation of combination ifosfamide and etoposide--a Children's Cancer Group and Pediatric Oncology Group study. J Clin Oncol. 2004 Jul 15;22(14):2873-6. link to original article contains verified protocol PubMed

VACA

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VACA: Vincristine, Adriamycin, Cyclophosphamide, DActinomycin

Regimen #1, Paulussen et al. 2001

Level of Evidence: Phase III

9-week cycles x 1 initial cycle, then proceed to local therapy

Local therapy:

  • Complete surgical removal of tumors is done when possible.
  • Patients not undergoing surgery receive 60 Gy radiation to the tumor bulk, with the tumor-bearing compartment receiving at least 44.8 Gy
  • Patients with incomplete surgical resection or poor histologic response received 44.8 Gy of radiation

Chemotherapy after local therapy for high risk patients involves 3 additional cycles of VACA as described above.

Regimen #2, Paulussen et al. 2008

Level of Evidence: Phase III

In Paulussen et al. 2008, this regimen was only part of a larger treatment scheme. See how this is incorporated with VAIA below.

21-day cycles x 10 cycles

References

  1. Paulussen M, Ahrens S, Dunst J, Winkelmann W, Exner GU, Kotz R, Amann G, Dockhorn-Dworniczak B, Harms D, Müller-Weihrich S, Welte K, Kornhuber B, Janka-Schaub G, Göbel U, Treuner J, Voûte PA, Zoubek A, Gadner H, Jürgens H. Localized Ewing tumor of bone: final results of the cooperative Ewing's Sarcoma Study CESS 86. J Clin Oncol. 2001 Mar 15;19(6):1818-29. link to original article contains verified protocol PubMed
  2. Grier HE, Krailo MD, Tarbell NJ, Link MP, Fryer CJ, Pritchard DJ, Gebhardt MC, Dickman PS, Perlman EJ, Meyers PA, Donaldson SS, Moore S, Rausen AR, Vietti TJ, Miser JS. Addition of ifosfamide and etoposide to standard chemotherapy for Ewing's sarcoma and primitive neuroectodermal tumor of bone. N Engl J Med. 2003 Feb 20;348(8):694-701. link to original article contains verified protocol PubMed
  3. Miser JS, Krailo MD, Tarbell NJ, Link MP, Fryer CJ, Pritchard DJ, Gebhardt MC, Dickman PS, Perlman EJ, Meyers PA, Donaldson SS, Moore S, Rausen AR, Vietti TJ, Grier HE. Treatment of metastatic Ewing's sarcoma or primitive neuroectodermal tumor of bone: evaluation of combination ifosfamide and etoposide--a Children's Cancer Group and Pediatric Oncology Group study. J Clin Oncol. 2004 Jul 15;22(14):2873-6. link to original article contains verified protocol PubMed
  4. Paulussen M, Craft AW, Lewis I, Hackshaw A, Douglas C, Dunst J, Schuck A, Winkelmann W, Köhler G, Poremba C, Zoubek A, Ladenstein R, van den Berg H, Hunold A, Cassoni A, Spooner D, Grimer R, Whelan J, McTiernan A, Jürgens H; European Intergroup Cooperative Ewing's Sarcoma Study-92. Results of the EICESS-92 Study: two randomized trials of Ewing's sarcoma treatment--cyclophosphamide compared with ifosfamide in standard-risk patients and assessment of benefit of etoposide added to standard treatment in high-risk patients. J Clin Oncol. 2008 Sep 20;26(27):4385-93. link to original article contains verified protocol PubMed

VAC/IE

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VAC/IE: Vincristine, Adriamycin, Cyclophosphamide, alternating with Ifosfamide, Etoposide

Regimen #1, Grier et al. 2003

Level of Evidence: Phase III

VAC:

21-day cycles, alternating with IE, for up to 17 total cycles of chemotherapy

IE:

21-day cycles, alternating with VAC, for up to 17 total cycles of chemotherapy

Local control of disease:
Starting on week 12. Local control plan can include radiation therapy, surgery, or both depending on physician judgement.

  • Surgery can be performed for resectable tumors. No radiation therapy is given for completely resected primary tumors with negative margins.
    • For residual tumor after surgery, 4500 cGy radiation is administered to the original tumor volume plus a 1 cm margin
  • If only radiation therapy is used, 4500 cGy of radiation is administered to the tumor volume plus a 3 cm margin, followed by 1080 cGy to only the preradiation tumor volume, for a total dose of 5580 cGy

Regimen #2, Miser et al. 2004

Level of Evidence: Phase III

VAC:

21-day cycles, alternating with IE, for up to 17 total cycles of chemotherapy

IE:

21-day cycles, alternating with VAC, for up to 17 total cycles of chemotherapy

Local therapy:
Starting on week 9.

  • Surgical removal of tumors is done when possible.
  • Radiation therapy to all metastatic sites of disease in addition to any radiation planned for primary tumor.
  • If only radiation therapy is used, 4500 cGy of radiation is administered to the tumor volume plus a 3 cm margin, followed by 1080 cGy to only the preradiation tumor volume, for a total dose of 5580 cGy
  • Residual tumor after surgery and lung metastases are treated with "dose-volume guidelines for gross residual disease"

References

  1. Grier HE, Krailo MD, Tarbell NJ, Link MP, Fryer CJ, Pritchard DJ, Gebhardt MC, Dickman PS, Perlman EJ, Meyers PA, Donaldson SS, Moore S, Rausen AR, Vietti TJ, Miser JS. Addition of ifosfamide and etoposide to standard chemotherapy for Ewing's sarcoma and primitive neuroectodermal tumor of bone. N Engl J Med. 2003 Feb 20;348(8):694-701. link to original article contains verified protocol PubMed
  2. Miser JS, Krailo MD, Tarbell NJ, Link MP, Fryer CJ, Pritchard DJ, Gebhardt MC, Dickman PS, Perlman EJ, Meyers PA, Donaldson SS, Moore S, Rausen AR, Vietti TJ, Grier HE. Treatment of metastatic Ewing's sarcoma or primitive neuroectodermal tumor of bone: evaluation of combination ifosfamide and etoposide--a Children's Cancer Group and Pediatric Oncology Group study. J Clin Oncol. 2004 Jul 15;22(14):2873-6. link to original article contains verified protocol PubMed

VAIA (VAI)

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VAIA: Vincristine, Adriamycin, Ifosfamide, DActinomycin
VAI: Vincristine, Adriamycin, Ifosfamide

Regimen #1, Paulussen et al. 2008

Level of Evidence: Phase III

Initial therapy:

21-day cycles x 4 initial cycles, then proceed to local therapy

Local therapy:

  • Surgical removal of tumors is done when possible.
  • For patients not undergoing surgery, with incomplete surgical resection, or poor histologic response, 54.4 Gy of radiation is administered
  • For patients with a good histologic response, 44.8 Gy of radiation is administered
  • Additional details about particular clinical scenarios can be found in the original reference

Chemotherapy after local therapy for high risk patients involves 10 additional cycles of VAIA as described above. Standard risk patients receive:

  • 10 cycles of VAIA as described above
  • OR 10 cycles of VACA:

VACA: Vincristine, Adriamycin, Cyclophosphamide, DActinomycin

21-day cycles x 10 cycles

Regimen #2, Paulussen et al. 2001

Level of Evidence: Phase III

9-week cycles x 1 initial cycle, then proceed to local therapy

Local therapy:

  • Complete surgical removal of tumors is done when possible.
  • Patients not undergoing surgery receive 60 Gy radiation to the tumor bulk, with the tumor-bearing compartment receiving at least 44.8 Gy
  • Patients with incomplete surgical resection or poor histologic response received 44.8 Gy of radiation

Chemotherapy after local therapy for high risk patients involves 3 additional cycles of VAIA as described above.

References

  1. Paulussen M, Ahrens S, Dunst J, Winkelmann W, Exner GU, Kotz R, Amann G, Dockhorn-Dworniczak B, Harms D, Müller-Weihrich S, Welte K, Kornhuber B, Janka-Schaub G, Göbel U, Treuner J, Voûte PA, Zoubek A, Gadner H, Jürgens H. Localized Ewing tumor of bone: final results of the cooperative Ewing's Sarcoma Study CESS 86. J Clin Oncol. 2001 Mar 15;19(6):1818-29. link to original article contains verified protocol PubMed
  2. Paulussen M, Craft AW, Lewis I, Hackshaw A, Douglas C, Dunst J, Schuck A, Winkelmann W, Köhler G, Poremba C, Zoubek A, Ladenstein R, van den Berg H, Hunold A, Cassoni A, Spooner D, Grimer R, Whelan J, McTiernan A, Jürgens H; European Intergroup Cooperative Ewing's Sarcoma Study-92. Results of the EICESS-92 Study: two randomized trials of Ewing's sarcoma treatment--cyclophosphamide compared with ifosfamide in standard-risk patients and assessment of benefit of etoposide added to standard treatment in high-risk patients. J Clin Oncol. 2008 Sep 20;26(27):4385-93. link to original article contains verified protocol PubMed

VIDE

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VIDE: Vincristine, Ifosfamide, Doxorubicin, Etoposide

Regimen

Level of Evidence: Phase II

21-day cycles x 6 initial cycles

Supportive medications:

  • 2 to 3 liters/m2 hydration per day
  • Recommended, but not required: Filgrastim (Neupogen) 5 mcg/kg SC daily x 10 days, starting 24 hours after completion of chemotherapy
  • Further therapy is dictated by patient characteristics & response; details can be found in the primary reference

References

  1. Juergens C, Weston C, Lewis I, Whelan J, Paulussen M, Oberlin O, Michon J, Zoubek A, Juergens H, Craft A. Safety assessment of intensive induction with vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) in the treatment of Ewing tumors in the EURO-E.W.I.N.G. 99 clinical trial. Pediatr Blood Cancer. 2006 Jul;47(1):22-9. link to original article contains verified protocol PubMed

VIDE -> VAI +/- HD SCT

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VIDE: Vincristine, Ifosfamide, Doxorubicin, Etoposide
VAI: Vincristine, DActinomycin, Ifosfamide
HD SCT: High Dose chemotherapy with busulphan and melphalan and Stem Cell Transplant

Regimen

Level of Evidence: Phase II

Initial therapy:

21-day cycles x up to 6 initial cycles

Local therapy:

  • Complete surgical removal of tumors is done when possible.
  • Patients not undergoing surgery receive radiation therapy (dosage/schedule not specified) concurrent with consolidation chemotherapy with VAI per the scenarios below.

Patients who presented with localized disease received consolidation with VAI:

21-day cycles x up to 8 cycles

Patients who presented with metastatic disease received one or more cycles of VAI as described above, but were also considered for high-dose chemotherapy and peripheral blood stem cell support after VAI:

  • Busulfan (Myleran) 150 mg/m2 IV once per day on days -6 to -3
  • Melphalan (Alkeran) 140 mg/m2 IV on day 2
  • Peripheral blood stem cell rescue on day 0, using at least 2 x 10^6 CD34+ cells/kg
  • Radiation therapy given 2 months after recovery from high-dose treatment

References

  1. Strauss SJ, McTiernan A, Driver D, Hall-Craggs M, Sandison A, Cassoni AM, Kilby A, Michelagnoli M, Pringle J, Cobb J, Briggs T, Cannon S, Witt J, Whelan JS. Single center experience of a new intensive induction therapy for ewing's family of tumors: feasibility, toxicity, and stem cell mobilization properties. J Clin Oncol. 2003 Aug 1;21(15):2974-81. link to original article contains verified protocol PubMed

Osteosarcoma

Cisplatin & Doxorubicin

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Regimen #1, Bramwell et al. 1992, Bramwell et al. 1997, Souhami et al. 1997

Level of Evidence: Phase III

21-day cycles x 3 cycles, definitive surgery on week 9, then another 3 cycles of therapy that starts 14-28 days after surgery

Supportive medications:

  • Prehydration: normal saline 400 mL/m2 and D5W 400 mL/m2 over 2 hours--the reference did not clarify if these two solutions are given at the same time
  • The volume of fluid for cisplatin continuous infusion is 2400 mL/m2 NS, with KCl 80 mEq/L and mannitol 32 g/m2
  • Posthydration: D5W 600 mL/m2 over 6 hours, with KCl 20 mEq/L and mannitol 8 g/m2; and NS 600 mL/m2 over 6 hours, with KCl 20 mEq/L, magnesium sulfate 2 mmol/L, and calcium gluconate 0.6 mmol/L--the reference did not clarify if these two solutions are given at the same time. Then D5W 600 mL/m2 over 12 hours, with KCl 20 mEq/L and mannitol 8 g/m2.
  • Furosemide (Lasix) 20-40 mg IV if urine output is <400 mL/m2 over 6 hours

Regimen #2, Lewis et al. 2007

Level of Evidence: Phase III

21-day cycles x 2 cycles, definitive surgery in a 14-day window between cycles 2 & 3, then another 4 cycles of therapy after surgery

Supportive medications:

  • 4 hours of prehydration prior to cisplatin
  • 24 hours of posthydration & mannitol after cisplatin
  • Recommended that fluid for cisplatin is isotonic saline with potassium chloride and mannitol

Regimen #3, Lewis et al. 2007 - dose intense

Level of Evidence: Phase III

14-day cycles x 3 cycles, definitive surgery in a 14-day window between cycles 3 & 4, then another 3 cycles of therapy after surgery

Supportive medications:

  • Filgrastim (Neupogen) or lenograstim 5 mcg/kg SC daily on days 4-13
  • 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

References

  1. Bramwell VH, Burgers M, Sneath R, Souhami R, van Oosterom AT, Voûte PA, Rouesse J, Spooner D, Craft AW, Somers R et al. A comparison of two short intensive adjuvant chemotherapy regimens in operable osteosarcoma of limbs in children and young adults: the first study of the European Osteosarcoma Intergroup. J Clin Oncol. 1992 Oct;10(10):1579-91. link to original article contains verified protocol PubMed
  2. Bramwell VH, Burgers MV, Souhami RL, Taminiau AH, Van Der Eijken JW, Craft AW, Malcolm AJ, Uscinska B, Kirkpatrick AL, Machin D, Van Glabbeke MM. A Randomized Comparison of two Short Intensive Chemotherapy Regimens in Children and Young Adults With Osteosarcoma: Results in Patients With Metastases: A Study of the European Osteosarcoma Intergroup. Sarcoma. 1997;1(3-4):155-60. link to original article contains verified partial protocol PubMed
  3. Souhami RL, Craft AW, Van der Eijken JW, Nooij M, Spooner D, Bramwell VH, Wierzbicki R, Malcolm AJ, Kirkpatrick A, Uscinska BM, Van Glabbeke M, Machin D. Randomised trial of two regimens of chemotherapy in operable osteosarcoma: a study of the European Osteosarcoma Intergroup. Lancet. 1997 Sep 27;350(9082):911-7. link to original article PubMed
  4. Lewis IJ, Nooij MA, Whelan J, Sydes MR, Grimer R, Hogendoorn PC, Memon MA, Weeden S, Uscinska BM, van Glabbeke M, Kirkpatrick A, Hauben EI, Craft AW, Taminiau AH; MRC BO06 and EORTC 80931 collaborators; European Osteosarcoma Intergroup. Improvement in histologic response but not survival in osteosarcoma patients treated with intensified chemotherapy: a randomized phase III trial of the European Osteosarcoma Intergroup. J Natl Cancer Inst. 2007 Jan 17;99(2):112-28. link to original article contains verified protocol PubMed

Cisplatin, Ifosfamide, Epirubicin

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Regimen

Level of Evidence: Phase II

Supportive medications:

  • Prehydration and posthydration with mannitol diuresis for cisplatin

21-day cycles x 3 cycles, then surgery, then

Postoperative chemotherapy:

Supportive medications:

  • Prehydration and posthydration with mannitol diuresis for cisplatin

28-day cycles x 3 cycles

References

  1. Basaran M, Bavbek ES, Saglam S, Eralp L, Sakar B, Atalar AC, Bilgic B, Ozger H, Onat H. A phase II study of cisplatin, ifosfamide and epirubicin combination chemotherapy in adults with nonmetastatic and extremity osteosarcomas. Oncology. 2007;72(3-4):255-60. Epub 2008 Jan 10. link to original article contains verified protocol PubMed

Cyclophosphamide & Etoposide

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Regimen

Level of Evidence: Phase II

Supportive hydration:

  • With mesna, 3000 mL/m2 hydration

at least 21-day cycles x 2 cycles, then restaging

Patients with no progression received an experimental protocol with:

  • Samarium-153 (Quadramet) 10 mCi/kg and/or Carboplatin (Paraplatin) and Etoposide (Vepesid) based on status of bone metastases (no further details about dose/schedule given)
  • Progression-free patients received reduced intensity stem cell transplant (preferably from a matched sibling donor (MSD))
  • Patients with no MSD received IL-2 5 days a week every 2 weeks x 12 cycles (reference did not specify if a cycle was 2 weeks, 4 weeks, or another length)

References

  1. Berger M, Grignani G, Ferrari S, Biasin E, Brach del Prever A, Aliberti S, Saglio F, Aglietta M, Fagioli F. Phase 2 trial of two courses of cyclophosphamide and etoposide for relapsed high-risk osteosarcoma patients. Cancer. 2009 Jul 1;115(13):2980-7. link to original article contains verified protocol PubMed

Cyclophosphamide & Topotecan

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Regimen

Level of Evidence: Phase II

21-day cycles x 12 to 14 cycles

Supportive medications:

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

References

  1. Saylors RL 3rd, Stine KC, Sullivan J, Kepner JL, Wall DA, Bernstein ML, Harris MB, Hayashi R, Vietti TJ; Pediatric Oncology Group. Cyclophosphamide plus topotecan in children with recurrent or refractory solid tumors: a Pediatric Oncology Group phase II study. J Clin Oncol. 2001 Aug 1;19(15):3463-9. link to original article contains verified protocol PubMed

Docetaxel & Gemcitabine

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Regimen

Level of Evidence: Retrospective

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

21-day cycles

Supportive medications:

  • Ondansetron (Zofran) prior to chemotherapy on days 1 & 8
  • Dexamethasone (Decadron) starting either the day before or the day of docetaxel, and continued for 2 days after docetaxel
  • H1 or H2 blockers such as Diphenhydramine (Benadryl) and Ranitidine (Zantac) prior to chemotherapy on days 1 & 8 per physician discretion
  • Some patients received Filgrastim (Neupogen) starting on day 9

References

  1. Navid F, Willert JR, McCarville MB, Furman W, Watkins A, Roberts W, Daw NC. Combination of gemcitabine and docetaxel in the treatment of children and young adults with refractory bone sarcoma. Cancer. 2008 Jul 15;113(2):419-25. link to original article contains verified protocol PubMed

Gemcitabine (Gemzar)

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Regimen

Level of Evidence: Phase II

8-week course, then

Maintenance therapy if patient does not have progressive disease:

28-day cycles

References

  1. Merimsky O, Meller I, Flusser G, Kollender Y, Issakov J, Weil-Ben-Arush M, Fenig E, Neuman G, Sapir D, Ariad S, Inbar M. Gemcitabine in soft tissue or bone sarcoma resistant to standard chemotherapy: a phase II study. Cancer Chemother Pharmacol. 2000;45(2):177-81. link to original article contains verified protocol PubMed

ICE - Ifosfamide, Carboplatin, Etoposide

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ICE: Ifosfamide, Carboplatin, Etoposide

Regimen

Level of Evidence: Phase II

The reference did not mention Mesna (Mesnex) being used.

  • Ifosfamide (Ifex) 1800 mg/m2 IV once per day on days 1 to 5
  • Carboplatin (Paraplatin) 400 mg/m2 IV "for 2 days"--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
  • Resection of disease was allowed after 4 cycles based on patient's response to ICE

21-day cycles, with next cycle starting as soon as ANC is at least 1000 and platelet count is at least 100,000

Supportive medications:

  • Depending on the study the patients were enrolled on, they received one of the following:
    • CCG-0894: Filgrastim (Neupogen) 5 or 10 mcg/kg/day SC daily, starting 24 hours after completing ICE, and to continue until day 18 if ANC is at least 1000, or until ANC is at least 1000 post nadir, whichever comes later
    • CCG-0924: PIXY 321 at doses of 500/750/1000 mcg/m2 daily or 500 mcg/m2 BID SQ, starting on day 5 and to continue until day 18 unless ANC reached 20,000 or platelet count is at least 900,000 for 2 days between days 13-18, or until ANC is at least 1000 and platelet count is at least 100,000, whichever comes later
    • CCG-0931: Filgrastim (Neupogen) 5 mcg/kg/day SC daily and IL-6 at 2.5, 3.75, or 5.0 mcg/kg SC BID, starting 24 hours after completing ICE. Filgrastim is continued until ANC is at least 1000, and IL-6 is continued until platelets are at least 100,000 for 2 consecutive days or until day 35, whichever comes sooner.

References

  1. Van Winkle P, Angiolillo A, Krailo M, Cheung YK, Anderson B, Davenport V, Reaman G, Cairo MS. Ifosfamide, carboplatin, and etoposide (ICE) reinduction chemotherapy in a large cohort of children and adolescents with recurrent/refractory sarcoma: the Children's Cancer Group (CCG) experience. Pediatr Blood Cancer. 2005 Apr;44(4):338-47. link to original article contains verified protocol PubMed

IE - Ifosfamide & Etoposide

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IE: Ifosfamide, Etoposide

Regimen

Level of Evidence: Phase II

  • Ifosfamide (Ifex) 3000 mg/m2 IV over 3 hours on days 1 to 4
    • Given in D5W 250-500 mL
  • Mesna (Mesnex) 3600 mg/m2/day (total dose of 14,400 mg/m2) IV continuous infusion on days 1 to 4
  • Etoposide (Vepesid) 75 mg/m2 IV over 1 hour on days 1 to 4
    • Given in D5W 250-500 mL

21 to 28-day cycles x 2 cycles, with next cycle starting when ANC >1500 and platelet count >100,000

Supportive hydration:

  • At least 2000 mL/m2/day of hydration with chemotherapy

References

  1. Gentet JC, Brunat-Mentigny M, Demaille MC, Pein F, Avet-Loiseau H, Berger C, De Lumley L, Pacquement H, Schmitt C, Sariban E, Pillon P, Bernard JL, Kalifa C. Ifosfamide and etoposide in childhood osteosarcoma. A phase II study of the French Society of Paediatric Oncology. Eur J Cancer. 1997 Feb;33(2):232-7. link to original article contains verified protocol PubMed

MA

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MA: High-dose Methotrexate, Adriamycin

Regimen

Level of Evidence: Phase III

  • Methotrexate (MTX) 12,000 mg/m2 IV over 4 hours on weeks 1, 2, 3, 6, 7, 10, 11
    • Given in D5W 1L with sodium bicarbonate 1 mEq/kg
  • Folinic acid (Leucovorin) 15 mg PO Q6H x up to 11 doses on weeks 1, 2, 3, 6, 7, 10, 11, starting 20 hours after the completion of methotrexate infusion
  • Doxorubicin (Adriamycin) 70 mg/m2 IV over 6 hours on weeks 4 & 8

Supportive medications:

  • 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 >7
  • Daily monitoring of methotrexate levels and creatinine

11-week course, then surgery during week 12, with further treatment based on pathologic response

Patients with good response received:

Supportive medications:

  • 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 >7
  • Daily monitoring of methotrexate levels and creatinine

28-day cycles x 3 cycles, then

  • Methotrexate (MTX) 12,000 mg/m2 IV over 4 hours on days 1, 8, 15
    • Given in D5W 1L with sodium bicarbonate 1 mEq/kg
  • Folinic acid (Leucovorin) 15 mg PO Q6H x up to 11 doses starting on days 1, 8, 15, 20 hours after the completion of methotrexate infusion

21-day course

Patients with poor response received:
Details were not listed about the length of each cycle. Other regimens have used 21 to 28-day cycles.

  • Etoposide (Vepesid) 75 mg/m2 IV over 1 hour on days 1 to 4
    • Given in NS 250-500 mL
  • Ifosfamide (Ifex) 3000 mg/m2/day (total dose of 12,000 mg/m2) IV over 3 hours on days 1 to 4, given together with mesna
    • Given in NS 250-500 mL
  • Mesna (Mesnex) 3600 mg/m2/day (total dose of 14,400 mg/m2) IV continuous 96-hour (4-day) infusion on days 1 to 4, given together with ifosfamide

5 cycles

Supportive medications:

  • 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 >7
  • Daily monitoring of methotrexate levels and creatinine
  • Up to 2 L/day hydration with ifosfamide & mesna

References

  1. Le Deley MC, Guinebretière JM, Gentet JC, Pacquement H, Pichon F, Marec-Bérard P, Entz-Werlé N, Schmitt C, Brugières L, Vanel D, Dupoüy N, Tabone MD, Kalifa C; Société Française d'Oncologie Pédiatrique (SFOP). SFOP OS94: a randomised trial comparing preoperative high-dose methotrexate plus doxorubicin to high-dose methotrexate plus etoposide and ifosfamide in osteosarcoma patients. Eur J Cancer. 2007 Mar;43(4):752-61. Epub 2007 Jan 30. link to original article contains verified protocol PubMed

MAP

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MAP: High-dose Methotrexate, Adriamycin, Platinol

Regimen #1, Bramwell et al. 1992 & Bramwell et al. 1997

Level of Evidence: Phase III

Note: The body of Bramwell et al. 1992 & Bramwell et al. 1997 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.

  • Methotrexate (MTX) 8000 mg/m2 IV over 4-6 hours on day 1
  • Folinic acid (Leucovorin) 12 mg/m2 IV Q6H x 10 doses or 15 mg/m2 PO Q6H x 10 doses, starting 24 hours after the start of methotrexate infusion
    • Monitor methotrexate level at "24 hours and 48 hours"--it is unclear in the reference if this is time after the start/end of methotrexate, beginning of leucovorin, or something else
    • Methotrexate levels higher than 1 x 10^-7 mol/L at 48 hours required additional leucovorin rescue
  • Doxorubicin (Adriamycin) 25 mg/m2 IV bolus on days 11 to 13
  • Cisplatin (Platinol) 100 mg/m2 IV continuous 24-hour infusion on day 11

21-day cycles x 2 cycles, definitive surgery on week 9, then another 2 cycles of therapy that starts 14-28 days after surgery

Supportive medications:

  • 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 8 to 10 mol/L. Note: the reference is not clear about when/if PO sodium bicarbonate is stopped, when IV sodium bicarbonate is started, or the administration rate of IV sodium bicarbonate.
  • Prehydration for cisplatin: normal saline 400 mL/m2 and D5W 400 mL/m2 over 2 hours--the reference did not clarify if these two solutions are given at the same time
  • The volume of fluid for cisplatin continuous infusion is 2400 mL/m2 NS, with KCl 80 mEq/L and mannitol 32 g/m2
  • Posthydration for cisplatin: D5W 600 mL/m2 over 6 hours, with KCl 20 mEq/L and mannitol 8 g/m2; and NS 600 mL/m2 over 6 hours, with KCl 20 mEq/L, magnesium sulfate 2 mmol/L, and calcium gluconate 0.6 mmol/L--the reference did not clarify if these two solutions are given at the same time. Then D5W 600 mL/m2 over 12 hours, with KCl 20 mEq/L and mannitol 8 g/m2.
  • With cisplatin, Furosemide (Lasix) 20-40 mg IV if urine output is <400 mL/m2 over 6 hours

Regimen #2, Bacci et al. 2000

Level of Evidence: Phase II

Supportive medications:

  • Hydration during and after methotrexate infusion

27-day cycles x 2 cycles, then definitive surgery, then proceed to postoperative chemotherapy. Amputated patients restart chemotherapy 3-5 days after surgery; patients who undergo limb salvage or rotation plasty restart chemotherapy 10-21 days after surgery.

If there is at least 90% tumor necrosis in the surgically removed specimen:

Supportive medications:

  • Hydration during and after methotrexate infusion

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

given once after postoperative chemotherapy cycle 3

If there is <90% tumor necrosis in the surgically removed specimen:

Supportive medications:

  • Hydration during and after methotrexate infusion

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

given once after postoperative chemotherapy cycle 3

Regimen #3, Winkler et al. 1984 (COSS-80)

Level of Evidence: Phase III

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.

21-day course, then

See note above about uncertainty about the exact schedule.

  • Methotrexate (MTX) 12,000 mg/m2 (maximum dose of 20,000 mg per cycle) IV over 4 hours on days 1 & 8
    • MTX is dissolved at a concentration of 20,000 mg/L in a solution containing 5% glucose
  • Folinic acid (Leucovorin) 15 mg/m2 PO Q6H x 12 hours on days 2 & 9, starting 24 hours after the completion of methotrexate infusion; additional leucovorin used for delayed methotrexate elimination
  • Cisplatin (Platinol) 120 mg/m2 IV over 5 hours on day 15

35-day course, then

Supportive medications:

  • 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 >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

See note above about uncertainty about the exact schedule.

  • Methotrexate (MTX) 12,000 mg/m2 (maximum dose of 20,000 mg per cycle) IV over 4 hours on days 1, 8, 29, 36
    • MTX is dissolved at a concentration of 20,000 mg/L in a solution containing 5% glucose
  • Folinic acid (Leucovorin) 15 mg/m2 PO Q6H x 12 hours on days 2, 9, 30, 37, starting 24 hours after the completion of methotrexate infusion; additional leucovorin used for delayed methotrexate elimination
  • Doxorubicin (Adriamycin) 45 mg/m2 IV bolus on days 15 & 16 (delayed during cycle 1 until after surgery)
  • Cisplatin (Platinol) 120 mg/m2 IV over 5 hours on day 43

Supportive medications for methotrexate:

  • 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 >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 cycles x 3 cycles, with surgery done during cycle 1 before doxorubicin; surgery is done 9-18 weeks after the start of chemotherapy

References

  1. Winkler K, Beron G, Kotz R, Salzer-Kuntschik M, Beck J, Beck W, Brandeis W, Ebell W, Erttmann R, Göbel U et al. Neoadjuvant chemotherapy for osteogenic sarcoma: results of a Cooperative German/Austrian study. J Clin Oncol. 1984 Jun;2(6):617-24. link to original article contains verified protocol PubMed
  2. Bramwell VH, Burgers M, Sneath R, Souhami R, van Oosterom AT, Voûte PA, Rouesse J, Spooner D, Craft AW, Somers R et al. A comparison of two short intensive adjuvant chemotherapy regimens in operable osteosarcoma of limbs in children and young adults: the first study of the European Osteosarcoma Intergroup. J Clin Oncol. 1992 Oct;10(10):1579-91. link to original article contains verified protocol PubMed content property of HemOnc.org
  3. Bramwell VH, Burgers MV, Souhami RL, Taminiau AH, Van Der Eijken JW, Craft AW, Malcolm AJ, Uscinska B, Kirkpatrick AL, Machin D, Van Glabbeke MM. A Randomized Comparison of two Short Intensive Chemotherapy Regimens in Children and Young Adults With Osteosarcoma: Results in Patients With Metastases: A Study of the European Osteosarcoma Intergroup. Sarcoma. 1997;1(3-4):155-60. link to original article contains verified partial protocol PubMed
  4. Bacci G, Ferrari S, Bertoni F, Ruggieri P, Picci P, Longhi A, Casadei R, Fabbri N, Forni C, Versari M, Campanacci M. Long-term outcome for patients with nonmetastatic osteosarcoma of the extremity treated at the istituto ortopedico rizzoli according to the istituto ortopedico rizzoli/osteosarcoma-2 protocol: an updated report. J Clin Oncol. 2000 Dec 15;18(24):4016-27. link to original article contains verified protocol PubMed

MAP/MA +/- BCD +/- Ifosfamide (Ifex)

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MAP: High-dose Methotrexate, Adriamycin, Platinol BCD: Bleomycin, Ccyclophosphamide, Dactinomycin

Regimen #1, Winkler et al. 1984 (COSS-80 - MA, BCD)

Level of Evidence: Phase III

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.

21-day course, then

See note above about uncertainty about the exact schedule.

Supportive medications for methotrexate:

  • 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 >7.4

35-day course, then

See note above about uncertainty about the exact schedule.

8-week cycles x 3 cycles, with surgery done during cycle 1 before doxorubicin; surgery is done 9-18 weeks after the start of chemotherapy

Supportive medications for methotrexate:

  • 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 >7.4

Regimen #2, Winkler et al. 1988 (COSS-82 - MAP +/- BCD, IP)

Level of Evidence: Phase III

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.

  • Doxorubicin (Adriamycin) 30 mg/m2 IV bolus on days 1 & 2
  • Cisplatin (Platinol) 90 mg/m2/day IV over 4 hours on day 3
  • Methotrexate (MTX) 12,000 mg/m2 (maximum dose of 20,000 mg per cycle) IV over 4 hours on days 22 & 29
    • MTX is dissolved at a concentration of 20,000 mg/L in a solution containing 5% glucose
  • Folinic acid (Leucovorin) 15 mg/m2 PO Q6H x 12 hours on days 23 & 30, starting 24 hours after the completion of methotrexate infusion; additional leucovorin used for delayed methotrexate elimination

35-day cycles x 2 cycles, then surgery

Supportive medications:

  • 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 >7.4
  • 12 hours of hydration prior to cisplatin & 20 hours of hydration after cisplatin; total amount of fluid given over 36hours of prehydration, cisplatin, and posthydration is NS 6 L/m2 with mannitol 8 g/L and potassium 20 mval/L.
  • Magnesium 180 mg/m2 PO "per day throughout the whole chemotherapy time"--as described in the cited reference Winkler et al. 1984

Patients who had a good response based on surgical pathology received:

  • Doxorubicin (Adriamycin) 30 mg/m2 IV bolus on days 1 & 2
  • Cisplatin (Platinol) 90 mg/m2/day IV over 4 hours on day 3
  • Methotrexate (MTX) 12,000 mg/m2 (maximum dose of 20,000 mg per cycle) IV over 4 hours on days 22 & 29
    • MTX is dissolved at a concentration of 20,000 mg/L in a solution containing 5% glucose
  • Folinic acid (Leucovorin) 15 mg/m2 PO Q6H x 12 hours on days 23 & 30, starting 24 hours after the completion of methotrexate infusion; additional leucovorin used for delayed methotrexate elimination

35-day cycles x 2 cycles

Supportive medications:

  • 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 >7.4
  • 12 hours of hydration prior to cisplatin & 20 hours of hydration after cisplatin; total amount of fluid given over 36hours of prehydration, cisplatin, and posthydration is NS 6 L/m2 with mannitol 8 g/L and potassium 20 mval/L.
  • Magnesium 180 mg/m2 PO "per day throughout the whole chemotherapy time"--as described in the cited reference Winkler et al. 1984

Patients who had a poor response based on surgical pathology received:

35-day cycles x 3 cycles

Supportive medications:

  • Mannitol given together with cisplatin; no further details provided

Regimen #3, Winkler et al. 1988 (COSS-82 - BCDM +/- AP)

Level of Evidence: Phase III

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.

35-day cycles x 2 cycles, then surgery

Supportive medications:

  • 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 >7.4

Patients who had a good response based on surgical pathology received:

35-day cycles x 2 cycles

Supportive medications:

  • 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 >7.4

Patients who had a poor response based on surgical pathology received:

21-day cycles x 6 cycles

Supportive medications:

  • 12 hours of hydration prior to cisplatin & 20 hours of hydration after cisplatin; total amount of fluid given over 36hours of prehydration, cisplatin, and posthydration is NS 6 L/m2 with mannitol 8 g/L and potassium 20 mval/L.
  • Magnesium 180 mg/m2 PO "per day throughout the whole chemotherapy time"--as described in the cited reference Winkler et al. 1984

References

  1. Winkler K, Beron G, Kotz R, Salzer-Kuntschik M, Beck J, Beck W, Brandeis W, Ebell W, Erttmann R, Göbel U et al. Neoadjuvant chemotherapy for osteogenic sarcoma: results of a Cooperative German/Austrian study. J Clin Oncol. 1984 Jun;2(6):617-24. link to original article contains verified protocol PubMed
  2. Winkler K, Beron G, Delling G, Heise U, Kabisch H, Purfürst C, Berger J, Ritter J, Jürgens H, Gerein V et al. Neoadjuvant chemotherapy of osteosarcoma: results of a randomized cooperative trial (COSS-82) with salvage chemotherapy based on histological tumor response. J Clin Oncol. 1988 Feb;6(2):329-37. link to original article contains verified protocol PubMed

MAP & Ifosfamide (Ifex)

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Regimen

Level of Evidence: Phase II

  • Methotrexate (MTX) 12,000 mg/m2 IV over 4 hours on day 1
    • If 4-hour methotrexate level is <1000 µM/L, the next cycle's Methotrexate (MTX) dose is increased by 2000 mg/m2
  • Folinic acid (Leucovorin) 15 mg (route not specified) Q6H x 11 doses (note: the reference says "11 cycles," but it is assumed this is the intended meaning), starting day 2, 24 hours after the start of methotrexate
  • Cisplatin (Platinol) 60 mg/m2/day (total dose of 120 mg/m2) IV continuous 48-hour infusion on days 8 & 9
  • Doxorubicin (Adriamycin) 75 mg/m2 IV continuous 24-hour infusion on day 10
  • Ifosfamide (Ifex) 3000 mg/m2/day (total dose of 15,000 mg/m2) IV continuous 120-hour (5-day) infusion on days 29-33, given together with mesna
  • Mesna (Mesnex) 3000 mg/m2/day (total dose of 15,000 mg/m2) IV continuous 120-hour (5-day) infusion on days 29-33, given together with ifosfamide

Supportive medications:

  • 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

42-day cycles x 2 cycles, then surgery

Postoperative chemotherapy:

  • Doxorubicin (Adriamycin) 90 mg/m2 IV continuous 24-hour infusion on day 1
  • Ifosfamide (Ifex) 3000 mg/m2/day (total dose of 15,000 mg/m2) IV continuous 120-hour (5-day) infusion on days 22 to 26, given together with mesna
  • Mesna (Mesnex) 3000 mg/m2/day (total dose of 15,000 mg/m2) IV continuous 120-hour (5-day) infusion on days 22 to 26, given together with ifosfamide
  • Methotrexate (MTX) 12,000 mg/m2 IV over 4 hours on day 36
    • If 4-hour methotrexate level is <1000 µM/L, the next cycle's Methotrexate (MTX) dose is increased by 2000 mg/m2
  • Folinic acid (Leucovorin) 15 mg (route not specified) Q6H x 11 doses, starting day 36, 24 hours after the start of methotrexate
  • Cisplatin (Platinol) 60 mg/m2/day (total dose of 120 mg/m2) IV continuous 48-hour infusion on days 43-44

Supportive medications:

  • 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 cycles x 3 cycles

References

  1. Bacci G, Briccoli A, Rocca M, Ferrari S, Donati D, Longhi A, Bertoni F, Bacchini P, Giacomini S, Forni C, Manfrini M, Galletti S. Neoadjuvant chemotherapy for osteosarcoma of the extremities with metastases at presentation: recent experience at the Rizzoli Institute in 57 patients treated with cisplatin, doxorubicin, and a high dose of methotrexate and ifosfamide. Ann Oncol. 2003 Jul;14(7):1126-34. link to original article contains verified protocol PubMed

Methotrexate, Etoposide, Ifosfamide

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Regimen

Level of Evidence: Phase III

  • Methotrexate (MTX) 12,000 mg/m2 IV over 4 hours on weeks 1, 2, 3, 7, 8, 12, 13
    • Given in D5W 1L with sodium bicarbonate 1 mEq/kg
  • Folinic acid (Leucovorin) 15 mg PO Q6H x up to 11 doses on weeks 1, 2, 3, 7, 8, 12, 13, starting 20 hours after the completion of methotrexate infusion
  • Etoposide (Vepesid) 75 mg/m2 IV over 1 hour on days 22 to 25 (week 4), 57 to 60 (week 9)
    • Given in NS 250-500 mL
  • Ifosfamide (Ifex) 3000 mg/m2/day (total dose of 12,000 mg/m2) IV over 3 hours on days 22 to 25 (week 4), 57 to 60 (week 9), given together with mesna
    • Given in NS 250-500 mL
  • Mesna (Mesnex) 3600 mg/m2/day (total dose of 14,400 mg/m2) IV continuous 96-hour (4-day) infusion on days 22 to 25 (week 4), 57 to 60 (week 9), given together with ifosfamide

Supportive medications:

  • 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 >7
  • Daily monitoring of methotrexate levels and creatinine
  • Up to 2 L/day hydration with ifosfamide & mesna

13-week course, then surgery during week 14, with further treatment based on pathologic response

Patients with good response received:

  • Methotrexate (MTX) 12,000 mg/m2 IV over 4 hours on weeks 1, 2, 3
    • Given in D5W 1L with sodium bicarbonate 1 mEq/kg
  • Folinic acid (Leucovorin) 15 mg PO Q6H x up to 11 doses on weeks 1, 2, 3, starting 20 hours after the completion of methotrexate infusion
  • Etoposide (Vepesid) 75 mg/m2 IV over 1 hour on days 22 to 25 (week 4)
    • Given in NS 250-500 mL
  • Ifosfamide (Ifex) 3000 mg/m2/day (total dose of 12,000 mg/m2) IV over 3 hours on days 22 to 25 (week 4), given together with mesna
    • Given in NS 250-500 mL
  • Mesna (Mesnex) 3600 mg/m2/day (total dose of 14,400 mg/m2) IV continuous 96-hour (4-day) infusion on days 22 to 25 (week 4), given together with ifosfamide

Supportive medications:

  • 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 >7
  • Daily monitoring of methotrexate levels and creatinine
  • Up to 2 L/day hydration with ifosfamide & mesna

28-day cycles x 3 cycles, then

  • Methotrexate (MTX) 12,000 mg/m2 IV over 4 hours on days 1, 8, 15
    • Given in D5W 1L with sodium bicarbonate 1 mEq/kg
  • Folinic acid (Leucovorin) 15 mg PO Q6H x up to 11 doses starting on days 1, 8, 15, 20 hours after the completion of methotrexate infusion

Supportive medications:

  • 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 >7
  • Daily monitoring of methotrexate levels and creatinine

21-day course

Patients with poor response received: Details were not listed about the precise schedule. Other regimens have used both medications both on day 1, with 21-day cycles.

5 cycles

References

  1. Le Deley MC, Guinebretière JM, Gentet JC, Pacquement H, Pichon F, Marec-Bérard P, Entz-Werlé N, Schmitt C, Brugières L, Vanel D, Dupoüy N, Tabone MD, Kalifa C; Société Française d'Oncologie Pédiatrique (SFOP). SFOP OS94: a randomised trial comparing preoperative high-dose methotrexate plus doxorubicin to high-dose methotrexate plus etoposide and ifosfamide in osteosarcoma patients. Eur J Cancer. 2007 Mar;43(4):752-61. Epub 2007 Jan 30. link to original article contains verified protocol PubMed

Samarium-153 (Quadramet) high dose, with stem cell support

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Regimen

Level of Evidence: Non-randomized

  • Peripheral blood progenetor cell (PBPC) or bone marrow harvest and cryopreservation of at least 2 x 10^6 CD34+ cells/kg
  • Samarium-153 (Quadramet) 30 mCi/kg IV on day 0
  • Filgrastim (Neupogen) or Sargramostim (Leukine) started when ANC <1000
  • On day +14, infuse peripheral blood progenetor cell (PBPC) or bone marrow cells
  • CBC followed twice per week until engraftment/hematologic recovery
    • Patients transfused for Hb <8, platelets <20,000

References

  1. Anderson PM, Wiseman GA, Dispenzieri A, Arndt CA, Hartmann LC, Smithson WA, Mullan BP, Bruland OS. High-dose samarium-153 ethylene diamine tetramethylene phosphonate: low toxicity of skeletal irradiation in patients with osteosarcoma and bone metastases. J Clin Oncol. 2002 Jan 1;20(1):189-96. link to original article contains verified protocol PubMed

Malignant fibrous histiocytoma (MFH) of bone

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