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Testicular germ cell metastatic VIP (etoposide iFOSFamide ciSplatin)

This protocol was published over 10 years ago and has been assessed by the reference committee as suitable to be reviewed as required. The review due date has been removed. If something in this protocol requires reference committee consideration, please click on the feedback button at the bottom of the page.

Read more about the as required review process in this factsheet.

Clinicians are advised to consult with a medical oncologist from a tertiary treatment centre with high volume experience in testicular cancer prior to use of this regimen.

Link to ANZUP testicular cancer surveillance recommendations

Check for clinical trials in this patient group. Link to Australian Clinical Trials website

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Cycle 1 to 4

Drug Dose Route Day
Etoposide * 75 mg/m2 IV infusion 1 to 5
ciSplatin 20 mg/m2 IV infusion 1 to 5
iFOSFamide 1,200 mg/m2 IV infusion 1 to 5
Mesna 1,200 mg/m2 IV infusion 1 to 5
Mesna 2,000 mg at 2 hours and 6 hours after completion of ifosfamide infusion PO 1 to 5
Pegfilgrastim 6 mg Subcut 6

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

Frequency:
21 days 
Cycles:
4 
Notes:

The VeIP regimen is preferred over this regimen in patients relapsing after BEP because etoposide is used in both BEP and VIP.

Drug status:

Etoposide, ifosfamide and cisplatin are on the PBS general schedule

Pegfilgrastim is PBS authority

Oral mesna is TGA registered but not PBS listed for this indication

Cost:
~ $1,400 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). These costs are reviewed and updated on eviQ at 6 monthly intervals. Anti-cancer drugs that are not included on the PBS do not have a cost included in eviQ protocols.

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.

Where oral drugs are available on the PBS for both 30- and 60-day prescriptions, the unit cost for the 30-day supply is used.

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 to 4

Day 1
Netupitant 300 mg (PO) 60 minutes before chemotherapy (fixed dose preparation with palonosetron)
Palonosetron 0.5 mg (PO) 60 minutes before chemotherapy (fixed dose preparation with netupitant)
Dexamethasone 8 mg (PO) 60 minutes before chemotherapy*
Etoposide 75 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 30 to 60 minutes
ciSplatin 20 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 60 minutes
iFOSFamide 1,200 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 2 hours (loaded with mesna)
Mesna 1,200 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
Dexamethasone 8 mg (PO) 60 minutes before chemotherapy
Etoposide 75 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 30 to 60 minutes
ciSplatin 20 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 60 minutes
iFOSFamide 1,200 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 2 hours (loaded with mesna)
Mesna 1,200 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
Netupitant 300 mg (PO) 60 minutes before chemotherapy (fixed dose preparation with palonosetron)
Palonosetron 0.5 mg (PO) 60 minutes before chemotherapy (fixed dose preparation with netupitant)
Dexamethasone 8 mg (PO) 60 minutes before chemotherapy
Etoposide 75 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 30 to 60 minutes
ciSplatin 20 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 60 minutes
iFOSFamide 1,200 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 2 hours (loaded with mesna)
Mesna 1,200 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 5
Dexamethasone 8 mg (PO) 60 minutes before chemotherapy
Etoposide 75 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 30 to 60 minutes
ciSplatin 20 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 60 minutes
iFOSFamide 1,200 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 2 hours (loaded with mesna)
Mesna 1,200 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 6
Dexamethasone 8 mg (PO) ONCE a day (or in divided doses) with or after food
Pegfilgrastim 6 mg (Subcut) inject subcutaneously on day 6 at least 24 hours after chemotherapy
Day 7 and 8
Dexamethasone 8 mg (PO) ONCE a day (or in divided doses) with or after food

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

* The dose of dexamethasone on day 1 is 8 mg as per eviQ RC consensus but may be increased to 12 mg at the clinician’s discretion. Link to ID 7 Prevention of antineoplastic induced nausea and vomiting.

Frequency:
21 days 
Cycles:
4 

Cycle 1 to 4

Drug Dose Route Day
Etoposide * 75 mg/m2 IV infusion 1 to 5
ciSplatin 20 mg/m2 IV infusion 1 to 5
iFOSFamide 1,200 mg/m2 IV infusion 1 to 5
Mesna 1,200 mg/m2 IV infusion 1 to 5
Mesna 2,000 mg at 2 hours and 6 hours after completion of ifosfamide infusion PO 1 to 5
Pegfilgrastim 6 mg Subcut 6

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

Frequency:
21 days 
Cycles:
4 
Notes:

The VeIP regimen is preferred over this regimen in patients relapsing after BEP because etoposide is used in both BEP and VIP.

Drug status:

Etoposide, ifosfamide and cisplatin are on the PBS general schedule

Pegfilgrastim is PBS authority

Oral mesna is TGA registered but not PBS listed for this indication

Cost:
~ $1,400 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). These costs are reviewed and updated on eviQ at 6 monthly intervals. Anti-cancer drugs that are not included on the PBS do not have a cost included in eviQ protocols.

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.

Where oral drugs are available on the PBS for both 30- and 60-day prescriptions, the unit cost for the 30-day supply is used.

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 to 4

Day 1
Netupitant 300 mg (PO) 60 minutes before chemotherapy (fixed dose preparation with palonosetron)
Palonosetron 0.5 mg (PO) 60 minutes before chemotherapy (fixed dose preparation with netupitant)
Dexamethasone 8 mg (PO) 60 minutes before chemotherapy*
Etoposide 75 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 30 to 60 minutes
ciSplatin 20 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 60 minutes
iFOSFamide 1,200 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 2 hours (loaded with mesna)
Mesna 1,200 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
Dexamethasone 8 mg (PO) 60 minutes before chemotherapy
Etoposide 75 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 30 to 60 minutes
ciSplatin 20 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 60 minutes
iFOSFamide 1,200 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 2 hours (loaded with mesna)
Mesna 1,200 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
Netupitant 300 mg (PO) 60 minutes before chemotherapy (fixed dose preparation with palonosetron)
Palonosetron 0.5 mg (PO) 60 minutes before chemotherapy (fixed dose preparation with netupitant)
Dexamethasone 8 mg (PO) 60 minutes before chemotherapy
Etoposide 75 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 30 to 60 minutes
ciSplatin 20 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 60 minutes
iFOSFamide 1,200 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 2 hours (loaded with mesna)
Mesna 1,200 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 5
Dexamethasone 8 mg (PO) 60 minutes before chemotherapy
Etoposide 75 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 30 to 60 minutes
ciSplatin 20 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 60 minutes
iFOSFamide 1,200 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 2 hours (loaded with mesna)
Mesna 1,200 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 6
Dexamethasone 8 mg (PO) ONCE a day (or in divided doses) with or after food
Pegfilgrastim 6 mg (Subcut) inject subcutaneously on day 6 at least 24 hours after chemotherapy
Day 7 and 8
Dexamethasone 8 mg (PO) ONCE a day (or in divided doses) with or after food

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

* The dose of dexamethasone on day 1 is 8 mg as per eviQ RC consensus but may be increased to 12 mg at the clinician’s discretion. Link to ID 7 Prevention of antineoplastic induced nausea and vomiting.

Frequency:
21 days 
Cycles:
4 
  • Relapsed or refractory metastatic germ cell tumours, salvage therapy
  • Metastatic germ cell tumours in patients who cannot tolerate the bleomycin in BEP (e.g. patients with underlying pulmonary disease)
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.

Read more about Hypersensitivity reaction
Emetogenicity HIGH

Suggested default antiemetics have been added to the treatment schedule, and may be substituted to reflect institutional policy.

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
Etoposide conversion factor

Note: Etopophos (etoposide phosphate) 113.6 mg is equivalent to etoposide 100 mg.
Doses in this protocol are expressed as etoposide.
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-induced encephalopathy assessment chart
Cisplatin dosing

Directly measured glomerular filtration rate (mGFR) is preferred for initial dosing when eGFR < 60 mL/min/1.73 m2, especially when cisplatin dose > 50 mg/m2 or when eGFR is unreliable (e.g., extremes of body composition, amputees, paraplegia).

Read more about prevention and management of cisplatin induced nephrotoxicity.
Hydration

Hydration helps to prevent cisplatin-induced nephrotoxicity.

The default regimen is appropriate for patients with normal electrolytes, kidney function, fluid status etc. and should be adjusted according to individual requirements.

Read more about cisplatin hydration regimens
Ototoxicity

Ototoxicity may occur with platinum-based therapy; patients should be monitored for signs and symptoms. Platinum compounds should be used with caution in patients with pre-existing conditions or risk factors.

Ototoxicity may become more severe in patients being treated with other drugs with nephrotoxic potential e.g. aminoglycosides.

An audiometry test should be performed if symptoms develop.

Read more about ototoxicity - tinnitus and hearing loss
Peripheral neuropathy

Assess prior to each treatment. If a patient experiences > grade 2 review by medical officer before commencing treatment as alternate regimen may be considered.

Read more about peripheral neuropathy

Link to chemotherapy-induced peripheral neuropathy screening tool
Mesna dosing and administration

There is evidence supporting variations in mesna doses and administration timings, with no clear evidence that one particular regimen is superior to 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.

Read more about haemorrhagic cystitis 
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, eGFR, LFTs, calcium and magnesium at baseline and prior to each cycle.
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 and fathering a child

Cancer treatment can have harmful effects on fertility and this should be discussed with all patients of reproductive potential prior to commencing treatment. It is important that all patients of reproductive potential use effective contraception whilst on therapy and after treatment finishes. Effective contraception methods and contraception timeframe should be discussed with all patients of reproductive potential.

Read more about the impact 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.

Note: Delay and dose reductions are not recommended as the efficacy of this treatment may be greatly compromised - clinicians are advised to consult with a medical oncologist from a tertiary treatment centre with high volume experience in testicular cancer if dose delay or reduction due to toxicities or renal or hepatic dysfunction is being contemplated; an alternative treatment regimen may need to be considered.

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: 

For more information see References & Disclaimer.

Cisplatin
  Interaction Clinical management
Nephrotoxic drugs (e.g. aminoglycosides, amphotericin, contrast dye, frusemide, NSAIDs) Additive nephrotoxicity Avoid combination or monitor kidney function closely
Ototoxic drugs (e.g. aminoglycosides, frusemide, NSAIDs) Additive ototoxicity Avoid combination or perform regular audiometric testing
Neurotoxic drugs (e.g. vincristine, paclitaxel) Additive neurotoxicity Monitor closely for neuropathy if combination used
Paclitaxel Administration schedule may influence the development of myelosuppression Minimise toxicity by administering paclitaxel first in regimens using the combination
Carbamazepine, phenytoin, valproate Decreased antiepileptic plasma levels Monitor antiepileptic serum levels and seizure frequency for efficacy; adjust dosage as appropriate or select alternative antiepileptic (e.g. clonazepam, diazepam, lorazepam)
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
Nephrotoxic drugs (e.g. aminoglycosides, amphotericin, contrast dye, frusemide, NSAIDs) Additive nephrotoxicity Avoid combination or monitor kidney function closely
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
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
NK-1 antagonist e.g. aprepitant, fosaprepitant, netupitant
  Interaction Clinical management
Dexamethasone Increased effects/toxicity of dexamethasone due to inhibition of its metabolism via CYP3A4

Reduce dose of antiemetic dexamethasone by approximately 50% when adding a NK-1 antagonist. For protocols that already recommend a NK-1 antagonist, the dose reduction of antiemetic dexamethasone has already been taken into account.

If dexamethasone is part of the chemotherapy protocol, dose reduction as per the product information is not routinely recommended in clinical practice and no additional dexamethasone is required for antiemetic cover. 
Warfarin

Reduced anticoagulant efficacy of warfarin due to increased clearance (aprepitant induces CYP2C9). *Note interaction only applicable to aprepitant/ fosaprepitant

INR should be monitored in the 2 week period, particularly at 7 to 10 days following the administration of aprepitant/ fosaprepitant
Combined oral contraceptive Reduced contraceptive efficacy due to increased clearance. *Note interaction only applicable to aprepitant/ fosaprepitant Alternative non-hormonal methods should be used during and for 1 month after stopping aprepitant/ fosaprepitant
CYP3A4 inducers (e.g. carbamazepine, phenytoin, phenobarbitone, rifampicin, St John’s wort etc.) Reduced efficacy of NK-1 antagonist possible due to increased clearance Avoid combination or monitor for decreased antiemetic effect. Consider using an alternative antiemetic regimen
CYP3A4 inhibitors (e.g. azole antifungals, clarithromycin, erythromycin, grapefruit juice, ritonavir etc.) Increased toxicity of NK-1 antagonist possible due to reduced clearance Avoid combination or monitor for increased adverse effects of NK-1 antagonist (e.g. headache, hiccups, constipation)
Drugs metabolised by CYP3A4 (e.g. etoposide, imatinib, irinotecan, midazolam, paclitaxel, vinblastine, vincristine etc.) Increased effects/toxicity of these drugs possible due to inhibition of CYP3A4 by NK-1 antagonist Avoid combination or monitor for increased toxicity especially with orally administered drugs
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 and Australian Injectable Drugs Handbook websites for further information.

Day 1 to 5

Approximate treatment time: 5 hours

General patient assessment prior to each day of treatment.

Peripheral neuropathy assessment tool.

Any toxicity greater than grade 2 should be reviewed by medical officer, however delay and dose reductions are not recommended as the efficacy of the treatment may be greatly compromised- clinicians are advised to consult with a medical oncologist from a tertiary treatment centre with high volume experience in testicular cancer if dose delay or reduction is being contemplated. An alternative treatment regimen may need to be considered.

Prime IV line(s).

Insert IV cannula or access TIVAD or CVAD.

Pre treatment medication

Verify antiemetics taken or administer as prescribed.

Verify dexamethasone taken or administer as prescribed.

Etoposide

Administer etoposide (irritant):
  • via IV infusion over 30 to 60 minutes
    • if using etoposide phosphate administer in ~ 50 mL sodium chloride 0.9% or glucose 5% over ~15 minutes
  • flush with ~ 100 mL sodium chloride 0.9%.
Infusion-related reaction:

Stop infusion at first sign of anaphylaxis or severe IRR and manage as per emergency. 

  • 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.
Potential adverse events:
  • rapid infusion may cause hypotension.

Cisplatin

Commence prehydration for cisplatin:
  • administer 10 mmol magnesium sulphate (MgSO4) in 1000 mL sodium chloride 0.9% over 60 minutes
  • ensure patient has passed urine prior to cisplatin administration as per institutional policy.
Administer cisplatin (irritant):
  • via IV infusion over 60 minutes
  • flush with 100 mL of sodium chloride 0.9%
  • observe for hypersensitivity reactions which can increase with the number of cycles administered and when given with concomitant radiation therapy. 
Infusion-related reaction (IRR):

Stop infusion at first sign of anaphylaxis or severe IRR and manage as per emergency. 

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).

Discharge information

Antiemetics - as/if prescribed.

Mesna tablets - as/if prescribed, with written instructions on how to take them.

Growth factor support - as/if prescribed, and arrangements for administration.

Patient information

Ensure patient receives protocol 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
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.
Haemorrhagic cystitis

An inflammatory process, characterised by diffuse bladder mucosal inflammation resulting in haemorrhage. Patients are at risk following blood and marrow transplant (BMT) or treatment with cyclophosphamide, ifosfamide and/or radiation therapy.

Read more about haemorrhagic cystitis

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 anti-cancer treatment, 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 and stomatitis
Diarrhoea

Read more about treatment induced diarrhoea
Fatigue

Read more about fatigue
Peripheral neuropathy

Typically symmetrical sensory neuropathy, affecting the fingers and toes, sometimes progressing to the hands and feet.  It is associated with several classes of anti-cancer drugs. These include taxanes, platinum-based compounds, vinca alkaloids and some drugs used to treat multiple myeloma.

Read more about peripheral neuropathy
Nephrotoxicity

Kidney dysfunction resulting from damage to the glomeruli, tubules or renal vasculature.
Ototoxicity

Tinnitus and hearing loss may occur due to damage in the inner ear. Tinnitus is usually reversible, while hearing loss is generally irreversible. Hearing loss is dose-related, cumulative and may be worse in those with pre-existing hearing problems.

Read more about ototoxicity - tinnitus and hearing loss
Hypomagnesaemia, hypokalaemia, hypocalcaemia

Abnormally low levels of magnesium, potassium and calcium in the blood.

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 and scalp cooling
Cardiotoxicity

Elevated risk of cardiovascular toxicity and metabolic syndrome.

Read more about cardiotoxicity associated with anti-cancer drugs.

4 cycles of BEP remain the standard therapy for patients with disseminated germ cell tumours. The VIP regimen may be considered a treatment alternative for patients with underlying pulmonary disease.

The evidence supporting this regimen comes from the intergroup trial which compared the standard therapy of bleomycin, etoposide and cisplatin (BEP) with etoposide, ifosfamide and cisplatin (VIP) in advanced germ cell tumours. The results of the trial were reanalysed using the IGCCCG staging system by Hinton et al.r

From October 1987 to April 1992, 286 eligible patients were randomised to receive either BEP or VIP. Progression-free survival (PFS), overall survival (OS), and toxicity were assessed for the treatment arms.r

Efficacy

With a median follow up of 7.3 years, the PFS rates were 64% versus 58% and the OS rates 69% versus 67% in the VIP and BEP arms respectively. For patients reclassified with the IGCCCG staging system, the PFS rates were 81%, 72% and 54% and the OS rates were 89%, 81% and 60% for good, intermediate and poor risk patients respectively. Difference in OS (VIP 62%, BEP 57%) and PFS (VIP 56%, BEP 49%) for the subset of patients reclassified as poor risk were not significantly different.r

Overall survival by treatment stage for patients classified as having poor prognosis by IGCCCGr

© Cancer 2003

Toxicity

Haematological toxicity was the most common toxicity in both arms. 3 possible drug related deaths occurred in good or intermediate risk patients. In the VIP arm, 1 good risk patient died from sepsis. In the BEP arm, 2 intermediate risk patients died from sepsis, 1 from pulmonary haemorrhage and 1 death typical of bleomycin after a total dose of 300 000 International units.

Treatment group Risk group Grade 3/4 toxicity(%)r
VIP
 		 Good prognosis 85
Intermediate prognosis 93
Poor prognosis 93
BEP Good prognosis 75
Intermediate prognosis 73
Poor prognosis 79
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These search filters have been developed to retrieve the most up to date evidence from PubMed, in real time, using specifically designed search filters built to meet our needs.

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Version 9

Date Summary of changes
31/01/2024

Protocol assessed by eviQ medical oncology reference committee and deemed suitable to be reviewed as required. Flag added, review date removed and version number increased to V.9. Read more about as required review protocol status in this factsheet.
19/07/2024 Late onset cardiotoxicity side effect block added to the protocol and patient information to align to ID 1617. 

Version 8

Date Summary of changes
27/07/2023

Protocol updated with ADDIKD guideline recommendations. 

PDF of previous protocol.

Version number changed to V.8.
12/12/2023 "Non-PBS" footnote for netupitant and palonosetron removed from detailed treatment schedule.

Version 7

Date Summary of changes
18/11/2021 Cisplatin changed from moderately to highly emetogenic as per NCCN, MASCC/ESMO and ASCO guidelines and medical oncology reference committee consensus. Treatment schedule antiemetics and clinical information updated to reflect the change. NK-1 antagonist added to interactions. Version number changed to V.7.

Version 6

Date Summary of changes
04/09/2020 Biosimilar drug added to clinical information. Version number changed to V.6.

Version 5

Date Summary of changes
16/04/2020 'Mesna dosing and administration' block added to clinical information. Version number changed to v.5

Version 4

Date Summary of changes
08/10/2019 Clinical information updated with PBS expanded indications for GCSF. Treatment schedule note updated.

Version 3

Date Summary of changes
08/03/2010 Review, new dose modifications and transferred to eviQ.
26/03/2010 Renal dose modifications for cisplatin changed.
02/07/2010 Haematological dose modifications updated ( 20% changed to 25% dose reduction).
26/07/2010 Patient information sheet modified ( G-CSF removed from table).
13/08/2010 Pegfilgrastim added to treatment schedule. G-CSF included in the table in patient information sheet.
26/08/2010 Encepholapathy related to Ifosfamide side effect added.
21/03/2011 New format to allow for export of protocol information.
Protocol version number changed to V.2.
Antiemetics and premedications added to the treatment schedule.
Additional Clinical Information, Key Prescribing table and Key Administration .table combined into new section titled Clinical Considerations.
Drug specific information placed behind the drug name link.
16/01/2012 PHC view updated.
30/11/2012 Reviewed at reference committee meeting. No change. 2 year review.
10/7/2013 Dose modifications for cisplatin updated.
09/05/2014 Reviewed at Medical Oncology Reference committee meeting. Minor changes. PHC view removed. 2 year review.
27/03/2015 Links to Germ Cell Tumour HPCT protocols added.
31/03/2017 Protocol discussed and decided to have a 5 year review period. Next due for review in 2019.
31/05/2017 Transferred to new eviQ website. Protocol version number changed to V.3.
22/06/2018

Antiemetics updated to be in line with international guidelines. Note to dexamethasone added.
25/03/2019 Protocol reviewed at Medical Oncology Reference Committee meeting. ANZUP surveillance recommendations added as related page. Next review in 5 years.

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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https://www.eviq.org.au/p/318

11 Oct 2024