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Osteosarcoma MAP (methotrexate, DOXOrubicin, cISplatin)

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

The treatment of sarcoma is complex and combined modality therapy is common; the involvement of a multidisciplinary team (MDT) 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 sarcoma should be considered for inclusion in a clinical trial. For details of centres that specialise in sarcoma care and current clinical trials visit the Australasian Sarcoma Study Group (ASSG) website.

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Cycle 1 to 4

Drug Dose Route Day
DOXOrubicin 37.5 mg/m2 IV * 1 and 2
ciSplatin 60 mg/m2 IV infusion ** 1 and 2
Pegfilgrastim 6 mg Subcut 3
Methotrexate 12,000 mg/m2 (maximum 20,000 mg) IV infusion 22 and 29
Calcium folinate (Leucovorin) 15 mg/m2 every 6 hours (for 4 doses) *** IV bolus 23 and 30
Frequency:
35 days
Cycles:
4

Cycle 5 and 6

Drug Dose Route Day
DOXOrubicin 37.5 mg/m2 IV * 1 and 2
Pegfilgrastim 6 mg S/C 3
Methotrexate 12,000 mg/m2 (maximum 20,000 mg) IV infusion 15 and 22
Calcium folinate (leucovorin) 15 mg/m2 every 6 hours (for 4 doses) *** IV bolus 16 and 23

* Various doses and schedules have been used in clinical trials. Alternate regimens administered doxorubicin as a single dose on D1. Doxorubicin has also been administered as a bolus, a 4 hour infusion and as a continuous infusion over 48 hours

** Cisplatin is only administered for cycles 1 to 4 and has been administered over 2 or 4 hours on day 1 and day 2 or as a continuous 72 hour infusion (120 mg/m2) on day 1

*** Commence 24 hours after the start of methotrexate infusion. Calcium folinate 15 mg/m2 is given IV for the first 4 doses, then IV/PO given every 6 hours until methotrexate level is less than 0.1 micromol/L. Calcium folinate rescue doses should be titrated to methotrexate level and any associated toxicity, see methotrexate toxicity

Frequency:
28 days 
Cycles:
2 
Notes:

In patients older than 40 years of age, consider using cisplatin and doxorubicin without high dose methotrexate.

Drug status:

All drugs in this protocol are on the PBS general schedule

Cost:
~ $1,990 "How this cost is calculated"

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

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

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

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

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

One off loading doses 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 antineoplastic drugs are reimbursed on the PBS.

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

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

Cycle 1 to 4

Day 1
Netupitant 300 mg (PO)

60 minutes before chemotherapy (fixed dose preparation with palonosetron) 
Palonosetron 0.5 mg (PO)

60 minutes before chemotherapy (fixed dose preparation with netupitant)
Dexamethasone 12 mg (PO) 60 minutes before chemotherapy
DOXOrubicin 37.5 mg/m2 (IV) over 5 to 15 minutes *
ciSplatin 60 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 2 hours **
Day 2
Dexamethasone 8 mg (PO) 60 minutes before chemotherapy
DOXOrubicin 37.5 mg/m2 (IV) over 5 to 15 minutes *
ciSplatin 60 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 2 hours **
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 at least 24 hours after chemotherapy
Day 4
Dexamethasone 8 mg (PO) ONCE a day (or in divided doses) with or after food.
Day 22
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
Methotrexate 12,000 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 4 hours. (Maximum 20,000 mg)
Day 23
Dexamethasone 8 mg (PO) ONCE a day (or in divided doses) with or after food.
Calcium folinate (Leucovorin) 15 mg/m2 (IV bolus) Commence 24 hours after the start of the methotrexate infusion. Calcium folinate 15 mg/m2 IV is given every 6 hours for the first 4 doses, then 15 mg/m2 IV/PO every 6 hours until methotrexate level is less than 0.1 micromol/L. ***
Day 24 and 25
Dexamethasone 8 mg (PO) ONCE a day (or in divided doses) with or after food.
Day 29
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
Methotrexate 12,000 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 4 hours. (Maximum 20,000 mg)
Day 30
Dexamethasone 8 mg (PO) ONCE a day (or in divided doses) with or after food.
Calcium folinate (Leucovorin) 15 mg/m2 (IV bolus) Commence 24 hours after the start of the methotrexate infusion. Calcium folinate 15 mg/m2 IV is given every 6 hours for the first 4 doses, then 15 mg/m2 IV/PO every 6 hours until methotrexate level is less than 0.1 micromol/L. ***
Day 31 and 32
Dexamethasone 8 mg (PO) ONCE a day (or in divided doses) with or after food.

Frequency:
35 days
Cycles:
4

Cycle 5 and 6

Day 1
Netupitant 300 mg (PO) 60 minutes before chemotherapy (fixed dose preparation with palonosetron)
Palonosetron 0.5 mg (PO) 60 minutes before chemotherapy (fixed dose preparation with netupitant)
Dexamethasone 12 mg (PO) 60 minutes before chemotherapy
DOXOrubicin 37.5 mg/m2 (IV)         over 5 to 15 minutes *
Day 2
Dexamethasone 8 mg (PO) 60 minutes before chemotherapy
DOXOrubicin 37.5 mg/m2 (IV) over 5 to 15 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 at least 24 hours after chemotherapy
Day 4
Dexamethasone 8 mg (PO) ONCE a day (or in divided doses) with or after food.
Day 15
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
Methotrexate 12,000 mg/m2 (IV infusion)         in 1000 mL sodium chloride 0.9% over 4 hours. (Maximum 20,000 mg)
Day 16
Dexamethasone 8 mg (PO) ONCE a day (or in divided doses) with or after food.
Calcium folinate (leucovorin) 15 mg/m2 (IV bolus)         Commence 24 hours after the start of the methotrexate infusion. Calcium folinate 15 mg/m2 IV is given every 6 hours for the first 4 doses, then 15 mg/m2 IV/PO every 6 hours until methotrexate level is less than 0.1 micromol/L. ***
Day 17 and 18
Dexamethasone 8 mg (PO) ONCE a day (or in divided doses) with or after food.
Day 22
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
Methotrexate 12,000 mg/m2 (IV infusion)         in 1000 mL sodium chloride 0.9% over 4 hours. (Maximum 20,000 mg)
Day 23
Dexamethasone 8 mg (PO) ONCE a day (or in divided doses) with or after food.
Calcium folinate (leucovorin) 15 mg/m2 (IV bolus)         Commence 24 hours after the start of the methotrexate infusion. Calcium folinate 15 mg/m2 IV is given every 6 hours for the first 4 doses, then 15 mg/m2 IV/PO every 6 hours until methotrexate level is less than 0.1 micromol/L. ***
Day 24 and 25
Dexamethasone 8 mg (PO) ONCE a day (or in divided doses) with or after food.

* Various doses and schedules have been used in clinical trials. Alternate regimens administered doxorubicin as a single dose on D1. Doxorubicin has also been administered as a bolus, a 4 hour infusion and as a continuous infusion over 48 hours

** Cisplatin is only administered for cycles 1 to 4 and has been administered over 2 or 4 hours on day 1 and day 2 or as a continuous 72 hour infusion (120 mg/m2) on day 1

*** Commence 24 hours after the start of methotrexate infusion. Calcium folinate 15mg/m2 is given IV for the first 4 doses, then IV/PO given every 6 hours until methotrexate level is less than 0.1 micromol/L. Calcium folinate rescue doses should be titrated to methotrexate level and any associated toxicity, see methotrexate toxicity

Frequency:
28 days 
Cycles:
2 

Cycle 1 to 4

Drug Dose Route Day
DOXOrubicin 37.5 mg/m2 IV * 1 and 2
ciSplatin 60 mg/m2 IV infusion ** 1 and 2
Pegfilgrastim 6 mg Subcut 3
Methotrexate 12,000 mg/m2 (maximum 20,000 mg) IV infusion 22 and 29
Calcium folinate (Leucovorin) 15 mg/m2 every 6 hours (for 4 doses) *** IV bolus 23 and 30
Frequency:
35 days
Cycles:
4

Cycle 5 and 6

Drug Dose Route Day
DOXOrubicin 37.5 mg/m2 IV * 1 and 2
Pegfilgrastim 6 mg S/C 3
Methotrexate 12,000 mg/m2 (maximum 20,000 mg) IV infusion 15 and 22
Calcium folinate (leucovorin) 15 mg/m2 every 6 hours (for 4 doses) *** IV bolus 16 and 23

* Various doses and schedules have been used in clinical trials. Alternate regimens administered doxorubicin as a single dose on D1. Doxorubicin has also been administered as a bolus, a 4 hour infusion and as a continuous infusion over 48 hours

** Cisplatin is only administered for cycles 1 to 4 and has been administered over 2 or 4 hours on day 1 and day 2 or as a continuous 72 hour infusion (120 mg/m2) on day 1

*** Commence 24 hours after the start of methotrexate infusion. Calcium folinate 15 mg/m2 is given IV for the first 4 doses, then IV/PO given every 6 hours until methotrexate level is less than 0.1 micromol/L. Calcium folinate rescue doses should be titrated to methotrexate level and any associated toxicity, see methotrexate toxicity

Frequency:
28 days 
Cycles:
2 
Notes:

In patients older than 40 years of age, consider using cisplatin and doxorubicin without high dose methotrexate.

Drug status:

All drugs in this protocol are on the PBS general schedule

Cost:
~ $1,990 "How this cost is calculated"

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

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

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

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

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

One off loading doses 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 antineoplastic drugs are reimbursed on the PBS.

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

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

Cycle 1 to 4

Day 1
Netupitant 300 mg (PO)

60 minutes before chemotherapy (fixed dose preparation with palonosetron) 
Palonosetron 0.5 mg (PO)

60 minutes before chemotherapy (fixed dose preparation with netupitant)
Dexamethasone 12 mg (PO) 60 minutes before chemotherapy
DOXOrubicin 37.5 mg/m2 (IV) over 5 to 15 minutes *
ciSplatin 60 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 2 hours **
Day 2
Dexamethasone 8 mg (PO) 60 minutes before chemotherapy
DOXOrubicin 37.5 mg/m2 (IV) over 5 to 15 minutes *
ciSplatin 60 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 2 hours **
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 at least 24 hours after chemotherapy
Day 4
Dexamethasone 8 mg (PO) ONCE a day (or in divided doses) with or after food.
Day 22
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
Methotrexate 12,000 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 4 hours. (Maximum 20,000 mg)
Day 23
Dexamethasone 8 mg (PO) ONCE a day (or in divided doses) with or after food.
Calcium folinate (Leucovorin) 15 mg/m2 (IV bolus) Commence 24 hours after the start of the methotrexate infusion. Calcium folinate 15 mg/m2 IV is given every 6 hours for the first 4 doses, then 15 mg/m2 IV/PO every 6 hours until methotrexate level is less than 0.1 micromol/L. ***
Day 24 and 25
Dexamethasone 8 mg (PO) ONCE a day (or in divided doses) with or after food.
Day 29
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
Methotrexate 12,000 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 4 hours. (Maximum 20,000 mg)
Day 30
Dexamethasone 8 mg (PO) ONCE a day (or in divided doses) with or after food.
Calcium folinate (Leucovorin) 15 mg/m2 (IV bolus) Commence 24 hours after the start of the methotrexate infusion. Calcium folinate 15 mg/m2 IV is given every 6 hours for the first 4 doses, then 15 mg/m2 IV/PO every 6 hours until methotrexate level is less than 0.1 micromol/L. ***
Day 31 and 32
Dexamethasone 8 mg (PO) ONCE a day (or in divided doses) with or after food.

Frequency:
35 days
Cycles:
4

Cycle 5 and 6

Day 1
Netupitant 300 mg (PO) 60 minutes before chemotherapy (fixed dose preparation with palonosetron)
Palonosetron 0.5 mg (PO) 60 minutes before chemotherapy (fixed dose preparation with netupitant)
Dexamethasone 12 mg (PO) 60 minutes before chemotherapy
DOXOrubicin 37.5 mg/m2 (IV)         over 5 to 15 minutes *
Day 2
Dexamethasone 8 mg (PO) 60 minutes before chemotherapy
DOXOrubicin 37.5 mg/m2 (IV) over 5 to 15 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 at least 24 hours after chemotherapy
Day 4
Dexamethasone 8 mg (PO) ONCE a day (or in divided doses) with or after food.
Day 15
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
Methotrexate 12,000 mg/m2 (IV infusion)         in 1000 mL sodium chloride 0.9% over 4 hours. (Maximum 20,000 mg)
Day 16
Dexamethasone 8 mg (PO) ONCE a day (or in divided doses) with or after food.
Calcium folinate (leucovorin) 15 mg/m2 (IV bolus)         Commence 24 hours after the start of the methotrexate infusion. Calcium folinate 15 mg/m2 IV is given every 6 hours for the first 4 doses, then 15 mg/m2 IV/PO every 6 hours until methotrexate level is less than 0.1 micromol/L. ***
Day 17 and 18
Dexamethasone 8 mg (PO) ONCE a day (or in divided doses) with or after food.
Day 22
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
Methotrexate 12,000 mg/m2 (IV infusion)         in 1000 mL sodium chloride 0.9% over 4 hours. (Maximum 20,000 mg)
Day 23
Dexamethasone 8 mg (PO) ONCE a day (or in divided doses) with or after food.
Calcium folinate (leucovorin) 15 mg/m2 (IV bolus)         Commence 24 hours after the start of the methotrexate infusion. Calcium folinate 15 mg/m2 IV is given every 6 hours for the first 4 doses, then 15 mg/m2 IV/PO every 6 hours until methotrexate level is less than 0.1 micromol/L. ***
Day 24 and 25
Dexamethasone 8 mg (PO) ONCE a day (or in divided doses) with or after food.

* Various doses and schedules have been used in clinical trials. Alternate regimens administered doxorubicin as a single dose on D1. Doxorubicin has also been administered as a bolus, a 4 hour infusion and as a continuous infusion over 48 hours

** Cisplatin is only administered for cycles 1 to 4 and has been administered over 2 or 4 hours on day 1 and day 2 or as a continuous 72 hour infusion (120 mg/m2) on day 1

*** Commence 24 hours after the start of methotrexate infusion. Calcium folinate 15mg/m2 is given IV for the first 4 doses, then IV/PO given every 6 hours until methotrexate level is less than 0.1 micromol/L. Calcium folinate rescue doses should be titrated to methotrexate level and any associated toxicity, see methotrexate toxicity

Frequency:
28 days 
Cycles:
2 
  • Neoadjuvant and adjuvant treatment of localised or metastatic high grade osteosarcoma of an extremity / axial skeleton (excluding craniofacial sites) - all disease sites amenable to complete surgical resection
    • age 40 or younger
Venous access

Central venous access device (CVAD) is required to administer this treatment.

Read more about central venous access device line selection
Antiemetics for multi-day protocols

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

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 or 12.5 mg IV every 6 hours when necessary.

Read more about preventing antineoplastic induced nausea and vomiting
Cumulative lifetime dose of doxorubicin

The total cumulative lifetime dose of doxorubicin is 450 to 500 mg/m2.

Reduce the total cumulative lifetime dose to 400 to 450 mg/m2 if elderly, prior mediastinal radiation, hypertensive cardiomegaly, concurrent therapy with high dose cyclophosphamide and some other cytotoxic drugs (e.g. dacarbazine, dactinomycin, etoposide, mitomycin, melphalan, vincristine and bleomycin).

Baseline clinical assessment, 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 anthracycline threshold is reached or if patient displays symptoms of cardiac impairment. Post treatment cardiac monitoring is recommended for patients who have received high levels of total cumulative doses of doxorubicin at the clinicians discretion.

Read more about cardiac toxicity associated with anthracyclines
Growth factor support

G-CSF (filgrastim, lenograstim, lipegfilgrastim or pegfilgrastim) is available on the PBS for the primary prevention of neutropenia.

Access the PBS website
Hydration

Hydration helps to prevent cisplatin-induced nephrotoxicity.

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

Read more about cisplatin hydration regimens
Hydration and urinary alkalinisation

Pre-hydration with sodium bicarbonate 8.4% infusion. Urinary pH must be greater than 7 prior to commencing methotrexate infusion. 
(Consider prescribing sodium bicarbonate oral capsules for administration prior to methotrexate infusion) Sodium bicarbonate 8.4% should continue until the methotrexate level is equal to or less than 0.1 micromol/L.
High dose methotrexate

Monitoring of methotrexate levels is essential as delayed methotrexate excretion is potentially an emergency situation. Methotrexate levels to be monitored every 24 hours until level is less than 0.1 micromol/L.

Methotrexate is renally eliminated. Renal function must be evaluated prior to treatment.

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.

Glucarpidase is recommended in patients with high dose methotrexate (HDMTX)-induced acute kidney injury and delayed methotrexate clearance. It can rapidly lower methotrexate levels and early administration within 48 to 60 hours from the start of the HDMTX infusion is critical, as life-threatening toxicities may not be preventable beyond this time point.r

Read more about high dose methotrexate-induced toxicity and methotrexate toxicity in sarcoma.
Methotrexate interactions

Avoid administering the following drugs in combination with high dose methotrexate: ciprofloxacin, NSAIDs, probenecid, proton pump inhibitors (PPIs) (e.g. esomeprazole, omeprazole, pantoprazole), sulphonamides (e.g. sulfamethoxazole (in Bactrim®, Septrin®)), penicillins (e.g. piperacillin (in Tazocin®)) and trimethoprim. Severe mucositis may occur if administered together.
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 neuropathy, cessation of cisplatin is recommended; review by medical officer before commencing treatment.

Read more about peripheral neuropathy

Link to chemotherapy-induced peripheral neuropathy screening tool
FBC at baseline and repeat prior to each treatment. EUCs, LFTs and CMP at baseline and regularly MTX level

FBC at baseline and repeat prior to each treatment. EUCs, LFTs and CMP at baseline and regularly throughout treatment as clinically indicated. 

Methotrexate levels to be monitored every 24 hours until the level is less than 0.1 micromol/L
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, including BCG, MMR, zoster and varicella 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.
Effects of cancer treatment on fertility

Cancer treatment can have harmful effects on fertility and this should be discussed with all patients of reproductive age prior to commencing treatment.

Read more about the effect of cancer treatment on fertility
Evidence for dose modifications is limited, and the recommendations made on eviQ are intended as a guide only. They are generally conservative with an emphasis on safety. Any dose modification should be based on clinical judgement, and the individual patient’s situation including but not limited to treatment intent (curative vs palliative), the antineoplastic 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. For more information see dosing considerations & disclaimer.

Dose reductions are complex and may not always follow guidelines for treatment toxicities in other tumour types, therefore consultation with the patients primary provider should be sought at all times.

References & Disclaimer

Cisplatin
  Interaction Clinical management
Nephrotoxic drugs (e.g. aminoglycosides, amphotericin, cisplatin, contrast dye, frusemide, NSAIDs) Additive nephrotoxicity Avoid combination or monitor renal function closely
Ototoxic drugs (e.g. aminoglycosides, frusemide, NSAIDs) Additive ototoxicity Avoid combination or perform regular audiometric testing
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) 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
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) 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, cisplatin, contrast dye, frusemide, NSAIDs) Additive nephrotoxicity Avoid combination or monitor renal 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
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 Antineoplastic agents may alter the anticoagulant effect of warfarin Monitor INR regularly and adjust warfarin dosage as appropriate; consider alternative anticoagulant (e.g. LMWH or unfractionated heparin)
Direct oral anticoagulants (DOACs) e.g. apixaban, rivaroxaban, dabigatran

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

DOAC and antineoplastic 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 Antineoplastic agents 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 antineoplastic 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 antineoplastic 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

Day 1 and 2 (cycles 1 to 4)

Approximate treatment time: 4 to 5 hours

General patient assessment prior to each day of treatment.

Peripheral neuropathy assessment tool

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).

Access port or CVC.

Pre treatment medication

Verify antiemetics taken or administer as prescribed.

Verify dexamethasone 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.

Cisplatin

Commence prehydration for cisplatin:
  • administer 10 mmol magnesium sulphate (MgSO4) in 1000 mL sodium chloride 0.9% over 60 minutes
  • followed by 200 mL of mannitol 20% over 15 minutes
    • mannitol should be administered via a controlled infusion
  • mannitol 10% may be used as per institutional policy; there is much variation in the use of mannitol and although there is no conclusive evidence that mannitol should be used, many sites have used it routinely without renal toxicity. The routine use of frusemide to increase urine flow is not recommended. Refer to your institutional guidelines and medical orders.
  • ensure patient has passed urine prior to cisplatin administration as per institutional policy.
Administer cisplatin (irritant):
  • via IV infusion over 2 hours
  • flush with 100 mL of sodium chloride 0.9%.
Post hydration:
  • 1000 mL sodium chloride 0.9% over 60 minutes.

Deaccess port or CVC.

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

Day 3 (cycles 1 to 4)

Subcutaneous injection

General patient assessment prior to each day of treatment.

Pegfilgrastim

  •  administer subcutaneously at least 24 hours post chemotherapy.

Day 22 and 29 (cycles 1 to 4)

General patient assessment prior to each treatment.

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

Prime IV line(s).

Access port or CVC.

Pre treatment medication

Verify antiemetics taken or administer as prescribed.

Verify dexamethasone taken or administer as prescribed.

Methotrexate infusion

Prehydration:
  • administer 100 mL sodium bicarbonate 8.4% in 1000 mL glucose 5% OR sodium chloride 0.9% over 4 hours
  • continue hydration with sodium bicarbonate 8.4% as prescribed
  • when urine pH is greater than 7 commence methotrexate
If the urine pH drops below 7 during the methotrexate infusion:
  • administer stat dose of 100 mL sodium bicarbonate 8.4% over 15 minutes
  • continue to test all urine for pH, if the pH continues to drop below 7 seek medical review as further doses of sodium bicarbonate may be required.

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

Administer methotrexate:
  • via IV infusion over 4 hours
  • the starting time of the methotrexate infusion must be documented as the leucovorin rescue is to commence exactly 24 hours after the start of the methotrexate and continue until the methotrexate level is less than 0.1  micromol/L.
  • flush with ~50 mL of sodium chloride 0.9%
Post methotrexate:
  • continue hydration with sodium bicarbonate 8.4% until methotrexate level is less than 0.1 micromol/L
  • continue to monitor all urine pH and fluid input and output
  • monitor methotrexate concentration every 24 hours until the level is less than 0.1 micromol/L

Read more about methotrexate toxicity

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

Day 23 and 30 (cycles 1 to 4)

General patient assessment prior to each day of treatment.

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

Calcium folinate (Leucovorin)

Commence 24 hours after the start of the methotrexate infusion and repeat every 6 hours until methotrexate level is less than 0.1 micromol/L

  • administer via IV bolus via the side port of the IV line over 1 to 2 minutes
  • flush with ~ 50 mL of sodium chloride 0.9%
  • first 4 doses to be administered IV, then IV/PO every 6 hours until methotrexate level is less than 0.1 micromol/L.

Deaccess port or CVC.

  • daily weight
  • monitor pH on all urine output
  • strict fluid balance input and output

Discharge information

Antiemetics
  • Antiemetics as prescribed.
Antidiarrhoeals
  • Antidiarrhoeals as prescribed.
Growth factor support
  • Arrangements for administration if prescribed.
Patient information
  • Ensure patient receives patient information sheet.

Day 1 and 2 (cycles 5 and 6)

Approximate treatment time:  30 to 60 minutes.

General patient assessment prior to each treatment.

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

Prime IV line(s).

Access port or CVC.

Pre treatment medication

Verify antiemetics taken or administer as prescribed.

Verify dexamethasone 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.

Deaccess port or CVC.

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

Day 3 (cycles 5 and 6)

Subcutaneous injection

General patient assessment prior to each day of treatment.

Pegfilgrastim

  •  administer subcutaneously at least 24 hours post chemotherapy.

Day 15 and 22 (cycles 5 and 6)

General patient assessment prior to each treatment.

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

Prime IV line(s).

Access port or CVC.

Pre treatment medication

Verify antiemetics taken or administer as prescribed.

Verify dexamethasone taken or administer as prescribed.

Methotrexate infusion

Prehydration:
  • administer 100 mL sodium bicarbonate 8.4% in 1000 mL glucose 5% OR sodium chloride 0.9% over 4 hours
  • continue hydration with sodium bicarbonate 8.4% as prescribed
  • when urine pH is greater than 7 commence methotrexate
If the urine pH drops below 7 during the methotrexate infusion:
  • administer stat dose of 100 mL sodium bicarbonate 8.4% over 15 minutes
  • continue to test all urine for pH, if the pH continues to drop below 7 seek medical review as further doses of sodium bicarbonate may be required.

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

Administer methotrexate:
  • via IV infusion over 4 hours
  • the starting time of the methotrexate infusion must be documented as the leucovorin rescue is to commence exactly 24 hours after the start of the methotrexate and continue until the methotrexate level is less than 0.1  micromol/L.
  • flush with ~50 mL of sodium chloride 0.9%
Post methotrexate:
  • continue hydration with sodium bicarbonate 8.4% until methotrexate level is less than 0.1 micromol/L
  • continue to monitor all urine pH and fluid input and output
  • monitor methotrexate concentration every 24 hours until the level is less than 0.1 micromol/L

Read more about methotrexate toxicity

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

Day 16 and 23 (cycles 5 and 6)

General patient assessment prior to each day of treatment.

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

  • daily weight
  • monitor pH on all urine output
  • strict fluid balance input and output

Calcium folinate (Leucovorin)

Commence 24 hours after the start of the methotrexate infusion and repeat every 6 hours until methotrexate level is less than 0.1 micromol/L

  • administer via IV bolus via the side port of the IV line over 1 to 2 minutes
  • flush with ~ 50 mL of sodium chloride 0.9%
  • first 4 doses to be administered IV, then IV/PO every 6 hours until methotrexate level is less than 0.1 micromol/L.

Deaccess port or CVC.

Discharge information

Antiemetics
  • Antiemetics as prescribed.
Antidiarrhoeals
  • Antidiarrhoeals as prescribed.
Growth factor support
  • Arrangements for administration if prescribed.
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
Headache
Bone pain

Bone pain, usually in the lower back or pelvis, associated with colony stimulating factors (filgrastim, lenograstim, lipegfilgrastim and pegfilgrastim). 
Nausea and vomiting

Read more about prevention of treatment induced nausea and vomiting
Taste and smell alteration

Read more about taste and smell changes
Red-orange discolouration of urine

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

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 neutropenia
Thrombocytopenia

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

Read more about thrombocytopenia
Anorexia

Loss of appetite accompanied by decreased food intake.

Read more about anorexia
Skin rash

Antineoplastic agents 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
Oral mucositis

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

Read more about oral mucositis
Diarrhoea

Read more about treatment induced diarrhoea
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 antineoplastic agents. These include taxanes, platinum-based compounds, vinca alkaloids and some drugs used to treat multiple myeloma.

Read more about peripheral neuropathy
Fatigue

Read more about fatigue
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 radiotherapy can occur with certain antineoplastic 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

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

Antineoplastic agents administered either alone or in combination with other drugs and/or radiation may cause direct or indirect hepatotoxicity. Hepatic dysfunction can alter the metabolism of some drugs resulting in systemic toxicity.
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
Pulmonary toxicity

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

Read more about pulmonary toxicity associated with antineoplastic drugs
Nail changes

Hyperpigmentation, paronychia, onycholysis, splinter haemorrhage, pyogenic granuloma formation, subungal haematoma and subungal hyperkeratosis are some of the nail changes associated with antineoplastic treatment.   

Read more about nail toxicities
Cognitive changes (chemo fog)

Changes in cognition characterised by memory loss, forgetfulness and feeling vague. This is also referred to as 'chemo brain' or 'chemo fog'.

Read more about cognitive changes (chemo fog) 

Delayed (onset months to years)
Cardiotoxicity

Anthracyclines are the most frequently implicated antineoplastic agents 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

A search of the literature did not find strong evidence to support the use of neoadjuvant or adjuvant MAP in the treatment of surgically resectable osteosarcoma. Although MAP is used as the standard of care, there are no comparative studies with other chemotherapy regimens. 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 Intergroup 0133r and EURAMOS-1 trials.r

Source Study & Year Published Supports Use Is the dose and regimen consistent with the protocol? Comments
Phase III trials (standard of care)
 		 Meyers et al 2005r Yes No doxorubicin 75 mg/m2 day 1 cisplatin 120 mg/m2 day 1 protocol 20 weeks duration
Bielack et al 2015r Yes No same doses but different schedules doxorubicin given as 48 hour infusion,         alternative cisplatin administration as 72 hour infusion
Winkler et al 1988r Yes No cisplatin 120 mg/m2day 1,  doxorubicin 30 mg/m2 days 1,2
Bacci et al 2000r Yes No methotrexate 8 g/m2 d1,28 cisplatin intra-arterially 120 mg/m2 over 72 hrs d7,34 doxorubicin 60 mg/m2 over 8 hours d9,36
Guidelines Date published/revised Supports Use Is the dose and regimen consistent with the protocol? Comments
NCCN 2016  Yes no doses  
BCCA 2012 Yes No

separate protocols cisplatin 100 mg/m2 d1 doxorubicin 75 mg/m2 d1 q3 weekly, methotrexate  8-12 g/m2 d1 leucovorin rescue 25 mg q6h repeating every 1-4 weeks
CCO - N/A -   -

Efficacy

Outcome Study No. of patients Control arm  Effect
Overall survival Meyers et alr  662  MAP (n=172) 6 yr OS 74%
Bielack et alr 716 MAP (359)

5yr OS 81%

(95% CI:74-86%)
Event free survival Meyers et alr 662 MAP (n=172)

3yr EFS 71%

5yr EFS 64%
Bielack et alr 716 MAP (359) 3yr EFS 74%

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 myelosuppression and febrile neutropaenia.

Grade 3 to 5 toxicityr

Incidence (n=2260)
Neutropaenia 93% (n=238)
Thrombocytopaenia 74% (n=264)
Febrile neutropaenia 54% (n=194)
Infection (neutrophils <1.0 x 109/L) 40% (n=142)
Mucositis 35% (n=112)
Non-neutropaenic infections 24% (n=67)
Hypophosphatemia 14% (n=49)
Neuropathy (motor) 5% (n=16)
Ototoxicity 5% (n=15)
Neuropathy (sensory) 3% (n=9)
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Version 2

Date Summary of changes
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.
06/06/2017 Approved and published on eviQ. Review in 1 year
15/06/2018 Protocol reviewed by Medical Oncology Reference Committee. No changes. Review 5 years.
25/10/2018 Link added to high dose methotrexate-induced toxicity document in clinical information.

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. Use is subject to eviQ’s disclaimer available at www.eviQ.org.au

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https://www.eviq.org.au/p/1901

22 Sep 2019