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Bladder/Urothelial neoadjuvant ddMVAC (dose dense methotrexate vinBLASTine DOXOrubicin 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.

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

Check for clinical trials in this patient group. Link to Australian Clinical Trials opens in a new tab or window website

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Cycle 1 to 3

Drug Dose Route Day
Methotrexate 30 mg/m2 IV bolus 1
DOXOrubicin 30 mg/m2 IV 2
vinBLASTine 3 mg/m2 IV 2
ciSplatin 70 mg/m2 IV infusion 2
Pegfilgrastim * 6 mg Subcut 3

*if filgrastim 5 micrograms/kg/day is used, administer ONCE daily (at least 24 hours post chemotherapy) on days 3 to 10

An alternative schedule is to give 3 cycles with all chemotherapy drugs administered on day 11

Frequency:
14 days 
Cycles:
3 to 6 pre cystectomy
Drug status:

All drugs (except G-CSF) in this protocol are on the PBS schedule opens in a new tab or window Pegfilgrastim  is PBS authority opens in a new tab or window

Cost:
~ $200 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, growth factor support 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 3

Day 1
Methotrexate 30 mg/m2 (IV bolus) over 3 to 5 minutes
Day 2
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 12 mg (PO) 60 minutes before chemotherapy
DOXOrubicin 30 mg/m2 (IV) over 5 to 15 minutes
vinBLASTine 3 mg/m2 (IV) in 50 mL sodium chloride 0.9% over 5 to 10 minutes
ciSplatin 70 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 60 minutes
Day 3
Dexamethasone 8 mg (PO) ONCE a day (or in divided doses) with or after food.
Pegfilgrastim 6 mg (Subcut) inject subcutaneously on day 3*
Day 4 and 5
Dexamethasone 8 mg (PO) ONCE a day (or in divided doses) with or after food.

*if filgrastim 5 micrograms/kg/day is used, administer ONCE daily (at least 24 hours post chemotherapy) on days 3 to 10

An alternative schedule is to give 3 cycles with all chemotherapy drugs administered on day 11

Frequency:
14 days 
Cycles:
3 to 6 pre cystectomy

Cycle 1 to 3

Drug Dose Route Day
Methotrexate 30 mg/m2 IV bolus 1
DOXOrubicin 30 mg/m2 IV 2
vinBLASTine 3 mg/m2 IV 2
ciSplatin 70 mg/m2 IV infusion 2
Pegfilgrastim * 6 mg Subcut 3

*if filgrastim 5 micrograms/kg/day is used, administer ONCE daily (at least 24 hours post chemotherapy) on days 3 to 10

An alternative schedule is to give 3 cycles with all chemotherapy drugs administered on day 11

Frequency:
14 days 
Cycles:
3 to 6 pre cystectomy
Drug status:

All drugs (except G-CSF) in this protocol are on the PBS schedule opens in a new tab or window Pegfilgrastim  is PBS authority opens in a new tab or window

Cost:
~ $200 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, growth factor support 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 3

Day 1
Methotrexate 30 mg/m2 (IV bolus) over 3 to 5 minutes
Day 2
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 12 mg (PO) 60 minutes before chemotherapy
DOXOrubicin 30 mg/m2 (IV) over 5 to 15 minutes
vinBLASTine 3 mg/m2 (IV) in 50 mL sodium chloride 0.9% over 5 to 10 minutes
ciSplatin 70 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 60 minutes
Day 3
Dexamethasone 8 mg (PO) ONCE a day (or in divided doses) with or after food.
Pegfilgrastim 6 mg (Subcut) inject subcutaneously on day 3*
Day 4 and 5
Dexamethasone 8 mg (PO) ONCE a day (or in divided doses) with or after food.

*if filgrastim 5 micrograms/kg/day is used, administer ONCE daily (at least 24 hours post chemotherapy) on days 3 to 10

An alternative schedule is to give 3 cycles with all chemotherapy drugs administered on day 11

Frequency:
14 days 
Cycles:
3 to 6 pre cystectomy

Indications:

  • neoadjuvant transitional cell carcinoma (TCC) of the bladder
    • operable muscle invasive bladder cancer stage T2-T4a, eligible for radical cystectomy

Cautions / Exclusions:

  • ECOG performance status 2 or greater
  • pre existing neuropathies Grade 2 or greater
  • significant hearing impairment/tinnitus.
  • left ventricular ejection fraction less than 50%.
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
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
Cumulative lifetime dose of anthracyclines

Cumulative doses should take into account all previous anthracyclines received during a patient’s lifetime (i.e. daunorubicin, doxorubicin, epirubicin, idarubicin and mitoxantrone). 

Criteria for reducing the total anthracycline cumulative lifetime dose include:

  • patient is elderly
  • prior mediastinal radiation
  • hypertensive cardiomegaly
  • concurrent therapy with high dose cyclophosphamide and some other cytotoxic drugs (e.g. bleomycin, dacarbazine, dactinomycin, etoposide, melphalan, mitomycin and vincristine).

Baseline clinical assessments include echocardiogram (ECHO) or gated heart pool scan (GHPS) and electrocardiogram (ECG) evaluation.

Patients with normal baseline cardiac function (left ventricular ejection fraction (LVEF) > 50%) and low risk patients require LVEF monitoring when greater than 70% of the anthracycline threshold is reached or if the patient displays symptoms of cardiac impairment. Post-treatment cardiac monitoring is recommended for patients who have received high levels of total cumulative doses of anthracyclines at the clinician's discretion.

Read more about cardiac toxicity associated with anthracyclines
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
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.
Methotrexate dosing and monitoring

Consider a directly measured GFR for initial dosing when eGFR < 60mL/min/1.73 m2, especially when eGFR is unreliable (e.g., extremes of body composition, amputees, paraplegia).

Consider monitoring of kidney function before, during and after methotrexate administration to identify signs of kidney function deterioration.

Methotrexate exits slowly from third space compartments (e.g. pleural effusions or ascites), resulting in a prolonged terminal plasma half-life and unexpected toxicity. In patients with significant third space accumulations, it is advisable to evacuate the fluid before treatment and to monitor plasma methotrexate levels.
Constipation

Prescribe prophylactic laxatives to prevent constipation related to the use of vinca alkaloids.
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 or greater peripheral neuropathy, a dose reduction, delay, or omission of treatment may be required; review by medical officer before commencing treatment.

Read more about peripheral neuropathy

Link to Anti-cancer drug induced peripheral neuropathy screening tool
Biosimilar drug

Read more about biosimilar drugs on the Biosimilar Awareness Initiative opens in a new tab or window 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 opens in a new tab or window
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. Possible suboptimal response to inactivated vaccines.

For more information about vaccinations in people with cancer refer to the Australian Immunisation Handbook opens in a new tab or window.
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 fetal 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 impact of cancer treatment on fertility opens in a new tab or window
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) opens in a new tab or window unless otherwise specified. Renal and hepatic dose modifications have been standardised where possible. For more information see dosing considerations & disclaimer.

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

Haematological toxicity
ANC x 109/L (pre-treatment blood test)
0.5 to less than 1.0 Delay treatment until recovery
less than 0.5 Delay treatment until recovery and reduce methotrexate, vinblastine, doxorubicin and cisplatin by 25% for subsequent cycles
Febrile neutropenia Delay treatment until recovery and reduce methotrexate, vinblastine, doxorubicin and cisplatin by 25% for subsequent cycles
Platelets x 109/L (pre-treatment blood test)
75 to less than 100 Refer to local institutional guidelines; it is the view of the expert clinicians that treatment should continue if patient is clinically well
50 to less than 75 Delay treatment until recovery
less than 50 Delay treatment until recovery and reduce methotrexate, vinblastine, doxorubicin and cisplatin by 25% for subsequent cycles
Kidney dosing recommendations 
  • Suggested dose modifications are based on the International Consensus Guideline on Anticancer Drug Dosing in Kidney Dysfunction (ADDIKD).
  • Where one or more drugs in a protocol is recommended to be avoided, consider using a clinically appropriate alternative treatment protocol instead.
  • Before dose adjusting or omitting a drug, consider treatment intent.
  • In kidney replacement therapy consult a multidisciplinary team consisting of oncology/haematology with nephrology and/or clinical pharmacology for the management of dosing. 
  • For complete information on individual drug recommendations please review the individual drug monograph in the ADDIKD guideline.
eGFR
(mL/min/1.73m2)		 Cisplatin Doxorubicin Methotrexate Vinblastine
≥ 60

Full dose

Full dose

Full dose

Full dose
45 - 59

Full dose*

OR

Consider a 25% reduction

Potential for increased risk of adverse events

Full dose

 

 

 

Full dose*

OR

Consider a 25% reduction

Potential for increased risk of adverse events

Full dose 

 

 

 
30 - 44

Avoid 

Not recommended - use alternative protocol

 

Alternative protocol

This drug may be given at this eGFR level (see ADDIKD guideline) however not recommended in this protocol

Alternative protocol

This drug may be given at this eGFR level (see ADDIKD guideline) however not recommended in this protocol

Alternative protocol

This drug may be given at this eGFR level (see ADDIKD guideline) however not recommended in this protocol
15 - 29

Avoid 

Not recommended - use alternative protocol

 

Alternative protocol

This drug may be given at this eGFR level (see ADDIKD guideline) however not recommended in this protocol

Avoid 

Not recommended - use alternative protocol

 

Alternative protocol

This drug may be given at this eGFR level (see ADDIKD guideline) however not recommended in this protocol
< 15
(without kidney replacement therapy)

Avoid 

Not recommended - use alternative protocol

 

Alternative protocol

This drug may be given at this eGFR level (see ADDIKD guideline) however not recommended in this protocol

Avoid 

Not recommended - use alternative protocol

 

Alternative protocol

This drug may be given at this eGFR level (see ADDIKD guideline) however not recommended in this protocol
* This differs from the ADDIKD guideline recommendations and is per RCM consensus and trial2.
Hepatic impairment
Hepatic dysfunction
Mild Reduce vinblastine and doxorubicin by 25%
Moderate Reduce vinblastine and doxorubicin by 50%
Severe Omit vinblastine and doxorubicin
Peripheral neuropathy
Grade 2 which is present at the start of the next cycle Reduce cisplatin and vinblastine by 25%; if persistent, reduce cisplatin and vinblastine by 50%
Grade 3 or Grade 4 Omit cisplatin and vinblastine
Mucositis and stomatitis
Grade 2 Delay treatment until toxicity has resolved to Grade 1 or less and reduce doses for subsequent cycles as follows:
1st occurrence: No dose reduction
2nd occurrence: Reduce methotrexate, vinblastine, doxorubicin and cisplatin by 25%
3rd occurrence: Reduce methotrexate, vinblastine, doxorubicin and cisplatin by 50%
4th occurrence: Omit treatment
Grade 3 or Grade 4 Delay treatment until toxicity has resolved to Grade 1 or less and reduce doses for subsequent cycles as follows:
1st occurrence: Reduce methotrexate, vinblastine, doxorubicin and cisplatin by 50%
2nd occurrence: Omit treatment

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)
Doxorubicin
  Interaction Clinical management
Cardiotoxic drugs (eg. bevacizumab, calcium channel blockers, propranolol, trastuzumab etc.) Increased risk of doxorubicin-induced cardiotoxicity Avoid combination or monitor closely for cardiotoxicity
Cyclophosphamide Sensitises the heart to the cardiotoxic effects of doxorubicin; also, doxorubicin may exacerbate cyclophosphamide induced cystitis Monitor closely for cardiotoxicity and ensure adequate prophylaxis for haemorrhagic cystitis when combination is used
Nephrotoxic drugs (e.g. aminoglycosides, amphotericin, contrast dye, frusemide, NSAIDs etc.) Additive nephrotoxicity Avoid combination or monitor kidney function closely
Glucosamine Reduced efficacy of doxorubicin (due to induction of glucose-regulated stress proteins resulting in decreased expression of topoisomerase II in vitro) The clinical effect of glucosamine taken orally is unknown. Avoid combination or monitor for decreased clinical response to doxorubicin
CYP2D6 inhibitors (e.g. SSRIs (esp. paroxetine), perhexiline, cinacalcet, doxepin, flecainide, quinine, terbinafine, ritonavir etc.) Increased toxicity of doxorubicin possible due to reduced clearance Monitor for doxorubicin toxicity
CYP3A4 inhibitors (e.g. aprepitant, azole antifungals, clarithromycin, erythromycin, grapefruit juice, ritonavir etc.) Increased toxicity of doxorubicin possible due to reduced clearance Monitor for doxorubicin toxicity
CYP3A4 inducers (e.g. carbamazepine, phenytoin, phenobarbitone, rifampicin, St John's wort etc.) Reduced efficacy of doxorubicin possible due to increased clearance Monitor for decreased clinical response to doxorubicin
Methotrexate
  Interaction Clinical management
Ciprofloxacin

NSAIDS

Probenecid

Proton pump inhibitors (e.g. esomeprazole, omeprazole, pantoprazole)		 Increased toxicity of methotrexate possible due to reduced clearance Avoid combination or monitor for methotrexate toxicity

Important note: with high-dose methotrexate therapy, many of these drug combinations are contraindicated
Sulphonamides and penicillins (e.g. sulfamethoxazole (in Bactrim®, Septrin®), piperacillin (in Tazocin®) etc.) Increased toxicity of methotrexate possible due to displacement from serum protein binding Avoid combination or monitor for methotrexate toxicity
Trimethoprim Increased toxicity of methotrexate possible due to additive antifolate activity Avoid combination or monitor for methotrexate toxicity
Mercaptopurine Increased toxicity of mercaptopurine possible due to reduced clearance Avoid combination or monitor for mercaptopurine toxicity
Nephrotoxic drugs (e.g. aminoglycosides, amphotericin, contrast dye, frusemide, NSAIDs) Additive nephrotoxicity Avoid combination or monitor kidney function closely
Hepatotoxic drugs (e.g. azathioprine, leflunomide, retinoids, sulfasalazine) Additive hepatotoxicity Avoid combination or monitor liver function closely
Folic acid (e.g. as in multivitamins)

Asparaginase (administered immediately prior or concurrently)		 Reduced efficacy of methotrexate possible due antagonism of its action Avoid combination or monitor for decreased clinical response to methotrexate
Note: asparaginase administered shortly after methotrexate can enhance its efficacy and reduce its toxicity
Infliximab Altered methotrexate concentration Monitor for signs of methotrexate toxicity or reduced efficacy
Vinblastine
  Interaction Clinical management
CYP3A4 and P-gp inhibitors (e.g. amiodarone, aprepitant, azole-antifungals, ritonavir, lapatinib, nilotinib, sorafenib, macrolides, ciclosporin, grapefruit juice etc.) Increased toxicity of vinblastine possible due to reduced clearance Monitor for vinblastine toxicity (esp. neurotoxicity, adynamic ileus)
CYP3A4 inducers (e.g. carbamazepine, phenytoin, phenobarbitone, rifampicin, St John’s wort etc.) Reduced efficacy of vinblastine possible due to increased clearance Monitor for decreased clinical response to vinblastine
Drugs undergoing P-gp-mediated elimination (e.g. dabigatran, loperamide, phenytoin etc.) Reduced efficacy of these drugs possible due to induction of P-gp by vinblastine resulting in increased clearance Avoid combination or monitor for decreased clinical response to interacting drugs
Mitomycin Increased risk of pulmonary toxicity when vinblastine administered following or concomitantly with mitomycin Avoid combination or monitor closely for pulmonary toxicity (i.e. interstitial infiltrates, pleural effusion resulting in respiratory distress and cough)
Ototoxic drugs (e.g. cisplatin, aminoglycosides, frusemide, NSAIDs) Additive ototoxicity (as reported with other vinca alkaloids) Avoid combination or perform regular audiometric testing
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 opens in a new tab or window and P‑gp opens in a new tab or window inhibitors. If treating VTE, avoid use with strong CYP3A4 opens in a new tab or window and P‑gp opens in a new tab or window inducers. 

Rivaroxaban: avoid concurrent use with strong CYP3A4 opens in a new tab or window and P‑gp opens in a new tab or window  inhibitors.

Dabigatran: avoid combination with strong P‑gp opens in a new tab or window 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 opens in a new tab or window

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 or address chemical compatibilities related to IV drug preparation and administration. 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 opens in a new tab or window and Australian Injectable Drugs Handbook opens in a new tab or window websites for further information.

eviQ is currently updating the way information is presented in the administration section, if you notice any discrepancies please let us know, via feedback@eviq.org.au.

Day 1

Approximate treatment time: 30 minutes

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

Anti-cancer drug patient assessment tool prior to each day of treatment.

Anti-cancer drug induced neuropathy screening tool prior to each treatment.

Prime IV line(s).

Insert IV cannula or access TIVAD or CVAD.

Pre treatment medication

Verify antiemetics taken or administer as prescribed.

Methotrexate

Administer methotrexate:
  • via IV bolus via a side port of freely flowing IV fluids, over 3 to 5 minutes 
    OR
  • via a minibag, over 5 to 15 minutes
  • flush with ~50 mL of sodium chloride 0.9%.

Remove IV cannula and/or deaccess TIVAD or CVAD. 

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

Day 2

Approximate treatment time: 4 hours

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

Anti-cancer drug patient assessment tool prior to each day of treatment.

Anti-cancer drug induced neuropathy screening tool prior to each treatment.

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.

Doxorubicin

Extravasation of a vesicant is a medical emergency. Monitor for signs of extravasation throughout administration.

Administer doxorubicin (vesicant):
  • over 5 to 15 minutes
    • via a minibag OR
    • by IV bolus via a side port of a freely flowing IV infusion
  • flush with ~150 mL of sodium chloride 0.9%.
Potential adverse events:
  • potential for flare reaction during administration of doxorubicin (facial flushing and red streaking along the vein), stop infusion and exclude extravasation before continuing at a slower rate of infusion
  • although rare, cardiac arrhythmias may occur during or immediately after doxorubicin administration, if sudden onset of dyspnoea, palpitations or irregular pulse occurs, stop administration and obtain urgent medical officer review.

Vinblastine

Extravasation of a vesicant is a medical emergency. Monitor for signs of extravasation throughout administration.

Administer vinblastine (vesicant):
  • via a minibag over 5 to 10 minutes
  • flush with ~150 mL of sodium chloride 0.9%.

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. 

Post hydration:
  • 1000 mL sodium chloride 0.9% over 60 minutes.

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.

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

Laxatives - ensure patient has prophylactic laxatives.

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)
Nausea and vomiting

Read more about prevention of treatment induced nausea and vomiting
Extravasation, tissue or vein injury

The unintentional instillation or leakage of a drug or substance out of a blood vessel into surrounding tissue. This has the potential to cause damage to affected tissue.

Read more about extravasation management
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
Flare reaction

Anthracycline flare reaction is caused by a localised allergic reaction. It is characterised by erythematous vein streaking, urticaria and pruritus which may occur during drug administration and is often associated with too rapid an infusion. Extravasation must be ruled out if flare occurs.
Red-orange discolouration of urine

Pink/red/orange discolouration of the urine. This can last for up to 48 hours after some anthracycline drugs.

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
Constipation
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
Fatigue

Read more about fatigue
Oesophagitis

Inflammation of the mucosal lining of the oesophagus.  It can progress to ulceration, haemorrhage, secondary infection and pain.
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
Photosensitivity

Increased sensitivity to ultraviolet (UV) light resulting in an exaggerated sunburn-like reaction accompanied by stinging sensations and urticaria.
Radiation recall

Erythematous or inflammatory skin reaction resembling severe sunburn at sites previously treated with radiation therapy can occur with certain anti-cancer drugs. Symptoms include vesiculation, desquamation and ulceration of the skin.

Read more about radiation recall
Hypomagnesaemia, hypokalaemia, hypocalcaemia

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

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
Nail changes

Hyperpigmentation, paronychia, onycholysis, splinter haemorrhage, pyogenic granuloma formation, subungual haematoma and subungual hyperkeratosis are some of the nail changes associated with anti-cancer drugs.   

Read more about nail toxicities
Pulmonary toxicity

Pulmonary toxicity may include damage to the lungs, airways, pleura and pulmonary circulation. 

Read more about pulmonary toxicity associated with anti-cancer drugs

Delayed (onset months to years)
Cardiotoxicity

Anthracyclines are the most frequently implicated anti-cancer drugs associated with cardiotoxicity, which typically manifests as a reduction in left ventricular ejection fraction (LVEF), cardiomyopathy, or symptomatic CHF. Anthracycline induced cardiotoxicity has been categorised into acute, early-onset chronic progressive and late-onset chronic progressive and is usually not reversible. The risk of clinical cardiotoxicity increases with a number of risk factors including higher total cumulative doses. 

Read more about cardiac toxicity associated with anthracyclines

The timing of chemotherapy when given as an adjunct to surgery has continued to provoke much debate over several years with proponents for neoadjuvant chemotherapy justifying their position on the basis of clinical trials such as SWOG 87103 and meta-analysis results as published by the ABC meta analysis collaboration;4 whilst proponents for adjuvant chemotherapy criticise these trials for slow accrual, low patient numbers and lack of use of cisplatin/gemcitabine regimens. Proponents for adjuvant chemotherapy may prefer to offer adjuvant chemotherapy to high-risk patients such as T3 and T4 and/or node positive tumours. Meta-analyses have also demonstrated survival advantage when adjuvant chemotherapy is used.

A search of the literature did not find strong evidence to support the use of ddMVAC (dose dense methotrexate/vinblastine/adriamycin/cisplatin) for the neoadjuvant treatment of muscle invasive bladder cancer. The expert reference panel supported publication of the protocol on the basis of the information summarised below. The committee was most strongly influenced by the results from the meta-analysis demonstrating an improvement in overall survival for classical MVAC and other platinum-based neoadjuvant chemotherapy in comparison to definitive treatment alone.4

A similar protocol ("classical" MVAC, 4 week cycles) has been used extensively for the treatment of advanced bladder cancer and may also be utilised in the neoadjuvant setting.3 ddMVAC is used in preference to classical MVAC due to its better side effect profile and trend to improved efficacy in advanced disease.5, 6

Source Study & Year Published Supports Use Is the dose and regimen consistent with the protocol? Comments
Phase III trials Pfister et al 20227 Yes Yes 6 cycles ddMVAC
Grossman et al 20033 Yes No 3 cycles classical MVAC regimen
Phase II trials Plimack et al 20121 Yes Yes

3 cycles ddMVAC
(dose regimen from Sternberg et al5)
Choueiri et al 20142 Yes Yes

4 cycles ddMVAC
(dose regimen from Sternberg et al5)
Observational studies Blick et al 20128 Yes Yes 3-4 cycles ddMVAC
(dose regimen from Sternberg et al5)
Case series - - -

-
Meta-analyses ABC Meta-analysis Collaboration 20054 Yes N/A Improved overall survival with use of neoadjuvant chemotherapy
Tjokrowidjaja et al 20139 Yes N/A Improved overall survival with use of neoadjuvant chemotherapy
Guidelines Date published/revised Supports Use Is the dose and regimen consistent with the protocol? Comments
NCCN v.1 2014  Yes Yes 3-4 cycles ddMVAC
(dose regimen from Sternberg et al5)
BCCA April 2008 Yes - Recommend neoadjuvant chemotherapy (no regimen specified) for T2b-T4 not T2a
CCO Feb 2013 Yes Yes -

Efficacy

Initial studies of neoadjuvant classical MVAC showed a 23% absolute complete response improvement over cystectomy alone, however whilst there was a trend towards improved overall survival, this was not significant.3 A subsequent 2005 meta-analysis of platinum-based neoadjuvant chemotherapy did demonstrate a statistically significant improvement in overall survival (see Kaplan-Meier curves below).4 There has been further confirmation of this in a 2013 meta-analysis of chemotherapy in muscle invasive bladder cancer, which revealed an improvement in overall and disease free survival for both neoadjuvant and adjuvant treatment in separate analyses.9 There has been no head-to-head trial of neoadjuvant and adjuvant chemotherapy.

Cisplatin-gemcitabine and ddMVAC regimens have been compared to classical MVAC in head-to-head trials in the advanced bladder cancer setting. Cisplatin-gemcitabine10 and ddMVAC5, 6 were associated with no detriment in efficacy but much improved side effect profile. Similar trials in the neoadjuvant setting are lacking. The advantages that ddMVAC provide over classical MVAC include improved tolerability of the regimen and shorter duration of treatment, allowing quicker progression to cystectomy.

Kaplan-Meier curves for overall survival4

© European Urology 2005

Blick et al retrospectively reviewed the records of 80 consecutive patients receiving a planned 3 or 4 cycles of ddMVAC neoadjuvantly for muscle invasive bladder cancer. Those eligible had T2-T4a disease, any nodal status, and no distant metastases. 75% of patients had cystectomy as definitive management; the remaining 25% underwent radical radiation therapy treatment.8

Complete (T0) pathological response was seen in 43% of those who underwent cystectomy. 2 year overall survival was 77% and 2 year disease free survival was 65%. Those who were node positive did considerably poorer than those who were node negative.

(A) Disease-free survival (B) Overall survival8

Plimack et al conducted a phase 2 trial comparing the effects of ddMVAC with classical MVAC in the neoadjuvant setting utilising historical controls. 44 patients with T2-T4 (and either N0 or N1, but M0) bladder cancer with ECOG 0 or 1 were planned for 3 cycles of neoadjuvant ddMVAC which was completed 3 to 8 weeks prior to cystectomy. The primary outcome was pathological response, with secondary outcomes including safety parameters, side effect profile and survival.1

Complete (T0) pathological response was seen in 35% of evaluable patients (those who underwent cystectomy) compared to 38% seen in the Grossman et al trial using classical MVAC. Median follow up was too short to have meaningful survival results. The side effect profile was much more favourable; in particular 11% had a grade 3/4 neutropaenia compared with 54% in the standard MVAC trial.1

Toxicity

A summary of the toxicities associated with this protocol are included in the table below. The most clinically significant toxicities for this treatment are neutropenia and neuropathy.

Toxicity8 Grade 1/2 (%)  Grade 3/4 (%)
Neutropenia 11 11
Neuropathy 9 0
Infection 6 0
Nausea/vomiting 59 6
Diarrhoea 9 3
Stomatitis 47 6
Fatigue 65 6
Dyspnoea 3 0
Reflux symptoms 3 0
Constipation 3 0

There have also been reports of grade 3 or 4 anaemia, thrombocytopenia, lymphopenia, hyponatraemia, hypokalemia and mucositis with this regimen. Toxicity data was only available for 34 of the 80 enrolled patients in the largest neoadjuvant accelerated MVAC study; however this data was consistent with toxicity data published in larger trials using this regimen in the advanced bladder setting.

© Cancer 2012

1
Plimack, E. R., J. H. Hoffman-Censits, R. Viterbo, et al. 2014. "Accelerated Methotrexate, Vinblastine, Doxorubicin, and Cisplatin Is Safe, Effective, and Efficient Neoadjuvant Treatment for Muscle-Invasive Bladder Cancer: Results of a Multicenter Phase II Study With Molecular Correlates of Response and Toxicity." J Clin Oncol.
2
Choueiri, T., S. Jacobus & J. Bellmunt. et al. 2014. "Neoadjuvant Dose-Dense Methotrexate, Vinblastine, Doxorubicin, and Cisplatin With Pegfilgrastim Support in Muscle-Invasive Urothelial Cancer: Pathologic, Radiologic, and Biomarker Correlates." J Clin Oncol. May 12 epub. DOI 10.1200/JCO.2013.52.4785.
3
Grossman, H. B., R. B. Natale, C. M. Tangen, et al. 2003. "Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer." N Engl J Med 349(9):859-866.
4
Advanced Bladder Cancer Meta-analysis, Collaboration. 2005. "Neoadjuvant chemotherapy in invasive bladder cancer: update of a systematic review and meta-analysis of individual patient data advanced bladder cancer (ABC) meta-analysis collaboration." Eur Urol 48(2);202-5.
5
Sternberg, C. N., P. H. de Mulder, J. H. Schornagel, et al. 2001. "Randomized phase III trial of high-dose-intensity methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) chemotherapy and recombinant human granulocyte colony-stimulating factor versus classic MVAC in advanced urothelial tract tumors: European Organization for Research and Treatment of Cancer Protocol no. 30924." J Clin Oncol 19(10):2638-2646.
6
Sternberg, C. N., P. de Mulder, J. H. Schornagel, et al. 2006. "Seven year update of an EORTC phase III trial of high-dose intensity M-VAC chemotherapy and G-CSF versus classic M-VAC in advanced urothelial tract tumours." Eur J Cancer 42(1):50-54.
7
Pfister, C., G. Gravis, A. Flechon, et al. 2022. "Dose-Dense Methotrexate, Vinblastine, Doxorubicin, and Cisplatin or Gemcitabine and Cisplatin as Perioperative Chemotherapy for Patients With Nonmetastatic Muscle-Invasive Bladder Cancer: Results of the GETUG-AFU V05 VESPER Trial." J Clin Oncol 40(18):2013-2022.
8
Blick, C., P. Hall, T. Pwint, et al. 2012. "Accelerated methotrexate, vinblastine, doxorubicin, and cisplatin (AMVAC) as neoadjuvant chemotherapy for patients with muscle-invasive transitional cell carcinoma of the bladder." Cancer 118(16):3920-3927.
9
Tjokrowidjaja, A., C. Lee and M. R. Stockler. 2013. "Does chemotherapy improve survival in muscle-invasive bladder cancer (MIBC)? A systematic review and meta-analysis (MA) of randomized controlled trials (RCT)." J Clin Oncol 31 (15_Suppl): abstract 4544.
10
von der, Maase H., S. W. Hansen, J. T. Roberts, et al. 2000. "Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study." J.Clin Oncol. 18(17):3068-3077.

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Version 10

Date Summary of changes
12/03/2024

Protocol assessed by eviQ urogenital medical oncology reference committee and deemed suitable to be reviewed as required. Flag added, review date removed and version number increased to V.10 Read more about as required review protocol status in this factsheet.
03/09/2024 Treatment schedule updated, Pegfilgrastim administration changed from day 4 to day 3 as per urogenital reference committee consensus.

Version 9

Date Summary of changes
27/07/2023

Protocol updated with ADDIKD guideline recommendations. New kidney dosing recommendation table added to dose modification section.

PDF of previous protocol.

Version number changed to V.9.

Version 8

Date Summary of changes
21/10/2022 Treatment schedule cycle changed to '3 to 6 pre cystectomy'. Patient information updated to include 'You will have 3 to 6 cycles'. Evidence updated to include Pfister et al 2022. Version number changed to V.8.

Version 7

Date Summary of changes
04/09/2020 Biosimilar drug added to clinical information. Version number changed to V.7.
11/11/2021 ID 4036 Bladder/Urothelial adjuvant or neoadjuvant ciSplatin and gemcitabine added as a related page.

Version 6

Date Summary of changes
04/05/2020 Treatment schedule cycle title changed to 'cycle 1 to 3'. Patient information updated to include 'You will have 3 to 4 cycles'. Day 2 approximate treatment time changed to 4 hours. Version number changed to V.6.

Version 5

Date Summary of changes
08/10/2019 Clinical information updated with PBS expanded indications for GCSF. Drug status updated.

Version 4

Date Summary of changes
09/05/2014 New protocol taken to Medical Oncology Reference Committee meeting.
22/06/2014 Protocol approved and published on eviQ.
27/03/2015 Reviewed electronically by Medical Oncology Reference Committee. No change. Review 2 years.
15/05/2015 Skin rash (Dryness, Erythema and Pruritus) side effect removed.
19/09/2016 Updated/added volume to vinblastine (50 mL sodium chloride 0.9%) in treatment schedule.
31/03/2017 Protocol discussed and decided to have a 5 year review period. Next due for review in 2020.
31/05/2017

Transferred to new eviQ website. Version number changed to V.2.

Antiemetic change: Netupitant/palonosetron combination has replaced aprepitant and a 5HT3 receptor antagonist in combination with dexamethasone for all highly emetogenic regimens.
10/05/2018 Haematological dose modifications updated as per consensus of the expert clinician group. Version number changed to V.3. 
25/06/2019 Protocol reviewed at Medical Oncology Reference Committee meeting on 15/03/2019. Treatment schedule note added regarding alternative dosing option. Filgrastim changed to pegfilgrastim in treatment schedule and patient information. Version number changed to V.4. 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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17 Apr 2025