4394-Colorectal metastatic trifluridine/tipiracil and beVACizumab

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).

Cycle 1 and further cycles

Drug	Dose	Route	Day
Trifluridine/tipiracil	35 mg/m² TWICE a day # (Cap dose at 80 mg/dose)	PO	1 to 5 and 8 to 12
beVACizumab	5 mg/kg	IV infusion	1 and 15

# The dose expressed is based on the trifluridine component. For information on number of tablets for starting dose of 35 mg/m² see trifluridine/tipiracil dosing table. Dosing may require rounding to the nearest tablet strength to enable delivery of a measurable dose. In heavily pre-treated patients consideration may be given to starting at a lower dose due to concerns about myelosuppression in addition to usual fluoropyrimidine toxicities.

Frequency:: 28 days

Cycles:: Continuous until disease progression or unacceptable toxicity

Notes:: Trifluridine/tipiracil consists of a thymidine-based nucleoside analogue (trifluridine), and thymidine phosphorylase inhibitor (tipiracil). Inclusion of tipiracil increases trifluridine exposure by inhibiting its metabolism by thymidine phosphorylase.

Drug status:

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

Trifluridine/tipiracil is PBS authority opens in a new tab or window only if it is the sole PBS-subsidised therapy

Trifluridine/tipiracil is available as 15 mg and 20 mg tablets

Cost:: ~ $3,610 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). 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
Trifluridine/tipiracil	35 mg/m² (PO) (Cap dose at 80 mg/dose)	TWICE a day #
beVACizumab	5 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 10 minutes *

Day 2 to 5 and 8 to 12
Trifluridine/tipiracil	35 mg/m² (PO) (Cap dose at 80 mg/dose)	TWICE a day #

Day 15
beVACizumab	5 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 10 minutes *

* It is the consensus of the eviQ reference committee that it is safe to give the initial dose of bevacizumab over 30 minutes.^rThe 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:: 28 days

Cycles:: Continuous until disease progression or unacceptable toxicity

Treatment schedule - Overview

Cycle 1 and further cycles

Drug	Dose	Route	Day
Trifluridine/tipiracil	35 mg/m² TWICE a day # (Cap dose at 80 mg/dose)	PO	1 to 5 and 8 to 12
beVACizumab	5 mg/kg	IV infusion	1 and 15

Frequency:: 28 days

Cycles:: Continuous until disease progression or unacceptable toxicity

Notes:: Trifluridine/tipiracil consists of a thymidine-based nucleoside analogue (trifluridine), and thymidine phosphorylase inhibitor (tipiracil). Inclusion of tipiracil increases trifluridine exposure by inhibiting its metabolism by thymidine phosphorylase.

Drug status:

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

Trifluridine/tipiracil is PBS authority opens in a new tab or window only if it is the sole PBS-subsidised therapy

Trifluridine/tipiracil is available as 15 mg and 20 mg tablets

Cost:: ~ $3,610 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). 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.

Treatment schedule - Detail

Cycle 1 and further cycles

Day 1
Trifluridine/tipiracil	35 mg/m² (PO) (Cap dose at 80 mg/dose)	TWICE a day #
beVACizumab	5 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 10 minutes *

Day 2 to 5 and 8 to 12
Trifluridine/tipiracil	35 mg/m² (PO) (Cap dose at 80 mg/dose)	TWICE a day #

Day 15
beVACizumab	5 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 10 minutes *

Frequency:: 28 days

Cycles:: Continuous until disease progression or unacceptable toxicity

Indications and patient population

Indications:

Metastatic colorectal cancer (CRC) in patients who have been previously treated with, or not considered a candidate for, fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, anti-VEGF therapy, and, if RAS wild-type, anti-EGFR therapy.
- ECOG performance status 0 to 1.

Clinical information

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
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 minimal or low	No routine prophylaxis required. If patients experience nausea and/or vomiting, consider using the low emetogenic risk regimen. Read more about preventing anti-cancer therapy induced nausea and vomiting
Oral mucositis	Oral mucositis is a common side effect with this treatment and may manifest as mouth and tongue ulceration. Early intervention may help to avoid dose alteration or interruption. Topical treatments (alcohol free) are recommended. Read more about oral mucositis and stomatitis
Diarrhoea	Antidiarrhoeals (e.g. loperamide) are usually prescribed with this treatment. Read more about treatment induced diarrhoea
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.
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).
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 and LFTs at baseline and prior to each cycle. For cycle 1, consider clinical review and FBC on day 15 and then as clinically indicated.
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

Dose modifications

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:

A maximum of 3 dose reductions are permitted for trifluridine/tipiracil to a minimum of 20 mg/m² twice daily, or a minimum of 15 mg/m² in severe renal impairment.
Do not escalate trifluridine/tipiracil dose after it has been reduced.
The following dose modification recommendations have been adapted from the product information, a study by Mayer et al^r, a review by Price et al^r and by consensus of the reference committee.

Haematological toxicity
ANC x 10⁹/L (pre-treatment blood test)
1.0 to less than 1.5	Refer to local institutional guidelines; it is the view of the expert clinicians that treatment should continue if patient is clinically well
less than 1.0	Delay treatment until neutrophils are greater than or equal to 1.0 Reduce trifluridine/tipiracil by 5 mg/m² for subsequent cycles
Febrile neutropenia	Delay treatment until neutrophils are greater than or equal to 1.0 Reduce trifluridine/tipiracil by 5 mg/m² for subsequent cycles
Platelets x 10⁹/L (pre-treatment blood test)
50 to less than 75	Delay treatment until platelets are greater than or equal to 75
less than 50	Delay treatment until platelets are greater than or equal to 75 Reduce trifluridine/tipiracil by 5 mg/m² 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	Trifluridine/tipiracil*
≥ 60	Full dose	No dose modification necessary
45 - 59	Full dose Potential for increased risk of renal adverse events	No dose modification necessary Higher incidence of ≥ Grade 3 and serious toxicity, dose delays and reductions than with mild kidney dysfunction. Use with caution and consider dose adjustment.
30 - 44	Full dose Potential for increased risk of renal adverse events	No dose modification necessary Higher incidence of ≥ Grade 3 and serious toxicity, dose delays and reductions than with mild kidney dysfunction. Use with caution and consider dose adjustment.
15 - 29	Full dose Potential for increased risk of renal adverse events	Reduce starting dose to 20 mg/m² twice daily One dose reduction to a minimum of 15 mg/m² twice a day is permitted based on individual safety and tolerability.
< 15 (without kidney replacement therapy)	Alternative protocol This drug may be given at this eGFR level (see ADDIKD guideline) however not recommended in this protocol	AVOID This drug has not been studied in patients with end stage kidney dysfunction.
* This drug was not included in the ADDIKD Guideline. Recommendations for trifluridine/tipiracil are based on the product information.

Hepatic impairment
Hepatic dysfunction:
Mild	No dose modifications necessary
Moderate	Limited data. Trifluridine/tipiracil is not recommended due to higher incidence of Grade 3/4 hyperbilirubinaemia in patients with moderate hepatic impairment.
Severe	Trifluridine/tipiracil is not recommended as it has not been studied in patients with severe hepatic impairment

Mucositis and stomatitis
Grade 2	No dose modifications necessary
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: 1^st occurrence: Reduce trifluridine/tipiracil by 5 mg/m² 2^ndoccurrence: Reduce trifluridine/tipiracil by further 5 mg/m² 3^rd occurrence: Reduce trifluridine/tipiracil by further 5 mg/m² 4^th occurrence: Discontinue trifluridine/tipiracil

Diarrhoea
Grade 2	No dose modifications necessary
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: 1^st occurrence: Reduce trifluridine/tipiracil by 5 mg/m² 2^ndoccurrence: Reduce trifluridine/tipiracil by further 5 mg/m² 3^rd occurrence: Reduce trifluridine/tipiracil by further 5 mg/m² 4^th occurrence: Discontinue trifluridine/tipiracil

Cease bevacizumab if any of the following occur:
haemorrhagic event grade 3 or greater pulmonary embolism, cerebrovascular event or arterial insufficiency arterial thromboembolic event grade 4 hypertension or persisting grade 3 hypertension nephrotic syndrome gastrointestinal perforation or fistula formation episode of reversible posterior leukoencephalopathy syndrome (RPLS).

Interactions

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:

MIMS - interactions tab opens in a new tab or window (includes link to a CYP-450 table) (login required)
Australian Medicines Handbook (AMH) – interactions tab opens in a new tab or window, tables opens in a new tab or window on drugs that may prolong the QT interval opens in a new tab or window, CYP enzymes opens in a new tab or window, P-glycoprotein interactions, opens in a new tab or window and seizure risk opens in a new tab or window (login required)
Micromedex Drug Interactions opens in a new tab or window (login required)
Cancer Drug Interactions opens in a new tab or window
Cytochrome P450 Drug Interactions opens in a new tab or window

For more information see References & Disclaimer.

Trifluridine/tipiracil
	Interaction	Clinical management
Trifluridine and tipiracil are not metabolised by cytochrome P450 enzymes. No formal pharmacokinetic drug interaction studies have been conducted with trifluridine/tipiracil.
Human thymidine kinase substrate antivirals (e.g. stavudine, zidovudine, telbivudine etc.)	Reduced efficacy of the antiviral agent possible due to competition with trifluridine for activation via thymidine kinases.	Avoid combination or monitor for possible decreased efficacy of antiviral agent. Consider switching to an alternative antiviral agent that is not a human thymidine kinase substrate (e.g. lamivudine, zalcitabine, didanosine, abacavir).
OCT2 or MATE1 inhibitors (e.g. cimetidine, dolutegravir etc.)	Increased toxicity of trifluridine/tipiracil possible due to reduced clearance	Use with caution and monitor for trifluridine/tipiracil toxicity.

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

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

Administration

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: 2 hours (initial); 1 hour (subsequent)

Safe handling and waste management

Safe administration

Pre treatment assessment

Check for adverse events during previous treatment.

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) with sodium chloride 0.9%.

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 and antiemetics taken or administer as prescribed, if required.

Treatment - Time out

Bevacizumab

Administer bevacizumab (5 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 minutes^r
if well tolerated and no previous hypersensitivity reactions:
- subsequent doses over 10 minutes (read more about the bevacizumab infusion times)
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.

Chemotherapy - Time out

Trifluridine/tipiracil

Administer trifluridine/tipiracil:

administer orally TWICE a day on days 1 to 5 and 8 to 12
to be swallowed whole with a glass of water; do not break, crush or chew
to be taken within one hour after the end of a meal

Note: missed doses should not be replaced, if a tablet is forgotten or vomited, normal dosing should be resumed at the next scheduled dose.

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

Approximate treatment time: 30 minutes

Handling of monoclonal antibodies and waste management

Safe administration

Pre treatment assessment

Check for adverse events during previous treatment.

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.

Pre treatment medication

Verify premedication and antiemetics taken or administer as prescribed, if required.

Prior to administration

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

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.

Treatment - Time out

Bevacizumab

Administer bevacizumab (5 mg/kg):

via IV infusion
subsequent doses over 10 minutes (read more about the bevacizumab infusion times)
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

Discharge medications

Trifluridine/tipiracil tablets - with written instructions on how to take them.

Antiemetics - as/if prescribed.

Antidiarrhoeals - as/if prescribed.

Patient information

Ensure patient receives protocol patient information sheet.

Side effects

The side effects listed below are not a complete list of all possible side effects for this treatment. Side effects are categorised into the approximate onset of presentation and should only be used as a guide.

Immediate (onset hours to days)
Hypersensitivity reaction	Anaphylaxis and infusion related reactions can occur with this treatment. Read more about hypersensitivity reaction
Nausea and vomiting	Read more about prevention of treatment induced nausea and vomiting
Headache

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
Abdominal pain	Dull ache, cramping or sharp pains are common with some anti-cancer drugs. These are caused by either increased or decreased gastrointestinal motility and can be associated with diarrhoea or constipation.
Anorexia	Loss of appetite accompanied by decreased food intake. Read more about anorexia
Diarrhoea	Read more about treatment induced diarrhoea
Constipation
Fatigue	Read more about fatigue
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
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.
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
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	High blood pressure is commonly associated with many anti-cancer drugs. Pre-existing hypertension should be controlled prior to initiation of drugs capable of causing hypertension.
Haemorrhage
Proteinuria	Read more about proteinuria
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)

Late (onset weeks to months)
Anaemia	Abnormally low levels of red blood cells (RBCs) or haemoglobin in the blood. Read more about anaemia
Hyperbilirubinaemia	An abnormal increase in the amount of bilirubin circulating in the blood which may result in jaundice.
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

Evidence

The evidence supporting this protocol is provided by a phase III, multicentre, international, open-label, randomised trial (SUNLIGHT) comparing trifluridine/tipiracil (FTD-TPI) and bevacizumab with (FTD-TPI) alone in patients with refractory metastatic colorectal cancer who have previously received treatment with fluoropyrimidine, irinotecan, oxaliplatin, an anti-VEGF monoclonal antibody or an anti-EGFR monoclonal antibody.^r

Between November 2020 and February 2022, 246 patients were assigned to each group and randomised 1:1 to receive FTD-TPI or bevacizumab with FTD-TPI.

The primary end point was overall survival (OS) and secondary end points were progression free survival (PFS), objective response (OR), disease control, quality of life and safety.

Efficacy

After a median follow up of 14.2 months in the combination group and 13.6 months in the FTD-TPI alone group; the median OS was 10.8 months and 7.5 months respectively (HR 0.61; 95% CI, 0.49 to 0.77; p<0.001). PFS was 5.6 months in the combination group and 2.4 months in the FTD-TPI group (HR 0.44; 95% CI, 0.36 to 0.54; p<0.001). OR was observed in 6.1% of patients in the combination group and in 1.2% of patients in the FTD-TPI group.^r

Kaplan-Meier curves for OS and PFS^r

Toxicity

Adverse events of any cause occurred in 98% of patients in each group. Severe adverse events (grade ≥ 3) were reported in 72.4% of patients in the combination group and in 69.5% of the FTD-TPI group. The most common adverse events that occurred during the treatment period in both groups were neutropenia, nausea and anaemia. The events that were more frequent in the combination group were hypertension, nausea and neutropenia. No treatment related deaths were reported.^r

Adverse Events^r

References References

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History

Version 1

Date

Summary of changes

19/03/2025

New protocol reviewed electronically and approved by the Medical Oncology Reference Committee.

Protocol published on eviQ. Review in 1 year.

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:: 19 March 2025
Review due:: 30 June 2026

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/4394

09 Jun 2025