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Non-Hodgkin lymphoma ICE (fractionated iFOSFamide cARBOplatin etoposide)

 ADDIKD Carboplatin dosing:

For dosing carboplatin, ADDIKD recommends that:

  • Directly measured glomerular filtration rate (mGFR) is the preferred kidney function value in the Calvert formula​, especially where estimated kidney function may be unreliable for accurate therapeutic dosing.
  • Where mGFR is unavailable, eGFR adjusted to an individual’s body surface area (BSA-adjusted eGFR) is a suitable alternative for use in the Calvert formula.
  • Kidney function should not be capped at 125 mL/min for use in the Calvert formula.
  • Recalculation of carboplatin doses at each cycle is unnecessary, except when baseline kidney function (e.g., eGFR) alters by > 20% or when there is a change in the clinical status of the patient.

For further information refer the eviQ Factsheet around carboplatin dosing and the carboplatin drug monograph within the ADDIKD guideline. To assist with calculations, use the eviQ Estimated Glomerular Filtration Rate (eGFR) and carboplatin dose calculators.

Patients with lymphoma should be considered for inclusion into clinical trials. Link to ALLG website, ANZCTR website and Lymphoma Australia website.

This protocol is based on limited evidence; refer to the evidence section of this protocol for more information.

The anticancer drug(s) in this protocol may have been included in the ADDIKD guideline. Dose recommendations in kidney dysfunction have yet to be updated to align with the ADDIKD guideline. Recommendations will be updated once the individual protocol has been evaluated by the reference committee. For further information refer to the ADDIKD guideline. To assist with calculations, use the eviQ Estimated Glomerular Filtration Rate (eGFR) calculator.

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Cycle 1 and 2

Drug Dose Route Day
Etoposide * 100 mg/m2 IV infusion 1 to 3
cARBOplatin 5 AUC (Cap dose at 800 mg) IV infusion 1
iFOSFamide 1,666 mg/m2 IV infusion 1 to 3
Mesna 1,666 mg/m2 IV infusion 1 to 3
Mesna 2,000 mg at 2 and 6 hours post completion of ifosfamide PO 1 to 3
Filgrastim 5 micrograms/kg Subcut 4 and continue daily until neutrophil recovery

* Etopophos (etoposide phosphate) 113.6 mg is equivalent to etoposide 100 mg. Doses in this protocol are expressed as etoposide.

Frequency:
21 days 
Cycles:
2 to 3
Notes:
  • This is an intense chemotherapy regimen; patients with poor ECOG performance status and significant co-morbidities may not be appropriate for this regimen.
  • This protocol may be used for mobilisation of peripheral blood haematopoietic stem cells. The dose of filgrastim for mobilisation is 10 micrograms/kg/day in divided doses and should be commenced from day +4 after the last cycle of chemotherapy.
Drug status:

Filgrastim: (PBS authority)

All other drugs in this protocol are on the PBS general schedule (with the exception of oral mesna)

Cost:
~ $1,210 per cycle "How this cost is calculated"

The cost displayed on the protocol is intended as rudimentary guide only for the Australian context.

The cost includes anti-cancer drugs only (not antiemetics, supportive medications or consumables), unless otherwise indicated.

Drug unit costs are taken directly from the Pharmaceutical Benefits Scheme (PBS) website (www.pbs.gov.au), MIMS Online and other sources. These costs are reviewed and updated on eviQ at 6 monthly intervals.

Where there are differing unit costs based on vial sizes and tablet strengths, the mean unit cost is used. The cost of oral continuous therapy is based on a 28 day month.

The protocol cost is derived from drug dose calculations based upon a default body surface area (BSA) of 1.8 m2; weight of 75 kg; and creatinine clearance of 75 mL/min.

One off loading doses and ongoing maintenance doses are not included in protocol cost calculations.

The cost displayed is the actual drug cost and does not necessarily reflect the cost incurred by the patient as many anti-cancer drugs are reimbursed on the PBS.

The supportive therapies (e.g. antiemetics, premedications, etc.), infusion times, diluents, volumes and routes of administration, if included, are listed as defaults. They may vary between institutions and can be substituted to reflect individual institutional policy.

Antiemetics if included in the treatment schedule are based upon recommendations from national and international guidelines. These are defaults only and may be substituted to reflect individual institutional policy. Select here for recommended doses of alternative antiemetics.

Cycle 1 and 2

Day 1
Etoposide 100 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 30 to 60 minutes
cARBOplatin 5 AUC (IV infusion) (Cap dose at 800 mg) in 500 mL glucose 5% over 30 to 60 minutes
iFOSFamide 1,666 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 2 hours (loaded with mesna)
Mesna 1,666 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 2 hours (loaded with ifosfamide)
Mesna 2,000 mg (PO) at 2 hours and 6 hours after completion of ifosfamide infusion
Day 2 and 3
Etoposide 100 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 30 to 60 minutes
iFOSFamide 1,666 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 2 hours (loaded with mesna)
Mesna 1,666 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 2 hours (loaded with ifosfamide)
Mesna 2,000 mg (PO) at 2 hours and 6 hours after completion of ifosfamide infusion
Day 4
Filgrastim 5 micrograms/kg (Subcut) inject subcutaneously once daily at least 24 hours post chemotherapy and continue until neutrophil recovery

  • Etopophos (etoposide phosphate) 113.6 mg is equivalent to etoposide 100 mg. Doses in this protocol are expressed as etoposide.
  • This protocol may be used for mobilisation of peripheral blood haematopoietic stem cells. The dose of filgrastim for mobilisation is 10 micrograms/kg/day in divided doses and should be commenced from day +4 after the last cycle of chemotherapy.

Frequency:
21 days 
Cycles:
2 to 3

Cycle 1 and 2

Drug Dose Route Day
Etoposide * 100 mg/m2 IV infusion 1 to 3
cARBOplatin 5 AUC (Cap dose at 800 mg) IV infusion 1
iFOSFamide 1,666 mg/m2 IV infusion 1 to 3
Mesna 1,666 mg/m2 IV infusion 1 to 3
Mesna 2,000 mg at 2 and 6 hours post completion of ifosfamide PO 1 to 3
Filgrastim 5 micrograms/kg Subcut 4 and continue daily until neutrophil recovery

* Etopophos (etoposide phosphate) 113.6 mg is equivalent to etoposide 100 mg. Doses in this protocol are expressed as etoposide.

Frequency:
21 days 
Cycles:
2 to 3
Notes:
  • This is an intense chemotherapy regimen; patients with poor ECOG performance status and significant co-morbidities may not be appropriate for this regimen.
  • This protocol may be used for mobilisation of peripheral blood haematopoietic stem cells. The dose of filgrastim for mobilisation is 10 micrograms/kg/day in divided doses and should be commenced from day +4 after the last cycle of chemotherapy.
Drug status:

Filgrastim: (PBS authority)

All other drugs in this protocol are on the PBS general schedule (with the exception of oral mesna)

Cost:
~ $1,210 per cycle "How this cost is calculated"

The cost displayed on the protocol is intended as rudimentary guide only for the Australian context.

The cost includes anti-cancer drugs only (not antiemetics, supportive medications or consumables), unless otherwise indicated.

Drug unit costs are taken directly from the Pharmaceutical Benefits Scheme (PBS) website (www.pbs.gov.au), MIMS Online and other sources. These costs are reviewed and updated on eviQ at 6 monthly intervals.

Where there are differing unit costs based on vial sizes and tablet strengths, the mean unit cost is used. The cost of oral continuous therapy is based on a 28 day month.

The protocol cost is derived from drug dose calculations based upon a default body surface area (BSA) of 1.8 m2; weight of 75 kg; and creatinine clearance of 75 mL/min.

One off loading doses and ongoing maintenance doses are not included in protocol cost calculations.

The cost displayed is the actual drug cost and does not necessarily reflect the cost incurred by the patient as many anti-cancer drugs are reimbursed on the PBS.

The supportive therapies (e.g. antiemetics, premedications, etc.), infusion times, diluents, volumes and routes of administration, if included, are listed as defaults. They may vary between institutions and can be substituted to reflect individual institutional policy.

Antiemetics if included in the treatment schedule are based upon recommendations from national and international guidelines. These are defaults only and may be substituted to reflect individual institutional policy. Select here for recommended doses of alternative antiemetics.

Cycle 1 and 2

Day 1
Etoposide 100 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 30 to 60 minutes
cARBOplatin 5 AUC (IV infusion) (Cap dose at 800 mg) in 500 mL glucose 5% over 30 to 60 minutes
iFOSFamide 1,666 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 2 hours (loaded with mesna)
Mesna 1,666 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 2 hours (loaded with ifosfamide)
Mesna 2,000 mg (PO) at 2 hours and 6 hours after completion of ifosfamide infusion
Day 2 and 3
Etoposide 100 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 30 to 60 minutes
iFOSFamide 1,666 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 2 hours (loaded with mesna)
Mesna 1,666 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 2 hours (loaded with ifosfamide)
Mesna 2,000 mg (PO) at 2 hours and 6 hours after completion of ifosfamide infusion
Day 4
Filgrastim 5 micrograms/kg (Subcut) inject subcutaneously once daily at least 24 hours post chemotherapy and continue until neutrophil recovery

  • Etopophos (etoposide phosphate) 113.6 mg is equivalent to etoposide 100 mg. Doses in this protocol are expressed as etoposide.
  • This protocol may be used for mobilisation of peripheral blood haematopoietic stem cells. The dose of filgrastim for mobilisation is 10 micrograms/kg/day in divided doses and should be commenced from day +4 after the last cycle of chemotherapy.

Frequency:
21 days 
Cycles:
2 to 3
  • Relapsed or refractory non-Hodgkin lymphoma
  • Usually used in transplant eligible patients for both salvage and peripheral blood stem cell (PBSC) mobilisation
Venous access required

IV cannula (IVC) or central venous access device (CVAD) is required to administer this treatment.

Read more about central venous access device line selection
Hypersensitivity/infusion related reaction

High risk with etoposide.

High risk with carboplatin. Hypersensitivity risk increases with number of cycles of carboplatin. 
Antiemetics for multi-day protocols

Antiemetic therapy should be administered throughout the duration of the chemotherapy protocol and to cover delayed nausea. The acute and delayed emetic risk of multi-day chemotherapy protocols will overlap depending on the individual drugs and their sequence of administration. More or less antiemetic cover may be required.

A NK1 receptor antagonist and a 5HT3 receptor antagonist in combination with dexamethasone are available on the PBS for primary prophylaxis of carboplatin induced nausea and vomiting.

Ensure that patients also have sufficient antiemetics for breakthrough emesis:

Metoclopramide 10 mg three times a day when necessary (maximum of 30 mg/24 hours, up to 5 days) OR

Prochlorperazine 10 mg PO every 6 hours when necessary.

Read more about preventing anti-cancer therapy induced nausea and vomiting
Ifosfamide induced encephalopathy

May occur in patients treated with high dose ifosfamide (~ 5 to 8 g/m2). Assess neurological function prior to each ifosfamide dose.

Read more about ifosfamide induced encephalopathy

Link to ifosfamide encephalopathy assessment chart
Haemorrhagic cystitis associated with high dose chemotherapy

Hydration regimen pre high dose cyclophosphamide or ifosfamide (as per local guidelines).
There is limited evidence and no consensus regarding hydration regimens and mesna dose, route or timing of administration.

Read more about haemorrhagic cystitis
Etoposide conversion factor

Note: Etopophos (etoposide phosphate) 113.6 mg is equivalent to etoposide 100 mg.
Doses in this protocol are expressed as etoposide.
Central nervous system (CNS) prophylaxis

Consider CNS relapse assessment in patients with high grade lymphoma. 

Read more about CNS prophylaxis in diffuse large cell lymphoma
Tumour lysis risk

Assess patient for risk of developing tumour lysis syndrome.

Read more about prevention and management of tumour lysis syndrome.
Mesna dosing and administration

There is evidence for several mesna doses as well as differing administration timings (e.g. 2, 4, 6, or 8 hours post initiation or completion of the ifosfamide/cyclophosphamide dose) with no clear evidence that one particular regimen is superior over another. The eviQ mesna recommendations may be based upon the individual trial/study or reference committee consensus and provide guidance on one safe way to administer the protocol. Individual institutional policy may vary and should be evidence based.
Pneumocystis jirovecii pneumonia (PJP) prophylaxis

­

Read more about prophylaxis of pneumocystis jiroveci (carinii) in cancer patients
Antiviral prophylaxis

­

Read more about antiviral prophylaxis drugs and doses
Antifungal prophylaxis ­

Read more about antifungal prophylaxis drugs and doses.
Biosimilar drug

Read more about biosimilar drugs on the Biosimilar Awareness Initiative page
Growth factor support

G-CSF (short or long-acting) is available on the PBS for chemotherapy induced neutropenia depending on clinical indication and/or febrile neutropenia risk.  

Access the PBS website
Blood tests

FBC, EUC, LFTs and LDH at baseline, and prior to each cycle and as clinically indicated.
Hepatitis B screening and prophylaxis

Routine screening for HBsAg and anti-HBc is recommended prior to initiation of treatment. Prophylaxis should be determined according to individual institutional policy.

Read more about hepatitis B screening and prophylaxis in cancer patients requiring cytotoxic and/or immunosuppressive therapy
Vaccinations

Live vaccines are contraindicated in cancer patients receiving immunosuppressive therapy and/or who have poorly controlled malignant disease.

Refer to the recommended schedule of vaccination for immunocompromised patients, as outlined in the Australian Immunisation Handbook.

Read more about COVID-19 vaccines and cancer.
Fertility, pregnancy and lactation

Cancer treatment can have harmful effects on fertility and this should be discussed with all patients of reproductive potential prior to commencing treatment. There is a risk of foetal harm in pregnant women. A pregnancy test should be considered prior to initiating treatment in females of reproductive potential if sexually active. It is important that all patients of reproductive potential use effective contraception whilst on therapy and after treatment finishes. Effective contraception methods and adequate contraception timeframe should be discussed with all patients of reproductive potential. Possibility of infant risk should be discussed with breastfeeding patients.

Read more about the effect of cancer treatment on fertility
Evidence for dose modifications is limited, and the recommendations made on eviQ are intended as a guide only. They are generally conservative with an emphasis on safety. Any dose modification should be based on clinical judgement, and the individual patient’s situation including but not limited to treatment intent (curative vs palliative), the anti-cancer regimen (single versus combination therapy versus chemotherapy versus immunotherapy), biology of the cancer (site, size, mutations, metastases), other treatment related side effects, additional co-morbidities, performance status and patient preferences.Suggested dose modifications are based on clinical trial findings, product information, published guidelines and reference committee consensus . The dose reduction applies to each individual dose and not to the total number of days or duration of treatment cycle unless stated otherwise. Non-haematological gradings are based on Common Terminology Criteria for Adverse Events (CTCAE) unless otherwise specified. Renal and hepatic dose modifications have been standardised where possible. For more information see dosing considerations & disclaimer.
The dose recommendations in kidney dysfunction (i.e.renal impairment) displayed may not reflect those in the ADDIKD guideline and have been included for historical reference only. Recommendations will be updated once the individual protocol has been evaluated by the reference committee, with this version of the protocol then being archived. Clinicians are expected to refer to the ADDIKD guideline prior to prescribing in kidney dysfunction.
International Consensus Guideline for Anticancer Drug Dosing in Kidney Dysfunction (ADDIKD).

For dosing carboplatin, ADDIKD recommends that:

  • Directly measured glomerular filtration rate (mGFR) is the preferred kidney function value in the Calvert formula​, especially where estimated kidney function may be unreliable for accurate therapeutic dosing.
  • Where mGFR is unavailable, eGFR adjusted to an individual’s body surface area (BSA-adjusted eGFR) is a suitable alternative for use in the Calvert formula.
  • Kidney function should not be capped at 125 mL/min for use in the Calvert formula.
  • Recalculation of carboplatin doses at each cycle is unnecessary, except when baseline kidney function (e.g., eGFR) alters by > 20% or when there is a change in the clinical status of the patient.

For further information refer the eviQ Factsheet around carboplatin dosing and the carboplatin drug monograph within the ADDIKD guideline. To assist with calculations, use the eviQ Estimated Glomerular Filtration Rate (eGFR) and carboplatin dose calculators.

Note: All dose reductions are calculated as a percentage of the starting dose

Haematological toxicity
Delay treatment until ANC is greater than 1.0 x 109/L and platelets greater than 50 x 109/L
Renal impairment
Creatinine clearance (mL/min)  
10 to 50 Reduce ifosfamide and etoposide by 25%
less than 10 Reduce ifosfamide and etoposide by 50%
  Recalculate carboplatin dose using Calvert formula
Hepatic impairment
Hepatic dysfunction
No dose modifications required

Drug interactions in eviQ protocols are under review and being updated to align with current literature. Further site-wide updates and changes will occur in due course. References & Disclaimer

The drug interactions shown below are not an exhaustive list. For a more comprehensive list and for detailed information on specific drug interactions and clinical management, please refer to the specific drug product information and the following key resources:  

Carboplatin
  Interaction Clinical management
Nephrotoxic drugs (e.g. aminoglycosides, amphotericin, cisplatin, contrast dye, frusemide, NSAIDs) Additive nephrotoxicity Avoid combination or monitor renal function closely
Ototoxic drugs (e.g. aminoglycosides, frusemide, NSAIDs) Additive ototoxicity Avoid combination or perform regular audiometric testing
Paclitaxel Administration schedule may influence the development of myelosuppression Minimise toxicity by administering paclitaxel first in regimens using the combination
Etoposide and Etoposide Phosphate
  Interaction Clinical management
CYP3A4 and P-gp inhibitors (e.g. amiodarone, aprepitant, azole-antifungals, ritonavir, lapatinib, nilotinib, sorafenib, macrolides, ciclosporin etc.) Increased toxicity of etoposide possible due to reduced clearance Avoid combination or monitor for etoposide toxicity
CYP3A4 inducers (e.g. carbamazepine, phenytoin, phenobarbitone, rifampicin, St John’s wort etc.) Reduced efficacy of etoposide possible due to increased clearance Avoid combination or monitor for decreased clinical response to etoposide
Glucosamine Reduced efficacy of etoposide (due to induction of glucose-regulated stress proteins resulting in decreased expression of topoisomerase II) Avoid combination or monitor for decreased clinical response to etoposide
Grapefruit juice Reduced efficacy of oral etoposide possible due to possible alteration of P-gp mediated intestinal transport of etoposide Avoid combination or monitor for decreased clinical response to etoposide
Ifosfamide
  Interaction Clinical management
Aprepitant Increased risk of ifosfamide-induced neurotoxicity due to increased levels of active metabolites Avoid combination or monitor closely for neurotoxicity; consider alternate antiemetic regimens
CYP3A4 inducers (e.g. carbamazepine, phenytoin, phenobarbitone, rifampicin, St John’s wort etc.) Increased toxicity of ifosfamide possible due to increased conversion to active and toxic metabolites Avoid combination or monitor for ifosfamide toxicity
CYP3A4 inhibitors (e.g. azole antifungals, clarithromycin, erythromycin, grapefruit juice, ritonavir etc.) Reduced efficacy of ifosfamide possible due to decreased conversion to active metabolites Avoid combination or monitor for decreased clinical response to ifosfamide
Nephrotoxic drugs (e.g. aminoglycosides, amphotericin, cisplatin, contrast dye, frusemide, NSAIDs) Additive nephrotoxicity Avoid combination or monitor renal function closely
Suxamethonium Potentiation of muscle relaxant effect possible Alert the anaesthetist if a patient has been treated with ifosfamide within ten days of planned general anaesthesia
CNS depressants (including opiates, opioids, phenothiazines) Increased risk of ifosfamide-induced neurotoxicity due to additive CNS effects Avoid combination or monitor for excessive CNS depression/encephalopathy
Mesna 
No specific or clinically significant drug interactions 
General
  Interaction Clinical management
Warfarin Anti-cancer drugs may alter the anticoagulant effect of warfarin. Monitor INR regularly and adjust warfarin dosage as appropriate; consider alternative anticoagulant.
Direct oral anticoagulants (DOACs) e.g. apixaban, rivaroxaban, dabigatran

Interaction with both CYP3A4 and P-gp inhibitors /inducers.

DOAC and anti-cancer drug levels may both be altered, possibly leading to loss of efficacy or toxicity (i.e. increased bleeding).

Apixaban: avoid concurrent use with strong CYP3A4 and P‑gp inhibitors. If treating VTE, avoid use with strong CYP3A4 and P‑gp inducers. 

Rivaroxaban: avoid concurrent use with strong CYP3A4 and P‑gp  inhibitors.

Dabigatran: avoid combination with strong P‑gp inducers and inhibitors.

If concurrent use is unavoidable, monitor closely for efficacy/toxicity of both drugs.
Digoxin Anti-cancer drugs can damage the lining of the intestine; affecting the absorption of digoxin. Monitor digoxin serum levels; adjust digoxin dosage as appropriate.
Antiepileptics Both altered antiepileptic and anti-cancer drug levels may occur, possibly leading to loss of efficacy or toxicity. Where concurrent use of an enzyme-inducing antiepileptic cannot be avoided, monitor antiepileptic serum levels for toxicity, as well as seizure frequency for efficacy; adjust dosage as appropriate.
Also monitor closely for efficacy of the anti-cancer therapy.
Antiplatelet agents and NSAIDs Increased risk of bleeding due to treatment related thrombocytopenia. Avoid or minimise combination.
If combination deemed essential, (e.g. low dose aspirin for ischaemic heart disease) monitor for signs of bleeding.
Serotonergic drugs, including selective serotonin reuptake inhibitors (SSRIs e.g. paroxetine) and serotonin noradrenaline reuptake inhibitors (SNRIs e.g. venlafaxine) Increased risk of serotonin syndrome with concurrent use of 5-HT3 receptor antagonists (e.g. palonosetron, ondansetron, granisetron, tropisetron, dolasetron, etc.) Avoid combination.
If combination is clinically warranted, monitor for signs and symptoms of serotonin syndrome (e.g. confusion, agitation, tachycardia, hyperreflexia).
For more information link to TGA Medicines Safety Update
Vaccines Diminished response to vaccines and increased risk of infection with live vaccines. Live vaccines (e.g. BCG, MMR, zoster and varicella) are contraindicated in patients on immunosuppressive therapy. Use with caution in patients on non-immunosuppressive therapy.
For more information; refer to the recommended schedule of vaccination for cancer patients, as outlined in the Australian Immunisation Handbook

eviQ provides safe and effective instructions on how to administer cancer treatments. However, eviQ does not provide every treatment delivery option, and is unable to provide a comprehensive list of cancer treatment agents and their required IV line giving set/filter. There may be alternative methods of treatment administration, and alternative supportive treatments that are also appropriate. Please refer to the individual product information monographs via the TGA website for further information.

Day 1

Approximate treatment time: 4 hours

General patient assessment prior to each treatment.

Any toxicity grade 2 or greater may require dose reduction, delay or omission of treatment and review by medical officer before recommencing treatment.

Prime IV line(s).

Insert IV cannula or access TIVAD or CVAD.

Note: A large volume of intravenous fluid may be given with this protocol. If weight increases by more than 1 kg from baseline or fluid balance becomes positive by one litre or any other signs of fluid overload are present, review by medical officer (diuretics may be required).

  • daily weight
  • dip stick all urine for haematuria
  • strict fluid balance input and output

Hydration if prescribed

Pre treatment medication

Verify antiemetics taken or administer as prescribed.

Etoposide

Administer etoposide (irritant):
  • via IV infusion over 30 to 60 minutes
  • rapid infusion may cause hypotension
  • observe for hypersensitivity
  • flush with ~ 100 mL sodium chloride 0.9%
  • if using etoposide phosphate administer in ~ 50 mL sodium chloride 0.9% or glucose 5% over ~15 minutes.
Stop infusion at first sign of reaction:
  • if symptoms are mild and resolve when infusion is stopped, consider recommencing infusion after review by medical officer at a slower rate.
  • for severe reactions seek medical assistance immediately and do not restart infusion.

Carboplatin 

Administer carboplatin (irritant):
  • via IV infusion over 30 to 60 minutes
  • observe for hypersensitivity reactions
  • flush with ~100 mL of sodium chloride 0.9%
  • hypersensitivity risk increases with number of cycles administered.
Stop infusion at first sign of reaction:
  • if symptoms are mild and resolve when infusion is stopped, consider recommencing infusion after review by medical officer at a slower rate
  • for severe reactions seek medical assistance immediately and do not restart infusion.

Ifosfamide infusion

Prior to administration:
  • assess neurological function at baseline and prior to each ifosfamide dose
    • inpatients: 4 hourly assessments until 24 hours after ifosfamide infusion is completed
    • outpatients: advise patient/carer of the potential for neurotoxicity
  • perform baseline urinalysis and monitor for haematuria prior to each ifosfamide dose
    • note the administration of mesna will cause a false positive for ketonuria
  • ensure patient receives at least 3 L of IV or oral fluids per day
Administer ifosfamide (irritant) with mesna:
  • via IV infusion over 2 hours
  • flush with ~100 mL of sodium chloride 0.9%

Oral Mesna

  • administer mesna 2000 mg orally at 2 hours and 6 hours post completion of ifosfamide/mesna infusion
  • if vomiting occurs within 2 hours of taking oral mesna, repeat the dose or give IV mesna
  • if patient cannot tolerate oral mesna, it may be given by IV bolus 
  • the oral mesna dose is equivalent to twice the IV dose.

Remove IV cannula and/or deaccess TIVAD or CVAD. 

Continue safe handling precautions until 7 days after completion of drug(s)

Days 2 and 3

Approximate treatment time: 3.5 hours

General patient assessment prior to each treatment.

Any toxicity grade 2 or greater may require dose reduction, delay or omission of treatment and review by medical officer before recommencing treatment.

Prime IV line(s).

Insert IV cannula or access TIVAD or CVAD.

Note: A large volume of intravenous fluid may be given with this protocol. If weight increases by more than 1 kg from baseline or fluid balance becomes positive by one litre or any other signs of fluid overload are present, review by medical officer (diuretics may be required).

  • daily weight
  • dip stick all urine for haematuria
  • strict fluid balance input and output

Hydration if prescribed

Pre treatment medication

Verify antiemetics taken or administer as prescribed.

Etoposide

Administer etoposide (irritant):
  • via IV infusion over 30 to 60 minutes
  • rapid infusion may cause hypotension
  • observe for hypersensitivity
  • flush with ~ 100 mL sodium chloride 0.9%
  • if using etoposide phosphate administer in ~ 50 mL sodium chloride 0.9% or glucose 5% over ~15 minutes.
Stop infusion at first sign of reaction:
  • if symptoms are mild and resolve when infusion is stopped, consider recommencing infusion after review by medical officer at a slower rate.
  • for severe reactions seek medical assistance immediately and do not restart infusion.

Ifosfamide infusion

Prior to administration:
  • assess neurological function at baseline and prior to each ifosfamide dose
    • inpatients: 4 hourly assessments until 24 hours after ifosfamide infusion is completed
    • outpatients: advise patient/carer of the potential for neurotoxicity
  • perform baseline urinalysis and monitor for haematuria prior to each ifosfamide dose
    • note the administration of mesna will cause a false positive for ketonuria
  • ensure patient receives at least 3 L of IV or oral fluids per day
Administer ifosfamide (irritant) with mesna:
  • via IV infusion over 2 hours
  • flush with ~100 mL of sodium chloride 0.9%

Oral Mesna

  • administer mesna 2000 mg orally at 2 hours and 6 hours post completion of ifosfamide/mesna infusion
  • if vomiting occurs within 2 hours of taking oral mesna, repeat the dose or give IV mesna
  • if patient cannot tolerate oral mesna, it may be given by IV bolus 
  • the oral mesna dose is equivalent to twice the IV dose.

Remove IV cannula and/or deaccess TIVAD or CVAD. 

Continue safe handling precautions until 7 days after completion of drug(s)

Day 4

Filgrastim

  • administer filgrastim by subcutaneous injection once daily at least 24 hours after last dose of chemotherapy and continue until neutrophil recovery

Discharge information

Antiemetics
  • Antiemetics as prescribed.
Mesna tablets
  • Mesna tablets with written instructions on how to take them.
Growth factor support
  • Arrangements for administration if prescribed.
Prophylaxis medications
  • Prophylaxis medications (if prescribed) i.e. tumour lysis prophylaxis, PJP prophylaxis, antifungals, antivirals.
Patient information
  • Ensure patient receives patient information sheet.

The side effects listed below are not a complete list of all possible side effects for this treatment. Side effects are categorised into the approximate onset of presentation and should only be used as a guide.

Immediate (onset hours to days)
Nausea and vomiting

Read more about prevention of treatment induced nausea and vomiting
Haemorrhagic cystitis

An inflammatory process, characterised by diffuse mucosal inflammation with haemorrhage involving the entire bladder. Patients are at risk following treatment with cyclophosphamide, ifosfamide and radiation therapy. 

Read more about haemorrhagic cystitis
Hypersensitivity reaction

Anaphylaxis and infusion related reactions can occur with this treatment.

Read more about hypersensitivity reaction 
Encephalopathy

Ifosfamide induced encephalopathy has been reported in 10 to 30% of patients receiving high dose ifosfamide. Common symptoms include confusion, ataxia, weakness, seizures, somnolence and hallucinations. Onset may be 2 to 48 hours after commencing treatment. When reversible, symptoms usually resolve within 1 to 3 days.

Read more about ifosfamide-induced encephalopathy
Taste and smell alteration

Read more about taste and smell changes
Bone pain

Bone pain, usually in the lower back or pelvis, associated with G-CSF.

Early (onset days to weeks)
Neutropenia

Abnormally low levels of neutrophils in the blood. This increases the risk of infection. Any fever or suspicion of infection should be investigated immediately and managed aggressively. 

Read more about immediate management of neutropenic fever
Thrombocytopenia

A reduction in the normal levels of functional platelets, increasing the risk of abnormal bleeding.  

Read more about thrombocytopenia
Oral mucositis

Erythematous and ulcerative lesions of the gastrointestinal tract (GIT). It commonly develops following chemotherapy, radiation therapy to the head, neck or oesophagus, and high dose chemotherapy followed by a blood and marrow transplant (BMT).

Read more about oral mucositis
Nephrotoxicity

Renal dysfunction resulting from damage to the glomeruli, tubules or renal vasculature.
Fatigue

Read more about fatigue
Diarrhoea

Read more about treatment induced diarrhoea
Anorexia

Loss of appetite accompanied by decreased food intake.

Read more about anorexia

Late (onset weeks to months)
Anaemia

Abnormally low levels of red blood cells (RBCs) or haemoglobin in the blood. 

Read more about anaemia
Alopecia

Hair loss may occur from all parts of the body. Patients can also experience mild to moderate discomfort of the hair follicles, and rarely pain as the hair is falling out.

Read more about alopecia

Efficacy

Infusional

The overall response rate to infusional ICE was 66.3%, with 24% of the patients achieving complete response (CR) and 42.3% partial response (PR). These results compare favourably with other second­ line regimens. 89% of responding patients proceeded to autologous transplantation. At a median follow up of 40 months, overall survival (OS) for all patients was 33% and event free survival (EFS) was 25% (see figure below). Those with CR to ICE had superior overall survival to those who had PR to ICE (65% v 30% p=0.003).r

© Journal of Clinical Oncology 1999

Fractionated

In the study of fractionated ICE, the overall response rate was 89%, including 29% CR and 60% PR. Amongst the patients with DLBCL (n=33), 36% achieved CR and 49%, PR. PBSCs were successfully collected after the second or third cycle of ICE in 61 patients and 59 proceeded to autologous transplantation. The overall survival of the whole cohort at 24 months was 65% whilst the event-free survival was 42% (see figures below).r

© Annals of Oncology 2006

Toxicity

Infusional

Grade 3 and 4 non­-haematological toxicities resulted in six patients failing to complete all 3 cycles of ICE. Five patients developed neurotoxicity ­4 had confusion due to ifosfamide ­induced encephalopathy (IIE) and 1 developed self-­limiting peripheral neuropathy. In each case the symptoms resolved but the patients with IIE did not receive further courses of ICE. One patient developed congestive cardiac failure and one developed SVT; neither of these patients received further cycles of ICE. 119 patients received all 3 cycles in a median time of 38 days ­the intent was for patients to receive the 3 cycles in 31 days. Thrombocytopenia was the dose­ limiting toxicity. A summary of the most common toxicities is found in the tables below.r

Toxicity Grade 1 % Grade 2 % Grade 3 % Grade 4 %
Platelet 29.4 10.8 14.2 15.2
Haemoglobin 23.9 32 22.6 3.9
Neutrophils 4.5 7.1 7.9 12.9
Toxicity All cycles %
Genitourinary 1.5
Cardiac 1.2
Peripheral neuropathy 0.6
Chemotherapy induced encephalopathy 2.5
Twofold increase in alkaline phosphate 11
Twofold increase in alanine transferase 9.8

© Journal of Clinical Oncology 1999

Fractionated

The major toxicities reported in the fractionated ICE study were haematological, with grade 4 thrombocytopenia in 51% and grade 4 neutropenia in 55%. The neutrophil nadir occurred between days 9 and 11 post-therapy and was brief, however 18 patients developed neutropenic sepsis requiring hospital admission. Non-haematological toxicities included 2 cases of CNS toxicity (grade 1 & 2), one case of haematuria and one case of (reversible) nephrotoxicity. Two patients developed cardiac complications with one case of atrial fibrillation and another of worsening cardiac failure.r

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Version 5

Date Summary of changes
22/09/2020 Biosimilar drug added to clinical information. Version number changed to V.5

Version 4

Date Summary of changes
16/04/2020 'Mesna dosing and administration' block added to clinical information. Version number changed to v.4
02/07/2020 Reviewed by Haematology Reference Committee with no significant changes, review in 4 years.

Version 3

Date Summary of changes
07/03/2014 New protocol taken to Haematology Reference Committee meeting.
12/05/2014 Approved and published on eviQ.
11/09/2015 Reviewed at RCM, no changes, review in 2 years, updated drug costs.

31/05/2017

Transferred to new eviQ website. Version number change to V.3.
25/05/2018 Reviewed by Haematology Reference Committee with no significant changes, review in 2 years
13/09/2019 Reviewed by Haematology Reference Committee, no changes made. Review in 5 years.
10/10/2019 Clinical information updated with PBS expanded indications for G-CSF. 

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31 Mar 2023