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Glioblastoma recurrent lomustine and beVACizumab

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

Check for clinical trials in this patient group. Link to Australian Clinical Trials opens in a new tab or window website

Avastin® (bevacizumab) is no longer available on the PBS and alternative biosimilars are now available. The rapid infusion administration instructions for subsequent doses of bevacizumab included in eviQ protocols are based on studies conducted using Avastin® (bevacizumab).

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Cycle 1 and further cycles

Drug Dose Route Day
Lomustine 90 mg/m2 * (Cap dose at 160 mg) PO 1
beVACizumab 10 mg/kg ** IV infusion 1, 15, 29

* It is the consensus of the eviQ Reference Committee that consideration should be given to starting lomustine at a lower dose of 70 mg/m² in patients who have previously experienced significant thrombocytopenia with prior temozolomide. Dosing may require rounding to the nearest capsule strength to enable delivery of a measurable dose.

** Bevacizumab may be administered as either 10 mg/kg every 14 days or 15 mg/kg every 21 daysr

Frequency:
42 days 
Cycles:

Continuous until disease progression or unacceptable toxicity

Drug status:

Bevacizumab is on the PBS general schedule opens in a new tab or window

Lomustine is TGA registered but not PBS listed for this indication.

Lomustine is available as 10 mg and 40 mg capsules

Cost:
~ $1,330 per cycle, excluding lomustine "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). These costs are reviewed and updated on eviQ at 6 monthly intervals. Anti-cancer drugs that are not included on the PBS do not have a cost included in eviQ protocols.

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.

Where oral drugs are available on the PBS for both 30- and 60-day prescriptions, the unit cost for the 30-day supply is used.

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, growth factor support 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 further cycles

Day 1
Granisetron 2 mg (PO) 60 minutes before chemotherapy
Lomustine 90 mg/m2 (PO) (Cap dose at 160 mg) ONCE every six weeks. Swallow whole on an empty stomach, one hour before food or two hours after food (Round dose to the nearest 10 mg or 40 mg)*
beVACizumab 10 mg/kg (IV infusion) in 100 mL sodium chloride 0.9% over 90 minutes (1st dose); if first dose is well tolerated subsequent doses may be administered over 20 minutes.**
Day 15 and 29
beVACizumab 10 mg/kg (IV infusion) in 100 mL sodium chloride 0.9% over 90 minutes (1st dose); if first dose is well tolerated subsequent doses may be administered over 20 minutes.**

* It is the consensus of the eviQ Reference Committee that consideration should be given to starting lomustine at a lower dose of 70 mg/m² in patients who have previously experienced significant thrombocytopenia with prior temozolomide. Dosing may require rounding to the nearest capsule strength to enable delivery of a measurable dose.

** Bevacizumab may be administered as either 10 mg/kg every 14 days or 15 mg/kg every 21 daysr (subsequent 15 mg/kg doses may be administered over 30 minutes). It is the consensus of the eviQ reference committee that it is safe to give the initial dose of bevacizumab over 30 minutes.r The rapid infusion administration instructions for subsequent doses of bevacizumab are based on studies conducted using Avastin® (bevacizumab). Refer to bevacizumab infusion times for more information.

Frequency:
42 days 
Cycles:

Continuous until disease progression or unacceptable toxicity

Cycle 1 and further cycles

Drug Dose Route Day
Lomustine 90 mg/m2 * (Cap dose at 160 mg) PO 1
beVACizumab 10 mg/kg ** IV infusion 1, 15, 29

* It is the consensus of the eviQ Reference Committee that consideration should be given to starting lomustine at a lower dose of 70 mg/m² in patients who have previously experienced significant thrombocytopenia with prior temozolomide. Dosing may require rounding to the nearest capsule strength to enable delivery of a measurable dose.

** Bevacizumab may be administered as either 10 mg/kg every 14 days or 15 mg/kg every 21 daysr

Frequency:
42 days 
Cycles:

Continuous until disease progression or unacceptable toxicity

Drug status:

Bevacizumab is on the PBS general schedule opens in a new tab or window

Lomustine is TGA registered but not PBS listed for this indication.

Lomustine is available as 10 mg and 40 mg capsules

Cost:
~ $1,330 per cycle, excluding lomustine "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). These costs are reviewed and updated on eviQ at 6 monthly intervals. Anti-cancer drugs that are not included on the PBS do not have a cost included in eviQ protocols.

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.

Where oral drugs are available on the PBS for both 30- and 60-day prescriptions, the unit cost for the 30-day supply is used.

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, growth factor support 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 further cycles

Day 1
Granisetron 2 mg (PO) 60 minutes before chemotherapy
Lomustine 90 mg/m2 (PO) (Cap dose at 160 mg) ONCE every six weeks. Swallow whole on an empty stomach, one hour before food or two hours after food (Round dose to the nearest 10 mg or 40 mg)*
beVACizumab 10 mg/kg (IV infusion) in 100 mL sodium chloride 0.9% over 90 minutes (1st dose); if first dose is well tolerated subsequent doses may be administered over 20 minutes.**
Day 15 and 29
beVACizumab 10 mg/kg (IV infusion) in 100 mL sodium chloride 0.9% over 90 minutes (1st dose); if first dose is well tolerated subsequent doses may be administered over 20 minutes.**

* It is the consensus of the eviQ Reference Committee that consideration should be given to starting lomustine at a lower dose of 70 mg/m² in patients who have previously experienced significant thrombocytopenia with prior temozolomide. Dosing may require rounding to the nearest capsule strength to enable delivery of a measurable dose.

** Bevacizumab may be administered as either 10 mg/kg every 14 days or 15 mg/kg every 21 daysr (subsequent 15 mg/kg doses may be administered over 30 minutes). It is the consensus of the eviQ reference committee that it is safe to give the initial dose of bevacizumab over 30 minutes.r The rapid infusion administration instructions for subsequent doses of bevacizumab are based on studies conducted using Avastin® (bevacizumab). Refer to bevacizumab infusion times for more information.

Frequency:
42 days 
Cycles:

Continuous until disease progression or unacceptable toxicity

Indication:

  • Glioblastoma after relapse or disease progression following standard therapy
    • ECOG performance status 0 to 2
    • in clinical settings where the steroid-sparing effects of bevacizumab are desirable.

Cautions:

  • Severe and prolonged cytopenias can occur - close monitoring of full blood count (FBC) is recommended and dose reductions as clinically indicated.
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
Caution with oral anti-cancer drugs

Select links for information on the safe prescribing, dispensing and administration of orally administered anti-cancer drugs. 

Read more about at COSA guidelines for the safe prescribing, dispensing and administration of systemic cancer therapy opens in a new tab or window and oral anti-cancer therapy opens in a new tab or window
Emetogenicity moderate to high

Although this treatment is classified as having moderate to high emetogenicity, routine antiemetic premedication may not be required. Consider prophylaxis with a 5HT3 receptor antagonist e.g. granisetron 2 mg PO daily and re-assess routinely.

Read more about preventing anti-cancer therapy induced nausea and vomiting
Gastrointestinal perforation

Bevacizumab has been associated with serious cases of gastrointestinal (GI) perforation and should be permanently discontinued in patients who develop it.
Haemorrhage

Patients treated with bevacizumab have an increased risk of haemorrhage, especially tumour associated haemorrhage and minor mucocutaneous haemorrhage (e.g. epistaxis). Bevacizumab should be used with caution in patients at risk of bleeding.
Hypertension

Pre-existing hypertension should be adequately controlled prior to commencing bevacizumab and blood pressure should be monitored during therapy. Commence or adjust antihypertensive medication as clinically indicated.
Proteinuria

Patients may be at increased risk of developing proteinuria when treated with bevacizumab. Baseline urinalysis for proteinuria is recommended prior to commencement of therapy, and as clinically indicated. Routine testing prior to each treatment is no longer recommended, as dose reductions for low/intermediate levels of proteinuria are not recommended.

Clinicians are advised to consider evaluating for proteinuria periodically (e.g. every 3 to 4 months) or in patients with clinical concerns (e.g. oedema/unexplained hypoalbuminemia) as treatment interruption may be required if proteinuria is significant (e.g. > 3 g/L).

Read more about proteinuria
Reversible posterior leukoencephalopathy syndrome (RPLS)

Bevacizumab should be discontinued in patients who develop reversible posterior leukoencephalopathy syndrome (RPLS). The risk of reinitiating bevacizumab therapy in patients previously experiencing RPLS is not known.

Read more about reversible posterior leukoencephalopathy syndrome (RPLS)
Thromboembolism

Both arterial and venous thromboembolic events have been observed in patients with this treatment.
Therefore, use with caution in patients at increased risk or with a history of thrombotic events (i.e., cerebrovascular and cardiovascular disease).
Wound healing

Bevacizumab may adversely affect wound healing and should not be initiated in patients with a serious non-healing wound or ulcer. Bevacizumab should be withheld at least 28 days prior to elective surgery. Bevacizumab can be restarted 28 days after surgery provided wound healing is complete.

Necrotising fasciitis, including fatal cases, has rarely been reported in patients treated with bevacizumab; usually secondary to wound healing complications, gastrointestinal perforation or fistula formation. Bevacizumab therapy should be discontinued in patients who develop necrotising fasciitis, and appropriate treatment should be promptly initiated.
Pulmonary toxicity

Lomustine should be administered with caution in patients with a baseline below 70% of predicted forced vital capacity (FVC) or carbon monoxide diffusing capacity (DLCO).

Baseline pulmonary function studies should be conducted along with follow up pulmonary function tests during treatment.

Respiratory symptoms indicative of pulmonary fibrosis may not appear for several months following initiation of treatment with lomustine. Onset usually occurs after six months of therapy with cumulative doses greater than 1,100 mg/m2. Delayed onset has been reported up to 17 years later. Withdrawal of the drug does not arrest fibrotic degeneration, and a number of deaths from acute respiratory failure have occurred. Pulmonary toxicity appears to be dose related.
Cerebral oedema

Some patients may require dexamethasone to reduce cerebral oedema.

For patients requiring high doses of dexamethasone (greater than 4 mg) for protracted periods, check BSL as clinically indicated, consider H2 antagonists or proton pump inhibitors, watch for opportunistic infections and consider prophylaxis if necessary. If patient is on enzyme-inducing anticonvulsant drugs, check anticonvulsant levels ~ 5 days after each alteration in dexamethasone dose if appropriate.

Read more about reducing cerebral oedema with dexamethasone
Biosimilar drug

Read more about biosimilar drugs on the Biosimilar Awareness Initiative opens in a new tab or window page
Blood tests

FBC, EUC, eGFR, LFTs at baseline and prior to each cycle. Repeat FBC at week 4 in cycle 1 and week 4 in subsequent cycles as clinically indicated. Check BSL regularly if patient is on corticosteroids.
Hepatitis B screening and prophylaxis

Routine screening for HBsAg and anti-HBc is NOT usually recommended for patients receiving this treatment.

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. Possible suboptimal response to inactivated vaccines.

For more information about vaccinations in people with cancer refer to the Australian Immunisation Handbook opens in a new tab or window.
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 fetal 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 impact of cancer treatment on fertility opens in a new tab or window
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) opens in a new tab or window 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
  • the following dose modification recommendations have been adapted from the clinical trials related to this protocolrr and consensus of the reference committee.
Haematological toxicity
Unlike most cytotoxics, late and prolonged nadirs of platelets and neutrophils are commonly seen with this regimen
ANC x 109/L (pre-treatment blood test)
1.0 to less than 1.5 Delay treatment until recovery and reduce lomustine by 25% for subsequent cycles
less than 1.0 Delay treatment until recovery and reduce lomustine by 50% for subsequent cycles
Febrile neutropenia Delay treatment until recovery and reduce lomustine by 50% for subsequent cycles
Platelets x 109/L (pre-treatment blood test)
75 to less than 100 Delay treatment until recovery
25 to less than 75 Delay treatment until recovery and reduce lomustine by 25% for subsequent cycles
less than 25 Delay treatment until recovery and reduce lomustine by 50% for subsequent cycles
Kidney dosing recommendations 
  • Suggested dose modifications are based on the International Consensus Guideline on Anticancer Drug Dosing in Kidney Dysfunction (ADDIKD).
  • Where one or more drugs in a protocol is recommended to be avoided, consider using a clinically appropriate alternative treatment protocol instead.
  • Before dose adjusting or omitting a drug, consider treatment intent.
  • In kidney replacement therapy consult a multidisciplinary team consisting of oncology/haematology with nephrology and/or clinical pharmacology for the management of dosing. 
  • For complete information on individual drug recommendations please review the individual drug monograph in the ADDIKD guideline.
eGFR
(mL/min/1.73m2)		 Bevacizumab Lomustine*
≥ 60

Full dose

Full dose
45 - 59

Full dose

Potential for increased risk of renal adverse events

Consider 25% reduction
30 - 44

Full dose 

Potential for increased risk of renal adverse events

Consider 30 to 50% reduction
15 - 29

Full dose

Potential for increased risk of renal adverse events

AVOID

Not recommended
< 15
(without kidney replacement therapy)

Full dose

Potential for increased risk of adverse events

AVOID

Not recommended

* This drug was not included in the ADDIKD guideline.Lomustine kidney dosing recommendations are based on Renal Drug Handbookr and RCM consensus.
Hepatic impairment
No specific recommendations. Although lomustine metabolites are mainly excreted by the kidney, the liver is involved in lomustine metabolism; patients with hepatic impairment should be monitored closely.
Mucositis and stomatitis
Grade 2 Delay treatment until toxicity has resolved to Grade 1 or less and reduce the dose for subsequent cycles as follows:
1st occurrence: No dose reduction
2nd occurrence: Reduce lomustine by 25%
3rd occurrence: Reduce lomustine by 50%
4th occurrence: Omit lomustine
Grade 3 or Grade 4 Delay treatment until toxicity has resolved to Grade 1 or less and reduce the dose for subsequent cycles as follows:
1st occurrence: Reduce lomustine by 50%
2nd occurrence: Omit lomustine
Pulmonary impairment
Lomustine should be administered with caution in patients with a baseline below 70% of predicted forced vital capacity (FVC) or carbon monoxide diffusing capacity (DLCO)
Cease bevacizumab if any of the following occur:

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: 

For more information see References & Disclaimer.

Bevacizumab
  Interaction Clinical management
Nephrotoxic drugs (e.g. aminoglycosides, amphotericin, contrast dye, frusemide, NSAIDs) Additive nephrotoxicity Avoid combination or monitor kidney function closely
Anthracyclines May enhance the cardiotoxic effect of anthracycline anti-cancer drugs Monitor for increased cardiotoxicity (e.g. congestive heart failure)
Sunitinib Microangiopathic haemolytic anaemia Monitor for haemolytic anaemia, thrombocytopenia, hypertension, elevated creatinine and neurological symptoms
Sorafenib Increased risk of toxicity, especially hand-foot syndrome Monitor for increased toxicity
Anti-EGFR monoclonal antibodies (e.g. cetuximab, panitumumab) Additive toxicity without additional treatment benefit Avoid combination
Medications known to cause GI perforation (e.g. methylnaltrexone, NSAIDs, steroids) Additive risk of GI perforation Avoid combination
Lomustine
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 opens in a new tab or window and P‑gp opens in a new tab or window inhibitors. If treating VTE, avoid use with strong CYP3A4 opens in a new tab or window and P‑gp opens in a new tab or window inducers. 

Rivaroxaban: avoid concurrent use with strong CYP3A4 opens in a new tab or window and P‑gp opens in a new tab or window  inhibitors.

Dabigatran: avoid combination with strong P‑gp opens in a new tab or window 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 opens in a new tab or window

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 or address chemical compatibilities related to IV drug preparation and administration. 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 opens in a new tab or window and Australian Injectable Drugs Handbook opens in a new tab or window websites for further information.

eviQ is currently updating the way information is presented in the administration section, if you notice any discrepancies please let us know, via feedback@eviq.org.au.

Day 1

Approximate treatment time: 90 minutes

Pre treatment assessment

Bevacizumab requires:

  • a baseline urinalysis for protein and repeat as clinically indicated (read more about proteinuria)
  • blood pressure check

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

Anti-cancer drug patient assessment tool prior to each day of treatment.

Prior to administration

Prime IV line(s).

Bevacizumab is only compatible with sodium chloride 0.9%, ensure IV lines are flushed with sodium chloride 0.9% pre and post administration.

Access TIVAD or CVAD.

Pre treatment medication

Verify premedication/antiemetics have been taken as prescribed, see treatment schedule detail for suggested medications.

Lomustine

Administer lomustine: 
  • orally ONCE a day on day 1 only
  • swallow whole with a glass of water; do not break, crush or chew
  • to be taken on an empty stomach, one hour before or two hours after food.

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

Bevacizumab

Administer bevacizumab (10 mg/kg):
  • via IV infusion 
  • first dose over 90 minutes 
    • the product information recommends giving the first dose over 90 minutes, it is the consensus of the eviQ reference committee that it is safe to give the initial dose of bevacizumab over 30 minutesr
  • if well tolerated and no previous hypersensitivity reactions:
  • observe for hypersensitivity reaction
  • flush with ~ 50 mL of sodium chloride 0.9%.
Infusion-related reaction (IRR)

Stop infusion at first sign of anaphylaxis or severe IRR and manage as per emergency.

Grade 1 or 2:
  • slow or hold rate of infusion, alert medical officer and monitor closely
  • administer symptomatic medications as prescribed
  • if symptoms are mild and resolve when infusion is stopped, consider recommencing infusion after review by medical officer at a slower rate
  • give any further doses with close monitoring, premedications should be considered and prescribed by the medical officer as per local policy.
Grade 3 or 4: 
  • stop infusion immediately 
  • seek urgent medical officer review, do not restart the infusion.

Post administration

Remove IV cannula and/or deaccess TIVAD or CVAD. 

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

Day 15 and 29

Approximate treatment time: 30 minutes

Pre treatment assessment

Bevacizumab requires:

  • a baseline urinalysis for protein and repeat as clinically indicated (read more about proteinuria)
  • blood pressure check

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

Anti-cancer drug patient assessment tool prior to each day of treatment.

Prior to administration

Prime IV line(s).

Bevacizumab is only compatible with sodium chloride 0.9%, ensure IV lines are flushed with sodium chloride 0.9% pre and post administration.

Insert IV cannula or access TIVAD or CVAD.

Pre treatment medication

Verify premedication/antiemetics have been taken as prescribed, see treatment schedule detail for suggested medications.

Bevacizumab

Administer bevacizumab (10 mg/kg):
  • via IV infusion 
  • first dose over 90 minutes 
    • the product information recommends giving the first dose over 90 minutes, it is the consensus of the eviQ reference committee that it is safe to give the initial dose of bevacizumab over 30 minutesr
  • if well tolerated and no previous hypersensitivity reactions:
  • observe for hypersensitivity reaction
  • flush with ~ 50 mL of sodium chloride 0.9%.
Infusion-related reaction (IRR)

Stop infusion at first sign of anaphylaxis or severe IRR and manage as per emergency.

Grade 1 or 2:
  • slow or hold rate of infusion, alert medical officer and monitor closely
  • administer symptomatic medications as prescribed
  • if symptoms are mild and resolve when infusion is stopped, consider recommencing infusion after review by medical officer at a slower rate
  • give any further doses with close monitoring, premedications should be considered and prescribed by the medical officer as per local policy.
Grade 3 or 4: 
  • stop infusion immediately 
  • seek urgent medical officer review, do not restart the infusion.

Post administration

Remove IV cannula and/or deaccess TIVAD or CVAD. 

Discharge information

Antiemetics - as/if prescribed.

Patient information

Ensure patient receives protocol 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)
Headache
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

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
Diarrhoea

Read more about treatment induced diarrhoea
Anorexia

Loss of appetite accompanied by decreased food intake.

Read more about anorexia
Gastrointestinal perforation

A rupture of the wall of the stomach, small intestine or large bowel. Symptoms include acute abdominal pain, tenderness and signs of sepsis. 
Epistaxis

Acute bleeding from the nostril(s), nasal cavity, or nasopharynx.
Oral mucositis and stomatitis

Erythematous and ulcerative lesions of the gastrointestinal tract (GIT). It commonly develops following anti-cancer treatment, 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 and stomatitis
Fatigue

Read more about fatigue
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
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.
Haemorrhage
Proteinuria

Read more about proteinuria
Thromboembolism

Arterial and venous thromboembolic events, including pulmonary embolism, deep vein thrombosis and cerebrovascular accidents can occur. Patients should be carefully assessed for risk factors, and consideration given for antithrombotic prophylaxis in high risk patients.
Hypertension associated with angiogenesis inhibitors

High blood pressure can occur with angiogenesis inhibitors and tyrosine kinase inhibitors. 
Reversible posterior leukoencephalopathy syndrome (RPLS)

A neurological disorder which may present with headache, seizures, lethargy, confusion, blindness and/or other visual and neurological disturbances. Mild to severe hypertension may also occur.

Read more about reversible posterior leukoencephalopathy syndrome (RPLS)
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. Transient elevation of transaminases, alkaline phosphatase and bilirubin levels has been observed with lomustine.
Nephrotoxicity

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

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 and scalp cooling
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

eviQ is currently updating the way information is presented in the evidence section to improve usability, consistency and facilitate easier update and maintenance. An updated evidence template is being implemented in a staged approach, first across new protocols, then existing protocols as they are reviewed. Find out more

A search of the literature did not find strong evidence to support any standard systemic therapy for recurrent glioblastoma. 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 systematic review by Ameratunga et al.r

The systematic review evaluated the role of anti-angiogenic therapy in patients with high-grade glioma in both the adjuvant and recurrent settings.r

Source Study & year published Supports use Is the dose and regimen consistent with the protocol? Comments
Systematic review Ameratunga et al 2018r Yes N/A -
Phase III trial Wick et al 2017r No Yes -
Phase II trial Taal et al 2014r Yes
 		 Yes (following dose reduction after the preplanned safety
review)		 Arm 1: lomustine (PO) 110 mg/m2 d1 q6w, 
Arm 2: bevacizumab (IV) 10 mg/kg, d1 q2w,
Arm 3: lomustine (PO) 110 mg/m2 d1 q6w and bevacizumab (IV) 10 mg/kg d1 q2w (lomustine dose subsequently reduced to 90 mg/m2)
Guidelines Date published/revised Supports use Is the dose and regimen consistent with the protocol? Comments
NCCN V.2 September 2021 Yes Yes Bevacizumab plus lomustine can be considered if bevacizumab monotherapy has failed and if continued steroid-sparing effects of bevacizumab is desired.
BCCA February 2022 Yes Yes Recommended after second relapse following metronomic dosing temozolomide or first relapse if not eligible for metronomic dosing temozolomide.
CCO March 2020 Yes Yes -
ESMO  April 2014 N/A N/A -

Efficacy

A summary of the efficacy results from the systematic review and clinical trials is shown in the tables below:

Systematic review Interventions Number of studies (patients) Overall survival (OS) benefits Progression-free survival (PFS) benefits Summary
Ameratunga et al 2018r Anti-angiogenic therapy vs no anti-angiogenic therapy in recurrent setting

For OS: 3 (910)

For PFS: 2 (762)

HR 0.99, 95% CI 0.85-1.16;  p=0.90

Level of evidence: moderate-certainty

HR 0.64, 95% CI 0.54-0.76; p<0.00001

Level of evidence: moderate-certainty
  • There is a lack of evidence for OS benefit for anti-angiogenic therapy over chemotherapy in recurrent glioblastoma.
  • Possible small improvement in OS when combining anti-angiogenic therapy with chemotherapy (questionable clinical significance).
  •  Strong evidence available to support prolonged PFS with bevacizumab   in recurrent glioblastoma.
Anti-angiogenic therapy combined with chemotherapy vs chemotherapy alone

For OS: 11 (3506)

For PFS: 10 (3464)

HR 0.92, 95% CI 0.85-1.00; p=0.05

Level of evidence: low-certainty

HR 0.72, 95% CI 0.66-0.77; p<0.00001

Level of evidence: high-certainty
Study Treatment arms (number of patients) Median OS (months, 95% CI) Median PFS (months, 95% CI) Summary
Wick et al 2017r Lomustine + bevacizumab (n=288) 9.1 (8.1-10.1)
HR 0.95, 95% CI 0.74-1.21; p=0.65		 4.2 (3.7-4.3)
HR 0.49, 95% CI 0.39-0.61; p<0.001		 Combination therapy with lomustine and bevacizumab, despite prolonged PFS, did not confer a survival advantage over lomustine monotherapy
Lomustine (n=149) 8.6 (7.6-10.4) 1.5 (1.5-2.5)
Taal et al 2014r Lomustine (n=46) 8 (6-11) 1 (1-3) Combination of bevacizumab and lomustine may have more activity than either drug administered alone. Further investigation in a phase III trial required
Bevacizumab (n=50) 8 (6-9) 3 (3-4)
Lomustine + bevacizumab (n=52) 12 (8-13) 4 (3-8)

Toxicity

A summary of the toxicities associated with this protocol are included in the table below:

Adverse eventsr

Lomustine alone (N=147) (%)

Lomustine + bevacizumab (N=283) (%)
Any adverse events 94.6 98.2
Treatment-related adverse events 53.1 85.2
Grade 3-5 adverse events 38.1 63.6
Treatment-related serious adverse events 9.5 38.5
Pulmonary embolism 0 4.9
Arterial hypertension 0.7 23.7
Haematological toxicities 49.7 53.7
Death 0.7 1.8
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Version 3

Date Summary of changes
19/03/2025

Protocol reviewed at the Neurological Reference Committee meeting on 21/02/2025. Bevacizumab 15 mg/kg every 21 days option added to treatment schedule overview and detail notes, and to patient information, to align with ID 733 Glioblastoma recurrent beVACizumab. Version number changed to V.3. Next review in 2 years.

Version 2

Date Summary of changes
18/06/2024

Protocol updated with ADDIKD guideline recommendations. New kidney dosing recommendation table added to dose modification section.

PDF of previous protocol.

Version number changed to V.2.

Version 1

Date Summary of changes
04/08/2022

New protocol approved electronically by Medical Oncology Reference Committee.
15/08/2022

Protocol published on eviQ. Review in 1 year.
21/10/2022

Bevacizumab treatment schedule note updated based on reference committee consensus to add that it is safe to give the initial dose of bevacizumab over 30 minutes.
16/03/2023 Protocol reviewed by Medical Oncology Reference Committee. No changes. Next review in 2 years.
10/01/2024 Drug cost updated to exclude lomustine.

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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07 Jul 2025