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Primary CNS lymphoma (PCNSL) consolidation high dose cytarabine - part 2

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 and 2

Drug Dose Route Day
Cytarabine (Ara-C) 3,000 mg/m2 IV infusion 1 and 2
Frequency:
28 days 
Cycles:
2 (commence next cycle at 28 days or after bone marrow recovery).

Consolidation is commenced after the completion of 'Primary CNS Lymphoma (PCNSL) R-MPV - Part 1' and whole brain radiation therapy (WBRT).1
Notes:
  • Prior to radiation therapy, all patients received 5 cycles of R-MPV. No further cycles of R-MPV were given if patients achieved CR; and if patients achieved PR after 5 cycles, 2 further cycles of R-MPV were given, ie. cycle 6: R-MV (no procarbazine) and cycle 7: R-MPV.r
  • The incidence of neurotoxicity related to the combination of WBRT and high dose methotrexate is significantly higher in patients older than 60 years of age; withholding WBRT in the primary setting in these patients should be strongly considered.
Drug status:

Cytarabine is available on the PBS general schedule

Cost:
~ $1,400 per cycle "How this cost is calculated"

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

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

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

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

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

One off loading doses and ongoing maintenance doses are not included in protocol cost calculations.

The cost displayed is the actual drug cost and does not necessarily reflect the cost incurred by the patient as many anti-cancer drugs are reimbursed on the PBS.

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

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

Cycle 1 and 2

Day 1
Dexamethasone 8 mg (PO) 60 minutes before chemotherapy
Palonosetron 0.25 mg (IV bolus) 30 minutes before chemotherapy
Cytarabine (Ara-C) 3,000 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 3 hours
Day 2
Dexamethasone 8 mg (PO) 60 minutes before chemotherapy
Cytarabine (Ara-C) 3,000 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 3 hours
Day 3 and 4
Dexamethasone 8 mg (PO) ONCE a day (or in divided doses) with or after food. Note: dexamethasone doses on day 3 and 4 may not be required and may be reduced or omitted at the clinicians discretion. *

* Link to ID 7 Prevention of chemotherapy induced nausea and vomiting

Frequency:
28 days 
Cycles:
2 (commence next cycle at 28 days or after bone marrow recovery).

Consolidation is commenced after the completion of 'Primary CNS Lymphoma (PCNSL) R-MPV - Part 1' and whole brain radiation therapy (WBRT).1

Cycle 1 and 2

Drug Dose Route Day
Cytarabine (Ara-C) 3,000 mg/m2 IV infusion 1 and 2
Frequency:
28 days 
Cycles:
2 (commence next cycle at 28 days or after bone marrow recovery).

Consolidation is commenced after the completion of 'Primary CNS Lymphoma (PCNSL) R-MPV - Part 1' and whole brain radiation therapy (WBRT).1
Notes:
  • Prior to radiation therapy, all patients received 5 cycles of R-MPV. No further cycles of R-MPV were given if patients achieved CR; and if patients achieved PR after 5 cycles, 2 further cycles of R-MPV were given, ie. cycle 6: R-MV (no procarbazine) and cycle 7: R-MPV.r
  • The incidence of neurotoxicity related to the combination of WBRT and high dose methotrexate is significantly higher in patients older than 60 years of age; withholding WBRT in the primary setting in these patients should be strongly considered.
Drug status:

Cytarabine is available on the PBS general schedule

Cost:
~ $1,400 per cycle "How this cost is calculated"

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

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

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

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

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

One off loading doses and ongoing maintenance doses are not included in protocol cost calculations.

The cost displayed is the actual drug cost and does not necessarily reflect the cost incurred by the patient as many anti-cancer drugs are reimbursed on the PBS.

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

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

Cycle 1 and 2

Day 1
Dexamethasone 8 mg (PO) 60 minutes before chemotherapy
Palonosetron 0.25 mg (IV bolus) 30 minutes before chemotherapy
Cytarabine (Ara-C) 3,000 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 3 hours
Day 2
Dexamethasone 8 mg (PO) 60 minutes before chemotherapy
Cytarabine (Ara-C) 3,000 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 3 hours
Day 3 and 4
Dexamethasone 8 mg (PO) ONCE a day (or in divided doses) with or after food. Note: dexamethasone doses on day 3 and 4 may not be required and may be reduced or omitted at the clinicians discretion. *

* Link to ID 7 Prevention of chemotherapy induced nausea and vomiting

Frequency:
28 days 
Cycles:
2 (commence next cycle at 28 days or after bone marrow recovery).

Consolidation is commenced after the completion of 'Primary CNS Lymphoma (PCNSL) R-MPV - Part 1' and whole brain radiation therapy (WBRT).1
  • Newly diagnosed 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 required

IV cannula (IVC) or central venous access device (CVAD) is required to administer this treatment.

Read more about central venous access device line selection
Emetogenicity MODERATE

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
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.
Tumour lysis risk

Assess patient for risk of developing tumour lysis syndrome.

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

­

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

­

Read more about antiviral prophylaxis drugs and doses
Antifungal prophylaxis ­

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
Blood tests

FBC, EUC, LFTs and LDH at baseline, and prior to each cycle and as clinically indicated.
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).
Haematological toxicity
G-CSF is recommended and should be given at physician's discretion if neutrophils are less than 1 x 109/L ANC. Treatment delay is not recommended. 
Renal and hepatic impairment
Consideration should be given to reducing doses of cytarabine in older patients and those with reduced renal or hepatic function. Elevations in liver function tests occur with both standard and high dose cytarabine. Significant liver function abnormalities may require discontinuation or a dose reduction. However doses of cytarabine less than 2 g/m2 r may be associated with inferior outcomes.

An increased risk of neurotoxicty has been associated with high dose cytarabine when creatinine clearance is less than 60 mL/min.

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
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.

Days 1 and 2

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).

Insert IV cannula or access TIVAD or CVAD.

  • baseline weight

Hydration if prescribed

Pre treatment medication

Verify antiemetics taken or administer as prescribed.

Commence corticosteroid eye drops prior to the first dose of cytarabine.

Cytarabine 

Prior to administration:

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 3 hours
  • flush with ~50 mL of sodium chloride 0.9%.

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

Remove IV cannula and/or deaccess TIVAD or 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.
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)
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.
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
Taste and smell alteration

Read more about taste and smell changes
Nausea and vomiting

Read more about prevention of treatment induced nausea and vomiting
Neurotoxicity

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

Read more about neurotoxicity associated with high dose 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
Thrombocytopenia

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

Read more about thrombocytopenia
Fatigue

Read more about fatigue
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
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
Diarrhoea

Read more about treatment induced diarrhoea
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

Late (onset weeks to months)
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) 
Anaemia

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

Read more about anaemia

Primary central nervous system lymphoma (PCNSL) represents an aggressive subset of lymphoma exclusively affecting the CNS (brain parenchyma, spinal cord, eyes, cranial nerves and/or meninges).r Diffuse large B-cell lymphoma (DLBCL) comprises the majority (90%) of PCNSL.r Landmark prospective randomised clinical trials have led to the accepted standard of high-dose methotrexate chemotherapy, and later the addition of high-dose cytarabine chemotherapy for the management of PCNSL.rrr

Rituximab has been shown to reduce CNS relapse from systemic DLBCL,r and evidence is now accumulating for a benefit with the addition of rituximab to standard methotrexate-containing treatment regimens.rrrrr The evidence supporting this protocol is provided by a phase II multicentre international trial involving 52 patients with primary CNS B-cell lymphoma receiving rituximab, methotrexate, procarbazine and vincristine, followed by consolidation reduced-dose whole-brain radiation therapy (rdWBRT) and cytarabine.r

Between October 2002 and February 2009, 52 patients received five 14-day cycles of induction chemotherapy with rituximab, methotrexate, procarbazine, and vincristine (R-MPV)r as follows:

  • day 1, rituximab 500 mg/m2; day 2, methotrexate 3.5 g/m2 (over 2 hours), vincristine 1.4 mg/m2; days 1-7, procarbazine 100 mg/m2/d (odd cycles only).
  • patients who achieved a complete response (CR) after five cycles received rdWBRT (23.40 Gy in 1.8-Gy fractions x 13) 3 - 5 weeks after chemotherapy completion.
  • patients who achieved a partial response (PR) after 5 cycles received another 2 cycles of R-MPV; If CR achieved after 2 further cycles then patients received rdWBRT (23.40 Gy in 1.8-Gy fractions x 13) 3 - 5 weeks after chemotherapy completion. If PR, stable disease (SD) or progression then patients offered WBRT (45 Gy in 25 fractions)
  • following radiation therapy, all patients received two-consolidation high-dose cytarabine cycles (each cycle 28 days) comprising cytarabine 3 g/m2/d on days 1 and 2 of each cycle.

The primary end point was 2 year PFS in patients who received rdWBRT and secondary end points were objective response rate to R-MPV, overall response rate (ORR), overall survival (OS), and neurocognitive outcome.

The R-MPV protocol has a high response rate and acceptable safety profile for the treatment of PCNSL. Similar results have been observed in two retrospective analysis of rituximab in addition with MPV or other combination chemotherapy protocolsrr, whilst a single centre phase-2 study has demonstrated autologous stem cell transplantation as a viable alternative to WBRT. r

R-MPV can  be safely delivered to older patients (i.e. >60 years), including those over 80 years, and it appears to be superior to other therapies (i.e. methotrexate-temozolimide) in this age group.rrOutcomes in older patients have been generally poor (median PFS: 6.5 - 10 months, median OS: 7.9 - 31 months), but this may be reflective of a reduction in the total methotrexate dose in these studies as a recent large multi-centre retrospective analysis has demonstrated that older patients (≥ 65 years) who complete methotrexate-based therapy (with minimal dose reductions) can achieve clinical outcomes similar to younger patients.rrr

Source Study & Year published 

Supports Use

 Is the dose and regimen consistent with the protocol?  Comments 
Phase II trials Shah et al 2007r Yes Yes -
Morris et al 2013r Yes  Yes  -
Omuro et al 2015r Yes Yes. Followed by autologous stem cell transplantation.  -
Retrospective studies  Hattori et al 2017r Yes  No. The dose of rituximab in R-MPV was reduced from 500 mg/m2 to 375 mg/m2 -
Houillier et al 2017r Yes  No. Total number of methotrexate doses was 6.   - 
Guidelines  Date published / revised Supports Use Is the dose and regimen consistent with the protocol?  Comments 
NCCN V.2. 2020 Yes Yes  -
BCCA - N/A  N/A  -
CCO  - N/A  N/A  -

Efficacy

Thirty-one patients (60%) achieved CR following 5 - 7 cycles of R-MPV and proceeded to rdWBRT. Of these, 2-year PFS was 77% and median PFS was 7.7 years. Median OS was not reached (with median follow up 5.9 years for survivors); 3 year OS was 87%. Overall median PFS was 3.3 years and median OS was 6.6 years. Following chemotherapy, cognitive assessment showed improvement in executive function (p<0.01) and verbal memory (p<0.05).r

Figure 1. CONSORT diagram showing treatment and outcome for all enrolled patients.

© Journal of Clinical Oncology 2013

Figure 2. Kaplan-Meier survival curves

Kaplan-Meier survival curves showing (A) OS and PFS for patients that received rdWBRT after achieving CR with 5 - 7 cycles of R-MPV; (B) PFS according to age for patients that received rdWBRT after achieving CR with 5 - 7 cycles of R-MPV; (C) Intent-to-treat OS and PFS for entire cohort; (D) Intent-to-treat PFS by age for entire cohort.

© Journal of Clinical Oncology 2013

Of 31 patients that received rdWBRT, 12 patients were progression-free and completed neuropsychological evaluations up to 48 months (median age 58 years). Baseline cognitive impairment was evident across several categories. Following induction chemotherapy (R-MPV), significant improvement in executive function (p<0.01) and verbal memory (p<0.05) were observed. No significant cognitive decline occurred during follow up except for motor speed (p<0.05) and memory performances fluctuated only mildly throughout the follow up period. Importantly, self-reported quality of life remained stable and there was no significant depressed mood observed.r

Toxicity

Morris et al 2013r

Toxicity 

(n=52)

 Grade 3 Grade 4 Grade 5
Renal 1 - -
Febrile neutropenia NR NR 3* (6%)
Pneumonitis - - 1*

Gastrointestional

- ileus

- perforated diverticulum

 1 1 -

Figure 3: Observed toxicities=grade 3 of all patients reported in the study (n=52).r NR not reported, *denotes same patient experienced grade 5 febrile neutropenia with pneumonitis. Regarding febrile neutropenia and other toxicities, an earlier interim report of the same study (n=30) previously reported by the same group revealed the following toxicities:

Shah et al 2007r

Toxicity 

(n=30)

Grade 3

 Grade 4 Grade 5

Febrile neutropenia

pre G-CSF

amendment**

(n=5)

- post G-CSF

amendment**

- All (n=30)

 -

2 (40%)

 

 

 

1 (4%)

 

 

3 (10%)

1 (20%)

 

 

 

 

 

 

1 (3%)
Renal 1 (3%) - -
Anaemia 3 (10%) - -
Thrombocytopenia 8 (27%) - -
Lymphocytopenia 12 (40%) - -

Figure 4: Observed toxicities=grade 3 of all patients reported in the interim study report (n=30).r **Due to complications of febrile neutropenia in 2 of the first 5 treated patients, a protocol amendment was made to include GCSF 5 µg/kg/d subcutaneously for 3-5 days with each cycle, starting 24 hours after last dose of procarbazine (odd cycles) and 96 hours after methotrexate or when methotrexate levels reached below 1x10-8mg/dL (even cycles).

It should be noted that in another independent retrospective analysis of rituximab in combination with differing chemotherapy regimens (n=121), 2 patients (2%) experienced grade 5 toxicity due to perforated viscera.r This appears to be a specific and recurrent complication affecting a small number of patients despite compliance with recommendations for pharmacologic gastric acid suppression within the protocol.r

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Version 3

Date Summary of changes
11/05/2016 Approved and published on eviQ..
31/05/2017

Transferred to new eviQ website. Version number change to V.2.
25/05/2018

Protocol reviewed at Haematology Reference Committee meeting:

  • Antiemetics updated to be in line with international guidelines. Note to dexamethasone added.
  • Version number changed to V.3.
10/10/2019

Clinical information updated with PBS expanded indications for G-CSF. 
27/03/2020

Reviewed by Haematology Reference Committee:

  • Dose modifications updated 
  • Evidence updated.
  • Review in 4 years.

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

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First approved:
Last reviewed:
Review due:

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/1906

31 Mar 2023