596 Ifosfamide Etoposide Ie Therapy

NCCP Chemotherapy Regimen
Ifosfamide Etoposide (IE) Therapyi

INDICATIONS FOR USE:
Regimen Reimbursement
INDICATION ICD10 Code Status
For the treatment of relapsed Ewing Sarcoma C41 00596a Hospital
For the treatment of osteosarcoma C41 00596b Hospital
TREATMENT:
The starting dose of the drugs detailed below may be adjusted downward by the prescribing clinician, using their
independent medical judgement, to consider each patients individual clinical circumstances.
Ifosfamide and etoposide are administered on Days 1 - 5 of a 21 day cycle for up to 7 cycles until disease
progression or unacceptable toxicity occurs.
Mesna is administered prior to the first dose of ifosfamide on Day 1 and is continued throughout the
chemotherapy up to 24 hrs after the ifosfamide infusion.
Facilities to treat anaphylaxis MUST be present when the chemotherapy is administered.
Note: Hydration therapy required for safe administration of ifosfamide (See Table below)
Admin. Day Drug Dose Route Diluent & Rate Cycle

Order
1 1,2,3,4, 5 Etoposide 100mg/m2 IV infusion 500ml NaCl 0.9% over 60min Every 21 days
2 1,2,3,4, 5 Mesnaa 360mg/m2 IV infusion 100ml NaCl 0.9% over 15min Every 21 days
1,2,3,4, 5 Ifosfamideb, c 1800mg/m2 IV infusion 500ml NaCl 0.9% over 4hours Every 21 days
3 1,2,3,4, 5 Mesna 360mg/m2 IV infusion 500ml NaCl 0.9% over 4hours Every 21 days
4 1,2,3,4, 5 Mesna 360mg/m2 IV infusion 100ml NaCl 0.9% over 15min Every 21 days
aMesna is used to protect against haemorrhagic cystitis. Refer to Adverse Reactions/Regimen Specific Complications
bIfosfamide: Suggested Hydration therapy. (Refer to local policy or see suggested hydration below). Ensure IV hydration 1L NaCL 0.9%
IV every 6 hours) is given, commencing prior to first dose of ifosfamide and continuing for 24 hours after the ifosfamide has stopped.
Furosemide should also be administered if required to ensure a urinary output of at least 100ml/hour Maintain strict fluid balance
during therapy, by (1) monitoring fluid balance and (2) daily weights. If fluid balance becomes positive by >1000mls or weight
increases by >1 Kg, the patient should be reviewed and consideration given to diuresing with furosemide
c Total cumulative dose of Ifosfamide generally should not exceed 72 g/m² as there is an increased risk of Renal Fanconi Syndrome in
children.
NCCP Regimen: Ifosfamide Etoposide (IE) Published: 25/05/2022

Version number: 1
Therapy Review: 25/05/2023
Tumour Group: Sarcoma ISMO Contributor: Dr. Mark Doherty
Page 1 of 6
NCCP Regimen Code: 00596
The information contained in this document is a statement of consensus of NCCP and ISMO or IHS professionals regarding their views of currently accepted
approaches to treatment. Any clinician seeking to apply or consult these documents is expected to use independent medical jud gement in the context of
individual clinical circumstances to determine any patient's care or treatment. Use of these documents is the responsibility of the prescribing clinician and is
subject to HSE’s terms of use available at http://www.hse.ie/eng/Disclaimer
This information is valid only on the day of printing, for any updates please check www.hse.ie/NCCPchemoregimens
ELIGIBILITY:
 Indications as above
 ECOG 0-2
 Adequate hepatic, renal and bone marrow function.
EXCLUSIONS:
 Hypersensitivity to ifosfamide, etoposide or any of the excipients.
 Pregnancy
 Lactation
PRESCRIPTIVE AUTHORITY:
 The treatment plan must be initiated by a Consultant Medical Oncologist
TESTS:
Baseline tests:
 FBC, liver and renal profile.
 Sodium, potassium, phosphate levels
Regular tests:
 FBC, liver and renal profile prior to each cycle.
 Sodium, potassium, phosphate levels
 Assess neurological function prior to each ifosfamide dose.
 Monitor for haematuria prior to each ifosfamide dose and every 8 hrs on treatment days.
Disease monitoring:
Disease monitoring should be in line with the patient’s treatment plan and any other test/s as
directed by the supervising Consultant.
DOSE MODIFICATIONS:
 Any dose modification should be discussed with a Consultant.

Version number: 1
Page 2 of 6
Haematological:
Table 1: Dose modification of ifosfamide and etoposide in haematological toxicity
9 9
ANC (x10 /L) Platelets (x10 /L) Dose
Greater than or And Greater than or equal to 100 Give 100%

equal to 0.75
Less than 0.75 Or Less than 100 Delay for 1 week*
 If counts recover then give 100%
 If counts do NOT recover by Day 22
then reduce dose by 20% and continue
with Q2 weekly dosing if possible
*If unable to give full dose after 1 week delay – use dose reduction as indicated
Renal and Hepatic Impairment:

Table 2: Dose modification of ifosfamide and etoposide in renal and hepatic impairment
Renal Impairment Hepatic Impairment
CrCl (ml/min) Dose Bilirubin (micromol/L) AST Dose
Etoposide >50 100% 26-51 or 60-180 50%
15-50 75% >51 or >180 Clinical decision
<15 50%
Subsequent doses should be based
on clinical response
Ifosfamide >60 100% Mild and moderate: no need for dose adjustment is
40-59 70% expected.
<40 Clinical decision Severe: not recommended, due to risk of reduced efficacy.
Dose reductions are probably not necessary for patients
with altered liver function. However ifosfamide is
extensively hepatically metabolised and some clinicians
recommend a 25% dose reduction for patients with
significant hepatic dysfunction (serum AST > 300units/L or
bilirubin > 51.3 micromol/L). Clinical decision.

Version number: 1
Page 3 of 6
Management of adverse events:

Table 3: Dose Modifications of Ifosfamide and Etoposide for Adverse Events
Adverse event Dose Modification
Mucositis and Stomatitis
Grade 3 or 4 Reduce etoposide and ifosfamide by 25%

Neurotoxicity
Grade 3 or 4 1st occurrence: Prolong ifosfamide infusion to 4-8 hours with the next
application, and administer methylene blue IV 50 mg every 8 hours
Prophylaxis for subsequent ifosfamide doses: Administer single dose methylene

blue 50mg IV 24 hours prior to ifosfamide dose, prolong ifosfamide infusion to 4-8
hours with the next application, and administer methylene blue IV 50 mg every 8
hours.
Further episodes: Consider substitution of ifosfamide with cyclophosphamide

1500mg/m2 day 1 only
SUPPORTIVE CARE:
EMETOGENIC POTENTIAL:
Ifosfamide – High (Refer to local policy).
Etoposide - Low (Refer to local policy).
 Consider increased risk of ifosfamide-induced neurotoxicity due to inhibition of CYP3A4 by aprepitant
PREMEDICATIONS: Not usually required.
OTHER SUPPORTIVE CARE:

G-CSF support is required with this regimen (Refer to local policy)
ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS:

The adverse effects listed are not exhaustive. Please refer to the relevant Summary of Product Characteristics for full
details.
 Neutropenia: Fever or other evidence of infection must be assessed promptly and treated
appropriately.
Ifosfamide
 Ifosfamide-induced encephalopathy: This may occur in patients treated with high doses of ifosfamide.
Neurological function should be assessed prior to each ifosfamide dose.
 Renal and urothelial toxicity: Ifosfamide is both nephrotoxic and urotoxic. Glomerular and tubular
kidney function must be evaluated and checked before commencement of therapy, as well as during
and after treatment. Urinary sediment should be checked regularly for the presence of erythrocytes
Version number: 1
Page 4 of 6
and other signs of uro/nephrotoxicity. During or immediately after administration, adequate amounts
of fluid should be ingested or infused to force diuresis in order to reduce the risk of urinary tract
toxicity. For prophylaxis of hemorrhagic cystitis, ifosfamide should be used in combination with
mesna. Ifosfamide should be used with caution, if at all, in patients with active urinary tract infections
Etoposide
 Hypersensitivity: Hypersensitivity reactions have been reported with etoposide. Monitor infusion of
etoposide for the first 15 minutes for signs of hypotension
DRUG INTERACTIONS:
 Current drug interaction databases should be consulted for more information.
 Increased nephrotoxicity may result from a combined effect of ifosfamide and other nephrotoxic drugs
e.g. aminoglycosides, platinum compounds Increased risk of ifosfamide-induced neurotoxicity due to
inhibition of CYP3A4 by aprepitant.
 Avoid combination of CYP3A4 inducers and ifosfamide. There is the possibility of increased toxicity of
ifosfamide due to increased conversion to active and toxic metabolites.
 Reduced efficacy of ifosfamide possible with CYP3A4 inhibitors due to decreased conversion to active
metabolites.
 CYP 3A4 enzyme inducers may increase the clearance of etoposide.
 CYP3A4 enzyme inhibitors may decrease the clearance of etoposide.
 P-gp inhibitors may decrease the clearance of etoposide.
 Current drug interaction databases should be consulted for more information.
REFERENCES:
1. Van Oosterom AT, et al. Results of randomized 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; 38:2397-406.
2. Miser JS, et al. 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;
5(8):1191-8.
3. Verma S, Bramwell V. Dose-intensive chemotherapy in advanced adult soft tissue sarcoma. Expert
Rev Anticancer Ther 2002; 2(2):201-15.
4. Dosage Adjustment for Cytotoxics in Renal Impairment January 2009; North London Cancer
Network.
5. Dosage Adjustment for Cytotoxics in Hepatic Impairment January 2009; North London Cancer
Network.
6. Floyd J and Kerr TA. Chemotherapy hepatotoxicity and dose modification in patients with liver
disease UptoDate https://www.uptodate.com/contents/chemotherapy-hepatotoxicity-and-dose-
modification-in-patients-with-liver-disease#H14
7. NCCP Classification Document for Systemic Anti-Cancer Therapy (SACT) Induced Nausea and
Vomiting. V4 2022. Available at:
https://www.hse.ie/eng/services/list/5/cancer/profinfo/chemoprotocols/nccp-classification-

Version number: 1
Page 5 of 6
document-for-systemic-anti-cancer-therapy-sact-induced-nausea-and-vomiting.pdf
8. Ifosfamide (Mitoxana®) Summary of product characteristics. Accessed: May 2022. Available
at:https://www.hpra.ie/img/uploaded/swedocuments/Licence_PA2299-028-
001_06092021170432.pdf
9. Etoposide Summary of product characteristics. Accessed May 2022. Available
001_17052021114619.pdf
10. Uromitexan® (mesna) Summary of Product Characteristics. Accessed Aug 2022. Available
001_22102019104556.pdf
Version Date Amendment Approved By

1 25/05/2022 Dr Mark Doherty
Comments and feedback welcome at oncologydrugs@cancercontrol.ie.
i
This is an unlicensed indication for the use of etoposide in Ireland. Patient’s should be informed of this and
consented to treatment in line with the hospital’s policy on the use of unlicensed medication and
unlicensed or “off label” indications. Prescribers should be fully aware of their responsibility in
communicating any relevant information to the patient and also ensuring that the unlicensed or “off label”
indication has been acknowledged by the hospital’s Drugs and Therapeutics Committee, or equivalent, in
line with hospital policy.

Version number: 1
Page 6 of 6

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NCCP Chemotherapy Regimen

Ifosfamide Etoposide (IE) Therapyi

Facilities to treat anaphylaxis MUST be present when the chemotherapy is administered.

Admin. Day Drug Dose Route Diluent & Rate Cycle

NCCP Regimen: Ifosfamide Etoposide (IE) Published: 25/05/2022

NCCP Regimen: Ifosfamide Etoposide (IE) Published: 25/05/2022

Greater than or And Greater than or equal to 100 Give 100%

Renal and Hepatic Impairment:

NCCP Regimen: Ifosfamide Etoposide (IE) Published: 25/05/2022

Management of adverse events:

Grade 3 or 4 Reduce etoposide and ifosfamide by 25%

Prophylaxis for subsequent ifosfamide doses: Administer single dose methylene

Further episodes: Consider substitution of ifosfamide with cyclophosphamide

 Consider increased risk of ifosfamide-induced neurotoxicity due to inhibition of CYP3A4 by aprepitant

PREMEDICATIONS: Not usually required.

OTHER SUPPORTIVE CARE:

ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS:

NCCP Regimen: Ifosfamide Etoposide (IE) Published: 25/05/2022

Version Date Amendment Approved By

Comments and feedback welcome at oncologydrugs@cancercontrol.ie.

NCCP Regimen: Ifosfamide Etoposide (IE) Published: 25/05/2022

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