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A - Regimen Name

ETOPIFOS Regimen
Etoposide-Ifosfamide
(may be part of IE-VAC)


Disease Site
Sarcoma - Ewing's
Sarcoma - Soft Tissue

Intent
Neoadjuvant
Adjuvant
Palliative

Regimen Category
Evidence-Informed :

Regimen is considered appropriate as part of the standard care of patients; meaningfully improves outcomes (survival, quality of life), tolerability or costs compared to alternatives (recommended by the Disease Site Team and national consensus body e.g. pan-Canadian Oncology Drug Review, pCODR).  Recommendation is based on an appropriately conducted phase III clinical trial relevant to the Canadian context OR (where phase III trials are not feasible) an appropriately sized phase II trial. Regimens where one or more drugs are not approved by Health Canada for any indication will be identified under Rationale and Use.

 
B - Drug Regimen

etoposide
100 mg /m² IV Days 1 to 5
ifosfamide
1800 mg /m² IV Days 1 to 5
mesna

Various dosing schedules have been used. The following is an example (from ASCO guideline, Hensley 2009):

Mesna

Route

Timing

20% of Ifosfamide dose

IV

15 minutes pre-Ifosfamide

40% of Ifosfamide dose

PO

4 hours and 8 hours post-ifosfamide 

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C - Cycle Frequency

ETOPIFOS:  Repeat every 3 weeks

IE-VAC:  Used in an alternating schedule with VAC* for a total of 14 cycles given every 3 weeks (7 of each) in the absence of progression or unacceptable toxicity.

Intensified IE-VAC (for Ewing's sarcoma):  Used in an alternating schedule with VAC* for a total of 14 cycles (7 of each) given every 2 weeks. G-CSF Prophylaxis is recommended with this regimen

 Note that only patients less than 50 years old were included in the clinical trial by Womer et al.
* Refer to VAC regimen.

 
D - Premedication and Supportive Measures

Antiemetic Regimen:

Moderate


Febrile Neutropenia Risk:

Moderate

Other Supportive Care:

  • Standard regimens for ifosfamide hydration should be followed. Refer to local guidelines.
  • Oral hydration is also strongly encouraged; poorly hydrated patients may need more IV hydration. Inadequate total hydration may result in dose-related hemorrhagic cystitis
 
E - Dose Modifications

Doses should be modified according to the protocol by which the patient is being treated. The following recommendations have been adapted from clinical trials or product monographs and could be considered.


 

Dosage with toxicity

Worst Toxicity / Counts (x109/L) in previous cycle

 

Worst Toxicity / Counts (x 109/L) in previous cycle

Action

ANC <1.5

OR

Platelet <  100

Hold *; consider G-CSF if repeated delay and reduce dose by 25% if delayed
>7 days despite G-CSF

Febrile Neutropenia

OR

ANC < 0.5 for ≥ 5-7 days

OR

Thrombocytopenic bleeding

OR

Platelets < 25

 Hold *, then 75% or consider GCSF if isolated neutropenia. If recurs despite GCSF, reduce dose by 25%

Cardiotoxicity**

 

 

Consider discontinuing ifosfamide when LVEF ≤ 45%

Grade 3 or 4 mucositis, diarrhea or typhlitis

 

 

Hold*; restart with 25% ↓ in dose with etoposide 

Grade 1 or 2 somnolence or other signs of encephalopathy

 

 

Hold ifosfamide; methylene blue 50mg IV q4h until resolution. Consider prophylactic methylene blue for subsequent cycles. Consider discontinuing or dose reduce for ifosfamide for next cycle.

Worst Toxicity / Counts (x109/L) in previous cycle   Worst Toxicity / Counts (x 109/L) in previous cycle Action

Grade 3 or 4 CNS toxicity

 

 

Manage appropriately.  Discontinue ifosfamide

Grade 3 related other organ / non-hematologic

 

 

*75% for suspect drug(s)

Grade 4 related other organ / non-hematologic;

Hypersensitivity

 

 

Discontinue

 


*Do not restart until platelets ≥ 100 x 109/L, ANC ≥ 1.5 x 109/L, and toxicities have recovered to ≤ grade 2 (and until resolution of neuro- or CNS toxicity).

**including any signs and symptoms of heart  failure, greater than 10% decline in LVEF to below the lower limit of normal, a greater than 20% decline in LVEF from any level, or LVEF ≤ 45%.

Management of Urotoxicity

Finding

Action

Microscopic hematuria

Hold ifosfamide until resolves. Consider increasing mesna dose (e.g. double) in subsequent cycle.

Macroscopic hematuria

Discontinue or reduce ifosfamide dose



Hepatic Impairment

Bilirubin

 

AST/ALT

Etoposide (% previous dose)
Ifosfamide*
(% previous dose)

1-2 x ULN

and/  or

<2 x ULN

50%

100%

2-4 x ULN

2-5 x ULN

25%

75%

> 4 x ULN

> 5 x ULN

Discontinue

Discontinue

*Based on clinical judgment – less conservative adjustments can be considered if hepatic changes are secondary to metastases rather than hepatic cirrhosis or hepatitis.

Renal Impairment

Creatinine Clearance (mL/min)
Etoposide (% previous dose)
Ifosfamide (% previous dose)

> 60

100%

100%

40-60

75% (if CrCl ≤ 50mL/min)

75%

20-40

75%

50%

< 20

 50% or Discontinue

Discontinue

Dosage in the elderly:

  • Exercise caution as the elderly population may have decreased hepatic, renal, cardiac or hematopoietic function.  Increases in ifosfamide half-life has been observed with advancing age; however, no significant changes in clearance were reported.
  • No dose adjustment required for etoposide

Children:

  • Safety and efficacy have not been fully established. Refer to treatment protocol for details. Side effects in children were reported to be similar to those in adults. Children 5 years of age or younger may be more susceptible to ifosfamide- induced renal toxicity than older children and adults.

 
F - Adverse Effects

Refer to etoposide, ifosfamide, mesna drug monograph(s) for additional details of adverse effects


Most Common Side Effects 

Less Common Side Effects, but may be
Severe or Life-Threatening

  • Dysgeusia (oral mesna)
  • Alopecia
  • Nausea, vomiting
  • Myelosuppression +/- infection, bleeding (may be severe)
  • Abdominal pain
  • Hemorrhagic cystitis (may be severe)
  • Neurotoxicity (including encephalopathy-may be severe)
  • Anorexia
  • Diarrhea
  • Flu-like symptoms
  • Nephrotoxicity (may be severe)
  • Injection site reactions
  • Hypersensitivity
  • Cardiotoxicity
  • Arrhythmia
  • Arterial thromboembolism
  • Venous thromboembolism
  • Hemolysis, hemolytic uremic syndrome
  • Pancreatitis
  • Pneumonitis
  • Rhabdomyolysis
  • SIADH
  • Secondary malignancies
  • Disseminated intravascular coagulation
  • Renal tubular acidosis
  • Radiation recall reaction
  • Rash
 
G - Interactions

Refer to etoposide, ifosfamide, mesna drug monograph(s) for additional details


  • Increased neurotoxicity has been reported with ifosfamide and aprepitant; caution and monitor closely if used together
  • P-glycoprotein inhibitors can reduce clearance and increase etoposide toxicity
  • Use drugs that inhibit phosphatase with caution (e.g. levimasole) due to increased etoposide toxicity
  • CYP3A4 inhibitors can decrease metabolism and increase etoposide levels.  Use with caution; may require dose adjustment
  • Monitor PT/INR closely for patients who are on warfarin due to possible increased anticoagulant effects
  • Glucosamine may decrease the efficacy of etoposide; avoid
  • Ifosfamide is a major substrate of CYP3A4 and a minor substrate of 2A6, 2B6, 2C8, 2C19 and 2C9. Inhibitors or inducers of these isoenzymes may decrease or increase the metabolism of ifosfamide.
  • Ifosfamide is also a weak inhibitor of CYP3A4 and a weak inducer of CYP2C8 and 2C9.
  • Drugs acting on the CNS have additive CNS effects with ifosfamide.  Discontinue if possible.
  • Hepatic-enzyme inducing drugs may increase ifosfamide toxicity; use with caution and monitor
  • Nephrotoxic, ototoxic and cardiotoxic drugs can increase the risk of ifosfamide toxicity; use with caution and monitor
 
H - Drug Administration and Special Precautions

Refer to etoposide, ifosfamide, mesna drug monograph(s) for additional details


Administration

Etoposide:

  • Maximum diluted concentration of 0.4 mg/mL
  • All premixed bag(s) should be attached to (0.22 micron) in-line filter.
  • Precipitation is unpredictable, depending on concentration, time after dilution, presence of crystallization nuclei, agitation, contact with incompatible surfaces and other factors.
  • Monitor solutions for precipitation before and during administration.
  • Dilute doses ≤100 mg in 250 mL NS or D5W, doses >100 mg to ≤200 mg in 500 mL, and doses> 200 mg in 1000 mL
  • The use of non-PVC containers and tubing is recommended due to the potential for polysorbate 80 leaching of diethylhexyl phthalate (DEHP), from polyvinyl chloride (PVC) containers and tubing into etoposide IV solution.
  • Larger volumes may be used for prehydration for Cisplatin or Ifosfamide dose.
  • Infuse over 30 to 60 minutes; Adjust rate if blood pressure drops. Etoposide should not be given by rapid I.V. injection.
  • May observe patient for 30 minutes after dose, to watch for hypotension.
  • Acrylic or ABS (a polymer composed of acrylonitrile. butadiene and styrene) infusion devices may crack if exposed to undiluted etoposide.

Ifosfamide:

  • May give bolus dose of mesna before ifosfamide infusion, with or without mesna admixed in ifosfamide solution, then followed by 2 doses of mesna by IV bolus or PO, see mesna monograph.
  • Add reconstituted drug to NS or D5W for infusion; the final concentration should be between 0.6 to 20 mg/mL.
  • May mix doses ≤2000mg in 100mL bag; Infuse over 30-60 minutes.
  • May mix doses >2000mg in 500-1000mL bag; Infuse over 1-4 hours.
  • May be admixed with mesna.
  • Oral hydration is strongly encouraged; poorly hydrated patients may need more IV hydration.
  • Inadequate total hydration may result in dose-related hemorrhagic cystitis.
  • Ifosfamide and Mesna Admixture
  • May be diluted in larger volumes for continuous infusion over 6-24 hours; May be infused using a CADD ambulatory infusion pump over longer periods.

Contraindications

  • Etoposide is contraindicated in patients with known hypersensitivity to etoposide or to any component of the formulation (polysorbate 80), with severe myelosuppression, or with severe hepatic and/or renal impairment. Patients with low serum albumin may be at an increased risk of toxicity.
  • Ifosfamide is contraindicated in patients with known hypersensitivity to the drug, with severe myelosuppression, severe renal and/or hepatic impairment, cystitis, obstructive uropathy, active infections/severe immunosuppression, or cerebral arteriosclerosis.
  • Avoid the use of live vaccines.

Other warnings/precautions

  • Mesna must be coadministered with ifosfamide.
  • Use with caution in patients with prior radiotherapy or anticancer therapy, concomitant aprepitant usage, hepatic or renal impairment, risk factors for cardiotoxicity, hypoalbuminemia, pre-existing cardiac disease, brain or extensive bone marrow metastases, concurrent or prior use of nephrotoxic agents or prior nephrectomy. Do not use within 10 to 14 days of surgery or within 3 months after nephrectomy.
  • Electrolytes imbalances must be corrected before treatment.
  • Alcohol can increase the risk of nausea/vomiting or neurotoxicity; avoid
  • Etoposide and ifosfamide are not recommended for use in pregnancy or breastfeeding. Effective contraception must be used by both sexes during ifosfamide treatment and for at least 12 months after treatment cessation. Fertility is usually affected.
 
I - Recommended Clinical Monitoring

Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.

 

Recommended Clinical Monitoring

  • CBC; Baseline and prior to each dose
  • Liver function tests; Baseline and prior to each dose
  • Renal function tests, including electrolytes; Baseline and prior to each dose
  • Urinalysis, for RBCs and specific gravity; before each ifosfamide dose
  • Clinical assessment of hypertension, infection, bleeding and cystitis,neurotoxicity (especially in patients with increased risk), rash, GI symptoms (including stomatitis), infusion site reactions and hypersensitivity; at each visit
  • Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version


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J - Administrative Information

Approximate Patient Visit
4.5 hours
Pharmacy Workload (average time per visit)
34.992 minutes
Nursing Workload (average time per visit)
54.167 minutes
 
K - References

Arndt CA, Nascimento AG, Schroeder G, et al. Treatment of intermediate risk rhabdomyosarcoma and undifferentiated sarcoma with alternating cycles of vincristine/doxorubicin/cyclophosphamide and etoposide/ifosfamide. Eur J Cancer 1998;34:1224–1229.

Arndt CA, Hawkins DS, Meyer WH, et al.  Comparison of results of a pilot study of alternating vincristine/doxorubicin/cyclophosphamide and etoposide/ifosfamide with

Etoposide and Ifosfamide drug monographs, Cancer Care Ontario.

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. 

Hensley ML, Hagerty KL, Kewalramani T, et al. American Society of Clinical Oncology (ASCO) 2008 clinical practice guideline update: use of chemotherapy and radiation therapy protectants. J Clin Oncol. 2009 Jan 1; 27(1):127-45.

IRS-IV in intermediate risk rhabdomyosarcoma: a report from the Children's Oncology Group.  Pediatr Blood Cancer 2008 Jan;50(1):33-6.

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.

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.

Womer RB, West DC, Krailo MD, Dickman PS, Pawel BR, Grier HG, Marcus K, Sailer S, Healey JH, Dormans JP, Weiss AR.  Randomized controlled trial of interval-compressed chemotherapy for the treatment of localized Ewing sarcoma:  a report from the Children's Oncology Group.  J Clin Oncol. 2012 Nov 20; 30(33): 4148-54. 

February 2018 aligned mesna dosing with ST-QBP; modified intents


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M - Disclaimer

Regimen Abstracts
A Regimen Abstract is an abbreviated version of a Regimen Monograph and contains only top level information on usage, dosing, schedule, cycle length and special notes (if available). It is intended for healthcare providers and is to be used for informational purposes only. It is not intended to constitute or be a substitute for medical advice, and all uses of the Regimen Abstract are subject to clinical judgment. Such information is provided on an “as-is” basis, without any representation, warranty, or condition, whether express, or implied, statutory or otherwise, as to the information’s quality, accuracy, currency, completeness, or reliability, and Cancer Care Ontario disclaims all liability for the use of this information, and for any claims, actions, demands or suits that arise from such use.
Information in regimen abstracts is accurate to the extent of the ST-QBP regimen master listings, and has not undergone the full review process of a regimen monograph.  Full regimen monographs will be published for each ST-QBP regimen as they are developed.
Regimen Monographs
Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.
The information set out in the drug monographs, regimen monographs, appendices and symptom management information (for health professionals) contained in the Drug Formulary (the "Formulary") is intended for healthcare providers and is to be used for informational purposes only. The information is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects of a particular drug, nor should it be construed to indicate that use of a particular drug is safe, appropriate or effective for a given condition. The information in the Formulary is not intended to constitute or be a substitute for medical advice and should not be relied upon in any such regard. All uses of the Formulary are subject to clinical judgment and actual prescribing patterns may not follow the information provided in the Formulary.
The format and content of the drug monographs, regimen monographs, appendices and symptom management information contained in the Formulary will change as they are reviewed and revised on a periodic basis. The date of last revision will be visible on each page of the monograph and regimen. Since standards of usage are constantly evolving, it is advised that the Formulary not be used as the sole source of information. It is strongly recommended that original references or product monograph be consulted prior to using a chemotherapy regimen for the first time.
Some Formulary documents, such as the medication information sheets, regimen information sheets and symptom management information (for patients), are intended for patients. Patients should always consult with their healthcare provider if they have questions regarding any information set out in the Formulary documents.
While care has been taken in the preparation of the information contained in the Formulary, such information is provided on an “as-is” basis, without any representation, warranty, or condition, whether express, or implied, statutory or otherwise, as to the information’s quality, accuracy, currency, completeness, or reliability.
CCO and the Formulary’s content providers shall have no liability, whether direct, indirect, consequential, contingent, special, or incidental, related to or arising from the information in the Formulary or its use thereof, whether based on breach of contract or tort (including negligence), and even if advised of the possibility thereof. Anyone using the information in the Formulary does so at his or her own risk, and by using such information, agrees to indemnify CCO and its content providers from any and all liability, loss, damages, costs and expenses (including legal fees and expenses) arising from such person’s use of the information in the Formulary.