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Adrenocortical carcinoma metastatic EDP (etoposide DOXOrubicin ciSplatin) and mitotane

 Life threatening adrenal crisis with mitotane:

Adrenal crisis, which may be life threatening or fatal, has been reported in the setting of shock, infection or severe trauma in patients treated with mitotane.

The treatment of adrenocortical carcinoma is complex and combined modality therapy is common; the involvement of a multidisciplinary team (MDT) including endocrinologists, medical oncologists familiar with the disease and urologists in the initial development and ongoing evaluation of the treatment plan, and the management of the sequelae associated with treatment is strongly recommended. Patients with adrenocortical carcinoma should be considered for inclusion in a clinical trial. For details of current clinical trials visit the Australian Clinical Trials website.

This protocol is not exportable and does not have a calculator.

Note: Mitotane is not TGA registered in Australia. The inclusion of mitotane on eviQ for metastatic adrenocortical carcinoma is an exceptional circumstance as per criteria set out in eviQ compliance with TGA registration and PBS listing for drugs policy.  Please note the potential liability is increased when prescribing off-label and that this liability lies with the prescriber.

The anticancer drug(s) in this protocol have been updated with the ADDIKD guideline recommendations (if applicable). Recommendations may differ from other protocols which have not been updated. For further information refer to the dedicated eviQ ADDIKD guideline webpage.

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Mitotane pre-phase

Drug Dose Route Day
Mitotane 1,000 mg PO 1 to 3
Mitotane 1,500 mg PO 4 to 6
Mitotane 2,000 mg PO 7

Note: Mitotane should be started a minimum of 1 week before the initiation of EDP chemotherapy as below, with the goal of attaining a blood level of 14 to 20 mg/L.r 

Cycle 1 

Drug Dose Route Day
Mitotane 2,000 mg PO 1 and 2
DOXOrubicin 40 mg/m2 IV 1
Etoposide * 100 mg/m2 IV infusion 2 to 4
ciSplatin 40 mg/m2 IV infusion 3 and 4
Mitotane 2,500 mg PO 3 to 5
Mitotane 3,000 mg PO 6 to 8
Mitotane 3,500 mg  PO 9 to 11
Mitotane 4,000 mg  PO 12 to 14
Mitotane Dose to be adjusted based on blood concentrations and tolerability ** PO 15 to 28

Cycle 2 to 6

Drug Dose Route Day
Mitotane Dose to be adjusted based on blood concentrations and tolerability ** PO 1 to 28
DOXOrubicin 40 mg/m2 IV 1
Etoposide * 100 mg/m2 IV infusion 2 to 4
ciSplatin 40 mg/m2 IV infusion 3 and 4
Frequency:
28 days
Cycles:
up to 6

Cycle 7 and further cycles

Drug Dose Route Day
Mitotane Dose to be adjusted based on blood concentrations and tolerability ** PO 1 to 28

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

** Mitotane dose to be adjusted based on blood concentrations and tolerability with the goal of attaining a blood level of 14 to 20 mg/L.r Dosing may require rounding to nearest tablet strength to enable delivery of a measurable dose.

Frequency:
28 days
Cycles:
Continuous until disease progression or unacceptable toxicity
Drug status:

Doxorubicin, etoposide and cisplatin are on the PBS general schedule. Mitotane is neither TGA registered or PBS listed for this indication.

Mitotane is available as 500 mg tablets. 

Cost:
not available "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.

Mitotane pre-phase

Day 1 to 3
Mitotane 1,000 mg (PO) in divided doses about the same time every day with consistent timing of the doses relative to food
Hydrocortisone 50 mg (PO) in divided 20-20-10 mg doses with or after food *
Day 4 to 6
Mitotane 1,500 mg (PO) in divided doses about the same times every day with consistent timing of the doses relative to food
Hydrocortisone 50 mg (PO) in divided 20-20-10 mg doses with or after food *
Day 7
Mitotane 2,000 mg (PO) in divided doses about the same times every day with consistent timing of the doses relative to food
Hydrocortisone 50 mg (PO) in divided 20-20-10 mg doses with or after food *

Note: Mitotane should be started a minimum of 1 week before the initiation of EDP chemotherapy as below, with the goal of attaining a blood level of 14 to 20 mg/L.r Dosing may require rounding to nearest tablet strength to enable delivery of a measurable dose.

Cycle 1

Day 1
Dexamethasone 8 mg (PO) 60 minutes before chemotherapy
Palonosetron 0.25 mg (IV bolus) 30 minutes before chemotherapy
DOXOrubicin 40 mg/m2 (IV) over 5 to 15 minutes
Mitotane 2,000 mg (PO)  in divided doses about the same times every day with consistent timing of the doses relative to food
Day 2
Dexamethasone 8 mg (PO) 60 minutes before chemotherapy
Etoposide ** 100 mg/m2 (IV infusion)  in 500 mL sodium chloride 0.9% over 30 to 60 minutes (if dose > 200 mg, dilute in 1000 mL sodium chloride 0.9%) 
Mitotane 2,000 mg (PO)  in divided doses about the same times every day with consistent timing of the doses relative to food
Day 3
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
ciSplatin 40 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 60 minutes
Etoposide ** 100 mg/m2 (IV infusion)  in 500 mL sodium chloride 0.9% over 30 to 60 minutes (if dose > 200 mg, dilute in 1000 mL sodium chloride 0.9%) 
Mitotane 2,500 mg (PO)  in divided doses about the same times every day with consistent timing of the doses relative to food
Day 4
Dexamethasone 8 mg (PO) 60 minutes before chemotherapy
ciSplatin 40 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 60 minutes
Etoposide ** 100 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 30 to 60 minutes (if dose > 200 mg, dilute in 1000 mL sodium chloride 0.9%) 
Mitotane 2,500 mg (PO) in divided doses about the same times every day with consistent timing of the doses relative to food
Day 5
Dexamethasone 8 mg (PO) ONCE a day (or in divided doses) with or after food
Mitotane 2,500 mg (PO)  in divided doses about the same times every day with consistent timing of the doses relative to food
Day 6 and 7
Dexamethasone 8 mg (PO) ONCE a day (or in divided doses) with or after food
Mitotane 3,000 mg (PO)  in divided doses about the same times every day with consistent timing of the doses relative to food
Day 8
Mitotane 3,000 mg (PO)  in divided doses about the same times every day with consistent timing of the doses relative to food
Hydrocortisone 50 mg (PO)  in divided 20-20-10 mg doses with or after food *
Day 9 to 11
Mitotane 3,500 mg (PO)  in divided doses about the same times every day with consistent timing of the doses relative to food
Hydrocortisone 50 mg (PO)  in divided 20-20-10 mg doses with or after food *
Day 12 to 14
Mitotane 4,000 mg (PO)  in divided doses about the same times every day with consistent timing of the doses relative to food
Hydrocortisone 50 mg (PO)  in divided 20-20-10 mg doses with or after food *
Day 15 to 28
Mitotane Dose to be adjusted based on blood concentrations and tolerability **** in divided doses about the same times every day with consistent timing of the doses relative to food
Hydrocortisone 50 mg (PO)  in divided 20-20-10 mg doses with or after food *

Cycle 2 to 6

Day 1
Dexamethasone 8 mg (PO) 60 minutes before chemotherapy
Palonosetron 0.25 mg (IV bolus) 30 minutes before chemotherapy
DOXOrubicin 40 mg/m2 (IV) over 5 to 15 minutes
Mitotane Dose to be adjusted based on blood concentrations and tolerability **** in divided doses about the same times every day with consistent timing of the doses relative to food
Day 2
Dexamethasone 8 mg (PO) 60 minutes before chemotherapy
Etoposide ** 100 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 30 to 60 minutes (if dose > 200 mg, dilute in 1000 mL sodium chloride 0.9%)
Mitotane Dose to be adjusted based on blood concentrations and tolerability **** in divided doses about the same times every day with consistent timing of the doses relative to food
Day 3
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
ciSplatin 40 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 60 minutes
Etoposide ** 100 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 30 to 60 minutes (if dose > 200 mg, dilute in 1000 mL sodium chloride 0.9%) 
Mitotane Dose to be adjusted based on blood concentrations and tolerability) **** in divided doses about the same times every day with consistent timing of the doses relative to food
Day 4
Dexamethasone 8 mg (PO) 60 minutes before chemotherapy
ciSplatin 40 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 60 minutes
Etoposide ** 100 mg/m2 (IV infusion)  in 500 mL sodium chloride 0.9% over 30 to 60 minutes (if dose > 200 mg, dilute in 1000 mL sodium chloride 0.9%) 
Mitotane Dose to be adjusted based on blood concentrations and tolerability **** in divided doses about the same times every day with consistent timing of the doses relative to food
Day 5 to 7
Dexamethasone 8 mg (PO) ONCE a day (or in divided doses) with or after food
Mitotane Dose to be adjusted based on blood concentrations and tolerability **** in divided doses about the same times every day with consistent timing of the doses relative to food
Day 8 to 28
Mitotane Dose to be adjusted based on blood concentrations and tolerability **** in divided doses about the same times every day with consistent timing of the doses relative to food
Hydrocortisone 50 mg (PO)  in divided 20-20-10 mg doses with or after food *
Frequency:
28 days
Cycles:
up to 6

Cycle 7 and further cycles 

Day 1 to 28
Mitotane Dose to be adjusted based on blood concentrations and tolerability **** in divided doses about the same times every day with consistent timing of the doses relative to food
Hydrocortisone 50 mg (PO)  in divided 20-20-10 mg doses with or after food *

* Hydrocortisone doses to be confirmed upon evaluation of adrenal function and in consultation with an endocrinologist. Hydrocortisone to be omitted in patient with confirmed Cushing's syndrome.

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

*** The full dose of dexamethasone on day 3 may not be required and may be reduced to 8 mg at the clinician’s discretion as per eviQ RC consensus. Link to ID 7 Prevention of chemotherapy induced nausea and vomiting.

**** Mitotane dose to be adjusted based on blood concentrations and tolerability with the goal of attaining a blood level of 14 to 20 mg/L.r Dosing may require rounding to nearest tablet strength to enable delivery of a measurable dose.

Frequency:
28 days
Cycles:
Continuous until disease progression or unacceptable toxicity

Mitotane pre-phase

Drug Dose Route Day
Mitotane 1,000 mg PO 1 to 3
Mitotane 1,500 mg PO 4 to 6
Mitotane 2,000 mg PO 7

Note: Mitotane should be started a minimum of 1 week before the initiation of EDP chemotherapy as below, with the goal of attaining a blood level of 14 to 20 mg/L.r 

Cycle 1 

Drug Dose Route Day
Mitotane 2,000 mg PO 1 and 2
DOXOrubicin 40 mg/m2 IV 1
Etoposide * 100 mg/m2 IV infusion 2 to 4
ciSplatin 40 mg/m2 IV infusion 3 and 4
Mitotane 2,500 mg PO 3 to 5
Mitotane 3,000 mg PO 6 to 8
Mitotane 3,500 mg  PO 9 to 11
Mitotane 4,000 mg  PO 12 to 14
Mitotane Dose to be adjusted based on blood concentrations and tolerability ** PO 15 to 28

Cycle 2 to 6

Drug Dose Route Day
Mitotane Dose to be adjusted based on blood concentrations and tolerability ** PO 1 to 28
DOXOrubicin 40 mg/m2 IV 1
Etoposide * 100 mg/m2 IV infusion 2 to 4
ciSplatin 40 mg/m2 IV infusion 3 and 4
Frequency:
28 days
Cycles:
up to 6

Cycle 7 and further cycles

Drug Dose Route Day
Mitotane Dose to be adjusted based on blood concentrations and tolerability ** PO 1 to 28

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

** Mitotane dose to be adjusted based on blood concentrations and tolerability with the goal of attaining a blood level of 14 to 20 mg/L.r Dosing may require rounding to nearest tablet strength to enable delivery of a measurable dose.

Frequency:
28 days
Cycles:
Continuous until disease progression or unacceptable toxicity
Drug status:

Doxorubicin, etoposide and cisplatin are on the PBS general schedule. Mitotane is neither TGA registered or PBS listed for this indication.

Mitotane is available as 500 mg tablets. 

Cost:
not available "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.

Mitotane pre-phase

Day 1 to 3
Mitotane 1,000 mg (PO) in divided doses about the same time every day with consistent timing of the doses relative to food
Hydrocortisone 50 mg (PO) in divided 20-20-10 mg doses with or after food *
Day 4 to 6
Mitotane 1,500 mg (PO) in divided doses about the same times every day with consistent timing of the doses relative to food
Hydrocortisone 50 mg (PO) in divided 20-20-10 mg doses with or after food *
Day 7
Mitotane 2,000 mg (PO) in divided doses about the same times every day with consistent timing of the doses relative to food
Hydrocortisone 50 mg (PO) in divided 20-20-10 mg doses with or after food *

Note: Mitotane should be started a minimum of 1 week before the initiation of EDP chemotherapy as below, with the goal of attaining a blood level of 14 to 20 mg/L.r Dosing may require rounding to nearest tablet strength to enable delivery of a measurable dose.

Cycle 1

Day 1
Dexamethasone 8 mg (PO) 60 minutes before chemotherapy
Palonosetron 0.25 mg (IV bolus) 30 minutes before chemotherapy
DOXOrubicin 40 mg/m2 (IV) over 5 to 15 minutes
Mitotane 2,000 mg (PO)  in divided doses about the same times every day with consistent timing of the doses relative to food
Day 2
Dexamethasone 8 mg (PO) 60 minutes before chemotherapy
Etoposide ** 100 mg/m2 (IV infusion)  in 500 mL sodium chloride 0.9% over 30 to 60 minutes (if dose > 200 mg, dilute in 1000 mL sodium chloride 0.9%) 
Mitotane 2,000 mg (PO)  in divided doses about the same times every day with consistent timing of the doses relative to food
Day 3
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
ciSplatin 40 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 60 minutes
Etoposide ** 100 mg/m2 (IV infusion)  in 500 mL sodium chloride 0.9% over 30 to 60 minutes (if dose > 200 mg, dilute in 1000 mL sodium chloride 0.9%) 
Mitotane 2,500 mg (PO)  in divided doses about the same times every day with consistent timing of the doses relative to food
Day 4
Dexamethasone 8 mg (PO) 60 minutes before chemotherapy
ciSplatin 40 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 60 minutes
Etoposide ** 100 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 30 to 60 minutes (if dose > 200 mg, dilute in 1000 mL sodium chloride 0.9%) 
Mitotane 2,500 mg (PO) in divided doses about the same times every day with consistent timing of the doses relative to food
Day 5
Dexamethasone 8 mg (PO) ONCE a day (or in divided doses) with or after food
Mitotane 2,500 mg (PO)  in divided doses about the same times every day with consistent timing of the doses relative to food
Day 6 and 7
Dexamethasone 8 mg (PO) ONCE a day (or in divided doses) with or after food
Mitotane 3,000 mg (PO)  in divided doses about the same times every day with consistent timing of the doses relative to food
Day 8
Mitotane 3,000 mg (PO)  in divided doses about the same times every day with consistent timing of the doses relative to food
Hydrocortisone 50 mg (PO)  in divided 20-20-10 mg doses with or after food *
Day 9 to 11
Mitotane 3,500 mg (PO)  in divided doses about the same times every day with consistent timing of the doses relative to food
Hydrocortisone 50 mg (PO)  in divided 20-20-10 mg doses with or after food *
Day 12 to 14
Mitotane 4,000 mg (PO)  in divided doses about the same times every day with consistent timing of the doses relative to food
Hydrocortisone 50 mg (PO)  in divided 20-20-10 mg doses with or after food *
Day 15 to 28
Mitotane Dose to be adjusted based on blood concentrations and tolerability **** in divided doses about the same times every day with consistent timing of the doses relative to food
Hydrocortisone 50 mg (PO)  in divided 20-20-10 mg doses with or after food *

Cycle 2 to 6

Day 1
Dexamethasone 8 mg (PO) 60 minutes before chemotherapy
Palonosetron 0.25 mg (IV bolus) 30 minutes before chemotherapy
DOXOrubicin 40 mg/m2 (IV) over 5 to 15 minutes
Mitotane Dose to be adjusted based on blood concentrations and tolerability **** in divided doses about the same times every day with consistent timing of the doses relative to food
Day 2
Dexamethasone 8 mg (PO) 60 minutes before chemotherapy
Etoposide ** 100 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 30 to 60 minutes (if dose > 200 mg, dilute in 1000 mL sodium chloride 0.9%)
Mitotane Dose to be adjusted based on blood concentrations and tolerability **** in divided doses about the same times every day with consistent timing of the doses relative to food
Day 3
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
ciSplatin 40 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 60 minutes
Etoposide ** 100 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 30 to 60 minutes (if dose > 200 mg, dilute in 1000 mL sodium chloride 0.9%) 
Mitotane Dose to be adjusted based on blood concentrations and tolerability) **** in divided doses about the same times every day with consistent timing of the doses relative to food
Day 4
Dexamethasone 8 mg (PO) 60 minutes before chemotherapy
ciSplatin 40 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 60 minutes
Etoposide ** 100 mg/m2 (IV infusion)  in 500 mL sodium chloride 0.9% over 30 to 60 minutes (if dose > 200 mg, dilute in 1000 mL sodium chloride 0.9%) 
Mitotane Dose to be adjusted based on blood concentrations and tolerability **** in divided doses about the same times every day with consistent timing of the doses relative to food
Day 5 to 7
Dexamethasone 8 mg (PO) ONCE a day (or in divided doses) with or after food
Mitotane Dose to be adjusted based on blood concentrations and tolerability **** in divided doses about the same times every day with consistent timing of the doses relative to food
Day 8 to 28
Mitotane Dose to be adjusted based on blood concentrations and tolerability **** in divided doses about the same times every day with consistent timing of the doses relative to food
Hydrocortisone 50 mg (PO)  in divided 20-20-10 mg doses with or after food *
Frequency:
28 days
Cycles:
up to 6

Cycle 7 and further cycles 

Day 1 to 28
Mitotane Dose to be adjusted based on blood concentrations and tolerability **** in divided doses about the same times every day with consistent timing of the doses relative to food
Hydrocortisone 50 mg (PO)  in divided 20-20-10 mg doses with or after food *

* Hydrocortisone doses to be confirmed upon evaluation of adrenal function and in consultation with an endocrinologist. Hydrocortisone to be omitted in patient with confirmed Cushing's syndrome.

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

*** The full dose of dexamethasone on day 3 may not be required and may be reduced to 8 mg at the clinician’s discretion as per eviQ RC consensus. Link to ID 7 Prevention of chemotherapy induced nausea and vomiting.

**** Mitotane dose to be adjusted based on blood concentrations and tolerability with the goal of attaining a blood level of 14 to 20 mg/L.r Dosing may require rounding to nearest tablet strength to enable delivery of a measurable dose.

Frequency:
28 days
Cycles:
Continuous until disease progression or unacceptable toxicity

Indications:

  • Unresectable locally advanced or metastatic adrenocortical carcinoma
    • ECOG performance status 0 to 2.

Cautions/Exclusions:

  • pre-existing neuropathies Grade 2 or greater
  • moderate/severe hepatic impairment (serum bilirubin ≥ 2 x ULN and/or serum transaminases ≥ 3 x ULN. For mitotane monotherapy transaminase ≤ 5 x ULN are acceptable)
  • significant hearing impairment/tinnitus
  • left ventricular ejection fraction less than 50%.
Caution with oral anti-cancer drugs

Select links for information on the safe prescribing, dispensing and administration of orally administered anti-cancer drugs. 

Read more about the Cancer Council Australia guidelines and oral anti-cancer therapy
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
Antiemetics for multi-day protocols

Patients being treated with multi-day anticancer protocols should receive antiemetics tailored to the emetogenic risk of the drugs administered each day during treatment and for two days after completion of the anticancer protocol.

No standard antiemetic regimen exists for multi-day anticancer protocols, however suggested default antiemetics have been added to the treatment schedule, and may be substituted to reflect institutional policy.

A combination of an NK1 receptor antagonist, 5HT3, and a steroid is accessible on the PBS for the prevention of nausea and vomiting associated with all moderate to highly emetogenic anti-cancer therapies.

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
Central nervous system (CNS) effects

A broad spectrum of CNS effects can occur in patients receiving this treatment. These reactions may or may not be reversible after treatment discontinuation.

Mood effects primarily included depression as manifested by lethargy, somnolence, sedation, dizziness or vertigo. Cognitive effects included mental impairment, confusion and ataxia. Speech effects included dysarthria.

Behavioural and neurological assessments should be made at regular intervals, especially when mitotane plasma levels exceed 20 mg/L.
Mitotane monitoring

Therapeutic drug monitoring recommended. Dose escalation following the protocol may lead to gastrointestinal and neurological toxicity.

Mitotane plasma levels should be monitored at frequent intervals (every 3-4 weeks) until the therapeutic window (a blood level of 14 to 20 mg/L) has been reached. Once the maintenance dose has been reached, the intervals can be extended. The first 6 months after beginning mitotane therapy mitotane plasma levels should be assessed at least once every four weeks and after 6 months analysis should be done at least every 8 weeks.
Hypoadrenalism

Mitotane may cause potentially permanent hypoadrenalism.

Patients should take gluco- and possibly mineralocorticoid (depending on blood pressure, serum potassium levels and plasma renin activity) replacement. Patients are likely to require steroid  replacement even after mitotane is discontinued. Steroid replacement should not be discontinued without evaluation for adequate adrenal function.

Additional steroids may be required in physiologic stress circumstances.

In patients with functioning tumours, adrenal steroid replacement should not be started until cortisol levels are less than or equal to normal.
Adrenal crisis

Mitotane, as an adrenolytic agent, may contribute to potentially life-threatening adrenal crisis in the setting of shock, severe trauma or infection and response to shock is impaired.

If shock, severe trauma or infection occurs, mitotane should be temporarily discontinued and steroids immediately given. Monitoring for escalating signs of shock is recommended.
Hypothyroidism

Thyroid dysfunction, in particular central hypothyroidism (low free T4 with low or normal TSH), may occur with this treatment. Monitor for signs and symptoms of thyroid dysfunction and manage as clinically appropriate.
Caution with higher body weight/recent weight loss

Fat tissue can act as a reservoir for mitotane. This could result in prolonged half-life and potential accumulation of mitotane in overweight or even normal weight patients. Closer monitoring in obese patients or patients with recent weight loss is recommended.
Ovarian macrocysts

Mitotane has been associated with development of ovarian macrocysts in premenopausal patients. Improvement after mitotane discontinuation has been reported in some cases.

Advise patients to report any abnormal vaginal bleeding, vaginal discharge or pain or pressure in the pelvic region.
Sex hormone disturbances

Mitotane has been associated with sex hormone disturbances including decreased blood androstenedione and decreased blood testosterone in females, increased sex hormone binding globulin in females and males, decreased blood free testosterone in males.

Routine monitoring of testosterone/oestrodial levels is recommended.
Etoposide conversion factor

Note: Etopophos (etoposide phosphate) 113.6 mg is equivalent to etoposide 100 mg.
Doses in this protocol are expressed as etoposide.
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.
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 chemotherapy-induced peripheral neuropathy screening tool
Corticosteroids

Diabetic patients should monitor their blood glucose levels closely. To minimise gastric irritation, advise patient to take immediately after food. Consider the use of a H2 antagonist or proton pump inhibitor if appropriate.

Read more about acute short term effects from corticosteroids
Blood tests

FBC, EUC, eGFR, LFTs, TFTs, calcium, magnesium and phosphate at baseline and prior to each cycle. DHEAS, ACTH and 24 hour urinary cortisol or serum cortisol at baseline, 4 weeks after being on stable dose, then every 3 to 4 months. Nadir FBC for every EDP cycle.
Hepatitis B screening and prophylaxis

Routine screening for HBsAg and anti-HBc is NOT usually recommended for patients receiving this treatment.

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

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

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

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

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

Read more about the 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:

  • The dose modifications below are based on a combination of the clinical trial,r product information and reference committee consensus.
  • All dose reductions are calculated as a percentage of the starting dose.
Haematological toxicity
ANC x 109/L (pre-treatment blood test)
1.0 to less than 1.5 Refer to local institutional guidelines; it is the view of the expert clinicians that treatment should continue if patient is clinically well
0.5 to less than 1.0 Delay treatment until recovery
less than 0.5 Delay treatment until recovery and consider reducing doxorubicin, cisplatin, etoposide and mitotane by 25% for subsequent cycles
Febrile neutropenia Delay treatment until recovery and consider reducing doxorubicin, cisplatin, etoposide and mitotane by 25% for subsequent cycles
Platelets x 109/L (pre-treatment blood test)
75 to less than 100 The general recommendation is to delay, however if the patient is clinically well it may be appropriate to continue treatment; refer to treating team and/or local institutional guidelines
50 to less than 75 Delay treatment until recovery
less than 50 Delay treatment until recovery and consider reducing doxorubicin, cisplatin, etoposide and mitotane 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 Etoposide Mitotane*
≥ 60

Full dose

Full dose

Full dose

No dose reduction required in kidney dysfunction.

 

 

 

 

 

 

 

 

 

 
45 - 59

Consider a 25 - 50% reduction^

Potential for increased risk of adverse events

Full dose 

Full dose

Increased risk of haematological adverse events
30 - 44

Avoid

Not recommended

Full dose 

Reduce by 25%

Increased risk of haematological adverse events
15 - 29

Avoid

Not recommended

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
(without kidney replacement therapy)

Avoid

Not recommended

Alternative protocol

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

Avoid

Not recommended

* This drug was not included in the ADDIKD guideline.

^ Extent of dose reduction should take into account: intent of treatment, performance status, potential total cumulative cisplatin exposure.
Hepatic impairment
Hepatic dysfunction
Mild Reduce doxorubicin and etoposide by 25%. Use mitotane with caution
Moderate Reduce doxorubicin and etoposide by 50%. Use mitotane with caution
Severe Omit doxorubicin, mitotane and etoposide
Peripheral neuropathy
Grade 2 which is present at the start of the next cycle Reduce cisplatin by 25%; if persistent, reduce cisplatin by 50%
Grade 3 or Grade 4 Omit cisplatin
Central nervous system toxicity
Grade 2, Grade 3 or Grade 4 Check Mitotane plasma level. Withhold mitotane until symptoms have resolved and restart 7-10 days after symptoms resolve with a lower dose (decrease by 500-1000 mg)
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 doxorubicin, cisplatin and etoposide by 25%
3rd occurrence: Reduce doxorubicin, cisplatin and etoposide by 50%
4th occurrence: Omit doxorubicin, cisplatin and etoposide
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 doxorubicin, cisplatin and etoposide by 50%
2nd occurrence: Omit doxorubicin, cisplatin and etoposide

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
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
Mitotane
  Interaction Clinical management
CYP3A4 substrates (e.g. atorvastatin, benzodiazepines, calcineurin inhibitors, clarithromycin, dihydroergotamine, simvastatin, rivaroxaban, apixaban, etc.) Reduced efficacy of these drugs possible due to induction of CYP3A4 by mitotane resulting in increased clearance Avoid combination or monitor for reduced efficacy of the interacting drugs
Warfarin Reduced anticoagulant efficacy of warfarin due enhancement of its metabolism by mitotane Monitor INR regularly and adjust warfarin dosage as appropriate; consider alternative anticoagulant (e.g. LMWH, unfractionated heparin)
Spironolactone Reduced efficacy of mitotane due to unknown mechanism Avoid combination
Central nervous system (CNS) depressants Enhanced CNS depression due to additive effect Use combination with caution
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 website for further information.

Day 1 to 7

This is a continuous oral treatment

General patient assessment prior to each treatment.

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

Pre treatment medication

Verify premedication taken or administer as prescribed.

Mitotane

  • administer orally in divided doses as prescribed on days 1 to 7
  • to be swallowed whole with a glass of water; do not break, crush or chew
  • may be taken with or without food; consistent association with food is necessary
  • to be taken about the same time each day

Note: missed doses should not be replaced; if a dose is forgotten or vomited, normal dosing should be resumed at the next scheduled dose.

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

Discharge information

Mitotane tablets 
  •  Mitotane tablets with written instructions on how to take them.
Steroid tablets 
  •  Steroid tables if prescribed with written instructions on how to take them.
Patient information
  • Ensure patient receives patient information sheet.

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

Day 1

Approximate treatment time: 30 to 60 minutes.

General patient assessment prior to each day of treatment.

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

Prime IV line(s).

Insert IV cannula or access TIVAD or CVAD.

Pre treatment medication

Verify dexamethasone taken or administer as prescribed.

Verify antiemetics taken or administer as prescribed.

Doxorubicin

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
  • ensure vein is patent and monitor for signs of extravasation throughout administration
  • flush with ~150 mL of sodium chloride 0.9%
  • 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 immediately and obtain urgent medical officer review.

Mitotane

This is a continuous oral treatment

  • administer orally in divided doses as prescribed on days 1 to 28
  • to be swallowed whole with a glass of water; do not break, crush or chew
  • may be taken with or without food; consistent association with food is necessary
  • to be taken about the same time each day
  • dose to be adjusted based on blood concentrations and tolerability (see treatment schedule and clinical information)

Note: missed doses should not be replaced; if a dose is forgotten or vomited, normal dosing should be resumed at the next scheduled dose.

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: 90 minutes

General patient assessment prior to each day of treatment.

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

Prime IV line(s).

Insert IV cannula or access TIVAD or CVAD.

Pre treatment medication

Verify dexamethasone taken or administer as prescribed.

Etoposide

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

Mitotane

This is a continuous oral treatment

  • administer orally in divided doses as prescribed on days 1 to 28
  • to be swallowed whole with a glass of water; do not break, crush or chew
  • may be taken with or without food; consistent association with food is necessary
  • to be taken about the same time each day
  • dose to be adjusted based on blood concentrations and tolerability (see treatment schedule and clinical information)

Note: missed doses should not be replaced; if a dose is forgotten or vomited, normal dosing should be resumed at the next scheduled dose.

Remove IV cannula and/or deaccess TIVAD or CVAD. 

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

Day 3

Approximate treatment time: 5 hours

General patient assessment prior to each day of treatment.

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

Cisplatin

Commence prehydration for cisplatin:
  • administer 10 mmol magnesium sulphate (MgSO4) in 500 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%.
Post hydration:
  • 500 mL sodium chloride 0.9% over 60 minutes.

20/11/23 ​Mannitol information removed to align with updated ID 184  Prevention and management of cisplatin induced nephrotoxicity.

Etoposide

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

Mitotane

This is a continuous oral treatment

  • administer orally in divided doses as prescribed on days 1 to 28
  • to be swallowed whole with a glass of water; do not break, crush or chew
  • may be taken with or without food; consistent association with food is necessary
  • to be taken about the same time each day
  • dose to be adjusted based on blood concentrations and tolerability (see treatment schedule and clinical information)

Note: missed doses should not be replaced; if a dose is forgotten or vomited, normal dosing should be resumed at the next scheduled dose.

Remove IV cannula and/or deaccess TIVAD or CVAD. 

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

Day 4

Approximate treatment time: 5 hours

General patient assessment prior to each day of treatment.

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

Prime IV line(s).

Insert IV cannula or access TIVAD or CVAD.

Pre treatment medication

Verify dexamethasone taken or administer as prescribed.

Cisplatin

Commence prehydration for cisplatin:
  • administer 10 mmol magnesium sulphate (MgSO4) in 500 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%.
Post hydration:
  • 500 mL sodium chloride 0.9% over 60 minutes.

20/11/23 ​Mannitol information removed to align with updated ID 184  Prevention and management of cisplatin induced nephrotoxicity.

Etoposide

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

Mitotane

This is a continuous oral treatment

  • administer orally in divided doses as prescribed on days 1 to 28
  • to be swallowed whole with a glass of water; do not break, crush or chew
  • may be taken with or without food; consistent association with food is necessary
  • to be taken about the same time each day
  • dose to be adjusted based on blood concentrations and tolerability (see treatment schedule and clinical information)

Note: missed doses should not be replaced; if a dose is forgotten or vomited, normal dosing should be resumed at the next scheduled dose.

Remove IV cannula and/or deaccess TIVAD or CVAD. 

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

Days 5 to 28

This is a continuous oral treatment

General patient assessment prior to each treatment.

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

Mitotane

  • administer orally in divided doses as prescribed on days 1 to 28
  • to be swallowed whole with a glass of water; do not break, crush or chew
  • may be taken with or without food; consistent association with food is necessary
  • to be taken about the same time each day
  • dose to be adjusted based on blood concentrations and tolerability (see treatment schedule and clinical information)

Note: missed doses should not be replaced; if a dose is forgotten or vomited, normal dosing should be resumed at the next scheduled dose.

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

Discharge information

Mitotane tablets 
  •  Mitotane tablets with written instructions on how to take them.
Steroid tablets 
  •  Steroid tables if prescribed with written instructions on how to take them.
Antiemetics
  • Antiemetics as prescribed.
Patient information
  • Ensure patient receives patient information sheet.

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

Day 1 to 28

This is a continuous oral treatment

General patient assessment prior to each treatment.

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

Pre treatment medication

Mitotane

  • administer orally in divided doses as prescribed on days 1 to 28
  • to be swallowed whole with a glass of water; do not break, crush or chew
  • may be taken with or without food; consistent association with food is necessary
  • to be taken about the same time each day
  • dose to be adjusted based on blood concentrations and tolerability (see treatment schedule and clinical information)

Note: missed doses should not be replaced; if a dose is forgotten or vomited, normal dosing should be resumed at the next scheduled dose.

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

Discharge information

Mitotane tablets 
  •  Mitotane tablets with written instructions on how to take them.
Steroid tablets 
  •  Steroid tables if prescribed with written instructions on how to take them.
Patient information
  • Ensure patient receives patient information sheet.

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

Immediate (onset hours to days)
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
Hypersensitivity reaction

Anaphylaxis and infusion related reactions can occur with this treatment.

Read more about hypersensitivity reaction 
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.
Nausea and vomiting

Read more about prevention of treatment induced nausea and vomiting
Red-orange discolouration of urine

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

Read more about taste and smell changes

Early (onset days to weeks)
Neutropenia

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

Read more about immediate management of neutropenic fever
Thrombocytopenia

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

Read more about thrombocytopenia
Adrenal insufficiency

Adrenal insufficiency is a common side effect with mitotane. Gluco- and sometimes mineralocorticoid replacement is required. Optimal dose of steroid replacement should be determined by monitoring free cortisol and corticotropin levels. 
Hypothyroidism
Side effects of corticosteroids

Insomnia, oedema, increased risk of infection e.g. oral thrush, gastric irritation, worsening of peptic ulcer disease, increased blood sugar levels, loss of diabetic control, mood and behavioural changes - including anxiety, euphoria, depression, mood swings, increased appetite and weight gain, osteoporosis and fractures (long term use), bruising and skin fragility are associated with corticosteroid use.
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
Oral mucositis

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

Read more about oral mucositis
Fatigue

Read more about fatigue
Neurological toxicities

Neurological events are a common side effect of mitotane especially when mitotane plasma levels are greater than 20 mg/L. Symptoms may include sedation, lethargy, somnolence, vertigo, depression, irritability, confusion and tremors. Close monitoring is recommended.
Diarrhoea

Read more about treatment induced diarrhoea
Anorexia

Loss of appetite accompanied by decreased food intake.

Read more about anorexia
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.
Nephrotoxicity

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

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

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

Read more about skin rash
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

Late (onset weeks to months)
Anaemia

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

Read more about anaemia
Aldosterone deficiency

A reduction in aldosterone biosynthesis resulting in various clinical and laboratory test manifestations, such as hypotension, hyponatremia, hyperkalemia, and acidosis.
Ovarian macrocysts

Mitotane may cause ovarian macrocysts in premenopausal patients. Complications include adnexal torsion and hemorrhagic cyst rupture.
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
Hyperpigmentation

Darkening of an area of skin caused by the overproduction of melanin.
Nail changes

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

Read more about nail toxicities

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 evidence supporting this protocol is provided by a phase 3 multicentre international randomised trial (FIRM-ACT) involving 304 patients comparing etoposide-doxorubicin-cisplatin (EDP) plus mitotane with streptozocin plus mitotane in patients with unresectable locally advanced/metastatic adrenocortical carcinoma.r

Between June 2004 and October 2009, 304 patients were randomised in a 1:1 ratio. 151 patients were randomised to EDP (etoposide 100 mg/m2 on days 2-4; doxorubicin 40 mg/m2 on day 1 and cisplatin 40 mg/m2  on days 3-4) every 4 weeks for 6 cycles. 153 patients were randomised to streptozotocin (1 g on days 1-5 in the first cycle and 2 g on day 1 in subsequent cycles) every 3 weeks for 6 cycles. All patients received mitotane continuously starting one week before initiation of chemotherapy with the goal of attaining a blood level of 14 to 20 mg/L. Crossover to alternative regimen was allowed after disease progression.r

The primary end point was overall survival (OS) and secondary end points were progression-free survival (PFS), tumour response and quality of life.r

Efficacy

At 6.5 years from study initiation, no significant difference in OS was demonstrated between EDP-mitotane (14.8 months, 95% CI 11.3-17.1) and streptozotocin-mitotane arms (12.0 months, 95% CI 10.3-13.6); HR = 0.79, 95% CI 0.61-1.02, p=0.07. Median PFS was 5.0 months (95% CI 3.5-6.9) in the EDP-mitotane group vs. 2.1 months (95% CI 2.04-2.33) in the streptozotocin-mitotane group (HR = 0.55, 95% CI 0.43-0.69, p<0.001). r

There was no significant difference in quality-of-life score change from baseline to evaluation according to EORTC QLQ-C30 questionnaire for both groups (-4.2 vs. 0, 95% CI -8.3–8.3, p=0.996).

Overall responser

© N Eng J Med 2012

Kaplan-Meier curves of progression-free (A) and overall (B) survivalr

© N Eng J Med 2012

Toxicity

Rates of serious (0.092 vs. 0.099, p=0.64) and non-serious (0.54 vs. 0.49, p=0.17) adverse events per month did not differ significantly between EDP-mitotane and streptozotocin-mitotane treatment groups.r

Treatment-related adverse eventsr

© N Eng J Med 2012

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Version 2

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.2.
19/01/2024

Other information about your treatment section in patient information updated to include short-term effects of steroids.
08/03/2024 Protocol reviewed electronically by urogenital reference committee, no updates required. Next review in 4 years.

Version 1

Date Summary of changes
15/09/2021 Protocol approved electronically by Medical Oncology Reference Committee and published on eviQ. Review in 1 year.
30/09/2022 Protocol reviewed electronically by Medical Oncology Reference Committee. no changes. Next review in 2 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/3937

19 Apr 2024