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Primary CNS lymphoma (PCNSL) MATRix (methotrexate cytarabine thiotepa and rituximab)

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; refer to the evidence section of this protocol for more information.

The anticancer drug(s) in this protocol may have been included in the ADDIKD guideline. Dose recommendations in kidney dysfunction have yet to be updated to align with the ADDIKD guideline. Recommendations will be updated once the individual protocol has been evaluated by the reference committee. For further information refer to the ADDIKD guideline. To assist with calculations, use the eviQ Estimated Glomerular Filtration Rate (eGFR) calculator.

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Cycle 1 to 4

Drug Dose Route Day
Rituximab 375 mg/m2 IV infusion -5 and 0
Methotrexate 500 mg/m2 IV infusion 1
Methotrexate 3,000 mg/m2 IV infusion 1
Calcium folinate (Leucovorin) 15 mg/m2 every 6 hours * IV bolus 2
Cytarabine (Ara-C) 2,000 mg/m2 TWICE a day IV infusion 2 and 3
Thiotepa 30 mg/m2 IV infusion 4

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

Frequency:
21 days 
Cycles:
4 
Notes:
  • This is an intensive protocol. It is designed to be given as induction therapy followed by consolidation therapy with either high dose therapy and autologous stem cell transplant or whole brain radiation therapy.
  • A series of 88 ‘real world’ patients (median age 61 years, range 28 to 76 years) from 9 European countries reported at ASH 2017 showed MATRix was feasible and effective for newly diagnosed PCNSL in routine practice however dose modifications were required in 40-54% of patients and there was evidence of a significant first cycle effect with 6 treatment related deaths (5 due to infectious toxicity; 4 in cycle 1 and 1 in cycle 2).  
  • Close monitoring and consideration of dose reductions is strongly recommended, especially during cycle 1, to avoid treatment associated complications.
  • The incidence of neurotoxicity related to the combination of WBRT and high dose methotrexate is significantly higher in patients aged greater than 60 years, withholding WBRT in the primary setting in these patients should be strongly considered.
Drug status:

Rituximab: (PBS authority)

Thiotepa: TGA registered but not PBS listed

Cytarabine and methotrexate are on the PBS general schedule

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 -5 and 0
Paracetamol 1,000 mg (PO) 60 minutes before treatment
Loratadine 10 mg (PO) 60 minutes before treatment
Hydrocortisone 100 mg (IV) 30 minutes before treatment
Rituximab 375 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9%

as per graded administration rate
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
Methotrexate 500 mg/m2 (IV infusion) in 250 mL sodium chloride 0.9% over 15 minutes
Methotrexate 3,000 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 3 hours
Day 2
Calcium folinate (Leucovorin) 15 mg/m2 (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.
Dexamethasone 8 mg (PO) ONCE a day with or after food (or in divided doses).
Cytarabine (Ara-C) 2,000 mg/m2 (IV infusion) TWICE a day in 500 mL sodium chloride 0.9% over 1 hour (every 12 hours)
Day 3
Dexamethasone 8 mg (PO) ONCE a day with or after food (or in divided doses).
Cytarabine (Ara-C) 2,000 mg/m2 (IV infusion) TWICE a day in 500 mL sodium chloride 0.9% over 1 hour (every 12 hours)
Day 4
Dexamethasone 8 mg (PO) ONCE a day with or after food (or in divided doses).
Thiotepa 30 mg/m2 (IV infusion) in 50 mL to 100 mL sodium chloride 0.9% over 30 minutes
Frequency:
21 days 
Cycles:
4 

Cycle 1 to 4

Drug Dose Route Day
Rituximab 375 mg/m2 IV infusion -5 and 0
Methotrexate 500 mg/m2 IV infusion 1
Methotrexate 3,000 mg/m2 IV infusion 1
Calcium folinate (Leucovorin) 15 mg/m2 every 6 hours * IV bolus 2
Cytarabine (Ara-C) 2,000 mg/m2 TWICE a day IV infusion 2 and 3
Thiotepa 30 mg/m2 IV infusion 4

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

Frequency:
21 days 
Cycles:
4 
Notes:
  • This is an intensive protocol. It is designed to be given as induction therapy followed by consolidation therapy with either high dose therapy and autologous stem cell transplant or whole brain radiation therapy.
  • A series of 88 ‘real world’ patients (median age 61 years, range 28 to 76 years) from 9 European countries reported at ASH 2017 showed MATRix was feasible and effective for newly diagnosed PCNSL in routine practice however dose modifications were required in 40-54% of patients and there was evidence of a significant first cycle effect with 6 treatment related deaths (5 due to infectious toxicity; 4 in cycle 1 and 1 in cycle 2).  
  • Close monitoring and consideration of dose reductions is strongly recommended, especially during cycle 1, to avoid treatment associated complications.
  • The incidence of neurotoxicity related to the combination of WBRT and high dose methotrexate is significantly higher in patients aged greater than 60 years, withholding WBRT in the primary setting in these patients should be strongly considered.
Drug status:

Rituximab: (PBS authority)

Thiotepa: TGA registered but not PBS listed

Cytarabine and methotrexate are on the PBS general schedule

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 -5 and 0
Paracetamol 1,000 mg (PO) 60 minutes before treatment
Loratadine 10 mg (PO) 60 minutes before treatment
Hydrocortisone 100 mg (IV) 30 minutes before treatment
Rituximab 375 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9%

as per graded administration rate
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
Methotrexate 500 mg/m2 (IV infusion) in 250 mL sodium chloride 0.9% over 15 minutes
Methotrexate 3,000 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 3 hours
Day 2
Calcium folinate (Leucovorin) 15 mg/m2 (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.
Dexamethasone 8 mg (PO) ONCE a day with or after food (or in divided doses).
Cytarabine (Ara-C) 2,000 mg/m2 (IV infusion) TWICE a day in 500 mL sodium chloride 0.9% over 1 hour (every 12 hours)
Day 3
Dexamethasone 8 mg (PO) ONCE a day with or after food (or in divided doses).
Cytarabine (Ara-C) 2,000 mg/m2 (IV infusion) TWICE a day in 500 mL sodium chloride 0.9% over 1 hour (every 12 hours)
Day 4
Dexamethasone 8 mg (PO) ONCE a day with or after food (or in divided doses).
Thiotepa 30 mg/m2 (IV infusion) in 50 mL to 100 mL sodium chloride 0.9% over 30 minutes
Frequency:
21 days 
Cycles:
4 

Indication:

  • Newly diagnosed primary CNS lymphoma (PCNSL) in patients up to 70 years or age with good ECOG status

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 rituximab.
Premedication

The product information states that premedication is required for this treatment.

Please refer to the treatment schedule for suggested premedication regimen. This may be substituted to reflect institutional policy.
Emetogenicity HIGH

Suggested default antiemetics have been added to the treatment schedule, and may be substituted to reflect institutional policy.

Ensure that patients also have sufficient antiemetics for breakthrough emesis:

Metoclopramide 10 mg three times a day when necessary (maximum of 30 mg/24 hours, up to 5 days) OR

Prochlorperazine 10 mg PO every 6 hours when necessary.

Read more about preventing anti-cancer therapy induced nausea and vomiting
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.
Cytarabine induced neurotoxicity

This may occur in patients treated with high dose cytarabine. Assess cerebellar function prior to each cytarabine dose.

Read more about neurotoxicity associated with high dose cytarabine and access the cytarabine cerebellar neurotoxicity assessment chart  
Ocular toxicities

Administer corticosteroid eye drops to minimise corneal toxicity from high dose cytarabine. Commence on the day of first dose of cytarabine and continue for at least 72 hours after completion of final cytarabine dose.

Read more about ocular toxicities associated with high dose cytarabine
Cytarabine syndrome

Treatment with cytarabine may cause a "cytarabine syndrome" characterised by flu-like symptoms, skin rash and occasionally chest pain.
Cutaneous effects of thiotepa

Thiotepa is partly excreted though the skin (as sweat) and therefore thiotepa associated skin toxicity is thought to be caused by concentration of thiotepa in the skin. It is therefore important to protect both the patient and health professionals from exposure.

Read more about the cutaneous effects of thiotepa
Pneumocystis jirovecii pneumonia (PJP) prophylaxis

PJP prophylaxis is recommended.

Myelosuppression may be exacerbated if trimethoprim/sulfamethoxazole is used in combination with methotrexate.

Read about prophylaxis of pneumocystis jirovecii (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 (short or long-acting) is available on the PBS for chemotherapy induced neutropenia depending on clinical indication and/or febrile neutropenia risk.  

Access the PBS website
Biosimilar drug

Read more about biosimilar drugs on the Biosimilar Awareness Initiative page
Blood tests

FBC, EUC, LFTs, LDH 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 are contraindicated in cancer patients receiving immunosuppressive therapy and/or who have poorly controlled malignant disease.

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

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

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

Read more about the 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 anti-cancer regimen (single versus combination therapy versus chemotherapy versus immunotherapy), biology of the cancer (site, size, mutations, metastases), other treatment related side effects, additional co-morbidities, performance status and patient preferences.Suggested dose modifications are based on clinical trial findings, product information, published guidelines and reference committee consensus . The dose reduction applies to each individual dose and not to the total number of days or duration of treatment cycle unless stated otherwise. Non-haematological gradings are based on Common Terminology Criteria for Adverse Events (CTCAE) unless otherwise specified. Renal and hepatic dose modifications have been standardised where possible. For more information see dosing considerations & disclaimer.
The dose recommendations in kidney dysfunction (i.e.renal impairment) displayed may not reflect those in the ADDIKD guideline and have been included for historical reference only. Recommendations will be updated once the individual protocol has been evaluated by the reference committee, with this version of the protocol then being archived. Clinicians are expected to refer to the ADDIKD guideline prior to prescribing in kidney dysfunction.
International Consensus Guideline for Anticancer Drug Dosing in Kidney Dysfunction (ADDIKD).

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

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.
Consider reducing or omitting cytarabine and thiotepa doses in older patients and/or those with co-morbidities.
Haematological toxicity
ANC x 109/L
0.5 to less than 1.5 Delay treatment until recovery.
less than 0.5 Delay treatment until recovery and consider reducing cytarabine* dose by 25% for subsequent cycles
Febrile neutropenia Delay treatment until recovery and consider reducing cytarabine* dose by 25% for subsequent cycles
Platelets x 109/L
25 to less than 90 Delayed treatment until recovery
less than 25 Delay treatment until recovery and consider reducing cytarabine* and thiotepa doses by 25% for subsequent cycles

* Cytarabine dose reduction is the omission of the 4th dose of the drug (i.e. the 2nd dose on day 3)

Renal impairment

Creatinine clearance must be greater than 80 mL/min prior to administration of full dose high dose methotrexate.

It is advised to reduce the methotrexate dose in proportion to the calculated creatinine clearance when this is less than 80 mL/min e.g. if creatinine clearance is 75 mL/min, then 75% of the calculated methotrexate dose is given.r

Methotrexate is contraindicated if CrCL is less than 30 mL/min.

An increased risk of neurotoxicity has been associated with high dose cytarabine when creatinine clearance is less than 60 mL/min.
Hepatic impairment
Hepatic dysfunction
Mild No dose modifications necessary
Moderate No dose modifications necessary
Severe Withhold treatment, consider alternative therapy.
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%

Drug interactions in eviQ protocols are under review and being updated to align with current literature. Further site-wide updates and changes will occur in due course. References & Disclaimer

The drug interactions shown below are not an exhaustive list. For a more comprehensive list and for detailed information on specific drug interactions and clinical management, please refer to the specific drug product information and the following key resources:  

Cytarabine
No specific clinically significant drug-drug interactions
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
Rituximab
  Interaction Clinical management
Antihypertensives Additive hypotensive effect Consider withholding antihypertensive medications 12 hours prior to the rituximab infusion
Thiotepa
  Interaction Clinical management
CYP2B6 inducers (e.g. phenytoin, phenobarbitone, ritonavir etc.) Increased toxicity of thiotepa possible due to increased conversion to its active metabolite (tepa) Avoid combination or monitor for increased toxicity of thiotepa
Drugs metabolised by CYP2B6 (e.g. bupropion, methadone, sertraline, sorafenib etc.) Increased effect/toxicity of these drugs possible due to inhibition of CYP2B6 by thiotepa resulting in reduced clearance Avoid combination or monitor for increased effect/toxicity of interacting drugs
Neuromuscular blockers (suxamethonium, pancuronium) Prolonged apnoea due to inhibition of pseudocholinesterase by thiotepa Caution advised if general anaesthesia required during or soon after treatment with thiotepa
NK-1 antagonist e.g. aprepitant, fosaprepitant, netupitant
  Interaction Clinical management
Dexamethasone Increased effects/toxicity of dexamethasone due to inhibition of its metabolism via CYP3A4

Reduce dose of antiemetic dexamethasone by approximately 50% when adding a NK-1 antagonist. For protocols that already recommend a NK-1 antagonist, the dose reduction of antiemetic dexamethasone has already been taken into account.

If dexamethasone is part of the chemotherapy protocol, dose reduction as per the product information is not routinely recommended in clinical practice and no additional dexamethasone is required for antiemetic cover. 
Warfarin

Reduced anticoagulant efficacy of warfarin due to increased clearance (aprepitant induces CYP2C9). *Note interaction only applicable to aprepitant/ fosaprepitant

INR should be monitored in the 2 week period, particularly at 7 to 10 days following the administration of aprepitant/ fosaprepitant
Combined oral contraceptive Reduced contraceptive efficacy due to increased clearance. *Note interaction only applicable to aprepitant/ fosaprepitant Alternative non-hormonal methods should be used during and for 1 month after stopping aprepitant/ fosaprepitant
CYP3A4 inducers (e.g. carbamazepine, phenytoin, phenobarbitone, rifampicin, St John’s wort etc.) Reduced efficacy of NK-1 antagonist possible due to increased clearance Avoid combination or monitor for decreased antiemetic effect. Consider using an alternative antiemetic regimen
CYP3A4 inhibitors (e.g. azole antifungals, clarithromycin, erythromycin, grapefruit juice, ritonavir etc.) Increased toxicity of NK-1 antagonist possible due to reduced clearance Avoid combination or monitor for increased adverse effects of NK-1 antagonist (e.g. headache, hiccups, constipation)
Drugs metabolised by CYP3A4 (e.g. etoposide, imatinib, irinotecan, midazolam, paclitaxel, vinblastine, vincristine etc.) Increased effects/toxicity of these drugs possible due to inhibition of CYP3A4 by NK-1 antagonist Avoid combination or monitor for increased toxicity especially with orally administered drugs
General
  Interaction Clinical management
Warfarin Anti-cancer drugs may alter the anticoagulant effect of warfarin. Monitor INR regularly and adjust warfarin dosage as appropriate; consider alternative anticoagulant.
Direct oral anticoagulants (DOACs) e.g. apixaban, rivaroxaban, dabigatran

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

DOAC and anti-cancer drug levels may both be altered, possibly leading to loss of efficacy or toxicity (i.e. increased bleeding).

Apixaban: avoid concurrent use with strong CYP3A4 and P‑gp inhibitors. If treating VTE, avoid use with strong CYP3A4 and P‑gp inducers. 

Rivaroxaban: avoid concurrent use with strong CYP3A4 and P‑gp  inhibitors.

Dabigatran: avoid combination with strong P‑gp inducers and inhibitors.

If concurrent use is unavoidable, monitor closely for efficacy/toxicity of both drugs.
Digoxin Anti-cancer drugs can damage the lining of the intestine; affecting the absorption of digoxin. Monitor digoxin serum levels; adjust digoxin dosage as appropriate.
Antiepileptics Both altered antiepileptic and anti-cancer drug levels may occur, possibly leading to loss of efficacy or toxicity. Where concurrent use of an enzyme-inducing antiepileptic cannot be avoided, monitor antiepileptic serum levels for toxicity, as well as seizure frequency for efficacy; adjust dosage as appropriate.
Also monitor closely for efficacy of the anti-cancer therapy.
Antiplatelet agents and NSAIDs Increased risk of bleeding due to treatment related thrombocytopenia. Avoid or minimise combination.
If combination deemed essential, (e.g. low dose aspirin for ischaemic heart disease) monitor for signs of bleeding.
Serotonergic drugs, including selective serotonin reuptake inhibitors (SSRIs e.g. paroxetine) and serotonin noradrenaline reuptake inhibitors (SNRIs e.g. venlafaxine) Increased risk of serotonin syndrome with concurrent use of 5-HT3 receptor antagonists (e.g. palonosetron, ondansetron, granisetron, tropisetron, dolasetron, etc.) Avoid combination.
If combination is clinically warranted, monitor for signs and symptoms of serotonin syndrome (e.g. confusion, agitation, tachycardia, hyperreflexia).
For more information link to TGA Medicines Safety Update
Vaccines Diminished response to vaccines and increased risk of infection with live vaccines. Live vaccines (e.g. BCG, MMR, zoster and varicella) are contraindicated in patients on immunosuppressive therapy. Use with caution in patients on non-immunosuppressive therapy.
For more information; refer to the recommended schedule of vaccination for cancer patients, as outlined in the Australian Immunisation Handbook

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

Day -5 and 0

Approximate treatment time: 4 to 6 hours (initial); 3 to 4 hours (subsequent) 

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.

Prime IV line(s).

Access CVAD.

Pre treatment medication

Verify antiemetics taken or administer as prescribed.

Rituximab

Prior to administration:
  • check baseline observations
  • check for previous adverse events during previous infusions
  • verify premedication has been taken. If not, administer 30 to 60 minutes prior to rituximab administration:
    • paracetamol 1000 mg orally AND
    • loratadine 10 mg orally (or similar antihistamine)
    • a steroid may also be included as a premed according to local guidelines
Initial infusion:
  • commence rituximab infusion at 50 mg/hr for 30 minutes
  • repeat observations prior to each rate increase
  • increase rate by 50 mg/hr every 30 minutes, up to a maximum of 400 mg/hr if observations are stable
  • flush with ~ 100 mL of sodium chloride 0.9%

If an infusion reaction occurs, temporarily discontinue the infusion and notify medical officer

  • when symptoms have completely resolved, recommence the infusion at half the rate prior to the reaction
  • for severe reactions stop infusion and manage as per emergency

Transient hypotension may occur. Consider withholding antihypertensive medication for 12 hours before and during infusion.

Subsequent infusions:

If an adverse event was experienced with initial infusion recommence infusion at the same rate as initial infusion

  • commence rituximab infusion at 100 mg/hr
  • repeat observations prior to each rate increase
  • increase rate by 100 mg/hr increments every 30 minutes to a maximum of 400 mg/hr if observations are stable
  • flush with ~ 100 mL of sodium chloride 0.9%

If an infusion reaction occurs, temporarily discontinue the infusion and notify medical officer

  • when symptoms have resolved, recommence the infusion at half the rate prior to the reaction
  • for severe reactions stop infusion and manage as per emergency

Read more about rapid infusion rituximab

Deaccess CVAD.

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 CVAD.

  • 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)

First dose of methotrexate:

Administer via IV infusion over 15 minutes

Note: 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.

Second dose of methotrexate (to commence immediately after the first dose):
  • administer via IV infusion over 3 hours
  • 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.

  • continue daily weight
  • continue to monitor pH on all urine output
  • strict fluid balance input and output
  • continue corticosteroid eye drops as prescribed

Pre treatment medication

Verify antiemetics taken or administer as 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%.

Cytarabine 

Prior to administration:

Ensure corticosteroid eye drops have been administered before starting cytarabine.

Verify that cytarabine neurological assessment has been performed prior to administration of cytarabine:

  • if the patient scores 0 then administer cytarabine as charted
  • if the patient scores 1 or above, do not administer the cytarabine and immediately notify medical officer.
Administer cytarabine:
  • via IV infusion over 60 minutes:
  • flush with ~50 mL of sodium chloride 0.9%.
Administer second dose of cytarabine 12 hours after first dose.

Continue corticosteroid eye drops for 72 hours after completion of the last dose of cytarabine.

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

Day 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.

  • continue daily weight
  • continue to monitor pH on all urine output
  • strict fluid balance input and output
  • continue corticosteroid eye drops as prescribed

Pre treatment medication

Verify antiemetics taken or administer as prescribed.

Thiotepa

Deaccess CVAD.

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

Discharge information

Antiemetics
  • Antiemetics as prescribed.
Corticosteroid eye drops
  • Continue corticosteroid eye drops for at least 72 hours after completion of final cytarabine dose.
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)
Nausea and vomiting

Read more about prevention of treatment induced nausea and vomiting
Cytarabine (Ara-C) syndrome

Flu-like symptoms including fever, myalgia and malaise can occur 6 to 12 hours after cytarabine administration. Symptoms generally resolve within 24 hours of completing therapy.
Taste and smell alteration

Read more about taste and smell changes
Neurotoxicity

High dose cytarabine has been associated with acute cerebellar syndrome and diffuse cerebral dysfunction.

Read more about neurotoxicity associated with high dose cytarabine
Headache
Ocular toxicities

Reversible corneal toxicity (keratitis), haemorrhagic conjunctivitis, vision loss and other ocular side effects can occur with high dose cytarabine.  Corticosteroid eye drops must be administered concurrently with treatment. 

Read more about ocular toxicities associated with cytarabine

Early (onset days to weeks)
Neutropenia

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

Read more about immediate management of neutropenic fever
Hepatotoxicity

Anti-cancer drugs 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.
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, radiation therapy to the head, neck or oesophagus, and high dose chemotherapy followed by a blood and marrow transplant (BMT).

Read more about oral mucositis
Anorexia

Loss of appetite accompanied by decreased food intake.

Read more about anorexia
Fatigue

Read more about fatigue
Diarrhoea

Read more about treatment induced diarrhoea
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.
Palmar-plantar erythrodysaesthesia (PPE) - hand-foot syndrome (HFS)

Bilateral erythema, tenderness, pain, swelling, tingling, numbness, pruritus, dry rash, or moist desquamation and ulceration of the palms and soles. It is also known as hand-foot syndrome (HFS). Symptoms appear to be dose dependent and palms are affected more than soles.

Read more about hand-foot syndrome associated with chemotherapy
Skin rash

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

Read more about skin rash
Dizziness

Feeling faint or lightheaded, weak or unsteady. Advise patients to stand up slowly from sitting down or lying down positions and increase fluid intake if dehydrated.
Cutaneous effects

Rash, erythema, pruritus and/or hyperpigmentation can occur during treatment with thiotepa. As thiotepa is partially excreted through the skin, it is important to protect both the patient and health professionals from exposure.

Read more about the cutaneous effects of thiotepa

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 anti-cancer drugs
Reduced libido and sexual dysfunction

Lowered sexual desire as well as any physical or psychological problem that interferes with the ability to have and/or enjoy sex. 

The evidence supporting this protocol is provided by a phase 2 multicentre international randomised trial (IELSG32) involving 227 patients who were randomised to one of three regimens; methotrexate/cytarabine, methotrexate/cytarabine/rituximab or methotrexate/cytarabine/thiotepa/rituximab (MATRix) in patients aged 18 to 70 years newly diagnosed primary CNS lymphoma.r

Between Feb 19, 2010 and Aug 27, 2014 75 patients were randomised to receive 4 cycles of methotrexate 3.5 g/m2 on day 1 plus cytarabine 2 g/m2 twice daily on days 2 and 3 (group A), 74 patients were randomised to receive 4 cycles of rituximab 375 mg/m2 on days -5 and 0 plus methotrexate 3.5 g/m2 on day 1 plus cytarabine 2 g/m2 twice daily on days 2 and 3 (group B) and 78 patients were randomised to receive methotrexate 3.5 g/m2 on day 1 plus cytarabine 2 g/m2 twice daily on days 2 and 3 plus thiotepa 30 mg/m2 on day 4 (group C; MATRix). The three groups repeated treatment every 3 weeks. Autologous peripheral blood stem cells were collected after the second chemotherapy course in patients without progressive disease. Patients with responsive or stable disease after the first stage were then randomly allocated between whole-brain radiation therapy and autologous stem cell transplantation.r

Consolidation WBRT (photons of 4–10 MeV; five fractions per week; fraction size 180 cGy) was started within 4 weeks from the last induction course. Whole-brain was irradiated by two opposite lateral fields including the first two cervical vertebrae and the posterior two-thirds of the orbits with 36 Gy, with the addition of a 9 Gy tumour-bed boost in patients in partial response; orbits were shielded after 30 Gy (after 36 Gy in the case of intraocular disease). The conditioning regimen of high-dose chemotherapy supported by ASCT consisted of carmustine 400 mg/m2 on day –6, and thiotepa 5 mg/kg every 12 hours on days –5 and –4 followed by re-infusion of autologous peripheral blood stem cells .

The primary end point of the first randomisation was centrally assessed complete remission after induction chemo(immuno)therapy and secondary end points were toxicity, overall survival, relapse rates and neurotoxicity. The primary endpoint of the second randomisation (to whole brain radiation therapy or autologous stem cell transplantation) was the 2 year progression-free survival.

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 trials by Ferreri et al.rr

Source Study & Year Published Supports Use Is the dose and regimen consistent with the protocol? Comments

Phase II trials

Ferreri et al. 2016r
Yes

Yes

-

Ferreri et al. 2017r
Yes

Yes

-

Guidelines

Date published/revised

Supports Use

Is the dose and regimen consistent with the protocol?

Comments

NCCN

N/A

N/A

-

-

BCCA

N/A

N/A

-

-
CCO October 2017 Yes Yes -

Efficacy

At median follow-up of 30 months patients treated with MATRix had a complete remission rate of 49% (95% CI 38–60), compared with 23% (14–31) of those treated with methotrexate–cytarabine alone (hazard ratio 0•46, 95% CI 0•28–0•74) and 30% (21–42) of those treated with methotrexate–cytarabine plus rituximab (0•61, 0•40–0•94). Furthermore, 96 (44%) of 219 patients remain progression free: 22 (29%) of 75 in those treated with methotrexate–cytarabine alone, 30 (43%) of 69 with addition of rituximab, and 44 (59%) of 75 with addition of rituximab and thiotepa.r

According to the treatment group (figure 1A), the 2-year progression-free survival was 36% (95% CI 31–41) for group A, 46% (40–52) for group B, and 61% (55–67) for group C (MATRix). Overall, 113 (52%) of 219 patients were still alive at a median follow-up of 30 months 27 (36%) of 75 in group A, 36 (52%) of 69 in group B, and 50 (67%) of 75 in group C (MATRix).r

The 2-year overall survival rate was 42% (95% CI 36–48) in group A, 56% (50–62) in group B, and 69% (64–74) in group C (MATRix) (figure 1B).r

Figure 1: Survival outcomes
(A) Progression-free survival and (B) overall survival curves of registered
patients divided according to induction treatment group. Tick marks represent
censored patients.

© Lancet 2016

Quality of life data was not reported in the original publication of this study.

Toxicity

Table 1. Comparison of treatment toxicity in the three groups.

© Lancet 2016

Grade 4 haematological toxicity was more common in patients in group C (MATRix) than in the other two groups, but infective complications were similar in the three groups (table 1). Grade 4 non-haematological toxicities were rare. 13 (6%) of 219 patients died of toxicity during induction (7 patients in group A, 3 in group B and 3 in group C) (table 1).r

Eight patients later died while off therapy and without evidence of disease after 10–14 months of follow-up; the causes of death were infections (two in group B, two in group C), neurological decline (one in group A, one in group B), sudden death (one in group B), and an unknown cause (one in group C).r

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Version 3

Date Summary of changes
06/08/2020 Dose modifications updated to be inline across PCNSL protocols. Version number increased to v.3.     
08/02/2022 PJP prophylaxis clinical information block updated.

Version 2

Date Summary of changes
09/03/2020 Biosimilar rituximab added to clinical information. Version number changed to v.2     
26/03/2020 Dose modification section updated. 

Version 1

Date Summary of changes
24/11/2017 New protocol taken to Haematology Reference Committee meeting.
22/01/2018 New protocol published on eviQ
25/10/2018 Link added to high dose methotrexate-induced toxicity document in clinical information.
10/10/2019 Clinical information updated with PBS expanded indications for G-CSF. 

The information contained in this protocol is based on the highest level of available evidence and consensus of the eviQ reference committee regarding their views of currently accepted approaches to treatment. Any clinician (medical oncologist, haematologist, radiation oncologist, medical physicist, radiation therapist, pharmacist or nurse) seeking to apply or consult this protocol is expected to use independent clinical judgement in the context of individual clinical circumstances to determine any patient's care or treatment. While eviQ endeavours to link to reliable sources that provide accurate information, eviQ and the Cancer Institute NSW do not endorse or accept responsibility for the accuracy, currency, reliability or correctness of the content of linked external information sources. Use is subject to eviQ’s disclaimer available at www.eviQ.org.au

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https://www.eviq.org.au/p/3374

31 Mar 2023