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Non-Hodgkin lymphoma RICE (rituximab infusional 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.

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
Rituximab 375 mg/m2 IV infusion *** 1
Etoposide * 100 mg/m2 IV infusion 1 to 3
cARBOplatin 5 AUC (Cap dose at 800 mg) IV infusion 2
iFOSFamide 5,000 mg/m2 IV infusion 2
Mesna 5,000 mg/m2 IV infusion 2
Mesna ** 2,000 mg at 2 and 6 hours post completion of ifosfamide PO 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.

** at 2 and 6 hours after completion of ifosfamide infusion

*** From dose 2 onwards, rituximab may be administered subcutaneously as a flat dose of 1,400 mg. For more information see the Non-Hodgkin lymphoma subcutaneous rituximab document.

Frequency:
21 days 
Cycles:
2 to 3
Notes:
  • Rituximab should be included in second line therapy if there is relapse after a reasonable remission (longer than 6 months); however rituximab should often be omitted in patients with primary refractory disease.r
  • This is an intense chemotherapy regimen and 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:

Rituximab SC: TGA registered but not PBS listed.

Filgrastim: (PBS authority)

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

Cost:
~ $1,700 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
Paracetamol 1,000 mg (PO) 60 minutes before treatment
Loratadine 10 mg (PO) 60 minutes before treatment
Hydrocortisone 100 mg (IV) 30 minutes before treatment
Rituximab 375 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% as per graded administration rate *
Etoposide 100 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 30 to 60 minutes **
Day 2
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 5,000 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 24 hours (loaded with mesna)
Mesna 5,000 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 24 hours (loaded with ifosfamide)
Day 3
Etoposide 100 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 30 to 60 minutes **
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

* From dose 2 onwards, rituximab may be administered subcutaneously as a flat dose of 1,400 mg. For more information see the Non-Hodgkin lymphoma subcutaneous rituximab document.

** 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

Cycle 1 and 2

Drug Dose Route Day
Rituximab 375 mg/m2 IV infusion *** 1
Etoposide * 100 mg/m2 IV infusion 1 to 3
cARBOplatin 5 AUC (Cap dose at 800 mg) IV infusion 2
iFOSFamide 5,000 mg/m2 IV infusion 2
Mesna 5,000 mg/m2 IV infusion 2
Mesna ** 2,000 mg at 2 and 6 hours post completion of ifosfamide PO 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.

** at 2 and 6 hours after completion of ifosfamide infusion

*** From dose 2 onwards, rituximab may be administered subcutaneously as a flat dose of 1,400 mg. For more information see the Non-Hodgkin lymphoma subcutaneous rituximab document.

Frequency:
21 days 
Cycles:
2 to 3
Notes:
  • Rituximab should be included in second line therapy if there is relapse after a reasonable remission (longer than 6 months); however rituximab should often be omitted in patients with primary refractory disease.r
  • This is an intense chemotherapy regimen and 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:

Rituximab SC: TGA registered but not PBS listed.

Filgrastim: (PBS authority)

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

Cost:
~ $1,700 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
Paracetamol 1,000 mg (PO) 60 minutes before treatment
Loratadine 10 mg (PO) 60 minutes before treatment
Hydrocortisone 100 mg (IV) 30 minutes before treatment
Rituximab 375 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% as per graded administration rate *
Etoposide 100 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 30 to 60 minutes **
Day 2
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 5,000 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 24 hours (loaded with mesna)
Mesna 5,000 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 24 hours (loaded with ifosfamide)
Day 3
Etoposide 100 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 30 to 60 minutes **
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

* From dose 2 onwards, rituximab may be administered subcutaneously as a flat dose of 1,400 mg. For more information see the Non-Hodgkin lymphoma subcutaneous rituximab document.

** 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
  • Relapsed or refractory CD20 positive B-cell non-Hodgkin lymphoma
  • Transplant eligible patients for both salvage and peripheral blood stem cell (PBSC) mobilisation
Venous access

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 and rituximab.

High risk with carboplatin. Hypersensitivity risk increases with number of cycles of carboplatin.
Premedication

The product information states that premedication is required for this treatment.

Please refer to the treatment schedule for suggested premedication regimen. This may be substituted to reflect institutional policy.
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
Subcutaneous rituximab

Please note that subcutaneous rituximab is no longer subsidised by the Pharmaceutical Benefit Scheme and is currently unavailable in Australia.

All patients must always receive their first dose of rituximab by intravenous administration. Subcutaneous (SC) rituximab must only be given at the second or subsequent doses. From dose 2 onwards, rituximab may be administered subcutaneously as a flat dose of 1,400 mg. If patient was not able to receive one full rituximab intravenous infusion dose, they should continue the subsequent dose with intravenous rituximab until a full IV dose is successfully administered.

Premedication consisting of an analgesic/antipyretic and an antihistamine should always be administered before each dose of rituximab SC. Premedication with glucocorticoids should also be considered, particularly if rituximab SC is not given in combination with steroid-containing chemotherapy.

 Read more about Non-Hodgkin lymphoma subcutaneous rituximab 
Rituximab rapid infusion

This regimen is not in line with the product monograph, however published literature indicates that it can be completed safely.

Read more about the rapid infusion of rituximab
Progressive multifocal leukoencephalopathy

Use of monoclonal antibodies may be associated with an increased risk of progressive multifocal leukoencephalopathy (PML), a rare but potentially fatal opportunistic viral infection of the brain. Patients must be monitored for any new or worsening neurological symptoms.

Read more about progressive multifocal leukoencephalopathy and the Therapeutic Goods Administration Medicines Safety update on progressive multifocal leukoencephalopathy from the Australian Government, Department of Health.
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.
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
Biosimilar drug

Read more about biosimilar drugs on the Biosimilar Awareness Initiative page
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
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 
Rituximab
  Interaction Clinical management
Antihypertensives Additive hypotensive effect Consider withholding antihypertensive medications 12 hours prior to the rituximab infusion
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

General patient assessment prior to each day of treatment.

Any toxicity grade 2 or greater may require delay of treatment and review by medical officer before commencing treatment.

Prime IV line(s).

Access 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

Rituximab

Prior to administration:
  • check baseline observations
  • check for previous adverse events during previous infusions
  • verify premedication has been taken. If not, administer 30 to 60 minutes prior to rituximab administration:
    • paracetamol 1000 mg orally AND
    • loratadine 10 mg orally (or similar antihistamine)
    • a steroid may also be included as a premed according to local guidelines
Initial infusion:
  • commence rituximab infusion at 50 mg/hr for 30 minutes
  • repeat observations prior to each rate increase
  • increase rate by 50 mg/hr every 30 minutes, up to a maximum of 400 mg/hr if observations are stable
  • flush with ~ 100 mL of sodium chloride 0.9%

If an infusion reaction occurs, temporarily discontinue the infusion and notify medical officer

  • when symptoms have completely resolved, recommence the infusion at half the rate prior to the reaction
  • for severe reactions stop infusion and manage as per emergency

Transient hypotension may occur. Consider withholding antihypertensive medication for 12 hours before and during infusion.

Subsequent infusions:

If an adverse event was experienced with initial infusion recommence infusion at the same rate as initial infusion

  • commence rituximab infusion at 100 mg/hr
  • repeat observations prior to each rate increase
  • increase rate by 100 mg/hr increments every 30 minutes to a maximum of 400 mg/hr if observations are stable
  • flush with ~ 100 mL of sodium chloride 0.9%

If an infusion reaction occurs, temporarily discontinue the infusion and notify medical officer

  • when symptoms have resolved, recommence the infusion at half the rate prior to the reaction
  • for severe reactions stop infusion and manage as per emergency

Read more about rapid infusion rituximab

Read more about subcutaneous rituximab

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.

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

Day 2

General patient assessment prior to each day of treatment.

Any toxicity grade 2 or greater may require delay of treatment and review by medical officer before commencing treatment.

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).

  • continue 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
  • 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 24 hours
  • encourage patient to void every couple of hours to reduce the time urine remains in the bladder
  • infusion must stop after 24 hours regardless of the volume left in the bag
  • flush with ~100 mL of sodium chloride 0.9%

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

Day 3

General patient assessment prior to each day of treatment.

Any toxicity grade 2 or greater may require delay of treatment and review by medical officer before commencing treatment.

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

Continue neurological assessment for 24 hours after ifosfamide treatment is completed.

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.

Mesna

  • administer orally 2 hours and 6 hours post completion of ifosfamide 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

Note: the administration of mesna causes a false positive ketonuria​.

Deaccess 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)
Hypersensitivity reaction

Anaphylaxis and infusion related reactions can occur with this treatment.

Read more about hypersensitivity reaction 
Nausea and vomiting

Read more about prevention of treatment induced nausea and vomiting
Headache
Flu-like symptoms
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
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
Bone pain

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

Read more about taste and smell changes

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
Skin rash

Anti-cancer drugs can cause a number of changes in the skin with maculo-papular rash the most common type of drug-induced skin reaction. 

Read more about skin rash
Nephrotoxicity

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

Read more about fatigue
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
Diarrhoea

Read more about treatment induced diarrhoea
Anorexia

Loss of appetite accompanied by decreased food intake.

Read more about anorexia
Injection-site reaction

Inflammation of or damage to the tissue surrounding the area where a drug was injected.

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
Progressive multifocal leukoencephalopathy (PML)

A rare opportunistic viral infection of the brain, usually leading to death or severe disability, can occur with monoclonal antibodies (e.g. rituximab, obinutuzumab, ofatumumab, brentuximab vedotin) and other targeted therapies (e.g. ibrutinib, ruxolitinib, idelalisib). Onset may occur up to months after the final dose.  

Read more about progressive multifocal leukoencephalopathy (PML)

The major evidence supporting this protocol is provided by a phase III multicentre international randomised trial (CORAL) involving 396 patients that compared R-ICE (rituximab, ifosfamide, carboplatin and etoposide) with R-DHAP (rituximab, dexamethasone, high-dose cytarabine and cisplatin) in patients with relapsed or refractory CD20+ diffuse large B-cell lymphoma (DLBCL).r

Between July 2003 and September 2007, 202 patients were randomised to receive R-ICE and 194 patients were randomised to receive R-DHAP. Both arms were given every 3 weeks for 3 cycles followed by ASCT and an additional rituximab dose was given on day -1 in the first course of each arm. The primary end point was the mobilization-adjusted response rate after three cycles of chemotherapy. Overall efficacy measurements were similar between R-DHAP and R-ICE with different toxicity profiles.r

Prior to CORAL, Kewalramani et al. were the first to investigate whether the addition of rituximab to the ICE regimen improved the complete remission rates in patients with relapsed or refractory DLBCL under consideration for ASCT. Thirty-six patients who had not received rituximab previously were treated with R-ICE every 2 weeks for 3 cycles. R-ICE appeared to improve CR rates when compared with historical controls treated with ICE.r

It should be noted that the CORAL study compared two rituximab combination chemotherapy regimens head to head and that there have been no randomised studies to confirm the efficacy of adding rituximab to ICE in this patient population.

Efficacy

In the CORAL study, the 3-year EFS rate was 31% (95% CI, 26% to 36%) and was not significantly different between the R-ICE and R-DHAP arms (26% and 35%, respectively; P=0.6). Three-year PFS was 37% (95% CI, 31% to 42%), and the R-ICE and R-DHAP arms were not significantly different (31% and 42%, respectively; P=0 .4). Three-year OS was 49% (95% CI, 43% to 55%), with no difference between the R-ICE and R-DHAP arms (47% and 51%, respectively; P=0.4). For patients who underwent ASCT, 3-year PFS was 53%. There was no difference between the numbers of patients who achieved CR (38%) and PR prior to ASCT. Response rates, PFS and OS were all significantly affected by prior use of rituximab, early relapse (<12 months) and the secondary IPI (prognostic index) (see Table 3 below).r In the earlier, non-randomised study the CR rate with R-ICE was 53% compared with 27% in historical controls treated with ICE (see Table 4 below). The PFS in this group was 54% at 2 years.r

© Journal of Clinical Oncology 2010

© Blood 2004

Toxicity

In the CORAL study, grade 3 to 4 haematologic toxicities were more severe in the R-DHAP arm than the R-ICE arm and included grade 4 renal toxicity in 11 patients.r

In the R-ICE arm 90 serious adverse events occurred in 58 patients, and in the R-DHAP arm 120 serious events occurred in 68 patients. In both arms, the most common serious adverse events were infections, with a similar rate of infection as a result of neutropenia (16%) in both arms.r

© Blood 2004

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Version 6

Date Summary of changes
16/04/2020 'Mesna dosing and administration' block added to clinical information. Version number changed to v.6
27/03/2020 Reviewed by Haematology Reference Committee with no significant changes, review in 4 years.
01/10/2021 Drug status updated: rituximab SC is TGA registered but no longer PBS listed.

Version 5

Date Summary of changes
09/03/2020

Biosimilar rituximab added to clinical information. Version number changed to V.5   

Version 4

Date Summary of changes
07/03/2014

New protocol presented at Haematology reference committee meeting.
15/05/2014 Approved and published on eviQ review in 2 years.
17/11/2014 Added link to ALLG, ANZCTR and Lymphoma Australia website with statement 'Patients with NHL should be considered for inclusion into clinical trials'.
11/09/2015 Reviewed at RCM, no changes. Updated drug costs.
31/05/2017

Transferred to new eviQ website. Version number change to V.3.
12/03/2018

Added:

  • Link to subcutaneous​ rituximab document underneath the treatment schedule.
  • Clinical information block on subcutaneous rituximab
  • Link to the subcutaneous rituximab document into administration section
  • Injection-site reaction side effect
  • Note about subcutaneous rituximab to the patient information
  • Version number changed to V.4.
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. 

The information contained in this protocol is based on the highest level of available evidence and consensus of the eviQ reference committee regarding their views of currently accepted approaches to treatment. Any clinician (medical oncologist, haematologist, radiation oncologist, medical physicist, radiation therapist, pharmacist or nurse) seeking to apply or consult this protocol is expected to use independent clinical judgement in the context of individual clinical circumstances to determine any patient's care or treatment. While eviQ endeavours to link to reliable sources that provide accurate information, eviQ and the Cancer Institute NSW do not endorse or accept responsibility for the accuracy, currency, reliability or correctness of the content of linked external information sources. Use is subject to eviQ’s disclaimer available at www.eviQ.org.au

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31 Mar 2023