Venous access
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Central venous access device (CVAD) is required to administer this treatment.
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Hypersensitivity/infusion related reaction
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High risk with etoposide.
High risk with asparaginase.
Acute anaphylactoid reactions are the most common dose-limiting toxicity, particularly with IV administration. Patients that develop hypersensitivity to the E. coli derived formulation may be able to switch to Erwinia asparaginase.
The Leunase brand of asparaginase (colaspase) is the only formulation for which the manufacturer advises an intradermal test dose prior to the initial dose or when a week or more has elapsed between doses. A negative skin reaction does not preclude the development of an allergic reaction and therefore the practice of a test dose is controversial.
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Antiemetics for multi-day protocols
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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. A combination of an NK1 receptor antagonist, 5HT3, and a steroid is available 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.
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Pre-hydration
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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.
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Methotrexate dosing and monitoring
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Directly measured GFR is preferred for initial dosing when eGFR < 60 mL/min/1.73 m2, especially when methotrexate dose ≥ 500 mg/m2 or when eGFR is unreliable (e.g., extremes of body composition, amputees, paraplegia).
Monitor kidney function before, during and after methotrexate administration to identify signs of kidney function deterioration. 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 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.
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Methotrexate interactions
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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.
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Asparaginase
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Asparaginase is associated with numerous toxicities including hypersensitivity, hepatotoxicity, coagulation abnormalities, pancreatitis, hyperlipidaemia, hyperglycaemia and CNS effects. Therefore routine monitoring and assessment of several parameters are required throughout treatment.
There are several different formulations of asparaginase available, each with different dosing and administration recommendations.
For comprehensive information on formulations, dosing, interactions, adverse reactions and specific monitoring parameters for asparaginase, see Management of asparaginase therapy document.
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Pancreatitis
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Pancreatitis can occur despite normal serum amylase, and can be fatal. In cases of clinical pancreatitis (unequivocal diagnosis based on lipase/amylase elevation, ultrasound and clinical findings) asparaginase treatment should be ceased and must not be resumed. Mild asymptomatic biochemical pancreatitis does not warrant discontinuing asparaginase therapy.
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Ifosfamide-induced encephalopathy
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May occur in patients treated with high dose ifosfamide (~ 5 to 8 g/m2). Assess neurological function prior to each ifosfamide dose.
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Haemorrhagic cystitis associated with high dose chemotherapy
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Hydration regimen pre high dose cyclophosphamide or ifosfamide (as per local guidelines).
There is limited evidence and no consensus regarding hydration regimens and mesna dose, route or timing of administration.
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Etoposide conversion factor
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Doses in this protocol are expressed as etoposide. Note: Etopophos (etoposide phosphate) 113.6 mg is equivalent to etoposide 100 mg.
Etoposide phosphate is the preferred formulation for this protocol, as solutions of conventional etoposide would exceed the maximum concentration of 0.4 mg/mL and may precipitate. All administration details in this protocol refer to etopophos.
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Corticosteroids
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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.
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Central nervous system (CNS) prophylaxis
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Consider CNS relapse assessment in patients with high grade lymphoma.
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Tumour lysis risk
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Assess patient for risk of developing tumour lysis syndrome.
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Mesna dosing and administration
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There is evidence supporting variations in mesna doses and administration timings, with no clear evidence that one particular regimen is superior to another. The eviQ mesna recommendations may be based upon the individual trial/study or reference committee consensus and provide guidance on one safe way to administer the protocol. Individual institutional policy may vary and should be evidence-based.
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Pneumocystis jirovecii pneumonia (PJP) prophylaxis
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PJP prophylaxis is recommended.
Myelosuppression may be exacerbated if trimethoprim/sulfamethoxazole is used in combination with methotrexate.
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Antiviral prophylaxis
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Antifungal prophylaxis
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Biosimilar drug
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Read more about biosimilar drugs on the Biosimilar Awareness Initiative page
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Growth factor support
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G-CSF (short or long-acting) is available on the PBS for chemotherapy induced neutropenia depending on clinical indication and/or febrile neutropenia risk.
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Blood product support
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The use of FFP and cryoprecipitate may be required to maintain fibrinogen levels to a normal range.
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Blood tests
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FBC at baseline and repeat prior to each treatment. EUC, eGFR, LFTs, LDH, BSL, serum uric acid, serum amylase and lipase at baseline and regularly throughout treatment as clinically indicated.
Asparaginase may cause a marked increase in plasma triglycerides and total cholesterol levels. Monitoring recommended.
During asparaginase therapy perform coagulation studies at baseline then at least once or twice weekly. Monitor fibrinogen levels at least twice weekly and consider monitoring antithrombin levels or APTT, PT, fibrinogen levels, pancreatic lipase prior to each dose of asparaginase (colaspase).
Monitor methotrexate levels every 24 hours until the level is less than 0.1 micromol/L.
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Hepatitis B screening and prophylaxis
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Routine screening for HBsAg and anti-HBc is recommended prior to initiation of treatment. Prophylaxis should be determined according to individual institutional policy.
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Vaccinations
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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.
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Fertility, pregnancy and lactation
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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.
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