Soft tissue sarcoma

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Single-agent regimens

Doxorubicin (Adriamycin)

Regimen

• Doxorubicin (Adriamycin) 75 mg/m2 IV bolus once on day 1

21-day cycles x up to 6 cycles, until progression of disease, unacceptable toxicity, or patient refusal

References

1. Bramwell VH, Anderson D, Charette ML. Doxorubicin-based chemotherapy for the palliative treatment of adult patients with locally advanced or metastatic soft-tissue sarcoma: a meta-analysis and clinical practice guideline. Sarcoma. 2000;4(3):103-12. doi: 10.1080/13577140020008066. link to original article PubMed
2. Lorigan P, Verweij J, Papai Z, Rodenhuis S, Le Cesne A, Leahy MG, Radford JA, Van Glabbeke MM, Kirkpatrick A, Hogendoorn PC, Blay JY; European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group Study. Phase III trial of two investigational schedules of ifosfamide compared with standard-dose doxorubicin in advanced or metastatic soft tissue sarcoma: a European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group Study. J Clin Oncol. 2007 Jul 20;25(21):3144-50. link to original article contains verified protocol PubMed

Epirubicin (Ellence)

Regimen

• Epirubicin (Ellence) 75 mg/m2 IV bolus once on day 1

21-day cycles x 2-6 cycles, or until disease progression

References

1. Mouridsen HT, Bastholt L, Somers R, Santoro A, Bramwell V, Mulder JH, van Oosterom AT, Buesa J, Pinedo HM, Thomas D, et al. Adriamycin versus epirubicin in advanced soft tissue sarcomas. A randomized phase II/phase III study of the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer Clin Oncol. 1987 Oct;23(10):1477-83. PubMed

Ifosfamide (Ifex)

Regimen #1, van Oosterom, et al. 2002

• Ifosfamide (Ifex) 3000 mg/m2 IV over 4 hours once daily on days 1-3
  • Each day's dose of ifosfamide is dissolved in 125 mL sterile water per 1000 mg of ifosfamide, mixed together with mesna in an additional 1 liter of dextrose/saline
• Mesna (Mesnex) 600 mg/m2 IV bolus once on day 1, immediately prior to mesna/ifosfamide infusion
• Mesna (Mesnex) 1500 mg/m2 IV over 4 hours on days 1-3, given together with ifosfamide
• Mesna (Mesnex) 500 mg/m2 IV two times per day on days 1-3, given at 4 and 8 hours after completion of ifosfamide and mesna

21-day cycles x at least 2 cycles, except in cases of rapid disease progression; continued until disease progression or unacceptable toxicity or patient refusal

Supportive medications:

• "Antiemetics were prescribed according to local conventions"
• 1 liter of fluid PO two times per day on days 1-3, taken 4 and 8 hours after completion of ifosfamide and mesna

Regimen #2, Lorigan, et al. 2007 - short infusion, Ifos 3

• Ifosfamide (Ifex) 3000 mg/m2 IV over 4 hours on days 1-3, given together with mesna
  • Each day's dose of ifosfamide is mixed together with mesna in 1 liter of normal saline
• Mesna (Mesnex) 600 mg/m2 IV bolus once on day 1, immediately prior to mesna/ifosfamide infusion
• Mesna (Mesnex) 1500 mg/m2 IV over 4 hours on days 1-3, given together with ifosfamide
• Mesna (Mesnex) 1200 mg/m2 IV two times per day on days 1-3, given at 4 and 8 hours after completion of ifosfamide and mesna
  • An alternative is to use oral mesna instead of intravenous: Mesna (Mesnex) 1200 mg/m2 PO two times per day on days 1-3, given at 2 and 6 hours after completion of ifosfamide and mesna

21-day cycles x up to 6 cycles, until progression of disease, unacceptable toxicity, or patient refusal

Supportive medications:

• Sodium bicarbonate 150 mmol IV once daily on days 1-3
• Patient with somnolesence or other signs of encephalopathy with ifosfamide received methylene blue 50 mg IV every 4 hours until resolution of symptoms. During cycles thereafter, patients would receive methylene blue 50 mg IV every 4 hours, starting 4 hours prior to ifosfamide on day 1, continuing until 72 hours after completion

Regimen #3, Lorigan, et al. 2007 - continuous infusion, Ifos 9

• Ifosfamide (Ifex) 3000 mg/m2/day IV continuous infusion over 72 hours (total dose per cycle: 9000 mg/m2) on days 1-3, given together with mesna
  • Each day's dose of ifosfamide is mixed together with mesna in 3 liters of normal saline
• Mesna (Mesnex) 600 mg/m2 IV bolus once on day 1, immediately prior to mesna/ifosfamide infusion
• Mesna (Mesnex) 3000 mg/m2/day IV continuous infusion over 72 hours (total dose per cycle: 9000 mg/m2) on days 1-3, given together with ifosfamide
• Mesna (Mesnex) 1800 mg/m2 IV over 12 hours once on day 4, starting after completion of ifosfamide and mesna
  • An alternative is to use oral mesna instead of intravenous: Mesna (Mesnex) 1200 mg/m2 PO three times on day 4, given 0, 2, and 6 hours after completion of ifosfamide and mesna

21-day cycles x up to 6 cycles, until progression of disease, unacceptable toxicity, or patient refusal

Supportive medications:

• Sodium bicarbonate 150 mmol IV once daily on days 1-3
• Patient with somnolesence or other signs of encephalopathy with ifosfamide received methylene blue 50 mg IV every 4 hours until resolution of symptoms. During cycles thereafter, patients would receive methylene blue 50 mg IV every 4 hours, starting 4 hours prior to ifosfamide on day 1, continuing until 72 hours after completion

References

1. van Oosterom AT, Mouridsen HT, Nielsen OS, Dombernowsky P, Krzemieniecki K, Judson I, Svancarova L, Spooner D, Hermans C, Van Glabbeke M, Verweij J; EORTC Soft Tissue and Bone Sarcoma Group. Results of randomised studies of the EORTC Soft Tissue and Bone Sarcoma Group (STBSG) with two different ifosfamide regimens in first- and second-line chemotherapy in advanced soft tissue sarcoma patients. Eur J Cancer. 2002 Dec;38(18):2397-406 link to original article contains verified protocol PubMed
2. Lorigan P, Verweij J, Papai Z, Rodenhuis S, Le Cesne A, Leahy MG, Radford JA, Van Glabbeke MM, Kirkpatrick A, Hogendoorn PC, Blay JY; European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group Study. Phase III trial of two investigational schedules of ifosfamide compared with standard-dose doxorubicin in advanced or metastatic soft tissue sarcoma: a European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group Study. J Clin Oncol. 2007 Jul 20;25(21):3144-50. link to original article contains verified protocol PubMed

Pazopanib (Votrient)

Regimen, van der Graaf, et al. 2012 - PALETTE

• Pazopanib (Votrient) 800 mg PO once daily

given until progression of disease, unacceptable toxicity, withdrawal of consent, or death

References

1. van der Graaf WT, Blay JY, Chawla SP, Kim DW, Bui-Nguyen B, Casali PG, Schöffski P, Aglietta M, Staddon AP, Beppu Y, Le Cesne A, Gelderblom H, Judson IR, Araki N, Ouali M, Marreaud S, Hodge R, Dewji MR, Coens C, Demetri GD, Fletcher CD, Dei Tos AP, Hohenberger P; EORTC Soft Tissue and Bone Sarcoma Group; PALETTE study group. Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2012 May 19;379(9829):1879-86. doi: 10.1016/S0140-6736(12)60651-5. Epub 2012 May 16. link to original article contains verified protocol PubMed

Combination regimens

AIM

AIM: Adriamycin, Ifosfamide, Mesna

Regimen #1, Patel, et al. 1998 - 5-day course, lower dose doxorubicin

• Doxorubicin (Adriamycin) 25 mg/m2/day IV continuous infusion over 72 hours (total dose per cycle: 75 mg/m2) on days 1-3
• Ifosfamide (Ifex) 2000 mg/m2 IV over 2 hours once daily on days 1-5 (total dose per cycle: 10,000 mg/m2)
• Mesna (Mesnex) 400 mg/m2 IV once on day 1, given simultaneously with the first dose of ifosfamide
• Mesna (Mesnex) 1200 mg/m2 IV continuous infusion over 5 days on days 1-5
  • Each day's dose of mesna is given in 2 liters of D5W with 100 mEq/L sodium acetate, 20 mEq/L potassium acetate, and 4 mEq/L magnesium sulfate

21-day cycles x up to 6 cycles, until maximum response, progression of disease, or unacceptable toxicity

Regimen #2, Patel, et al. 1998 - 4-day course, higher dose doxorubicin

• Doxorubicin (Adriamycin) 30 mg/m2/day IV continuous infusion over 72 hours (total dose per cycle: 90 mg/m2) on days 1-3
• Ifosfamide (Ifex) 2500 mg/m2 IV over 3 hours once daily on days 1-4 (total dose per cycle: 10,000 mg/m2)
• Mesna (Mesnex) 500 mg/m2 IV once on day 1, given simultaneously with the first dose of ifosfamide
• Mesna (Mesnex) 1500 mg/m2 IV continuous infusion over 4 days on days 1-4
  • Each day's dose of mesna is given in 2 liters of D5W with 100 mEq/L sodium acetate, 20 mEq/L potassium acetate, and 4 mEq/L magnesium sulfate

21-day cycles x up to 6 cycles, until maximum response, progression of disease, or unacceptable toxicity

References

1. Patel SR, Vadhan-Raj S, Burgess MA, Plager C, Papadopolous N, Jenkins J, Benjamin RS. Results of two consecutive trials of dose-intensive chemotherapy with doxorubicin and ifosfamide in patients with sarcomas. Am J Clin Oncol. 1998 Jun;21(3):317-21. link to original article contains protocol PubMed

Epirubicin (Ellence) & Ifosfamide (Ifex)

Regimen

• Epirubicin (Ellence) 45 mg/m2/day IV continuous infusion over 2 days (total dose per cycle: 90 mg/m2) on days 2-3
• Ifosfamide (Ifex) 2500 mg/m2/day IV continuous infusion over 5 days (total dose per cycle: 12,500 mg/m2) on days 1-5, given together with mesna
  • Each day's dose of ifosfamide is mixed together with mesna in 3 liters of "fluids with electrolytes"
• Mesna (Mesnex) 1500 mg/m2 IV continuous infusion over 5 days (total dose per cycle: 7500 mg/m2) on days 1-5, given together with ifosfamide

21-day cycles

Supportive medications:

• G-CSF 5 mcg/kg SC once daily on days 6-15 or "until recovery of leukocytes"
• Ondansetron (Zofran) 8-24 mg per day prn nausea
• Dexamethasone (Decadron) (dose/schedule not specified) for antiemesis if necessary

References

1. Reichardt P, Tilgner J, Hohenberger P, Dörken B. Dose-intensive chemotherapy with ifosfamide, epirubicin, and filgrastim for adult patients with metastatic or locally advanced soft tissue sarcoma: a phase II study. J Clin Oncol. 1998 Apr;16(4):1438-43. link to original article contains verified protocol PubMed

Gemcitabine (Gemzar) & Docetaxel (Taxotere)

Regimen #1, Hensley, et al. 2002 & 2008 - no prior radiation

• Gemcitabine (Gemzar) 900 mg/m2 IV over 90 minutes once daily on days 1 & 8, given first
• Docetaxel (Taxotere) 100 mg/m2 IV over 1 hour once on day 8, given second

21-day cycles x 6-8 cycles, given until progression of disease or unacceptable toxicity; Hensley, et al. 2008 did not specify a maximum number of cycles

Supportive medications:

• Dexamethasone (Decadron) 8 mg PO BID on days 7-9 (the day before, the day of, and day after docetaxel)
• Patients could receive diuretics at physician discretion for peripheral edema related to docetaxel
• One of the following growth factors (varies depending on reference):
  • G-CSF 150 mcg/m2 (dose rounded to 300 or 480 mcg) SC once daily on days 9-15 as primary neutropenia prophylaxis; could be stopped before day 15 if ANC >1200/uL on two separate measurements
  • Pegfilgrastim (Neulasta) 6 mg SC once on either day 9 or 10 (only one dose given)

Regimen #2, Hensley, et al. 2002 & 2008 - patients who received prior radiation

• Gemcitabine (Gemzar) 675 mg/m2 IV over 90 minutes once daily on days 1 & 8, given first
• Docetaxel (Taxotere) 75 mg/m2 IV over 1 hour once on day 8, given second

21-day cycles x 6-8 cycles, given until progression of disease or unacceptable toxicity; Hensley, et al. 2008 did not specify a maximum number of cycles

Supportive medications:

• Dexamethasone (Decadron) 8 mg PO BID on days 7-9 (the day before, the day of, and day after docetaxel)
• Patients could receive diuretics at physician discretion for peripheral edema related to docetaxel
• One of the following growth factors (varies depending on reference):
  • G-CSF 150 mcg/m2 (dose rounded to 300 or 480 mcg) SC once daily on days 9-15 as primary neutropenia prophylaxis; could be stopped before day 15 if ANC >1200/uL on two separate measurements
  • Pegfilgrastim (Neulasta) 6 mg SC once on either day 9 or 10 (only one dose given)

References

1. Hensley ML, Maki R, Venkatraman E, Geller G, Lovegren M, Aghajanian C, Sabbatini P, Tong W, Barakat R, Spriggs DR. Gemcitabine and docetaxel in patients with unresectable leiomyosarcoma: results of a phase II trial. J Clin Oncol. 2002 Jun 15;20(12):2824-31. link to original article contains verified protocol PubMed
2. Hensley ML, Blessing JA, Mannel R, Rose PG. Fixed-dose rate gemcitabine plus docetaxel as first-line therapy for metastatic uterine leiomyosarcoma: a Gynecologic Oncology Group phase II trial. Gynecol Oncol. 2008 Jun;109(3):329-34. link to original article contains verified protocol PubMed

GIST (Gastrointestinal Stromal Tumor) - neoadjuvant therapy

Imatinib (Gleevec)

Regimen, Eisenberg, et al. 2009 - RTOG 0132

• Imatinib (Gleevec) 600 mg PO once daily

given for 8-12 weeks prior to surgery, stopped on the day prior to surgery, resumed as soon as possible postoperatively, and continued for 2 years as postoperative adjuvant therapy

References

1. Eisenberg BL, Harris J, Blanke CD, Demetri GD, Heinrich MC, Watson JC, Hoffman JP, Okuno S, Kane JM, von Mehren M. Phase II trial of neoadjuvant/adjuvant imatinib mesylate (IM) for advanced primary and metastatic/recurrent operable gastrointestinal stromal tumor (GIST): early results of RTOG 0132/ACRIN 6665. J Surg Oncol. 2009 Jan 1;99(1):42-7. link to original article contains verified protocol PubMed

GIST (Gastrointestinal Stromal Tumor) - adjuvant therapy

Imatinib (Gleevec)

Regimen #1, Joensuu, et al. 2012 - 3 years of treatment

Showed improved recurrence-free survival with 36 months of therapy as compared to 12 months of therapy.

• Imatinib (Gleevec) 400 mg PO once daily

36-month course, treatment started within 12 weeks after surgery

Regimen #2, Dematteo, et al. 2009 - 1 year of treatment

• Imatinib (Gleevec) 400 mg PO once daily

1-year course; treatment started within 12 weeks after surgery

References

1. Dematteo RP, Ballman KV, Antonescu CR, Maki RG, Pisters PW, Demetri GD, Blackstein ME, Blanke CD, von Mehren M, Brennan MF, Patel S, McCarter MD, Polikoff JA, Tan BR, Owzar K; American College of Surgeons Oncology Group (ACOSOG) Intergroup Adjuvant GIST Study Team. Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: a randomised, double-blind, placebo-controlled trial. Lancet. 2009 Mar 28;373(9669):1097-104. link to original article contains verified protocol PubMed
2. Joensuu H, Eriksson M, Sundby Hall K, Hartmann JT, Pink D, Schütte J, Ramadori G, Hohenberger P, Duyster J, Al-Batran SE, Schlemmer M, Bauer S, Wardelmann E, Sarlomo-Rikala M, Nilsson B, Sihto H, Monge OR, Bono P, Kallio R, Vehtari A, Leinonen M, Alvegård T, Reichardt P. One vs three years of adjuvant imatinib for operable gastrointestinal stromal tumor: a randomized trial. JAMA. 2012 Mar 28;307(12):1265-72. doi: 10.1001/jama.2012.347. link to original article contains verified protocol PubMed

GIST (Gastrointestinal Stromal Tumor) - metastatic or unresectable disease

Imatinib (Gleevec)

Regimen

Standard dose therapy

• Imatinib (Gleevec) 400 mg PO once daily

given until progression of disease or unacceptable toxicity; patients who progressed on imatinib 400 mg PO once daily could receive high-dose therapy, as described below

High-dose therapy

• Imatinib (Gleevec) 400 mg PO twice per day

given until progression of disease or unacceptable toxicity

References

1. Blanke CD, Rankin C, Demetri GD, Ryan CW, von Mehren M, Benjamin RS, Raymond AK, Bramwell VH, Baker LH, Maki RG, Tanaka M, Hecht JR, Heinrich MC, Fletcher CD, Crowley JJ, Borden EC. Phase III randomized, intergroup trial assessing imatinib mesylate at two dose levels in patients with unresectable or metastatic gastrointestinal stromal tumors expressing the kit receptor tyrosine kinase: S0033. J Clin Oncol. 2008 Feb 1;26(4):626-32. doi: 10.1200/JCO.2007.13.4452. link to original article contains verified protocol PubMed