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Primary CNS lymphoma (PCNSL) MBVP (methotrexate carmustine teniposide prednisolone)

 Teniposide drug supply:

Teniposide was removed from the Australian Register of Therapeutic Goods (ARTG) in June 2017 as global production was ceased. Access to teniposide may still be available via the Special Access Scheme. 

Patients with lymphoma should be considered for inclusion into clinical trials. Link to ALLG website, ANZCTR website and Lymphoma Australia website.

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

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Cycle 1 and 2

Drug Dose Route Day
Prednisolone * 60 mg/m2 ONCE a day PO 1 to 5
Methotrexate 3,000 mg/m2 IV infusion 1 and 15
Calcium folinate (Leucovorin) ** 25 mg every 6 hours IV bolus 2 and 16
Teniposide *** 100 mg/m2 IV infusion 2 and 3
Carmustine 100 mg/m2 IV infusion 4
Filgrastim **** 5 micrograms/kg Subcut 5 and 16 and continue daily until ANC> 1 x 109/L

* Methylprednisolone 60 mg/m2 was used in the original study Poortmans et al 2003, however it is the consensus of the Haematology Reference Committee that prednisolone 60 mg/m2 be used.

** Commence 24 hours after the start of methotrexate infusion and repeat every 6 hours until methotrexate level is less than 0.05 micromol/L

*** Due to the discontinuation of teniposide, it is the consensus of the eviQ Haematology Reference Committee that etoposide 100 mg/m2 IV is administered on day 2r to replace the teniposide 100 mg/m2 IV dose on day 2 and 3 at the clinician's discretion.

**** Stop 24 hours before day 15 methotrexate.

Frequency:
28 days 
Cycles:
2 
Notes:
Radiotherapy

This protocol is based on the study by Poortmans et al 2003,r where consolidation with WBRT was started within 4 weeks from the last chemotherapy course. Patients were treated with 39 to 40 Gy in fractions of 1.5 to 1.8 Gy with five fractions a week. Optionally, the RT fields could be limited after 30 Gy to the original tumour area only.

  • There is data to suggest that reduced dose WBRT for patients in CR is associated with good long term disease control rates and very low rates of long term neurotoxicity.r
  • The incidence neurotoxicity related to the combination of WBRT and high dose methotrexate is significantly higher in patients aged older than 60 years; withholding WBRT in the primary setting in these patients may be considered.rr
For these reasons, the Haematology Reference Committee recommends the following:
  • patients < 60 years and in CR: consolidation WBRT 23.4 Gy in 13 fractions (1.8 Gy/fraction)
  • patients > 60 years and in CR: consider omitting WBRT
  • patients of any age in PR or PD: WBRT 36 Gy in 20 fractions (1.8 Gy/fraction). A boost of 9 Gy in 5 fractions may be used in selected patients.

CT planning with compensation is encouraged to reduce dose heterogeneity throughout the treatment volume. Patients should be treated in an immobilisation shell.

Intrathecal (IT) Treatment

IT treatment is not recommended upfront in the diagnostic setting, as there is low level evidence on the efficacy of IT prophylaxis.r Up to 20% of patients with PCNSL will have leptomeningeal disease (positive cerebrospinal fluid (CSF) cytology) at diagnosis, most of whom will clear the CSF following induction of high dose methotrexate.

CSF testing is recommended in all patients at diagnosis and if the CSF cytology/flowcytometry is positive a repeat CSF test is recommended half way through induction. If the CSF has cleared, then no further action is required. However if the CSF cytology/flowcytometry continues to be positive despite intravenous treatment, then the addition of IT chemotherapy is recommended.r

Intrathecal methotrexate

When given as prophylaxis in addition to systemic intravenous methotrexate in primary treatment, IT methotrexate confers no clinical advantage and is not recommended but it may be useful where CSF cytology/flowcytometry yields positive findings.r

Rituximab

There is some literature to indicate the addition of rituximab in this setting may be beneficial, although further study is required to verify whether this results in significant improvement to patient outcome.r

Drug status:

Prednisolone and methotrexate are on the PBS general schedule

Carmustine is TGA approved as second line therapy but not PBS reimbursed.

Teniposide was removed from the ARTG in June 2017 due to worldwide production cessation. Access to teniposide may still be available via the Special Access Scheme. 

Filgrastim: (PBS authority)

Prednisolone is available as 25 mg, 5 mg and 1 mg tablets

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 and 2

Day 1
Prednisolone 60 mg/m2 (PO) ONCE a day on days 1 to 5. Take in the morning with food.
Methotrexate 3,000 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 3 hours
Day 2
Prednisolone 60 mg/m2 (PO) ONCE a day on days 1 to 5. Take in the morning with food.
Calcium folinate (Leucovorin) 25 mg (IV bolus) over 1 to 2 minutes. Commence 24 hours after the start of methotrexate infusion and repeat every 6 hours until methotrexate level is less than 0.05 micromol/L
Teniposide 100 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 30 to 60 minutes (in non-PVC containers only) *
Day 3
Prednisolone 60 mg/m2 (PO) ONCE a day on days 1 to 5. Take in the morning with food.
Teniposide 100 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 30 to 60 minutes (in non-PVC containers only) *
Day 4
Prednisolone 60 mg/m2 (PO) ONCE a day on days 1 to 5. Take in the morning with food.
Carmustine 100 mg/m2 (IV infusion) in 500 mL glucose 5% over 2 hours (in non-PVC containers only)
Day 5
Prednisolone 60 mg/m2 (PO) ONCE a day on days 1 to 5. Take in the morning with food.
Filgrastim 5 micrograms/kg (Subcut) inject subcutaneously ONCE a day and continue until neutrophils are greater than 1 x 10^9/L. Cease 24 hours prior to day 15 chemotherapy.
Day 15
Methotrexate 3,000 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 3 hours
Day 16
Calcium folinate (Leucovorin) 25 mg (IV bolus) over 1 to 2 minutes. Commence 24 hours after the start of methotrexate infusion and repeat every 6 hours until methotrexate level is less than 0.05 micromol/L
Filgrastim 5 micrograms/kg (Subcut) inject subcutaneously ONCE a day and continue until neutrophils are greater than 1 x 10^9/L. Cease 24 hours prior to day 15 chemotherapy.

* Due to the discontinuation of teniposide, it is the consensus of the eviQ Haematology Reference Committee that etoposide 100 mg/m2 IV is administered on day 2r to replace the teniposide 100 mg/m2 IV dose on day 2 and 3 at the clinician's discretion.

Frequency:
28 days 
Cycles:
2 

Cycle 1 and 2

Drug Dose Route Day
Prednisolone * 60 mg/m2 ONCE a day PO 1 to 5
Methotrexate 3,000 mg/m2 IV infusion 1 and 15
Calcium folinate (Leucovorin) ** 25 mg every 6 hours IV bolus 2 and 16
Teniposide *** 100 mg/m2 IV infusion 2 and 3
Carmustine 100 mg/m2 IV infusion 4
Filgrastim **** 5 micrograms/kg Subcut 5 and 16 and continue daily until ANC> 1 x 109/L

* Methylprednisolone 60 mg/m2 was used in the original study Poortmans et al 2003, however it is the consensus of the Haematology Reference Committee that prednisolone 60 mg/m2 be used.

** Commence 24 hours after the start of methotrexate infusion and repeat every 6 hours until methotrexate level is less than 0.05 micromol/L

*** Due to the discontinuation of teniposide, it is the consensus of the eviQ Haematology Reference Committee that etoposide 100 mg/m2 IV is administered on day 2r to replace the teniposide 100 mg/m2 IV dose on day 2 and 3 at the clinician's discretion.

**** Stop 24 hours before day 15 methotrexate.

Frequency:
28 days 
Cycles:
2 
Notes:
Radiotherapy

This protocol is based on the study by Poortmans et al 2003,r where consolidation with WBRT was started within 4 weeks from the last chemotherapy course. Patients were treated with 39 to 40 Gy in fractions of 1.5 to 1.8 Gy with five fractions a week. Optionally, the RT fields could be limited after 30 Gy to the original tumour area only.

  • There is data to suggest that reduced dose WBRT for patients in CR is associated with good long term disease control rates and very low rates of long term neurotoxicity.r
  • The incidence neurotoxicity related to the combination of WBRT and high dose methotrexate is significantly higher in patients aged older than 60 years; withholding WBRT in the primary setting in these patients may be considered.rr
For these reasons, the Haematology Reference Committee recommends the following:
  • patients < 60 years and in CR: consolidation WBRT 23.4 Gy in 13 fractions (1.8 Gy/fraction)
  • patients > 60 years and in CR: consider omitting WBRT
  • patients of any age in PR or PD: WBRT 36 Gy in 20 fractions (1.8 Gy/fraction). A boost of 9 Gy in 5 fractions may be used in selected patients.

CT planning with compensation is encouraged to reduce dose heterogeneity throughout the treatment volume. Patients should be treated in an immobilisation shell.

Intrathecal (IT) Treatment

IT treatment is not recommended upfront in the diagnostic setting, as there is low level evidence on the efficacy of IT prophylaxis.r Up to 20% of patients with PCNSL will have leptomeningeal disease (positive cerebrospinal fluid (CSF) cytology) at diagnosis, most of whom will clear the CSF following induction of high dose methotrexate.

CSF testing is recommended in all patients at diagnosis and if the CSF cytology/flowcytometry is positive a repeat CSF test is recommended half way through induction. If the CSF has cleared, then no further action is required. However if the CSF cytology/flowcytometry continues to be positive despite intravenous treatment, then the addition of IT chemotherapy is recommended.r

Intrathecal methotrexate

When given as prophylaxis in addition to systemic intravenous methotrexate in primary treatment, IT methotrexate confers no clinical advantage and is not recommended but it may be useful where CSF cytology/flowcytometry yields positive findings.r

Rituximab

There is some literature to indicate the addition of rituximab in this setting may be beneficial, although further study is required to verify whether this results in significant improvement to patient outcome.r

Drug status:

Prednisolone and methotrexate are on the PBS general schedule

Carmustine is TGA approved as second line therapy but not PBS reimbursed.

Teniposide was removed from the ARTG in June 2017 due to worldwide production cessation. Access to teniposide may still be available via the Special Access Scheme. 

Filgrastim: (PBS authority)

Prednisolone is available as 25 mg, 5 mg and 1 mg tablets

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 and 2

Day 1
Prednisolone 60 mg/m2 (PO) ONCE a day on days 1 to 5. Take in the morning with food.
Methotrexate 3,000 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 3 hours
Day 2
Prednisolone 60 mg/m2 (PO) ONCE a day on days 1 to 5. Take in the morning with food.
Calcium folinate (Leucovorin) 25 mg (IV bolus) over 1 to 2 minutes. Commence 24 hours after the start of methotrexate infusion and repeat every 6 hours until methotrexate level is less than 0.05 micromol/L
Teniposide 100 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 30 to 60 minutes (in non-PVC containers only) *
Day 3
Prednisolone 60 mg/m2 (PO) ONCE a day on days 1 to 5. Take in the morning with food.
Teniposide 100 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 30 to 60 minutes (in non-PVC containers only) *
Day 4
Prednisolone 60 mg/m2 (PO) ONCE a day on days 1 to 5. Take in the morning with food.
Carmustine 100 mg/m2 (IV infusion) in 500 mL glucose 5% over 2 hours (in non-PVC containers only)
Day 5
Prednisolone 60 mg/m2 (PO) ONCE a day on days 1 to 5. Take in the morning with food.
Filgrastim 5 micrograms/kg (Subcut) inject subcutaneously ONCE a day and continue until neutrophils are greater than 1 x 10^9/L. Cease 24 hours prior to day 15 chemotherapy.
Day 15
Methotrexate 3,000 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 3 hours
Day 16
Calcium folinate (Leucovorin) 25 mg (IV bolus) over 1 to 2 minutes. Commence 24 hours after the start of methotrexate infusion and repeat every 6 hours until methotrexate level is less than 0.05 micromol/L
Filgrastim 5 micrograms/kg (Subcut) inject subcutaneously ONCE a day and continue until neutrophils are greater than 1 x 10^9/L. Cease 24 hours prior to day 15 chemotherapy.

* Due to the discontinuation of teniposide, it is the consensus of the eviQ Haematology Reference Committee that etoposide 100 mg/m2 IV is administered on day 2r to replace the teniposide 100 mg/m2 IV dose on day 2 and 3 at the clinician's discretion.

Frequency:
28 days 
Cycles:
2 

Indication:

  • Primary CNS lymphoma (PCNSL)

Caution:

  • This protocol may not be suitable for immunodeficient patients such as those with advanced HIV disease. Seek further specialist advice.
Venous access

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 teniposide.
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. 

As a steroid has been included as part of this protocol, additional antiemetic steroids are not 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
Pre-hydration

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 0.05 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 0.05 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.
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.
Pulmonary toxicity

Carmustine should be administered with caution in patients with a baseline less than 70% of predicted forced vital capacity (FVC) or carbon monoxide diffusing capacity (DLCO) or those who have had prior thoracic radiotherapy.

Conduct baseline pulmonary function studies and repeat as clinically indicated during treatment.

Read more about pulmonary toxicity associated with antineoplastic drugs.
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
Tumour lysis risk

Patients are at high risk of developing tumour lysis syndrome, prophylaxis is recommended.

Read more about the prevention and management of tumour lysis syndrome.
Pneumocystis jiroveci pneumonia (PJP) prophylaxis

PJP prophylaxis is recommended. Dapsone is preferred in patients being treated with high-dose methotrexate. Avoid trimethoprim/sulfamethoxazole 160/80 mg PO due to increased risk of methotrexate toxicity.

If trimethoprim/sulfamethoxazole 160/80 mg PO cannot be avoided, cease PJP prophylaxis 48 hours prior to methotrexate infusion and recommence upon neutrophil recovery.

Read about prophylaxis of pneumocystis jiroveci (carinii) in cancer patients
Antiviral prophylaxis

Antiviral prophylaxis is recommended.

Read more about antiviral prophylaxis drugs and doses
Antifungal prophylaxis

Antifungal prophylaxis is recommended.

Read more about antifungal prophylaxis drugs and doses.
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
Blood tests

FBC, EUC, LFTs, LDH and BSL at baseline, prior to each treatment and regularly throughout treatment. Methotrexate levels to be monitored every 24 hours until level is less than 0.05 µ/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. Suggested dose modifications are based on clinical trial findings, product information and reference committee consensus. 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: All dose reductions are calculated as a percentage of the starting dose

Haematological toxicity
ANC x 109/L and Platelets x 109/L (pre-treatment blood test)
Delay treatment until recovery if neutrophils are less than 2 and platelets are less than 75.
Age older than 60 years
The incidence of neurotoxicity related to the combination of WBRT and high dose methotrexate is significantly higher in patients aged older than 60 years; withholding WBRT in the primary setting in these patients may be considered.
Renal impairment
Creatinine clearance must be greater than 80 mL/min prior to administration of high dose methotrexate.
It is advised to reduce the methotrexate dose in proportion to the calculated creatinine clearance when this is less than 100 mL/min e.g. if creatinine clearance is 75 mL/min, then 75% of the calculated methotrexate dose is given.r
Hepatic impairment
Hepatic dysfunction
Mild No dose modifications necessary
Moderate No dose modifications necessary
Severe Reduce methotrexate by 25%
Mucositis, stomatitis and diarrhoea
Grade 3 or Grade 4 Diarrhoea and ulcerative stomatitis require interruption of therapy otherwise haemorrhagic enteritis and death from intestinal perforation may occur: reduce methotrexate by 25%
Pulmonary impairment
Carmustine should be administered with caution in patients with a baseline less than 70% of predicted FVC or DLCO or those who have had prior thoracic radiotherapy.

References & Disclaimer

Carmustine
  Interaction Clinical management
Cimetidine Increased toxicity of carmustine (esp. myelosuppression) due to reduced clearance Avoid combination
Melphalan, bleomycin, cyclophosphamide Reduced threshold for carmustine induced pulmonary toxicity Monitor closely for pulmonary toxicity (esp. if cumulative dose of carmustine exceeds 475 mg/m2)
Phenytoin Increased risk of seizure due to decreased phenytoin serum levels Monitor phenytoin serum levels and seizure frequency closely, adjust dosage accordingly
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
Teniposide
  Interaction Clinical management
Anticonvulsants (e.g. phenytoin, phenobarbitone) Reduced efficacy of teniposide possible due to increased clearance Avoid combination or monitor for decreased clinical response to teniposide. Consider increasing the dose of teniposide
Prednisolone
  Interaction Clinical management
Antidiabetic agents (e.g. insulin, glibenclamide, glicazide, metformin, pioglitazone, etc) The efficacy of antidiabetic agents may be decreased Use with caution and monitor blood glucose
Azole antifungals (e.g. fluconazole, itraconazole, ketoconazole, posaconazole) Increased toxicity of prednisolone possible due to reduced clearance Avoid combination or monitor for prednisolone toxicity
Oestrogens (e.g. oral contraceptives) Increased toxicity of prednisolone possible due to reduced clearance Avoid combination or monitor for prednisolone toxicity. Dose reduction of prednisolone may be required
Ritonavir Increased toxicity of prednisolone possible due to reduced clearance Avoid combination or monitor for prednisolone toxicity
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

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 CVC.

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

Pre treatment medication

Verify antiemetics taken or administer as prescribed.

Prednisolone

  • administer orally ONCE a day on days 1 to 5
  • to be taken in the morning with or immediately after food

Note: if a dose is forgotten or vomited, contact treating team.

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)

Methotrexate:
  • administer via IV infusion over 3 hours
  • the starting time of the methotrexate infusion must be documented as the calcium folinate (leucovorin) rescue is to commence exactly 24 hours after the start of the methotrexate and continue until the methotrexate level is less than 0.05  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 0.05 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 0.05 micromol/L

Note: Start calcium folinate (leucovorin) rescue 24 hours after commencement of methotrexate infusion and repeat every 6 hours until methotrexate level is less than 0.05 micromol/L.

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

Days 2 and 3

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.

Note: A large volume of intravenous fluid may be 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).

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

Hydration if prescribed

Pre treatment medication

Verify antiemetics taken or administer as prescribed.

Prednisolone

  • administer orally ONCE a day on days 1 to 5
  • to be taken in the morning with or immediately after food

Note: if a dose is forgotten or vomited, contact treating team.

Prime  IV line(s) with sodium chloride 0.9%.

  • Use non-PVC tubing with teniposide.

Teniposide

Administer teniposide (irritant):
  • via IV infusion over 30 to 60 minutes
  • use non PVC containers and tubing
  • rapid infusion may cause hypotension
  • observe for hypersensitivity
  • flush with ~ 100 mL sodium chloride 0.9%.
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.

Note: Start calcium folinate (leucovorin) rescue 24 hours after commencement of methotrexate infusion and repeat every 6 hours until methotrexate level is less than 0.05 micromol/L.

Calcium Folinate (Leucovorin)

  • administer by IV bolus via a side port of the IV line over 1 to 2 minutes
  • flush with ~ 50mL of sodium chloride 0.9%.

Deaccess CVC.

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

Day 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) with glucose 5%: 

  • Use non-PVC tubing with carmustine.

Access CVC.

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

Pre treatment medication

Verify antiemetics taken or administer as prescribed.

Note: Continue to administer calcium folinate (leucovorin) every 6 hours until methotrexate level is less than 0.05 micromol/L.

Prednisolone

  • administer orally ONCE a day on days 1 to 5
  • to be taken in the morning with or immediately after food

Note: if a dose is forgotten or vomited, contact treating team.

Carmustine 

Administer carmustine (irritant):
  • via IV infusion over 2 hours
    • infusion of less than 2 hours may lead to injection site pain or burning
  • use non PVC containers and tubing
  • protect from light
  • flush with ~100 mL of  glucose 5%
  • the alcohol diluent may cause a reaction; characterised by agitation, facial flushing and epiphora
  • if reaction occurs, slow the infusion rate and ensure patient is reviewed by a medical officer
  • hyperpigmentation may occur along the veins closest to the injection site. 

Deaccess CVC.

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

Day 5

Prednisolone

  • administer orally ONCE a day on days 1 to 5
  • to be taken in the morning with or immediately after food

Note: if a dose is forgotten or vomited, contact treating team.

Filgrastim

  • administer filgrastim by subcutaneous injection on day 5 once daily and continue until neutrophil recovery

Day 15

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 CVC.

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

Pre treatment medication

Verify antiemetics 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)

Methotrexate:
  • administer via IV infusion over 3 hours
  • the starting time of the methotrexate infusion must be documented as the calcium folinate (leucovorin) rescue is to commence exactly 24 hours after the start of the methotrexate and continue until the methotrexate level is less than 0.05  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 0.05 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 0.05 micromol/L

Note: Start calcium folinate (leucovorin) rescue 24 hours after commencement of methotrexate infusion and repeat every 6 hours until methotrexate level is less than 0.05 micromol/L.

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

Day 16

Note: A large volume of intravenous fluid may be 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).

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

Hydration if prescribed

Note: Start calcium folinate (leucovorin) rescue 24 hours after commencement of methotrexate infusion and repeat every 6 hours until methotrexate level is less than 0.05 micromol/L.

Calcium Folinate (Leucovorin)

  • administer by IV bolus via a side port of the IV line over 1 to 2 minutes
  • flush with ~ 50mL of sodium chloride 0.9%.

Filgrastim

  • administer filgrastim by subcutaneous injection on day 16 once daily and continue until neutrophil recovery

Deaccess CVC.

Discharge information

Antiemetics
  • Antiemetics as prescribed.
Growth factor support
  • Arrangements for administration if prescribed.
Prophylaxis medications
  • Prophylaxis medications (if prescribed) i.e. tumour lysis prophylaxis, PJP prophylaxis, antifungals, antivirals.
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)
Hypersensitivity reaction

Anaphylaxis and infusion related reactions can occur with this treatment.

Read more about hypersensitivity reaction 
Nausea and vomiting

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

Read more about taste and smell changes
Headache
Bone pain

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

Early (onset days to weeks)
Fluid retention and oedema

An excess amount of fluid around the cells, tissues or serous cavities of the body, leading to swelling.
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.
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
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
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
Anorexia

Loss of appetite accompanied by decreased food intake.

Read more about anorexia
Fatigue

Read more about fatigue
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

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

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
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) 
Pulmonary toxicity

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

Read more about pulmonary toxicity associated with antineoplastic drugs

A search of the literature did not find strong evidence to support the use of MBVP in the treatment of PCNSL. 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 phase II study by Poortmans et al.r

Up to the early 1990s whole-brain radiotherapy (WBRT) was the standard treatment for patients with primary central nervous system lymphoma (PCNSL). However, since then many studies have been published on the efficacy of high dose Methotrexate (HD-MTX)-based chemotherapy. Despite the absence of phase III data, sufficient phase II data have been accumulated to allow consensus on the improved efficacy of sequential chemo- and radiotherapy over radiotherapy alone.rrrr

The evidence supporting this protocol is provided by a prospective phase II trial of the European Organization for Research and Treatment of Cancer (EORTC) involving 52 patients. The purpose of the trial was to confirm the feasibility and estimate the efficacy of methotrexate (MTX), teniposide, carmustine and methylprednisolone (MBVP) chemotherapy combined with radiotherapy (RT) for patients with non-AIDS-related primary CNS lymphoma (PCNSL) treated in a multicentre setting.r

Between October 1997 and February 2002, 52 patients were registered to receive two cycles of methotrexate (MTX), teniposide, carmustine and methylprednisolone (MBVP) every 28 days followed by consolidating RT.r

The primary end point was response rate and safety of this chemotherapy regimen. Secondary end points were duration of response, progression-free survival, overall survival, improvement of cognitive functions, and quality of life.r

The MBVP regimen followed by RT has a high response rate and an acceptable toxicity.r

Source Study & Year Published Supports Use Is the dose and regimen consistent with the protocol? Comments
Phase II trials Poortmans et al 2003r Yes Yes
N/A N/A N/A
Case series N/A N/A N/A
Observational studies N/A N/A N/A
Guidelines Date published/revised Supports Use Is the dose and regimen consistent with the protocol? Comments
NCCN N/A N/A N/A
BCCA N/A N/A N/A
CCO N/A N/A N/A

Efficacy

After a median follow up of 27 months, the overall response rate was 81%.r

© Journal of Clinical Oncology

Toxicity

Grade 3 and 4 haematologic toxicity was observed in 78% of patients for WBC count only, 24% of patients for platelets and in 14% of patients for anaemia. Grade 3 and 4 non-haematologic toxicity was limited and included a grade 4 infection in two patients and a grade 3 infection in six patients, neurologic toxicity in six patients, a possible treatment-induced depression in one patient, stomatitis in four patients (one grade 4), genitourinary toxicity in three patients (one grade 4), thromboembolic complications in four patients (one grade 4), liver toxicity in two patients (one grade 4), allergic reactions (including hypotension) in two patients, and skin toxicity in one patient. The acute chemotherapy-induced toxicity was mainly leukocytopenia which caused death in 5 patients despite hospitalization.r

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Version 3

Date Summary of changes
11/10/2013 Presented at Haematology reference committee meeting (new Protocol).
02/12/2013 Published on eviQ review in 2 years.
18/08/2014 Added link to ALLG, ANZCTR and Lymphoma Australia website with statement 'Patients with lymphoma should be considered for inclusion into clinical trials'.
09/09/2014 The default infusion fluid for carmustine was changed from 'sodium chloride 0.9% in 250 mL' to 'glucose 5% in 500 mL' as per eviQ standard. Sodium chloride 0.9% may be used as an alternative infusion fluid.
  Removed
  • for patients who can not tolerate methotrexate in combination with cytarabine due to toxicities, from the indications.
11/09/2015 Reviewed at RCM, no changes. Review in 2 years. Updated drug costs.
03/06/2016 Changed leucovorin rescue to 24 hours post MTX from 36 hours post.

31/05/2017

Transferred to new eviQ website. Version number change to V.3.
25/05/2018

Reviewed by Haematology Reference Committee:

  • Treatment schedule: teniposide discontinued. Note added about replacement of teniposide with etoposide as per the Haematology Reference Committee consensus.
  • Review in 2 years.
18/10/2018 Teniposide drug status changed and flag added to the top of the protocol to reflect global production cessation. 
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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The currency of this information is guaranteed only up until the date of printing, for any updates please check:

https://www.eviq.org.au/p/1566

22 Jul 2019