Doxorubicin (75) and Ifosfamide Therapy: NCCP Chemotherapy Regimen

NCCP Chemotherapy Regimen
DOXOrubicin (75) and Ifosfamide Therapy
INDICATIONS FOR USE:

Regimen Reimbursement
INDICATION ICD10 Code Status
Neoadjuvant treatment of high risk soft tissue sarcoma C49 00392a Hospital
Treatment of locally advanced unresectable or metastatic soft tissue C49 00392b Hospital
sarcomas
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.
DOXOrubicin and ifosfamide are administered on Days 1, 2 and 3 of a 21 day cycle for up to 6 cycles or until disease
progression or unacceptable toxicity develops. 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.
Note:
 Hydration therapy required for safe administration of ifosfamide ( See Table below)
Facilities to treat anaphylaxis MUST be present when the chemotherapy is administered.
Day Drug Dose Route Diluent & Rate Cycle

1,2,3 DOXOrubicina 25mg/m2 IV bolus Slow bolus with 0.9% NaCl Every 21 days for up to 6 cycles
1 Mesna 900mg/m2 IV infusion 100mls NaCl 0.9% over 10 Every 21 days for up to 6 cycles
minutes immediately before the
infusion of Ifosfamide
1,2,3, Ifosfamideb 3000mg/m2 IV infusion 1L NaCl 0.9% over 3 hours Every 21 days for up to 6
cycles
1,2,3 Mesna 3000mg/m2 IV infusion 1L NaCl 0.9% over 24 hours Every 21 days for up to 6
continuous infusion cycles
commencing the same time as
the ifosfamide infusion
Mesna is used to protect against haemorrhagic cystitis. Refer to Adverse Reactions/Regimen Specific Complications
aLifetime cumulative dose of doxorubicin is 450mg/m 2
In establishing the maximal cumulative dose of an anthracycline, consideration should be given to the risk factors outlined belowi and
to the age of the patient.
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
NCCP Regimen: DOXOrubicin 75 and Published: 20/12/2016

Version number: 4
Ifosfamide therapy Review: 06/01/2026
Tumour Group: Sarcoma IHS/ISMO Contributor:
Page 1 of 5
NCCP Regimen Code: 00392 Prof Maccon Keane
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 judgement in the context of
individual clinical circumstances to determine any patient's care or treatment. Use of these documents is the responsibly 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 0-1
 Adequate hepatic, renal, and bone marrow function
EXCLUSIONS:
 Hypersensitivity to DOXOrubicin, ifosfamide 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
 Cardiac function using ECG and MUGA or ECHO (LVEF ≥ 50% to administer DOXOrubicin) if >65
years or if clinically indicated (eg smoking history, hypertension).
Regular tests:
 FBC, liver and renal profile prior to each cycle
 Cardiac function using MUGA or ECHO if clinically indicated
 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.
Haematological:
Table 1: Dose modification of DOXOrubicin and Ifosfamide in haematological toxicity
9 9
ANC (x10 /L) Platelets (x10 /L) Dose
≥1.5 and ≥100 100%

1 to <1.5 Or 70to <100 80%
<1 or <70 Delay one week
<0.5 And neutropenic fever 80%

Version number: 4
Page 2 of 5
Renal and Hepatic Impairment:

Table 2: Dose modification of DOXOrubicin and Ifosfamide in renal and hepatic impairment
Drug Renal Impairment Hepatic Impairment
DOXOrubicin No dose reduction required. Clinical decision in Total Bilirubin Dose
severe impairment (micromole/L)
20-51 50%
51-85 25%
>85 Omit
If AST 2-3 x ULN give 75% dose
If AST > 3 x ULN give 50% dose
Ifosfamide GFR (ml/min) Dose Dose reductions are probably not necessary
>60 100% for patients with altered liver function.
However ifosfamide is extensively hepatically
40-59 70% metabolised and some clinicians recommend
<40 Clinical decision a 25% dose reduction for patients with
significant hepatic dysfunction ( serum AST >
300IU/L or bilirubin > 51.3 micromol/L (4)
The SPC states that it is not recommended in
patients with a bilirubin >17 micromol/L or
transaminases >2.5xULN
Management of adverse events:

Table 3: Dose Modification of DOXOrubicin and Ifosfamide for Adverse Events
Adverse reactions Recommended dose modification
Mucositis Grade≥3 Reduce both drugs to 80%
Neurotoxicity Grade ≥ 3 Discontinue ifosfamide
SUPPORTIVE CARE:
EMETOGENIC POTENTIAL:
DOXOrubicin: Moderate (Refer to local policy)
Ifosfamide: High (Refer to local policy)
Consider increased risk of ifosfamide-induced neurotoxicity due to inhibition of CYP3A4 by aprepitant
PREMEDICATIONS:
None usually required
OTHER SUPPORTIVE CARE:

G-CSF support is required with this regimen (Refer to local policy)
Proton Pump Inhibitor prophylaxis (Refer to local policy)

Version number: 4
Page 3 of 5
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.
 Cardiotoxicity: DOXOrubicin is cardiotoxic and must be used with caution, if at all, in patients with severe
hypertension or cardiac dysfunction
 Extravasation: DOXOrubicin causes pain and tissue necrosis if extravasated (Refer to local policy).
 Red discolouration of urine: This may occur for 1-2 days after administration of doxorubicin.
 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 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.
 Infertility: Both DOXOrubicin and ifosfamide have genotoxic effects and may cause infertility. Women
should not become pregnant during and up to 6 months after treatment and men are also advised not to
father a child during this time.
DRUG INTERACTIONS:
 DOXOrubicin cardiotoxicity is enhanced by previous or concurrent use of other anthracyclines, or other
potentially cardiotoxic drugs (e.g. 5-FU, cyclophosphamide,paclitaxel or trastuzumab) or with products
affecting cardiac function (e.g. calcium antagonists).
 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.
 Current drug interaction databases should be consulted for more information
ATC CODE:
DOXOrubicin L01DB01
Ifosfamide L01AA06
REFERENCES:
1. Grobmyer SR et al. Neo-adjuvant chemotherapy for primary high-grade extremity soft tissue sarcoma. Ann
Oncol 2004;15:1667-72.
2. Dosage Adjustment for Cytotoxics in Renal Impairment. North London Cancer Network. Available at
http://londoncancer.org/media/65600/renal-impairment-dosage-adjustment-for-cytotoxics.pdf
3. Dosage Adjustment for Cytotoxics in Hepatic Impairment. North London Cancer Network. Available at
http://londoncancer.org/media/65594/hepatic-impairment-dosage-adjustment-for-cytotoxics.pdf
Version number: 4
Page 4 of 5
4. Motzer RJ, Mazumdar M, Sheinfeld J et al. Sequential dose-intensive paclitaxel, ifosfamide, carboplatin, and
etoposide salvage therapy for germ cell tumor patients. J Clin Oncol. 2000;18(6):1173-80.
5. DOXOrubicin 2mg/ml Concentrate for Solution for Infusion. SmPC. HPRA. Accessed Dec 2020. Available at:
https://www.hpra.ie/img/uploaded/swedocuments/Licence_PA2315-083-001_26022020112618.pdf
6. Mitoxana 1g Powder for Sterile Concentrate. SmPC. HPRA. Accessed Dec 2020. Available at
https://www.hpra.ie/img/uploaded/swedocuments/Licence_PA2299-028-001_15102019093147.pdf
7. NCCP Classification Document for Systemic Anti-Cancer Therapy (SACT) Induced Nausea and Vomiting. V2
2019. Available at: https://www.hse.ie/eng/services/list/5/cancer/profinfo/chemoprotocols/nccp-
classification-document-for-systemic-anti-cancer-therapy-sact-induced-nausea-and-vomiting.pdf
Version Date Amendment Approved By

1 20/12/2016 Prof Maccon Keane
Updated to new NCCP template
Inclusion of standardized hydration
2 16/01/2019 Prof Maccon Keane
therapy recommendations for
ifosfamide
Standardisation of dose
3 10/07/2019 modifications for ifosfamide in Prof Maccon Keane
hepatic toxicity
Updated tests, emetogenic
4 06/01/2021 potential, adverse events and drug Prof. Maccon Keane
interactions.
Comments and feedback welcome at oncologydrugs@cancercontrol.ie.
1
Cardiotoxicity is a risk associated with anthracycline therapy that may be manifested by early (acute) or late
(delayed) effects.
Risk factors for developing anthracycline-induced cardiotoxicity include:
• high cumulative dose, previous therapy with other anthracyclines or anthracenediones
• prior or concomitant radiotherapy to the mediastinal/pericardial area
• pre-existing heart disease
• concomitant use of other potentially cardiotoxic drugs
In establishing the maximal cumulative dose of an anthracycline, consideration should be given to the risk factors
above and to the age of the patient

Version number: 4
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NCCP Chemotherapy Regimen

DOXOrubicin (75) and Ifosfamide Therapy

INDICATIONS FOR USE:

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

Day Drug Dose Route Diluent & Rate Cycle

NCCP Regimen: DOXOrubicin 75 and Published: 20/12/2016

≥1.5 and ≥100 100%

NCCP Regimen: DOXOrubicin 75 and Published: 20/12/2016

Renal and Hepatic Impairment:

Management of adverse events:

DOXOrubicin: Moderate (Refer to local policy)

Ifosfamide: High (Refer to local policy)

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

OTHER SUPPORTIVE CARE:

NCCP Regimen: DOXOrubicin 75 and Published: 20/12/2016

ADVERSE EFFECTS / REGIMEN SPECIFIC COMPLICATIONS

Version Date Amendment Approved By

Comments and feedback welcome at oncologydrugs@cancercontrol.ie.

NCCP Regimen: DOXOrubicin 75 and Published: 20/12/2016

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